Functional PDF

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Leclerc, Gauvin ∙ Functional Materials

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Functional
Materials
|
For Energy, Sustainable Development and
Biomedical Sciences
Edited by
Mario Leclerc and Robert Gauvin
Editors
Prof. Mario Leclerc Dr. Robert Gauvin
Department of Chemistry Scientific Liaison Officer
Université Laval Québec Center for Functional Materials (CQMF)
Quebec, Canada Quebec, Canada
Email: mario.leclerc@chm.ulaval.ca Email: rgauvin@cqmfscience.com
ISBN 978-3-11-030781-8
e-ISBN (PDF) 978-3-11-030782-5
e-ISBN (EPUB) 978-3-11-038819-0
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detailed bibliographic data are available on the Internet at http://dnb.dnb.de.
© 2014 Walter de Gruyter GmbH, Berlin/Boston

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Printing and binding: Hubert & Co. GmbH & Co. KG, Göttingen
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Foreword
When asked to write a foreword for this new book on functional materials, I initially
hesitated to comply with the request for a few simple reasons. First of all, new journals
and books on functional materials are sprouting these days like cabbage in the spring.
This is even more the case for original research papers printed in the usual disci-
plinary journals in chemistry, physics, medicine, and engineering. Consequently, it is
almost impossible to critically keep track and differentiate important studies from the
less significant ones. Moreover, not every original contribution contains completely
novel work, as many of them are instead additions to already well-known facts or well-
accepted lines of thought. In addition, the word “functional” implies that the material
serves a specific and defined purpose in a unique manner; but many contributors to
the field forget or overlook the fact that the material under consideration or subject
under study is just one of many components in a device and its function only evolves
through interplay with all the other components in the device. Note that even the sim-
plest of all rechargeable batteries as an example of a device contains at least a dozen
different functional materials, which all need to comply with the overall performance
of the battery. Thus, compatibility of materials is an important issue frequently over-
looked by eager researchers.
These critical remarks should not be misunderstood. We do not argue against aca-
demically motivated research in materials science. On the contrary, we think that high
quality work aiming at improved, optimized, and – to some extent – novel functional
materials is a necessity. We would merely like to express a warning against exagger-
ated promises and hopes that have no basis in the world of practice. After all, research
on functional materials must envisage practical solutions and is never justified as a
purely academic exercise. The clash between academic ideas and the reality of the
industry and the markets is nowhere harsher than in this field of science.
Despite these critical remarks, it is highly appreciated that this book is not simply
a review of the vast body of literature of the recent years, as it holds the focus upon
various aspects of application. Moreover, it selects only a few topics in favor of a solid
and thorough treatment of the relevant aspects. It is particularly pleasing that poly-
mer colloids receive much attention. Polymer colloids have seen an impressive revival
as a subject of academic research. This is a bit surprising at first sight, given the sit-
uation that emulsion and suspension polymerization processes have served as major
industrial processes in the mass production of polymers, to supply markets with ma-
terials for the coatings and adhesives industry, as textile and leather modifiers and as
constituent in cosmetics, just to mention a few. However, the widespread interest in
nanotechnology has guided the researchers to develop methods which not simply aim
at the synthesis of new molecules, but rather target the production of defined objects.
These nanosized objects are not only composed of different molecules, each type of
molecule contributing different functions to the object, but they also exhibit a defined
VI | Foreword
shape and size distribution, have a defined and controllable surface structure, and a
structured internal composition.
Similar cases are characteristic of the synthesis of mesoporous materials, which
have a long history as absorbents and filtering materials in industry, but have also
found new attention, with the desire to embed more functions into these materials
than was previously possible. This includes better control of pore structure and pore
size distribution. Here again, the target of the synthesis is the object, and not the indi-
vidual molecule which would only later be subject to further processing. Similarly,
nanoscale pigments have been available through industrial processes for decades.
Nevertheless, academic interest centers on the development of novel pigments with
particular size distribution, surface structure, and function, as well as specific elec-
tromagnetic properties. The definition of viable conditions for mass production by in-
dustrially acceptable processes is a key to the success of such research.
All of these aspects are treated in this book. In addition, materials for energy
storage (batteries and capacitors) as well as fuel cells are brought to the readers’s
attention. Last but not least, materials aiming towards application in the vast field
of biomedicine are discussed, described, and critically evaluated. Biocompatibility,
safety aspects, and the essential approval by the authorities are important aspects not
to be overlooked in this area, requiring extensive knowledge in both materials science
and medicine.
In summary, this book comes at a good time, when a large body of academic liter-
ature has been accumulated and is waiting for a critical inspection in the light of the
real demands of application. This book will provide valuable information to a critical
readership and should receive wide-spread recognition from the scientific community.
September 2014 Professor Gerhard Wegner

Emeritus scientific member
Max-Planck Institute for Polymer Research
Mainz, Germany
Preface
Energy, health, and environment are certainly at the top of the list of priorities in the
challenges facing society worldwide for the next 50 years. Functional materials are
providing new solutions and opportunities to ensure sustainable energy and environ-
ment, as well as improved medical care for the future. By its nature, the field of func-
tional materials is highly interdisciplinary, comprising basic sciences such as physics,
chemistry, and biology, as well as applied sciences and engineering. In this regard,
this book brings together the expertise of multiple experts and gives an overview of
emerging trends in this field of research. It allows the reader to associate a multitude
of functional materials with their respective application, in a way that has not pre-
viously been done in existing books covering smart or functional materials. As one
can imagine, this interdependence between synthesis, structure, properties, and per-
formance of functional materials requires applied and theoretical chemistry, physics,
biology, and engineering tools in order to ensure the development of novel and effi-
cient technologies (Fig. 1).
Synthesis
Properties
Structure
Performance
Fig. 1. The field of functional materials is by definition interdisciplinary, involving scientists from
various backgrounds in designing and synthesizing new materials with structure and properties
tailored in order to achieve optimal performance.
This book is addressed to experts as well as graduate students interested in the most
recent developments in the field of functional materials. It includes 15 chapters which
are organized in three sections focusing on (1) the synthesis and applications of func-
tional materials, (2) novel materials for energy applications, and (3) new trends in
functional materials for sustainable development and biomedical applications. The
chapters have been written by recognized experts in their respective fields and cover
topics ranging from fundamental concepts in synthesis to applied research projects.
Recent examples of how functional materials are improving many aspects of technol-
ogy currently available to us on a daily basis are also discussed. The authors are all
VIII | Preface
members of the Quebec Center for Functional Materials (CQMF), a research center lo-
cated in Quebec, Canada, and are internationally known for their work in the devel-
opment of innovative and state-of-the-art functional materials.
In summary, this book provides an overview of the recent advances made in syn-
thesis, characterization, and computer modeling, as well as various applications in-
volving functional materials, and should be of great interest for the scientific commu-
nity working in this area of research. The authors are grateful to Mrs. Patricia Basque
(CQMF), and Mr. Philippe Dufour (NanoULaval) for their collaboration, and to Mrs.
Karin Sora (De Gruyter), Mrs. Julia Lauterbach (De Gruyter), and Mrs. Kathleen Prüfer
(De Gruyter) for their assistance in editing this book. We also acknowledge financial
support from the FRQNT-Strategic Networks Funding Program, which provides the op-
portunity to bring scientists and engineers together in order to develop novel and in-
novative technologies.
Québec, August 2014 Mario Leclerc

Robert Gauvin
Contents
Foreword | V
Preface | VII
Contributing authors | XVII
About the editors | XXIII
R. Gauvin
1 Introduction | 1
Part I: Functional materials: Synthesis and applications
A. Al Shboul, F. Pierre, and J. P. Claverie

2 A primer on polymer colloids: structure, synthesis and
colloidal stability | 9
2.1 Introduction | 9
2.2 Polymer colloids inside out | 10
2.2.1 How many polymer chains per particle? | 10
2.2.2 How many particles? | 10
2.2.3 Are the chains immobile within the nanoparticle? | 12
2.2.4 Morphology of polymeric nanoparticles | 13
2.3 Preparation of polymer nanoparticles | 17
2.3.1 Emulsion polymerization | 18
2.3.2 Miniemulsion polymerization | 22
2.3.3 Microemulsion polymerization | 24
2.3.4 Self-assembly in selective solvents | 25
2.4 Colloidal stabilization | 26
2.4.1 Electrostatic stabilization | 26
2.4.2 Steric stabilization | 30
2.4.3 Depletion stabilization | 31
2.4.4 Future directions | 33
S. Rondeau-Gagné and J.-F. Morin

3 Synthesis, functionalization and properties of fullerenes and
graphene materials | 37
3.2 Fullerenes | 37
X | Contents
3.2.1 General considerations | 38

3.2.2 Synthesis and purification of fullerenes | 39
3.2.3 Chemical and physical properties of C60 | 40
3.2.4 Chemical functionalization of C60 | 42
3.2.5 Applications | 45
3.3 Graphene | 47
3.3.1 Production of graphene | 49
3.3.2 Graphene in energy conversion devices | 52
J. Florek, R. Guillet-Nicolas, and F. Kleitz

4 Ordered mesoporous silica: synthesis and applications | 61
4.2 Ordered mesoporous silica (OMS) | 62
4.2.1 Principle of synthesis | 63
4.2.2 Mesostructure diversity and tailoring | 69
4.3 Functionalization of ordered mesoporous silica | 78
4.4 Morphology control | 80
4.5 Selected applications of functionalized ordered
mesoporous silica | 82
4.5.1 Functionalized MSNs as controlled drug delivery platforms | 83
4.5.2 Functionalized mesoporous materials for extraction
chromatography (EXC) applications | 88
4.5.3 Mesoporous organic-inorganic hybrid membranes for
water desalination | 91
A. Ritcey
5 Nanoparticles: Properties and applications | 101
5.2 Synthetic methods | 101
5.2.1 Particle nucleation and growth | 102
5.2.2 Synthesis in inverse micelles | 104
5.3 Particle aggregation and stabilization of colloidal suspensions | 105
5.4 Colloidal quantum dots | 107
5.5 Metal nanoparticles | 110
5.6 Metal oxide nanoparticles | 112
5.6.1 Titanium dioxide | 112
5.6.2 Iron oxide | 113
5.6.3 Silica | 115
5.7 Polymeric nanoparticles | 115
5.8 Advanced architectures and hybrid systems | 117
Contents | XI
N. Allard and M. Leclerc

6 Conjugated polymers for organic electronics | 121
6.2 Processable conjugated polymers | 122
6.3 Applications in renewable energy | 126
6.3.1 Organic solar cells | 126
6.3.2 Conjugated polymers for organic solar cells | 128
6.4 Applications in micro-electronics | 130
6.4.1 Field-effect transistors | 130
6.4.2 Conjugated polymers for field-effect transistors | 132
6.5 Applications in lighting | 133
6.5.1 Light-emitting diodes | 133
6.5.2 Conjugated polymers for light-emitting diodes | 135
6.6 Summary | 136
A. Soldera
7 Theoretical tools for designing microscopic to macroscopic properties
of functional materials | 139
7.1 Methods | 140
7.1.1 The link between microscopic and macroscopic scales | 140
7.1.2 Ab initio methods | 142
7.1.3 Bridging the gap between ab initio and atomistic levels | 146
7.1.4 Atomistic simulation | 147
7.1.5 Bridging the gap between atomistic and mesoscale levels | 151
7.2 Examples | 151
7.2.1 Quantum studies | 152
7.2.2 Atomistic simulation | 156
7.3 Summary | 164
Part II: Development of new materials for energy applications
S. B. Schougaard and D. Bélanger

8 Electrochemical energy storage systems | 171
8.2 Metrics and performance evaluation | 171
8.3 Models and theory of electrochemical charge storage | 173
8.3.1 Battery operation – a Faradaic process | 174
8.3.2 Electrochemical capacitor operation – a non-Faradaic process | 175
8.4 Electrolytes | 178
8.5 Electrode materials | 180
8.5.1 Electrochemical capacitors | 180
XII | Contents
8.5.2 Hybrid electrochemical capacitors | 181

8.5.3 Lithium battery electrode materials | 183
8.5.4 Negative (anode) electrode materials | 184
8.5.5 The positive (cathode) electrode | 185
8.5.6 Electrode production | 186
8.6 Summary | 186
D. Rochefort
9 Functional ionic liquids electrolytes in lithium-ion batteries | 189
9.1.1 Historical overview | 190
9.1.2 What are ionic liquids? | 191
9.1.3 Key properties as electrolytes | 192
9.2 Ionic liquids as Li and Lithium-ion battery electrolytes | 193
9.3 Functional ionic liquid electrolytes | 194
9.3.1 Overview of functional ionic liquids | 195
9.3.2 Solid electrolyte interphase | 196
9.3.3 Transport of lithium ions | 197
9.3.4 Electroactive ionic liquids as redox shuttles | 198
9.3.5 Perspectives | 202
C. de Bonis, A. D’Epifanio, B. Mecheri, S. Licoccia, and A. C. Tavares

10 Solid polymer proton conducting electrolytes for fuel cells | 207
10.2 Proton exchange membranes | 209
10.2.1 Nafion® | 210
10.2.2 Alternative sulfonated ionomers and membranes | 213
10.3 Characterization of solid polymer electrolytes | 218
10.3.1 Proton conductivity | 218
10.3.2 States of water and water mobility | 222
10.4 Summary | 233
P. Bénard, A.-M. Beaulieu, D. Durette, and R. Chahine

11 Supercritical adsorption of hydrogen on microporous adsorbents | 241
11.2 Fundamentals of supercritical adsorption | 242
11.3 Supercritical adsorption isotherms | 246
11.3.1 Virial expansion of the excess density in terms of pressure | 246
11.3.2 Basic analytic models of the adsorption isotherm | 252
11.3.3 Self-consistent approaches | 256
11.4 The thermodynamics of adsorption | 257
11.4.1 Properties of surface potential | 259
Contents | XIII
11.5 Microporous adsorbents for hydrogen storage | 261

11.5.1 Activated carbons | 261
11.5.2 Single wall nanotubes | 262
11.5.3 Metal organic frameworks | 263
Part III: New trends in sustainable development and biomedical

applications
D. Mantovani, L. Levesque, G. Sabbatier, M. Leroy, D. G. Seifu, R. Tolouei,

V. Montaño, M. Cloutier, I. Bilem, C. Loy, M. Byad, C. Paternoster, C. A. Hoesli,
B. Drouin, G. Laroche
12 Advanced materials for biomedical applications | 277
12.2 History of biomaterials | 278
12.3 Basics in material science for biomaterial applications | 280
12.3.1 Biomaterial properties | 280
12.3.2 Biometals | 280
12.3.3 Bioceramics | 281
12.3.4 Biosynthetic polymers | 282
12.3.5 Natural polymers | 284
12.4 Biomedical applications | 286
12.4.1 Cardiovascular system | 286
12.4.2 Musculoskeletal system | 291
12.4.3 Visceral organs | 300
12.4.4 Nervous system and sensory organs | 304
12.4.5 Esthetic applications | 310
12.4.6 Skin | 312
12.5 Future trends | 319
12.5.1 Tissue engineering basic concepts | 319
12.5.2 Scaffolds | 319
12.5.3 Surface modification | 323
12.5.4 Stem cells | 323
12.5.5 Bioreactors | 324
12.5.6 Computational models | 324
12.6 Summary | 326
M.-A. Fortin
13 Nanoparticles for magnetic resonance imaging (MRI) applications
in medicine | 333
13.1 The basics of MRI in medicine | 337
13.2 Relaxivity: the performance of MRI contrast agents | 339
XIV | Contents
13.3 Synthesis and characterization of magnetic nanoparticles | 340

13.3.1 Synthesis of magnetic nanocrystals | 340
13.3.2 Nanoparticle coatings for MRI applications | 344
13.3.3 Physicochemical characterization | 346
13.4 Physical properties of magnetic nanoparticles | 347
13.5 MR relaxation properties of magnetic nanoparticles | 352
13.5.1 Relaxivity of paramagnetic CAs | 353
13.5.2 Relaxivity of superparamagnetic CAs | 356
13.5.3 Relaxometric performance of MRI CAs at clinical magnetic field
strengths | 358
13.6 Biological performance of magnetic nanoparticles for MRI | 358
13.6.1 In vivo barriers | 360
13.6.2 Impact of nanoparticle size and surface on colloidal stability and
blood retention | 361
13.6.3 Directing nanoparticles in vivo | 362
13.6.4 Toxicity | 363
13.7 Summary | 364
J. Greener
14 Microfluidics for synthesis and biological functional materials:
from device fabrication to applications | 375
14.2 A practical introduction to microfluidic reactors for
material synthesis | 376
14.2.1 Microfluidic reactor geometries | 376
14.2.2 Device fabrication materials | 377
14.2.3 Fabrication of polymer-based planar microreactors
and components | 380
14.3 Manipulating and measuring precursor reagent streams
in microchannels | 383
14.3.1 High surface area to volume ratios in microchannels | 383
14.3.2 Rapid heat transfer | 384
14.3.3 Control of concentrations | 384
14.3.4 Controlling “time on chip” | 386
14.3.5 Control of hydrodynamics and mass transfer | 386
14.3.6 Characterization in microchannels | 389
14.4 Microfluidics for polymer microparticles | 391
14.4.1 Manipulating the shaping of liquid precursors | 392
14.4.2 Effect of the channel wall | 392
14.4.3 Emulsification of precursor droplets | 393
14.4.4 Channel geometries to achieve emulsified droplets | 393
14.4.5 Multiple emulsions | 395
Contents | XV
14.4.6 Forming linear threads and two-dimensional interfaces | 395

14.4.7 Converting liquid precursors into solid micro-materials | 397
14.4.8 Scale up: a circuit analysis of microfluidic flow in a highly
parallelized microreactor | 397
14.5 Microfluidics for synthesis of functional nanoparticles | 400
14.5.1 Microfluidics for highly controlled nanoparticle synthesis | 401
14.6 Biomaterials | 402
14.6.1 Tissue engineering and membranes | 403
14.6.2 Microenvironments for encapsulated cells | 404
14.6.3 Biofilms | 406
14.6.4 Microdevices utilizing functional biomaterials | 407
14.7 Summary | 410
T. Lefèvre, F. Byette, I. Marcotte, and M. Auger

15 Protein- and peptide-based materials: a source of inspiration
for innovation | 415
15.2 Basics of proteins, peptides and polypeptides | 417
15.2.1 Polypeptides are sequences of amino acids | 417
15.2.2 Polypeptides can adopt various conformations | 418
15.2.3 Polypeptides possess various levels of structural organization | 419
15.3 Functional materials from fibrous proteins | 420
15.3.1 Resilin & abductin | 421
15.3.2 Byssus (mussel anchoring threads) | 422
15.3.3 Silk | 425
15.4 Functional materials from globular proteins | 429
15.4.1 Natural proteins | 429
15.4.2 Artificial proteins | 430
15.5 Functional materials from synthetic peptides | 432
15.6 Summary | 435
B. Riedl, V. Vardanyan, W. N. Nkeuwa, A. Kaboorani, V. Landry, B. Poaty, M. Vlad,

and C. Sow
16 Nanocomposite coatings | 443
16.2 Coating formulations | 446
16.2.1 Chemical components | 446
16.2.2 Mixing techniques | 447
16.2.3 Application and curing | 449
16.3 Nanoparticle additives | 449
16.4 Coating characterization | 454
16.4.1 Mechanical properties | 454
XVI | Contents
16.4.2 Optical properties | 456

16.4.3 X-ray imaging and particle aggregation | 459
16.4.4 Weathering and artificial aging | 459
16.5 Bio-based coatings | 460
16.6 Future developments | 462
16.7 Summary | 463
Index | 465
Contributing authors
Nicolas Allard Ibrahim Bilem
Department of Chemistry Department of Mining, Metallurgical
Université Laval and Materials Engineering
Quebec, QC, Canada Université Laval
e-mail: nicolas.allard.4@ulaval.ca and
Chapter 6 Centre de recherche du CHU de Québec
Québec, QC, Canada
Ahmad Al Shboul e-mail: ibrahim.bilem.1@ulaval.ca
Department of Chemistry Chapter 12
Université du Québec à Montréal (UQAM)
Montréal, QC, Canada Michael Byad
e-mail: al_shboul.ahmad@courrier.uqam.ca Department of Mining, Metallurgical
Chapter 2 and Materials Engineering
Université Laval
Michèle Auger and
Department of Chemistry Centre de recherche du CHU de Québec
Université Laval Québec, QC, Canada
Quebec, QC, Canada e-mail: michael.byad.1@ulaval.ca
e-mail: michele.auger@chm.ulaval.ca Chapter 12
Chapter 15
Frédéric Byette
Ann-Marie Beaulieu Department of Chemistry
Research Institute on Hydrogen Université du Québec à Montréal
Université du Québec à Trois-Rivières (UQTR) and
Trois-Rivières, QC, Canada Université de Montréal
e-mail: Ann-Marie.Beaulieu@uqtr.ca Montréal, QC, Canada
Chapter 11 e-mail: frederic.byette@umontreal.ca
Chapter 15
Daniel Bélanger
Department of Chemistry Richard Chahine
Université du Québec à Montréal (UQAM) Department of Electrical Engineering and
Montréal, QC, Canada Computer Engineering
e-mail: belanger.daniel@uqam.ca Université du Québec à Trois-Rivières
Chapter 8 Trois-Rivières, QC, Canada
e-mail: richard.chahine@uqtr.ca
Pierre Bénard Chapter 11
Research Institute on Hydrogen
Université du Québec à Trois-Rivières (UQTR) Jerome P. Claverie
Trois-Rivières, QC, Canada Department of Chemistry
e-mail: pierre.benard@uqtr.ca Université du Québec à Montréal (UQAM)
Chapter 11 Montréal, QC, Canada
e-mail: claverie.jerome@uqam.ca
Chapter 2
XVIII | Contributing authors
Maxime Cloutier Marc-André Fortin

Department of Mining, Metallurgical Department of Mining, Metallurgical,
and Materials Engineering and Materials Engineering
Université Laval Université Laval and
and Centre de recherche du CHU de Québec
Centre de recherche du CHU de Québec Québec, QC, Canada
Québec, QC, Canada e-mail: marc-andre.fortin@gmn.ulaval.ca
e-mail: maxime.cloutier.1@ulaval.ca Chapter 13
Chapter 12
Robert Gauvin
Catia de Bonis Quebec Center for Functional Materials
Department of Chemical Science and Québec, QC, Canada
Technology & NAST Center e-mail: rgauvin@cqmfscience.com
University of Rome Tor Vergata Chapter 1
Rome, Italy
e-mail: catia.de.bonis@uniroma2.it Jesse Greener
Chapter 10 Department of Chemistry
Université Laval
Alessandra D’Epifanio Québec, QC, Canada
Department of Chemical Science and e-mail: jesse.greener@chm.ulaval.ca
Technology & NAST Center Chapter 14
University of Rome Tor Vergata
Rome, Italy Rémy Guillet-Nicolas
e-mail: alessandra.d.epifanio@uniroma2.it Department of Chemistry and Centre de
Chapter 10 Recherche sur les Matériaux Avancés (CERMA)
Université Laval
Bernard Drouin Québec, QC, Canada
College François Xavier Garneau e-mail: remy.guillet-nicolas.1@ulaval.ca
e-mail: bdrouin@cege-fxg.qc.ca Chapter 4
Chapter 12
Corinne A. Hoesli
David Durette Department of Mining, Metallurgical and
Department of Chemistry, Biochemistry Materials Engineering
and Physics Université Laval
Université du Québec à Trois-Rivières Centre de recherche du CHU de Québec
Trois-Rivières, QC, Canada and
e-mail: David.Durette@uqtr.ca McGill University
Chapter 11 Québec, QC, Canada
e-mail: corinne.hoesli@mcgill.ca
Justyna Florek Chapter 12
Department of Chemistry and Centre de
Recherche sur les Matériaux Avancés (CERMA) Alireza Kaboorani
Université Laval Department of Wood and Forest Sciences
Québec, QC, Canada Université Laval
e-mail: justyna-agata.florek.1@ulaval.ca Québec, QC, Canada
Chapter 4 e-mail: alireza.kaboorani.1@ulaval.ca
Chapter 16
Contributing authors | XIX
Freddy Kleitz Lucie Levesque

Department of Chemistry and Centre de Department of Mining, Metallurgical and
Recherche sur les Matériaux Avancés (CERMA) Materials Engineering
Université Laval Université Laval
Québec, QC, Canada and
e-mail: freddy.kleitz@chm.ulaval.ca Centre de recherche du CHU de Québec
Chapter 4 Québec, QC, Canada
e-mail: lucie.levesque.2@ulaval.ca
Véronic Landry Chapter 12
Department of Wood and Forest Sciences
Université Laval Silvia Licoccia
Québec, QC, Canada Department of Chemical Science and
e-mail: veronic.landry@fpinnovations.ca Technology & NAST Center
Chapter 16 University of Rome Tor Vergata
Rome, Italy
Gaétan Laroche e-mail: licoccia@uniroma2.it
Department of Mining, Metallurgical Chapter 10
and Materials Engineering
Université Laval Caroline Loy
and Department of Mining, Metallurgical
Centre de recherche du CHU de Québec and Materials Engineering
e-mail: gaetan.laroche@gmn.ulaval.ca and
Québec, QC, Canada
Mario Leclerc e-mail: caroline.loy.1@ulaval.ca
Université Laval
Québec, QC, Canada Diego Mantovani
e-mail: mario.leclerc@chm.ulaval.ca Department of Mining, Metallurgical and
Chapter 6 Materials Engineering
Université Laval
Thierry Lefèvre and
Department of Chemistry Centre de recherche du CHU de Québec
Université Laval Québec, QC, Canada
Québec, QC, Canada e-mail: diego.mantovani@gmn.ulaval.ca
e-mail: thierry.lefevre@chm.ulaval.ca Chapter 12
Chapter 15
Isabelle Marcotte
Marie Leroy Department of Chemistry
Department of Mining, Metallurgical Université du Québec à Montréal
and Materials Engineering Montréal, QC, Canada
Université Laval e-mail: marcotte.isabelle@uqam.ca
and Chapter 15
Centre de recherche du CHU de Québec
Québec, QC, Canada
e-mail: marie.leroy.1@ulaval.ca
Chapter 12
XX | Contributing authors
Barbara Mecheri Bouddah Poaty

Department of Chemical Science Department of Wood and Forest Sciences
and Technology & NAST Center Université Laval
University of Rome Tor Vergata Québec, QC, Canada
Rome, Italy e-mail: bouddah.poaty-poaty.1@ulaval.ca
e-mail: barbara.mecheri@uniroma2.it Chapter 16
Chapter 10
Bernard Riedl
Vanessa Montaño-Machado Department of Wood and Forest Sciences
Department of Mining, Metallurgical Université Laval
and Materials Engineering Québec, QC, Canada
Université Laval e-mail: Bernard.Riedl@sbf.ulaval.ca
and Chapter 16
Centre de recherche du CHU de Québec
Québec, QC, Canada Anna Ritcey
e-mail: vanessa.montano-machado.1@ulaval.ca Department of Chemistry
Chapter 12 Université Laval
Québec, QC, Canada
Jean-François Morin e-mail: anna.ritcey@chm.ulaval.ca
Université Laval
Québec, QC, Canada Dominic Rochefort
e-mail: jean-francois.morin@chm.ulaval.ca Department of Chemistry
Chapter 3 Université de Montréal
Montréal, QC, Canada
William Nguegang Nkeuwa e-mail: dominic.rochefort@umontreal.ca
Department of Wood and Forest Sciences Chapter 9
Université Laval
Québec, QC, Canada Simon Rondeau-Gagné
e-mail: william.nguegang-nkeuwa.1@ulaval.ca Department of Chemistry
Chapter 16 Université Laval
Québec, QC, Canada
Carlo Paternoster e-mail: simon.rondeau-gagne.1@ulaval.ca
Department of Mining, Metallurgical Chapter 3
and Materials Engineering
Université Laval Gad Sabbatier
and Department of Mining, Metallurgical and
Centre de recherche du CHU de Québec Materials Engineering
e-mail: carlo.paternoster@gmail.com and
Québec, QC, Canada
Florian Pierre e-mail: gad.sabbatier.1@ulaval.ca
Université du Québec à Montréal (UQAM)
Montréal, QC, Canada
e-mail: pierre.florian@courrier.uqam.ca
Chapter 2
Contributing authors | XXI
Steen B. Schougaard Ana C. Tavares

Department of Chemistry Institut National de la Recherche Scientifique
Université du Québec à Montréal (UQAM) Énergie, Matériaux et Télécommunications
Montréal, QC, Canada (INRS-EMT)
e-mail: schougaard.steen@uqam.ca Varennes, QC, Canada
Chapter 8 e-mail: ana.tavares@emt.inrs.ca
Chapter 10
Dawit G. Seifu
Department of Mining, Metallurgical Ranna Tolouei
and Materials Engineering Department of Mining, Metallurgical
Université Laval and Materials Engineering
and Université Laval
Centre de recherche du CHU de Québec and
Québec, QC, Canada Centre de recherche du CHU de Québec
e-mail: dawit-gezahegn.seifu.1@ulaval.ca Québec, QC, Canada
Chapter 12 e-mail: ranna.tolouei@gmail.com
Chapter 12
Armand Soldera
Department of Chemistry Vahe Vardanyan
Université de Sherbrooke Department of Wood and Forest Sciences
Sherbrooke, QC, Canada Université Laval
e-mail: Armand.Soldera@USherbrooke.ca Québec, QC, Canada
Chapter 7 e-mail: vahe.vardanyan.1@ ulaval.ca
Chapter 16
Caroline Sow
Department of Wood and Forest Sciences Mirela Vlad
Université Laval Department of Wood and Forest Sciences
e-mail: caroline.sow@sogel.ca Québec, QC, Canada
Chapter 16 e-mail: mirela.vlad@fpinnovations.ca
Chapter 16
About the editors
Mario Leclerc was awarded a Ph.D. in chemistry from Univer-
sité Laval, Quebec City, Canada, in 1987, under the guidance of
Prof. R.E. Prud’homme. After a short post-doctoral stay at INRS-
Energie et Matériaux near Montréal with professor L.H. Dao, he
joined the Max-Planck-Institute for Polymer Research, in Mainz,
Germany, as a post-doctoral fellow in the research group of
Prof. Dr. G. Wegner. In 1989, he accepted a position of professor
at the department of chemistry of Université de Montréal. He
returned to Université Laval in 1998 where he has held since 2001 the Canada Research
Chair for Electroactive and Photoactive Polymers. Prof. Leclerc has co-authored about
250 papers published in leading scientific journals which have been cited more than
16 000 times. According to Science Citation Index, he has an h-index of 64. His cur-
rent research activities include the synthesis and characterization of new oligomers
and polymers for applications in micro-electronics, energy, sensors, and genomics.
Robert Gauvin holds a Mechanical Engineering degree from Uni-

versité Laval (Québec, Qc, Canada) and has worked as R&D
Engineer in the medical device industry (AltertekBio, Sainte-
Foy, Qc, Canada) prior to attending graduate school. Following
his Ph.D. studies in Biomedical Engineering at Université Laval
and at the Georgia Institute of Technology (Atlanta, GA, USA),
he was awarded Postdoctoral Research Fellowships at the Mas-
sachusetts Institute of Technology (Harvard-MIT Division of
Health Sciences and Technology, Cambridge, MA, USA) and at the Wyss Institute for
Biologically Inspired Engineering (Harvard Medical School, Boston, MA, USA). After
completion of his postdoctoral research, he joined the Personnel Protection Section
as Staff Scientist for Defense Research and Development Canada (DRDC-Valcartier,
Qc, Canada), before accepting the position of Scientific Liaison Officer at the Quebec
Center for Functional Materials (CQMF, Qc, Canada). He also served as the elected
Chair of Scientific and Professional Development of TERMIS-North America from 2010
to 2013 and holds a Research Professor position at the Department of Surgery (Fac-
ulty of Medicine) of Université Laval. Dr. Gauvin is co-author of over 35 peer-reviewed
journal articles, 4 review articles and 3 book chapters. He presented his work at over
50 national and international conferences and is a reviewer for numerous scientific
journals in the fields of biomedical engineering and material sciences.
R. Gauvin
1 Introduction
Since its beginning, materials science has evolved from the use of inert structural ma-
terials to materials with tailored properties which allow reactive capacities, such as
the intrinsic ability to respond to stimuli and environmental changes, and activation
of specific functions according to these changes. Improvements and innovations in
the fields of chemistry, physics, and engineering have allowed better understanding
of the structure-property-performance relationships and precise control of the com-
position of materials. As a result, considerable developments have been made in the
engineering of innovative functional materials, and research is currently addressing
numerous fields such as photovoltaics, batteries, electrolytes, supercapacitors, en-
ergy conversion, biomaterials, tissue engineering, medical imaging, nanotechnology,
microfluidics, and computer modeling, to name just a few. Functional materials are
therefore expected to have a considerable impact on many aspects of our lives such as
energy, transportation, life sciences, and environment. As applied research tends to
be a very dynamic and innovation-driven field, writing a book on functional materi-
als is therefore a never-ending enterprise, as a new technology appears on the market
every month. This book is designed in such a way that the reader will learn about
functional materials and the types of applications they are designed for. Thus, it will
be possible to correlate emerging functional materials with the underlying concepts
that were involved in their design, although these might still be developed in the fu-
ture. The book is divided into three sections and covers the synthesis and applications
of functional materials (Part I), novel materials for energy applications (Part II), and
new trends in functional materials for sustainable development and biomedical ap-
plications (Part III).
Part I comprises six chapters focusing on the various approaches to preparation
and synthesis of organic and inorganic functional materials. Since the most promising
technologies for increased efficiency and improved reliability involve controlling the
composition and the microstructure of novel materials, it is essential for the reader
to understand the underlying concepts directing the synthesis and the generation of
their assembly. In Chapter 2, the fundamental concepts of colloids and polymeriza-
tion in dispersed medium are introduced. A colloid is a dispersion of very fine objects
in a fluid, these objects being solids, liquids or gas, and the corresponding colloidal
dispersion being referred to as a suspension, an emulsion or foam. Polymer colloids
are used for a large number of applications, ranging from coatings, adhesives, inks,
impact modifiers, drug-delivery vehicles, etc. The domain of colloidal stabilization
is therefore a fascinating and vibrant area of science and this chapter presents im-
portant technological advances combining physical chemistry and fluid dynamics re-
lated to colloids and polymer chemistry. Chapter 3 illustrates the tremendous influ-
ence fullerene and graphene have had on various technologies in recent years. These
2 | Introduction
carbon-based materials are undoubtedly amongst the most-studied materials in both

academic and industrial laboratories since the discovery of fullerenes in 1985, carbon
nanotubes in 1991, and graphene in 2004. Due to their great structural diversity, nu-
merous applications can be envisioned for these materials, and recent synthetic meth-
ods for the design of functional mesostructured materials are presented. Some per-
spectives of these applications in catalysis, selective sorption, and biomedical devices
are reviewed, as well as numerous methods of modification available for modulation
of the surface properties, introduction of functionalities, and control of size and shape
of the particles of these mesoporous solids. Chapter 4 presents an overview of materi-
als of a porous structure with features in the nanometer range which have emerged
as key elements in the development of future technologies including miniaturized
electronics, magnetic and optical devices, environmentally-friendly catalysts, mate-
rials for pollutant removal, biocompatible implants, and drug delivery systems. The
nanopore size range offers vast potential for elaborate functional systems with tailored
properties, as the size and volume of the pores in a given material have a profound
influence on its final properties, such as adsorption/desorption capability, diffusion
mechanisms, storage capacity, density, and mechanical stability. A few examples are
presented, such as nanoporous materials used as highly selective sorbents, selective
membranes, systems for energy storage or energy conversion, recyclable solid cata-
lysts, low k-dielectrics, sensors, biomaterials for drug delivery, and contrast agents for
medical imaging. Chapter 5 focuses on the properties of nanomaterials for the synthe-
sis and design of functional materials based on the fundamental structures of these
particles. The fabrication of nanostructures using “top-down” and “bottom-up” ap-
proaches is described. As their name implies, top-down methods involve the creation
of nanosized entities from larger blocks of matter, including mechanical size reduc-
tion by crushing and grinding, as well as more sophisticated lithographic techniques.
Bottom-up approaches, on the other hand, seek to build nanostructures from smaller
components, typically atoms or molecules, and therefore frequently involve elements
of self-assembly or supramolecular chemistry. Chapter 6 covers the synthesis of conju-
gated polymers for organic electronics applications. These polymers have recently re-
ceived a great deal of attention since they combine the features of metals or inorganic
semiconducting materials (excellent electrical and optical properties), with those of
synthetic polymers (flexibility, ease of processing and low cost). This synergy makes
these functional materials useful in existing optoelectronic devices and creates com-
pletely new technological opportunities. For instance, polymeric semiconductors are
considered to be one of the most promising materials for lowering the cost of solar
energy. The electrical conductivity of these polymer materials has therefore enabled
a wide range of technologies such as photovoltaics, field-effect transistors, and light
emitting diodes, which are expected to foster the upcoming era of plastic and print-
able electronics. Chapter 7 covers the computational approaches and theoretical tools
which are used to investigate the composition and performance of various functional
materials in silica. This chapter demonstrates that a complex structure can be stud-
1 Introduction | 3
ied as an assembly of a multitude of building blocks, and that optimization of these

functional units can lead to improved performance of the macroscopic properties of a
material. Moreover, the versatility of the available chemical processes combined with
theoretical modeling enables the design of compounds with well-defined and tunable
properties.
Part II addresses common challenges regarding the development of functional
materials for energy applications including improved performance, conversion effi-
ciency, energy density, and sustainability. Since the efficient use of energy is directly
linked to its production and conservation, energy must ideally be stored for further
use or made available for portable applications once it has been generated from a
readily available source. Thus, there is a tremendous need for electrochemical storage
devices such as high energy density batteries and supercapacitors. Similarly, the stor-
age of hydrogen is also of great interest as it represents the principal fuel source for
electric vehicles. As fuel cells allow electrochemical oxidation of hydrogen-rich fuel
into electrical current, they produce clean energy directly in the form of current and
do not require recharging. Therefore, the drive for innovation in sustainable, clean,
efficient, and portable energy is now stronger than ever. Chapter 8 discusses electro-
chemical energy storage systems such as batteries and supercapacitors. The ability to
efficiently store and retrieve electrical energy is at the heart of the mobile revolution
and is currently of great concern globally. Efficient and low-cost energy storage sys-
tems will be required to meet this challenge. Two of the candidates most likely to meet
these high power, high energy density requirements are optimized lithium-ion batter-
ies and advanced electrochemical capacitors. This chapter presents the fundamental
concepts associated with electrochemical energy storage systems using the thermo-
dynamics, kinetics, structure, and mass transport properties of battery materials. In
Chapter 9 the design of ionic liquid electrolytes for lithium-ion batteries is explained
to highlight the fact that although the redox behaviour and the kinetics of dissolved
species are important, the electrolyte plays a crucial role in the electrochemistry of ad-
vanced systems such as energy storage devices. Indeed, the design of the electrolyte
will affect the transport of lithium ions and the range of operational voltage, thereby
affecting the power and energy density values of the system. Ionic liquids have the
potential to play an important role in the development of electrolytes, which will in-
crease the overall performance and improve the efficiency of energy storage devices.
Continuing with this topic, Chapter 10 focuses on solid electrolytes, which are materi-
als capable of conducting ions used in many electrochemical devices including batter-
ies, fuel cells, sensors, electrolyzers, and electrodialysis systems for water purification
and saltwater desalination. These electrochemical cells are devices capable of pro-
ducing electrical energy from spontaneous chemical reactions. For example, proton
exchange membrane fuel cells are considered attractive power sources for portable
applications and for the automotive industry. Nevertheless, these systems still suffer
from limitations, discussed in this chapter, hindering the competition of this technol-
ogy with lead-acid batteries, fossil fuels, and internal combustion engines. Chapter 11
4 | Introduction
introduces the basic concepts related to supercritical adsorption of hydrogen on mi-

croporous adsorbents. Physical adsorption on microporous adsorbents is widely used
in a number of industrial physicochemical processes such as gas separation and pu-
rification or catalytic support. Materials-based storage of gases such as hydrogen can
be achieved through chemical binding or through absorption inside a solid metal hy-
dride matrix. Activated carbons have been proposed as a means of storing gases such
as natural gas at room temperature, and have been widely studied for hydrogen stor-
age applications, due to their availability and the possibility of tailoring their porous
structures through various chemical and physical treatments. For hydrogen, storage
applications require low temperature operation and highly microporous activated car-
bon matrices with high specific surface areas, due to the small value of the binding
energies between carbon structures and molecular hydrogen. This chapter will cover
the thermodynamic description of these systems, which regulates the energy scale re-
quired for charging and discharging gases through these devices.
Part III groups together the design, synthesis and fabrication of novel functional
materials according to new trends in sustainable development and biomedical appli-
cations. Chapter 12 gives a detailed overview of advanced materials used in biomed-
ical applications. More specifically, it aims to summarize the fields of implants and
prostheses from a materials science and engineering point of view. Since biomaterials
are at the interface between medicine, life sciences, and materials science, the num-
ber of strategies for their design and engineering is almost infinite, spanning from
the control of surface roughness, the conjugation of signal peptides for cell adhesion
and drug encapsulation, to biodegradable materials which will be replaced during
the healing process. The synthetic and biological materials and devices available to
repair or replace damaged tissues and organs are reviewed herein. Following on from
the previous chapter, an introduction to the synthesis of functionalized nanoparticles
for bioimaging and diagnostic applications is provided in Chapter 13. The develop-
ment of magnetic nanoparticles as contrast agents for vascular, molecular, and cel-
lular magnetic resonance imaging (MRI) applications has been exponential during
the last decade. Nanoparticles generating contrast in MRI is one of the most direct
applications of nanotechnology. This chapter is an introduction to the principles un-
derlying the performance of nanoparticulate-based MRI contrast agents. It addresses
the main considerations guiding the design and physicochemical characterization of
magnetic nanoparticles. The fundamental aspects of nanoparticle magnetism and re-
laxometric characterization are discussed, as well as examples of applications in bi-
ological models. While introducing the fundamentals of microfluidics, Chapter 14 re-
views important considerations regarding the synthesis of synthetic and biological
functional materials on the microscale. The topics covered range from the introduction
of key concepts in microfluidics and reactor fabrication to their utilisation in the study
and synthesis of new micromaterials for various applications. Chapter 15 provides a
concise description of natural and synthetic polypeptides, from peptides to globular
and fibrous proteins, for the development of functional materials. Proteins and pep-
1 Introduction | 5
tides are promising building blocks for the conception of materials, as they can be
tailored for a broad variety of functions, structures and properties, possess the ability
to self-assemble into complex architectures, respond to specific environmental stim-
uli, bind to specific receptors and ligands, and resist mechanical stresses and strains.
Through several examples, general principles and important areas of research regard-
ing polypeptide-based materials are described, as well as their considerable potential
in various, and possibly unanticipated, application fields. Chapter 16 introduces as-
pects of chemistry and physics of coatings reinforced with nanoparticles, especially
for wood substrates intended for common indoor and outdoor use. Nanoparticle rein-
forcement can improve resistance to UV degradation, water absorption, and wear and
tear without affecting the most important characteristics of paints and coatings: bril-
liance, color and transparency. This applied research example provides a good illus-
tration of how even the simplest everyday paint or varnish requires extensive research
and design in order to be competitive and display optimal properties.
Functional materials are at the center of most technology advancements. This
book covers three important fields in the development of functional materials: energy,
environment, and biomedical applications. These topics are explained and discussed
from an experimental and theoretical perspective, as an understanding of material
properties is fundamental to the development of novel functionalities and technolo-
gies. It is therefore believed that this book will be of great interest to any scientist keen
to broaden their knowledge in both the fundamentals and applications of functional
materials.
|
Part I: Functional materials: Synthesis
and applications
A. Al Shboul, F. Pierre, and J. P. Claverie
2 A primer on polymer colloids: structure, synthesis
and colloidal stability
2.1 Introduction
A colloid is a dispersion of very fine objects in a fluid [1]. These objects can be solids,
liquids or gas, and the corresponding colloidal dispersion is then referred to as sus-
pension, emulsion or foam. Colloids possess unique characteristics. For example, as
their size is smaller than the wavelength of light, they scatter light. They also offer a
large interfacial surface area, meaning that interfacial phenomena are of paramount
importance in these dispersions. The weight of each dispersed particle being small,
gravity and buoyancy forces are not sufficient to counteract the thermal random mo-
tion of the particle, named Brownian motion (in tribute to the 19th century botanist
Robert Brown who first characterized it). The particles do not remain in a dispersed
state indefinitely: they will sooner or later aggregate (phase separation). Thus, the col-
loidal state is in general metastable and colloidal stability is one of the key features to
take into account when working with colloids.
Among all colloids, the polymer colloid family is one of the most widely inves-
tigated [2]. Polymer colloids are used for a large number of applications, ranging
from coatings, adhesives, inks, impact modifiers, drug-delivery vehicles, etc. The
particles range in size from about 10 nm to 1 000 nm (1 μm) in diameter. They are
usually spherical, but numerous other shapes have been observed. Polymer colloids
are not uncommon in nature. For example, natural rubber latex, the secretion of the
Hevea brasiliensis tree, is in fact a dispersion of polyisoprene nanoparticles in wa-
ter. Synthetic polymer colloids, also called synthetic latexes, play a prominent role
in industrial chemistry. Interest in synthetic latexes developed during the Second
World War, when the Japanese Navy threatened access to natural Hevea, an impor-
tant raw material for tire manufacturing at that time. It appeared judicious to produce
synthetic polymers under the same aspect, so that downstream operations on the
elastomer processing units could remain unchanged. This led to the development of
the emulsion polymerization process, one of the most versatile polymerization pro-
cesses [3, 4]. The words latex, polymer colloids, and dispersed polymer nanoparticles
are used interchangeably for any kind of stable colloidal submicronic polymer dis-
persions in a solvent, which in the majority of cases is water. In this chapter we will
present a few salient features of polymer colloid structure, followed by data on the
synthesis of these colloids, and finally we will give several key points on colloidal
stability.
10 | Part I Functional materials: Synthesis and applications
2.2 Polymer colloids inside out
2.2.1 How many polymer chains per particle?
Let us consider a polymeric sphere of diameter (dp ) = 20 nm, constituted of poly-

styrene (molecular weight 105 g/mol). Thus, the weight of a single polymer chain is
m = 105 /Na = 1.7 ⋅ 10−19 g, where (Na ) is the Avogadro number. The volume (V) of one
spherical nanoparticle is V = π/6 d3p = 4.2 ⋅ 10−21 l. Knowing that polystyrene den-
sity (ρ) is ρ = 1 040 g l−1 , the average number of polymer chains per polymer particle is
Vρ/m = 26. The average number of chains per particle for representative particle sizes
and polymer molecular weights is listed in Table 2.1. Core-shell particles, whereby a
core particle of a given material is engulfed in a shell of another component, form an
important class of polymer colloids. For example, hybrid nanoparticles made up of an
inorganic core and a polymer shell find wide application in various fields of materials
science such as optics, catalysis, microelectronics, biology, and medicine [5]. As an-
other example, let us consider a 20 nm diameter silica particle surrounded by a 5 nm
polymeric layer (molecular weight 105 g/mol), which contains 61 polymer chains. At
first glance, this number may seem large in comparison to the 26 chains constituting
a 20 nm particle. However, it should be remembered that most of the weight of a par-
ticle resides in its outer layer. For core-shell particles, the volume of the shell becomes
larger than the volume of the core when the shell thickness is 12.5 % of the core dia-
meter.
Table 2.1. Number of polymer chains per particle for various polymer nanoparticles.
Particle Outer Polymer Number of

diameter molecular chains per
(nm) weight particle
(g/mol)
Spherical, polystyrene 20 105 26

5
Spherical, polystyrene 100 10 3 200
4
Spherical, polystyrene 20 10 260
Core-shell 30 105 61
Core = silica (20 nm)
Shell = polystyrene
2.2.2 How many particles?
Three main parameters characterize a polymer dispersion, namely the particle diam-
eter in nanometers (dp ), the solid content (SC), i.e., the weight percentage of solid in
the dispersion, and the particle number (Np ), which is the number of polymer parti-
cles per unit volume of dispersion. These three parameters are interrelated and they
2 A primer on polymer colloids: structure, synthesis and colloidal stability | 11
cannot be varied independently of one another. Simple geometrical arguments can be

used to demonstrate that:
SC
Np = 6 ⋅ 1025 3 , (2.1)
dp ρ
where ρ is the density in g/l of the polymer particle in water. Usually, Np will consist
of between 1013 and 1019 particles/l, which correspond respectively to dilute and con-
centrated dispersions. The final use of the polymer dispersion dictates what the val-
ues of Np , SC, and dp should be. For example, when the polymer dispersion is dried
to form a polymer film, the solid content should be as high as possible in order for the
film to form rapidly. Dispersions with an SC of 60 % and higher are used in the man-
ufacture of aqueous paints (such as acrylic paints). For polymers with a density close
to one, volume fraction and SC are similar. For a monodisperse particle distribution
(i.e., particles all have the same diameter), the theoretical maximum volume fraction is
74 %, which corresponds to a cubic close-packed arrangement of spheres (also called
face-centered cubic, or FCC) [6]. As the nanoparticle arrangement is similar to that
of molecules in a crystal, this state is referred to as a colloidal crystal (Fig. 2.1). The
periodic arrangement of particles and the voids in between them acts as a diffraction
grating for light, with the resulting effect that colloidal crystals are brightly colored.
This explains why they are also called photonic crystals [7]. The majority of colloidal
crystals are prepared with inorganic materials such as silica, although polymer col-
loidal crystals have also been developed [8, 9].
Fig. 2.1. Scanning electron microscopy images of

crystalline assemblies of 100 nm polystyrene nano-
500 nm particles (reprinted with permission from [10]).
When latex is dried, water first evaporates until the particles are in close contact
(stage I of film formation, Fig. 2.2). If the particles are monodisperse and hard (high
glass transition temperature, Tg ), and if the arrangement is devoid of defects (a con-
dition which is practically difficult to achieve), then a colloidal crystal is formed (see
Fig. 2.1). If the particles are deformable (low Tg ), the particles are compressed into
a rhombic dodecahedral arrangement (stage II). Since Tg is low, the polymer from
one particle will diffuse in adjacent particles, resulting in the formation of a continu-
ous film (stage III). The three stages of film formation represent a simplified view of
Stage I
water
evaporates
Stage II
particle deforms
Stage III
interparticle
diffusion
Fig. 2.2. Schematic representation of the film formation process from a latex and freeze-fracture
transmission electron micrograph image of a latex film at stage II (reprinted with permission
from [12]). The marker bar represents 370 nm.
the formation of a film from latex. The film formation process is in fact much more
complex [11], a fact with important repercussions in the domain of coating technology.
Returning to a dispersion of polymer nanoparticles, we have seen that for a vol-
ume fraction of 74 %, monodisperse latex takes the form of a crystal-like solid. Prac-
tically, the latex does not flow anymore and has an infinitely high viscosity as soon
as the volume fraction reaches 64 % [13, 14]. At this point, the spheres are randomly
packed, and long-range motions are impossible. However, free flowing latexes with
volume fractions higher than 64 % can nonetheless be obtained. In this case, the la-
tex must have a polydisperse size distribution, whereby small particles can be lodged
in the voids created by large particles [15].
2.2.3 Are the chains immobile within the nanoparticle?
When Tg of the polymer is above room temperature, the polymer chains are frozen and
the chains can be considered immobile within the time frame of the experiment. When
Tg is below room temperature, various models such as the Rouse model or the repta-
tion model, can be used to estimate the self-diffusion coefficient (D) of the chains. Let
us consider a case for which the value of D = 10−20 m2 /s [16], which corresponds to a
low value of D that would either be encountered for a high molecular weight chain, or
at temperatures just above Tg . The diffusion length scale (L) can be approximated as
L = (DT)0.5 , where (T) is the diffusion time. In a time interval T = 1 month, the diffu-
sion length scale L will be 161 nm, which is larger than the size of the particles that we
will consider in this chapter. Thus, above Tg the chains diffuse freely within the time
scale of the experiment, whereas below Tg the chains are immobile. So the remain-
ing question is whether the Tg of the nanoparticle corresponds to the Tg of the bulk
polymer. Before answering this question, one should consider the environment of the
nanoparticle. The solvent in which the nanoparticle is suspended (such as water, for
example) can act as a plasticizer, resulting in a lower Tg . Hydroplasticization is gener-

ally thought to be responsible for a decrease in Tg of approximately 12°C for styrenic
and acrylic polymer nanoparticles suspended in water [17]. As a result of the polymer
chains being confined in a small nanoparticle, Tg deviates from the bulk value. This
so-called confinement effect is due to the combination of interfacial and size effects.
Interfacial effects are influenced by the specific interaction between the particle sur-
face and its environment, whereas size effects occur when the particle size is of the
same order of magnitude as the characteristic size of the region in which cooperative
motion occurs. Although no exact number can be given, one would expect that size
effects are important for nanoparticles smaller than 10 nm. Numerous observations on
polymeric thin films also confirm that size effects are only significant for films thinner
than approximately 20 nm [18]. However, data on the Tg of polymeric nanoparticles are
still very much controversial. For example, recent data indicate that in water, the Tg
of polystyrene nanoparticles with a diameter of 90 nm is 58°C lower than bulk Tg [19].
The relatively simple picture presented in the above paragraph only applies to
simple nanoparticles composed of a single homopolymer. Usually one would prepare,
characterize, and utilize nanoparticles made up of a large number of components, ei-
ther under the form of blends of homopolymers or of copolymers with various archi-
tectures. This point is introduced in the following paragraph.
2.2.4 Morphology of polymeric nanoparticles
As polymers are rarely miscible, phase separation often occurs within nanoparticles,
leading to the formation of a nanostructured object with a specific morphology – that
is to say, with a specific arrangement of each of the polymeric phases. Unraveling the
morphology of a polymer nanoparticle is not a simple task. It is often achieved by
transmission electron microscopy (TEM) with selective staining of one of the phases,
although other techniques such as nuclear magnetic resonance (NMR, [20]) or differ-
ential scanning calorimetry (DSC) have also been used [21].
Starting with a simple blend of two non-compatible polymers, numerous mor-
phologies can be obtained such as core-shell particles, hemispherical particles like
half-moons, particles with various inclusions, etc. (Fig. 2.3). Among all of these, kinet-
ically trapped morphologies should be distinguished from thermodynamic morpholo-
gies. The latter is usually attained when the particle has been exposed to temperatures
above Tg , as in this case the chain’s mobility is high enough to reach the lowest en-
ergy conformation. Thermodynamically speaking, the system is constituted of three
phases: two polymers and the continuous phase. In a seminal study on the coales-
cence of immiscible droplets [22], Torza and Mason defined spreading coefficients Sij
as
Si = 𝛾jk − (𝛾ik + 𝛾ij ), (2.2)
whereby 𝛾ij defines the interfacial tension between the i and j phases. If the continu-
ous phase is numbered 2 and the polymer phase 1 is the one for which 𝛾12 > 𝛾23 , then
S1 < 0. There are only three possible sets of values for Si , corresponding to three dif-
ferent equilibrium morphological configurations (Fig. 2.3).
1 3
S1 < 0 S1 < 0 S1 < 0

S2 < 0 S2 < 0 S2 > 0
S3 > 0 S3 < 0 S3 < 0
Complete engulfing Partial engulfing No engulfing
Fig. 2.3. Possible equilibrium configurations corresponding to the three sets of Si . The continuous
medium is phase 2.
In fact, the analysis by Torza and Mason relies on simplified scenarios. A more rigorous
approach, developed by Sundberg et al. [23], indicates that equilibrium morphologies
depend not only on the exact values of the respective surface tensions 𝛾ij , but also on
the amount of each polymer and the surface coverage of the particle by a surfactant
(Fig. 2.4). We will see below that surfactants are indispensable to impart colloidal sta-
bility to the polymer nanoparticles.
0% 10% 15% 25% 50% 100%
Fig. 2.4. Predicted morphologies of a polymer particle consisting of two polymers (polystyrene in
black and poly-n-butylmethacrylate in grey) suspended in water with various surface coverage by
sodium dodecyl sulfate (% surface saturation). Reprinted with permission from [23].
As mentioned above, the main technique for unraveling the morphological features
of polymer nanoparticles is TEM. A selective positive stain is used to discriminate one
of the polymer phases. For example, osmium tetroxide can be used to stain polymers
containing benzene rings or isolated double bonds. For simple cases (such as core
shell particles), it is possible to assess the morphology without sectioning the particles
in thin layers with a microtome. However, for more complex cases the particles must
be microtomed after embedding in a hard resin or the morphology may be wrongly
Fig. 2.5. Simulated TEM pictures of a single

composite particle consisting of polystyrene
in black and poly-n-butylmethacrylate in grey,
microtomed at a thickness of 90 nm, as pre-
dicted by the software UNHLATEXTM_EQMORPH
(Advanced Polymer Laboratory, University of
New Hampshire). Reprinted with permission
250 nm from [23].
attributed. TEM pictures must also be analyzed with great care. For example, Fig. 2.5
illustrates all possible TEM pictures of a single type of nanoparticle, depending on its
preparation and its orientation under the TEM beam.
The morphological features of particles consisting of two homopolymers are very
different from those obtained from polymers with more complex architectures. Among
these, amphiphilic diblock copolymers, which consist of a hydrophobic and a hy-
drophilic block, have been the most studied [24, 25]. Such copolymers, comprised of
a hydrophilic and a hydrophobic block self-assemble in water in order to shield the
hydrophobic units from water. Water is then qualified as a selective solvent, as it is a
good solvent for one part of the block and a poor solvent for the other one. Organic
solvents can also be selective, resulting in reverse structures with hydrophilic units
on the inside and hydrophobic on the outside. Several equilibrium morphologies are
possible, the most classical ones being polymeric spherical and cylindrical micelles
and vesicles (Fig. 2.6). The self-assembly of amphiphilic polymers is dictated by the
value of the critical packing parameter (P), where P = V/(a0 lc ), where V is the volume
of the hydrophobic block, lc is the end-to-end distance between both extremities of
the hydrophobic block, and a0 is the cross-section between both blocks. This param-
eter, first introduced by Israelachvili to predict the assembly of non-polymeric sur-
factants [26], is a nondimensional number which measures the curvature of the cone
generated by the surface enveloping both blocks. Low values of P are obtained for
asymmetric block copolymers formed by a short hydrophobic and a long hydrophilic
block. They self-assemble into spherical polymeric micelles, whereby the hydrophilic
block is solvated, whereas the hydrophobic one forms the core of the micelle. When the
hydrophobic block becomes longer, packing into a sphere is impossible and the mi-
celles become elongated (so-called cylindrical micelles). Eventually, for a high pack-
ing number, lamellar phases are formed, whereby two diblock copolymers in a head-
to-tail conformation generate a locally planar arrangement. These lamellar structures
can fold in on themselves to form a vesicle. Polymer vesicles are often called polymer-
somes [27]. Importantly, at the length-scale of the polymer, the vesicle interface is flat,
and the curvature of the interface is nearly null, thus the diameter of the vesicle is in-
Spherical Cylindrical ‘Polymersomes’

micelles micelles
lc
a0
v
High Medium Low

curvature curvature curvature
P≤⅓ ⅓≤P≤½ ½≤P≤1
Fig. 2.6. Various self-assembled structures formed by amphiphilic block copolymers in a block-
selective solvent. Reprinted with permission from [28].
dependent of the structure of the block copolymer and mainly depends on preparation
conditions (stirring, temperature, ionic strength, etc.).
The value of the packing parameter can only be used to predict equilibrium mor-
phology. Practically, this condition is achieved when the amphiphilic chains are able
to diffuse through the solvent and probe several conformations until they form the
structure of lowest energy. This is the case when the amphiphilic polymer has nonzero
water solubility (when the self-assembly is performed in water), thus for polymers
with a rather long hydrophilic block. In this case, self-assembly (Fig. 2.6) occurs when
the concentration of polymers in water is above a critical concentration, called criti-
cal assembly concentration (CAC), in reference to the critical micellar concentration
(CMC) observed for small molecule surfactants. It should however be mentioned that
CAC are usually very low (frequently in the μmol/l or below), whereas CMC are usu-
ally higher. Various techniques have been devised to precisely measure CAC, the most
classical being monitoring the change of the fine structure fluorescent emission band
of an organic fluorophore (pyrene), for various concentrations of polymer [29]. Below
the CAC, the polymer chains are dissolved as individual entities, whereas above CAC,
self-assembled have a structured form, but a fraction of the polymer chains (at con-
centration CAC) is solubilized in water. In the latter case, the soluble polymer chains
and self-assembled chains exchange during the experiment. Does this mean that self-
assembled structures are always dynamic and exchange with dissolved chains? Not at
all, it is in fact possible to prepare self-assembled polymer colloids for polymers with
virtually zero solubility in the solvent. Various techniques exist and will be described
below, but it is important to remember that the resulting self-assembled object may be
in a kinetically trapped conformation.
Fig. 2.7. Self-assembly of block-copolymers

into star polymeric micelles and crew-cut
Star micelles Crew-cut micelles polymeric micelles.
Polymeric spherical micelles, the most commonly encountered self-assembled poly-

meric object, can thus be classified into two distinct categories using the terminology
first introduced by Eisenberg (Fig. 2.7, [30, 31]). Star micelles in water are composed
of a long hydrophilic and a short hydrophobic block, are in dynamic exchange with
freely dissolved polymer chains, and adopt a thermodynamically favored conforma-
tion. They have a low but nonzero CAC, and they form spontaneously when the poly-
mer is added to water. By contrast, crew-cut micelles, consisting of a long hydrophobic
and a short hydrophilic block, are kinetically frozen (Fig. 2.7). Their CAC is virtually
zero and no dynamic exchange process occurs within a reasonable time period. Lastly,
they can only be formed by an indirect method (see below).
2.3 Preparation of polymer nanoparticles
There are so many methods of preparing polymer nanoparticles that an entire book
would not be sufficient to cover them all. This section will present two main classes
of preparation techniques, the first belonging to the class of heterophase polymer-
izations, and the second to the class of self-assembly. Within heterophase polymer-
izations [32], three techniques will be introduced: emulsion, miniemulsion and mi-
croemulsion polymerizations. Other techniques, such as suspension and dispersion
polymerizations will not be covered as they usually lead to micron-size particles. Het-
erophase polymerization (Table 2.2) is the class of polymerization reactions in which a
polymer is formed in a nonsolvent (typically water). Most of these polymerizations are
radical polymerizations because free radicals, unlike carbanions and carbocations, do
not react with water or other solvents currently employed for polymerization. Emul-
sion polymerization is a process whereby a monomer which is mostly water insoluble
is polymerized in water using a water-soluble radical initiator. The resulting product
is a latex, that is to say a dispersion of polymer nanoparticles in water. This is the main
polymerization technique for obtaining polymer nanoparticles. Besides conventional

emulsion polymerization, miniemulsion polymerization and microemulsion polymer-
ization also lead to the formation of latexes. If the monomer is soluble in the solvent
but not the polymer, the process is referred to as dispersion polymerization. If both
monomer and radical initiators are insoluble in water, then large particles are ob-
tained – this process is referred to as suspension polymerization.
Table 2.2. Main features of heterophase polymerization.
Polymer- Emulsion Dispersion Suspension

ization Conventional Microemulsion Miniemulsion
Continuous water water water organic water
Phase solvents or
mixture
alcohol/water
Monomer – sparingly – in micelles – in pre- – soluble – low sol-
soluble in formed in the ubility in
water stable continuous water
– in droplets droplets phase – droplets
– in particles
Initiator water-soluble water-soluble water-soluble soluble in the soluble in the
or insoluble continuous monomer
phase
Dispersant ionic/nonionic ionic/nonionic ionic/nonionic soluble hydrosoluble
surfactant surfactant surfactant polymer polymer
Product stable latex stable stable latex stable latex suspension
10 to 500 nm transparent 50 to 500 nm 0.1 to 0.5 μm; (> 5 μm)
latex dispersions
10 to 20 nm < 20 μm
2.3.1 Emulsion polymerization
Emulsion polymerization is a remarkably simple experiment to conduct which usu-

ally leads to a high yield of monodisperse nanoparticles [2]. Numerous variants ex-
ist, such as, for example, the seeded emulsion polymerization, whereby small nano-
particle seeds are used as nuclei for polymerization, thus superseding the need for
nucleation. By using several monomers, a very large number of particle morphologies
can be attained. Emulsion polymerization is one of the major processes used in indus-
try for the production of polymers. Among the monomers polymerized in emulsion, let
us cite the acrylic monomers, fluorinated and chlorinated monomers such as vinyli-
dene chloride, vinyl chloride or tetrafluoroethylene, vinyl acetate and its copolymers,
styrene, and butadiene [4].
Emulsion polymerization presents numerous advantages:

– As water has a very high heat capacity, the dispersed system allows good control
of the exothermicity of the polymerization reaction.
– The viscosity in the latex remains low, even when SC reaches 50 % or above, in
contrast with solution polymerization, where viscosity skyrockets as SC increases.
– Emulsion polymerization yields high molecular weight polymers, usually higher
than solution or bulk polymerization under similar conditions. This is due to the
fact that the radicals are compartmentalized in separate particles. Their life span
is usually longer than in bulk.
– The rates of emulsion polymerizations are usually higher than solution polymer-
izations.
– Emulsion polymerization is a very handy way of manufacturing sticky rubbers
or other viscoelastic compounds, since the particles are surrounded by a layer of
emulsifier that prevents them from coagulating.
– Last but not least, emulsion polymerization does not require any organic solvent.
There is of course a price to pay for all these advantages:

– First, latexes are very fragile and are prone to flocculation (coagulation). Latexes
are always stabilized by convenient surfactants, necessary to retain the colloidal
state (see below). However, the surfactant can be undesirable in the final product.
– One key step during the polymerization process is nucleation, which is often
found to be highly variable and difficult to reproduce. This often results in latexes
presenting variable particle sizes.
Let us consider a typical emulsion polymerization recipe: 400 g of an organic mono-

mer, 1 000 g of water, 4 g of a surfactant, for example sodium dodecyl sulfate (SDS),
and 1 g of a water soluble radical initiator such as potassium persulfate. As the cmc
of SDS is 2.4 g/l at room temperature, then approximately 4 − 2.4 = 1.6 g of SDS are
engaged in forming micelles. Since on average each SDS micelle is constituted of
50 molecules, there are 6.7 ⋅ 1019 micelles in the system. These micelles are swollen
by the monomer: each gram of micelle can accommodate around 0.5 g of styrene
within its core. Furthermore, a small amount of styrene (0.3 g) is simply dissolved
in water (styrene has a low but nonzero aqueous solubility). Thus, from the initial
400 g of styrene monomer, approximately 399 g are neither in the aqueous phase
nor in the micelles. If the system is not stirred, a separate organic phase will ap-
pear on top of the aqueous phase, but under mechanical stirring large droplets (1–10
microns in diameter) stabilized by a small amount of surfactant will form. If the
water-soluble radical polymerization initiator is added at this point, emulsion poly-
merization is triggered. A series of colloidal events ensue which were first described by
Harkins [33], and which is referred to as the mechanism of emulsion polymerization
(Fig. 2.8).
Stage 1 I : Initiator
I M : Monomer
: Surfactant
MM
M I M+I
M I
Monomer swollen
micelle 2-10 nm
M M MM M M
M
M MM
MM M
I
Monomer swollen
polymer particle
Stage 2
M
MM M M MMM
M M
M MM MM MM
MM M M I M I
M I
I
I M
MM MM
M M
M M
Monomer M M
droplet MM
1-10 microns I
Stage 3
M M
MM M M MMM
M M M
M MM MM
MM M M
I M I
M MM MM
M M
I M M M
M M I
MM
I
Fig. 2.8. The three stages in Harkins’ model for emulsion polymerization.
Stage I: Nucleation
The radical initiator, dissolved in water, decomposes to form free radicals which sub-
sequently form free radical oligomers by reacting with the low amount of monomers
dissolved in the aqueous phase. Each time a monomer is inserted, the oligomer be-
comes less and less water-soluble and eventually diffuses to the organic phase. As-
suming that the monomer droplets have an average diameter of 10 microns, and using
equation (2.1), one finds that there are 2 ⋅ 1012 droplets in the system. The total sur-
face area provided by all these droplets is 650 m2 . By contrast, the 6.7 ⋅ 1019 micelles,
with an average diameter of 4 nm, present a surface area of 3 400 m2 . Statistically, the
radicals are captured by the micelles which are swollen by monomers, and on poly-
merization, the micelle is transformed into a growing polymer particle. The formation
of polymer particles is referred to as nucleation which, according to this model, occurs
in the micelles and is a case of micellar nucleation. Generally, only a small fraction of
the micelles are used for particle nucleation, the rest serving as a surfactant reservoir
to stabilize growing particles. When no more micelles are present, the nucleation is
terminated. At this point there are typically 1014 –1018 particles per liter of emulsion
and the overall conversion is of the order of 1–10 %. Nucleation can also take place
when the surfactant concentration is below CMC. This is referred to as homogeneous
nucleation. In this case, the radical oligomer grows into the aqueous phase; it even-
tually precipitates, forming a very small particle (so-called primary particle), which
serves as a nucleus for a polymer particle. Homogeneous nucleation leads to latexes
with a lower Np , usually consisting of between 1013 –1015 particles per liter.
Stage II: Steady state

Once nucleation is terminated, Np remains constant. Polymerization occurs within the
particle where monomer concentration is high (the polymer is swollen by the mon-
omer). Each time a monomer is polymerized in a polymer particle, another one dif-
fuses from the aqueous phase to the particle and yet another diffuses from a mono-
mer droplet to the aqueous phase. Thus, the monomer droplets act as monomer reser-
voirs and the monomer concentration in the particle (Cp ) remains constant during this
stage. Two antagonistic factors control Cp : the swelling of the polymer particle by the
monomer, which is entropically favorable for the polymer, and the increase of particle
surface upon swelling by the monomer, which is associated with an increase in sur-
face energy. These two contributions are balanced in the Morton–Kaizermann–Altier
equation:
2V0 𝛾
0 = ln(1 − φp ) + φp + χφ2p + , (2.3)
RTr
where χ is the Flory—Huggins interaction parameter between the polymer and the
monomer, r the radius of the particle, φp the volume fraction of the polymer in the
particle, and V° the molar volume of the monomer. From this equation, φp can be cal-
culated, followed by Cp (Table 2.3, [34]).
During stage II, Cp and Np remain constant. Therefore, the rate of polymerization
is constant; this stage is the steady state period of the polymerization. Similar to the
nucleation state, radicals formed in the aqueous phase enter the particles at regular
intervals. If the particle already contains a radical, then chances are that the two radi-
Table 2.3. Monomer solubility in polymer particles (Cp ) and in water (Cw ) for the emulsion polymer-
ization of common monomers.
Monomer Cp (mol/l) Cw (mol/l)

Styrene 5.5 0.0043
Methyl methacrylate (MMA) 6.6 0.15
Butyl methacrylate (BMA) 3.8 0.0025
Butyl acrylate (BUA) 5.0 0.0064
Vinyl acetate (VAC) 7.5 0.5
cals, being in close proximity, will terminate. Thus, except for very large polymer par-
ticles, the particle can only contain 0 or 1 radical, and the average number of radicals
per particle is n = 12 . In certain cases (for example after a transfer to monomer), radi-
cals can exit the particle before another radical entry occurs, and in this case, n ≺ 12 .
Large particles can accommodate two or more radicals without termination, and in
this case, n ≻ 12 .
Stage III
At this point the monomer droplets have disappeared and the monomer concentration
in the particle diminishes. Often, a gel effect (Trommsdorff effect) occurs: in short, the
polymerization rate increases significantly due to a drastic increase of n (radical ter-
mination is slowed by the high internal viscosity of the particle). Furthermore, as the
monomer is consumed in the polymer particles, the particles shrink during this stage.
Although emulsion polymerization is by far the most widely practised hetero-
phase emulsion polymerization technique, it also suffers from intrinsic limitations.
For example, its mechanism implies that the monomer diffuses through the aqueous
phase. Therefore, monomers with extremely low aqueous solubility (Table 2.3) are of-
ten difficult to polymerize. In this case miniemulsion polymerization should be used.
2.3.2 Miniemulsion polymerization
The use of miniemulsions to form polymer nanoparticles was pioneered by Ugelstad

and El-Aasser [35]. Miniemulsions are dispersions of critically stabilized oil in wa-
ter droplets prepared by shearing a system containing oil, water, a surfactant, and
a hydrophobe [36–38]. In miniemulsion polymerization, the monomer is emulsified to
form a stable miniemulsion ranging in size from 100 to 500 nm. Each of these droplets
becomes an independent nanoreactor for the polymerization, and the resulting poly-
mer particles form an exact replica of the initial nanodroplets.
One of the key features of miniemulsion polymerization is the colloidal stability of
the initial droplets. In conventional oil-in-water emulsions, droplets of various sizes
are formed and rapidly phase separate into one separate oil-phase when stirring is
stopped. Ostwald ripening, the diffusion of the oil phase through the aqueous phase
(Fig. 2.9) is responsible for this gradual coarsening of the emulsion. This process is
driven by the difference in Laplace pressure between droplets having different radii:
the oil diffuses from the smallest to the largest droplets. Besides Ostwald ripening,
mass transfer between droplets can occur when they collide. This collision mechanism
is most conspicuous in highly sheared systems and leads to either fusion or fission of
the droplets.
Ostwald ripening
Diffusion through
continuous phase
Collisions
fission
+
fusion
Fig. 2.9. Schematic representations of Ostwald ripening and the fission and fusion mechanisms of
droplets.
Ostwald ripening can be effectively suppressed by the addition of a small amount of

a hydrophobic compound (called hydrophobe) to the oil (Fig. 2.10). The hydrophobe
cannot diffuse from one droplet to another and is trapped in each droplet. If the emul-
sified oil was to diffuse from a small to a larger droplet, the hydrophobe concentration
would increase in the smaller droplet (Fig. 2.10), which is not favorable thermodynam-
ically due to osmotic pressure increase. Therefore, the presence of the hydrophobe in
each droplet efficiently prevents Ostwald ripening. Hexadecane is the most commonly
used hydropobe, but numerous other hydrophobes have been shown to successfully
prevent Ostwald ripening [36–37]. Similar to direct miniemulsion, osmotic pressure
in reverse miniemulsion (water-in-oil emulsion) can effectively be suppressed by an
agent soluble only in the aqueous phase, a so-called “lipophobe”, such as an inor-
ganic salt [39].
The formulation of a miniemulsion is relatively simple: nearly any type of oil and
surfactant can be miniemulsified to lead to metastable droplets with sizes usually
ranging from 50–500 nm. The dispersion requires a high-energy mechanical device,
usually a probe sonicator is used, but other devices such as high pressure homogeniz-
ers (for example a commercial microfluidizer), can also be employed.
H
H
H H
H H H H
H H
H H
Fig. 2.10. Suppression of Ostwald ripening by addition of a hydrophobe to the emulsified oil.
Miniemulsion polymerization has become increasingly popular in recent years be-

cause it is an extremely versatile tool for preparing polymer nanoparticles and also
for encapsulating hydrophobic compounds within polymer particles. Encapsulation
of lipophilic drugs [40], bactericides [41], functional oligomers [38], and even inor-
ganic particles [42] has been achieved by this method. However, miniemulsion is not
an ideal technique for small nanoparticles (d < 50 nm). Recently, much effort has
been made to prepare miniemulsions which don’t require sonication of high-shear
homogenization [43].
2.3.3 Microemulsion polymerization
In microemulsion, the monomer is initially confined to micelles and no droplets are

present. Polymerization occurs within the micelle. It has been estimated that approxi-
mately one out of ten micelles is nucleated and becomes a polymer particle, the other
micelles serving as monomer reservoir and surfactant reservoir. The resulting disper-
sion is thus formed of small polymer particles which are nonetheless larger than the
original micelles. Their size ranges from 10–50 nm [44–45]. Microemulsion polymer-
ization prevents several specific characteristics which are worth mentioning. Firstly,
due to their very small size (Fig. 2.11), the nanoparticle dispersion is translucent and
does not significantly scatter light. Polymer molecular weights are also usually very
high; for a system composed of small particles, the number of particles is very high
(see equation (2.1)), and once a radical enters a micelle, another radical entry into the
same micelle leading to termination is unlikely. As a result, most if not all particles
contain one radical during polymerization, and as Np is very high, polymerization is
extremely rapid.
EMA S BMA EHMA
Fig. 2.11. Nanolatexes of polyethylmethacrylate (EMA), polystyrene (S), butyl methacrylate (BMA),
and 2-ethylhexylmethacrylate (EHMA) obtained by microemulsion polymerization. For these nanola-
texes, a cobalt-based catalyst was used to limit polymer molecular weight. Reprinted with permis-
sion from [46].
In contrast to metastable miniemulsions, which are only obtained after a high-energy

mixing step, microemulsions are thermodynamically stable and form spontaneously.
However, their formulation is particularly difficult. They require large amounts of sur-
factant, often larger amounts than monomer. In the ternary phase diagram (water,
monomer, surfactant), the stability region for the microemulsion is extremely narrow.
Thus, a slight change in monomer concentration, temperature or other operating pa-
rameters can result in loss of the microemulsion [47, 48].
2.3.4 Self-assembly in selective solvents
As mentioned above, block copolymers with long hydrophobic sequences form crew-
cut micelles upon self-assembly in water. However, due to the lack of exchange
mechanism, the self-assembly process is not spontaneous and it requires an indi-
rect preparation route. The method generally employed consists of transferring the
block copolymer from a good solvent, in which both blocks are soluble, to a selec-
tive solvent, in which only one of the blocks is soluble. The main requirement is that
the good solvent and the selective solvent be miscible. Among the usual combina-
tions of good and selective solvents, one finds THF/water or DMF/water. Once the
self-assembly step is performed, the good solvent is removed, either by dialysis or
by repeated centrifugations, although care should be taken to avoid flocculation of
the nanoparticles during centrifugation. During the addition of the selective solvent,
the solvation environment changes: it is first a good solvent, then an intermediate
quality solvent, whereby micellization and rapid exchange between micellar and
free polymer occurs, and finally it becomes a highly selective solvent, whereby the
micelle configuration is frozen [30, 31]. Ternary phase diagrams for the polymer and
both solvents are often extremely complex. Depending on the experimental design
(polymer concentration and rate of selective solvent addition), a given trajectory will
be followed on the phase diagram when the selective solvent is added [49], and var-
ious zones of predominance will be visited. The result of the self-assembly process
corresponds to the first structure for which exchange between micellar and dissolved
chains is slow relative to the duration of the experiment.
2.4 Colloidal stabilization
As mentioned above, polymer nanoparticles are not colloidally stable unless they are
stabilized, for example by a surfactant. Several mechanisms can be used to provide
colloidal stability; they are based on (1) electrostatic stabilization, (2) steric stabi-
lization, and (3) depletion mechanism. When the system is not colloidally stable it
will coagulate or flocculate, resulting in the formation of coagulum, or floc. Both
terms refer to the formation of particular aggregates, although for polymer colloids,
the word coagulum is usually employed for compact aggregates which cannot be re-
dispersed, whereas flocs are loosely bound aggregates, which in some cases can be
redispersed into free flowing colloids. Although the colloidal stabilization of polymer
nanoparticles at low solid content does not present any major difficulty, at high solid
content (above 50 %), systems are prone to flocculate and one cannot rely on a sin-
gle mechanism (electrostatic, steric, depletion) to impart colloidal stabilization. As
a last note, several manufacturers commercially produce surfactant-free polystyrene
latexes, for example as a tool for calibrating light-scattering instruments. Surfactant-
free does not mean charge-free (residual charges from the emulsion polymerization
initiator are present on the particle surface), and this low number of charges is suffi-
cient to impart colloidal stability.
2.4.1 Electrostatic stabilization
Electrostatic stabilization is the predominant strategy used to stabilize polymer col-

loids in aqueous media. It is effective as soon as charges are immobilized at the sur-
face of the nanoparticle. This can be achieved in a variety of ways: most commonly
a charged surfactant will be added to the colloidal dispersion. In the case of the an-
ionic surfactant sodium dodecyl sulfate (C12 H25 –O–SO−3 Na+ ), the hydrophobic tail
(C12 H25 ) adsorbs on the surface of the particle, leaving the polar sulfate head (OSO−3 )
at the interface between the particle and the aqueous phase. The sodium counter ion
is ‘free’ in water. Thus, the polymer nanoparticle is decorated by negative charges via
the adsorption of the surfactant (sulfate heads, Fig. 2.12). Note that in this case, the
adsorbed surfactant is in dynamic equilibrium with the dissolved surfactant, there-
fore they are not static punctual charges per se. However, the mathematical descrip-
tion of electrostatic stabilization is not affected by the presence of this dynamic equi-
librium.
The simplest (and inaccurate) explanation for the electrostatic stabilization mech-
anism is the presence of an electrostatic repulsion between the two negatively charged
nanoparticles (assuming that an anionic surfactant is used). This is far from satisfying
and more information can be gleaned by considering the electrical potential of a sin-
gle charged spherical nanoparticle immersed in water (Fig. 2.12). Due to the presence
of surface charges, ions of opposite charge are condensed (adsorbed) at the proximity
of the particle surface. The liquid layer where these ions are located is called the Stern
layer. Further away from the Stern layer, the ions are attracted by their close neighbors,
but they can also exchange with freely diffusing ions in the solution. Far away from
the particle surface, the spatial distribution of cations and anions is homogeneous
(concentration c∞ ), and the attraction (or repulsion) by the charged particle surface
is entirely screened. Thus, an intermediate layer exists between the Stern layer and
the free solution containing ions of low (but non-zero) mobility, which feel the elec-
trostatic potential generated by the surface charge. It is referred to as the diffuse layer
(Fig. 2.12), and the Stern and diffuse layers combined form the double layer. Let us now
consider two charged nanoparticles approaching one another. When the diffuse lay-
ers interpenetrate, the concentration of ions in the overlap region becomes larger than
the concentration of ions which are free in solution, resulting in an increase of osmotic
pressure. The system will thus tend to separate the two charged nanoparticles in order
to recover osmotic equilibrium. Therefore, the ‘force’ which repels two charged nano-
particles is principally osmotic in nature and is often called an electro-osmotic force.
By solving the Poisson–Boltzmann equation using a number of assumptions [50],
one finds that the electrical potential (V(r)) generated from the surface is maximal at
the surface and decreases exponentially with r, where r is the distance from the sur-
face of the nanoparticle (Fig. 2.12). The characteristic decay length of this exponential
is 1/κ, which is referred to as the Debye length of the diffuse layer. The quantity 1/κ
is often used as a measurement of the thickness of the double layer. The electrostatic
potential has nearly entirely vanished at a distance 2/κ from the surface and thus, the
distance at which the surfaces of two approaching nanoparticles start to electrostat-
ically interact is 4/κ. The mathematical expression of the Debye length (Fig. 2.12) is
relatively simple and only takes temperature and ionic strength of the medium into
account, with a characteristic exponent of −1/2. Thus, the higher the ionic strength,
the faster the surface charges will be screened by other charges and the steeper the de-
cay of the electrostatic potential. In Table 2.4, values of Debye lengths are consigned
for various electrolytes and concentrations. For divalent and trivalent cations, the De-
bye length becomes very small, even at moderate ionic strength; thus nanoparticles
can approach each other at very close proximity without any electrostatic repulsion.
In these conditions of ionic strength, the electrostatic stabilization is ineffective. It
is thus not surprising that Al3+ -containing salts such as aluminum sulfate are used
industrially as flocculants. Inversely, at very low ionic strength, the diffuse layer ex-
tends very far into the solution, and even at low solid content the diffuse layers of
each polymer nanoparticle interpenetrate. As the ions and the surrounding hydrat-
ing water in the diffuse layer have low mobility, the viscosity of the latex increases
significantly. Such an effect is referred to as an electroviscous effect. A spectacular ex-
periment for demonstrating this effect consists of deionizing the continuous phase of
a monodisperse latex with an equimassic mixture of acidic and basic ion exchange
resins. When the ionic strength is low enough, the latex looks like an opalescent vis-
cous gel which will immediately return to liquid on addition of a pinch of salt.
V(r) 2
1 –kr Particle
V(r) = 64 RT c∞ ϒ 0 e
k Stern layer
1 RTεε0 0.301 Diffuse layer
= ≈
2
K F 2 c∞ zi
I
–ζ i
Buffer concentration c∞
1/k
Fig. 2.12. Representation of the double layer around a charged nanoparticle (charge = z) and
electrostatic potential V(r) (in absolute value) versus distance from the nanoparticle surface (r).
The potential depends on the temperature (T), the concentration of ions in the solution (c∞ ), and
the term 𝛾o = tan h (zFΨ/4RT) where (Ψ) is the potential at the surface and (F) the Faraday constant.
The Debye length (1/κ) depends on the ionic strength, defined as I = Σ(c∞ z2i ), where zi is the re-
spective charge of each ion in solution. The potential (ζ) corresponds to the value of the electro-
static potential at the interface between the Stern and the diffuse layer.
Table 2.4. Debye length in nm versus electrolyte concentration.
Electrolyte Debye length (1/κ) in nm

concentration
(mol/l) NaCl MgCl2 Al(NO3 )3
−5
10 96.2 55.5 39.2
10−4 30.4 17.5 12.4
10−3 9.6 5.6 3.9
10−2 3.1 1.8 1.2
10−1 1 0.5 0.3
So far, only the repulsive electro-osmotic force was considered to describe the in-
teraction of charged nanoparticles. However, other interactions are at stake and a sim-
plified description of all the interactions between two charged nanoparticles was pro-
posed by Derjaguin and Landau [51], Verwey and Overbeek [52], in what constitutes
the DLVO theory. The interaction potential (Fig. 2.13) between two polymer particles
is given by the summation of an attractive van der Waals potential, Va , the repulsive
electro-osmotic potential, Vr described above, and a repulsive very short action Born
potential, Vb , which prevents the two nanoparticles from interpenetrating. The over-
all potential presents two minima (Fig. 2.13). A deep primary minimum is located at a
short distance which corresponds to the distance at which the two nanoparticles are in
close contact. When the particles fall into this minimum, they are (irreversibly) coag-
ulated. A maximum height (Vm ) is present at intermediate distance. Lastly, a shallow
secondary minimum is present at large distance The energy difference ΔVf represents
the energy barrier that a particle must cross in order to reach the primary minimum.
The higher this barrier, the more stable the colloid. It is generally accepted that under
normal conditions a barrier of ΔVf = 15 RT is sufficiently high for the colloid to be
stable. As the Debye length is shorter with higher ionic strength, the increase in ionic
strength is one of the key factors responsible for a decrease of ΔVf and therefore for
the loss of colloidal stabilization.
Primary
V maximum
V = Vr + Va + Vb
2
1 –kr
Vr = 64RT c∞ ϒ 0 e
k
–AR
Vm Va =
Vr
12r
Vb ΔVf
Secondary
Va mininum
Primary
mininum
Fig. 2.13. Interaction energy versus H, where H is the distance separating two spheres. Vb is the
Born repulsive potential, Va is the van der Waals attractive potential (lower dashed line), and Vr is
the electrostatic potential (upper dashed line). The radius of each sphere is R and the composite
Hamaker constant (which takes both the sphere and the continuous medium into account) is A.
2.4.2 Steric stabilization
Another method of stabilizing latex particles is to physically prevent their approach

by introducing a hairy layer of solvated polymer at their surface. If the hairy layers
are sufficiently thick, the two spheres will only be able to approach each other up to a
distance at which the van der Waals attraction is small relative to thermal energy (kT).
For a particle of 20 nm size (Fig. 2.14), a layer a few nanometers thick will be sufficient.
However, for larger particles, very thick layers need to be employed as the reach of the
van der Waals attraction increases with particle size. Thus, it is easier to stabilize small
particles by a steric mechanism. From Fig. 2.14, one may infer the size of the hairy
layer which is necessary to impart steric stabilization. It is possible to convert layer
thickness into polymer molecular weight, provided specific information on the poly-
mer conformation in the solvent is available. Such information can be gathered ex-
perimentally (using viscosimetric or light scattering experiments) or theoretically (via
atomistic calculations). The rule of thumb is that the radius of gyration of the chain is
Rg ≈ 0.05 MW0.5 . For a particle of diameter 200 nm, a hairy layer of 6.6 nm provides a
stabilization of 2 kT, which corresponds to a molecular weight of 17 000 g/mol.
When sterically stabilized particles approach each other, interpenetration of the
hairy layers results in a restriction of their accessible configurations, which is unfavor-
able in terms of entropy. Furthermore, the concentration of hairs in the overlap region
increases, which results in a local increase of osmotic pressure. To maintain osmotic
equilibrium, the solvent will tend to decrease the local concentration of hairs, which
results in separation of the particles. Thus, steric stabilization is osmotic in nature [53].
Steric stabilization can be achieved by several means. For example, non-ionic sur-
factants, consisting of a hydrophobic unit and a pegylated water-soluble polymer can
impart steric stabilization. The reader should be aware that these surfactants exhibit
a cloud point, that is to say a temperature above which they are not soluble [54]. In-
deed, at low temperature, the pegylated chain is soluble in water due to the presence of
hydrogen bonds between water and the oxygen atom of the pegylated chain. This rep-
resents an enthalpic contribution to the heat of dissolution of the polymer. At higher
temperature, the entropic cost associated with the liberation of the hydrogen bonded
water molecules offset the enthalpic gain and the pegylated chain becomes insoluble
in water. Cloud points are dependent on the nature and concentration of the surfac-
tant and the nature of the ions present in the continuous phase.
Another method of achieving steric stabilization relies on the use of water-soluble
polymers which are introduced during polymerization and act as chain transfer
agents. For example, polyvinyl pyrollidone (PVP) is susceptible to hydrogen abstrac-
tion (chain transfer) in α to the carbonyl group. During an emulsion polymerization,
the hydrogen abstraction step is followed by the insertion of hydrophobic monomers,
resulting in the formation of a graft amphiphilic copolymer on a PVP backbone. This
amphiphilic graft polymer, formed in situ during polymerization, serves as steric
stabilizer.
–2
–4
–6
–8
Va/kT
–10 dp = 20 nm
–12 dp = 200 nm
dp = 500 nm
–14
–16
–18
0 5 10 15 20
r (nm)
Fig. 2.14. Effect of the particle diameter on the van der Waals attraction between two particles. The
potential of interaction was calculated using the analytical expression for van der Waals potential
presented in [55]. The horizontal line corresponds to an attraction potential of 2 kT. A Hamaker con-
stant of 0.95 ⋅ 10−20 J, corresponding to the Hamaker constant of polystyrene in water, was used to
create this graph.
Steric stabilization is usually considered to be insensitive to ionic strength but sensi-

tive to temperature. Unlike electrostatic stabilization, steric stabilization is also effec-
tive in organic mediums, provided the hairy layer is soluble in the solvent. Finally, in
aqueous mediums, a very efficient method of stabilizing a colloid consists of the elec-
trosteric mechanism, whereby the hairy layer is constituted of a polyelectrolyte [56],
as it combines the features of electrostatic and steric stabilization.
2.4.3 Depletion stabilization
In the depletion stabilization mechanism, the stabilizing polymer does not inter-
act directly with the nanoparticle surface, but is simply dissolved in the continuous
medium. Thus, the choice of stabilizer is greatly simplified, as its only structural
requirement is that it be soluble in the solvent. However, this mechanism is to be
handled with great care, as the same molecule can act as either stabilizer or floccu-
lant [57]. The stabilization mechanism occurs when the medium is concentrated in
stabilizer (or dilute in nanoparticles). Inversely, depletion occurs when the medium
is dilute in polymer (or concentrated in nanoparticles). Practically, stabilization by
depletion occurs at stabilizer concentrations which are so high that it is difficult to use
under most experimental conditions. The reverse is unfortunately true: it is a com-
mon observation that flocculation of a stable dispersion is triggered upon addition of
a soluble polymer.
When a polymer is dissolved in the solvent, its center of mass cannot approach
the surface of the nanoparticle (Fig. 2.15). Therefore, each nanoparticle is surrounded
by an imaginary layer which cannot be visited by the center of mass of the dissolved
polymer. The thickness of this depletion layer is equal to Rg [58]. When two nano-
particles approach one another, their depletion layers overlap. In the overlap volume,
the depletion layer is shared by two particles, with the consequence that solvent has
been released outside the depletion layer. Thus, the volume of solvent accessible to
the polymer increases. Lowering the polymer concentration results in a decrease of its
chemical potential, which is favorable thermodynamically. This is the basis for deple-
tion flocculation.
Rg
Particle Particle Particle Particle
Depletion zone
V
Depletion
stabilisation
d/Rg
d : Inter-particle distance 2 1 Depletion
flocculation
Fig. 2.15. Sketch of the interaction potential between two spheres immersed in a solvent containing
a polymer (radius of gyration Rg ) dissolved in the solvent.
Let us now consider the case where the nanoparticle suspension is very dilute. When
two nanoparticles approach each other, they will have to first repulse (or exclude) dis-
solved polymer chains before the depletion layers start to overlap. Compression of
the polymer chains starts to occur when the inter-particle distance is equal to 2 Rg .
When the inter-particle spacing is further reduced, the conformation of the polymer
chain is changed from a random coil to a conformation which is more geometrically
constrained and less entropically favorable. Thus, an energy barrier must be crossed
in order for the depletion layers to overlap and the particles to flocculate. According
to Napper, if this barrier is higher than 20 kT [53], then the colloid is protected from
flocculation. However, this is only the case if the concentration of polymer dissolved in
the solvent is high and if the polymer molecular weight is high. Indicative calculations
are presented in [53] for a polystyrene latex stabilized by a non-ionic surfactant with
17 ethylene oxide units. Depletion stabilization occurs when a 1 000 g/mol polyethy-
lene glycol polymer is added at a concentration of 380 g/l or above. Any lower concen-
tration results in destabilization by depletion flocculation. If a 10 000 g/mol polyethy-
lene glycol is used instead, stabilization occurs for concentration greater than 55 g/l.
Obviously such high concentrations are impractical, as they will lead to very high vis-
cosity.
2.4.4 Future directions
The field of colloidal stabilization is a fascinating and vibrant area of science which
combines physical chemistry and fluid dynamics. For example, recently a new form of
particle stabilization, named haloing, was discovered. It occurs when an uncharged
nanoparticle is immersed in a medium containing very small, highly charged nano-
particles [59]. The domain also has exceedingly important technological repercus-
sions, ranging from advanced materials to drug delivery. The small chapter presented
here only scratches the surface of the field, and the interested reader should consult
the references listed below.
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S. Rondeau-Gagné and J.-F. Morin
3 Synthesis, functionalization and properties of
fullerenes and graphene materials
3.1 Introduction
Carbon-based materials are undoubtedly amongst the most studied materials in both
academic and industrial laboratories since the discovery of fullerenes in 1985 [1]. Prior
to this discovery, three carbon allotropes were known, namely amorphous carbon,
graphite, and diamond. These rather abundant naturally occurring materials have
been used by human kind for centuries for different applications, ranging from energy
production to fabrication of luxury goods. Although very useful, these carbon mate-
rials were perceived as low-tech and not much research regarding their physical or
chemical properties was undertaken. However, everything changed very rapidly with
the discovery of fullerene in 1985 and carbon nanotubes in 1991 [2], and a renaissance
of carbon materials took place in many scientific areas. These new carbon allotropes
showed very interesting properties, especially electronic ones, due to their delocalized
π-electron system. While the research and development related to fullerenes and car-
bon nanotubes were at their prime, graphene, a layer of graphite one atom thick, was
isolated for the first time in 2004 [3], giving new reasons for scientists to be excited
about new forms of carbon materials. With such a diversity of structures, a plethora
of applications can be envisioned for these materials, including electronic, biomed-
ical, energy, aerospace, water treatment, and so on. In this chapter, we will discuss
the synthesis and chemical modifications of two of these materials, more particularly
fullerene-C60 and graphene. A brief discussion of their applications in materials sci-
ence is also presented.
3.2 Fullerenes
Discovered in 1985 by Robert Curl, Harold Kroto, and Richard Smalley, fullerenes have
brought about a revolution in materials science, chemistry, and physics [4, 5]. With
their amazing properties, these carbon clusters have stimulated research and incorpo-
rated into different types of devices, often leading to increased efficiency and unique
properties [6, 7]. Among this family, C60 is particularly interesting, since it is symmet-
rical, reactive towards different kinds of reagents, and can be prepared in relatively
large quantities (the most abundant of all fullerenes). Therefore, it is not surprising
that an increasing number of scientific papers on C60 synthesis and characterization
have been published over the past two decades. The chemistry of this new carbon
allotrope is wide-ranging and extends from chemical functionalization to encapsula-
tion of atoms and molecules. In this section, the chemistry of fullerene C60 and the
properties that make it a major building block in modern chemistry will be looked at
in detail.
3.2.1 General considerations
Fullerenes are a new family of compounds consisting entirely of sp2 -hybridized car-
bon atoms. From a structural point of view, fullerene C60 is perfectly spherical and
consists of twelve pentagons and twenty hexagons. However, depending on their
size, fullerenes can adopt different shapes. For example, the shape of C70 is ovoid
rather than spherical. Also, fullerenes can have from twenty to a hundred carbon
atoms [8–10]. The first mention of fullerenes in the literature was by Osawa in 1970, as
he predicted that the corannulene was, in fact, a sub-structure of C60 [11]. However,
it was only fifteen years later that his hypothesis was confirmed by Curl, Kroto, and
Smalley in an experiment aiming at “[. . . ] understanding the mechanism by which long-
chain carbon molecules are formed in interstellar space and circumstellar shells” [1].
By vaporizing a rotating graphite target with a laser beam, fullerenes were produced
and detected by mass spectrometry (peaks at m/z = 720.7 and 841.8 for C60 and C70 ,
respectively). The importance of this discovery for materials science and nanotech-
nology was rewarded by the Nobel committee in 1996 [12].
Fig. 3.1. C60 (a) and its Schlegel re-

(a) (b) presentation (b).
Although its single and double bonds alternate, C60 is not aromatic. Despite the pres-
ence of 32 aromatic rings, C60 has 60 π-electrons, and therefore does not meet the
criteria of the Hückel rule: 2(N + 1)2 with N = 0, 1, 2, 3, . . . , for three-dimensional
molecules [13]. As an indication of this anti-aromatic character, C–C bond junctions
[6 : 6] are slightly smaller (1.40 Å) than the C–C bonds of the [5 : 6] junctions (1.45 Å),
meaning that the [6 : 6] junctions and [5 : 6] junctions have double and single bond
character, respectively. The van der Waals diameter of C60 is 1.1 nm. Table 3.1 summa-
rizes some interesting properties of this carbon allotrope [14].
3 Synthesis, functionalization and properties of fullerenes and graphene materials | 39
Table 3.1. Some interesting properties of C60 .
Inner diameter 3.48 Å

Crystalline network FCC
Density 1.72 g/cm
Thermal conductivity 0.4 W/mK
Electronic affinity 2.65 eV
1st ionization potential 7.58 eV
Band gap 1.7 eV
Solubility o-DCB (25°C) 27 mg/mL
Solubility CS2 (25°C) 12 mg/mL
Solubility toluene (25°C) 3.2 mg/mL
3.2.2 Synthesis and purification of fullerenes
Synthesis of fullerenes can be achieved using various techniques and processes. Gen-
erally, these techniques require sublimation of simple carbon feedstock such as gas
(methane, ethylene, and acetylene), solvents (methanol, ethanol, and hydrocarbons)
or solid (graphite) at high temperature [15]. The formation mechanism of fullerenes is
still a source of debate among the scientific community, but the most plausible hypoth-
esis seems to be nucleation of carbon particles [16]. Production of fullerenes always
results in the formation of several types of fullerenes, which differ in size. However,
C60 and C70 are the two major isomers formed after pyrolysis. Interestingly, it is possi-
ble to control the C60 /C70 ratio by changing various synthetic parameters. Nowadays,
the most commonly used production route for the large-scale synthesis of fullerene is
the flame method. This method requires installations allowing control of multiple pa-
rameters, such as pressure, flame temperature, concentration of carrier, gas and oxy-
gen/carbon ratio. The flame production method consists of the sublimation of carbon
rods with a flame fed with benzene or acetylene. On sublimation, carbon grows around
a center of nucleation and forms different types of fullerenes within the residual soot
from which they can then be isolated. For best results, it is important to introduce a
certain amount of carrier gas such as H2 or O2 . In the best production conditions, the
mass percentage of fullerene collected is about 20%. It is worth mentioning that some
companies have been using this method to produce a total of 40 metric tons of C60
per year [17].
Following the production of fullerenes, a problem arises: purification. Indeed,
given that the fullerenes obtained have very similar polarity, size, and low solubility
in most common solvents, purification so as to obtain pure fullerene clusters is very
difficult. Several purification methods, such as high-performance liquid chromatog-
raphy (HPLC), have been developed in order to isolate the fullerene C60 [18, 19]. This
technique is the most frequently used for the purification of different-sized fullerenes.
It is also the only known method for separation of larger fullerenes (> C76 ). However,
this method is very expensive when hundreds of milligrams or even grams of mate-
N
(DBU)
C60, C70, C>76 C70 DBU + C60 (99,5%)
C>76 DBU
Fig. 3.2. Complexation of C≥70 with DBU.
rial are needed. In addition, modern chromatography columns cannot separate more
than one gram per hour, which makes it a time-consuming method. Thus, purification
of large quantities of fullerenes is very difficult. To overcome this problem, a tech-
nique using a chemical agent, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), has been de-
veloped, enabling the isolation of pure C60 with excellent yields [20]. This technique
relies on complexation between large fullerenes (≥C70 ) with low reduction potential
and DBU, leading to a precipitation of the C≥70 ⋅ DBU complex and leaving the C60 in
solution. Figure 3.2 presents the general complexation of C≥70 with DBU.
3.2.3 Chemical and physical properties of C60
Because of its structure, its incredible electronic and electrochemical properties, and
its specific reactivity, C60 is very attractive to the scientific community. Its most remark-
able property is undoubtedly its triply degenerated LUMO orbital, which can accom-
modate up to six electrons upon electrochemical reduction [21]. This property makes
C60 a unique electron acceptor for different applications, especially in electronics.
Thus, as shown in Fig. 3.3, six reversible redox processes can be observed in controlled
electrochemical experiments (cyclic voltammetry) [22]. It is important to mention that
C70 has a doubly degenerated LUMO orbital which can accept up to four electrons.
However, the level of the nondegenerated LUMO + 1 is sufficiently close in energy to
accept two additional electrons, which gives C70 similar electronic properties to those
of C60 .
This remarkable electron affinity is still not fully understood and continues to be
investigated by the scientific community. Studies on bowl-shaped subunits of C60 are
particularly useful and may help in gaining insights into the electronic properties of
fullerenes [23]. The study of fullerene subunits also allows more understanding of
their reactivity. As a simple model, the fullerene C60 can be considered a collection
of pyracyclene units, as shown in Fig. 3.4. The pyracyclene unit is anti-aromatic (4n π-
electrons). By accepting two electrons, anionic units are formed, each having a 4n +2
electrons structure which leads to aromaticity and thereby enhances stability. The for-
mation of cyclopentadienide units is thought to give to C60 its “n-type” character. The
c60 at –10°c
10 µA
5 µA
–1.0 –2.0 –3.0

Potential (Volts vs Fc/Fc+)
Fig. 3.3. Electrochemical reduction of C60 as observed by cyclic voltammetry (CV) [22].
formation mechanism of cyclopentadienide via direct electron transfer or nucleophilic

reaction is shown in Fig. 3.4 [24].
Since the electronic properties of fullerenes are those most exploited, several stud-
ies have been conducted to control and modify them, especially the LUMO energy level
of C60 , in order to improve its performance in various types of electronic devices. This
is particularly important in solar cells, in which C60 derivatives are used as electron-
accepting units [24]. Modulation of the LUMO energy level of C60 can be accomplished
+2 e–
Nu–
Nu
Fig. 3.4. Formation of cyclopentadienide unit via direct electron transfer or nucleophilic addition.
through various covalent and supramolecular functionalizations [25–30]. Generally,

the electronic level of the orbitals in a fullerene can be modified by incorporating dif-
ferent electron-accepting or electron-withdrawing groups. A strong electron-donating
group increases the electron density of C60 , which thereby increases the LUMO energy
level. An electron-accepting substituent has exactly the opposite effect. In addition,
a through-space electronic phenomenon called periconjugation also allows modula-
tion of the electronic properties of the fullerene [31]. A through-space electron transfer
is possible by an orbital overlapping between a substituent and C60 , resulting in an in-
crease or decrease of the electron density of C60 . Thus, the direct consequence of this
change in electron density is the modulation of electronic levels.
3.2.4 Chemical functionalization of C60
Since the discovery of fullerenes several studies have been conducted to improve their
solubility in common solvents. As mentioned previously, a second objective of the
functionalization of fullerenes is modulation of their properties, mainly the electronic
properties. In order to make these changes, chemists have attempted to use conven-
tional tools of organic chemistry. However, functionalization does not proceed with
the same ease on every fullerene. In fact, fullerenes of different sizes have different
reactivity toward organic reactions, and C60 is one of the most reactive fullerenes. Re-
action on its highly curved structure promotes the release of cyclic strain. Moreover,
as a result of being perfectly spherical and symmetric, it is possible to perform regios-
elective reactions on the fullerene cage, which greatly facilitate product purification.
The main functionalization methods are [3 + 2] and [4 + 2] cycloaddition reactions,
as well as nucleophilic reactions.
One of the most useful functionalization reactions on C60 is the [3 + 2] cycloaddi-
tion. The most famous reaction is the Prato reaction [32, 33]. Using C60 in the presence
of an amino acid, usually a sarcosine derivative and an aldehyde, cycloaddition takes
place at a [6,6] junction of the fullerene core, resulting in the formation of a fulleropyr-
rolidine. The general Prato reaction and its mechanism are shown in Fig. 3.5.
The Prato reaction is a very useful reaction for the formation of several deriva-
tives because it has important advantages over other methods. Essentially, this reac-
tion does not require the use of toxic reagents, catalysts or unstable organometallic
reagents. Some side products may be formed during the reaction, which usually leads
to a 60–80% conversion of C60 into fulleropyrrolidine (30 to 40% yield overall). Prop-
erties of the parent fullerenes can be modulated through two side groups, which can be
of different chemical nature. This reaction is mainly used in the synthesis of function-
alized polymer [34], donor-acceptor complexes [35], functionalization of peptides [36],
and synthesis of water-soluble derivatives of C60 [37]. It is noteworthy that fulleropy-
rrolidines can also be obtained by thermal ring opening of aziridine [38].
R2
N R1
R2
O 1) N COOH
H
H R1 2) C60, toluene, reflux
R2
N R1
H R1 H R1
R2 OH O O
N + Cycloaddition [3+2]
H R2 N H N
O H R1 + O R2 +
–
Fig. 3.5. The Prato reaction.
Another widely used type of fullerene functionalization is the [4 + 2] cycloaddition.

Such functionalization can be carried out via three main methods: by generating a
nucleophilic carbon from a α-halo ester, by the thermal addition of diazo compounds
followed by thermolysis (or photolysis), or by a carbene addition. One of these three
methods is particularly interesting, and is called the Bingel reaction [39]. This reaction
requires the use of a halogenated diester which, in the presence of a strong base and
C60 , forms a fullerene derivative bearing a cyclopropane moiety. This type of derivative
is called methanofullerene. The general reaction is shown in Fig. 3.6.
O O O O
X
RO RO
OR OR
O O NaH, C60
–
RO OR Toluene, reflux
X
Fig. 3.6. The Bingel reaction.
Functionalization of C60 by this method has several advantages. First, given that the
synthesis of diester compounds is relatively easy, the reaction is very versatile and
can be applied to a variety of compounds. Another advantage is that the ester groups
can easily be post-functionalized to form more complex architectures. In addition, the
synthetic yields are generally very good (50% or more), and this reaction occurs regios-
electively at the [6,6] junctions of the fullerene core. It is noteworthy that the α-halo
ester may be formed in situ from a diester and a dihalogen (Br2 or I2 ) in the presence
of DBU.
Nucleophilic addition is also another very interesting method of C60 functional-
ization [40–43]. This reaction is much less common in the literature and is often used
strictly for synthetic ease. Nonetheless, this method allows the preparation of several
types of useful derivatives whose properties and functions depend on the atom di-
rectly attached to C60 . In most cases, the nucleophilic species is an acetylenic or ben-
zylic carbon, but it can also be a heteroatom such as oxygen or nitrogen. An example
of a nucleophilic substitution reaction on C60 with an acetylide derivative is shown in
Fig. 3.7.
+
R Li E
R R2
E
Fig. 3.7. Nucleophilic substitution of an acetylenic carbon on C60 .
Usually, the nucleophilic moiety is formed on a terminal alkyne in the presence of a

strong base, such as the non-nucleophilic lithium hexamethyldisilylamide (LHMDS),
or n-butyllithium. The resulting carbanion generated can be added to C60 , thus trans-
ferring the negative charge onto the cage, more specifically onto the adjacent carbon
of the newly formed bond. An electrophilic species must then be added to quench
this anion. The electrophilic species can be of various natures such as a proton, an
alkyl chain, a benzoyl group, etc. Similar to functionalization methods previously pre-
sented, the nucleophilic addition has several advantages. First, this method allows a
wide range of derivatives from readily available terminal alkyne derivatives to be ob-
tained. Given that two different side groups (nucleophiles and electrophiles) can be
added to C60 in a single reaction, the number of possible combinations is astonishing.
Nucleophilic addition also allows the synthesis of derivatives with very good yields
(40–60%). Purification of the reaction media is also simplified, as few side products
are formed during the reaction. There is, however, the possibility that polyaddition
products will be formed. This side reaction can be minimized by controlling the re-
action temperature and the number of equivalents of acetylide in the reaction media.
The reaction is also very difficult to control, and a difference of one minute between
various additions of reagents may significantly affect the reaction yield.
Although nucleophilic addition is a promising class of functionalization reac-
tions for fullerenes, another type of reaction leading to water-soluble polysubstituted
derivatives has proven to be very useful for biological applications [44, 45]. Experi-
mental conditions are found to be relatively harsher than in other types of functional-
ization, but the products obtained have interesting properties and specific reactivity.
In a first step, fullerene is halogenated using high-pressure F2 gas for a long period
of time. Thereafter, by adding a nucleophile and an organic catalyst, it is possible
to carry out nucleophilic substitution on the fullerene cage. However, the rules of
nucleophilic substitution are somewhat changed with a fullerene. In fact, given the
shape of the C60 cage, the normal SN 2 reaction is geometrically impossible. Thus, the
reaction mechanism is still controversial and many studies have been conducted to
determine it precisely. Since the reaction requires long exposure to a gaseous halo-
gen, few manipulations are necessary. It is also possible to introduce a wide variety
of nucleophilic species, which allows several types of derivatives with completely
different properties, depending on the nucleophile chemical nature, to be obtained.
However, the exact number of substituents inserted onto the fullerene cage is very
difficult to control and may vary significantly, which is a major drawback when pure
materials are needed, as is the case for biological applications. Currently, the best
estimate of substitution ratio comes from the study by nuclear magnetic resonance
(NMR) spectroscopy.
Encapsulation of various metals and molecules in the C60 core is also an in-
creasingly popular functionalization method. This technique leads to endohedral
species, called endofullerenes, with interesting properties and rather unusual struc-
tures [46, 47]. Generally used with higher fullerenes (C80 and above), encapsulation
of small molecules and metals is also feasible with C60 [48]. By opening the C60 cage
using laser or chemicals, it is possible to introduce small molecules such as H2 or
He. It is also possible to introduce lanthanides and metals. These new endohedric
fullerenes have a very interesting advantage. Since the introduction of molecules into
the core does not alter the electronic structure, there is no loss of π electrons and,
thereby, the electronic properties of pristine C60 are conserved [49]. This last point is
the main reason why formation of endofullerenes is an increasingly popular avenue
for fullerene functionalization, especially in organic electronics.
3.2.5 Applications
As shown previously, fullerenes have a number of interesting properties. It is there-

fore not surprising to see fullerenes in several complex architectures and in a variety
of applications ranging from organic electronics to biotechnology. We present below
some of the most interesting applications for which fullerenes are becoming important
building blocks and components.
Given its strong n-type character, C60 is the building block of choice in organic
electronics, particularly in organic photovoltaics [50, 51]. In a bulk heterojunction so-
lar cell (Fig. 3.8), a blend made of a p-type, light-harvesting polymer (electron-donor)
and a methanofullerene, the C61 -phenylbutyricmethyl ester (PCBM), which serves as
electron-acceptor [52–54]. When the polymer absorbs a photon from the solar spec-
trum, an exciton is formed. This exciton can migrate into the polymer-PCBM blend
by means of various photophysical processes and thereby generate an electric cur-
rent. This type of solar cell is increasingly used, and their conversion efficiency is con-
stantly increasing. In the field of organic photovoltaics, C60 is also increasingly used
as an electron acceptor in artificial photosynthesis systems [55, 56]. These types of
system are studied to gain insights into the photophysical processes of charge trans-
fer/separation and energy generation. Understanding these phenomena makes the
creation of more efficient and green devices to collect solar energy for generating elec-
tricity possible.
– +
Aluminum
OCH3
O
PEDOT-PSS
ITO
Plastic foil
Ligh
MDMO-PPV
(a) PCBM (b) PC61BM
Fig. 3.8. (a) Architecture of a bulk heterojunction solar cell and (b) structure of the PCBM
methanofullerene commonly used as electron acceptor.
The fullerene C60 is also widely used in molecular electronics. Given its ability to ac-
cept multiple electrons reversibly, and its high stability versus redox processes, C60 is
a promising building block for the fabrication of monomolecular transistors and the
construction of flash memory [57]. Thus, it has been demonstrated that self-assembled
monolayers containing ethynyl-bridged C60 can be formed on gold (Fig. 3.9). These
monolayers can store two charges in a stable way, making them excellent surface ca-
pacitors, which paved the way to surface molecular electronics.
Fullerenes are also found in rather unusual applications in nanoscience. These
new applications exploit several structural properties of fullerenes, such as their
spherical structure. Due to this spherical structure, C60 is often used as a “wheel” in
nanocars and nanovehicles (Fig. 3.10) [58, 59]. By creating different models of these
nanocars and studying their behavior on a gold surface with a scanning tunneling mi-
croscope (STM), it was recently demonstrated that fullerenes do not slide but literally
roll over the surface. This result helps gain understanding of molecular movement
and how to control it in order to further develop useful nanomachines.
–2.9
–3.0
–3.1
Orbital energy (eV)

H3C H3C H3C H3C H3C H 3C –3.2
OMe
–5.4
O2N F3C MeO
SH –5.6
1
–5.8
–6.0
SH SH SH SH SH
2 3 4 5 6 C60 3 5 1 2 4 6
Fig. 3.9. Fullerene/thiol-terminated molecules used in flash memory devices [57].
OC10H21 OC10H21
H
H21C10O H21C10O H
H
H21C10O OC10H21 OC10H21
H21C10O
H21C10O OC10H21 2
H OC10H21 OC10H21 H21C10O

OC10H21
H 2
H H21C10O
H21C10O H21C10O 2
OC10H21 H
Fig. 3.10. Some examples of C60 -containing nanocars.
Finally, applications have even been found in medicine and pharmacology for full-
erene C60 [60, 61]. Despite significant solubility problems often resulting in accumula-
tion in the kidneys, C60 and its water-soluble derivatives can be used in medicine for
the treatment of particular diseases such as AIDS [62], in medical imaging [63], and as
an antioxidant [64]. In the case of diseases like AIDS, it has been shown that C60 can
cause inhibition of the protease enzyme, which significantly reduces the replication
rate of these viruses. In medical imagery, endohedral derivatives represent an inter-
esting avenue, due to the possibility of including heavy ions such as Gd, currently
used in magnetic resonance imaging (MRI), in their core. C60 has also demonstrated
interesting antioxidant properties and cancer cytotoxicity, mainly due to its ability to
generate singlet oxygen.
3.3 Graphene
Unlike carbon nanotubes and fullerenes, graphene, an all-carbon 2D polymer, is a nat-

urally abundant material, which makes it very attractive and has prompted a rapid
technology market penetration [65–67]. However, graphene does not exist as such,
but rather as stacks of sheets commonly known as graphite. The molecular structure
of graphite is represented in Fig. 3.11. Graphene exists in different forms, including
one-atom thick layer, double layers, and several-layers, and each of them has par-
ticular optical and electronic properties which will not be discussed here. In some
ways, a one-atom thick graphene sheet can be seen as an unzipped carbon nanotube,
although the “graphene nanoribbon (GNR)” would be more appropriate to describe
this material in this case, since the unzipping of a carbon nanotube would lead to a
graphene sheet with a finite width.
Individual
graphene
sheet
0.34 nm
Fig. 3.11. Molecular structure of graphite.
Defect-free graphene is a semimetal, zero gap semiconducting material owing to the

alternation of single and double carbon bonds which allow electron delocalization
all along the structure of the graphene sheet [68]. The high value of electron mobil-
ity measured at room temperature (∼ 15 000 cm2 V−1 s−1 ) is a few orders of magnitude
higher than silicon, making graphene highly valuable for electronic applications such
as transparent conducting electrodes, energy conversion, circuitry, transistors, capac-
itors, and so on [69].
In order to be isolated, graphene sheets must be separated from each other
through exfoliation. This process is not simple, since rather strong van der Waals
interactions between the graphene sheets have to be broken, which requires quite a
large amount of energy. Graphite can be exfoliated using mechanical methods, such
as the famous “scotch-tape” method [3], or by using solvents whose surface energies
match that of graphene [70]. However, none of the methods of producing graphene
from graphite yield large amount of materials, thus limiting the scope of this strat-
egy for many applications. Another way of producing graphene is to prepare it from
the bottom-up using reactive carbon species as feedstock. The so-called “physical
method” can yield very high quality graphene with tunable properties such as size,
shape, and physical properties, although some issues need to be addressed regarding
purity and batch-to-batch variability. In order to make highly pure nanographenes
(NG) and nanoribbons (GNR), an “all-organic” approach involving synthetic organic
chemistry can be used.
In the following section, we will briefly describe the more common methods, both
“physical” and “all-organic” approaches, for the production of graphene and GNR.
We will also present some of the most useful strategies to functionalize them cova-
lently before we end this chapter by briefly presenting different areas of application
for graphene.
3.3.1 Production of graphene
Physical methods
One of the most popular methods of producing graphene from carbonaceous feed-
stock is chemical vapour deposition (CVD) [71]. In this technique, graphene is pro-
duced when a transition metal surface is heated to 750°C and higher, depending on
the gas, and exposed to hot hydrocarbon gases such as methane or acetylene. Using
the CVD method, large sheets of highly pure graphene, mostly single-layer, can be
produced. When proper metallic substrate is used, the graphene sheets can be trans-
ferred to other substrates such as silicon for electronic applications. When liquid pre-
cursors such as hexane are used as the carbon feedstock on a polycrystalline copper
foil, graphene sheets of a few centimeters can be prepared and transferred easily to
other substrates [72].
Inspired by the production of carbon nanotubes, researchers used the arc dis-
charge method to produce graphene. This method of production has the advantage
of repairing graphene while it is formed, in addition to decreasing significantly
the amount of amorphous carbon produced during the process. In this method, a
graphite-based anode and cathode are exposed to a 100-ampere current, leading
to a discharge which produces highly reactive carbon species. This process can be
achieved under hydrogen (H2 ) [73] or air [74] to produce graphene in optimized con-
ditions.
Another way of producing graphene is to use epitaxial growth of metal or silicon
carbide (SiC) substrate. In the latter technique, SiC is heated to an elevated tempera-
ture (> 1 200°C) under vacuum in order to displace the Si atoms, whose sublimation
rate is higher than carbon, thus concentrating carbon atoms at the surface. The car-
bon atoms rearrange at high temperature to form uniform sheets of graphene [75].
Similarly, metallic surfaces can be use as a seed for the growth of graphene of quality,
allowing the study of its intrinsic physical properties [76].
Important methods for the production of graphene do not involve the transfor-
mation of a carbon feedstock, but rather the transformation of naturally occurring
graphite. When graphite is used as a starting material, the challenge is to break the van
der Waals interactions between the graphene sheets in order to individualize them.
One of the most efficient techniques is the oxidation of graphite to form graphene ox-
ide, followed by a reduction process to produce individualized graphene sheets [77].
This method allows the low-cost production of a very large quantity of graphene at
once, although the quality of the final material is far from that obtained by other phys-
ical methods. Basically, natural graphite is heated in a strong oxidizing acidic mixture
to produce exfoliated sheets of graphene oxide (GO) which can be solubilized or sus-
pended in different solvents, including water (Fig. 3.12; [78]). Then, GO can be reduced
using thermal annealing or a chemical reducing agent such as hydrazine, NaBH4, vita-
min C or pyrogallol to produce graphene. The quality of the final material depends on
the conditions used, but usually a significant amount of oxygen is still present after the
reduction process. Thus, this production method can be used for a limited number of
potential applications and is unlikely for the production of electronic-grade graphene.
For this reason, discussion of this technique will not be extended further here. How-
ever, GO is a very useful intermediate in the covalent functionalization of graphene
sheet.
Graphite
Oxidation
Exfoliation
Graphene oxide Fig. 3.12. Preparation of GO from graphite [78].

Another method which uses graphite as the starting material is exfoliation. The
greatest advantage of this technique over the oxidation/reduction process described
above is that graphene sheets are not chemically transformed, so the sp2 carbon atom
network is not disrupted, thus keeping the band structure and the electronic prop-
erties intact. In this regard, exfoliated graphite opens the way to large-scale produc-
tion of electronic-grade graphene without a complex production setup. The strategy
behind this technique is to use a stabilizer which will force the graphene sheets to
separate by forming van der Waals interactions that are at least as strong as the inter-
sheet interactions. Hence, stabilizers which show a high affinity for graphene have to
be used. Among the most efficient are stabilizers with π-conjugated moieties such as
perylene [79] and tetracyanoquinodimethane [80], and a polar group which enables
dispersion in a polar solvent. More classical surfactants such as sodium dodecylben-
zene sulfonate (SDBS) also give good results [81].
Stabilizer
(Energy)
Graphite
Stabilized Graphene
Fig. 3.13. Dispersion of graphene sheets through exfoliation.
Solvent molecules can also be used to exfoliate graphite efficiently. Solvents such
as ortho-dichlorobenzene (ODCB) [82], N-methylpyrrolidone (NMP) [70], and perflu-
orinated solvents [83] are examples of solvents which have been used to disperse
graphene sheets. An external source of energy such as heat or ultrasound is often
required to make this process work.
All-organic methods
Although graphene with a high level of purity can be obtained via the above-men-
tioned physical methods, none of them allow perfect control over the size and shape
of the resulting sheets [84–86]. For this reason, chemists and materials scientists have
been attempting for decades to produce well-defined graphene nanosheets with cus-
tomized properties using of organic chemistry, although research still needs to be done
in this area to make the whole process more efficient in terms of time and quantity of
materials produced.
One way of producing graphene nanosheets or nanoribbons is by preparing a
polyphenylene-type dendrimer or polymer which is rigidified by intermolecular cross-
linking reactions known as Scholes reactions, as shown in Fig. 3.14 [87–90]. In this
case, owing to its finite width, the resulting GNR is a semiconductor. Besides, because
alkyl chains can be installed into the periphery of the nanoribbons, the resulting ma-
terials are soluble in common organic solvent, thus enabling their characterization.
This good solubility also allows the semiconducting GNR to be processed from solu-
tion to form thin films on various kinds of substrates, opening the way for the use
of GNRs in organic electronics. Many other types of nanoribbons with various band
gap and carbon atom configuration have been synthesized using this intramolecular
cross-linking approach.
In addition to nanoribbons, finite graphene nanosheets can be constructed using
the intramolecular cross-linking approach (Fig. 3.15; [91]). Again, the band gap of these
semiconducting materials can be directly modulated by the size of the nanosheets.
The addition of functional groups such as ester, alkyne, ether, triarylamine, aryl, and
transition metals to the periphery of graphene nanosheets is another efficient strategy
for modulating the electronic properties [88].
3.3.2 Graphene in energy conversion devices
One of the most promising applications of graphene in electronic devices is its use
as transparent electrode to eventually replace commonly used semiconductors such
as ITO, which suffers from significant disadvantages: rarity of indium, chemical sen-
sitivity, and poor mechanical properties [92, 93]. The high transparency (97.7% for a
single-layer sheet), high electron mobility, excellent chemical stability, and mechani-
cal properties of graphene make it a “near-perfect” material for electrode fabrication.
The applications that would benefit the most from all the qualities of graphene are
undoubtedly organic solar cells (OSCs) and light-emitting diodes (LEDs), in which
transparent electrodes are necessary to let the light in to and out of the devices. For
example, Peumans and coworkers replaced ITO by solution-processed graphene in
P3HT-based bulk heterojunction (BHJ) solar cells and observed that the devices suf-
fered only a slight decrease in conversion efficiency compared to ITO-based devices
(η = 0.4% and 0.8% for graphene and ITO, respectively; [94]). The efficiency can be
increased (η = 1.2%) when CVD graphene is used, since the sheet resistance is lower
than for solution-processed graphene [95]. As for BHJ solar cells, graphene can also be
used as different components of DSSCs. More specifically, graphene can be used as a
transparent counter electrode to replace the expensive Pt/ITO often used to inject elec-
trons into the electrolytes. When redox couples other than I−3 /I2 are used, graphene
counter electrodes show higher catalytic activity than Pt/ITO [96].
I
a b
Br Br + (HO)2B Br Br x x
I
2 3 4 x= TMS
c
5 x= H
d
1+5
x y
6
z
x y
7
z
Fig. 3.14. Preparation of a graphene nanoribbon through an all-organic process [90].
Besides electrode fabrication, graphene can be used as electron acceptor (or n-

type materials) in BHJ solar cells, although its transparency might be an important
drawback to consider. By replacing PCBM with graphene in a blend with poly(3-
octylthiophene) (P3OT), efficiency of η = 1.4% was obtained [97]. Dai and coworkers
showed that covalent functionalization of graphene with C60 led to an electron accep-
tor with improved properties compared to C60 or graphene alone [98].
Graphene oxide can also be used as hole-transporting material (HTL) on top of
the ITO electrode in BHJ solar cells. In addition, to change the work function of ITO
to better match that of active materials, GO protects the surface of ITO from chemi-
cal deterioration due to ambient conditions [93]. In a P3HT-based device, efficiency of
up to η = 3.5% was measured, which is almost the same as that measured for a similar
device using PEDOT:PSS as the HTL material [99].
1 2 3
–12 H –56 H –106 H
4 5 6
Fig. 3.15. Preparation of a graphene nanosheet through an all-organic process [91].
Summary
Although carbon nanomaterials have their place in a huge number of different tech-
nological applications, one can expect to witness even more research activities in
this area in the years to come. Some challenges still need to be overcome in order
for these nanomaterials to be widely used in commodity devices. Purity, uniformity,
batch-to-batch consistency, processability, and price are important issues which must
be addressed in the near future to go beyond the simple academic object of study.
Moreover, real efforts have to be made to better control their properties by develop-
ing synthetic methods which will allow controlled introduction of chemical functions.
This could give rise to new electronic and optical properties from which unique appli-
cations could be developed.
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J. Florek, R. Guillet-Nicolas, and F. Kleitz
4 Ordered mesoporous silica: synthesis
and applications
4.1 Introduction
Porous materials were initially defined in terms of their adsorption properties, and
thus distinguished by their pore size range. Pore size usually refers to pore width, i.e.,
the diameter or distance between opposite walls in a solid. According to the IUPAC
definition [1], porous solids are then divided into 3 classes: microporous (< 2 nm),
mesoporous (2–50 nm) and macroporous (> 50 nm) materials. Additionally, the term
“nanoporous”, which refers to pores in the nanometer size range (< 100 nm), is in-
creasingly being used.
Materials with pores in the nanometer range have emerged as key elements for
the development of future technologies including miniaturized electronics, magnetic
and optical devices, environmentally friendly catalysts, materials for pollutant re-
moval, biocompatible implants, and drug delivery systems [2–4]. The nanopore size
range offers vast potential for the construction of elaborate functional systems with
tailor-made properties. As a few examples, nanoporous materials may be used as
highly selective sorbents, permselective membranes, systems for energy storage or
energy conversion, recyclable solid catalysts, low k-dielectrics, sensors, biomateri-
als for drug/gene delivery or medical imaging, etc. Furthermore, nanoscale pores
enable confinement effects which can restrict the growth of crystals and quantum
objects, shift the phase behavior of fluids, or create compatible hybrid interfaces.
Nano-reactors able to perform size- and shape-selective chemical conversions are
also being developed on the basis of nanoporous solids. In such systems, coopera-
tive/complementary chemical processes may be realized in the confined space of the
nanopores, acting as spatially-functionalized cavities in analogy to enzymatic active
sites. However, it is important to keep in mind that the size and volume of the pores
in a given material have a profound influence on the final properties of the solid,
such as adsorption-desorption processes, diffusion mechanisms, storage capacity,
size exclusion, confinement, density, mechanical stability, etc.
Many types of synthetic nanoporous materials, such as ordered microporous and
mesoporous materials, controlled pore glasses, gels, pillared clays, anodic alumina,
porous polymers, carbon nanotubes, and so forth, have been intensively studied [5–7].
In general, the main attribute is that nanoporous materials exhibit high surface area,
and the only way to generate such materials with the desired surface area is through
a structuring of the solid at the nanometer level. In many cases, this is achieved with
procedures which rely on structuring through the addition of porogen species or tem-
plates, which can be single organic molecules or supramolecular aggregates, most
frequently. In addition, some other methods are based on the use of solid templates,
namely the nanocasting techniques [8–10]. All of these templating pathways are used
to synthesize nanoporous materials with a high level of control over their structural
and textural properties. These categories of solids are generally viewed as high per-
formance materials for applications in catalysis, separation or storage. As discussed
by Schüth and Schmidt [11], their regular pore system with its exceedingly high sur-
face area can be used to introduce guests (e.g., molecules, clusters, macromolecules,
or particles) that are stabilized by the solid framework and spatially organized, which
enables the development of functional materials.
In particular, the use of supramolecular assemblies (i.e., micellar aggregates) as
structure-directing agents (SDAs) allowed the synthesis of a new family of mesoporous
silica and aluminosilicate compounds, which was designated M41S [12, 13]. These
solids were the first examples of solids exhibiting ordered arrangements of mesopores
with a narrow pore size distribution. This discovery was a major breakthrough, which
then opened up a whole field of research, and great new possibilities in many areas
of chemistry and materials science. In this chapter, the authors focus first on general
aspects related to the synthesis and functionalization of ordered mesoporous silica
(OMS) materials. Then, a few recent developments concerning the use of function-
alized mesoporous silica will be presented, with special emphasis on modern drug
delivery and separation applications.
4.2 Ordered mesoporous silica (OMS)
In the area of ordered mesoporous materials, silica-based systems are still the most
widely studied. There are several reasons for this: the great variety of possible struc-
tures, the precise control of the hydrolysis-condensation reactions possible due to the
lower reactivity (compared to transition metals for example), enhanced thermal sta-
bility, and a great variety of functionalization methods available. In addition, meso-
porous silica is fairly biocompatible, which is of great importance for biomedical ap-
plications (see below, Section 4.5).
The characteristic approach for the synthesis of ordered mesoporous materials
is the use of liquid crystal-forming templates which enable the specific formation of
pores with a predetermined size. Among the different materials reported in 1992 by
the scientists at Mobil Corporation [12], the one named MCM-41 (Mobil Composition of
Matter №41) exhibits a highly ordered hexagonal array of cylindrical mesopores with
a relatively narrow pore size distribution. This new type of solid is thus characterized
by periodic arrangements of pores, but the framework pore walls are built of amor-
phous silica. In general, the combination of powder X-ray diffraction (XRD), transmis-
sion electron microscopy (TEM), and gas physisorption analysis enables reliable char-
acterization of ordered mesoporous materials (Fig. 4.1). In particular, the hexagonal
arrangement of uniform pores of MCM-41 can be clearly visualized by TEM (Fig. 4.1(a)).
The Mobil synthesis performed in alkaline medium led to three well-defined struc-
tures: MCM-41, MCM-48, and MCM-50. Vartuli et al. [14] showed that the surfactant-
to-silica mole ratio is a critical variable in the formation of M41S materials. Us-
ing tetraethoxysilane (TEOS) with cetyltrimethylammonium chloride (CTAC, C16 H33
(CH3 )3 NCl), they found that progressively increasing the surfactant-to-silica molar
ratio from 0.5 to 2.0 resulted in hexagonal (< 1), cubic Ia3̄d (1–1.5), lamellar (1.2–2),
and uncondensed cubic octamer (> 2) mesoscale structures. The structure of MCM-48
belongs to the Ia3̄d space group (Fig. 4.1c), which has also been found in the binary
water/cetyltrimethylammonium bromide (CTAB) system [15]. This three-dimensional
(3D) porous structure is considered to be bicontinuous with a simplified representa-
tion of two 3D mutually intertwined networks of rods [16, 17]. The unit cell parameter
measured for cubic MCM-48 usually ranges in between 8 nm and 10 nm. MCM-50 is a
lamellar mesostructure in the as-synthesized form. However, removal of the template
results in the collapse of this layered structure unless the material has previously been
stabilized.
Since the discovery of the MCM family in the early 90s, considerable progress has
been achieved regarding the synthesis, characterization, and porosity control of or-
dered mesoporous silica. An impressive diversity of synthesis approaches have been
developed, which now enables the formation of various OMS (e.g., MSU [19], SBA-15
[20], SBA-16 [20], FDU [21], KIT-6 [22], etc.) with a great variety of morphological, struc-
tural, and textural properties [23, 24]. However, for all the materials, the concepts in-
volved in their synthesis usually remain quite similar and can be seen mainly as a com-
bination of three key features: (1) surfactant, co-surfactant, solvent, and co-solvent
types, (2) controlled polymerization of suitable inorganic species, and (3) interactions
between the inorganic (silica) precursor and the organic templating agents.
4.2.1 Principle of synthesis
For the synthesis of OMS, two main routes are possible. These are based on the in-
teractions between organic moieties, known as structure-directing-agents (SDAs) or
templates, and the silica precursors, which ultimately lead to the formation of an or-
dered hybrid mesophase (as illustrated in Fig. 4.2). After extended polymerization and
condensation of the silicates (or poly-silicic acid species for low pH synthesis condi-
tions), mesoporosity is then created through the removal of the template.
While the general concept is similar, there are differences between these two path-
ways:
– In pathway A, i.e., the cooperative self-assembly route, the mesophase is created
through the addition of the silica precursor to the micellar system. Prior to mix-
ing, no liquid crystalline phase exists; only isotropic micelles are present in the
solution. The self-assembly reorganization of the micelles occurs in situ, cooper-
700
600
Volume adsorbed (cm3/g)

500
0.25
400 0.20
Dv(d) (cm3/A/g)
0.15
300
0.10
200
0.05
100 Ads. 0.00

0 1 2 34 5 678
Des. Pore width (nm)
0
20 nm 0.0 0.2 0.4 0.6 0.8 1.0
P/P0
(a) (b)
2 3 4 5 6 2 3 4 5 6
2Θ 2Θ
(c)
Fig. 4.1. (a) Transmission electron microscopy image of MCM-41. Reprinted with permission
from [24]. (b) Nitrogen adsorption-desorption isotherms (−196°C) and corresponding NLDFT pore
size distribution for calcined MCM-41 silica (BET surface area: 1 070 m2 g−1 . Total pore volume:
0.92 cm3 g−1 ; NLDFT pore size: 4.1 nm). Reprinted with permission from [18]. (c) Examples of powder
X-ray patterns obtained for ordered mesoporous silica mesophases shown with their pore topology.
On the left: MCM-41 with p6mm symmetry, on the right: MCM-48 with Ia3̄d symmetry. Reprinted
with permission from [24].
atively with the formation and polymerization of the inorganic network around
them, leading ultimately to a highly organized hybrid mesophase.
– In pathway B, i.e., the true liquid-crystal templating (TLCT), a pre-formed liquid
crystalline phase is used as a template for the infiltration of the silica precursors.
The polymerization of the inorganic network is then triggered around this micellar
organization. This synthesis pathway was successfully used by Attard et al. [25] to
synthesize OMS with various mesostructures, and especially mesoporous silica
monoliths.
Most often, however, the so-called cooperative self-assembly takes place between
the templating species and the mineral network precursors with synchronized self-
assembly and inorganic network formation, yielding highly organized mesoscopic
architectures. This cooperative formation mechanism, which was first proposed by
Stucky, Schüth and co-workers, is now largely accepted by most researchers as an
explanation for the mesophase formation [24, 26–28].
Liquid solution Mixture of solution and precipitation

Surfactant
Inorganic Species
Cooperative Cooperative aggregation Liquid crystal Further polymerization
A nucleation and phase separation formation with and condensation of
molecular inorganics inorganics
Template Elimination
Mesoporous framework
of final product
Liquid crystal Incorporation Transformation Template

formation of inorganics’ of precursors to elimination
precursor aimed materials
B
Fig. 4.2. The two main synthesis pathways for the formation of ordered mesoporous materials:
A, cooperative self-assembly and B, true liquid-crystal templating. Reprinted with permission
from [23].
Cooperative self-assembly and hybrid interfaces

In practice, synthesis starts with the dissolution of an amphiphilic molecule, i.e., sur-
factant that can be ionic or non-ionic, in water. Here, the surfactant-inorganic hy-
brid mesophase forms cooperatively from the species present in solution which are
not in a liquid crystalline state prior to mixing of the precursors. Quaternary cationic
surfactants, Cn H2n+1 N(CH3 )3 Br (n = 8–22), are the most common for the synthesis
of ordered mesoporous silica materials with pores ≤ 5 nm. The commercially avail-
able C16 TAB is widely used for the synthesis of M41S silicas. In order to synthesize
materials with larger pores, swelling agents (SAs) can be used, but they generally
lead to poorly reproducible syntheses and low-quality materials due to the hetero-
geneous dispersion of the SAs in the system. Alternatively, amphiphilic non-ionic tri-
block copolymers were also proposed as self-assembling SDAs, and these have be-
come more and more popular as they allow the design of OMS with larger pores and
thicker walls in acidic or neutral media [19, 29]. Nowadays, the commercially available
Pluronics™ ((EO)x -(PO)y -(EO)x ) are widely used for the syntheses of large pore ordered
mesoporous silicas, e.g., SBA-15, SBA-16 or KIT-6 (vide infra).
When dissolved in aqueous solutions, if proper conditions are met, ionic surfac-
tants or block copolymers assemble into isotropic micelles due to their amphiphilic
behavior. Alkoxysilanes, e.g., TEOS, are then added to this stock solution. Inorganic
silica precursors are then catalytically hydrolyzed producing silanol groups due to the
non-neutral nature of the media. Silanols further condense, forming polymeric silica-
based species which aggregate around the micellar structures. The cooperative self-
assembly process eventually leads to a supramolecular templating, which results in
the hybrid mesophase formation (Fig. 4.2A).
Achieving a well-defined segregation of the organic and inorganic domains at the
nanometric scale plays an essential role in the synthesis of OMS. Indeed, it is the na-
ture of this hybrid interface that governs the assembly process, and thus the overall
quality of the resulting material. The key thermodynamic factors affecting the forma-
tion of a hybrid interface were identified by Huo et al. [27, 28]. In their model, described
as charge density matching, the free energy of the mesostructure formation (ΔGms ) is
considered the sum of the free energy contributions of the inorganic-organic interface
(ΔGinter ), the inorganic framework (ΔGinorg ), the self-assembly of the organic molecules
(ΔGorg ), and a contribution of the solution (ΔGsol ). The final hybrid mesophase consists
of the ordered arrangement with the lowest interface energy.
As explained previously, in the cooperative assembly route the template concen-
tration may be well below that necessary for obtaining liquid crystalline assemblies
or even micelles. Therefore, the creation of a compatible hybrid interface between the
inorganic walls and the organic templates (ΔGinter ) is essential for the generation of
a well-ordered mesoscopic hybrid structure with appropriate curvature. From the ki-
netic point of view, the formation of an organized hybrid mesostructure results thus
from a well-balanced combination of inorganic polymerization, organization of the
SDA, and organic-inorganic phase separation. Hence, two aspects are essential to fine-
tune the mesophase formation: the reactivity of the inorganic precursors (polymer-
ization rate, isoelectric point, etc.) and the interactions involved in generating the
hybrid interface. Here, a generalized cooperative mechanism of formation can be de-
scribed based on the specific (electrostatic) interactions between the inorganic pre-
cursor (I) and the surfactant head group (S). Soler-Illia et al. [30] summarized six
possible cooperative interaction pathways for the assembly of the hybrid mesophase,
which were originally proposed by Huo et al. [27, 28] and later extended by Pinnavaia
[19, 31]. As presented in Fig. 4.3, in the simplest case, the ionic surfactant and the in-
organic species are oppositely charged, leading to electrostatic interactions (S+ I− or
S− I+ ). Since the synthesis of MCM-41 and MCM-48 silicas is carried out in strongly al-
kaline media, silica oligomers have a negative charge that interacts with the positive
charge of the cationic CTAB molecules (S+ I− mechanism). These two direct routes can
be completed by two indirect ones, i.e., interactions between surfactants and inor-
ganic moieties with the same charges through the use of a counter-ion [28]. For ex-
S–I+ S+I–
O M O M
M O H+ O M O
O
OH O–
M +
M
O H O–
O O
H
+
M O H M O–
H
S+X–I+ S–M+I–
O M O M
O M O H+ M O
O
OH O–
M +
M
O H O–
O O
H
H+
M O M O–
H
Fig. 4.3. Schematic representation of the dif-
O O
SI O
S (IX) O ferent types of organic-inorganic hybrid inter-
O M O M faces for mesostructure formation. S corre-
M O M O H+ sponds to the surfactant species, and I to the
O O
OH
inorganic framework. M+ and X− are correspond-
OH
M M +
OH O H ing counter-ions. Solvent molecules are repre-
O O
H
H+
sented as triangles. Reprinted with permission
M OH M O
H from [30].
ample, the S+ X− I+ pathway can explain the mesophase formation under acidic con-
ditions and in the presence of halide anions (X− = Cl− , Br− ), whereas the S− M+ I−
route is characteristic of base-catalyzed synthesis in the presence of alkaline metal
ions (M+ = Na+ , K+ ).
Moreover, following the early development of the so-called MSU synthesis which
was performed in neutral conditions using non-ionic block copolymers, a novel as-
sembly approach was proposed and denoted No Io [19]. In this pathway, mesophase
formation is driven by hydrogen-bonding forces. Later on, Zhao et al. proposed the
use of non-ionic triblock copolymers (i.e., the Pluronics) and acidic conditions to syn-
thesize SBA-15 silica and other related large pore materials [20]. However, in this case,
as the silicic acid species are positively charged and the block copolymer could also
be positively charged, the No Io route was thus derived to a (No H+ )(X− I+ ) pathway. Fi-
nally, a last concept, the S0 I0 interaction is associated with materials called HMS [31],
where silicate species interact with a neutral SDA through hydrogen-bonding between
the hydroxyl groups of hydrolyzed silicate species and polar amine head groups.
Hydrothermal treatment and template removal

Most common syntheses are carried out in aqueous media at temperatures close to
room temperature (< 60°C), depending on the type of material. After this step, a hy-
drothermal treatment (HT) or aging can be performed for over a few hours or up to
several days in order to achieve a more complete condensation of the silica frame-
work. Even if this aging step is not always mandatory, it usually greatly improves the
quality and organization of the resulting OMS [32, 33]. Moreover, mesophase tailor-
ing can be performed during this treatment [22, 34, 35]. Even mesophase transitions
are possible in some cases, because variations in the charge density of the silicate-
based framework may occur upon condensation [26]. Furthermore, various organics
(i.e., co-surfactants) can also be added to the mother liquid in order to modulate the
“soft” mesostructure of the material during this stage [24].
After aging, the resultant product is cooled, recovered by filtration or centrifuga-
tion if the particles are nanosized, and properly dried in air. The mesoporous mate-
rial is finally obtained after the removal of the organic template. The most common
method for the elimination of the organic moieties is calcination (at temperatures
usually above 500°C)[36]. Calcination allows the complete removal of organic species
from surfactant-templated silicas. However, when as-made materials containing large
amounts of organics are calcined, some carbon deposits or coke formation may be ob-
served. To avoid this contamination, calcination should be performed under sufficient
air flow with slow heating rates (1°C min−1 ) and an extended period of heating once
the 500–550°C plateau is reached (4 to 8 h). Calcination is the most efficient and conve-
nient method for the removal of organic templates, but the silanol condensation which
occurs during this process has two major impacts on the resulting mesostructure: (1) a
pronounced decrease of the unit cell of the material (shrinking), and (2) an increase
in surface hydrophobicity. Framework condensation can be limited by adjusting the
temperature and the duration of the hydrothermal treatment [36]. Furthermore, for
copolymer-templated materials especially (e.g., SBA-type and KIT-6 silicas), a brief ex-
traction step using an ethanol/HCl mixture can be performed prior to calcination, in
order to improve efficiency and limit detrimental exothermic effects [37, 38]. In addi-
tion, the surface silanol density can be easily restored after calcination by performing
controlled acidic (aqueous) treatments [39, 40], in order to carry out more efficient
post-grafting procedures [41]. Note that calcination is often recommended when OMS
are designed for biomedical applications because it removes all trapped SDA organic
species. This aspect is of tremendous importance because residual amounts of free
surfactants (e.g., CTAB), which typically remain after liquid extraction, were found
to be toxic [42, 43]. On the other hand, calcined OMS were found to be “reasonably”
biocompatible [44, 45].
Other methods for template removal include liquid extraction [46], acid treat-
ments [47], H2 O2 oxidation under microwave irradiation [48], supercritical CO2 extrac-
tion [49] and ozone treatment [50]. Each method causes noticeable variations in the
final properties of the porogen-free materials. For example, prolonged (12–24 hours)
or multiple liquid extraction steps (e.g., Soxhlet extraction) can be used in the case
of organic-inorganic hybrid materials in which some organic functionalities must be
preserved after template removal. In contrast, H2 O2 oxidation under microwave irra-
diation cannot be used with functionalized organic–inorganic hybrids, but it enables
complete removal of the template while generating porous materials with higher pore
volume and a more hydrophilic surface than calcined counterparts, and this in a very
short time (< 15 min) [51].
4.2.2 Mesostructure diversity and tailoring
Tailoring of the textural and structural properties of the material, i.e., pore size, pore
shape, and connectivity, is essential, especially regarding the potential application
of OMS in catalysis, selective sorption, sensing technologies, and so on. Various pa-
rameters may be tuned, but the most important are the choice and ratios of reactants,
synthesis time and temperature, and the use of additives. By carefully adjusting these
parameters, a large diversity of materials can be synthesized. The most frequent or-
dered mesoporous silica materials are compiled in Table 4.1, along with their struc-
tural characteristics.
Table 4.1. Structural parameters of the most common ordered mesoporous silicas (OMS).
OMS SDA system Type of Pore Typical References

interaction mesostructure pore size (nm)
MCM-41 Cn (CH3 )3 N+ Br− or Cl− S+ I− 2D hexagonal 1.5–10.0 [12–14]
8 ≤ n ≤ 18 p6mm
MCM-48 Cn (CH3 )3 N+ Br− or Cl− S+ I− 3D cubic Ia3̄d 1.5–4.6 [14, 26, 37]
12 ≤ n ≤ 18
SBA-1 Cn (C2 H5 )3 N+ Br− or Cl S+ X− I+ 3D cubic Pm3̄n 1.5–3.0 [27, 28]
12 ≤ n ≤ 18
SBA-3 Cn (CH3 )3 N+ Br− or Cl S+ X− I+ 2D hexagonal 1.5–3.5 [33, 52]
12 ≤ n ≤ 18 p6mm
SBA-12 Brij 76 (C18 EO10 ) (So H+ )(X− I+ ) 3D hexagonal 3.0–5.0 [53, 61]
(intergrowth)
SBA-15 P123 (EO20 PO70 EO20 ) (No H+ )(X− I+ ) 2D hexagonal 4.0–15.0 [20, 37, 61]
p6mm
SBA-16 F127 (EO106 PO70 EO106 ) (No H+ )(X− I+ ) 3D cage-like cubic 4.7–12.0 [35, 54, 61]
F127 + P123 Im3̄m
F127 + BuOH
KIT-6 P123 + BuOH (No H+ )(X− I+ ) 3D cubic Ia3̄d 4.0–12.0 [22, 55]
FDU-1 B50-6600 (No H+ )(X− I+ ) 3D cage-like cubic 8.0–14.0 [21, 56]
(EO39 BO47 EO39 ) Fm3̄m
FDU-12 F127 (No H+ )(X− I+ ) 3D cage-like cubic 6.0–12.5 [57, 58]
or KIT-5 F127 + TMB Fm3̄m
MSU-H P123 No Io 2D hexagonal 7.5–12.0 [59, 60]
p6mm
TMB = trimethylbenzene
Triblock copolymer-templated large pore silica

SBA-15 (Santa Barbara Acid №15). A breakthrough in the preparation of ordered meso-
porous silica was made by Zhao and Stucky in 1998 [20, 61], who used poly(ethylene
oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymers for the synthe-
sis of the large pore SBA-15 material. The synthesis is simple and based on the use of
organic silica sources, such as TEOS or tetramethoxysilane (TMOS), in combination
with diluted acidic aqueous solution of a Pluronic-type triblock copolymer (2–7 wt%
in water), such as P123 (EO20 –PO70 –EO20 ). As discussed above, the hybrid interface
formation is here suggested to follow a (N0 H+ ) (X− I+ ) model, since the block copolymer
could be positively charged under the reaction conditions.
Evidently, the use of triblock copolymers expands the accessible range of meso-
pore sizes. Mesoporous silicas obtained with such copolymers usually exhibit uniform
large pores with diameters well above 5 nm and quite thick walls, the latter providing
high thermal stability and improved hydrothermal stability compared to OMS synthe-
sized with ionic surfactants, e.g., M41S materials [62]. To compare, MCM-41 materials
usually showed a wall thickness of about 1 nm. SBA-15 silica can be synthesized with
pore sizes ranging between 5 nm and 12 nm and thick walls (3.0–6.5 nm in width), de-
pending on the reagent ratios, pH, and aging temperature (Figs. 4.4(a), (c); [38]). This
material exhibits a large surface area of around 800-1 000 m2 g−1 and pore volume
up to 1.5 cm3 g−1 . A TEM image showing the hexagonal structure of SBA-15 is presented
in Fig. 4.4(a).
SBA-15 silica is of growing interest for a wide range of applications (e.g., sorbent,
support for catalysts and biomolecules, nanoreactor, solid template, etc.). At first,
SBA-15 was thought to be a large pore equivalent of MCM-41, which has unconnected
mesoporous cylindrical channels. However, studies showed that the pore size distri-
bution of SBA-15 is rather bimodal, whereby the larger, hexagonally ordered structural
mesopores are connected by smaller pores (micropores or small mesopores) located
inside the silica walls [37, 63–66]. These pores are not ordered and most probably orig-
inate from the penetration of the PEO blocks of the copolymer inside the silica frame-
work. Owing to the interaction of the hydrophilic chains of the P123 copolymer with
the polymerizing silica species during the mesophase formation of SBA-15, some EO
groups are occluded in the silica walls. After removal of P123, SBA-15 exhibits therefore
a secondary pore system in its framework wall (i.e., intra-wall pores). These intra-wall
pores are usually in the micropore-small mesopore (∼ 2–3 nm) range, but the actual
size and associated volume are highly dependent on the details of the synthesis (see
below).
SBA-16. In the family of copolymer-templated materials, ordered mesoporous silicas

consisting of interconnected large cage-like pores are also of significant interest. A sil-
ica mesophase related to SBA-15 is the material designated SBA-16 (cubic Im3̄m sym-
metry), which is synthesized in a similar way, but using a different nonionic triblock
copolymer, e.g., Pluronic F127 (EO106 –PO70 –EO106 ). This large pore silica consists of
50 nm 100 nm
(a) (b)
1000
0.14
900 0.12
500
Dv(d) (cm3/A/g)
800
0.10 130°C
0.08
100°C
700 0.06
0.04
400
600 0.02
500 0.00 300
0 2 4 6 8 10 12 14
400 Pore width (nm)
200
300
200
100
Ads.
100
Des.
0 0
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
P/P0 P/P0
(c) (d)
Fig. 4.4. (a) TEM image showing the 2D hexagonal arrangement of the mesopores in SBA-15.
Reprinted with permission from [2]. (b) TEM image of cage-like SBA-16 silica aged at 100°C, viewed
along the [111] direction. Reprinted with permission from [2]. (c) Nitrogen adsorption-desorption
isotherm (−196°C) and corresponding NLDFT pore size distribution for SBA-15 (BET surface area:
875 m2 g−1 ; Total pore volume: 1.26 cm3 g−1 ; NLDFT pore size: 8.5 nm). Reprinted with permission
from [18]. (d) Nitrogen adsorption-desorption isotherms (−196°C) of SBA-16 samples aged at 100°C
or 130°C, as indicated. Insert shows a scheme of the pore structure. Reprinted with permission
from [54].
spherical cavities of 6–11 nm in diameter organized in a body-centered cubic (bcc) ar-

ray, and the cavities are 3D interconnected through mesoporous openings of 2–4 nm
(Figs. 4.4(b), (d)) [54, 61, 67]. Pluronic F127 presents a high hydrophilic to hydrophobic
volume ratio (high EO/PO ratio), which is favorable for the formation of highly curved
globular micelles under aqueous conditions.
KIT-6 (Korea Institute of Technology №6). Another member of the family of triblock
copolymer-based silica mesophases is the large pore equivalent of MCM-48 known as
KIT-6. One of the easiest methods of generating this interesting mesophase was intro-
duced in 2003 by Kleitz et al. [22, 55], who used a blend of Pluronic P123 and n-butanol
for the structure-direction, along with a fine tuning of the acid concentration. This
KIT-6 silica material exhibits a structure with cubic Ia3̄d symmetry, and the pore net-
work topology can be described as an interpenetrating bicontinuous network of highly
interconnected channels (shown schematically in Fig. 4.5; [68]). The mesopore struc-
ture of KIT-6 is thus 3D interconnected and built of two continuous ordered channel
systems separated by a silica wall which follows the infinite periodic minimal surface
(IPMS) called the Gyroid surface (G) [22, 55, 69]. The porosity of KIT-6 is quite similar
in nature to that of SBA-15, although subtle differences have been observed [70]. KIT-6
silica has high pore volume and large accessible pores tailored between 5 and 12 nm,
with additional intra-wall pores as well [22, 51, 55, 69, 71]. Several other methods of
producing a large pore cubic Ia3̄d silica have been reported [72–74].
[111]
(a) 50 nm (b)
Fig. 4.5. (a) Representative TEM of mesoporous KIT-6 silica. Shown is a view along the [111] direc-
tion. (b) Representation of the Gyroid G infinite periodic minimal surface, which is followed by the
silica walls in KIT-6. Also shown is an alternative representation of the Ia3̄d structure, as two inter-
woven networks of branched cylindrical channels. The G surface separates the two sub-frameworks
of rod-like mesopores. Reprinted with permission from [70].
Some tools for tailoring structure and porosity

A method of tuning the pore size of surfactant-directed inorganic materials is to sim-
ply change the length of the surfactant carbon chain. Usually, a linear relationship is
observed between pore size and length of the carbon chain of a molecular template.
With Cn TAB (n = 8–18), the pore size of the as-synthesized MCM-41 material increases
by about 0.45 nm when increasing n by two carbon atoms. Kruk et al. [75, 76] also
confirmed that the pore size of calcined MCM-41 and MCM-48 materials increases al-
most linearly using Cn TAB surfactants with chain lengths of 8 to 16 carbons. How-
ever, this simple strategy is applicable only as long as the surfactant is soluble and
leads to the formation of a mesophase. It seems that the shortest chain surfactant from
which a mesophase could be created is with n = 8. On the other hand, long-chain sur-
factants (n > 20) are not easily available and are practically insoluble in water, and
the mesophases obtained are sometimes rather poorly ordered [12, 13, 77]. Similarly,
changes in molecular geometry and chain length of nonionic block copolymers per-
mit fine tuning of the pore size of large pore mesoporous silica. There, the adjustment
of pore size can be continuously performed by varying the concentration of SDA and
changing the composition of the copolymer or the block size [61, 78, 79]. Indeed, the
ratio of hydrophilic to hydrophobic blocks (EO/PO) in the block-copolymer can be de-
cisive for the nature of the mesostructure. In general, lowering this ratio results in the
formation of lamellar mesostructures, while higher ratios favor the packing of spher-
ical micelles into cubic mesophases [79]. For instance, triblock copolymers possess-
ing long hydrophilic chains (i.e., high EO/PO ratio), such as F127, lead to materials
with highly curved cage-like pores (e.g., SBA-16, KIT-5; [58]). In these cases, simulta-
neous tailoring of the cage dimensions and pore openings of these cage-like silicas
is also feasible by using copolymer blends (P123 mixed with F127), both under con-
trol of synthesis temperature and time [35]. The EO/PO ratio of the copolymer has a
marked influence on pore size and wall thickness of the resulting materials. Alfreds-
son et al. investigated the influence of the variation in block copolymer composition
in the synthesis of SBA-15 [79, 80]. Their results established that, for synthesis condi-
tions where a hexagonal mesostructure is obtained, an increase in PO chain length
resulted in larger pores. On the contrary, an increase in EO chain length led to thicker
walls.
Another convenient way to tailor the pore size of an OMS is to vary the temper-
ature and duration of the HT. Applying aging treatments at different temperatures
and for prolonged periods (from 24 hours up to several days) can efficiently modu-
late the nature of the mesophase. This type of treatment can either be performed di-
rectly in the mother liquid or at a different pH in fresh solutions (typically water or
alcohol). For instance, MCM-41 silica could be restructured at elevated temperatures
in its mother liquid, resulting in pore size expansion from 3.5 to 6 nm [34, 81]. More-
over, this approach usually results in a material with enhanced stability and higher
structural quality owing to denser walls [82]. This improved stability could arise from
increased condensation of the silanols within the silicate framework, i.e., better silica
polymerization, leading to less silanol groups, thus less shrinkage occurring during
calcination, and thicker walls. In the case of large pore OMS prepared with triblock
copolymers, such as SBA-15 or KIT-6, both synthesis and aging temperature strongly
influence the mesostructure formation of these OMS, and this by altering micelle hy-
drophobicity and silica condensation. The solution reactions leading to mesophase
formation are usually performed within a range of 35°C to 45°C depending on the block
copolymer. Increasing the synthesis temperature within this range and beyond ren-
ders the EO groups more hydrophobic, leading to micelles with larger hydrophobic
core volume and smaller hydrophilic regions [78]. The temperature and duration of
the hydrothermal aging, which is then applied after this first synthesis step, are also
critical. The aging temperature is usually between 40°C to 150°C (often 90–100°C).
The mesopore size of SBA-15 is easily tailored from about 5 nm up to 12 nm simply by
increasing the aging temperature from 60°C to 140°C. Also, substantially larger pore
volumes are obtained and the nature of the intra-wall porosity is drastically modi-
fied, depending on the HT temperature applied (Fig. 4.6, [22, 55, 63, 66, 83–89]). It
is proposed that SBA-15 prepared with aging between 35°C and 60°C exhibits micro-
pores with no apparent connection between mesopores. In contrast, at 100°C, SBA-15
shows both the presence of micropores and larger connections between the ordered
mesopores. At 130°C, the material shows no more micropores, but much larger pore
interconnections are present [66]. Note that an aging of 12 hours to several days is nor-
mally required to produce silica materials with satisfying quality. Similar to SBA-15,
the mesopore size of the cubic Ia3̄d KIT-6 silica can be varied within a comparable
range of diameters [22]. Also, the size of the spherical mesopores of cage-like materi-
als (e.g., SBA-16, FDU-1, KIT-5) can be tailored by applying different aging temperatures
and times. However, in this case, not only the main mesocage is enlarged, but the pore
openings of the cages also become wider upon prolonged hydrothermal treatment.
Fine tuning of pore size and mesostructure can also be performed by adjusting
the solution pH upon addition of given amounts of acid or base during synthesis.
This is, for example, well-established for MCM-41 and MCM-48 syntheses [90, 91]. It is
usually explained by the strong influence that the solution pH has on the degree of
condensation and polymerization of the inorganic oligomeric species, on the charge
density of the polyelectrolyte inorganic species involved, and on the micellar organi-
zation. Indeed, as reported by Ryoo, adjusting the pH of the reaction mixture in situ
during the synthesis of MCM-48 favors the formation of cubic mesophase [92]. More-
over, the materials (MCM-type) prepared with careful monitoring and adjustment of
the pH often demonstrate a high degree of long-range order [91]. For block copolymer-
templated syntheses, usually performed in acidic media, pH also has great impor-
tance. For SBA-15, it is the key parameter to control the overall kinetics of the syn-
thesis. SBA-15 can be synthesized in various acid concentrations [38, 93, 94], however,
some noticeable differences in the structural order, particle morphology, and poros-
ity features of the resulting solids have been observed. Syntheses performed with acid
concentration ≥ 1.5 mol l−1 led to very rapid precipitation [61]. Furthermore, high acid
content may somewhat influence the micellar organization [95], although little effect
on the micelle shape has been observed, before addition of TEOS, with [HCl] up to
2 mol l−1 [93].
The addition of electrolyte salts, such as NaCl or KCl, obviously affects surfactant
packing and the interactions between surfactant molecules and silica. The surface
charge density of the surfactant micelles can be modified by adsorbed counter-ions.
The surfactant molecules may then self-assemble into a mesophase with, for exam-
ple, a lower surface charge density, and mesophase transitions could take place upon
modification of the surface curvature. Usually, inorganic salts have a strong influence
Front view Side view
(a) No connections
(b) Connections 2–3 nm diameter
(c) Large mesoporous connections
Fig. 4.6. The effects of hydrothermal aging temperature on the pore structure of SBA-15-type ma-
terials: (a) low temperature aging (35–60°C); main mesopores: 5–6 nm - wall thickness: 4 nm –
micropore volume: ∼ 0.3 cm3 g−1 ; (b) aging at 80–100°C; main mesopores: 7–9 nm – wall thickness:
3.2 nm – micropore volume ∼ 0.1 cm3 g−1 ; (c) high temperature aging (> 120°C); main mesopores:
> 9 nm – wall thickness: 2 nm – no micropores. Reprinted from [70].
on the values of CMC (critical micellar concentration) and CMT (critical micellar tem-
perature) of the triblock copolymer micelles, which can both be decreased or increased
upon salt addition. Salting-out electrolytes (lyotropic ions) such as KCl, NaCl or K2 SO4 ,
are not adsorbed in the copolymer micelles. These salts dehydrate the hydrophilic por-
tion of the block copolymer, inducing a pronounced reduction in the preferential inter-
facial curvature of the micelles. On the other hand, salting-in electrolytes (hydrotropic
ions) are adsorbed in the micelles and tend to inhibit their growth, which could thus
increase the preferential interfacial curvature [73, 96]. The Zhao group was the first
to use the salting-out effects caused by the addition of electrolytes to triblock copoly-
mer solutions to produce various well-defined mesostructures [97]. It should be kept
in mind, however, that not only the aggregation behavior of the copolymer micelles
is affected by salt additions, but the presence of electrolytes will influence hydrolysis
and condensation, and the kinetics of aggregation of the inorganic species.
Dissolving hydrophobic additives inside the core of the micelles is largely ex-
ploited to increase the pore size of mesoporous silicas. They can alter the interface
energy of the system, ultimately leading to changes in numerous features, e.g., micelle
shape and size, mesophase transition, enlargement of mesopores and/or variation in
the morphology of the final products [23, 24]. Trimethylbenzene (TMB) has been one
of the most widely used additives [33, 98], although aliphatic hydrocarbons such as
hexane have been used as well [99]. For example, it was shown that the pore size of
MCM-41 can be altered in a controlled manner between 2 nm and 10 nm by addition
of TMB [13]. An almost linear relationship was found between TMB concentration
and final pore size. Hydrocarbons or hydrophobic aromatics are regarded as swelling
agents that are preferentially solubilized in the core of the micelles. In contrast, co-
surfactant molecules, such as short-chain n-alcohols or n-amines, are accumulated
in the palisade layer of the micellar aggregates and therefore induce more intricate
effects, whereby both the mesophase behavior and the d-spacing of the mesoscop-
ically ordered material can be affected [100]. The MCM-48 syntheses performed by
Ryoo et al. [101] (addition of EtOH) and by Schumacher et al. [102] (addition of tri-
ethylamine) are good illustrations of the complex roles of these additives.
The use of TMB to swell the pores of the triblock copolymer-based OMS is also
widespread. SBA-15 materials with pore sizes of 15–16 nm can be obtained with this
additive. However, the quantity introduced has to be cautiously controlled for reten-
tion of the ordered mesoporous mesostructure [103–105]. The silica materials exhibit-
ing pores reaching 30 nm which were obtained by addition of TMB to the synthe-
sis mixture were in fact disordered foam-like structures [105]. Also, additives and HT
modulation (time and temperature) can be synergistically combined to tailor poros-
ity of SBA-15 [85]. TMB can also be used to control the phase transition in the tri-
block copolymer F127 system, leading to large pore OMS [106]. Similarly, for block
copolymer-templated OMS synthesized in acidic media, the use of co-surfactant addi-
tives can lead to complex systems [107, 108]. The synthesis of KIT-6 silica is a perfect
example. This material is uniquely obtained in very high phase purity by carefully con-
trolling both the addition of a co-surfactant (n-butanol) and the acidity of the mother
liquid ([HCl] < 0.8 M) [22]. In fact, in these syntheses using n-butanol, the adjustment
of the HCl concentration to 0.3–0.7 M is a prerequisite for directing the formation of a
given silica-based mesophase. In this way, it actually became possible to synthesize
several large pore cubic silica mesophases (Ia3̄d, Im3̄m, and Fm3̄m) in a wide range of
reagent compositions (see Fig. 4.7 for the diagram of product phases, as a function of
reagent ratios; [109]).
3.2
H H
+
2.8
H + + +
H + +
2.4 H + +
+ + +
TEOS (molar ratio)
H
+
2.0
+
H + +
1.6 H H +
+
H +
1.2 H + + + +
H + + +
+ + Ia-3d
+ H 2-D hex
0.8 + Disordered
Mixed with 2-D hex to Ia-3d
Mixed Ia-3d to disordered
0.4
0.0 0.4 0.8 1.2 1.6 2.0 2.4 2.8
(a) BuOH (molar ratio)
3.0
Im-3m
F Fm-3m
D D D
D Disordered
D
2.5 D D D D
Disordered
D D D D D
TEOS (molar ratio)
2.0 D D D D D
D D D
1.5 F
– D D D
Im3 m
F F D
–
Fm3 m
1.0 F F
F 2-D hex
D D
D D D D D
Disordered
0.5
0.0 0.5 1.0 1.5 2.0 2.5 3.0
(b) BuOH (molar ratio)
Fig. 4.7. Diagrams of mesophase structures synthesized using blends of triblock copolymer and
n-butanol. The diagrams are established according to XRD measurements. (a) Each sample is
prepared with a molar ratio of 0.017 P123/x TEOS/y BuOH/1.83 HCl/195 H2 O. Reprinted with per-
mission from [22]. (b) Each sample is prepared with a molar ratio of 0.0035 F127/x TEOS/y BuOH/
0.91 HCl/117 H2 O. Reprinted with permission from [109].
4.3 Functionalization of ordered mesoporous silica
The available methods for the functionalization of ordered mesoporous materials are
vast, and a considerable number of studies have been dedicated to potential appli-
cations of functionalized mesoporous materials, especially in heterogeneous cataly-
sis. This section is not intended to be a comprehensive survey of the topic; instead it
should only provide a brief overview of the various strategies which have been devel-
oped to modify mesoporous materials.
OMS are promising in many applications because of their unique porous proper-
ties. However, in order to be useful, they usually need to be functionalized. Depending
on the requirements of the synthesis and/or the targeted application, various strate-
gies to introduce useful functions to OMS can be considered. It is important to note that
only the most common methods will be presented in this brief section. As illustrated
in Fig. 4.8, there are two main strategies available to integrate (organic or inorganic)
functionalities to OMS [41, 110].
– Post-synthetic modification, which is usually performed by grafting or impregna-
tion/adsorption methods on porogen-free OMS. This approach allows functional-
ization of the pores and the external surface.
– Direct addition of the functionalities during the synthesis of OMS. This “one-pot”
process is also described as co-condensation. In this method, both the silica walls
and pores can be modified. A variation of this method consists of the sequen-
tial addition of organosilanes or metal-precursors at different synthetic stages.
This approach may allow control of the spatial localization of the functionalities
[111, 112].
Both methods have their own advantages and drawbacks [110, 111, 113]. Post-grafting
functionalization relies on the reaction of organosilanes (e.g., amino-, thio- , phospho-
silanes, etc.) with the free silanol groups of the pore surface. Indeed, even after calci-
nation at 550°C, the pristine OMS is not fully condensed and some silanols are still
available for grafting even if their density is quite low (1–2 SiOH nm−2 ; [24]). Post-
grafting is usually performed by treating the OMS powder in organic solutions of the
organosilane under reflux for a prolonged period. This method has several advan-
tages: ease of implementation, it does not alter the mesostructure, and it also offers
a great versatility in the choice of introduced groups. However, in some cases, a pref-
erential reaction of organosilanes at the pore entrance can be observed, leading to
an inhomogeneous distribution of functionalities. If very large molecules are grafted,
some pore blocking may occur [110].
In contrast, ordered mesoporous organosilicas can be obtained by co-condensa-
tion of tetraalkoxysilanes (TEOS or TMOS) and terminal trialkoxyorganosilanes of the
type (R󸀠 O)3 Si-R (where R󸀠 is either methyl or ethyl, and R is a non-hydrolyzable organic
group). Here, the functional groups are most often placed dangling on the surface, but
also partly inside the framework walls [114–117]. In fact, the organoalkoxysilane plays
Direct synthesis or post synthesis
Ion
M+ exchange
Substitution
grafting L Silyalation Enzyme
M E
L encapsulation
Nano-
Immobilization particle
Non-silica material
Organic-inorganic
Surface coating hybrid framework
Mesoporous materials High surface area (1000 m2/g)

(MCM–41, –48, SBA–15, etc) Narrow pore size distribution
Thermal stability
Fig. 4.8. Schematic representation of the different methods available for the functionalization
of OMS. Reprinted with permission from [110].
two roles, since it acts as a building block in the inorganic structure, co-condensing
with the tetraalkoxysilane precursor, and it supplies organic functionality. A wide va-
riety of functional groups can be incorporated using this method (e.g., vinyl, phenyl,
aminopropyl, imidazole, cyanopropyl, mercaptopropyl, etc.). The mercaptopropyl
groups are especially interesting since these groups can subsequently be oxidized
with nitric acid and/or H2 O2 to yield sulfonic acid groups [118]. However, the choice
of a suitable organosilane precursor is usually limited by the conditions of synthesis,
and the template removal must be performed by solvent extraction or careful acid
treatment.
The impregnation/adsorption pathway is also an important post-synthesis meth-
od for modifying OMS with organics or inorganic species. This technique is based on
the capillary introduction of a volatile solvent containing the precursors or molecules
of interest inside the mesopores of the solid. After evaporation of the solvent, the func-
tional group is then chemically linked (grafted) to the OMS by a subsequent thermal
treatment. Different techniques can be used [111, 119], but the incipient wetness, which
employs a minimal amount of solvent at the limit of the powder wetness, has been
shown to be very effective [120]. As a nice example, Choi et al. have successfully ap-
plied this technique to confine polymerization of vinyl monomers (e.g., styrene, acry-
lates) selectively on the mesopore surface of SBA-15 silica [121]. The incipient wetness
is a very versatile tool which usually leads to a rather homogeneous distribution of

functional species inside the pore network of the OMS [120, 122].
4.4 Morphology control
Morphology control is indispensable in many of the advanced applications envi-

sioned for functional mesoporous materials [123]. Perm-selective membranes, micro-
spheres or monoliths are important for sorption, separation and chromatography
purposes. Porous thin films or fibrous structures are relevant for electronics, optics,
low k-dielectrics, and sensing applications. Colloidal particles or nano-spheres are
preferred for biomedical systems to be used in drug delivery or magnetic resonance
imaging (MRI) with contrast agents. The first ordered mesoporous materials which
were synthesized were typically finely divided powders consisting of small particles
(< 10 μm) with no well-defined morphology. Since then, a wide variety of shapes,
including thin films, (nano)spheres, fibers, tubes, macroporous-mesoporous mono-
liths, and many other complex morphologies have been described for ordered meso-
porous materials (Fig. 4.9; [124–135]). Mesoporous solids with controlled macroscale
morphology can either be designed by processing conditions such as dip-coating,
spin-coating or emulsion templating, or alternatively, formed spontaneously through
self-organization processes which are mostly based on kinetic regimes. Due to the
amorphous nature of the silica walls, simultaneous modulation of both the mesoscale
(hybrid mesophase) and macroscale (particle size and shape) is possible during syn-
thesis. However, it has to be kept in mind that formation of the mesophase and growth
of the morphology influence one another and cannot be seen as separate aspects [23].
With the ongoing emergence of complex nanostructures, controlling both mesopore
structures and morphologies of MSNs at the nanoscale is not straightforward and
requires a thorough understanding of the chemistry involved [136].
Mesoporous particles with spherical morphology are easily synthesized under al-
kaline aqueous conditions. For instance, Huo and Schüth [137] reported in 1997 the
preparation of hard transparent spheres from an emulsion at room temperature. Inge-
niously, Grün and Unger modified the Stöber synthesis of monodisperse spheres per-
formed in the presence of ethanol and ammonium hydroxide [138] and could success-
fully prepare almost monodispersed mesoporous MCM-41 and MCM-48 spheres [102].
Also, pseudomorphic transformation of commercially available pre-shaped spherical
silica particles (5 to 800 μm) can also be used to produce ordered mesoporous MCM-41
and MCM-48-like particles with a spherical morphology. In this latter method, amor-
phous silica is progressively and locally dissolved under mild alkaline conditions and
re-precipitated at the same rate in the presence of the surfactant, without modifying
the global spherical morphology [139, 140]. Finally, the synthesis of hollow particles
is achievable, for example, by spray-drying techniques, based on very rapid solvent
evaporation and retention of the pre-formed shapes [141].
(a) (b)
50 μm 1 μm
(c) (d)
50 nm 50 nm
Fig. 4.9. Illustration of possible OMS morphologies: (a) SEM images of mesoporous silica fibers
(image: R. Guillet-Nicolas, F. Kleitz, U Laval), (b) ordered mesoporous silica colloidal spheres (im-
age: R. Guillet-Nicolas, F. Kleitz, U Laval), (c) TEM images of ordered mesoporous MCM-48 silica
nanospheres (image: R. Guillet-Nicolas, F. Kleitz, U Laval), and (d) representative TEM image of an
ordered mesoporous silica thin film. Reprinted with permission from [126].
Among these, morphologies, spheres, and especially nanospheres, are most interest-
ing for the biomedical world because these objects may interact well with cells and
do not exhibit sharp edges or preferential faces [142]. Most of the current mesoporous
spherical particle syntheses are actually derived from the seminal work of Grün, which
described the synthesis of colloidal spheres of MCM-41 and MCM-48 [102, 143]. In 2001,
Cai et al. [144] and Mann et al. [145] both reported the first successful syntheses of indi-
vidualized MCM-41 nanoparticles. However, the term Mesoporous Silica Nanoparticles
(MSNs) was popularized in 2003 by Victor Lin, who published the first facile prepa-
ration of functionalized MCM-41 nanoparticles for drug delivery applications [146].
This synthesis provided homogeneous spherical particles with a diameter ≤ 200 nm
and good porosity features, making them excellent candidates for cellular applica-
tions. Following this breakthrough, many efforts were devoted to developing MSNs
with controllable particle and pore sizes [136]. In particular, in 2008, Kim et al. re-
ported the first synthesis of MCM-48 nanospheres with high pore ordering and highly
uniform particle size (Fig. 4.10(c); [147]). By using a modified version of the Stöber syn-
thesis, and Pluronic F127 as a “particle-designer” agent in alkaline media again, they
successfully formed monodisperse MSNs with controllable sizes within the range of
70–500 nm [148].
However, the main drawback of the most common MSN protocols remains the
relatively small pore sizes of the synthesized particles. Indeed, because almost all
syntheses are performed with CTAB-like molecules as SDAs, a maximum pore size of
4–4.5 nm is achieved. Swelling agents can be used to reach larger pores, but as for the
classical OMS, they lead to a decrease or a loss in mesostructure ordering [149]. How-
ever, this latter aspect is not necessarily of critical importance for most biomedical
applications. Triblock copolymers may also be suggested as SDAs to produce particles
with larger pore size, while keeping mesoscopic ordering. Unfortunately, obtaining
MSNs in acidic medium is more difficult than in alkaline medium (more complex in-
teractions occurring during synthesis, and difficulties associated with kinetic control).
In this area, He et al. [150] and Kim et al. [151] recently proposed two different pathways
leading to pellet-shaped SBA-15 silica (large pores) of 300–600 nm (see Fig. 4.10). Both
methods are based on restricting the growth of the SBA-15 particles. The first group
used ZrIV multivalent metal ions to “cut” the micellar aggregates in situ, whereas the
latter employed Pluronic P104 as SDA, and specific synthesis conditions to favor initial
nucleation and growth of primary particles while limiting further aggregation [152]. Al-
ternatively, by mixing fluorocarbon-surfactant (e.g., FC-4) with the classical Pluronics,
Han et al. successfully synthesized a new family of large pore MSNs which were called
IBN [153]. These new materials could have great potential for biomedical applications
as they exhibit spheroidal shapes with required particle dimensions (Fig. 4.10(c)) and
fairly large pores (> 8 nm; [154, 155]).
(a) (b) (c)
200 nm 200 nm 100 nm
Fig. 4.10. TEM images of large pore ordered MSNs: (a) SBA-15 pellets obtained using the proto-
col described by He et al. [150], (b) Kim et al. [151] (images: R. Guillet-Nicolas, F. Kleitz, U Laval),
and (c) IBN-like material obtained by Hartono et al. Reprinted with permission from [155].
4.5 Selected applications of functionalized ordered

mesoporous silica
Applications of mesoporous materials have been considered in many areas, includ-

ing catalysis, optoelectronics, sensors, sorption, biomedical materials, environmen-
tal remediation, green chemistry, and most recently, energy storage and conversion
[5, 156–159]. In this chapter, emphasis is placed on recent developments in the area
of sorbents and materials for chromatographic extraction, as well as new innovative
drug delivery systems.
4.5.1 Functionalized MSNs as controlled drug delivery platforms
Targeted drug delivery is one of the greatest challenges in modern medicine. To ad-
dress the limitations of conventional drug delivery systems, mesoporous silica nano-
particles (MSNs) are considered robust inorganic alternatives to polymeric nano-
particles, owing to their high porosity, biocompatibility, and ease of modification.
MSNs have thus captivated a lot of interest worldwide and have emerged as promis-
ing carrier materials for controlled and vectorized delivery of drugs [160–175]. Their
stable mesoporous structure and well-defined surface properties make mesoporous
silicas good matrices to host a wide variety of drugs and biologically active species
for local and controlled drug delivery applications [149, 176–179]. Another attractive
advantage is that amorphous silica is fairly degradable in aqueous solution, and thus
problems related to the removal of the material after use can be avoided. Moreover,
there are large numbers of silanol groups covering the mesoporous silica walls which
are susceptible of undergoing chemical or biochemical functionalization, which is
one of the key aspects for the prospect of biological applications of these materials.
An ideal drug delivery system should enable efficient healing at the lowest drug
concentration and dosage frequency, while being both patient-friendly and safe. Ow-
ing to their outstanding features, which allow both the loading of various drugs or
bioactive species and the adequate functionalization needed for in vitro and in vivo
purposes, stimuli-responsive MSNs can be seen as truly promising carriers for deliv-
ering precise doses of drugs to targeted sites. Moreover, by combining diagnosis and
therapeutic tools, theranostic MSN-based platforms may be designed [164, 166].
The concept of controlled drug delivery comprises 4 major steps:
(1) The fabrication of a biocompatible device that will efficiently encapsulate high
loading of the desired drug(s).
(2) No premature release prior to reaching the target location is needed in order to
protect the healthy organs and/or cells, i.e., avoidance of side effects due to non-
specific interactions, and prevent the decomposition/denaturing of the drugs.
(3) Efficient and sustained release of the drug at the targeted location.
(4) Easy clearance of the biocompatible and/or biodegradable carrier by natural
pathways.
Such a strategy is expected to enhance the drug efficiency while minimizing the re-
quired quantities owing to enhanced bioavailability at the key location [180–182].
Nevertheless, the key challenge still remains to simultaneously achieve precise tar-
geting and proper colloidal stability, especially in real physiological media [122, 183].
To achieve these goals, several controlled drug delivery systems (CDDS) have been pro-
posed based on various external or internal stimuli, e.g., temperature, time, chemical
reactions, enzymes or pH, to name a few [184–189].
With MSNs, the sequestration of the drug inside the porous network is usually
realized through the functionalization of the inner and/or outer pore surface with var-
ious barriers acting as “gates”, such as proteins, polymers, macrocycles, or even nano-
particles. These “gatekeepers” respond to a specific chemical or environmental stim-
ulus which will induce their (reversible) removal upon exposure, hence triggering the
drug release. Barriers are of prime importance as immediate drug release is commonly
observed after administration in sink conditions, when drugs are simply adsorbed into
non-modified MSNs [177, 190]. However, the release behavior of pristine MSNs should
be considered with great care as it is also dependent on the conditions chosen to sim-
ulate the different body fluids [191]. The main MSN-CDDS are summarized in Table 4.2.
Among these, the systems based on drug release triggered by pH variations have been
widely investigated. Indeed, since the pH variations within the body and/or cells are
well-known, they can be advantageously used for target drug delivery. For example,
the pH difference between normal and cancer cells may be used for the specific target-
ing of tumor cells using MSNs [192].
Because of the extreme importance of cancer therapy, most of the research involv-
ing MSNs has so far been dedicated to the release of compounds in an acidic environ-
ment, i.e., cancer cells where pH is mildly acidic [166, 182, 189]. However, MSN-CDDS
could also be synthesized for drug delivery applications where release is triggered
at neutral or physiological pH. This feature is, for instance, of high interest for oral
delivery applications because the pH in the human gastrointestinal tract naturally
varies, i.e., the stomach is highly acidic (pH = 1.2) compared to the small intestine
(pH = 6.5–7.0) and colon (pH = 7.0–8.0), making a neutral pH-triggered approach a
smart strategy for oral delivery of drugs into the intestine. This is highly desirable as
it improves patient compliance and convenience [193, 194].
In 2007, Kawi reported a simple and fast method for encapsulating protein-loaded
NH2 –SBA-15 with polyacetic acid, creating a smart pH-responsive protein delivery
system for the first time [195]. This material exhibited almost no premature release
in pH = 1.2 (less than 2%) during the first five hours, being compatible with the
United States Pharmacopeia and the National Formulary (USP–NF) guidelines for
gastro-resistant compounds, i.e., less than 10% drug release after 2 hours in gastric
conditions [196]. However, in this example, protein release at pH = 7.4 was only 40%
after 35 hours, limiting somewhat the efficiency of this system. This low release in
physiological conditions was linked to the poor colloidal and chemical stability of the
materials. Another method of generating pH-responsive MSN-CDDS is to incorporate
positive charges into the mesopore channels of MSNs by means of trimethylammo-
nium (TA) groups [197]. These groups allow efficient adsorption of anionic molecules
and minimize their release under acidic pH owing to unfavorable electrostatic interac-
tions. At neutral pH the strong electrostatic repulsions then trigger a sustained release
of the loaded drug. This original system showed excellent drug sequestration ability
in an acidic environment and appreciable drug release in physiological media. How-
ever, if such materials are not coated or properly encapsulated, the drug loaded inside
the pores might be denatured by the acidity of the stomach environment, ultimately
altering the bioactivity of the molecule once released in the intestine.
Table 4.2. Some controlled drug delivery systems (CDDS) using MSNs, reported in the literature.
Adapted with permission from [172].
Class Examples Schematic structure
Structure I Au Nps
Nanoparticles CdS Nps
Functiionalized NPs External
Fe3 O4 Nps
Drug molecule stimuli
ZnO Nps
Modification group Mesoporous silica
Structure II Cyclodextrin (CD) α-CD CB[6]
OH O
Macrocyclic Cucurbit[6]uril O N N
Stalk
HO OH 6 N N
organic (CB[6]) O 6
CD
External
O O stimuli
molecules Dibenzo-24-crown-8 BD24C8 O
O
O
O
O O
(DB24C8)
Structure III Linear polyamine Linear molecules
Linear Saccharide
molecules derivative
Linear polymer External
stimuli or
Peptide sequence
Structure IV Polymer layers
Multilayer Biomolecules
External
shell coating Polyelectrolyte stimuli
multilayers
Mesoporous silica
Structure V Functional molecule
Pore Polymer
modification Azobenzene External External
derivatives impeller stimuli stimuli
(a) Functional molecule (b) Nanoimpeller

or polymer
Furthermore, this approach can only be used with anionic compounds. In 2011, the
Cheng group [198] improved this system by introducing a hydrazone bond to synthe-
size MSN–hydrazone–TA materials. The TA groups can further be eliminated through
the progressive hydrolysis of hydrazone bonds in gastric pH conditions, leading to
a rapid and complete release of the drug only once the intestine has been reached.
This time-dependent and pH-sensitive MSN-CDDS was shown to enable accurate de-
livery of therapeutic drugs to the targeted tissue (colon), while limiting premature
release during gastric emptying. Here, high biocompatibility was found and no cy-
totoxicity, even at a high nanoparticle concentration, i.e., 500 μg ml−1 . In another
example, Sun et al. [199] also developed a pH-responsive oral delivery system, this
time by exploiting coordination between an anti-tumor-active poly-oxo-metalate and
amino-functionalized MCM-41 mesoporous silica nanosphere. Their results indicate
zero premature release in stomach and small intestine conditions, whereas release
was observed in colon conditions due to the pH increase. In this system, the gating
effect is believed to be based on the rupture of the coordinate bond between the metal
centers and the amino groups in mildly basic conditions. Importantly, no cytotoxicity
was observed with healthy human amniotic cells. Unfortunately, the polyoxometalate
clusters only showed modest inhibition when tested on human malignant tumor cell
lines derived from different tissues.
From the perspective of delivery of active compounds through the gastrointestinal
tract, the use of nanocapsules or coatings would be highly beneficial to completely
isolate and protect the active compound from the acidity of the stomach. As such,
one could argue that focus should be placed on the development of simple, efficient,
biocompatible and/or biodegradable materials. Furthermore, in vivo colloidal and
chemical stability of functionalized MSNs is a critical aspect of this technology. In this
case, addressing the issue of premature release of bioactive compounds loaded in the
nanocarriers is extremely critical, especially with costly drugs. In most reported cases,
the drug is just physically adsorbed into the pores, which may cause undesired leach-
ing of the cargo before it reaches the target site making these systems less effective
in therapeutic targeting. In this context, Kleitz and Qiao described a new system in
which an azo prodrug is covalently bound to MSNs and the drug is released via reduc-
tion of the azo bond by the enzyme azoreductase, which is present in the microflora
of the colon. Hence, enzyme-responsive MSNs have been designed for a site-specific
delivery to the colon, which is achieved by a combination of passive targeting via
the nanoparticles and selectivity of the cargo itself towards the colonic azoreductase.
In this system, sulfasalazine (SZ, a prodrug firstline therapy for inflammatory bowel
disease (IBD)) was covalently attached to the mesopore surface of MCM-48 silica
nanospheres acting as the enzyme-responsive carrier, and the molecule could then
be reduced to 5-ASA and sulfapyridine by the azo-reductase bacteria inside a simu-
lated colon medium (see Fig. 4.11). The chemical binding of the prodrug on the pore
surface prevents premature release of the drug. Monodisperse MCM-48 nanospheres
(∼ 150 nm) were chosen as an inorganic scaffold due to their proven superiority in
adsorption and release, owing to their 3D continuous pore network and their very
high surface area. This system responded very well to the enzyme and no release was
observed before the particles were exposed to the simulated colon medium. The cova-
lent attachment of SZ onto nanoparticles thus clearly ensures zero release in stomach
(pH 1.2) or intestine (pH 7.4), and at the same time this system also has great potential
for delivering therapeutics to the right locations i.e., inflamed tissues or cancer cells,
therefore reducing side effects and improving bioavailability of the drugs. With this
type of carrier, one could hope that high concentrations of drug-loaded nanoparticles
will reach the inflamed tissues and cells, with high in vivo efficacy ensured by zero
premature release.
Leading candidates for the next generation therapeutic carriers may also be pH-
responsive systems. As discussed above, this approach has received a lot of attention
for cancer treatment application, owing to the noticeable pH difference between nor-
mal and cancer cells [197, 200, 201]. Particularly interesting are strategies based on the
use of proteins as stimuli-responsive gating systems [202, 203]. Among their advan-
Toluene N N
N N
Δ N N
N
N N
Me N
THF/TEA N
O N N N
Me O Si I N N
N N N
O N
MCM-48 Me M-IP M-IP-SZ
0 N
O N N
̶OH = O Si I = N S NH =
50nm O HO N 0
HOOC SZ
(a)
Enzyme NH2 NH2

Azo mediated NH2 NH2 NH2
release NH2
N N reductase N
N N NH2
NH2
N H2N
N N N NN N N NH2
N N NH2 H2N NH2
N N N N N N
N N N N
N N N N
N N
N N H2N
N N N N N N NH2
N N
N NH2
NH2 NH2
NH2 NH2
NH2 = Sulfapyridine NH2 = 5-ASA

(b)
Fig. 4.11. (a) Synthesis of the enzyme-responsive drug delivery system based on mesoporous silica
nanoparticles with 3D pore structure. (b) Representation of the process of enzymatic release of
5-ASA and sulfapyridine from the nanoreactors in the presence of azoreductase bacteria. Reprinted
with permission from [188].
tages, these materials are characterized by high biocompatibility and biodegradabil-

ity, abundance of reactive groups which can be used for chemical modifications, i.e.,
grafting [204, 205]. Similarly, being able to enhance colloidal stability in the desired
release media constitutes a major improvement, as it will lead to a more homogeneous
and efficient delivery of the active compound to the target location.
In this area, our laboratory evaluated the potential of the nutraceutical MSN
conjugates as a new pH-responsive oral drug delivery system showing low toxic-
ity and sufficient colloidal stability (Fig. 4.12; [206]). In this work, nutraceutical-
functionalized mesoporous silica particles have been developed for the protection and
site-specific release of gastro-sensitive compounds via the oral route. This innovative
approach makes use of the fully biocompatible and biodegradable nutraceutical β-
lactoglobulin, which serves as a pH-responsive gating device. This nano-conjugation
led to significantly enhanced colloidal stability (a prerequisite for most drug delivery
or cell tracking applications), while the functionality of β-lactoglobulin was fully pre-
served, i.e., the gelation and gating effect was observed, and thus it could be used for
protecting and/or delivering bioactive components (i.e., via pH-controlled delivery).
Nutraceutical proteins, such as β-lactoglobulin (a member of the albumin family,
present in cow’s milk) or soy protein isolates, clearly offer the advantages of low cost
and excellent biocompatibility. By using bio-conjugation chemistry smartly, it was

possible to synthesize a pH-responsive system showing limited premature release in
acidic media (mimicking stomach acidity). In contrast, when the particles where sus-
pended in physiological intestine conditions (pH 7.4), sustained release was observed
for 24 hours, together with enhanced colloidal stability over 48 hours. Moreover, the
differences in drug release which were observed at pH = 5 could also make this
system very attractive from the perspective of cancer therapeutics. In addition, since
β-lactoglobulin is a major by-product of the dairy industry, its production is quite cost-
effective compared to other complex and expensive systems. As such, this approach
is hence also inscribed in a strategy of smart recycling of industrial waste.
IBU/ACR
APTES grafting loading
Toluene Hexane/DMSO
110°C, overnight RT, 24 hours
EDC
activation
pH responsive Succinylated MES/
release β-lactoglobulin DMSO-MES
grafting RT, 2 hours
pH > 5 pH < 5
: –NH2 : Succynilated β-Lactoglobulin (pH > 5)
: Ibuprofen (IBU)/Acridine (ACR) : Succynilated β-Lactoglobulin (pH < 5)
Fig. 4.12. Schematic representation of the post grafting, bio-functionalization, and pH-responsive
release of a drug/dye from β-lactoglobulin-modified-MSNs. Reprinted with permission from [206].
4.5.2 Functionalized mesoporous materials for extraction chromatography (EXC)

applications
Historically, the first system for adsorption of heavy metal ions based on mesoporous
silica supports was used for the trapping of mercury [207]. It was proven that silica ma-
terials containing thiols (or thiol derivatives) were particularly effective as sorbents for
the capture of environmentally harmful Hg2+ . Soon after, several other silica materi-
als, modified mainly with amino- or phosphonate-groups, were applied for adsorb-
ing metals, such as Cu2+ , Zn2+ , Ni2+ , or Fe3+ [208, 209]. Later it was proposed that
silica-based inorganic-organic hybrid sorbents could also be versatile for sequestrat-
ing/extracting radionuclides [210, 211]. For instance, functionalized MCM-41 materi-
als grafted with acetamide-phosphonate ligands have shown promising properties for
Am3+ and Pu3+ decontamination from acidic aqueous solutions [212].
Evidently, the development of new sequestration materials for the nuclear in-
dustry is essential from a health and environmental protection point of view, as they
not only provide an appropriate solution to nuclear wastes, but also enable their
detection if coupled with the appropriate analytical methodologies. The incident in
Fukushima Dai-Ichi, Japan, and the long-term consequences of this event are con-
vincing reminders that sequestration/detection of long-lived radionuclides is critical.
The expected consequences of radiological/nuclear events and their aftermath on
agriculture, population, and the environment have led the scientific community to
rethink its approach to monitoring methods based on radiochemical separation [213].
With this objective in mind, our laboratory described a simple and effective function-
alization of large pore 3D cubic mesoporous KIT-6 silica to produce a new family of
selective sorbents for radionuclides [214, 215]. Using a simple one-step post-grafting
method, phosphonate groups were chemically anchored to the silica surface, provid-
ing a highly selective and durable functionalization for the extraction of actinides
(see Fig. 4.13).
Extraction experiments performed with this material demonstrated extremely
rapid kinetics (< 1 min) and high selectivity towards actinide extraction, especially
uranium (VI). The unique spatial configuration of the 3D cubic mesoporous hybrid
induced much higher selectivity and adsorption capacity than other sorbents, and the
material is applicable over a range of conditions (pH = 4, room temperature) which
are relevant for real environmental analysis. In addition to these unique extraction
performances, synthesis of the mesoporous hybrid EXC chromatography materials is
very simple and easily scalable, which represents a true alternative for the replace-
ment of currently non-recyclable commercial EXC resins at an acceptable cost. The
high extraction efficiency of the functionalized KIT-6 sorbent for U (VI) at relatively
neutral pH could also lead to alternative analytical strategies for uranium wastewa-
ter management, and environmental and biological monitoring from the perspective
of anthropogenic contamination. In addition, such materials are mandatory for all
aspects of the nuclear fuel cycles, from mining (treatment of wastewater) to fuel
reprocessing (separation of impurities).
Well-defined mesoporous materials can also provide opportunities in the highly
valuable area of rare-earth elements [216–218]. Nowadays, the importance of rare-
earth elements (REEs) in the global economy is booming as they are used in numerous
advanced technologies more and more. High purity REEs are needed for the produc-
tion of magnets, chemical sensors or lasers, computers, plasma screens, cell phones,
cameras, and so forth; however, natural REE resources are either very limited or their
CH3
–OH CH3 –O CH3
H3C O Toluene,
O Si O reflux, 24h O
–OH + –O Si
N2 atm
P O P O
O
–OH O –O O
CH3
CH3 CH3
SBA-15/KIT-6 DPTS SBA-15-P/KIT-6-P
(a)
SPE cartridge
mg U g–1 sample
U/TEVA SBA-15-P KIT-6-P
(b) U extraction capacity
Fig. 4.13. (a) Schematic representation of the synthesis of the extracting agent-functionalized
SBA-15-P/KIT-6-P materials. (b) Comparison of the extraction capacities of different phosphonate-
functionalized materials and photograph of an SPE cartridge assembled with the KIT-6-based sor-
bent. Reprinted with permission from [215].
extraction/separation processes are not acceptable in terms of sustainable develop-

ment [219, 220]. Therefore, it is certainly of value to develop efficient sorbents for the
extraction and valorization of REEs, also from alternative sources, for instance, indus-
trial and mining wastes. Commercially, extraction and purification of REEs is based on
multiple liquid-liquid extraction (LLE) or chromatographic-based resin separations.
However, these approaches are hampered by several issues. Because of the subtle dif-
ferences between the various REEs, extraction and purification of REEs is very time-
consuming and involves multiple extraction/purification steps. In order to substan-
tially improve this process and provide a greener alternative to LLE, novel functional
nanoporous hybrid materials were proposed demonstrating enhanced selectivity to-
wards heavier REEs in comparison to commercially available products. In this case,
KIT-6 silica was modified with the diglycolylamide (DGA) ligand to generate an effi-
cient sorbent for REEs extraction applications (Fig. 4.14; [221]). For this, the DGA lig-
and was chemically grafted to the silica surface, which enabled the resulting hybrid
materials to be cycled and regenerated, a key feature in the development of sustain-
able and cost-effective resin-type materials minimizing waste production. The choice
of KIT-6 silica was motivated here by the highly interconnected nature of the porous
network of this material, which is expected to reduce the risk of pore blocking and to
be beneficial for diffusion of liquids through the system, all being obvious advantages
in chromatographic processes. Extraction of REEs was tested in a solid-liquid system,
and distribution coefficients (named Kd ) from batch extraction tests were obtained.
Clearly, these new sorbents showed excellent stability upon recycling and demon-
strated greater selectivity than commercially available DGA resins under the extrac-
tion conditions tested. Most importantly, some of the new sorbents exhibited a much
higher affinity for the separation of heavier lanthanides (i.e., yttric earths), being most
relevant for the electronics industry. These hybrid sorbents also showed specificity to-
wards Eu and Gd and low competitive behavior with other non-lanthanide trivalent
ions and actinides, which are problematic in the commercial extraction of REEs. The
perspective for this new system will be to minimize the number of extraction steps
used for the purification of REEs as far as possible. Functionalized nanoporous mate-
rials with a high surface area and high pore volume can offer high contact efficiency
with solutions and high adsorption capacities while preserving adequate flow and
transport properties if properly structured. Using such materials may indeed enable
the substantial reduction of the number of steps needed for separation of these critical
elements, and thus decrease both the required time and the waste production.
4.5.3 Mesoporous organic-inorganic hybrid membranes for water desalination
Nowadays, water scarcity, brought about by population growth and industrializa-

tion, is one of the major challenges facing society. Desalination of brackish or sea-
water is one of the most effectively implemented solutions. However, an alternative
process to the conventional desalination technologies, e.g., distillation and reverse
osmosis (RO), is the thermally-driven membrane distillation (MD; [222]). Typically,
such a membrane maintains water at the pore entrance and allows water evapo-
ration, leaving the non-volatile salts behind [205]. Membrane distillation has some
benefits, although its industrial application remains low. This lack of commercial
success is mostly the result of the dominance of reverse osmosis processes, mem-
DGA-functionalized KIT-6
50 nm
Fig. 4.14. On the left: high-resolution SEM image of the functional organic-inorganic hybrid KIT-6.
On the right: diglycolylamide(DGA)-modification of the surface of KIT-6 silica to generate the meso-
porous rare-earth element (REE) sorbents. Reprinted with permission from [221].
brane flux decay, and the use of macroporous (0.2–0.7 mm), hydrophobic polymeric
membranes [224, 225]. These hydrophobic polymeric membranes are often plagued
by fouling and pore wetting issues, and thus the development of new membrane ma-
terials which will overcome these limitations is necessary. In this area, membranes
based on nanoporous, inorganic-organic hybrid materials represent a potential al-
ternative, with adequate chemical and thermal stability and appropriate pore struc-
ture [226, 227]. Within this context, the use of nanoporous organosilica thin-film
membranes (∼ 20 cm2 in size) with highly ordered pores (∼ 2 nm) has been suggested
(Fig. 4.15; [228]). The mesoporous hybrid membranes were prepared by the dip-coating
technique using 1,2-bis(triethoxysilyl)ethane, as a single bridged silicon source, in the
presence of Pluronic F68 (E080 P030 EO80 ). After adequate drying, the films were then
calcined in air at 300°C to preserve the organic groups in the framework walls.
These mesoporous films exhibit excellent desalination performance in the case of
synthetic salt solutions with feed temperatures between 20 and 60°C (using a vac-
uum MD process). These membranes produced pure water across a large range of
salt concentrations (10–150 g l−1 NaCl) at average temperatures ≤ 60°C, without ex-
hibiting the usual degradation. Furthermore, the results revealed excellent salt rejec-
tion (> 99.9%) and good water fluxes (up to 13 kg m−2 h−1 at 60°C). Here, it was hy-
pothesized that the organic moieties placed within the siloxane framework conferred
enough hydrophobicity to the pore walls to form a liquid/vapor interface at the pore
entrance, whilst the small mesopore size was crucial in preventing pore wetting. This
most recent development could indeed open up a potentially scalable process for fab-
ricating high-performance membranes for efficient water desalination.
Salt water Membrane Fresh water
H2O Na+ Cl–

(a)
20 100
98
Water flux, kg m–2 hr–1
15
Salt Rejection, %
96
10
Flux(OS) 94
Flux(PS)
5
Salt Rejection(OS) 92
Salt Rejection(PS)
0 90
0 20 40 60 80 100 120 140
Time, min
(b)
Fig. 4.15. (a) Schematic representation of the water desalination process by membrane distilla-
tion using a periodic mesoporous organosilica (the mesoporous structure of the hybrid mem-
brane is shown by TEM). (b) Comparison of organosilica (OS) membrane (square symbols) and
pure silica (PS) membrane (cross symbols) in 50 g l−1 feed concentration run at 60°C. Filled sym-
bols represent water fluxes and open symbols represent salt rejection. Reprinted with permission
from [228].
Acknowledgments
The authors would like to thank NSERC (Canada) and FQRNT (Province of Quebec) for
their financial support.
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A. Ritcey
5 Nanoparticles: Properties and applications
5.1 Introduction
The ever-increasing importance of nanoparticles to the development of functional ma-

terials is incontestable. A simple keyword search of the scientific literature [1] reveals
the accelerating growth of nanoparticle research over the past decade and, as illus-
trated in Fig. 5.1, nearly 60 000 publications treating this subject appeared in 2012
alone. New scientific journals dedicated to the field of nanoscience have also been
created [2] and are rapidly establishing their place among high impact periodicals.
60000
50000
Number of publications
40000
30000
20000
10000
0
2000 2002 2004 2006 2008 2010 2012
Publication year
Fig. 5.1. Annual number of publications retrieved by a keyword search for “nanoparticles” [1].
Within this context, the following pages can only scratch the surface of the title subject
and cannot in any way be considered a complete review of the literature. It is hoped,
however, that the selected examples will provide the reader with a valid apprecia-
tion of the enormous potential of functional nanoparticles in materials science. In ad-
dition, this chapter treats some fundamental issues of nanoparticle preparation and
handling through a general approach that is relevant to many diverse specific systems.
5.2 Synthetic methods
Most introductions to the fabrication of nanostructures begin with a reference to the

contrasting “top-down” and “bottom-up” approaches, terms first applied to the field
of nanoscience by the Foresight Institute in 1989 [3]. As their name implies, top-down
methods involve the creation of nanosized entities from larger blocks of matter. Exam-
ples include mechanical size reduction by crushing and grinding as well as more so-
phisticated lithographic techniques. Bottom-up approaches, on the other hand, seek
to build nanostructures from smaller components, typically atoms or molecules, and
therefore frequently involve elements of self-assembly or supramolecular chemistry.
In the case of nanoparticles, the large majority of preparation methods are based on
controlled precipitation, that is, the nucleation and growth of particles from a super-
saturated solution. Supersaturation can be achieved by a chemical reaction, such as
reduction, hydrolysis, condensation or decomposition, which converts a soluble pre-
cursor to the desired, sparingly soluble, material.
5.2.1 Particle nucleation and growth
Any solution process that leads to the generation of a sparingly soluble species will
result in the eventual nucleation of a second, typically solid, phase. The thermody-
namics of nucleation includes two considerations: the decrease in free energy associ-
ated with the phase transition (usually crystallization), and the increase in free energy
associated with the necessary creation of the solid-liquid interface. The free energy of
nucleation can therefore be written as
ΔGnucleation = n ⋅ ΔḠ crystallization + ΔGsurface , (5.1)
where ΔḠ crystallization is the molar free energy of crystallization and n is the number of
moles of the substance i in the nucleus. ΔḠ crystallization depends on the concentration
of i, [i], according to
[i]sat
ΔḠ crystal = RT ln , (5.2)
[i]
and thus becomes increasingly negative as the concentration exceeds saturation at
[i]sat .
The second contribution to ΔGnucleation can be expressed as
ΔGsurface = σ ⋅ A, (5.3)
where σ is the interfacial energy and A is the surface area of the nucleus. This compo-
nent is always positive. Nucleation can only occur if the crystallization process liber-
ates sufficient energy to cover the cost of creating the new interface between the par-
ticle seed and the solution. Importantly, although the absolute value of both ΔGsurface
and ΔGcrystallization increase with nucleus size, the former is proportional to the surface
area, whereas the latter is proportional to the volume. In the simple case of a spherical
nucleus of radius r, ΔGsurface varies with r2 and ΔGcrystallization with r3 . These dependen-
cies (dashed lines) are illustrated schematically in Fig. 5.2 and lead to the presence
of a maximum, labeled rcr , in the sum of the two contributions. Nuclei smaller than
the critical size rcr are thermodynamically unstable and will spontaneously disappear
as indicated by the left-pointing arrow. Nuclei larger than the critical size, however,
will spontaneously grow, since in this size regime increasing size corresponds to a
decrease in free energy, as indicated by the arrow to the right.
ΔGsurface
ΔGnucleation
Fig. 5.2. Free energy of nucleation as a function

rcr Nucleus
size of nucleus size. Contributions from surface and
crystallization energies are shown as dashed
lines. rcr denotes the critical nucleus size and the
ΔGcrystallization arrows indicate the direction of spontaneous size
evolution.
How can particle nucleation occur if small nuclei are unstable and disappear rather
than grow? The answer lies in random concentration fluctuations which allow for the
spontaneous formation of aggregates that, upon formation, already exceed the crit-
ical size. Clearly, the probability of the formation of stable nuclei will therefore de-
crease with increasing critical size. As the concentration is increased beyond satura-
tion, ΔGcrystallization becomes increasingly negative, permitting the formation of stable
nuclei of smaller size. Nucleation, in turn, becomes more probable. These thermo-
dynamic considerations explain the general behavior illustrated by the well-known
LaMer diagram provided in Fig. 5.3 [4, 5].
The process of nanoparticle formation can be divided into three phases. In the
early stages, immediately following the initiation of the reaction responsible the gen-
eration of the particle forming species, the concentration is lower than the solubility
and there is thus no thermodynamic driving force for the formation of a second phase.
As the reaction proceeds, the concentration increases, eventually reaching saturation.
Particle nucleation, however, does not occur immediately because of the free energy
cost of creating a new interface. As outlined above, nucleation requires that the so-
lution become super-saturated to the point where ΔḠ crystallization , as given by equa-
tion (5.2), is sufficient to cover the cost of the new surface. This point is labeled the
critical nucleation concentration in Fig. 5.3. Once the critical concentration is reached,
nucleation begins, removing material from solution. As nucleation proceeds, the so-
lution concentration decreases and eventually falls below the critical value for nu-
clei formation. After this point, no new nuclei are formed and any material remaining
in solution or generated by further reaction can only contribute to particle growth.
The concentration profile of the LaMer diagram has important implications for the
Concentration
Critical nucleation
concentration
Solubility
Growth
Pre- Nucleation Time
nucleation
Fig. 5.3. LaMer diagram illustrating the evolution of solution concentration during the nucleation
and growth process.
size distribution of the resulting particle population. Conditions which restrict the du-
ration of the nucleation stage favor populations of low polydispersity. Simultaneous
nucleation, followed by growth in a common medium, will lead to particles of quasi-
identical size.
5.2.2 Synthesis in inverse micelles
In the presence of an appropriate surfactant, small amounts of water can be dispersed

in an organic medium to form inverse micelles. As illustrated in Fig. 5.4, an inverse
micelle can be viewed as a nanometer-sized water droplet surrounded by a surfactant
layer. The capacity to dissolve reactants in the water core, combined with the constant
exchange of the aqueous phase between micelles during collisions, allows for chemi-
cal reactions to be carried out in the confined volume of the enclosed water reservoir.
In general, if the reaction leads to a solid product, nanoparticles are obtained. This
method has been employed for the preparation of nanoparticles from a diverse variety
of materials, including metals, metal oxides, and even organic compounds [6]. The in-
verse micelle approach typically offers exceptional control of particle size, which can
be conveniently modulated through the variation of simple system parameters such
as the relative quantities of solvent, surfactant, and reagents. Furthermore, in certain
cases, essentially monodisperse size-distributions are obtained. For example, we have
employed the inverse micelle approach to prepare single crystal yttrium fluoride nano-
particles with the exquisite size control illustrated in Fig. 5.5 [7, 8].
H2 O
Fig. 5.4. Schematic representa-
tions of (a) an inverse micelle,
and (b) content exchange during
(a) (b) micellar collisions.
Fig. 5.5. (H3 O)Y3 F10 nanocrystals prepared by the in-

50 nm X300000 1300x1030 pixels 4/29/2004
4.16852 s
verse micelle method [7, 8].
5.3 Particle aggregation and stabilization of

colloidal suspensions
The free energy of the interface between two immiscible phases is always positive. If
this were not the case, the free energy of the system would decrease with increasing
interfacial area and the phases would spontaneously divide into progressively smaller
and smaller domains, leading to miscibility. Since interfacial energy is positive, sus-
pensions of nanoparticles are necessarily thermodynamically unstable. Kinetically
stable colloidal suspensions can, however, be obtained by ensuring sufficient inter-
particle repulsion. Common stabilization strategies fall into two main categories; elec-
trostatic and steric.
Electrostatic stabilization involves the introduction of a surface charge to the
nanoparticles and is primarily restricted to aqueous systems, since solvents other
than water are unable to support the necessary charge separation. Many inorganic
nanoparticles, such as those composed of sparingly soluble salts or metal oxides, are
naturally charged when dispersed in water. Surface charge is frequently determined
by equilibria controlling ion adsorption and dissolution or the protonation and depro-
tonation of surface moieties. In other cases, surface charge can be introduced by the
adsorption of charged species, such as the citrate ion. Electrostatic repulsion between
particles of like charge serves as a barrier to aggregation and, if sufficiently strong
with respect to the van der Waals attraction, can result in a stable suspension.
The interplay of van der Waals attractions and electrostatic repulsion was quan-
titatively captured by Derjaguin, Verwey, Landau, and Overbeek in what is commonly
known as DVLO theory [9]. The basic outcome of DVLO calculations is illustrated in
Fig. 5.6. Both electrostatic repulsion, shown as the dashed line, and van der Waals
attractions, represented by the dotted line, become stronger as particles are brought
closer together. Importantly, the exact way in which each of the two forces varies with
separation distance is different: interparticle van der Waals attractions vary inversely
to distance squared, whereas electrostatic repulsion follows an exponential depen-
dency. The net force is weakly attractive at large distances. However, as the particles
approach each other, electrostatic repulsion increases faster than the attractive force.
This leads to the appearance of a repulsive barrier in the net interaction curve. Parti-
cles able to cross this barrier will reach very small separation distances where attrac-
tive forces dominate and aggregation will occur.
Electrostatic repulsion
Repulsive barrier
Interaction energy
Van der Waals attraction
Interparticle distance
Fig. 5.6. Interaction energy between two particles as a function of separation. The net interaction,
shown as the solid line, is the sum of electrostatic repulsion and attractive van der Waals forces.
The stability of a colloidal suspension therefore depends on the height of the repul-
sive barrier with respect to the energy of particle collisions. If particles collide with
sufficient energy to pass the repulsive barrier, they will fall into the attractive well and
aggregate. Once in contact, there is no driving force for spontaneous re-dispersion,
and in this respect, aggregation is irreversible. Collision energy is determined by the
kinetic energy of the colliding particles, which depends on temperature and follows
a Boltzman distribution centered at 3/2 kT. Importantly, at a given temperature, colli-
sions are not all of the same energy and there is a nonzero probability that some will
have sufficient energy to pass the barrier. In fact, given enough time, all of the particles
in a suspension will eventually reach the aggregated state. The stability of a colloidal
suspension therefore depends on the time scale of observation, and for most applica-
tions colloids are typically considered to be kinetically stable if the repulsive barrier
exceeds 10 kT. The thermodynamically stable state remains the aggregated one; the
repulsive barrier simply serves to delay the inevitable.
The second common strategy for stabilization employs steric repulsion. In this
approach, polymer chains are attached to the particle surface, either through chem-
ical grafting or simple adsorption. As two particles come together, a repulsive force
will be felt at the point of chain overlap. Although conceptually simple, as illustrated
by Fig. 5.7, repulsive contributions from both osmotic pressure and chain deforma-
tion must be taken into account, and the quantitative treatment of steric stabilization
rapidly becomes complex [10]. Steric stabilization can be employed in both aqueous
and organic media, and with the appropriate choice of surface ligand nanoparticles
can be dispersed in any carrier liquid.
Fig. 5.7. Schematic illustration of steric stabilization

through surface grafting of polymer chains.
5.4 Colloidal quantum dots
Among the panoply of functional nanoparticles, it is probably the family known as

quantum dots which exhibits the most striking example of size-dependent proper-
ties. Quantum dots are nanocrystals of inorganic semi-conductor materials which pos-
sess unique optical properties arising from the electronic confinement imposed by the
small size of the particles [11, 12].
The electronic structure of bulk semiconductors is characterized by two distinct
bands, the valence band which contains the electrons that bond the material together,
and, at higher energy, the conduction band, which is essentially devoid of electrons at
low temperature. Energies between the valence band and the conduction band, that
is, within the so-called band gap, are forbidden. Electrons can, however, be promoted
from the valence band across the band gap into the conduction band, if supplied with
sufficient energy. For a bulk semiconductor, optical absorption will therefore begin at
the band gap energy and, because of the band nature of the excited state, the optical
absorption spectrum will appear as a continuum above the band gap. In contrast to the
band structure of bulk semiconductors, quantum dots are characterized by a series of
discrete electronic quantized levels, and their optical spectra correspondingly exhibit
discrete electronic transitions.
The promotion of an electron from the valence band to the conduction band re-
sults in the creation of an electron-hole pair known as an exciton. The electron-hole
pair is bound by Coulombic interactions which are relatively small when compared
to kT and, in a bulk semiconductor, considerable charge separation is possible. In

the case of a quantum dot, particle size is reduced below the characteristic distance
of charge separation for the electron-hole pair and confinement effects become pro-
nounced [13]. The energies of the electron and hole levels are sensitive to the degree of
confinement and, as a result, the optical absorption spectra of quantum dots depend
strongly on their size. As the exciton becomes increasingly confined, the energy of the
primary transition increases and the corresponding absorption band moves to shorter
wavelengths, as illustrated for PbSe in Fig. 5.8.
8.1 nm
Absorbance (arbitrary units)
6.5 nm
4.8 nm
4.6 nm
3.6 nm
3.3 nm
800 1200 1600 2000 2400 Fig. 5.8. Absorption spectra of PbSe quantum dots of
Wavelength (nm) various sizes. Reprinted with permission from [13].
Quantum dots have received considerable attention as functional materials because

of their luminescence properties. Here, exciton confinement also plays an important
role by greatly enhancing the probability of radiative recombination. Radiative recom-
bination is the return of an electron from the conduction band to the valence band ac-
companied by emission of a photon. The wavelength of emission is thus determined
by the band gap and is highly size-dependent. This is illustrated in Fig. 5.9 for a series
of CdSe quantum dots, removed from the reaction medium at different times during
particle synthesis [14]. As the particles grow larger, the emission spectra systemati-
cally shift to longer wavelengths.
Early research on quantum dots primarily involved materials exhibiting absorp-
tion and emission within the visible region of the spectrum. As recently discussed
by Shirasaki et al. [15], quantum dots show great potential as emitters in thin film
light-emitting devices. For this application, quantum dots offer several important ad-
vantages with respect to organic fluorophores. For example, the characteristic narrow
emission band of quantum dots assures high color purity, and the tunability of the
1.0
0.5 min
10 min
15 min
Normalized PL Intensity
60 min
120 min
0.5
280°C
0.0
400 450 500 550 600 650 700
Wavelength (nm)
Fig. 5.9. Temporal evolution of the photoluminescence spectra of crude solutions of colloidal
CdSe nanocrystals during their growth at 280°C. Adapted with permission from [14].
emission color through particle size allows for the fabrication of multicolor devices
from a single material. More recently, research activity has been increasingly focused
on the development of narrow band gap materials which emit in infrared [16–18]. Cur-
rent efforts aim at infrared emission for applications in bioimaging, telecommunica-
tions, and solar cells.
A solar cell is a device which converts the sun’s energy to electricity. The avail-
ability of efficient solar cells, amenable to large scale production at reasonable cost,
will clearly have major positive repercussions for the environmental impact of future
human activity and economic development. Numerous designs for solar cells have
been proposed and all involve the following three basic processes: the absorption of
light to generate electron-hole pairs, the separation of charge carriers, and the cap-
ture of the charges by external electrodes. One of the primary limitations of solar cell
performance is the low efficiency of the primary photoconversion step [13]. The solar
spectrum is relatively broad, and only photons absorbed by the solar cell can lead to
charge separation. The incorporation of narrow gap quantum dots in hybrid solar cells
can thus lead to improvements in light harvesting in the infrared region [19]. Quantum
dots are also being developed for novel solar energy conversion strategies. For exam-
ple, cell performance can be enhanced through a process known as multiple exciton
generation [20]. In this process, single photons with energy surpassing twice that of
the band gap can produce two or more electron-hole pairs. This leads to improved cell
efficiency, since in the absence of multiple exciton generation, the excess energy of
high energy photons is lost as heat. Significantly, the confinement of charge carriers
greatly enhances the probability of multiple exciton generation, leading to exciting

prospects for the application of quantum dots in next generation solar cells [20].
Clearly the role of quantum dots as functional materials extends beyond the lim-
ited examples cited here. Furthermore, current research involves particles of increas-
ingly complex composition and structure [18], as well as new paradigms, such as the
control of properties through ligand-mediated processes [21]. The interested reader is
encouraged to consult more complete treatises on the subject.
5.5 Metal nanoparticles
Metal nanoparticles are ubiquitous and have been known since antiquity. The unique
optical properties of colloidal noble metals, exploited in ancient times to stain glass,
are today at the basis of exciting new developments in both fundamental science and
the design of novel optical materials.
The interaction of light with metallic nanostructures is dominated by the collec-
tive excitation of free electrons, known as the surface plasmon; illustrated in Fig. 5.10.
The optical excitation of plasmon is the most efficient process by which light interacts
with matter [22] and confers the ability to concentrate and manipulate light at dimen-
sions below the diffraction limit onto metal nanostructures. Plasmonics is a rapidly
growing field of research and has recently been identified [23] as a potential pervasive
technology, offering opportunities to achieve unprecedented optical functionalities.
Electric field
Fig. 5.10. Schematic representation of the polarization of metal nanoparticles

by excitation of the surface plasmon.
Although light of all frequencies can induce electron oscillations in metals, the inter-
action is particularly efficient at the characteristic plasmon resonance frequency. Plas-
mon frequency depends on a variety of factors, including the identity of the metal, the
dielectric constant of the surrounding medium, and particle size [24–26]. The size de-
pendence of plasmon frequency is illustrated in Fig. 5.11 for a series of gold particles.
The surface plasmons of neighboring nanoparticles in close proximity can couple, and
for this reason assemblies of metal nanoparticles have plasmon frequencies which dif-
fer from those of the isolated constituent particles. The coupled plasmon resonance
60 nm
8 nm
4.6 nm
120 nm
Absorbance (a.u.)
2.5 nm
Fig. 5.11. Plasmon extinction spectra

of aqueous suspensions of gold nano-
300 400 500 600 700 particles of varying size. Adapted with
Wavelength (nm) permission from [26].
depends on the distance of separation in a known way, and can thus be exploited to
probe nanosystems through a novel application known as the plasmon ruler [27–29].
Such a ruler allows determination of separation distances in media (solution) which
are not accessible with electron or scanning probe microscopy.
The surface plasmon is probably best known for its role in surface-enhanced spec-
troscopies. The surface oscillation of electric charges generated by plasmon excita-
tion leads to significant enhancement in the local electromagnetic field [30], which in
turn modifies the probability of optical transitions for molecules located within the
affected region. For example, in the case of surface-enhanced Raman scattering, nor-
mally weak Raman signals can be enhanced by many orders of magnitude [31], leading
to such exceptional sensitivities that single molecule detection becomes possible [32].
The intense local fields generated by excitation of nanoparticle plasmon can
also modify the fluorescence properties of nearby molecules through a phenomenon
known as metal-enhanced fluorescence [33]. The exact mechanism of fluorescence
enhancement is not fully understood and probably involves more than one photo-
physical process. Firstly, the intense local field associated with the surface plasmon
can increase the excitation of flourophores in proximity. Additional enhancement
effects are also possible through interactions between the excited state fluorophore
and the metal nanoparticle. In particular, if the resonance frequencies are matched,
the excited state fluorophore can couple with a neighboring metal nanoparticle to
excite the plasmon. The plasmon can then relax radiatively to emit light. With this
mechanism, the emission spectrum will be identical to that of the fluorophore, even
though the nanoparticle is the emitting species. Typically, metal-enhanced fluores-
cence has a much shorter lifespan than that of the fluorophore alone, supporting
the conclusion that the nanoparticle is the emitting species. It has been suggested
that it is best to think of the fluorophore-metal complex as the emitting species [34].
Plasmon-enhanced fluorescence offers exiting possibilities in the development of
ultra-sensitive methods, probes, and devices for biomedical detection.
The majority of scientific publications in the field of nanoparticle plasmonics in-
volve either silver or gold. This is, in part, because of the ease of particle synthesis,
with gold and silver nanoparticles being readily accessible by the reduction of water-
soluble salts. Furthermore, nanoparticles of these two metals exhibit resonance plas-
mon frequencies located within the visible region of the spectrum. Silver has the more
intense plasmon of the two [35], but gold is biocompatible and more stable in bio-
logical media. Despite the prevalence of silver and gold, current research is looking
beyond these two metals for next generation technologies [36, 37].
Metal nanoparticles are currently being employed in applications other than
those based on their plasmonic properties. For example, silver nanoparticles have
important antibacterial and anti-fungal properties [38] and are being incorporated
into a growing number of consumer products such as antiseptic sprays, antimicro-
bial bandages, and sports clothing. Metals are also known to catalyze a number of
important organic reactions. Since surface area plays a predominant role in catalytic
activity, the increased specific surface area associated with decreasing particle size
can improve efficiency, and supported metal nanoparticles are widely used as solid
catalysts [39, 40].
5.6 Metal oxide nanoparticles
The wide range of properties and applications related to this diverse class of nanoma-
terials will be illustrated by consideration of three specific examples; titanium dioxide
(TiO2 ), iron oxide (Fe3 O4 and Fe2 O3 ), and silicon dioxide, or silica (SiO2 ).
5.6.1 Titanium dioxide
Titanium dioxide is highly reflective in the visible region of the spectrum, and for this
reason has been long utilized as a pigment material [41]. Small particles of titanium
dioxide are the brightest of all commercial white pigments, and the 2010 global pro-
duction of nanoscale TiO2 is estimated at 5 000 metric tons [42]. The primary applica-
tion is in paints and other opaque coatings, but TiO2 is also a frequent component of
personal care products such as toothpaste and sunscreen.
Transition metal oxides are semi-conductors, and thus share some of the elec-
tronic properties and applications described above for quantum dots. TiO2 is a wide
band gap material and absorbs UV light in the 280–400 nm wavelength range [41].
Upon absorption, an electron is elevated from the valence band to the conduction
band to generate an electron-hole pair, and TiO2 nanoparticles have been employed
to enhance photoconversion in solar cells [43]. The electron-hole pair can also partic-
ipate in charge transfer to chemical species adsorbed at the semiconductor surface,
leading to chemical reactions through a process known as photocatalysis [44]. The
excited state conduction band electron can serve to reduce an accepter molecule,
whereas the valence level hole can accept an electron from a neighboring donor
species. These photoinduced electron transfer processes are governed by the posi-
tion of the semiconductor bands with respect to the redox potentials of the surface
adsorbed molecules. In the case of TiO2 , the position of the valence band leads to
a particularly high oxidation potential for the photoinduced holes. The holes can
thus readily react with adsorbed water to produce hydroxyl radicals, which in turn
are strongly oxidizing and able to convert organic compounds to CO2 and water. For
this reason, TiO2 nanoparticles can be used as antibacterial [45] and water treatment
agents [46], and have even been demonstrated to split water into hydrogen and oxy-
gen [47]. Since the photocatalytic process requires migration of electrons and holes to
the TiO2 surface, nanoparticles, with their characteristically large surface to volume
ratio, show greater catalytic activity than the corresponding bulk material.
5.6.2 Iron oxide
The second important category of metal oxide nanoparticles is that composed of the
iron oxides. These functional materials are primarily of interest for their magnetic
properties. A variety of oxides are known, differing in the oxidation state of iron and
the crystal structure. The two main forms are magnetite (Fe3 O4 ), which contains both
Fe (II) and Fe (III) in a 1 : 2 ratio, and the gamma phase of iron (III) oxide (𝛾-Fe2 O3 ),
known as maghemite.
As is the case for other transition metals, the magnetic moments of iron atoms
and ions arise from the presence of unpaired electrons in the d orbitals. Within small
regions of a bulk material, the individual neighboring atomic magnetic moments are
generally aligned with one another to form a magnetic domain. The magnetization
within each domain points in a uniform direction, but the magnetization of differ-
ent domains may point in different directions, as illustrated in Fig. 5.12. The domain
structure can be modified by the application of an external magnetic field to increase
magnetization in a given direction. If the domains do not return to a random state after
removal of the external field, a permanent magnet will result.
Fig. 5.12. Schematic representation of a multidomain magnetic

material.
The novel properties of magnetic nanoparticles appear when particle size is reduced to
below domain size, which is of the order of 100 nm [48]. Small iron oxide nanoparticles
are monodomain and exhibit what is known as superparamagnetic behavior.
The direction of magnetization within a domain can randomly flip at a character-
istic frequency determined by what is known as the Néel relaxation time. At a given
temperature, the Néel relaxation time decreases with decreasing particle size and, in
the case of small nanoparticles, is generally much shorter than typical observation
times. Under these conditions, known as the superparamagnetic state, the magnetiza-
tion of the nanoparticle averages to zero. However, when an external magnetic field is
applied to an assembly of superparamagnetic nanoparticles, their magnetic moments
tend to align along the applied field, leading to a net magnetization. Superparamag-
netic nanoparticles can be dispersed in a carrier liquid to form what is known as a fer-
rofluid [49]. When placed in a magnetic field gradient, a ferrofluid moves to the region
of highest flux. This means that ferrofluids can be precisely positioned and shaped
by an external magnetic field. Ferrofluids are found in a large number of commercial
devices, including audio speakers, vacuum seals, switches, and sensors [50]. We have
recently demonstrated the fabrication of a ferrofluidic deformable liquid mirror, based
on the system shown in Fig. 5.13 [51, 52].
Clearly, the role of magnetic nanoparticles as functional materials is not restricted
to their use in ferrofluids. In particular, iron oxide nanoparticles are being increasingly
employed in medical applications, including, for example, their use as contrast agents
in magnetic resonance imaging, [53] as discussed elsewhere in this volume.
Fig. 5.13. Magnetically deformable mirror prepared

by coating an appropriate ferrofluid with a reflective
monolayer of silver nanoparticles. The central defor-
mation is generated by the magnetic field from an
underlying permanent magnet.
5.6.3 Silica
Nanoparticles composed of silica have a large number of applications in materials

science. Silica is a very versatile substance offering a number of attractive proper-
ties, including, for example, chemical and thermal stability and biocompatibility
[54]. Furthermore, the surface of silica can be readily functionalized with organic or
biologically active molecules, a key requirement for biological imaging or sensing
applications.
One important example of the use of silica is in the preparation of lumines-
cent nanoparticles by the encapsulation of fluorophores [55, 56]. Luminescent nano-
particles are used in many fields of application, the most prevalent being bioimaging.
Fluorescence organic molecules typically exhibit enhanced properties when dis-
persed in the silica matrix, which protects them against both collisional quenching
and photodegradation [57]. In addition, for applications in living systems, nano-
particles have been reported to offer significant advantages over organic molecules
with respect to resistance to metabolic disintegration, low toxicity, and adequate
bioavailability [58]. Fluorescent doped silica nanoparticles have been demonstrated
as promising probes for the detection of specific ionic species [57], intercellular sens-
ing [55], cellular imaging [56], and even the diagnosis of cancer [59].
One very important class of silica nanoparticles are the mesoporous materi-
als [60, 61]. The high surface area of these materials makes them inherently inter-
esting for catalysis. They are also receiving a great deal of attention as drug delivery
platforms [62], and can be designed to offer sophisticated functionalities such as
stimulus-responsive gated release [63]. Since the preceding chapter of this volume is
dedicated to mesoporous materials, no further details will be provided here.
5.7 Polymeric nanoparticles
Polymer microbeads and nanoparticles are used on a very large scale as latex paints.
As aqueous suspensions, latexes are environmentally friendly, practically odorless
and faster drying than their oil-based counterparts. Latexes are typically obtained
by the well-known process of emulsion polymerization [64]. More recently, polymer
nanoparticles have been attracting additional interest as host matrices for the prepa-
ration of novel hybrid materials. Polymers offer great versatility as host matrices. The
large inventory of existing polymers means that a number of properties, such as polar-
ity, elasticity and refractive index, can all be adjusted to meet specific requirements.
The formation of polymer nanoparticles is achieved by the dispersion of the mon-
omer into small droplets prior to the initiation of the polymerization reaction. Many
considerations influence the exact choice of the method of monomer dispersion, but
for the preparation of nanosized particles, miniemulsion polymerization is often the
method of choice [65]. The process of miniemulsion polymerization is illustrated in
Fig. 5.14. In contrast to emulsion polymerization, in which the monomer must diffuse
through the continuous phase to feed particle growth, in the miniemulsion process,
all of the monomer is pre-dispersed as nanodroplets prior to the initiation step. Thus,
in miniemulsion polymerizations, each droplet acts as an independent preformed
nanoreactor. Miniemulsion polymerization is therefore particularly well-suited to the
preparation of doped nanoparticles, since dopants can be dissolved in the monomer
at the desired concentration before dispersion [65]. For example, we have employed
this approach for the preparation of polystyrene nanoparticles doped with a lumi-
nescent lanthanide complex, as illustrated in Fig. 5.15 [66]. As reviewed elsewhere
[65], this approach can be extended beyond molecular dopants, and miniemulsion
polymerization is finding increasing interest for the encapsulation of solid nano-
materials.
H2O
Ultrasound
Monomer
Emulsion Miniemulsion
Surfactant
Polymerization
Polymer nanoparticles
Fig. 5.14. Schematic depiction of miniemulsion polymerization.
Fig. 5.15. Transmission electron microscope image of

x60 000 polystyrene nanoparticles prepared by miniemulsion
0.2 μm
polymerization. Reprinted with permission from [66].
5.8 Advanced architectures and hybrid systems
The examples provided above illustrate the immense diversity of functional nano-
particles and their role in developing technologies. For the most part, the present
discussion has, however, been limited to monolithic particles. In reality, nanoparticle
architecture is becoming increasingly sophisticated, and a cursory review of cur-
rent scientific literature is sufficient to ascertain the growing trend toward multi-
component, multi-function materials, such as core-shell and doped nanoparticles.
For example, metal cores have been coated with fluorescent dye-functionalized silica
shells to combine plasmonic and luminescence properties in nanoparticles designed
for biomedical detection [67]. Core-shell architectures have also been employed to
facilitate energy transfer and upconversion luminescence in lathanide-doped ma-
terials [68]. These are only two examples of the exciting future of nanoparticles as
functional materials. The possibilities are essentially endless. Promising new ma-
terials are being reported daily and any attempt to adequately review the scientific
literature in this field becomes outdated before even going to press.
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N. Allard and M. Leclerc
6 Conjugated polymers for organic electronics
Conjugated polymers have received a great deal of attention from both academic and
industrial laboratories, since they combine the best features of metals or inorganic
semiconducting materials (excellent electrical and optical properties), with those of
synthetic polymers (mechanical flexibility, simple processing, low cost). This syn-
ergy makes these functional materials useful in existing optoelectronic devices, and
creates completely new technological opportunities. For instance, polymeric semicon-
ductors are considered to be one of the most promising materials to lower the cost of
solar energy. Since they can be dissolved in common solvents, processing techniques
such as inkjet printing, spin coating and large scale roll-to-roll coating techniques,
widely used for thermoplastics, are now available for the low-cost production of
printed photovoltaic devices. All of these properties will help to establish the so-
called plastic electronics era, which includes light-emitting diodes and field-effect
transistors.
6.1 Introduction
There is hardly an aspect of our lives which is not touched by polymeric materials. In
the fields of optics and electronics, synthetic polymers are traditionally used in ap-
plications such as packaging, electrical insulators, and photoresists. However, new
opportunities have emerged with the development of electroactive and photoactive
conjugated polymers. This chapter will describe several examples which demonstrate
the tremendous innovation potential of these novel functional materials.
As with many other important discoveries, the development of the field of con-
jugated polymers was somehow accidental. A student of Professor Hideki Shirakawa
at the Tokyo Institute of Technology was working on the preparation of polyacety-
lene (Fig. 6.1) by the Ziegler–Natta polymerization method. By mistake, this student
prepared a multimolar concentration of the catalyst, instead of the usual millimolar
concentration, and obtained a thin polyacetylene film which looked like a metallic
foil instead of the usual dark, powdery material. During a visit to Japan, Professor
A.G. MacDiarmid (Department of Chemistry, University of Pennsylvania) met Profes-
sor Shirakawa and was fascinated by this shiny polymeric film. He invited him to come
to Philadelphia to investigate this new form of polyacetylene in more detail. In 1977,
in collaboration with Professor A.J. Heeger, a colleague from the Physics Department,
this team reported that upon partial oxidation with iodine or bromine (so-called
doping reaction), the conductivity of the intrinsically semiconducting polyacetylene
increased more than a millionfold (up to 100 S/cm) [1]. These days, electrical con-
ductivities of up to 105 S/cm are now obtained with some highly crystalline forms of
polyacetylene. The delocalized electronic structure (alternation of single and double

bonds) of polyacetylene is responsible for the good intrachain and interchain mobility
of the charge carriers (radical cations or their negative analogs) created upon doping.
This delocalized (conjugated) structure is also responsible for a strong absorption
in the UV-visible range. This group (Shirakawa, MacDiarmid, Heeger) eventually re-
ceived the 2000 Nobel Prize in Chemistry for this discovery [2–4]. Unfortunately, this
first conducting polymer is still very difficult to process and unstable in the presence
of oxygen.
Rapidly, many scientists investigated more stable conjugated polymers. For in-
stance, in the early 1980s, a lot of studies were devoted to electropolymerized poly-
thiophene [5], polypyrrole [5, 6], and polyaniline [7] (Fig. 6.1). This method has the
advantage of being capable of preparing thin films of these infusible and insoluble
rigid-rod conjugated polymers in one step. Depending upon the electrochemical po-
tential, it is possible to switch between the undoped semiconducting state and the
oxidized conducting state. Interestingly, these redox processes are also accompanied
by color changes (electrochromism). However, the ultimate goal remains the devel-
opment of polymeric materials which combine the electrical and optical features of
metals or semiconductors with the processing advantages and mechanical properties
of traditional polymers.
S N NH
n n H n n
Polyacetylene Polythiophene Polypyrrole Polyaniline
Fig. 6.1. First generation of conjugated polymers.
6.2 Processable conjugated polymers
The attempts to fulfill these requirements led to the development of a second genera-
tion of processable conjugated polymers. A first example of processable polyacetylene
was demonstrated by Edwards and Feast in 1980 [8]. Using ring-opening metathesis
polymerization (ROMP), a soluble polymeric non-conjugated precursor could be con-
verted into a polyacetylene thin film and a volatile by-product upon heating (Fig. 6.2).
This two-step procedure was not perfect, but it was the first example of a processable
and potentially conjugated polymer. A similar approach was developed for the prepa-
ration of poly(para-phenylene) (PPP) [9].
A breakthrough occurred in 1985–86 with the syntheses of highly conjugated and
processable poly(3-alkylthiophene)s [10]. The fact that these five-membered rings can
exhibit an anti co-planar conformation (Fig. 6.3) reduces the steric hindrance devel-
oped by the presence of the solubilizing side-chains. Thus, the coexistence of both pla-
narity (important to keep the delocalized and conjugated structure) and processability
F3C CF3 F3C CF3

WCI6 F3C CF3
Δ
+
n
n
Fig. 6.2. Synthesis of polyacetylene from a processable precursor.
was demonstrated for the first time. For instance, it is interesting to note that process-
able alkyl-substituted polyacetylenes, polyanilines, and poly(para-phenylene)s are
non-planar and have poor electrical properties. Some researchers describe these
types of substituted conjugated macromolecules as hairy-rod polymers, this configu-
ration facilitating the dispersion and interactions with the solvent. Following these
first studies on poly(3-alkylthiophene)s, it became quite clear that the synthesis of
well-defined head-to-tail coupled poly(3-alkylthiophene)s, which should yield to the
lowest steric hindrance from the side chains and possibly a more efficient three-
dimensional packing, would lead to a significant improvement in the performance of
these polymeric materials [11]. Therefore, in attempts to bring more reliable synthetic
procedures to the field of electronic materials, a variety of synthetic tools have been
implemented, allowing significant advances in this research field. Among other ad-
vantages, these investigations led to the first preparations of well-defined regioregular
poly(3-alkylthiophene)s by McCullough and Rieke in 1992 (Fig. 6.3, [12, 13]). Further,
these relatively complicated polymerization procedures have been optimized and sim-
plified, leading to the Grignard metathesis method (GRIM, [14]). For instance, this new
method eliminates the need for highly reactive metals and can be performed at low
temperatures. Among all poly(3-alkylthiophene)s investigated, regioregular poly(3-
hexylthiophene), or (P3HT), has become the polymer of choice, exhibiting the best
electrical and optical properties in addition to adequate processability. The synthesis
of air-stable, semi-transparent, highly conducting poly(3,4-ethylenedioxythiophene),
or (PEDOT), is another example of rational design of a conjugated polymer with op-
timized structural and physical properties [15]. Both P3HT and PEDOT are currently
the most utilized conjugated polymers and are commercially available from various
sources.
In the meantime, the focus shifted from the synthesis of highly conductive poly-
mers to the design of stable semiconducting polymers through collaborations between
physicists and engineers. This new driving force was based on the aim to initiate the
so-called plastic electronics era, where micro-electronic devices could be printed
on different substrates using practical processing methods. For this purpose, the
electronic properties of the existing polymers have to be chemically tuned to obtain
low bandgap semiconducting materials. This bandgap tuning can be achieved in
various ways. For instance, the rigidification of the conjugated backbone, the intro-
duction of electron-withdrawing or electron-donating side groups, and the increase
of the quinoid (versus aromatic) character of the main chain have been widely used
Oxidation R
R or
electropolymerization S
S n
S
R
R
R Kumada
(Mc Cullough) S
Br [Ni]cat. S n
S
R
R
R Negishi
(Rieke) S
Br S Br S n
[Ni]cat.
R
R
R Kumada
(GRIM) S
Br Br S n Fig. 6.3. Synthesis of processable
S [Ni]cat.
R poly(3-alkylthiophene)s.
in the past few years to modulate the bandgap of such conjugated polymers [16].
However, one of the most efficient approaches involves the utilization of electron-
rich or electron-poor units leading to alternating push-pull architecture. As shown
in Fig. 6.4, when these two different moieties are combined in an alternating copoly-
mer, hybridization occurs between the molecular orbitals of the electron-rich unit
and of the electron-poor unit, leading to a significant modulation of the copolymer
bandgap. Usually, the energy level of the highest occupied molecular orbital (HOMO)
of the resulting copolymer is determined by the electron-rich unit, while the energy
level of the lowest unoccupied molecular orbital (LUMO) is mainly influenced by the
electron-poor unit.
LUMO
LUMO
Electron-rich
moiety
Eg Electron-poor
moiety
HOMO
HOMO
Fig. 6.4. Hybridization of the HOMO-LUMO energy
D D-A A levels in donor-acceptor (push-pull) copolymers.
S
S N N
N N Suzuki S S
(RO)2B B(OR)2 + S S
N Br Br [Pd]cat. n
N
R R R R R
R
O N O
O N O
R3Sn S S SnR3 Stille S S
+
Si S
Br S Br [Pd]cat. n
R R Si
R R R
R
R O N O
O N O
Br S R DHAP S
+ S S n
R S Br S [Pd]cat.
R
Fig. 6.5. Typical polymerization reactions for conjugated alternating copolymers.
Over the years, a third generation of semiconducting copolymers have therefore been
synthesized to satisfy the needs of various electronic applications [17]. Unfortunately,
there are relatively few synthetic methods which allow efficient preparation of such
alternating copolymers; most of these copolymers being obtained via Suzuki [18] or
Stille [19] cross-coupling polymerization (Fig. 6.5). These state-of-the-art methods gen-
erally involve numerous synthetic steps and organometallic reagents which give rise
to metal waste and various by-products. Therefore cheaper, environmentally friendly
and more efficient synthetic procedures would clearly be a great asset for the sustain-
able preparation of affordable conjugated polymers. In order to solve these problems,
the utilization of the latest synthetic developments in organic chemistry, termed di-
rect (hetero)arylation, is very appealing. These new reactions allow for the forma-
tion of carbon-carbon bonds between (hetero)arenes and aryl halides. Hence, they
do not require organometallic intermediates, thereby significantly reducing both syn-
thetic steps and cost (see Fig. 6.5). Moreover, this new direct (hetero)arylation poly-
merization (DHAP) method, which only produces acid as a by-product, has recently
attracted a lot of interest [20]. Although these reactions are not easily controlled for
compounds having more than one type of C-H bond, they can sometimes lead to the
synthesis of branched or crosslinked polymers. A fine-tuning of the reaction condi-
tions and careful choice of the monomers may suppress these unwelcome side re-
actions. All of these step-growth polymerization methods (Suzuki, Stille, DHAP) can
lead to number-average molecular weights of up to 100 kDa/mol in the best case, and
must exhibit polydispersity indexes of about 2 according to the Carother equation. Fi-
nally, it is important to note that most recently-developed monomers (e.g. carbazoles,
dithienosiloles, thienopyrrolodiones, etc.) bear flexible side-chains which are far from
the conjugated backbone, reducing the steric hindrance created within these hairy-rod
chemical structures.
These chemical tools allowed chemists and engineers to synthesize a large num-
ber of semiconducting polymers for the manufacture of diverse electronic devices
such as light-emitting diodes, field-effect transistors, solar cells, and a continuously
growing list of other applications. For instance, water-soluble luminescent conjugated
polymers have allowed the specific, rapid and ultra-sensitive detection of unlabeled
DNA, RNA, or proteins. This relatively young field of chemical and biological sensors
based on semiconducting conjugated polymers is expanding rapidly but will not be
further discussed in this chapter. For those interested in these biomedical applica-
tions, the authors recommend several reviews and the references therein [21, 22].
6.3 Applications in renewable energy
6.3.1 Organic solar cells
Solar energy represents an attractive solution to fulfill our needs regarding green and
renewable energy, while protecting the environment at the same time. For example,
one should be aware that the sun provides in one hour what humanity consumes dur-
ing one year. However, the large scale development of this technology is somewhat
limited by the relatively high cost of producing and installing a solar panel versus its
moderate efficiency. Many studies suggest that the cost of a solar panel must be de-
creased by a factor of 5 to 10 in order to compete with other already known energy
sources such as hydro, nuclear, wind or fossil. Electroactive and photoactive conju-
gated polymers are considered to be one of the most promising ways to lower the
price of solar energy. They can be solubilized in common solvents and processed us-
ing techniques such as inkjet printing, spin coating and large scale roll-to-roll coating
techniques, which are widely used for thermoplastics and are available for the man-
ufacture of various devices. In particular, bulk heterojunction (usually a blend of a
polymeric p-type semiconductor with an n-type fullerene derivative) solar cells offer
great opportunities, with power conversion efficiency (PCE) now approaching thresh-
old values (a PCE of 10 % with a lifespan of 5–10 years) for large scale commercial-
ization. Indeed, the most efficient polymeric materials can now reach power conver-
sion efficiencies of over 9 % in a single-layer configuration [23]. These new functional
materials should help to initiate new and competitive manufacturing of photovoltaic
devices.
Different types of device architecture have been utilized for the manufacture of
organic photovoltaic devices. As mentioned above, the most common configuration is
called the bulk heterojunction (BHJ) approach (Fig. 6.6). Glass is usually employed as
common substrate, although plastics can be used to generate flexible devices. A layer
of semi-transparent indium-tin oxide (ITO), which acts as the anode, is deposited on
the substrate. After deposition of the anode, PEDOT, a semi-transparent and highly
conductive polymer (described in Section 6.1), is spin-coated from a water-based so-
lution on top of ITO for the purpose of enhancing the hole transport and improving
contacts between the ITO electrode and the organic BHJ layer. Then the active layer,
which is a bulk heterojunction of a donor (p-type semiconductor) and an acceptor (n-
type semiconductor), usually from an organic solution containing both components,
is deposited over the PEDOT layer. Such a structure provides large surface area in-
terfaces which allow the generation of a charge separated state with efficient sub-
sequent charge migration through 3-D percolation networks. The donor is usually a
p-type semiconducting conjugated polymer, while the acceptor is generally a process-
able fullerene derivative such as [6,6]-phenyl-C61 -butyric acid methyl ester (PCBM) or
its C71 analog; fullerenes being known to support stable and mobile negative charge
carriers (see Chapter 3). Finally, a reflective metallic layer acting as the cathode is gen-
erally evaporated or printed on top of the assembly.
Metal
Polymer: PCBM
PEDOT
ITO
Fig. 6.6. Standard architecture for an organic
Glass or plastic solar cell.
As shown in Fig. 6.7, upon illumination, the semiconducting BHJ active layer absorbs
some of the photons leading to the formation of excitons (Step 1). For instance, these
excitons may come from the excitation of an electron from the HOMO of the polymer to
its LUMO, creating bound electron-hole pairs (Step 2). These excitons can then migrate
about 10–20 nm within the polymer phase (related to their lifespan and mobility) to
reach the acceptor phase. The nanoscale BHJ morphology is particularly helpful for
this purpose: at this boundary, the electron in the LUMO of the polymer is transferred
to the LUMO of the acceptor (Step 3). After this photo-induced electron transfer, the
positive charge carriers and the electrons, which are no longer held by Coulombic in-
teractions, travel through their respective percolated phases to reach their respective
electrodes (Step 4). It is important to mention that a similar mechanism is observed
when light is absorbed by the fullerene derivative or any other n-type semiconductor;
the only major difference being the fact that the electron transfer involves the HOMO
of the semiconductors. Interestingly, despite the relative complexity of all these in-
terfaces and physical mechanisms, internal quantum efficiency of close to 100 % has
been reported, implying that for some optimized nanoscale morphology, essentially
every absorbed photon results in a separated pair of charge carriers which are col-
lected at the electrodes [24].
1. LUMO 2. LUMO –
LUMO LUMO
hv AI AI
ITO ITO
HOMO HOMO
HOMO HOMO
+
Polymer PCBM Polymer PCBM
4. LUMO 3. LUMO –
LUMO – – LUMO
– AI AI
ITO ITO
HOMO HOMO
+ HOMO HOMO
+ +
Polymer PCBM Polymer PCBM
Fig. 6.7. General working mechanism of an organic solar cell.
6.3.2 Conjugated polymers for organic solar cells
While the manufacture and working mechanism of an organic solar cell may seem rel-
atively simple, finding the optimal conjugated polymer and obtaining the right mor-
phology (which depends upon the blend ratio, solvent, deposition technique, temper-
ature, etc.) is still a big challenge. For instance, as a first requirement, the semicon-
ducting polymer must be stable in air. Consequently, its HOMO energy level should
be under −5.2 eV, which is about the air-oxidation threshold. Also, as mentioned pre-
viously, there must be an electron transfer between the LUMO of the donor and the
LUMO of the acceptor. To make this electron transfer possible, there must be an ener-
getic difference of about 0.3 eV between these LUMO energy levels (the same is true
when the electron transfer takes place through the HOMO energy levels). In addition,
it is preferable for the HOMO energy level of the polymer to be as low as possible, since
the open circuit voltage (Voc ) is mostly defined by the difference between the LUMO of
the acceptor and the HOMO of the polymer. Moreover, since the polymer is the main
light absorber when blended with fullerene derivatives, it is necessary that the poly-
mer absorbs as much sunlight as possible. Thus, bandgaps between 1.2 and 1.9 eV are
desired, since they correspond to the maximum intensity of the solar emission spectra
and allow for the best compromise between optimized photocurrent and photovoltage
(Fig. 6.8).
OCH3 Energy (eV)

4.00 3.00 2.50 2.00 1.75 1.50 1.25 1.00
O
Photon flux AM 1.5 (m–2 .s–1 .nm–1)

5x1018
Polymer Ideal Zone
PCBM Low JSC Low VOC
Donor 18
4x10
Lumo Acceptor
3x1018
> 0.3 eV –4.3 eV
Aluminum
Band gap 2x1018
1.2–1.9 eV
ITO VOC max
1x1018
Homo
0
–6.1 eV
300
400
500
600
700
800
900
1000
1100
1200
Wavelength (nm)
Fig. 6.8. Properties needed for conjugated polymers and photon flux spectra of the sun.
Once a good polymer/fullerene composite with the right morphology is found, a device
is created and tested to determine the PCE. For this purpose, the electrodes are con-
nected and light is beamed through the ITO electrode using a solar simulator (AM1.5G)
imitating the sun irradiation at a tilted angle of 37 degrees (Pin is of 100 mW/cm2 ).
At the same time, a potential sweeping is applied. After data processing, a typical
J-V curve from which the fill factor (FF), the short-circuit current density (Jsc ), and the
open-circuit voltage (Voc ) can be obtained, is used to calculate the PCE of the device
(Fig. 6.9). Pmax represents the maximum power which can be produced by such a solar
cell. This last parameter is important for the characterization of the fill factor, which
describes the overall quality of the device.
Current density (mA/cm2)
VPmax VOC Pout FF x JSC x VOC

PCE = =
Pin Pin
JPmax x VPmax
JPmax FF =
Pmax Jsc x VOC
JSC
Potential (V)
Fig. 6.9. Typical J-V curve obtained for a photovoltaic device.

Hundreds of polymeric structures have been synthesized and investigated in the

last few years, but only three main polymers (P3HT [25, 26], PCDTBT [25, 27], and
PTB7 [23]) have demonstrated good and reproducible PCEs, with a lifespan of up to
7 years for PCDTBT (Fig. 6.10). However, large, stable, and low-cost modules will have
to be developed and tested under “real” conditions in order to reach commercial ap-
plications.
C4H9
H9C4 C2H5 O C2H5

O
S O F
C6H13 N N S
S S S
S n n S S n
N
O
P3HT H17C8 C8H17 PCDTBT PTB7
PCE = 6.5% PCE = 7.9% H9C4 C2H5 PCE = 9.2%
Fig. 6.10. Most widely studied conjugated polymers for organic solar cells.
6.4 Applications in micro-electronics
6.4.1 Field-effect transistors
Field-effect transistors (FETs) are electronic switches widely utilized in electronic de-
vices such as displays, computer logics, radio frequency identification tags (RFID),
etc. The vast majority of these devices are currently made from monocrystalline, poly-
crystalline or amorphous silicon. In FETs, one of the main performance criteria is the
charge mobility which can be simply related to the on/off switching speed of the de-
vice. Higher switching speeds permit applications in high performance electronics.
These widely used silicon compounds have shown charge carrier mobility of up to
900 cm2 /V s for monocrystalline silicon [28] used in high performance electronic de-
vices, and up to 1 cm2 /V s for amorphous silicon [28] utilized in standard electronic
systems.
Although silicon-based devices perform very well, they are relatively difficult to
produce and cannot be used in flexible devices, whereas conjugated polymer-based
devices can be solution-processed at low temperatures and easily coated onto flexible
devices. Despite these great possibilities, polymer-based FETs will probably only com-
pete with amorphous silicon. Indeed, amorphous or semi-crystalline semiconducting
polymers do not exhibit the necessary long-range organization to lead to very high
charge carrier mobility.
In most cases, an FET is constituted of three electrodes: the gate, the source,
and the drain. It is also composed of a dielectric layer and of a semiconducting layer.
Figure 6.11 shows the different configurations for organic FETs (OFETs). The two most
D S Semiconductor
Semiconductor D S
Dielectric Dielectric
Gate Electrode Gate Electrode
(a) (b)
Gate Gate
Gate dielectric Dielectric
Semiconductor D S
D S Semiconductor
Substrate Substrate
(c) (d)
Fig. 6.11. Schematic description of OFETs with (a) bottom-gate top-contact (BG/TC), (b) bottom-gate
bottom-contact (BG/BC), (c) top-gate bottom-contact (TG/BC), and (d) top-gate top-contact (TG/TC)
structures [29].
frequent configurations are bottom-gate top-contact (BG/TC; (a)) and bottom-gate

bottom-contact (BG-BC; (b)) due to their relatively simple production.
The general working mechanism of an OFET starts by applying a potential to the
gate while a potential is constantly applied between the source and the drain (see
Fig. 6.12). If a negative potential is applied to the gate (VGS ), positive charge carriers
are formed at the interface between the semiconducting polymer and the dielectric
layer. Then, due to the potential between the source electrode and the drain electrode,
these positive charge carriers travel through the semiconducting layer, forming a p-
type OFET. The drain-source current (IDS ) first follows ohmic behavior as a function
of the applied drain-source potential (VDS ), then saturates at high voltages. If a pos-
itive potential is applied at the gate, negative charge carriers are formed at the poly-
mer/dielectric interface creating n-type OFET.
These OFETs are mainly characterized by three values: the charge carrier mobil-
ity (μ), the Ion /Ioff ratio, and the threshold voltage (VT ). The charge mobility refers to
the speed at which the charges formed in the semiconductor layer travel between the
source and the drain electrodes. These values can be determined from I-V curves, sim-
ilar to those reported in Fig. 6.12. The higher the charge mobility, the faster switching
between the on and off states of the OFET can occur. This charge mobility is numbered
either in hole mobility or electron mobility depending on the potential applied at the
gate. The Ion /Ioff ratio refers to the ratio between the current when the transistor is at
the on-state and when it is at the off-state. While multiple switching happens in the
device even if there is no potential applied at the gate, residual charges are still in
the semiconducting layer, creating an electric current at the off state. Therefore, it is
important to have Ion /Ioff ratios as high as possible so that clear switching is always
possible. The threshold voltage corresponds to the minimum potential which needs
to be applied at the gate to obtain switching. It is necessary from a commercial point
of view to have a low and stable threshold voltage. The electronic properties of the
polymeric semiconductor and the nature of the dielectric layer play a major role in the
values of the threshold voltage.
VGS
0V
–60 –20V
–40V
–60V
–80V
–40 –100V
IDS/uA
–20
0 –20 –40 –60 –80 –100

VDS/V Fig. 6.12. Typical I-V curve of a p-type OFET.
6.4.2 Conjugated polymers for field-effect transistors
Conjugated polymers need to possess some critical properties in order to be good can-
didates for OFET applications. First, the semiconducting polymers must be stable over
time and, as mentioned earlier, must possess a HOMO energy level lower than −5.2 eV
to be air-stable. Stability is important, but the main factor which allows conjugated
polymers to attain high mobility is their ability to form highly organized films. It has
been shown that the closer the π-stacking is, the better the charge carrier mobility.
The strategy for obtaining a polymer with good packing properties is to use planar
conjugated units which will drive efficient π-stacking. To obtain processable materi-
als, alkyl chains are added along the conjugated backbone. Obviously, adding alkyl
chains is not necessarily good for the π-stacking efficiency, but the goal is to find a
compromise between the alkyl chains needed for solubility and the π-stacking in or-
der to obtain good mobility when solution-processed. In addition to polymer chain
stacking, there is also the point of how these stacks of polymer chains are oriented
relative to the substrate. It has also been shown that the packing of these polymers
should be oriented perpendicular to the surface in order to permit good charge circu-
lation through the source and drain electrodes [30]. See Fig. 6.13 for examples of the
best polymers reported so far for OFETs. Obviously they exhibit the right combination
of processability, π-stacking, and polymer chain orientations onto the substrates.
C10H21 C8H17
S H13C6 F F
C8H17
N N
N O O N
S S S S n
S F F
O S n n S O
N S N
H17C8 H33C16 C16H33 C6H13
C10H21 C8H17
PDTT-C8C10 CDT-BTZ N-CS2DPP-OD-TEG

μh= 10.5 cm2V–1s–1 μh= 5.5 cm2V–1s–1 μe= 2.36 cm2V–1s–1
Fig. 6.13. Efficient conjugated polymers for p-type and n-type OFETs [31–33].
6.5 Applications in lighting
6.5.1 Light-emitting diodes
Light-emitting diodes (LEDs) are mostly used as lighting sources. Today, they can be
found in a large variety of electronic devices acting as electronic displays or light
indicators. The first LED was demonstrated in 1936 by George Destriau in the labo-
ratory of Marie Curie. When a potential is applied to ZnS:P powder placed between
two electrodes, the emission of a low intensity red light can be observed. That dis-
covery led to the development of a large variety of red, orange, yellow, and green
inorganic light-emitting diodes. In 1962, General Electric commercialized the first in-
organic LED which was based on phosphorous doped gallium arsenide (GaAs:P) [34].
Light-emission from an organic material was only reported for the first time in 1963
by Martin Pope and his collaborators at New York University. They demonstrated
that an anthracene crystal placed between two silver electrodes could emit blue
light [35]. Unfortunately, the lifespan of this type of device was far shorter than those
obtained with inorganic-based devices. The real interest in organic material for LED
came from the research of Ching W. Tang and Steven Van Slyke at Eastman Kodak
Research Laboratories in 1987. They invented an organic LED (OLED) based on a thin
evaporated layer of tris(8-hydroxyquinoline)aluminum (AlQ3 ), which led to high elec-
troluminescence yield and interesting lifespans [36]. It was only in 1990 that the first
polymeric LED (PLED) based on a π-conjugated polymer was demonstrated, when
Sir Richard Friend and his collaborators at the University of Cambridge observed a
green light emission from a thin film of poly(para-phenylenevinylene), or PPV, placed

between two electrodes [37]. Since that discovery, a large number of small molecules,
oligomers, and polymers have been synthesized and used in light-emitting devices.
It is important to recall here that OLEDS are generally prepared using small vacuum-
processed organic molecules, whereas polymers have the advantage of being solution
processable, providing better opportunities for making large-area devices. Today,
many electronic devices made of OLEDs such as flat screen televisions, mp3 players,
digital cameras, and smartphones are commercially available and a number of com-
panies, such as Universal Display, Cambridge Display Technology (CDT), and Philips
produce lighting sources from conjugated small molecules, oligomers or polymers.
A large number of different configurations exist for OLEDs and PLEDs resulting
in different lifespans and efficiency. The simplest device configuration, and the first
which was demonstrated, consists of a light-emitting material sandwiched between
two electrodes. Electroluminescence is defined by the emission of light induced by
charge recombination. Therefore, in order for LEDs to function, charges must be in-
jected into the material. An electron is removed from the HOMO of the light-emitting
material at the cathode, creating a positive charge carrier. Inversely, at the cathode
an electron is inserted in the LUMO of the light-emitting material creating a negative
charge carrier. The hole and the electron travel to their opposite electrodes under the
influence of the applied electric field. They can also recombine to form an excited state
commonly called exciton. That exciton can be either in the singlet state, where the
spins of the electron/hole pairs are in the opposite direction, or in the triplet state
where the spins of the electron/hole pairs are in the same direction. The singlet state
is the only one which can lead to light emission in fluorescent conjugated polymers
(Fig. 6.14). However, phosphorescent materials can help to increase the efficiency of
such devices. It is interesting to note that light-emitting diodes behave essentially in
the opposite manner to photovoltaic devices; in other words, they create light from
electricity whereas solar cells produce electricity from the light source.
transporting
Cathode
transporting
Emitting
layer
layer
Anode
Hole
Electron
layer
Fig. 6.14. Schematic working mechanism for LEDs.

In the case of the simple device made of only two electrodes and the light-emitting
material, the efficiency of the charge recombination is very low since the charge can
directly travel to the respective opposite electrode, leading to poor electrolumines-
cence. A large number of device architectures have been developed in order to contain
the electrons and holes in the light-emitting material. First, the light-emitting layer is
“sandwiched” between a hole-transporting layer and an electron-transporting layer to
maximize the containment of the charge carriers in the emitting layer (Fig. 6.15). Fur-
thermore, in order to contain even more charge carriers within the emitting layer, the
previous structure was optimized by adding a hole and electron blocking layer around
the emitting layer (Fig. 6.15). Containing the charges in the light-emitting material al-
lows for better efficiency and stability of the OLEDs and PLEDs. Such a multi-layered
structure is more adequate for vacuum-processed molecules than solution-processed
polymers and can explain the superior properties of OLEDs versus PLEDs. However,
the development of so-called orthogonal solvents (for instance, aqueous versus non-
aqueous polymeric solutions) could lead to multi-step depositions and lead to more
efficient PLEDs.
Cathode
Electron transporting layer

Cathode Hole blocking layer
Electron transporting layer Light-emitting material

Cathode Light-emitting material Electron blocking layer
Light-emitting material Hole transporting layer Hole transporting layer
Anode Anode Anode
Substrate Substrate Substrate
Efficiency and stability
Fig. 6.15. Examples of architectures for OLEDs and PLEDs.
6.5.2 Conjugated polymers for light-emitting diodes
In order to commercially produce viable PLEDs made of conjugated polymers, they

must be soluble enough to be solution-processed and chemically stable over time.
A high glass transition temperature is also needed, since heat can be produced in the
device during its use and the morphology of the polymer film has to remain intact.
From an electronic point of view, the polymer should possess good charge injection
and charge transport to produce efficient PLEDs. Dependent upon the color needed,
the bandgap of the polymer needs to be tuned. High bandgap polymers can produce
blue emission, while low bandgap polymers can produce a red emission. To obtain
a clear and clean color, the emission spectra of the polymer should be as narrow as
possible. In terms of performance, the device must present high electroluminescence
quantum efficiency (φEL ). That quantum efficiency is defined by the ratio of the num-
ber of photons emitted over the number of charges injected. This quantum efficiency
characterizes the electronic processes in the device but does not measure the light pro-
duced. Different approaches have been used to characterize the emitted light. First,
there are two units to characterize the light intensity: lumen (lm) and candela (cd).
Lumen corresponds to the total quantity of light emitted in all directions, whereas can-
dela represents the quantity of light emitted at a certain angle. In the literature, there
are three main parameters to measure in order to fully characterize the light emitted
by a LED. These are luminance (Lmax ), which is reported in candela per square me-
ter (cd/m2 ); luminous efficiency (LEmax ), reported in candela per ampere (cd/A), and
power efficiency (PE) in lumen per watt (lm/W). The latter is the figure of merit for
characterizing LEDs and is widely used by the lighting industry. Traditional lighting
technologies mostly rely on incandescent, fluorescent or halogen lamps. While light
bulbs show the lowest efficiency (10–35 lm/W), fluorescent or halogen lighting devices
are more efficient with power efficiency (PE) ranging from 50 to 100 lm/W. With perfor-
mance of about 15 lm/W, the best polymer-based light-emitting diodes (PLEDs) are not
yet competing with the best lighting sources [38, 39]. Future investigations should find
strategies to enhance (by about one order of magnitude) the luminosity of such de-
vices, probably by developing new multi-layered configurations and phosphorescent
polymeric materials. However, it is important to repeat here that vacuum-processed
OLEDs have already achieved the required electronic and optical properties to make
commercial devices.
6.6 Summary
Conjugated polymers are an important class of electroactive and photoactive mate-

rials. In the last 10–15 years, this research field has literally exploded owing to their
applications in energy, micro-electronics, and lighting, to name a few. However, in
order to obtain the desired performance with polymeric semiconductors, different pa-
rameters at the molecular and supramolecular levels (such as electronic structure,
molecular weight, regioregularity, solubility, morphology, etc.) must be carefully con-
trolled. These parameters are different for each application and should be considered
during the design of polymer molecular structures, the choice of monomers, and the
polymerization reactions.
With respect to applications, it is quite evident that conjugated polymers are
promised a bright future. Research is not only being conducted in academic institu-
tions, but many companies of all sizes are now involved in R&D projects devoted to
semiconducting polymers. On the basis of this tremendous momentum, it is firmly
believed that over the next few years conjugated polymers will continue to address
important problems of society, such as the production of renewable energy with min-
imum detrimental effects on the environment or printed electronic sensors for smart
packaging applications. As Benjamin Braddock (Dustin Hoffman) is told in The Gradu-
ate: “there is a great future in plastics. . . [or should we now say plastic electronics?] . . .
think about it” [40].
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[40] http://www.youtube.com/watch?v=PSxihhBzCjk (Accessed January 28, 2014)
A. Soldera
7 Theoretical tools for designing microscopic to
macroscopic properties of functional materials
The very essence of science is to unveil the huge palette of surrounding mysteries.
Deciphering the forces that sustain an object in water, or understanding how an ap-
ple falls from a tree are some well-known findings which have made a huge step to-
wards comprehending our world for humanity. Our contemplation of the world thus
changes according to the current advancements of science. Thanks to the extensive
progress made with experimental techniques and computers, it has become possible
to reveal some aspects of the behavior of the microscopic domain. From a computa-
tional viewpoint, approaches in solving present-day problems are certainly different
than those used 50 years ago. In the realm of functional materials, have we actually
reached what Dirac desired in 1929 in the Proceedings of the Royal Society of London.
Series A, Containing Papers of a Mathematical and Physical Character, Vol. 123, No. 792
(6 April 1929):
The underlying physical laws necessary for the mathematical theory of a large part of physics
and the whole of chemistry are thus completely known, and the difficulty is only that the exact
application of these laws leads to equations much too complicated to be soluble. It therefore
becomes desirable that approximate practical methods of applying quantum mechanics should
be developed, which can lead to an explanation of the main features of complex atomic systems
without too much computation.
This chapter intends to address the issue raised by Dirac to a certain extent. More
specifically, we will explore whether codes and computers are efficient enough to re-
veal the behavior of the complex atomic systems which ultimately lead to the world we
know. This would mean that, by improving computer performance, such as reaching
exascale computing and beyond, solving the “equation of everything” [1] i.e., the fa-
mous Schrödinger’s equation, the whole mechanism of the microscopic world would
be revealed. At the risk of disappointing the reader, the answer seems to be “No, it
cannot”, as claimed by Philip W. Anderson (Nobel prize in Physics in 1977) [2]. Viscos-
ity is an illustrative example. It can be roughly explained by the presence of dissipa-
tive forces which cannot be deduced as a result of solving the Schrödinger’s equation.
The answer actually divides two wholly opposed viewpoints: reductionism and emer-
gence [3, 4]. Reductionism envisions understanding a system through its “elementary”
constituents and their interactions. Emergence can be summarized by the vision of
Plato: the whole is greater than and different to the sum of its parts. Between these
two opposing perspectives, obtaining a clear response is not straightforward. Molec-
ular simulation is in some sense to illuminate this antagonism. Although this chapter
is not intended to discuss this aspect in detail, such a reflection should nevertheless
be kept in mind.
The first part of the chapter is devoted to those issues ongoing from microscopic
to macroscopic scales, and thus the importance of possessing notions in statistical
thermodynamics to make meaningful molecular modeling. Examples of this state-
ment are presented in the second part of the chapter, and aim to illustrate the different
uses of simulation. These two examples originate from collaborations with my distin-
guished colleagues from the Quebec Centre for Functional Materials (CQMF), Profes-
sors Claverie and Morin, who are also authors of Chapters 2 and 3 in this book.
7.1 Methods
7.1.1 The link between microscopic and macroscopic scales
At the heart of molecular simulation it is necessary to establish the link between micro
and macro scales. Statistical physics is the branch of science which provides the tools
to build this bridge. However, relationships are first established for systems with no or
very weak interactions. Molecular simulation can be seen as an experiment performed
with a computer using a code [5]. It thus provides the means to apply such tools in com-
plex systems such as functional materials. However, special care is needed with regard
to applying these tools. The following example illustrates the nature of the problem
when deducing macroscopic properties from the microscopic realm. Without a doubt,
it takes some liberties from a rigorous approach which would necessitate a greater dis-
cussion of statistical physics. It is actually intended to give a simple overview of the
general issues required to relate the micro and the macro states and their properties, as
schematically summarized in Fig. 7.1. Consider a glass of water in a room whose ambi-
ent temperature is 10°C. Now, a Maxwell demon [6], instead of opening a gate to select
molecules with specific velocity, measures the speed of the water molecules inside the
glass of water by observing each individual water molecule. Moreover, he clearly ig-
nores any uncertainty principle raised by Heisenberg (see equation (7.2)). Accordingly,
he is able to provide the speed (vo ) of one molecule of water. The equipartition theo-
rem indicates that the square of speed is related to the temperature¹. He thus finds that
the computed temperature is very high, strictly higher than the ambient temperature.
Despite his demon character, he is astonished and says “Hey, there is some nonsense
going on here”.
Back to reality, the actual incongruity comes from applying the equipartition the-
orem to the speed of only one molecule. The real explanation is summarized in Fig. 7.2.
Distributions need to be considered, and the Maxwell–Boltzmann distribution must
be applied in this case in order to compute an average value. By integrating the sta-
1 More rigorously, each degree of freedom described by the square of any coordinate corresponds to
1/2 kB T, where kB is the Boltzmann constant.
7 Theoretical tools for designing functional materials | 141
°C
5 0
4 0 νo
3 0
2 0
1 0
0 0
1 0
2 0
ν2 α T To >> 10°C Fig. 7.1. Principle of inconsistency in measur-

ing only properties of a single molecule.
tistical weights over the whole domain, or, in the case of discreteness, by adding up
all the possibilities, the result is one. Distributions are thus required to handle mi-
croscopic properties. Only then can the comparison between speeds measured at the
microscopic level and the value of the macroscopic temperature be undertaken in a
meaningful fashion. Applying this rule appropriately is at the heart of molecular sim-
ulation. Instead of speed, you can think of any other microscopic property, be it a
scalar, a vector or a tensor. Of course, it is not applied when you are only interested in
the configuration exhibiting the minimum energy, as in the crystal.
Micro Macro
ν2 α T
Distribution ρ(ν)
(Maxwell-boltzmann) Fig. 7.2. Distribution is required
Vo
when microscopic properties are
compared to macroscopic values;
vo is the result of the fishing in
V Fig. 7.1.
In Gibbs’ approach to statistical thermodynamics, the calculation of the average of a

distribution depends on the statistical ensemble of systems being applied. Consider a
distribution of systems in which the probability is described by pi for the appearance
of the ith system. Then ∑i pi = 1. For the sake of clarity, the integral form is not in-
troduced here. To compute the system ensemble average of a property (A), one needs
to compute, ⟨A⟩ = ∑i Ai pi where Ai is the value of the property A for the ith system.
At this point, the ergodic hypothesis must be introduced briefly. It specifies that the
value of A over a huge number of systems at a specific time, ⟨A⟩ equals the average
stemming from considering the distribution of the property of a single system over
a “long” period of time, A.̄ When Ā = ⟨A⟩ the computed property can be compared
to the experimental one. For a more detailed description of the ergodic hypothesis,
interested readers are referred to the seminal book of Allen and Tildesley [7]. How-
ever, computing Ā is time-consuming and it can be difficult to obtain by simulation.
A most accurate representation of ⟨A⟩ is thus mandatory. Experimentally, ergodicity
is not attained in certain systems, such as molecular glasses and polymers. However,
conceptually, a simulation code must be ergodic.
The different scales have thus been exposed. The intent of this chapter is not to
provide the theoretical development underlying each scale. A list of books focusing on
this topic is available at the end of the chapter. This chapter aims to reveal the “very
substance”, as Gargantua said to Pantagruel, of molecular simulation, and to empha-
size the main difficulties most students will encounter during this course. The bridge
between scales will also be discussed.
7.1.2 Ab initio methods
“In the beginning was” Schrödinger’s equation, whose expression when it is not time-
dependent is:
Hψ̂ (r)⃗ = Eψ (r)⃗ (7.1)
This equation indicates that the Hamiltonian operator H,̂ acts on a wave function, ψ,
which depends on coordinates of electrons r ⃗ (considering only electronic contribu-
tion). This operation leads to the energy (eigenvalue) multiplied by the same wave
function which is then known as an eigenfunction. In bounded states² the resulting
energies are quantified. A difference in energy between two levels is then related to
a frequency which can be measured experimentally. Introducing the Dirac notation,
the ensuing equation (Fig. 7.3) can be represented similar to the one shown in Fig. 7.2,
and indicates that the resulting energy corresponds to an average. However, there is a
clear distinction to be made between these two averages. For the quantum average in
Fig. 7.3, the microscopic state, described by ψ, is known; in this case, the ensemble is
constituted only of systems in the ψ state, which is not necessarily an eigenstate of the
Hamiltonian. In statistical thermodynamics, in addition to the quantum uncertainty,
there is uncertainty regarding the state of the system; thus, the ensemble average of
Fig. 7.2 is over a distribution of systems in different states, each with its own statistical
weight.
Micro
Macro
ψ Ĥ ψ E
Distribution Fig. 7.3. Schrödinger’s equation in Dirac’s notation.
In the kingdom of electrons, it might seem amazing that no classic apparatus is able to
reveal one electron specifically. What is the actual problem? In a first step, we consider
our classical world, and try to use our understanding of it to disclose the microscopic
2 The electron confined to the field exerted by the nuclear charge is an example of confined state.
environment. The use of the adjective ‘classic’ indicates that the world is governed by
the classical laws of physics, such as the Newtonian laws of mechanics, or Maxwell
equations in optics. So, if we want to find our way in a room in the middle of the night
and avoid any untimely meetings with chairs, we need a flashlight. Does this light
change our environment? The answer is clearly no. Walls do not move, nor does their
shape change as a result of the beam of our flashlight. Can we use such an experiment
at the electron scale? Before answering this question, we have to answer to at least
two other ones.
First question: is the electron a particle, or a wave? The answer depends on the
kind of experiment carried out to reveal the presence of the electron. To symbolize this
problem, we use the image of the 2D world proposed by Carl Sagan in his famous book,
Cosmos, to represent the fourth dimension [8]. A cylinder is a 3D object. Its base lies on
the (x, y) plane. The demon (taking a little break from fishing for water molecules) has
only two possibilities for examining it: through the x or y axis, and along the z axis.
He actually changes color according to the direction he looks. In the first case, he ob-
serves a rectangle while in the second situation, a circle is revealed to him (Fig. 7.4).
Accordingly, dependant on the experience of looking at the cylinder from two possi-
ble observation points, the cylinder is either a rectangle or a circle. In the same way,
the electron is either a particle or a wave, depending on the type of instrument used
to observe it. Let us take a brief detour from this particular wave-particle duality of
electrons. In the late nineteenth century, the electron was recognized as carrying a
negative charge instead of being considered to be embedded in ether. The existence of
subatomic corpuscles was evidenced by J.J. Thomson in 1897 [9]. However, De Broglie
showed in his Ph.D. thesis published in 1924 that particles, e.g., electrons, behave as
waves. This was experimentally confirmed the following year [10].
y
Fig. 7.4. In a 2D world, is a cylinder
X a rectangle or a circle?
The second question concerns the fact that the position and momentum (velocity
times weight) of the electron cannot be determined at precisely the same time, i.e.
Heisenberg’s uncertainty principle:
h
σpx σx ≥ , (7.2)
4π
where σpx and σx are the standard mean deviation of (respectively) momentum and
position along the x axis, and h is the Planck constant.
The intrinsic behavior of electrons is thus barely grasped, is even impossible to
grasp, by classical methods. Using an analytic tool, i.e. the equivalent of the flash-
light but for electrons, the state of the electron will automatically change. How then is
the configuration of electrons uncovered? By using mathematics! Very unpopular an-
swer, as I usually hear from the students in my quantum chemistry class! The reader
can however be reassured: the purpose of this overview of simulation applied to func-
tional materials is not to develop mathematical models. It is aimed at explaining how
mathematics is used to grasp details that govern the microscopic world. Mathemat-
ical description can be retrieved from those textbooks suggested at the end of this
chapter.
The equation in Fig. 7.3 indicates that the state of the system, and accordingly of
the electrons, can be described by a mathematical function (ψ), called the wave func-
tion. When it is squared, this equation leads to a physically relevant result: the prob-
ability of finding an electron somewhere in the space (Born interpretation). However,
it can only be solved analytically for one electron. Indeed, adding another electron,
combined with the fact that electrons are indistinguishable particles (being fermions),
as well as the presence of a spin and Heisenberg’s uncertainty principle make analyt-
ical solution of Schrödinger’s equation impossible. Computing Coulomb interactions
between these two negative charges becomes thus unfeasible, since their distance of
separation remains unknown. Accordingly, approximations are required. The prereq-
uisite in manipulating approximations to solve the Schrödinger equation gives rise to
different approaches. They can be roughly classified into three major types: ab initio
(Hartree–Fock method and derivatives), density functional theory (DFT), and semi-
empirical methods. Ab initio is a Latin phrase which means “from the beginning”. In
this approach, only fundamental constants are used and no experimental data are
introduced to compensate for the use of approximations. These approximations thus
lead to numerous commercial or freeware codes such as Gaussian [11, 12], Gamess [13],
DMol [3] Accelrys [14], and others. The Hartree–Fock method is the most common ab
initio approximation employed by scientists. The usual approximation employed by
chemists is to handle hydrogen atomic orbitals³. The intrinsic reason for employing
hydrogenoid atomic orbitals comes from the fact that Coulombic interactions between
electrons can be reduced to a central core problem. This makes it much easier to cal-
culate, through the introduction of the mean-field concept: each electron undergoes
interactions with all other electrons. In order to get the final wave function, a self-
consistency procedure is then applied. Nevertheless, initial wave functions are nec-
essary. Hydrogenoid wave functions are chosen since they correspond to the exact
solutions of the Schrödinger’s equation applied to the hydrogen atom. For practical
3 Physicists usually prefer the plane waves approach.

reasons, these wave functions are replaced by linear combinations of Gaussian type
orbitals (GTO), or Slater orbitals. A notation for GTO was introduced by Pople⁴ et al. to
indicate the number of Gaussian functions used to describe the different hydrogenoid
orbitals forming a basis set of equations. The essence of the basis set consists of func-
tions which fit the hydrogenoid atomic orbitals, such as 6-31g. 6-31g actually means
that 6 Gaussian functions depict the core electrons and the valence electrons are repre-
sented by a combination of two functions (Double Zeta), represented by 3 and 1 Gaus-
sian functions respectively; g stands for Gaussian orbitals. Specific functions can then
be added, such as polarization functions (d, p) to enhance directional effects, or dif-
fuse functions (+), to take long-range effects due to the presence of electronic delocal-
ization in the studied system. Post-Hartree–Fock methods, such as the Møller–Plesset
perturbation theory (MP), are aimed at refining this approach, but require more Cen-
tral Processing Units (CPU) and are therefore time-consuming.
In order to improve computer efficiency, the Density Functional Theory (DFT)
method offers a very interesting alternative. Within this approach, total energy is ex-
pressed in terms of total electron density, instead of the wave function which depends
on atomic position. This functional, i.e., the function of a function is inferred from
computations or experimental measurements. The PBE and hybrid B3LYP functionals
are the most commonly used, hybrid meaning that it also contains a Hartree–Fock
component. However, the choice of functional must be carried out carefully, since
a universal functional is not yet available. To further increase computer efficiency,
CPU and time consuming methods such as multiplication of overlap matrices can be
removed. These omitted data must then be balanced by experimental data such as the
heat of formation. The most-employed semi-empirical codes are the Austin model 1
(AM1) and Parameterized Model (PM3).
The main drawback in using quantum calculations is the prohibitive demand on
CPU. This problem increases with the number of atoms. As a typical example, the
computer time for the Hartree–Fock approach is proportional to N4 (which is the total
number of integrals to be evaluated), where N is the number of basis functions used to
described the studied system. For DFT, the computer time increases to N3 . DFT is gen-
erally employed for large systems. In practice, optimization (i.e. finding the structure
of lowest energy), can be carried out using a low level basis set. It can then be fol-
lowed by calculations carried out at a higher level of theory without the optimization
step, leading to single point energy. Alternatives also exist to address problems stem-
ming from larger systems such as polymers, where long range and large time scale
are relevant factors in computing properties. Thus, instead of considering electrons
as wave functions, the atomistic approach depicts atoms as particles with electronic
interactions embedded in a force field.
4 Nobel Prize in chemistry in 1998 “for his development of computational methods in quantum chem-
istry", shared with Kohn “for his development of the density-functional theory”.
The Schrödinger’s equation and the different approximations are used when spe-
cific interactions involving electrons are of importance: electronic conjugation, proton
dissociation, infrared and NMR spectra, hyperpolarizabilities and others. However, it
is not always necessary to consider specifically all electrons during calculations. As
an atom moves in a medium, interactions with other atoms can be approximated in
many cases. This link to another level is discussed in the following section.
7.1.3 Bridging the gap between ab initio and atomistic levels
The graph shown in Fig. 7.2 corresponds to the Maxwell–Boltzmann distribution of

gas molecules. It may be used to reveal the bridge between the electronic and atomic
levels [15]. Rather than debating this 3D distribution, we focus on the distribution of
momentums in one direction only (x axis), which has the following form:
1 1/2
p2x
f(px ) = ( ) exp (− ), (7.3)
2πmkB T 2mkB T
where m is the weight of the particle, kB is the Boltzmann constant, and T is the tem-
perature. Again, this equation might seem complex, but it is essential to further under-
stand this approach. The shape of this distribution corresponds to a Gaussian curve
that presents the following generic form:
1 x2
g(x) = exp (− 2 ) , (7.4)
σ√2π 2σ
where σ is the standard mean deviation. This Gaussian curve is found in many systems
containing purely random events: tossing coins, dice etc. . . For example, let’s consider
tossing coins, for which the result can be either heads or tails. One event can be tossing
a coin 30 times. What is then the probability that in these 30 flips, the result is 15 times
heads, and thus 15 times tails? This event is actually x in equation (7.4), and the prob-
ability that this event occurs is g(x). However, in order for the discreteness⁵ (flipping
the coins, or the microscopic level) to reach continuity (Gaussian curve, and thus the
macro level), the number of events must be important. In fact, there is a theorem,
the central limit theorem, which actually specifies that the standard mean deviation
varies as 1/√N, where N is the number of events.
By comparing equations (7.3) and (7.4), it can be found that σpx = √mkB T. Inserting
this value into equation (7.2) leads to the conclusion that uncertainty in the x position
of a particle of weight m must be greater than h/(4π√mkB T). Thus at 300 K, the pre-
cision in the position of the electron is of the order of 15 Å, while for the hydrogen
5 This discretization of the distribution must be put in parallel with the measuring of the velocity of
the water molecules one by one as the demon did.
(van der Waals radius rH = 1.2 Å) and carbon atoms (van der Waals radius rC = 1.7 Å),
it is 0.35 and 0.1 Å respectively. This confirms that electrons are quantum particles,
since we have no idea where they can be located. Moreover, heavy atoms such as car-
bon atoms can be considered to be governed by classical mechanics. However, the
classical character of the hydrogen atom is difficult to establish clearly, although it
can generally be considered to be a particle, and can then be described by classical
equations.
7.1.4 Atomistic simulation
At the heart of any atomistic simulation we find the force field. Originally stemming
from vibrational spectroscopy, it was applied to depict interactions between all atoms,
including non-bonding terms. For example, consider an atom in a specific environ-
ment, for instance two linked sp3 carbon atoms. This environment can be defined by
a particular potential energy surface (PES). Such a PES does not change greatly if the
same environment is found in another system or molecule. Following the previous ex-
ample, the number of molecules possessing this C–C link is unlimited. A force field
is then aimed at representing the PES as accurately as possible. To achieve this goal,
a force field in fact consists of (1) equations in which terms tend to grasp specific in-
teractions, and (2) parameters which stem from the fit of these equations to the dif-
ferent PES. Experiments or quantum calculations are carried out to accurately depict
the PES. Returning to the C–C link, we will show how PES associated with interactions
stemming from this molecular characteristic is computed, and subsequently reveal the
great diversity in force fields. We actually describe the link between two carbon atoms
in a simple ethane molecule.
200
Eh = k (d–d0 )2 Harmonic function
180
160
EM = Ediss. [1–exp(–α (d–d0 ))]2
140
Energy (kcal/mol)
120
Morse function
100
80
60 4
40 2
20 0 Fig. 7.5. Potential energy with respect
1.4 1.5 1.6 1.7
0 to the C–C distance in an ethane
0 1 2 3 4 5 6 molecule. The dotted curve repre-
C-C distance (A) sents the actual energy behavior.
The PES associated with the C–C elongation can be computed using quantum
methods. It is in fact reduced to a simple curve (Fig. 7.5). The potential energy is thus
computed, while the distance between two carbon atoms in an ethane molecule is var-
ied. A dotted line, joining the different data, is displayed. The Morse function is usu-
ally employed to fit these data: it is displayed in gray in Fig. 7.5. As can be seen, three
parameters are required to fit the curve: the dissociation energy, Ediss. , a parameter
which describes the width of the potential well, do , which corresponds to the distance
of minimum in potential energy, the actual equilibrium distance between the two car-
bon atoms, and α which defines the well width. Since a covalent bond is exposed to
small fluctuations around do most of the time, the Morse function can be expanded
in a Taylor development at d = do until the third term. This leads to a harmonic func-
tion (in black in Fig. 7.5), revealing in fact an elastic behavior (Hooke’s law). The three
parameters of the Morse function used to fit the data are then replaced by only two
fitting parameters: the spring constant, k = Ediss. α2 (stemming from the Taylor devel-
opment), and the equilibrium distance, do . The link between two atoms can thus be
described by either of these two functions. The harmonic function is usually preferred
to the Morse function since it needs two fitting parameters instead of three, and more
importantly it does not use an exponential function which consumes more CPU time.
Nevertheless, as can be observed in the inset of Fig. 7.5, a quadratic function is not
sufficient to describe interactions between two atoms properly. Computational data
are thus fitted by a 4th or 6th order polynomial. The higher the order, the better the
fit, and thus less important errors leading to better transferability (i.e., the availability
of a force field for the study of a great number of systems). Depending on the kind of
calculations to be carried out, several functions are thus available. In fact, there are
other parameters which also differentiate the force fields:
– Parameterization: what is the chosen value for do , 1.53 or 1.54 Å, or is greater pre-
cision needed? Actually, the equilibrium value depends on the kinds of systems
investigated and the type of calculation carried out.
– Environment: how many different environments of an atom are needed? Consider
the sp2 carbon atom. If only one series of fitting parameters is selected, one will
certainly encounter problems when willing to differentiate between alkene and
ketone bonding. In the case of second generation force field, carbon atoms can
have 20 different environments, making such a force field more transferable.
In summary, interactions between two linked atoms require a function and parame-
ters specific to each atom in order to be represented. However, the potential energy to
describe a molecule in a medium needs additional terms. They are characterized in
Fig. 7.6, where 4 atoms are schematically displayed.
The force field equation is in fact separated into two terms: bonding and non-
bonding equations.
φ rij
θ
Fig. 7.6. Representation of the variables discussed in equations (7.5–7.9).
Bonding interaction terms

The bonding interaction terms depend on the internal coordinates of the molecule,
i.e., bonds, valence angles, and dihedral angles. Accordingly, its simplest expression
consists of the sum of all the terms that are functions of stretching, bending, and tor-
sion found in a molecule. Thus, in addition to the stretching term previously defined,
a simplified force field, usually classified as a class I generation force field, possesses
valence and dihedral angle terms to describe the bonding interactions.
– Stretching term:
Estretching (d) = ks (d − do )2 (7.5)
where d is the atomic distance at which the stretching potential energy is com-
puted, ks and do are the spring constant and the value of atomic distance for which
the stretching potential energy is zero respectively. This actually corresponds to
the black curve in Fig. 7.5.
– Bending term:
EBending (θ) = kθ (θ − θo )2 (7.6)
where θ is the valence angle at which the bending potential energy is computed,
kθ and θo are the spring constant and the valence angle for which the bending
potential energy is zero respectively.
– Dihedral term:
3
Ediheadral (φ) = ∑ Vn [1 − cos(nφ − φ0n )] (7.7)
n=1
where φ is the torsion angle at which the dihedral potential energy is computed,
Vn corresponds to the potential energy barrier, and φ0n the phase.
Other forms of bonding terms exist in a class I force field, such as the out-of-plane
term, due to variations in the planarity of a group of atoms as in the ester group. More-
over, due to increasing computational efficiency, bonding interaction cross terms, as
well as higher terms in Taylor development, can be added to better depict the PES,
leading to second generation force fields which cover a greater number of compounds
and thus have greater transferability. Accordingly, a great variety of force fields exists:
pcff, COMPASS, OPLS, MM2, MM4, UFF, AMBER, ESFF, CVFF, etc. [16–18]. Although
not explored in this chapter, interested readers are invited to read about the work of
Sun [16].
Non-bonding interaction terms

Non-bonding terms express the interactions between linked atoms separated by a cer-
tain number of atoms (2 in Fig. 7.6), as well as between atoms belonging to different
molecules. They generally consist of two terms.
– van der Waals interactions
Aij Bij
EijLJ (rij ) = 12 − 6 (7.8)
rij rij
where Aij and Bij are fitting parameters, and rij is the actual distance between
atoms i and j. The equation displayed in (7.8) corresponds to the Lennard-Jones
potential: it is formed by a repulsive (in r−12 −6
ij ) and a dispersive (in rij ) term. While
the latter term results from the London–Keesom–Debye interactions [19], the for-
mer term can have different forms. The r−12 ij behavior can be substituted by an
exponential decay, exp(−ρrij ) to yield the Buckingham potential, or a less abrupt
function, r−9
ij [20].
– Electrostatic, or Coulomb potential energy:
qi qj
EijCoulomb (rij ) = (7.9)
4πεo rij
where qi , qj , and εo are respectively the partial charges of atoms i, j, and the di-
electric constant. The partial charges reproduce the first nonzero multipolar com-
ponent. They stem from the difference in electronegativity between atoms sharing
a bond.
Different equations are thus available to portray the whole PES. The approach used
to establish the PES from experiments or calculations can lead to different fitting pa-
rameters and also contribute to the great diversity of available force fields. The Monte-
Carlo method [21] and molecular mechanics consist of direct use of a force field. Static
properties such as energies [22], infrared spectra [23], and mechanical properties [24]
can be computed with the latter approach. Molecular dynamics (MD) is required to
reveal dynamic properties, such as autocorrelation function [25, 26] and relaxation
times [27]. It consists of integrating equations of motions, usually the second law of
Newton, to give mobility to atoms considered to be simple particles with interactions,
as previously stated. Most useful information is obtained by using MD. However, the
main problem with MD simulation is that the time period covered is usually small. In
order to integrate Newton’s equations, a time step (δt) is required for which various
types of integrators could be used. For example, a peculiarity of the Verlet algorithm
and its derivatives is the use of an “important” time step: δt = 1 fs, or 10−15 s. This
means that to produce a trajectory, i.e., a series of conformations during 1 ns, solv-
ing the equations would necessitate 1 000 000 integrations! Each integration consists
of computing the velocity and position of all atoms, according to the selected force
field (second law of Newton). So why would it be necessary to use such a low integra-
tion step? The main reason stems from the fact that all of the motions involving atoms
must be correctly reproduced. The most rapid motion existing among atoms is the C–
H stretching vibration, of the order of 10 fs. Thus, an integration step of 1 fs using the
Verlet algorithm makes the use of MD available to accurately describe atoms’ motions.
To increase the duration of MD, it is necessary to diminish the number of integration
calculations and/or increase the integration step. One method is to replace C–H with
a bigger “C” atom whose force field parameters will definitely be different to the whole
atom description. Such a procedure is called coarse-grained simulation and it is at the
beginning of the mesoscale level simulation.
7.1.5 Bridging the gap between atomistic and mesoscale levels
As the duration of MD increases, dissipative effects emerge. The Newton equations

of motion occur in systems with constant energy. In order to introduce a temperature
term into a system, various algorithms can be used. However, dissipative effects lead-
ing to an exchange of energy cannot be easily inserted into such systems, since all
these effects take place at the mesoscale level. The purpose is thus to reproduce the
general behavior in a more efficient way. The actual problems stemming from atom-
istic simulation are the large number of degrees of freedom. We must therefore distin-
guish between those that are of interest for the simulation and those that must reach
equilibrium rapidly. The general behavior of big molecular systems must be correctly
simulated, while specific details can be neglected at the mesoscale level. Let us con-
sider a polymer mixed in a solvent, where the polymer behavior is the main interest.
Details of the solvent molecules can actually be ignored in the simulation of such a
system. Similarly, if this polymer corresponds to a very long chain, details of atoms
or valence angles and dihedral angles are not of importance in describing how the
polymer behaves. On the other hand, the center of mass of a group of atoms whose
length can be Kuhn’s length is more important. Dissipative particle dynamics simula-
tion uses such approximations, and is very promising. We recently published a study
where we showed that water channels can be formed in fuel cell membranes by ap-
plying shearing. They are observed only for long chains and low water content [28].
Despite growing interest, mesoscale simulation is not discussed in this chapter.
The focus is on scales where chemical functionality is explicitly pictured, i.e., the
quantum computational and atomistic domains. Examples of the applications of these
two domains of approximation will be the focus of the next section.
7.2 Examples
Molecular simulation is a powerful tool but it must be manipulated with great care.
Calculations can be run easily (push-button temptation stemming from the simple
handling of commercial codes), providing some data. Conclusions can then be drawn
rapidly, but how effective are they exactly? Many questions must be answered in or-
der to run a simulation efficiently. For instance, is the pertinent portion of the phase
space correctly explored? Have the right calculation characteristics been chosen, such
as the functional in DFT or the force field in atomistic simulation? Instead of exposing
a list of criteria which must be fulfilled before extracting any meaningful conclusion
from calculations, this section will emphasize the procedure that must be employed.
Since molecular simulation is based on approximations, correlation of results stem-
ming from calculations with experimental data must be carried out first. Corrections
can then be brought to the type of calculation or to the protocol used. Examples will
be discussed in order to illustrate this procedure.
The very purpose of simulations performed in the lab is to guide the synthesis
or formulation of new compounds through a better understanding of the molecular
interactions that give rise to the macroscopic properties. Functional materials partic-
ularly suit this approach, since small changes in the molecule can lead to important
changes in the final properties. Accordingly, if molecular simulation can deal with
such changes, new molecules with enhanced properties can be proposed. Molecular
simulation is thus particularly aimed at supporting experimentalists in their studies.
7.2.1 Quantum studies
Quantum calculations are of particular interest to guide experimentalists in the de-

velopment of materials and the optimization of their properties. Two illustrations of
this objective are reviewed. The first example is related to collaboration between our
laboratory and the laboratory of our colleague Professor Jean-François Morin, author
of Chapter 3 in the current book. The other example deals with a study carried out in
our laboratory.
Electronic properties [29]

Professor Morin and his group study organic and molecular electronics (Chapter 3).
Such compounds are very promising materials due to their great ability to tune
their properties by modifying their chemical structure. Among these compounds,
fullerene (C60 ) is a very interesting n-type candidate, since it can easily accommodate
negative charges in a reversible way. The reason for this peculiarity stems from the
presence of a triply degenerate lowest unoccupied molecular orbital (LUMO) level
which allows the addition of up to six electrons to a single fullerene cage. However,
the LUMO of C60 is 4.5 eV, which is too high for electronic applications. Variations of
this value can be addressed through the addition of specific groups. Molecular sim-
ulation then becomes of great interest, since the effect of this group on the value of
the LUMO can be rapidly revealed. Nevertheless, comparison with experimental data
must first be carried out. Koopmans theorem is used to compute approximate ioniza-
tion energy, considering that it corresponds to the negative of the highest occupied
molecular orbital (HOMO). Computing electron affinity, i.e., negative of LUMO, is less
straightforward, due mainly to the fact that it is a virtual molecular orbital.
A series of new molecules derived from molecules with an ethynyl-bridged func-
tion and linked to fullerene have been synthesized by Professor Morin’s group and
have also been characterized electrochemically. Selection of the appropriate func-
tional and basis set was first carried out. The ensuing values for the LUMO were
compared to computational data (Fig. 7.7, left). Despite an underestimation of the
LUMO, a linear relationship was obtained for almost all of the synthesized com-
pounds. However, the LUMO of the molecule possessing a penta-fluoro phenyl group
at the α position of the ethynyl-bridge in the fullerene (Fig. 7.7, right), was found out of
range, with a very low LUMO. The experimental LUMO was −3.84 eV. Using the PBE
functional, a value of −4.05 eV was computed. The chemical structure of the molecule
indicates that it mainly possesses one degree of freedom that is the torsion angle (φ)
associated with the bond linking the penta-fluoro phenyl group to the fullerene. This
dihedral angle was turned in 10° steps. At each step, the LUMO was calculated. The
resulting graph is shown in Fig. 7.7 on the right. As observed in this graph, the value
of the dihedral angle greatly influences the value of the LUMO.
–3.85 –3.70
–3.90 –3.75 OC8H17
Lumo simulated/eV
Lumo simulated/eV
3
–3.95 φ
–3.80 F
2
–4.00 F
5 BM
–3.85 F
1
F
4
PC
–4.05 F
6
–3.90
8
–4.10
–3.95
–4.15
–4.00
–4.20
–4.05
0
C6
–4.25
–4.10
10 20 30 40 50 60 70 80
–4.00
–3.98
–3.96
–3.94
–3.92
–3.90
–3.88
–3.86
–3.84
–3.82
φ (deg.)
Lumo experimental /eV
Fig. 7.7. LUMO with respect to the dihedral φ.
When fluorine atoms are in an ortho position relative to the 1-ethynyl-4-(octyloxy)ben-

zene group, φ = 10° (position shown schematically in Fig. 7.7, right), the highest value
of LUMO (−3.71 eV) is obtained. Rotating the phenyl group until the fluorine atoms are
approximately at the same distance from the fullerene (φ = 80°), results in a much
lower LUMO energy level (−4.05 eV). This difference of 10 % between the two values
can be directly attributed to the δ− character of fluorine atoms, in agreement with the
electrochemical results. In fact, substituting the fluorine atoms with hydrogen atoms
in the phenyl group (leading to compound 3 in Fig. 7.7, left) does not have any impact
on the value of LUMO by rotating the dihedral angle. Accordingly, calculations show
that LUMO can be tuned when a hexa-fluoro phenyl group is linked to C60 . Molecular
simulation thus acts as a guide to the synthesis of new compounds. More specifically, it
does not give the final molecule, but gives hints for the development of new functional
materials. In other words, molecular simulation can be used to guide the synthesis of
new and more efficient materials. A different approach, resulting in a proposition of
very new molecules based on simulations, will be developed in the next paragraph.
Design of new membranes [30, 31]

Polymer electrolyte membrane fuel cells (PEMFC) are the primary system being de-
veloped for use in automotive applications. The perfluorinated polymer Nafion® re-
mains extensively used as a PEM. Since it cannot be operated at low humidity and/or
at temperatures above 100°C, great efforts have been dedicated to proposing alterna-
tives to this copolymer. They can be roughly classified into two main approaches. The
first series of molecules is derived from the structure of Nafion® , i.e., they possess a
polytetrafluoroethylene (PTFE) backbone and randomly distributed fluorinated ether
side chains, each terminated with a sulfonic acid group. The second type of molecule
possesses the sulfonate acid part mentioned above, but the rest of the core is gen-
erally polyether ether ketone (PEEK)-like. The limited development of new classes of
membranes may stem from the lack of understanding of the factors contributing to
the morphology, conductivity, and hydration of Nafion® . Great effort has been made
to develop new membranes through trial and error and serendipity, although these
strategies are not discussed in this chapter.
Nafion® is a long polymer chain with a huge degree of freedom. Its polytetraflu-
oroethylene (PTFE) backbone is extremely hydrophobic, while the fluorinated side
chains have high electron affinity which promotes the dissociation of the proton of
the sulfonic acid, making it a superacid. Due to the electronic contribution, quantum
method is the appropriate approach for dealing with proton dissociation. Rather than
considering all the chains, our group performed calculations focused on trifluoro-
sulfonic acid (TfOH), CF3 SO3 H. Our methodology was then to find conformation of
minimum energy as a water molecule is added to the system. Infrared spectra were
computed at each step and compared to experimental ones, which allowed us to no-
tice that considering only one TfOH is not sufficient to accurately describe the infrared
spectra. Two acidic molecules were found to be sufficient. However, studies with three
TfOH molecules involve an important number of degrees of freedom (important con-
figurational space), making access to all potential energy wells hazardous. The agree-
ment between selected computed and experimental frequencies indicated that the
structural changes occurring during proton dissociation could be used. This sequence
of molecular systems can be seen as a flip book (i.e., a book with a series of pictures
that vary gradually from one page to the next, so that when the pages are turned
rapidly, the pictures appear to animate by simulating motion or some other change
(Wikipedia)). Each image of the sequence corresponds to the addition of one water
molecule. Initially, the two sulfonic acid groups form a complex through hydrogen
bonding. Analysis of the structural changes as a function of added water molecules
reveals that only one sulfonic group, the protogenic group, is affected by the inclusion
of water molecules before the first proton dissociation occurs. In fact, the distance be-
̂
tween the two sulfur atoms remains relatively constant at 4.3 Å, as well as the HO–H
angle ∼ 178°, as shown in Fig. 7.8. It was then argued that new bis-sulfonic acid molec-
ular scaffolds possessing this optimal S–S distance and comparable behavior of the
̂ angle might perform as well as or better than Nafion® . This molecule is shown
HO–H
in Fig. 7.8: the distance between the two sulfur atoms and the angle correspond to the
geometrical characteristics computed in trifluorosulfonic acids. By calculation, it is
demonstrated that they exhibit the same structural behavior as the bis-sulfonic sys-
tem when water molecules are added to the system. Moreover, the rigid structure that
supports the two sulfonic groups can possibly help reduce the water content necessary
for the first proton dissociation, and lead to a very low pKa. Ultimately, the mechani-
cal properties of the ensuing membrane may be improved. Synthesis of the proposed
molecules is currently underway. At the moment of editing this book, the molecule
had not yet been synthesized. Its synthesis is clearly not straightforward.
1st proton dissociation
0 1 2 3
180
6 4.3 Å
OH-O
θOH-O(deg.)
160
dS-S(A)
5
S-S
140
4
0 1 2 3
n/2 H2O
Fig. 7.8. Some architectural features of the two TfOH molecules and the new molecule are compara-
ble.
Molecular simulation is thus a complementary tool to experiment with in order to

guide the design of new molecules with optimal properties. It is the combination of
simulation and experiment that yields interesting conclusions, in agreement with the
principle of emergence. The next section focuses on the use of atomistic simulation to
provide insight into molecular interactions.
7.2.2 Atomistic simulation
Thermal transitions of polymers such as melting points (Tm ) and glass transition tem-
peratures (Tg ) can be difficult to measure experimentally. For example, the thermal
transition of rigid rod polymers can be so high that the compound starts decomposing
when the transition temperature is reached. In other cases, the transition can be very
weak and hardly observable with the usual instrumental techniques, such as differen-
tial scanning calorimetry (DSC), or differential mechanical analysis (DMA). Recently,
nanomaterials have become more important due to their potential industrial applica-
tions. However, the measurement of thermal transitions of dispersed nanoparticles
in a continuous phase is often problematic, as the amount of material constituting
the nanoparticles can be very small. Nevertheless, the knowledge of their thermal
transitions is a key parameter for understanding the morphology of the nanoparticle,
as well as its ability to aggregate. In this regard, atomistic simulation is well-suited
for studying nanomaterials, as it probes comparable dimensions and thus provides a
valuable tool for the prediction of thermal properties in functional materials. It has
to be pointed out that, due to the great number of atoms required to represent a tran-
sition, quantum calculations cannot describe such phenomena. Measurement of Tm
and Tg is explained in the following section.
The melting transition [32]

Fundamental properties of crystals at the nanoscale are significantly different to those
of bulk crystals and melting and crystallization temperatures rarely correspond to
those of the bulk. Properties of nanocrystals are also strongly influenced by their shape
and size. An efficient way to clarify experimental observations relies on the use of ap-
propriate computational tools to probe the very nature of interactions at stake. The
study of Tm stems from a collaboration with Professor Jérôme Claverie, author of Chap-
ter 2 in the current book. Professor Claverie and his group are interested in functional
groups containing polyethylene (PE), such as the carboxylic acid group. Recently, they
demonstrated that nanoparticles of PE are thermoreversible [33]. Understanding this
phenomenon is not straightforward and the use of molecular simulation becomes a
reliable asset in unveiling the fundamental nature of this thermoreversibility.
Simulation of the melting point of functional materials conforms to this vision.
From a simulation viewpoint, the question was: how can interactions inside a PE
nanoparticle affect the melting point? A protocol had thus to be carefully designed
to model such a transition and consists of a simple but realistic representation of the
actual material. A nanocrystal constituted of alkane chains of fixed length was used
to mimic the PE nanocrystals. How to compute the melting point? It is known that it is
a first order transition (heat capacity tends to infinite) with latent heat. Moreover, in
the case of alkane chains, conformations change from all-trans to a Boltzmann distri-
bution of the rotameric states. These experimental facts are then considered in order
to envision by simulation the melting transition. The pcff force field was used, since
it was created specially to simulate polymers appropriately. First, calculations were
performed on a crystal formed with chains 24 atoms long, 4 chains in each x and y di-
rection, as shown in Fig. 7.9. The crystal is in the vacuum.
Tm
250 300 350 400
1.0
σe x % Trans 0.9
0.8
0.7
15.6
11.7
Cv (J/g-K)
l 7.8
3.9
0.0
160
E_VdW
0
z –160
y
y –320
x 250 300 350 400
Temp (K)
Fig. 7.9. Simulation of the melting point.
From the original nanocrystal, MD are run at different temperatures, each tempera-
ture leading to a trajectory. In fact, positions and velocities of each atom are recorded,
making visualization of the melting phenomenon possible, as well as the computa-
tion of many properties (temperature, pressure, local dynamics, and so on). In order to
observe the melting transition, three properties are reported with respect to tempera-
ture: van der Waals energy, heat capacity, and percentage of the trans-rotameric states
(Fig. 7.9). It has to be mentioned that the heat capacity is computed using the fluctua-
tion formula, (⟨E2 ⟩ − ⟨E⟩2 / kb T2 ), where E is the energy, kb is the Boltzmann constant,
and T is the temperature. The thermodynamic definition (𝜕⟨E⟩/ 𝜕T)V of heat capacity
cannot be used since the thermodynamic limit⁶ is not attained. As shown in Fig. 7.9, it
is observed that a transition occurs at the same temperature for the three properties
reported, which clearly corresponds to the melting temperature of the nanocrystal. All
details on the simulation can be found in Metatla et al., as we only present the main
conclusions of the study [32].
In Fig. 7.10, melting temperatures are reported with respect to the inverse of
the thickness of the crystals. The lines correspond to the linear fit using the Gibbs–
6 The thermodynamic limit is attained when N/V = constant with N → ∞ and V → ∞.

0.95
Functionalized PE
0.90 experience
0.85
Tm/T°m
0.80 Alkanes
Alkanes experience
0.75 simulation
0.70
0.65
0.2 0.3 0.4 0.5 0.6
1/l (nm–1)
Fig. 7.10. Gibbs–Thomson equation representation reporting experimental (dark blue line) and sim-
ulated (blue line) Tm for alkane chains, and experimental Tm for functionalized PE (dotted line).
Thomson equation:
Tm 2σe 1
=1− (7.10)
Tom Δhm l
where Tom and Δhm are the melting temperature and the melting enthalpy per unit vol-
ume of bulk alkane chain respectively, σe is the interfacial tension of the crystal in
the plane normal to z (Fig. 7.9), and l is the crystal thickness in nm. There is excel-
lent agreement in the slope between experimental and simulated data. Such accuracy
reveals the precision of the procedure and the description of the σe /Δhm ratio.
If we compare simulated data with experimental values stemming from function-
alized PE, there is a clear discrepancy in the slope. This difference is in fact of great
interest and fostered this collaboration. Clearly, the dissimilarity in the slope relies
on the value of the interfacial tension, σe ⋅ Δhm can be considered comparable to
alkane and PE chains, while changes in the interfacial tension directly result from al-
terations at the surface. The occurrence of defects brought by chain loops or function-
alized groups modifies σe . The presence of these defects can be definitely simulated,
leading to a change in the slope (Fig. 7.10), approaching that displayed by functional-
ized PE. Such treatment is undoubtedly a molecular viewpoint of the surface problem.
Supported by experiments, this result should lead to interesting conclusions. Further
simulations are presently being carried out, and first data reveal that the presence of
defects on the surface lead to a change in Tm .
The glass transition [34–41]

The glass transition temperature (Tg ) has been known since ancient Egypt, as crafts-
men knew how to process a glassy material by heating it above a certain temperature
in order to shape it to a certain design. They may not have handled glass as glassblow-
ers from Murano Island do nowadays, but they had identified that glass is fragile and
is a very malleable material above it. More than three thousand years later, in 1995,
the Nobel Prize-winning physicist, Philip W. Anderson (already encountered at the
beginning of this chapter), wrote in the magazine Science: “The deepest and most in-
teresting unsolved problem in solid state theory is probably the theory of the nature
of glass and the glass transition.” It is peculiar that this unique phenomenon remains
an unsolved problem. This is due to the fact that the time and length domains it covers
are huge: from nanoseconds (10−9 sec) to years (108 sec), highlighting the problems
of polymer aging. It is thus very difficult for an experiment or a theory to uncover this
domain entirely. Can atomistic simulation possibly reveal such phenomenon? At first
glance, the response is clearly negative. But let’s have a look at what exactly glass tran-
sition is. Following that, the protocol and some results will be exposed, and it will be
left to the reader to decide whether atomistic simulation is capable of dealing with the
glass transition of polymers.
At high temperature, a polymer chain can reach many states. More particularly,
the different rotameric states⁷ associated with a bond along the backbone bonds are
reachable, as the chain is not restricted in its movements at all. As the temperature
is decreased, crossing the energetic barrier between rotameric bonds in order for the
bond to rotate occurs less often. The polymer thus reaches a state which makes it very
difficult for the backbone to move. Imagine the 15-block puzzle displayed in Fig. 7.11, in
which you want to move the G block. You need to move several blocks to make a space
available near G. One motion thus involves several motions. This observation incorpo-
rates the concept of cooperation, in fact. This important concept in the study of glass
transition corresponds to the fact that positions of neighboring entities (molecules or
bonds) are strongly correlated, leading to a modulation of density extending over a
certain molecular scale.
The glass transition phenomenon is thus a longer-range phenomenon than the
length scale associated with several molecules. In some ways, it confirms that atom-
istic simulation is not the best tool for dealing with this complex transition. However,
Roe and Rigby [42] first showed that it is possible to simulate the glass transition of
polymers by using atomistic simulated dilatometry. As in experiments, the dilatomet-
ric technique consists of reporting the specific volume i.e., the inverse density, with
respect to temperature. As the system cools down, the specific volume is reported for
different temperatures. The departure from a linear relationship between specific vol-
ume and temperature yields the value of Tg , which effectively corresponds to the tran-
7 A rotameric state is defined by a well in the potential energy as a bond is rotated.

G I a s
s T r a
n s i t
i O n
Fig. 7.11. A 15-block puzzle representing a polymer chain
in the glassy state.
sition from the rubbery to the vitreous phases. Examples are shown in Fig. 7.12. In fact,
numerous atomic simulation studies can be found in the literature. The main draw-
back of this method is that a great disparity is found in the values of Tg higher than,
equal to or lower than the experimental values. Questions necessarily arise about the
pertinence of and the interest in using all-atomistic simulation to compute Tg . One of
the reasons is that atomistic MD simulations mainly inspect the region of space located
near the initial portion. Moreover, the length scale associated with the glass transi-
tion should exceed the domain available with atomistic simulations; coarse-grained
simulations addressing the underlying theories accountable for the occurrence of
the glass transition [43]. Nevertheless, meaningful information can be extracted from
such studies: the effect of side chain, tacticity, and so on. Atomistic simulation must
be considered a very complementary tool, as shown in the next paragraph.
Prior to any simulation, great care must be taken to select the appropriate force
field. It must be chosen properly in order to specifically address the problem it is re-
quired to solve. The glass transition temperature of polymers can be greatly affected
by the choice of the force field, as shown in Fig. 7.12. Simulated dilatometries of one
polymer, isotactic PMMA, using two force fields, AMBER (black circles) and AMBER-
OPLS (gray diamonds), are displayed in Fig. 7.12. The difference in the force fields stays
in computation of the partial charges in the Coulomb potential energy (equation (7.9)).
In the latter force field, partial charges have been computed in order to reproduce liq-
uid density, while in AMBER, charges have been computed using the ESPR method
based on quantum calculations. AMBER-OPLS was deliberately chosen, since a glass
transition is observed when it is used (black circles in Fig. 7.12).
Once a glass transition temperature simulation has been completed, two ques-
tions must be raised: what is the degree of trust attached to the conclusions stemming
from this analysis, and does this transition correspond to the experimentally observed
glass transition temperature? One way to answer these questions is to get reproducible
values of Tg and compare the stemming analysis to experimental data and theories.
The focus is thus to develop a procedure based on physics and statistical physics con-
cepts to compute Tg . The different steps are summarized in Fig. 7.13 and in the follow-
ing paragraph.
1.04
Specific volume (cm3.g–1 )
1.00
0.96
Fig. 7.12. Simulated dilatometric

0.92
curves for iso-PMMA according to
0 50 100 150 200 250 300 350 400 450 two first generation force fields:
Temperature (°C) AMBER (⧫), and AMBER-OPLS (∙).
Appropriate exploration of the configurational space is a key issue. It corresponds to

Step 1 in Fig. 7.13. The algorithm used for generating polymer chains (100) is very pow-
erful and was built by Theodorou and Suter [44], based on the Self-Avoiding Walk
protocol and the Rotational Isomeric States model [45, 46]. For each polymer chain,
the radius of gyration (Rg ) is then computed (Step 2). A Maxwell–Boltzmann-like dis-
tribution is obtained. Polymer chains which exhibit Rg with the most probable values
are selected. An additional criterion based on the lowest energy is then completed
to finally select ten configurations (Step 3). This number of configurations is consid-
ered a reasonable compromise between accurate representation of the configuration
(through Steps 1 to 3), and CPU capability. It is thus a way of circumventing the cen-
tral limit theorem. A heating-cooling process is then performed to relax the system
(Step 4). At this stage, Tg can be computed when the system has cooled down. How-
ever, it has been shown that this value is not reproducible. In fact, in order to effec-
tively characterize a small portion of the configurational space representative of the
entire domain, the simulated system must approach reality. The conclusion reached
was that the simulated polymers in their glassy state were not in mechanical equilib-
rium, leading to Step 5, which consists of getting 𝜕E/ 𝜕V = 0, where the internal pres-
sure and the external stress are made equal. Entropy and vibrational energy should
be introduced, but there are negligible quantities for this kind of simulation. When
this step has been completed, numerous properties such as mechanical properties
and values of Tg are found to be reproducible. This procedure was applied to get Tg
of organic glasses whose values are in very good agreement with experimental data.
We can thus suspect that the glass transition has been accurately reproduced, and that
local characteristics of this phenomenon can be disclosed. It has to be mentioned that
this procedure was transposed to simulate glass transition of molecular glasses [47]
and liquid crystalline phases [48] with the same reliable results.
As an illustrative example, Fig. 7.14 shows values of Tg for a series of vinyl polymers
computed following the procedure described in the previous paragraph with respect
Generation
of 100
1 configurations
16
14
configurations
12
10 Computation
Number of
8 of the Rg
6 2
4
2
0
20 40 60 80 100 120 140 160
1. Higher probability 2 selection

2. Energetic criteria criteria
3
1.08
VSp/cm3 .g–1
1.04 Heating-Cooling
process
4
1.00
0.96
100 150 200 250 300
Temperature/°C Tg
–7650
–7660 1.08
Energy/kcal mol–1
–7670
–7680
VSp/cm3 .g–1
–7690
Mechanical 1.04
–7700 5 Equilibrium
–7710 1.00
–7720
–7730
0.96
27500 28000 28500 29000 29500 100 150 200 250 300
Volume/Å3 Temperature/°C
Fig. 7.13. Procedure for computing reproducible values of Tg .
to the experimental values. The linear relationship is excellent, which makes the iden-
tification of molecular events that lead to changes in Tg feasible. Thanks to the use of
MD, specific local dynamics can be revealed. Two generic vectors have been selected:
along C (backbone)-H, and originating from Cα (side chain), shown in Fig. 7.15. Anal-
ysis of the movement of these vectors according to temperature yields a correlation
time associated with each motion at a specific temperature. This correlation time can
be inserted into an Arrhenian diagram: the natural logarithm of this correlation time
is displayed with respect to the inverse of the temperature. Surprisingly, a non-linear
560
540
520 CH3 n
n n
500 N
480 X CH3
R n
460 O O N
Simulated Tg/K
440 n
CH3
420
n
400
380
360
340 n
320 O O
300 CH3
280 n
400
480
460
440
200
280
380
260
300
360
240
420
340
220
320
180
Experimental Tg/K
Fig. 7.14. Simulated and experimental Tg of a series of vinyl polymers and

linear fitting highlighting the correlation.
fit is observed. Arrhenian behavior, i.e., a linear relationship where the slope is re-
lated to the activation energy, is expected. The physical sense beneath the non-linear
fit is related to the occurrence of cooperation along the polymer chains, as schemati-
cally shown in Fig. 7.11. An equation which is better-suited to improving the fit of the
traditional Arrhenius equation is the Vogel–Fulcher–Tamman equation:
Eeff
τ = τo exp ( ), (7.11)
T − To
where the three fitting parameters τo , To , and Eeff correspond respectively to the cor-
relation time for infinite temperature, Vogel temperature, and the effective activation
energy. The behavior of the effective activation energy with Tg for the different vinyl
polymers studied is of particular interest. Figure 7.15 shows the behavior of Eeff for the
two bonds. Values of Eeff related to the C–H bond (in blue) are relatively constant. This
means that the carbon backbone, to which C–H movement is related, possesses an in-
trinsic dynamic that does not influence Tg . Conversely, Eeff associated with the motion
of the side chain (dark blue) reveals a linear relationship with Tg . In fact, the dynamics
associated with this bond correspond to three motions: librational motion (not con-
sidered in the analysis), side chain rotation, and overall motion of the chain. The two
latter movements cannot be separated easily. As a consequence, they are studied si-
multaneously, leading to a molecular analysis of the coupling between the side chain
and the backbone. A linear relationship is used to fit the data. The Tg of a hypothetic
chain reduced to only a carbon backbone, and for which Eeff = 0 was found to be 250 K.
This is in fact close to the actual Tg of PE, which is of the order of 280 K. Thus, side
Backbone 20
dynamics
18
Effective Ea (kcal/mol)
16
14
X 12
R
10
Backbone/side
chain coupling 8
250 300 350 400 450 500 550

Tg /K
Fig. 7.15. Local dynamics in simulated vinyl polymers.
chains greatly influence the backbone motions which ultimately yield differences in
the value of Tg through specific coupling.
7.3 Summary
Molecular simulation is becoming a very powerful tool in the lab and is not just for the-
oreticians. A corollary to this situation is that it has great difficulty finding its niche.
It is theory for experimentalists, and experiment for theoreticians. Moreover, extreme
caution should be exercised in interpreting ensuing results, as misleading interpreta-
tion can be very problematic. The examples presented in this chapter show that metic-
ulous protocols must be established. Clearly, simulations must be used as a tool to
complement experiment and theory. Consequently, these studies emphasize the great
strength of molecular simulation in unveiling molecular characteristics, thus acting
as a real guide in the design of new molecules with improved properties. Moreover,
codes and computers are now efficient enough to bring a new perspective to those
properties. Local phenomena can be scrutinized and molecular simulation acts as a
microscope. Can it solve the antagonism raised by the difference between the two vi-
sions of the world, reduction and emergence? We will see in the future!
In fact, increasing computer capacity and efficiency of codes, the molecular origin
of a property can be definitely disclosed at different length and time scales. The mul-
tiscale approach, as highlighted in this chapter, thus becomes more and more attrac-
tive. The very purpose is to make the most of conclusions stemming from one scale by
linking them to data extracted at another scale. A property can thus be comprehended
along the complete spectrum of interactions. This viewpoint has become so important
that Martin Karplus, Michael Levitt, and Arieh Warshel were awarded the 2013 Nobel
Prize in Chemistry “for the development of multiscale models for complex chemical
systems”.
Molecular simulation
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lems. Wiley, New York, 2001.
– Jensen F. Introduction to computational chemistry. 2nd ed. John Wiley & Sons, Chichester, UK,
Hoboken, USA, 2007.
– Leach AR. Molecular modelling: principles and applications. 2nd ed. Prentice Hall, Harlow, Eng-
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– Cramer CJ. Essentials of computational chemistry: theories and models. 2nd ed. John Wiley &
Sons, Chichester, UK, Hoboken, USA, 2004.
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and molecular modeling principles and applications. Berlin: Springer; 2008.
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2008.
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New York.
Multiscale simulation
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Quantum calculation
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New York, Oxford, 1994.
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2009.
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Atomistic simulation
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|
Part II: Development of new materials for energy
applications
S. B. Schougaard and D. Bélanger
8 Electrochemical energy storage systems
8.1 Introduction
The ability to efficiently store and retrieve electrical energy is at the heart of the mo-
bile revolution which has swept through society since the late 1980s. The develop-
ment of green energies such as solar and wind, which could ultimately be used for
transportation in hybrid and electric cars, began during the same period. Making this
“green” transition will require an efficient, low cost energy storage system. Two of
the most promising candidates to meet the high power-high energy density storage
requirements are lithium-ion batteries and advanced electrochemical capacitors. Yet
the current state-of-the art performance requires improvements to meet customer ex-
pectations. To this end, the active materials still need to be perfected.
Materials used in energy storage systems which convert chemical energy into elec-
trical energy must have unique properties for this specific application. A wide variety
of materials such as metal, metal oxides, and even polymers have been used for this
purpose over the past two centuries. One of the first batteries developed which has
reached widespread commercial use is the lead-acid battery. This battery still occu-
pies a major segment of the energy storage market today, due to its use in cars and
other automotives. Other common battery technologies include alkaline and nickel-
cadmium cells. Materials used in current and future energy storage systems must sat-
isfy design criteria such as low cost, stability, low environmental impact, and toxicity,
and must be produced from widely available resources. This is obviously not the case
for all batteries thus far developed. Safety is also a major concern due to the quest for
higher energy and power density, which require more reactive materials.
The aim of this chapter is to present the fundamental concepts associated with
electrochemical energy storage systems in such a way that they will be accessible to a
broad audience working in the area of functional materials. Firstly, the metrics used to
evaluate the performance of batteries will be described. Secondly, the inner workings
of electrochemical energy storage will be explained using thermodynamic, kinetic,
structure, and mass transport properties of battery materials. The current state-of-the
art materials used in these electrochemical energy storage systems will also be pre-
sented.
8.2 Metrics and performance evaluation
The most fundamental characteristic of any energy storage system is how much en-
ergy per unit of mass can be stored (specific energy), and how fast this energy can be
retrieved and/or stored (power density). Alternatively, the storage capacity and power
172 | Part II Development of new materials for energy applications
density may be expressed in terms of volume, when space constraints are more rel-
evant. Electrochemical energy storage systems may be analyzed using several differ-
ent protocols, one of the most common being the constant current. Here, the current
is sourced (controlled) and the potential (voltage) is measured as a function of time.
Importantly, several different units and nomenclatures are used to express the con-
trolled current. Among the more common ones are A/g, A/cm2 and C-rate, where x C
represents full discharge in C/x hour, so that a current density of C/10 represents full
charge in 10 hours. Batteries and electrochemical capacitors differ in their fundamen-
tal charge storage mechanism; as such, it is not surprising that their electrochemical
responses are also different (Fig. 8.1).
10A/g 5A/g 1A/g

1.2 4.2
0.9 3.8
Potential (V)
Potential (V)
0.6 3.4
0.3 3.0 0.2A/g

0.005A/g
0.05A/g
0 2.6
0 40 80 120 160 0 40 80 120 160
Capacity (mA.h/g) Capacity (mA.h/g)
(a) (b)
Fig. 8.1. Potential vs. capacity curves. (a) electrochemical capacitor, and (b) battery. The stored
energy is proportional to the area under the curve when extended to 0 V.
From Fig. 8.1 it is evident that capacity is dependent on the current density used. To
put this into a meaningful metric, the power density can be defined as the product of
voltage and current density. As this product varies over the charge/discharge cycle,
an average is normally cited. This definition makes comparison of different devices
according to their power delivery ability and their total energy density in the Ragone
Plot possible (Fig. 8.2).
Figure 8.2 shows that electrochemical capacitors provide high power while batter-
ies provide high energy density. It is therefore important to understand the required
specifications for a specific application before choosing a battery or an electrochem-
ical capacitor. However, for an electric car, it is not a question of battery or electro-
chemical capacitor, since both serve distinct design parameters; i.e., electrochemical
capacitors are ideal for storing the power generated when the car decelerates rapidly
(e.g., regenerative braking), and for the high power needed when the car accelerates
from a standing position. However, the battery is essential to give the car a significant
range of autonomy due to its high energy density.
107
Capacitors
106
Combustion
Specific power (W/kg)
105 engine
104
103 Electrochemical
capacitors
100 Batteries Fuel
cells
10
1
0.01 0.1 1 10 100 1000 Fig. 8.2. The Ragone Plot comparing
Specific energy (Wh/kg) different energy technologies.
For historical reasons, the energy storage capability of the electrochemical capacitor
is often expressed as capacitance (units: Farad (F)), using the idealized properties of
capacitors i.e., E = Q/C where Q is the stored charge, E is the potential, and C is the ca-
pacitance (see below). This relationship leads to W = 1/2 CE2 , so the stored energy (W)
is proportional to the capacitance.
Caution: Specific energy, specific power, and capacities are highly dependent on the
current density. As a rule of thumb, these values should not be extrapolated. Moreover,
care should be taken to identify the mass or volume on which the analysis is based (the
entire device including housing, the electrode, or the active material).
8.3 Models and theory of electrochemical charge storage
Electrochemical energy storage takes place by separating the connection between

two electrodes into two different charge transport paths, one for the ions (electrolyte)
which blocks the electrons, and one for the electrons (external circuit) which blocks
the ions (Fig. 8.3). The external circuit serves as the point where the electric energy is
injected or retrieved. It is this electrical energy that is converted into chemical energy
in the device.
The major difference between the electrochemical capacitor and the battery is the
processes which take place at the electrodes. In the battery it is the chemical process of
electron transfer, i.e., oxidation/reduction, while in the capacitor the energy is stored
electrostatically as “charges” on the electrode surfaces.
External circuit
e–
Li+ + e–+ TiS2

Negative electrode
Positive electrode
Li+ + e–
Conducts
Ions Electrons
Electrolyte Yes No
LiTiS2
Li
External No Yes
circuit
Li+
Electrolyte
Fig. 8.3. Schematic of an electrochemical cell.
8.3.1 Battery operation – a Faradaic process
The separation of the charge transport allows the separation of the redox reaction (cell
reaction) into two Faradaic reactions (half cell), which occur simultaneously in two dif-
ferent locations. A Faradaic process involves a gain or loss of at least one electron. For
example, the relevant reactions during charging are given below for the first lithium
metal battery developed by Whittingham [1]:
Half cell (positive electrode): LiTiS2 → TiS2 + Li+ + e−
Half cell (negative electrode): Li+ + e− → Li (8.1)
Cell reaction: LiTiS2 → Li + TiS2
The operational principle of charging relies on electrons and lithium ions released
from the oxidation of LiTiS2 to TiS2 in the positive electrode being transported to the
negative electrode by the external circuit (e− ) and electrolyte (Li+ ) where they are used
to form Li(0). Therefore, the overall process does not generate or remove electrons or
ions; they are only transported by the energy source in the external circuit to a location
where they have higher potential energy. Thermodynamics tells us that the work done
by the electrons in the external circuit during discharge cannot exceed the chemical
energy stored in the chemical reaction of the battery. Moreover, the maximum work
possible for an electron in the external circuit is its potential energy, measured as the
voltage between the positive and the negative electrode when no current is flowing (E).
The maximum work that can be done by the chemical reaction (at constant pressure
and temperature) is its Gibbs free energy (Δ r G). This relationship leads to:
Δ r G = −nFE, (8.2)
where F is the Faraday constant 96 485 C/mol, and n is the number of electrons trans-
ferred (1 for the Li/TiS2 cell reaction). Δ r G can be determined from either thermo-
dynamic tables, calorimetry, first principles, or empirical considerations, which are
especially useful when designing new battery materials.
Armed with a method for approximating the potential of a battery (the y-axis of
Fig. 8.1(b)), another for predicting the maximum theoretical value for the x-axis would
be useful. The challenge is determining the charge transferred through the external
circuit by the reaction of one gram of reactant in (1). Thus:
theoretical capacity [in C/g] = nF/M, (8.3)
where M is the molecular mass of the reactant (g/mol), F is the Faraday constant, n is
the number of electrons transferred per formula unit. (Note: 1 C/g = 1/3.6 mAh/g).
8.3.2 Electrochemical capacitor operation – a non-Faradaic process
The mechanism behind the electrochemical capacitor differs fundamentally from the
battery, as no redox reaction occurs (e.g. no electron transfer). The classical electro-
chemical double layer capacitor comprises two porous carbon electrodes in the pres-
ence of an appropriate electrolyte, separated by a porous and inert separator. At the
electrode/electrolyte interface, opposite charges accumulate on the electrode surface
(within the porous structure) and in the electrolyte. At equilibrium, the electronic
charges in the electrode are counterbalanced by ionic charges from the electrolyte.
This leads to the formation of an electrochemical double layer, whose thickness is in
the nanometer range. The energy of an electrochemical double layer capacitor is de-
termined by the potential being developed and the capacitance of the electrodes, as
discussed previously in the metrics section.
The first description of a model for the double layer was proposed by Helmholtz,
and is illustrated in Fig. 8.4(a) [2]. In this simple model, which is similar to that of
a two-plate capacitor, two layers of opposite charge are present at the electrode/
electrolyte interface and are separated by a distance of molecular order. The Gouy–
Chapman model considers the fact that in contrast to the electrode, for which the
excess of charge is confined to the surface, the excess of charge required in the elec-
trolyte for charge compensation is spread over a thickness which depends on the con-
centration of the electrolyte and is referred to as a diffuse layer (Fig. 8.4(b)). A third
model, known as the Gouy–Chapman–Stern model, combines the first two models
and includes a first compact layer next to the electrode surface, followed by a diffusion
layer. In this model, the inner Helmholtz plane (IHP) refers to the plane that crosses
the species of the first layer, and the outer Helmholtz plane (OHP) passes through
the centres of solvated ions which are close to the electrode surface (Fig. 8.4(c)). The
effect of specific adsorption and the predominance of water molecules (in aqueous
electrolytes) for which the dipoles are oriented according to the electrode charge
was later proposed in a model by Grahame, Bockris, Devananthan, and Muller as
illustrated in Fig. 8.4(d) [3].
Diffusion Stern Diffusion Stern

layer layer layer layer
D
ψ0 ψ0 ψ0
Diffusion layer
Positively charged surface

Solvated
cation
Anion
ψ ψ
Solvent
Primary Secondary
Inner
solvent solvent
plane Outer plane
layer layer
(a) (b) (c) (d)
Fig. 8.4. Schematic representation of the: (a) Helmholtz, (b) Gouy–Chapman, (c) Gouy–Chapman–
Stern, and (d) Bockris et al. models for the electrochemical double layer [2, 3].
The capacitance (C) of such an interface can be roughly estimated by analogy with a
double plate capacitor using the equation:
C = εr ε0 A/d, (8.4)
where εr is the dielectric constant of the electrolyte, ε0 is the dielectric constant of

vacuum, A is the area of the electrode, and d is the thickness of the double layer. From
this equation, a typical double layer capacitance of 10–15 μF cm−2 can be estimated
for metals in pure water by taking a value of 5 for the dielectric constant of a first layer
of water molecules and the radius of a water molecule [3].
Since the capacitance of an electrode material is related to its surface area, an
obvious approach to improvement has been to develop porous materials with a
large surface area. The pores of these materials are classified into four categories:
ultramicropores (< 1 nm), micropores (< 2 nm), mesopores (2–50 nm); and macro-
pores (> 50 nm). However, it is now clear that parts of the surface area are not electro-
chemically accessible when the pore size is smaller than the diameter of the electrolyte
ions. Nonetheless, recent studies have demonstrated a significant increase of capaci-
tance for electrodes presenting micropores (< 2 nm), which are smaller than the size
of hydrated ions [4].
Another important parameter of an electrochemical capacitor is the cell voltage.
Figure 8.5 shows a schematic representation of an ideal electrochemical double layer
capacitor, in which both electrode/electrolyte interfaces behave similarly. Initially, the
two electrodes have the same potential and therefore the potential of the cell is null.
When the electrochemical capacitor is charged, electrons are forced to flow through
an external circuit from one electrode to the other. The electrode which accumulates
electrons is termed the negative electrode, and cations from the electrolyte move to the
electrode surface under the influence of the electric field. Simultaneously, the second
electrode, from which electrons have been removed, becomes the positive electrode,
which is accompanied by displacement of anions of the electrolyte to the electrode
surface. Note that the terms negative and positive are used instead of anode and cath-
ode. This is because in contrast to the latter, which refers to the electrode where elec-
tron transfer occurs and involves a change in the oxidation state of the electrode or
solution species (see above), no electron transfer occurs between the electrodes and
the electrolyte in a classical electrochemical double layer. In these instances, the two
electrodes are said to be blocking electrodes.
Porous carbon Current collector
+ – – + + – + –
+ – + –
+–
Electric
+ – – + charge + – + –
+ – + –
+ – – + + – + –
+– + – + –
Electric
Liquid double layer Liquid
(electrolyte) capacitor (electrolyte)
ψ0+ψ1
ψ0 ψ0
Discharged state
ψ0–ψ1
Charged state
Fig. 8.5. Schematic representation of the charges of each component (electrodes and electrolyte)
of an electrochemical capacitor at the electrode/electrolyte interface (top) and the potential profile
(bottom) for both its discharged and charged states.
Upon charging by application of a constant current, the double layer will become
charged to a level that will depend on the applied potential (Fig. 8.6). In the case of an
ideal electrochemical capacitor, the potential of each electrode varies linearly but in
opposite directions, with the charge passed during the charging process of the device.
The potential of each electrode can vary up to a limit, determined by the potential at
which oxidation or reduction of electrolytes commences.
Voltage
0
Potential/Reference
Fig. 8.6. Variation of the potential of the positive (- - -) and

negative (– –) electrodes as a function during constant current
– charge/discharge together with the evolution of the voltage
Charge (—) of the electrochemical capacitor.
8.4 Electrolytes
From the operational principles of the battery and electrochemical capacitor, it is clear
that the energy required for transportation of charge through the electrolyte and the
potential limits outside which the electrolyte is oxidized or reduce, are key physico-
chemical design parameters.
Transport of species in solution (mass transport) is related to three phenomena:
diffusion, migration, and convection. Convection, which is forced movement of the liq-
uid including all its components, is only of importance in flow-batteries [5]. Diffusion,
which is important in batteries, is the process by which high concentration solutions
flow towards low concentration at a speed proportional to the concentration differ-
ence until equilibrium has been reached. Migration is the mechanism by which an
electric field moves charged species through a solution, and is crucial in both batter-
ies and electrochemical capacitors. Importantly, only migration can carry the current
required to close the circuit in Fig. 8.3. The drag force caused by moving ions through
the solution has two effects. First, there is a significant resistance to charge transport.
This leads to Ohm’s law behavior, where the current (I) is proportional to the poten-
tial difference between the electrodes (E), and conductivity (κ) is proportional to the
concentration of free ions (C+ , C− ) and their mobility (u+ , u− ), i.e.,
Iionic = E ∗ κ and κ ∝ u+ C+ + u− C− (8.5)
The energy lost to resistive heating in the electrolyte should be kept to a minimum,
which suggests that C and u should be maximized. Electrolytes should therefore be
highly concentrated, low viscosity solutions of free ions. This is a challenge, since as
the concentration of electrolyte increases, so does the tendency for ion-pairing. The
result is a viscous solution and a significant fraction of ions that are no longer free to
engage in migration. The second effect of the drag force is that it is different for ions
of different sizes. This leads to strong concentration differences during high current
operation, which the diffusion process is slow to counteract. In particular, the lithium
ion in the Li-battery electrolyte typically moves at only about 65 % of the speed of the
counter-ion. This leads to major problems during high power operation, since only
lithium ions can take part in the charge transfer at the electrodes.
The electrochemical potential range of stability of the electrolyte limits the max-
imum quantity of energy that can be stored per electron. For example, in aqueous
electrolytes used for electrochemical capacitors, this value is set at 1.23 V by the ther-
modynamic standard potentials of the H2 O/O2 and H2 O/H2 redox systems. However,
in practice a much lower value of about 1 V can be achieved. A typical nonaqueous-
based device using acetonitrile or propylene carbonate as solvent can, however, reach
close to 3 V. Even higher cell voltage could be obtained using materials with a wider
potential range of stability, such as room temperature ionic liquids, which are salts
that are liquid at room temperature. A list of common electrolyte systems is given in
Table 8.1.
Table 8.1. Various types of electrolytes and relevant properties.
Electrolyte type Example Practical Potential Comment

conductivity window
(mS/cm)
Aqueous solutions KCl (aq) ∼ 100 ∼ 1.23 V Cheap, nontoxic,
nonflammable,
limited potential
window.
Nonaqueous solutions LiPF6 in or- ∼ 10 ∼ 4.3 V Flammable, large
ganic carbon- potential window,
ates compatible with
low potential an-
odes.
Ionic liquids 1-ethyl- ∼ 0.1–30 > 5V Nonflammable,
3-methyl- large potential
imidazolium window.
dicyanamide
(EMI-DCA)
Polymer Polyethylene ∼ 0.1 > 4V One of the two
oxide com- ions may be linked
bined with to the polymer to
LiPF6 . improve selective
ion transport.
Solid Lix POy Nz < 0.1 at room Highly de- Only high temper-
temperature. pendent on ature or thin film
system cho- application due to
sen. poor conductivity.
8.5 Electrode materials
8.5.1 Electrochemical capacitors
Carbon is the material of choice for the fabrication of electrode materials of electro-
chemical capacitor. This is primarily because its low cost, its good electrochemical
stability, high conductivity, and high specific surface area. A large variety of other
types of materials such as conducting polymers and metal nitrides have been used
for this application, but arguably the most promising materials are metal oxides such
as ruthenium dioxide and manganese oxide.
Carbon can be produced in various morphologies and shapes. Initial studies
mainly dealt with high specific surface area powders and high area fibers. Activated
carbons are the most widely investigated, but other forms such as templated car-
bons, aerogels, nanotubes, nano-onions, and graphene have also been examined for
electrochemical capacitor applications [6].
Carbon materials commonly used in electrochemical capacitors are characterized by
a high specific surface area which ranges from 1 000 to 2 500 m2 /g. Depending on the
production method, the porous texture of the carbon materials will display a variable
pore size distribution. As mentioned previously, it is now well-established that not
all of the porous surface area of the carbon material is active in the charge storage
process. Indeed, by taking a low value of 10 μF cm−2 for the double layer capacitance,
the expected specific capacitance of 250 F/g cannot be reached for the highest surface
area materials. Instead, the typical specific capacitance of standard activated carbons
in organic electrolyte is about 100 F/g [6]. It is possible to attain a higher value (150 F/g)
in aqueous electrolytes (e.g. aqueous KOH) due to the pseudocapacitive contribution
of oxygenated surface groups such as quinone. These surface functional groups will
also contribute to the wettability of carbon, thereby improving the capacitance of the
electrode.
Several single metal and mixed metal oxides have been investigated for their ap-
plication as active electrode materials for electrochemical capacitors. One is ruthe-
nium dioxide (RuO2 ), which is characterized by pseudocapacitive behavior that, in
contrast to capacitive materials such as carbon, is Faradaic in origin. Thus, pseudo-
capacitive electrode materials undergo reversible redox reaction involving change of
oxidation states of the metallic species [7]. These redox reactions are distributed over
a large potential range, and are consequently characterized by a rectangular cyclic
voltammogram shape and a linear charge/discharge profile such as the one shown by
carbon electrodes (Fig. 8.7). On the other hand, most other metal oxides are charac-
terized by Faradaic redox processes (in fact they are battery material) which usually
encompass a relatively small potential window. Therefore, a symmetric electrochemi-
cal capacitor based on such material for both the positive and negative electrodes will
be characterized by a relatively small cell voltage, and would be almost useless unless
the Faradaic metal oxide is used with a complementary electrode material in a hybrid
electrochemical capacitor, as discussed below.
Another pseudocapacitive material that has attracted attention in the past decade
is MnO2 . It is obtained in various crystalline forms, including many tunnel and layer
structures which allow cation exchange. Amorphous or poorly crystallized MnO2 was
also widely investigated as an electrochemical capacitor material. These poorly crys-
tallized compounds consist of a random arrangement of MnO6 octahedra, which leads
to an intergrowth of different structures, alternating tunnels of different sizes along-
side water molecules and alkaline cations (e.g. Na+ , K+ ). The charge storage processes
for the MnO2 electrode can occur by two mechanisms depending on the nature of
the oxide, and involves cations (C+ = H+ , Li+ ) from the electrolyte in both cases, the
Mn3+ / Mn4+ redox interconversion (equation (8.6)) and the following electrochemical
reactions:
MnOOC → MnO2 + C+ + e− (8.6)

−
+
(MnO2 )surface + C + e → (MnO−2 C+ )surface (8.7)
Spectroscopy investigations, typically using thin-film MnO2 electrodes, have con-

firmed that the Mn3+ / Mn4+ redox couple is primarily responsible for the observed
pseudocapacitance in mild aqueous electrolytes, as demonstrated for poorly crystal-
lized manganese dioxides using in-situ Mn K-Edge x-ray absorption and x-ray photo-
electron spectroscopy [8].
8.5.2 Hybrid electrochemical capacitors
A conventional electrochemical capacitor is usually comprised of two identical capac-

itive electrodes in a symmetrical configuration. On the other hand, in a hybrid electro-
chemical capacitor, one of the capacitive electrodes is replaced by a Faradaic elec-
trode. Several types of hybrid electrochemical capacitors have been developed; the
most common entails the positive electrode of a symmetric carbon/carbon electro-
chemical capacitor being replaced with an electrode characterized by a much higher
charge-storage capability. These include pseudocapacitive and Faradaic electrode ma-
terials, such as conducting polymers and metal oxides such as MnO2 , NiOOH and
PbO2 [8]. This type of electrochemical device, also called asymmetric capacitor, takes
advantage of the best performance characteristics of electrochemical capacitors and
batteries. This can be achieved by the fast charge storage process of the capacitive
negative electrode and by the increase of the specific capacity of the cell due to the
Faradaic charge storage mechanism of the positive electrode. In addition, by selecting
two electrodes characterized by different operating ranges it is possible to extend the
voltage of an aqueous hybrid electrochemical capacitor beyond the thermodynamic
limit of 1.23 V, as illustrated in Figs. 8.7(b) and (c).
8
I (mA cm–2)
Negative electrode 4 Positive electrode

(porous carbon) (porous carbon)
–1.0 –0.5 0 0.5 1.0 1.5 2.0

E (V) vs NHE
–4
(a) –8
8
I (mA cm–2)
Negative electrode 4 Positive electrode

(porous carbon) (MnO2)
–1.0 –0.5 0 0.5 1.0 1.5 2.0
E (V) vs NHE –4
(b) –8
Positive electrode
8 (PbO2)
I (mA cm–2)
4
Negative electrode
(porous carbon)
–1.0 –0.5 0 0.5 1.0 1.5 2.0

E (V) vs NHE
–4
(c) –8
Fig. 8.7. Schematic representation of cyclic voltammograms for three different configurations of
aqueous-based electrochemical capacitors (ECs), in which areas shaded in black and white repre-
sent the potential window of the positive and negative electrode, respectively for: (a) symmetric car-
bon//carbon device in 1 M H2 SO4 , (b) asymmetric activated carbon//MnO2 device in 0.5 M K2 SO4 ,
and (c) asymmetric activated carbon//PbO2 device in 1 M H2 SO4 . NHE, normal hydrogen electrode,
I, measured current, and E, electrode potential.
The operating range of an electrode material in a given electrolyte can be assessed

by cyclic voltammetry (Fig. 8.7). Figure 8.7(c) shows that the electrochemical potential
window of an activated carbon electrode ranges from −0.4 to 0.7 V in H2 SO4 (aque-
ous). Therefore, it can be used as a negative electrode of a hybrid device comprising
of a PbO2 positive electrode, with a range of electroactivity between 1.2 and 1.8 V, over
which the interconversion of PbO2 to PbSO4 is:
−
PbO2 + 4H+ + SO2−
4 + 2e → PbSO4 + 2H2 O (8.8)
Thus, Fig. 8.7(c) indicates that a carbon/PbO2 hybrid electrochemical capacitor can
deliver a cell voltage of about 2.3 V, in contrast to a carbon/carbon device, which will be
limited to 1.1 V at the most (Fig. 8.7(a)). In a symmetrical device, each carbon electrode
operates in a limited electrochemical window of about 0.55 V, which is only 50 % of
the full electrochemical potential window of carbon (Fig. 8.7(a), white or black areas).
This means that the resulting capacitance (F/g) of the symmetrical device is only 25 %
that of a single carbon electrode.
1/CEC = 1/C+ + 1/C− (8.9)
The use of a positive electrode with a larger capacitance (capacity) and a com-
plementary electrochemical window will result in full utilization of the carbon ma-
terial and will increase the energy density due to the capacitive and pseudocapac-
itive/Faradaic behavior of each electrode. Similarly, a carbon/MnO2 hybrid electro-
chemical capacitor can deliver a slightly larger cell voltage than a carbon/carbon de-
vice, since the electrochemical potential window of an MnO2 electrode extends to
slightly more positive value than a carbon electrode (Fig. 8.7(b)). The former is ar-
guably the most thoroughly investigated hybrid electrochemical capacitor due to the
fact that MnO2 is characterized by low cost, low toxicity, natural abundance, and en-
vironmentally friendly use in mild aqueous electrolytes.
8.5.3 Lithium battery¹ electrode materials
Charge storage requires that the charge/discharge cycle can be repeated thousands of
times. In batteries, this is a severe limitation for the type of chemical reactions which
can be employed since high yield is required (for example, a 99.99 % yield per cycle for
1 000 cycles leads to a 10 % total capacity loss). In fact, only three types of reactions
are currently being used in lithium batteries: insertion, alloying, and conversion.
1 Batteries where an intercalation electrode is used, both positive and negative electrodes, are known
as lithium-ion batteries.
8.5.4 Negative (anode) electrode materials
The simplest negative electrode is arguably metallic lithium. However, difficulties in

plating lithium uniformly lead to dendrite formation in liquid electrolytes. In turn,
this can lead to short-circuiting the electrodes, entailing thermal runaway and even
explosions. Graphitic carbon where Li(0) atoms are nominally intercalated between
graphene sheets is used to circumvent this problem (Fig. 8.8).
Electrolyte
Fig. 8.8. Lithium (large circles) intercalation into graphite.

Current Graphite The reaction leads to a slight increase of the unit cell without
collector destroying the layered structure.
The limited capacity of the graphite lithium insertion reaction (339 mAh/g for LiC6 )
has led to the search for new materials for its replacement. A promising candidate is
silicon, which forms an alloy that can store 4.4 Li per Si atom (theoretical capacity
4 200 mAh/g). The accompanying 400 % volume change is however a major design
challenge, since it causes not only stress cracking of the silicon particle, but also in
the entire composite electrode. Another important property of all low potential nega-
tive electrodes is their lack of thermodynamic stability relative to the reduction of the
electrolyte. Fortunately, in organic carbonate electrolytes this reaction leads to the for-
mation of a thin layer at the solid electrolyte interface (SEI), which allows Li-ions to
pass and limits further reactions between electrode and electrolyte; see Fig. 8.9.
Electrolyte
Solvent
reduction
Li2CO3, alkoxides
Li2O, RCO2Li
Li+
Li+
Fig. 8.9. The solid electrolyte interface (SEI) layer
Current Graphite SEI Electrolyte formation (top) and ionic transport (bottom) at the
collector anode.
8.5.5 The positive (cathode) electrode
Most practical positive electrode materials are based on redox cycling of 4th row transi-
tion metals. These are combined with highly electronegative elements like oxygen and
fluorine to form solid-state structures, where elevated oxidation states of the metal are
stable. Unique to the structures selected for battery electrodes is that they are elec-
tron conductors and allow insertion and extraction of lithium ions to compensate the
change in metal ion oxidation state associated with the redox process.
c
b
b a
a b
c a
(a) (b) (c)
Fig. 8.10. Materials with (a) 3D, (b) 2D, and (c) one 1D lithium transport path, exemplified by a
spinel, layered α-NaFeO2 , and an olivine structure, respectively.
These intercalation compounds can be classified according to the dimensionality of

the lithium ions transport path, i.e. 3D, 2D, and 1D (Fig. 8.10). Arguably, the most well
known 3D material is the spinel LiMnTMO4 (TM: transition metal ion), which offers
“5V” vs. Li+ /Li. However, problems with Mn dissolution and electrolyte stability have
strongly limited its practical application. The 2D materials with α-NaFeO2 structure
have not suffered a similar fate. In fact, LiCoO2 , which was used in the first Li-ion bat-
tery launched by Sony in 1993, is still used in most cellphones today. More recently
Li(Ni0.8 Co0.15 Al0.05 )O2 , which has the same layered structure, has been targeted for
electric car batteries due to its vastly improved safety characteristics and lower cost.
Surprisingly, even a material with a 1D lithium transportation path, olivine LiFePO4 ,
has been commercialized. This material, once carbon coated, offers elevated storage
capacity, high power, and remarkable safety characteristics. However, its lithium in-
sertion/extraction mechanism is still a subject of intense debate. Yet it is clear that the
phase boundary between the lithium-poor heterosite FePO4 phase and the lithium-
rich olivine LiFePO4 phase formed during cycling plays a major role in reaction kinet-
ics. While insertion materials currently dominate the market, some transformation
materials have also been proposed. One notable example is nanosized FeF3 , which
is believed to convert reversibly into LiF and Fe, entailing a remarkable theoretical
capacity of 712 mAh/g.
8.5.6 Electrode production
The common positive electrode materials are hard ceramics with limited electronic
and ionic conductivity. They are therefore produced as small particles which are
mixed with conducting carbon particles and polymer binders and cast as thin films
(10–100 μm) onto metallic current collectors. This open composite structure allows
the electrolyte to penetrate the electrode. As such, it provides improved ionic and
electronic conduction compared to the active material itself. Unsurprisingly, the de-
tailed structure and composition of the electrode has a profound effect on the power
performance of the battery [9], and must consequently be optimized for the specific
application.
8.6 Summary
Batteries and electrochemical capacitors are currently the technologies which allow
efficient electrical energy recovery. There are further great hopes both in industry
and in society as a whole that batteries may become the energy vector which makes
the use of solar, wind, and hydro energy in cars and trucks widely possible. Current
technology, however, does not fully reach the expectations of the average consumer.
Specifically, autonomy, i.e., driving distance per charge, appears to be a concern. The
challenge over the coming years will therefore be to improve the energy density of the
batteries or the charging times, to make them comparable to refuelling with gasoline
or diesel. Chemistries which have been identified as capable of yielding increased
energy density include lithium air and Li-sulphur, which pose unique challenges in
their own right. The alternative is to design batteries which allow for unprecedented
high charging rate, such as 70 % of a complete charge within five minutes. This rapid
charge will then be used for emergency charging in the few instances where the
average driver needs to travel beyond the range of a single charge within one day.
Obtaining such extreme redox kinetics will require that the charge compensating ions
involved in the redox process travel over very short distances inside the solid material.
As such, the distinction between the hybrid electrochemical capacitor and battery be-
comes less clear, since both rely on redox process in a thin layer of the solid. It will
therefore be fascinating to see if joint research in these fields will be able to combine
the high power of the electrochemical capacitor with the high energy density of the
battery in a single device.
Further reading
Readers interested in methods used for the production of various carbon materials will find valuable
information in the monographs by Kinoshita [10] and Conway [11]. Similarly, those interested in infor-
mation about the inner workings of batteries may consult references [12] and [13].
References
[1] Whittingham, M.S. Electrical Energy Storage and Intercalation Chemistry (1976) Science, 192,
1126–1127.
[2] Bard, A.J., Faulkner, L.R. Electrochemical methods Fundamentals and applications. 2nd edition.
John Wiley & Sons, New York, 2001.
[3] Bockris, J.O’M., Khan, S.U.M. Surface electrochemistry A molecular level approach, Plenum
Press, New York, 1993.
[4] Simon, P., Gogotsi, Y. Materials for electrochemical capacitors (2008) Nature Materials, 7,
845–854.
[5] Shin, S.-H., Yun, S.-H., Moon, S.-H. A review of current developments in non-aqueous re-
dox flow batteries: characterization of their membranes for design perspective. (2013)
RSC Advances. 3, 9095–9116.
[6] Frackowiak, E. Carbon materials for supercapacitor application (2007) Physical Chemistry
Chemical Physics, 9, 1774–1785.
[7] Conway, B.E. Transition from ’supercapacitor’ to ’battery’ behavior in electrochemical energy
storage (1991) Journal of the Electrochemical Society, 138, 1539–1548.
[8] Long, J.W., Bélanger, D., Brousse, T., Sugimoto, W., Sassin, M.B., Crosnier, O. Asymmetric
electrochemical capacitors-Stretching the limits of aqueous electrolytes (2011) MRS Bulletin,
36, 513–522.
[9] Yu, D.Y.W, Donoue, K., Inoue, T., Fujimoto. M., Fujitani, S. Effect of electrode parameters on
LiFePO4 cathodes. Journal of the Electrochemical Society (2006), 153, A835–A9.
[10] Kinoshita, K. Carbon: Electrochemical and physiochemical properties. John Wiley & Sons,
New York, 1988.
[11] Conway, B.E. Electrochemical Supercapacitors: Scientific Fundamentals and Technological
Applications, Kluwer Academic/Plenum Publishers, New York, 1999.
[12] Newman, J., Thomas-Alyea, K.E., Electrochemical Systems. 3rd edition. John Wiley & Sons,
New York, 2004.
[13] Reddy, T.B., Linden’s Handbook of Batteries. McGraw-Hill Companies. Inc., New York. 2011.
D. Rochefort
9 Functional ionic liquids electrolytes in
lithium-ion batteries
9.1 Introduction
When thinking about functional materials and their applications, advanced catalysts,
light harvesting materials, photovoltaic systems, biosensors and other systems usu-
ally come to mind, rather than electrolytes or ionic liquids. The reason is that we are
not in the habit of thinking about electrolytes as materials, and even less as materials
which can be functionalized. The origin of the interpretation of electrolytes as specta-
tor constituents of an electrochemical system can be traced back to our first encoun-
ters with electrochemical cells where the electrolyte, an aqueous solution of an inert
salt like KCl for instance, serves the purpose of balancing charges during the more im-
portant processes taking place at the electrode. While this might be true for the study
of redox behavior and the kinetics of dissolved species and other basic electrochem-
ical systems, the electrolyte plays a crucial role in the electrochemistry of advanced
systems such as energy storage devices. Charge is stored from ions forming the elec-
trical double-layer in electrochemical capacitors and carbonates are involved in the
formation of the solid electrolyte interface stabilising the anode of lithium-ion batter-
ies. In the latter, the design of the electrolyte will affect the transport of lithium ions
and the limits of the voltage of operation, thereby impacting the power and energy
density values of the system. These are only a few examples showing that develop-
ment of improved electrolytes must take place parallel with that of electrode material.
For reasons that will be explained, ionic liquids have the potential to play an important
role in the development of electrolytes which will increase the overall performance of
energy storage devices.
The aim of this contribution is to introduce the reader to the use of ionic liquids
as electrolytes in lithium-ion batteries. It will become clear that ionic liquids are still
far from being successfully widely applied in commercial batteries. This chapter will
serve the purpose of stimulating interest by demonstrating the progress and potential
developments which could stem from research into ionic liquid electrolytes, rather
than simply providing a list of articles on the subject. The more general topic of ionic
liquid-based electrolytes has already been the subject of several reviews and books
[1–6]. Contributions with a focus on electrolytes for energy storage devices and bat-
teries in particular [7–9] can be consulted as additional sources of information to this
chapter, which is dedicated to the discussion of functional ionic liquids (ILs).
The first section will cover general knowledge of ionic liquids which is required in
order for the reader unacquainted to ILs to understand the origin of the properties that
are responsible for their interest as electrolytes. Next, the use of typical ionic liquids
as battery electrolytes will be examined to show how their intrinsic properties, mostly
of high stability, can be an advantage in the development of safer and more efficient
lithium-ion batteries. Finally, the last section will deal with ionic liquids as organic
molecules which can be modified to bear a functional group. It will be demonstrated
that the modification, by known and accessible synthetic procedures, can provide ad-
ditional benefits to the use of ionic liquids as electrolytes. This represents the true
potential of the use of IL, which is to allow the development of customized solvents-
electrolytes which can perform tasks that no other conventional solvents can achieve.
Examples of ionic liquids designed to act as redox shuttles, to promote the forma-
tion of the solid electrolyte interphase, and to increase lithium ion transport will be
discussed. Before going into detail about advanced functional ionic liquid materials,
a quick glance at what exactly ionic liquids are is necessary.
9.1.1 Historical overview
The concept of ionic liquids is not a new one, or one that has spontaneously emerged
from a specific discovery. Their development stems from studies on molten salts
with a high melting point and, appropriate to this text, their electrochemical reac-
tions [10]. The most famous early example of the study of ionic liquid is attributed
to Paul Walden, who reported about salts such as ethylammonium nitrate which
“allow the reproduction at ordinary temperatures of the phenomena observed with
fused inorganic salts at higher temperature, and permit an approach to the condi-
tions prevailing in ordinary aqueous and non-aqueous solutions” in 1914 [11]. The
field of ionic liquids that we know now, a hundred years later, has been defined by
several key periods. The 1960s saw the beginning of the “chloroaluminate era”, dur-
ing which alkali-aluminum chloride systems were studied for the development of low
temperature molten salts. An important contribution to this era came from a program
in the U.S. Air Force aimed at developing electrolytes for thermal batteries [12]. Low
temperature electrolytes were obtained with chloroaluminate anions and organic
cations such as alkylpyridinium and dialkylimidazolium, which are now widely used
in ionic liquids. Such chloroaluminate ionic liquids are, however, reactive to water,
and while this does not represent a huge problem in the field of batteries studied
and produced in controlled environments, their reactivity hindered their use in many
other applications. The next major period occurred in the 1990s, when air and water
stable alkylimidazolium ionic liquids were demonstrated, using anions such as BF−4 ,
PF−6 , Br− , CN− , and later triflates, mesylates and bis(trifluoromethane)sulfonimide
(TFSI) [13–15]. The discovery of water stable ionic liquids resulted in a tremendous
increase in interest as depicted by the publication trend shown in Fig. 9.1. Ionic liquids
are now the focus of numerous research groups and a very broad range of applications
in the fields of electrochemistry [1, 2], catalysis [16–18], and analytical sciences [19,
20], to name but a few. Ionic liquids have also reached beyond the academic world and
found applications in industry [21]. The BASIL™ process, involving the ionic liquid
1-methylimidazolium chloride which is reused for the synthesis of alkoxyphenylphos-
phines, is the first and certainly the most famous example of a commercial process
using ionic liquids. While there are currently no ionic liquids commercialized as elec-
trolytes in batteries or supercapacitors, there is a huge research effort worldwide to
reach this goal. This is exemplified in Fig. 9.1, which shows that if the total amount
of publications on ionic liquids continues increasing over the years, the fraction of
those related to lithium-ion batteries will become larger, highlighting the relevance
of this chapter.
% of publications related to Li-ion batteries

2.0
6000
5000
Number of publications
1.5
4000
1.0
3000
2000
0.5
1000
0 0.0
1995 2000 2005 2010
Year of publication
Fig. 9.1. Analysis of the publication trends on the topic of ionic liquids. Only papers written in
English were selected for the compilation. The squares show the percentage of total publications
(gray bars) that were related to lithium-ion batteries.
9.1.2 What are ionic liquids?
Ionic liquids are broadly defined as salts, usually composed of a cation of organic
structure and an inorganic anion. When certain conditions relating to the chemical
structure are fulfilled (discussed below), such a combination of cation and anion can
melt at low temperatures, well below ambient in some cases. Provided with enough
thermal energy, any salt will reach a liquid phase composed exclusively of ions. NaCl
for instance melts at 800°C, and the resulting liquid phase has a viscosity of 1.03 cP
and a conductivity of 3.6 S cm−1 [22]. In order to make a clear distinction between these
high temperature molten salts and those able to form a liquid phase around room tem-
perature, a restrictive but generally accepted definition of ionic liquids is “salts with
a melting point below 100°C”. It should be noted that the set point of 100°C, used as
a comparison to limit the liquid phase of the ubiquitous liquid, water, is purely arbi-
trary and is not based on any particular property of ILs. However, this definition is very
helpful in setting a boundary between the molten salts which can be used in systems
operating at moderate temperatures and those requiring high temperatures. This is
especially true for electrolytes, such as those developed for Li-ion batteries and other
electrochemical energy storage devices which are meant to work at temperatures rang-
ing from −40 to +80°C. When used as electrolytes in their pure form, ionic liquids must
be liquid in this temperature range, so the general definition given above will not be
an issue in this chapter.
At the molecular level, what distinguishes typical ionic liquids (such as those
found in Fig. 9.2) from high temperature molten salts, NaCl for example, is a com-
bination of the low level of symmetry of the cation and charge delocalization on the
ions. This combination translates into systems for which ion packing in a solid state is
very difficult and results in a low lattice enthalpy [23]. In addition to the low symme-
try, longer flexible chains on the structure bring conformation flexibility, which fur-
ther reduces the melting point and renders crystallization more difficult. Ionic liquids
generally present a supercooling state in which crystallization does not occur even if
below the freezing point [24, 25]. The families of ionic liquids presented in Fig. 9.2 are
certainly the most studied, but this list is far from exhaustive. Considering the many
different possible substituents on the structures and different combinations of cations
and anions, billions of ionic liquid formulations could possibly exist.
9.1.3 Key properties as electrolytes
Several key properties of ionic liquids result from the nature of their components and
the strong ionic interactions existing between them. These interactions hold the con-
stituents strongly together, making the liquid very difficult to vaporize. Having an elec-
trolyte with a high boiling point and a very small (even immeasurable in some cases)
vapour pressure adds to the stability and safety of batteries. This is also a desirable fea-
ture which allows the operation of cells at higher temperatures than with conventional
organic solvents. However, due to these strong intermolecular interactions, ionic liq-
uids are often more viscous than solvent-solute systems, resulting in a lower conduc-
tivity. Since they are entirely composed of ions, the concentration of charge carriers is
very high, and ionic liquids should therefore be able to transport high currents. Their
conductivity is, however, limited by their viscosity and non-ideal ionicity, meaning
that the ions are screened by surrounding counter-ions and do not behave as freely
moving charges. Overall, their conductivity can be high enough for electrochemical
applications but remains in the same range as organic solvent-solute systems. The
excellent electrochemical stability is also a property which makes for a strong case in
the application of ionic liquids in batteries. Ionic liquids that begin oxidizing at poten-
tials above those of carbonates or acetonitrile can be useful for the application of high
voltage cathode materials. Imidazoliums, by far the most studied family of cations,
are reduced, however, at the anode at potentials above those of lithium deposition
R2 R1 R1
R1 R2
R1 R3 R4 N +
R2 R4 P +
R2 N+
N N
R3 R3
Alkylimidazolium Tetraalkylammonium Tetraalkylphosphonium Dialkylpyrrolidinium
R1 R1 R1 R2 R1
R2 R2
N+
N+ N+
S+
O R3 R2
(R4)2N N(R3)2
Dialkylpiperidinium Dialkylmorpholinium Guanidinium Trialkylsulfonium
CI–, Br–, I– BF4– PF6– CH3SO4– CF3SO3–

Halides Tetrafluoroborate Hexafluorophosphate Methyl sulfate Trifluoromethane-
sulfonate
O O O O
N– N– N–
C C S S S S
N N F3 C CF3 F F
O O O O
Dicyanamide (DCN) Bis(trifluoromethyl- Bis(fluorosulfonyl)imide
sulfonyl)imide (TFSI) (FSI)
Fig. 9.2. Cations and anions of common air and water stable organic room temperature ionic liquids.
and intercalation in some other materials. Various types of cations (phosphoniums

and pyrrolidiniums), which lack an aromatic system, can be used instead of imida-
zoliums, however, providing better cycling stability. Other properties such as tunable
water miscibility (due to the nature of the anion) and solvating power can be taken
advantage of for several applications.
9.2 Ionic liquids as Li and Lithium-ion battery electrolytes
Like all batteries and electrochemical cells, Li and Li-ion batteries are composed of
two electrodes (the positive cathode and negative anode) separated by an electrolyte.
Operation of Li-ion batteries is based on the reversible intercalation of Li-ions in ox-
ides (cathode) and graphite (anode) [26–28]. A Li battery is similar in construction,
but metallic lithium is used at the anode instead of graphite or another intercalating
material. While Li-ion batteries are secondary (i.e., rechargeable) batteries, lithium
batteries are primary devices which cannot usually be recharged, due to the forma-
tion of dendrites at the anode surface following the reduction of Li-ions. Controlling
Li deposition during recharging is an important issue due to the very high capacity of
Li(0) anodes. Ionic liquids have shown promising results in that field, but this topic
will not be discussed further here [29, 30]. For both types of battery, the electrolyte has
the important role of ionic conduction for the transportation of lithium ions between
the electrodes and balancing the charge passing through the external circuit as cur-
rent. The electrolyte should be sufficiently fluid to allow rapid ion diffusion, should be
good at solvating ions (high dielectric constant), and should be electrochemically and
thermally stable. The idea behind the use of ionic liquids as battery (and other elec-
trochemical energy storage devices) electrolyte is to take advantage of the intrinsic
properties of ILs which increase the thermal and electrochemical stability of the de-
vice. Replacing traditional volatile and flammable solvents with ionic liquids would
provide safer batteries, decreasing the risk of self-combustion and explosion in the
event of abuse or an accident of the system. The increased electrochemical stability
would also allow the use of high potential cathodes, thereby increasing the operating
voltage and the energy of the battery. On the downside, the significant disadvantages
of ionic liquids, mostly their high viscosity and low transport, will decrease the overall
cell performance, explaining in part why ionic liquid electrolytes have not yet made it
to commercial batteries, cost being another issue.
The most studied types of anode and cathode material for lithium and lithium-ion
batteries have been tested in cells with ionic liquid electrolytes. An extensive list can
be found in a review paper by A. Lewandowski [8]. The ionic liquids which have been
the most studied for batteries are based on the alkylimidazolium and pyrrolidinium
families. Ionic liquids based on imidazolium have the lowest viscosity, which is highly
important to favor charge transport by the Li-ions. Pyrrolidiniums are more stable
towards the reduction reaction than imidazoliums, which usually decompose at the
Li(0) and graphite anodes. The TFSI anion is the most reported due to the low viscos-
ity of the ionic liquids employing it, but tetrafluoroborate and hexafluorophosphate
have been studied extensively due to their wide application in conventional battery
electrolytes. There are currently no commercial lithium batteries based on ionic liquid
electrolytes, but research is progressing and studies on lab-scale stacked prototypes
are showing promise and helping to identify current technological challenges [31, 32].
In addition to the thermal stability they confer to electrochemical systems, ionic liq-
uids might very well make their place in batteries by achieving tasks which no other
electrolyte based on solvent-solute systems can do.
9.3 Functional ionic liquid electrolytes
The preceding section demonstrated the use of typical ionic liquids as Li-ion battery
electrolytes, taking advantage of their intrinsic thermal and electrochemical stability
to improve related properties in the battery. In this section, ionic liquids modified with
a functional group will be evaluated in the performance of certain tasks essential to
efficient battery operation. Such functionalization of ionic liquids is usually done on

organic cations (imidazoliums, phosphoniums or ammoniums) and uses well-known
chemistries which are generally accessible to research groups not specialized in or-
ganic molecule synthesis. The application of functional ionic liquids for generation
of the solid electrolyte interphase (SEI), to improve Li-ion transport and to prevent
over-oxidation of cathodes will be discussed.
9.3.1 Overview of functional ionic liquids
In a 2001 publication, R. Rogers (University of Alabama, U.S.A.) et al. demonstrated

the first example of an ionic liquid with a structure that was developed for a specific
purpose [33]. These “task-specific ionic liquids” or TSIL, were obtained by modify-
ing imidazoliums with a functional group based on the chemical structure of extrac-
tants used to extract heavy metal ions from non-aqueous solvents (Fig. 9.3). By com-
bining functionalized imidazoliums with the hydrophobic PF−6 anion, the ionic liq-
uids were non-miscible with water, allowing the extraction of Hg2+ and Cd2+ from
the ionic liquid from an aqueous phase. The distribution ratios obtained with vari-
ous TSIL based on the structures shown in Fig. 9.2 were above 300 for both M2+ ions
with pure TSIL. In comparison, the distribution ratio for both ions with the unmod-
ified 1-butyl-3-methylimidazolium: PF6 extracting phase were below unity, showing
the role of the functional group. This is a strong demonstration of how a properly de-
signed ionic liquid can perform the task of a solute-solvent system without requiring
dissolved additives. Several advantages are associated with this concept of adding a
functional group directly to the molecular structure of one of the constituents of a
liquid phase. The common benefits of ionic liquids such as low volatility, intrinsic
conductivity, and thermal stability are retained in TSIL and can facilitate the recycla-
bility of the liquid phase. These advantages motivated the development of numerous
functionalized ionic liquids over the years.
R
R
N + N N N
PF6–
H H
Fig. 9.3. Functional (task-specific) ionic liq-
S uids based on alkylimidazoliums modified with
R thiourea (top) and thioether (bottom) for the ex-
N + N R
traction of heavy metal ions. R represents a C3−6
PF6– alkyl chain.
Currently, TSIL are being developed for CO2 capture [34, 35], catalysis [36–39], and
extraction or solubilization of insoluble materials [40, 41]. There are only a few exam-
ples of functional ionic liquids being designed as electrolytes for energy storage and
conversion systems. Apart from specific examples of lithium and lithium-ion batteries
(discussed below), dye-sensitized solar cells [42], and lithium-air batteries [43], the
majority of papers on the functionalization of ionic liquids used as electrolytes are
based on ether modification to decrease viscosity and therefore address one of the
major limitations of ionic liquids [44]. In fact, most of the cations presented in Fig. 9.2
were functionalized with an ether group on one of their alkyl chains and their electro-
chemical behaviour was studied later. While modifying ionic liquids to reduce their
viscosity is highly important for their application as electrolytes, this chapter focuses
on ionic liquids functionalized with a reactive group designed to be involved in some
of the electrochemical reactions taking place during battery operation. The selected
examples presented below provide an overview of the possibilities offered by the use
of functional ionic liquid electrolytes in lithium and lithium-ion batteries.
9.3.2 Solid electrolyte interphase
During the first cycle of operation of Li-ion batteries, a passivation layer is formed at
the anode. This layer, called solid electrolyte interphase (SEI), is generated by the re-
duction of electrolyte (and additives if present), resulting in a complex mixture of inor-
ganic and organic materials with a thickness in the nanometer range [45]. The SEI pas-
sivates the anode which prevents further electrolyte decomposition, but allows Li-ions
to permeate and ensures good cyclability with sufficient cell performance. Common
solvents based on carbonates used in Li-ion battery electrolytes (ethylene, diethyl,
dimethyl, propylene carbonates) will typically decompose at the anode, generating
Li2 CO3 , polycarbonates, and several other species [45]. Additives like vinylene carbon-
ate (VC) are commonly added to the electrolyte to accelerate SEI formation and prevent
excessive generation of gases from the reduction of the carbonate solvents [46].
As it is usually done with electrolytes based on conventional solvents, VC and
other carbonates can be dissolved in ionic liquids (5–10 wt %) to accelerate SEI forma-
tion [47]. However, some issues related to the reduction of the ionic liquid itself (imida-
zolium) and limited Li+ intercalation might occur [8]. In the case of lithium batteries,
in which the anode is metallic lithium, and where Li deposition-dissolution processes
are involved rather than intercalation (as in graphite), the irreversible decomposition
of 1,3-substituted imidazolium cations essentially blocks the anode surface and de-
creases cell output. An approach taken by M. Egashira (Yamaguchi University, Japan)
to better control the SEI in Li batteries using ionic liquid electrolytes is to modify imi-
dazolium salts with cyano groups [48–50]. Examples of such functional ionic liquids
are presented in Fig. 9.4. The idea that motivated the design of these ionic liquids was
to deliberately incorporate a functionality of the cation that, once decomposed, will
enter the composition of the SEI to provide a stable film compatible with cell oper-
ation. The chemistry of the SEI is controlled by the solvent itself rather than via the
use of additives. The results obtained showed that the cyano group on the ionic liquid
accelerated the imidazolium ring opening reaction, leading to SEI formation [48]. The
SEI layer formed from CN-modified imidazolium on a stainless steel anode provided
a reversible lithium deposition and dissolution. There was no passivation on elec-
trodeposited Li with an electrolyte based on unmodified 1-ethyl-3-methylimidazolium
(EMIM) cation electrolyte. The capacity of a LiCoO2 cathode obtained in an electrolyte
composed of a mixture of the cyano-substituted quaternary ammonium TFSI (Fig. 9.4)
and EMIM TFSI was measured at 110 mAh/g, slightly lower than could be obtained in
conventional electrolytes [50]. Functional ionic liquids based on guanidinium cations
bearing ether groups have also been studied in lithium batteries to improve Li depo-
sition [44]. Interestingly, the authors reported the plating of Li on a Ni anode even if
the cathodic potential limit of their ionic liquids was higher than that of Li+ reduction.
This was attributed to the formation of the SEI, which was obtained by decomposition
of the functional ionic liquid (no SEI-forming additives were added). Their electrolyte
also provided good passivation in a Li/LiFePO4 cell, but the capacity obtained (110–
120 mAh/g) was lower than for conventional electrolytes, most likely due to the higher
viscosity of IL-based electrolytes.
N + N CN
–
TFSI
Fig. 9.4. Imidazolium and ammonium ionic liquids functional-

TFSI–
N+ CN ized by cyano groups used to improve SEI formation in Li bat-
teries.
9.3.3 Transport of lithium ions
One of the major limitations arising from the use of ionic liquids as electrolytes for
Li-ion batteries is the low transport numbers for Li+ . For a battery to work at high
power rates during charging and discharging, the amount of ionic charge by the Li+
ions moving across the electrolyte must be as high as possible. The fraction of charge
transported by the lithium ions, represented by the transport number, is necessarily
lower in ionic liquids than in typical electrolytes due to the absence of solvent in the
former. This is clearly demonstrated by comparison of the equations for the transport
number of Li+ (tLi+ ) for the two systems:

uLi+
Ionic liquid C+ A− + Li+ A− salt: tLi+ =
uLi+ + uC+ + 2uA−
uLi+
Li+ A− salt in solvent: tLi+ =
uLi+ + uA−
In these equations, ui represents the mobility of the ion i. In other words, there is a
high concentration of cations other than Li+ in ionic liquids that participates in charge
transport, but these other ions will not intercalate and therefore won’t contribute to
energy storage. To address this issue, neutral lithium ion-complexing additives such
as glymes (oligoethers of CH3 (CH2 CH2 O)n CH3 composition) have been added to ionic
liquid electrolytes to reduce the interactions with the anion [51]. In this case, the ion-
icity of the ionic liquid – LiTFSI electrolyte was found to increase with the addition
of glyme. M. Watanabe (Yokohama University, Japan) demonstrated that by selecting
the appropriate anion, mixtures of Li salts and glymes formed a liquid phase on their
own with ionic liquid properties [52, 53]. Fig. 9.5 shows the structure of such an ionic
liquid in which the cation is composed of a Li+ solvated by a molecule of tetraglyme.
This family of ionic liquids are hence called solvate ionic liquids. Because of such sol-
vated complexes, the Li ions interact less with the TFSI anion, behave like an ion in a
neutral solvent and provide a high transport number. In the Li(tetraglyme)-TFSI, the
tLi+ was as high as 0.51 [52], representing a significant improvement to that of mixtures
of imidazolium ionic liquid with Li salts, which are found below 0.1 [54, 55].
O – O O O
S N S CF3 Li+
F3C
O O O O Fig. 9.5. Structure of a Li(glyme) ionic liquid based
on tetraglyme and the TFSI anion.
Lithium batteries employing LiFePO4 and LiNi1/3 Mn1/3 Co1/3 O2 as low (3V) and high
(4 V) voltage cathodes have been studied with the pure Li-(CH3 O(CH2 CH2 )3 CH3 )-TFSI
ionic liquid as the electrolyte [56]. The cell capacities as a function of cycle number
are shown in Fig. 9.6. Good stability was obtained for the LiFePO4 cells for 600 cycles,
showing stable electrochemical reactions at both positive and negative electrodes in
the ionic liquid. Decomposition of the electrolyte is likely to occur at higher potentials,
which could explain the important capacity loss in the 4 V cells (Fig. 9.6(b)).
9.3.4 Electroactive ionic liquids as redox shuttles
Redox shuttles are electroactive molecules added to the Li-ion battery electrolytes to
prevent oxidation of the cathode over the level required for charging (over-oxidation)
4.0 4.2
3.7 3.9
Cell Voltage/V
Cell Voltage/V
3.4 3.6
3.1 3.3
1st 300th 1st
2.8 50th 400th 3.0 10th 200th
100th 500th 50th 300th
200th 600th 100th 400th
2.5 2.7
0 50 100 150 200 0 25 50 75 100 125 150 175
Capacity/mAhg–1 Capacity/mAhg–1
(a) (b)
Fig. 9.6. Charge-discharge profiles of (a) Li/LiFePO4 , and (b) Li/LiNi1/3 Mn1/3 Co1/3 O2 cells using
Li(glyme)-TFSI ionic liquid electrolyte (C/8 rate at 30°C). Reproduced by permission from [56].
[57–59]. The operating principle is shown in Fig. 9.7. The over-oxidation of cathode
material leads not only to the irreversible degradation of the electrode, but will also
generate radicals, oxygen, and other reactive species which can cause a rapid ther-
mal runaway leading to explosion of the battery. Under normal operation, the redox
shuttle has no function and should not interfere with the processes involved in charg-
ing or discharging the battery. When current is passed through a fully charged (oxi-
dized) cathode, the redox shuttle (R-S[R]) will however be oxidized (to R-S[O]), thereby
preventing over-oxidation. The now oxidized shuttle will diffuse (D[O]) to the anode
to be reduced to complete the cycle and will become available to diffuse back to the
cathode (D[R] in Fig. 9.7).
The motivation behind the development of functional ionic liquids which can be
used as redox shuttle is two-fold. Firstly, there is the very appealing idea of combin-
ing the stability inherent to ionic liquids with the cathode protection offered by the
redox shuttle principle to develop a bi-functional electrolyte for safer batteries. Sec-
ondly, the modification of the ionic liquid could address the general solubility issues of
electroactive organic molecules in solvents and ionic liquids, leading to much higher
concentrations of redox moieties in the electrolyte. This higher concentration could
provide better protection, especially when high currents are applied to charge the bat-
tery in a shorter time. The following equation shows the direct relationship between
the maximum current (IMAX ) which can be carried out between two electrodes sepa-
rated by a distance (L) from the redox shuttle, and its concentration (C), in which n is
the number of charge per shuttle, F is the Faraday constant, A is the surface area of
the electrode, and D is the diffusion coefficient of the shuttle [60]:
nFADC
IMAX = (9.1)
L
If a pure electroactive ionic liquid phase can be used (that is, if its viscosity is not too
high) the concentration of redox moiety in the liquid could exceed 2 M, which could
never be obtained by simply dissolving a redox molecule in an ionic liquid [61].
A
e
e
e
R–S R–S
[O] [O]
D[O]
e
R–S R–S
[R] [R]
D[R]
Anode Cathode
Fig. 9.7. Operating principle of a redox shuttle dissolved in a Li-ion battery electrolyte. R–S[O] and
R–S[R] are the redox shuttle in its oxidized and reduced states, respectively, D shows the diffusion
of the shuttle in the two states between the electrodes. Reproduced by permission from [65].
O N +
Link CF3 N
Side Chain O
S –
N + –N O O N O
Fe N O S S
n S F3C CF3
O O O
CF3 O
Fig. 9.8. Two types of electroactive ionic liquids studied as redox shuttle for Li-ion batteries,
obtained by the modification of imidazolium with ferrocene (left) and 2,5-di-tert-butylmethoxy-
benzyne (right).
The first demonstration of the use of electroactive ionic liquids as redox shuttle was
recently reported by our group [62]. In this report, an imidazolium-based ionic liquid
was functionalized with ferrocene as the redox moiety (Fig. 9.8).
The 1-ferrocenylmethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)
amide (Fc-MIm TFSI; Fig. 9.8, left with n = 3) ionic liquid was dissolved in ethylene
carbonate–diethyl carbonate solvent (EC-DEC + 1.5 M LiTFSI) and incorporated into
a coin-type cell with a Li4 Ti5 O12 (LTO) cathode and a Li foil anode. LTO has a very
low charging potential (1.6 V vs. Li/Li+ ) and while not usable as commercial battery
material, it was used to demonstrate the concept. Figure 9.9 shows the specific ca-
pacity curves for the charge/discharge cycles of the test coin-type cell, starting with
a full charge, followed by a 100 % overcharge for a Li/Li4 Ti5 O12 coin cell at a C/10
rate. In this figure, the unmodified electrolyte (i.e., without electroactive ionic liquid)
is the solid line and the electrolyte containing 10 % of Fc-MIm TFSI is represented by
the broken lines. The overcharging situation appears very clearly for the cell without
redox shuttle added where the voltage increases sharply to a 4 V cut-off after the
charging plateau at 1.6 V for Li4 Ti5 O12 material. Adding the redox ionic liquid TO the
electrolyte prevents reaching the cut-off voltage of 4 V. A plateau is rather observed at
∼ 3.36 V, corresponding to the onset potential for oxidation of the ferrocene moiety
on the ionic liquid and demonstrating the protection against over-charging by the
shuttle mechanism.
No Fc-MIm TFSI, all cycles

4.0 10% Fc-MIm TFSI, 1st cycles
10% Fc-MIm TFSI, 2nd cycles
10% Fc-MIm TFSI, 3rd cycles
3.5
Cell voltage (V)
3.0
2.5
2.0
1.5
1.0
–50 0 50 100 150 200 250 300 350 400

Specific capacity (mAh/g)
Fig. 9.9. Capacity curves (C/10) for Li/Li4 Ti5 O12 cells using EC/DEC (1.5 M LiTFSI) electrolyte either
pure (solid line), or modified with 10 % Fc-MImTFSI (broken lines). The parameters were set to a full
charge followed by a 100 % overcharge and a cut-off at 4 V. Reproduced by permission from [62].
The use of Fc-MIm TFSI presents two important limitations. First, the electroactive
ionic liquid is very viscous due to a large cation and additional intermolecular interac-
tions between the ferrocene and imidazolium aromatic systems [63]. The high viscosity
prevented the use of an ionic liquid as an undiluted phase, but its dilution at 10 vol %
in an ethylene carbonate–diethyl carbonate solvent (EC-DEC + 1.5 M LiTFSI) provided
an electrolyte with acceptable viscosity (7.1 cP) and conductivity (5.5 mS/cm) for a use
in Li-ion cells [62]. The second challenge is related to the low oxidation potential of
ferrocene. The onset for the oxidation of Fc-MIm TFSI in the carbonate electrolyte (at
10 vol %) is 3.4 V vs. Li/Li+ , which is very close to the charging potential of LiFePO4 ,
a common Li-ion battery cathode material. In order to apply the electroactive ionic liq-
uid shuttle principle to this cathode material, a second series of ionic liquids was de-
signed, based on the successful commercial shuttle 2,5-di-tert-1,4-dimethoxybenzene
(DDB) [64]. These ionic liquids, dissolved in the EC-DEC + 1.5 M LiTFSI solution; start
being oxidized at potential values between 3.81 and 3.94 V vs. Li/Li+ due to the higher
redox potential of the DDB moiety (Fig. 9.8) [64]. Preliminary results in coin-type cells
using LiFePO4 cathodes demonstrated cathode protection capabilities against over-
charging (Fig. 9.10). Notably, the concentration in the redox shuttle was increased up
to 1 M due to the high solubility of imidazolium TFSI ionic liquid in carbonates. In
comparison, the poor solubility of DDB limits its working concentration in batteries
below 0.1 M.
4.4
4
Potential\V vs Li/Li+
3.6
3.2
2.8
0 50 100 150 200 250 300 350
Time\h
Fig. 9.10. Voltage profile of a Li/LiFePO4 cell containing 1 M of the 2,5-di-tert-1,4-dimethoxybenzene-

based ionic liquid in 0.7 M LiTFSI EC/DEC (1 : 2 v/v).
9.3.5 Perspectives
Ionic liquids with various structures and properties have been applied and are still be-
ing studied to replace conventional electrolytes in energy storage devices. Advances
in understanding of how the structure of ionic liquid components affects its properties
made several of these discoveries possible. The application of functional ionic liquids
is likely to follow a similar pattern. The examples provided in this text demonstrate
the potential of task-specific ionic liquids to address specific issues of energy stor-
age devices although their application usually decreases the device performance. The
challenge is to determine if (and how) some of the most important viscosity, conduc-
tivity, and melting point limitations caused by the increase in ion size when adding a
large and complex (e.g., aromatic) functional group can be overcome. Therefore, more
work remains to be done to better understand the structure and the interactions taking
place between molecules in ionic liquids bearing a functional group.
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C. de Bonis, A. D’Epifanio, B. Mecheri, S. Licoccia, and A. C. Tavares
10 Solid polymer proton conducting electrolytes
for fuel cells
10.1 Introduction
Numerous practical applications based on electrochemical cells use solid electrolytes.

These include batteries, fuel cells, sensors, electrolyzers, and also water purification,
electrodialysis, and seawater desalination [1–7].
An electrochemical cell is a device capable of producing electrical energy from
spontaneous chemical reactions (ΔGo < 0), or driving chemical reactions through an
external source of electrical energy (ΔGo > 0). Electrochemical cells contain two elec-
trodes (the anode and the cathode) with an electrolyte between them. Reactions at
the anode (oxidation) and at the cathode (reduction) are the driving forces of an elec-
trochemical cell. Oxidation refers to the loss of electrons by a chemical species (re-
ductant) and reduction to the gain of electrodes by a chemical species (oxidant). In
an electrochemical cell the electronic current flowing outside the cell equals the ionic
current flowing within the cell [8].
An electrolyte is a material able to conduct ions which is usually an electrical insu-
lator [8]. Electrolytes can be solutions (e.g., KOH, H2 SO4 ), molten salts (e.g. Li2 CO3 ),
solid ion conducting polymers (e.g., perfluorinated polymers bearing sulfonic acid
groups or benzyltrimethylammonium groups), and ionic crystals (e.g., ZrO2 :Y2 O3 ,
Na3 Zr2 PSiO12 ).
Solid electrolytes conducting O2− , H+ , Li+ , Na+ , Ag+ , F− , Cl− , OH− ions have been
reported for many years now. The conductivity range is typically 10−3 S/cm < σ <
10 S/cm depending on the material structure and operating temperature. For the pur-
pose of comparison, the conductivity of a solid electrolyte at room temperature is in-
ferior to that of a liquid electrolyte. For example, σ(KOH) = 0.6 S cm−1 (30%, 20°C),
σ(H2 SO4 ) = 0.82 S cm−1 (5.2 M, 20°C), and σ(Nafion® ) ≈ 0.07 S cm−1 (fully hydrated,
20°C).
Solid electrolytes can be used in electrochemical cells as ion exchange mem-
branes to allow the passage of ionic current between the anode and the cathode
placed on opposite sides of the electrolyte, or in the electrodes when mixed (elec-
tronic and ionic) conductivity is needed [5, 9]. Ion conductivity σi is given by:
σi = zi ⋅ Ci ⋅ μi , (10.1)
where zi is the ion charge, Ci is the density of mobile ions, and μi the ion mobility. Thus,
a solid electrolyte has a large number of mobile ions. Ion conductivity is an activated
transport; therefore it increases exponentially as temperature increases:
Ea
σ = A exp (− ), (10.2)
RT
where A is a proportional constant, Ea is the activation energy, R is the universal gas

constant (8.314 J mol−1 K−1 ), and T the temperature (in K).
There are two main classes of solid electrolytes: crystalline (or ionic) solids and
ion conducting polymers. In crystalline solid electrolytes, ion conductivity occurs by
means of ions hopping through energetically equivalent sites in the crystal structure.
High conductivity requires a large number of mobile ions, or in other words, a large
number of accessible empty sites, either vacancies or interstitial sites. A practical way
of increasing the density of mobile ions is by doping the crystalline solid with het-
erovalent ions forming solid solutions. For example, replacing three Li+ ions with one
Al3+ ion in Li4−3x Alx SiO4 to generate cation vacancies, or by replacing Zr4+ ions by Y3+
ions in yttria stabilized zirconia to generate anion vacancies. The activation energy
controls ion mobility. The empty and occupied sites should have similar potential en-
ergies with a low activation energy barrier for ion hopping between neighboring sites.
Ion mobility is thus related to the crystal structure. Ionic solids with a densely packed
crystal structure are characterized by large activation energy (1 eV or higher) and low
conductivity. Ionic solids such as α-AgI, RbAg4 I5, and Na β-Al2 O3 are known as fast
ion conductors, formed by solid frameworks with open conduction pathways, and are
characterized by low values of activation energy, for example 0.03 eV for AgI above
420 K. Practical applications of this class of compounds include, for example, ion se-
lective electrodes (Ag2 S for Ag+ and LaF3 for F− ), molten salts electrochemical cells
(Na β-alumina in ZEBRA batteries), and oxygen anion conductors (yttria stabilized zir-
conia) for solid oxide fuel cells and oxygen sensors.
Solid polymer electrolytes (SPE) consist of polymer backbones functionalized
with a high concentration of fixed ionic charges. The function of the SPE is deter-
mined by the charge of the ion exchange groups and the nature of the counter ions,
and can be classified as follows [10]:
(a) cation exchange membranes have anionic charged groups (-COO− , -SO−3 , etc.) and
cations can selectively permeate through them;
(b) anion exchange membranes have cationic charged groups (e.g. -NR+3 ) and anions
can selectively permeate through them;
(c) amphoteric ion exchange membranes contain randomly distributed cationic and
anionic functional groups;
(d) bipolar ion exchange membranes are bi-layer membranes with both a cation and
an anion exchange membrane layer;
(e) mosaic ion exchange membranes, which have separate domains with cationic and
anionic groups.
Types (a) and (b) are those used industrially.
Due to the presence of ionic groups, ion exchange membranes adsorb water molecules
to an extent dependent on the surrounding relative humidity. The electrical conduc-
tivity of ion exchange membranes depends on the concentration, size, and charge of
the ions, as well as on the water content, chemical structure, and morphology of the
membranes. In particular, ion mobility depends on its charge density and degree of
solvation [11].
Ion exchange membranes are used for the dehumidification of gases, in humidity
sensors, actuators, pervaporation, facilitated transport, and in electrochemical pro-
cesses such as electrodialysis, brine electrolysis, redox flow vanadium batteries, and
solid polymer electrolyte fuel cells [10]. A significant amount of the work on SPEs is
relevant to proton exchange membrane fuel cells, therefore this application has been
targeted for this chapter, with emphasis on SPEs functionalized with sulfonic acid
groups.
10.2 Proton exchange membranes
A fuel cell is an electrochemical device which converts the energy from a fuel into
electricity, and those using proton exchange membranes (PEM) are among the most
promising because of their potential application in portable electronics, stationary
and automotives. They operate between room temperature and 140°C and can use hy-
drogen, methanol or other liquid fuels. During operation the fuel is oxidized at the
anode, generating protons and electrons. The electrons flow from anode to cathode
through the external circuit, whereas the protons cross the electrolyte membrane to
reach the cathode. An oxygen reduction reaction takes place and water is produced:
Anode: H2 → 2 H+ + 2 e− (10.3)
+ −
Cathode: 1/2 O2 + 2 H + 2 e → H2 O (10.4)
Overall: H2 + 1/2 O2 → 2 H2 O (10.5)
The proton exchange membrane is the core component of PEM fuel cells. In order
to achieve high efficiency, the membrane must possess the following features: (a) high
proton conductivity to support high current with minimal resistive losses, (b) low per-
meability to reactants, (c) chemical and electrochemical stability under operating con-
ditions, (d) adequate mechanical strength and stability, and (e) production costs com-
patible with the intended application.
PEMs can be classified according to their polymer backbone as hydrocarbon mem-
branes, partially halogenated hydrocarbon membranes, and perfluorocarbon mem-
branes. The most common cation exchange group used for fuel cell applications is
the sulfonic acid group because it is a very strong acid (apparent pk −6 for –CF2 SO3 H
and 0–1 for alyl/alkyl –SO3 H), although phosphonic acid (pk1 = 2–3, pk2 = 7–8) and
imidazole are also protogenic groups of potential interest for operating temperatures
above 100°C and low relative humidity (RH) [10, 12].
PEMs rely on the mobility of protons in the aqueous network formed inside the
solid polymer [13]. Proton transport proceeds through the membrane following two
main mechanisms [14]. The first is the vehicle mechanism, where the proton diffuses
with the vehicle water. The counter diffusion of unprotonated water allows the net
transport of protons. Therefore, the observed conductivity depends on the rate of ve-
hicle diffusion and can be expressed as a function of the water self-diffusion coeffi-
cient (DH2 O ), which represents a measure of the average mobility of water in the mem-
brane. The other mechanism is known as the Grotthuss mechanism, “proton hopping”
or “structure diffusion”. In this process, the water molecules show pronounced local
dynamics but reside on their sites. The process consists of two steps: (1) proton transfer
from one water molecule to the other by hydrogen bonds, (2) consequent reorientation
of water dipoles resulting in the formation of an uninterrupted trajectory for proton
migration. A schematic description of two typical proton conduction mechanisms is
shown in Fig. 10.1 The prevalence of one mechanism or the other depends on the hy-
dration level of the membrane, and it has been suggested that proton hopping is more
significant for high water contents [15]. The activation energy for proton conduction
in SPEs depends on the water content, and typically decreases from 0.4–0.5 eV for dry
membranes (contain only residual water molecules) and 0.1 eV for fully hydrated and
swollen membranes [16].
S S S S
Fig. 10.1. Simplified scheme of the proton transfer in

Nafion® by the Grotthuss mechanism (solid lines) and the
S S S S vehicle mechanism (dotted lines). Adapted with permission
from [17].
10.2.1 Nafion®
The key ionomer currently used in PEM fuel cell applications is Nafion® , which is
produced by DuPont. Nafion® is a perfluorosulfonic acid polymer (PFSA). It has a
polytetrafluoroethylene (PTFE) backbone, which confers high chemical inertness, and
side chains consisting of perfluorinated vinyl polyether ending in sulfonic acid groups
(–SO3 H), which give proton exchange capability to the polymer. The chemical struc-
ture is shown in Fig. 10.2, where the values of n, x, and y can be varied to produce
materials with different equivalent weights.
Nafion® shows excellent proton conductivity (0.09 to 0.12 S cm−1 at 80°C and RH be-
tween 34 and 100% RH [18]) and mechanical strength, as well as high thermal and
chemical stability. The structure of Nafion® as a function of its water content has
been the topic of many investigations and it has been investigated by swelling stud-
ies, infrared spectroscopy, small angle x-ray scattering, and transmission electron
CF2 CF2
CF y
CF2 x
CF2 O
O CF2 O
CF z CF2 S
O OH
Fig. 10.2. Chemical structure of the
CF3 Nafion® ionomer.
microscopy to name a few [19]. These studies have shown that a hydrated membrane
contains two phases, an ionic phase which is associated with the hydrated sulfonic
acid groups, and a non-ionic phase which is the perfluorinated matrix. The actual
form of the phases depends on the water content. Since the early 1970s several mod-
els have been proposed for prediction of ionic transport properties of Nafion® , de-
scribing the way in which ionic groups aggregate. These models include the Mauritz–
Hopfinger Model [20], the Yeager Three Phase Model [21], and the Gierke Cluster
Network Model [22]. In the cluster network model proposed by Gierke and Hsu, the
structure is an inverted micelle in which the ion exchange sites are separated from the
fluorocarbon backbone, thus forming spherical clusters, connected by short narrow
channels; see Fig. 10.3.
Thus, with increasing water content, the clusters grow and form transitory in-
terconnections with one another. This network of collapsed channels leads to a
percolation-type phenomenon. Gierke and Hsu also used the percolation theory to
correlate electrical conductivity with the water content of the membrane, expressed
as λ, i.e., the number of water molecules per sulfonic group. According to this theory,
there is a critical amount of water available in the membrane, below which ion trans-
port is extremely difficult due to the absence of extended pathways. The percolation
threshold in Nafion® is around λ = 2 [20], as shown in Fig. 10.4, where conductivity
data is plotted against λ. At low hydration level, i.e., λ in the range of 1–2, it is rea-
5.0nm
SO–3 SO–3 SO–3 SO–3

SO–3 SO–3
SO–3 SO –
SO–3 3
SO–3 SO–3
4.0nm 1.0nm–
SO –
3 SO3 SO–3
SO–3 SO–3 SO–3 SO–3

– SO –
SO–3 –
SO–3 SO
3
SO 3 3
Fig. 10.3. Gierke’s cluster network model of Nafion® membranes.

Reprinted with permission from [22].
sonable to consider that all water molecules absorbed by the Nafion® membrane are
associated with the sulfonate heads because of the hydrophobic nature of the back-
bone and the hydrophilic nature of the sulfonic groups. Moreover, hydronium ions
will be localized on the sulfonate heads and conductivity will be extremely low, as
the amount of water absorbed is insufficient for the formation of a continuous water
phase [23]. For λ in the range of 3–5, the counterion clusters continue to grow and,
as λ approaches 5, the membrane will become more conductive since some counte-
rion clusters may connect. However, there is still insufficient water for all clusters to
coalesce. Molecular dynamics simulations indicate that 5 water molecules form the
primary hydration shell for the sulfonic groups and any additional water molecules
are not as strongly bound and thus form a free phase [24]. For λ ≥ 6, counterion clus-
ters coalesce to form larger clusters and eventually a continuous phase is formed and
the conductivity threshold is overcome.
0.10
0.08
Conductivity/Scm–1
0.06
0.04
0.02
0.00
0 5 10 15 20 25
Mole ratio H2O/SO3H
Fig. 10.4. Variation of the proton conductivity of Nafion® as a function of the water content in the
membrane. Reprinted with permission from [4].
Since proton mobility relies on the formation of a continuous aqueous network inside
the ionomer, proton conductivity shows a strong dependence on the hydration level of
the PEM, as shown in Fig. 10.4 for Nafion® . A humidification system is thus necessary
to keep the membrane hydrated during fuel cell operation, which represents a major
cost of the fuel cell system [25].
While water sorption improves proton conductivity, it also leads to morphological
instability and, at elevated water content, to membrane swelling [26]. The maximum
working temperature of all Nafion® -based fuel cells is limited to 80–90°C due to the
loss of mechanical strength of the membrane determined, at higher temperature and
large hydration, by the plasticizing effect of water. Moreover, under dynamic condi-
tions, swelling cycles contribute to mechanical fatigue.
In fact, one of the key challenges in the design of proton exchange membranes
is the retention of high conductivity at low water content [3], especially at high tem-
peratures [25]. Overall, operation at high temperature (> 100°C) is desirable to reduce
PEM fuel cell costs and to promote large-scale commercialization: it enhances reaction
kinetics at both electrodes thus reducing the catalyst loading on both electrodes, it al-
lows more efficient utilization of the waste heat, and simplifies the water and thermal
management systems [25].
Nafion® membranes possess an additional major hurdle which inhibits large-
scale commercialization of fuel cells operating with liquid fuels. The unique mi-
crostructure of the Nafion® ionomer results in a high crossover rate of liquid fuels
from the anode to the cathode through the membrane [27]. This not only lowers fuel
utilization at the anode but also increases the overpotential of the cathode, hence
lowering the cell performance.
All of these drawbacks essentially imply that the Nafion® membrane cannot be
used “as is” for fuel cell applications in a wide temperature range, relative humidity
(RH) and liquid fuels. Substantial effort is being made to develop membranes with
appropriate electrochemical and other physico-chemical properties under operating
conditions [28–30]. Different approaches are being pursued and include: (a) the devel-
opment of alternative ionomers based on non perfluorinated polymers [31, 32], on pol-
yarylene or on aliphatic main chains [33–38], (b) the modification of existing ionomer
membranes through the formation of blends and composites [29], and (c) the synthe-
sis of new hybrid systems [39, 40].
10.2.2 Alternative sulfonated ionomers and membranes
Among the alternative polymers to Nafion® , arylene main-chain polymers, such as

poly(ether ketone), poly(ether sulfone), poly(benzimidazole), and poly(phenylene
sulfone), as shown in Fig. 10.5, have been widely investigated [34–36, 41–44].
Such polymers are inexpensive and possess high chemical and mechanical sta-
bility at temperatures higher than 90–100°C [34–36]. Moreover, their aromatic struc-
ture offers the possibility of electrophilic and nucleophilic substitutions, to prepare
ionomers with the desired features for PEMFC and DMFC applications [45]. The most
important modification regards the introduction of sulfonic acid moieties to obtain
proton-conducting aromatic polymers. Several methods have been developed for the
preparation of proton-conducting electrolytes, including direct sulfonation of a poly-
mer backbone, total synthesis from monomer building blocks, and grafting of func-
tional groups onto a polymer main chain [46]. In general, the larger the number of sul-
fonic acid groups per structural unit, the larger the membranes’ ionic exchange capac-
ity and water uptake and the higher their conductivity. However, excessive swelling of
O O C
(a) n
CH3 O
O C O S
(b) CH3 O n
H
N N
NH N
n
(c)
Fig. 10.5. Chemical structure of (a) Polyetheretherketone; (b) Udel Polysulfone;

and (c) Poly(2,2󸀠 -m-(phenylene)-5,5󸀠 -bibenzimidazole).
the membranes could lead to dilution of the charge carriers and to lower proton con-
ductivity [33].
Some variations on Nafion® ’s hydration scheme are expected for sulfonated pol-
yarylene membranes. Sulfonated polyarylenes with sulfonic acid groups bound di-
rectly to the aromatic chain have less pronounced hydrophobic/hydrophilic separa-
tion with respect to Nafion® because their backbones are less hydrophobic and flex-
ible, and their sulfonic acid groups are less acidic and therefore also less polar. As a
consequence, narrower channels and a less-connected network of clusters are present
in the microstructure of sulfonated polyetherketones, resulting in a higher depen-
dence of the transport properties on water content due to percolation concepts [27].
A schematic representation of the microstructure of sulfonated polyetherketone com-
pared with that of Nafion® is shown in Fig. 10.6. As illustrated in Fig. 10.7, high con-
ductivity levels are achieved only with a high degree of sulfonation. This results in
low mechanical properties and a high rate of methanol crossover due to excessive
swelling [47].
Several strategies have been used to overcome the excessive swelling of highly sul-
fonated polyarylenes. These include the synthesis of aromatic polymer chains cross-
linked covalently by organic spacers such as α,ω-dihalogenoalkanes [48], the use of
partially fluorinated backbones [31], placing the protogenic groups on short pendant
side chains to increase the separation between the polymer main chains and the sul-
fonic acid groups [49], or building multi-block copolymers using coupling reactions
between hydrophilic and hydrophobic macromonomers [29]. Polymers with pendant
NAFION Sulfonated polyetherketone (PEEKK)

–(CF2–CF2)n–CF–CF2– O
O–(CF2–CF–O)m–CF2–CF2–SO3H O
CF3 O SO3H
O
1 nm
: –SO3–
: Protonic
charge
carrier
: H2O
• Wide channels • Narrow channels

• More separated • Less separated
• Less branched • Highly branched
• Good connectivity • Dead-end channels
• Small –SO3–/–SO3– • Large –SO3–/–SO3–
separation separation
• pKa~–6 • pKa~–1
Fig. 10.6. Schematic representation of the microstructures of Nafion® and a sulfonated polyether-
ketone. Reprinted with permission from [27].
sulfonic acid groups in side chains are in general more stable against hydrolysis than
those with sulfonic acid groups attached directly to the polymer backbone. In addi-
tion, sulfonic acid groups on pendant side chains have a higher degree of freedom,
which results in better phase separation and higher proton conductivity with respect
to random sulfonated analogues [50, 51].
Hydrophilic-hydrophobic multiblock copolymers are considered an interesting
step forward in the rational design of PEMs. The ideal morphology has been pur-
sued by controlling the microphase separation in segmented block copolymers where
hydrophilic sulfonated polymer segments form an interconnected 3D network re-
sponsible for efficient proton transport especially at low relative humidity [52–54],
while a complementary network of hydrophobic non-sulfonated segments causes a
reinforcing effect, preventing excessive swelling in water and enhancing mechanical
0.15
Dow T = 300 K
800
S-POP
Nafion
0.10 625
1100
σ/S cm–1
Dow
1000
0.05 S-PEK
S-PEEKK 730
700
S-POP
833
0 10 20 30 40 50
n = [H2O]/[–SO3H]
Fig. 10.7. Proton conductivity (measured at room-temperature) of two Dow membranes, Nafion® ,
two sulfonated poly(arylene ether ketone)s (SPEK and S-PEEKK), and sulfonated poly(phenoxy-
phosphazene) (S-POP) as a function of the degree of hydration n; the number below the compound
acronym/name indicates the equivalent weight of the ionomer. Reprinted with permission from [47].
properties [55, 56]. Proton and water transport increase significantly with increasing
block length because the longer block induces a more developed phase separation
[57]. However, their synthesis is often complex, thus increasing the materials’ cost.
Overall, synthetic approaches based on structure-property relationships of ionomers
represent a very promising method of obtaining more efficient proton-conducting
membranes with the desired features for fuel cell applications [31, 57, 58].
Anhydrous proton-conducting electrolytes consist of a more or less inert polymer
matrix which is swollen with an appropriate proton solvent, usually phosphoric acid.
These membranes are appealing for fuel cell operation at temperatures well above
100°C without the need for humidification. One of such membrane is poly(2,2󸀠 -m-
(phenylene)-5,5󸀠 -bibenzimidazole) (PBI) whose structure is shown in Fig. 10.8. Non-
modified PBI shows very low proton conductivity. It is therefore necessary to dope the
polymer with sulfuric or phosphoric acid to increase its proton conductivity [59, 60].
However, acid leaching from the membranes and corrosion of cell components are
two of the problems limiting the performance of fuel cell devices based on such
membranes.
Alternative concepts use amphoteric heterocycles such as imidazole as a proton
conducting species “imbibed” in a polymer matrix. Proton transport occurs through
heterocyclic hydrogen-bonded networks under both anhydrous and low relative hu-
midity conditions. As for sulfonic acid-based ionomers, ion conductivity depends on
the local mobility of the heterocycles within the polymer films and on the effective
concentration of mobile protons in the membranes [12, 60–64]. The proton conductiv-
ity of these systems increases with the addition of strong acids due to the protonation
of some of the heterocycles within the polymer matrix [64, 65].
Recently, ionic liquids have also been proposed for high temperature proton
conductors, mainly due to their anhydrous high conductivity and good thermal sta-
bility. Nevertheless, the conductivity of ionic liquid-based composite membranes is
lower than that of the original ionic liquids. Therefore, only a few groups have re-
ported demonstrations of the ionic liquid-based solid membrane electrolytes in fuel
cells [66–68].
The composite strategy, where an inorganic phase is dispersed within the iono-
meric host has been demonstrated to be another effective way of improving the trans-
port and mechanical properties of ionomers. Several advantages can be obtained by
using composite membranes, such as: (a) improving the self-humidification of the
membrane at the anode side, (b) suppressing the fuel crossover, e.g., methanol in
DMFC, and (c) improving the mechanical strength of membranes without excessively
sacrificing proton conductivity [39, 40, 69]. Solid inorganic compounds can be classi-
fied as inert hygroscopic fillers, proton conductive fillers, and hydrophilic and proton
conductive fillers. They include: hygroscopic oxides (SiO2 , TiO2 , SnO2 ), clays, zeolites,
heteropoly acids, and zirconium phosphonates [39, 70–73]. For example, (a) hygro-
scopic fillers, e.g., SiO2 , TiO2 , SnO2 , and zeolites improve water retention and dimen-
sional stability of the membranes [74, 75], (b) the operation of fuel cells fed with liquid
fuels was sucessfully extended to high temperature [76, 77], and (c) beta and faujasite
zeolites improved proton conductivity and the DMFC performance of Nafion® [73, 78].
Composite membranes containing exfoliated layered compounds or 1D structures
such as nanotubes or nanorods as fillers are also an effective strategy for improving
relevant properties of electrolytes [76, 79]. The presence of one- and two-dimensional
nanomaterials, which have substantially different properties to those of nanometric
spherical particles, can enhance mechanical strength while acting as a physical bar-
rier to fuel crossover [76, 80, 81]. Performance of composite electrolytic membranes is
in fact strongly related to the polymer/inorganic phase interfacial properties. In detail,
the higher the interface interaction between the polymer and the dispersed particles,
the greater the filler’s influence on the original characteristics of the polymer [82, 83].
Composite membranes are generally prepared by casting the polymer solution
with an inorganic component. The main disadvantage of such composite systems is
related to the fact that it is very difficult to obtain homogenous systems, where the
inorganic particles are well dispersed in the polymeric matrix. Therefore, when appli-
cable, in-situ sol-gel synthesis of the inorganic filler in the hydrophilic clusters of the
PEM is a preferred alternative to the nanocasting method [73, 76].
According to recent reports [76, 83, 84], endeavours to identify the conditions un-
der which inorganic-organic membranes provide properties superior to those shown
by their polymer-only counterparts have been successful, and there is every rea-
son to be optimistic that MEAs based on nanocomposite membranes have a role to
play in liquid feed fuel cells, or in the highly strategic operating conditions of low
RH at 110–130°C. Current hurdles persist: membrane electrical resistance and long-

term durability under fuel cell operation. Surface functionalization of the inorganic
fillers with protogenic groups is being exploited to boost membrane conductivity
[73, 85–87]. However, in-depth studies of aging and degradation under realistic oper-
ating conditions are still needed to enable the synthesis of more advanced materials
and alignment with current targets.
10.3 Characterization of solid polymer electrolytes
The performance of H2 /O2 and liquid feed fuel cells is strongly influenced by the pro-
ton and water transport properties of the PEM. The fuel cell ohmic loss is proportional
to the ionic resistance of the PEM, and high conductivity is essential to assure the
required performance. Water molecules in the membrane increase proton mobility
according to the vehicle mechanism, but a high water uptake by the membrane de-
creases the density of sulfonic acid groups or charge carriers [88]. Therefore, changes
in water content and water mobility have an impact on the proton conductivity of
membranes [78, 88].
This section provides a short description and application of complementary char-
acterization tools (proton conductivity measurements, dynamic vapor sorption, and
differential scanning calorimetry) used to assess transport properties of PEMs. Al-
though these are the first properties to be considered when evaluating PEMs for po-
tential use in fuel cells, it should be stressed that other chemical, morphological,
mechanical, and thermal properties are also critical for the definition of the “ideal”
electrolyte for fuel cell applications and the study of structure–property relationships.
These properties can be studied by means of several characterization techniques in-
cluding bulk chemical analysis and ion exchange capacity, thermal gravimetric anal-
ysis, transmission electron microscopy, small-angle x-ray scattering, tensile tests, dy-
namic mechanical analysis, fuel cell life, and Fenton’s tests [28, 89–91].
10.3.1 Proton conductivity
The proton conductivity of a membrane is determined by measuring its resistance

against the flow of a direct current or an alternative current at controlled temperature
and hydration level. The conductivity σ is calculated by the equation:
l
σ= , (10.6)
RS
where l is the distance between the two probe electrodes and S the cross-sectional area
of the membrane.
In the dc method, the potential difference across two probe electrodes in contact
with the membrane follows Ohm’s law over a wide range of current densities and the
resistance can be determined from the slope of the line ΔE vs j. In the ac method,
a periodic small-amplitude ac signal (voltage or current) is applied and the associ-
ated response (current or voltage) coming from the cell is measured [92]. The voltage
response to a sinusoidal current signal is a sinusoid, at the same frequency (ω) but
shifted in phase (φ):
it = i0 sin(ωt) (10.7)
Et = E0 sin(ωt + φ) (10.8)
The impedance, Z, is defined as the ratio of the voltage to the current at a given fre-
quency:
E E sin(ωt + φ)
Z= t = 0 (10.9)
it i0 sin(ωt)
By applying Euler’s relationship, the impedance can be expressed as a complex func-
tion with a real and an imaginary part:
Z = Z0 (cos φ + j sin φ) (10.10)
In an electrochemical system, slow kinetic reactions and diffusion of chemical

species can impede the flow of electrons. Electrochemical systems can thus be con-
sidered analogous to the resistors, capacitors, and inductors which hinder the flow
of electrons in an electrical circuit. In the case of a simple resistor, the phase shift is
zero degrees and the current is in phase with the voltage. Thus, according to equa-
tion (10.9), the impedance is purely real and independent of the frequency. For an
ohmic resistance Zt = R. Fig. 10.8 shows typical impedance data in the form of a Bode
plot obtained for a Nafion® 117 membrane using a four-probe cell (see below) at 100%
relative humidity. First, the frequency region over which the impedance has a con-
stant value is identified, and the impedance value taken to calculate the membrane’s
conductivity using equation (10.6) [93].
Electrochemical impedance spectroscopy is the most commonly used method for
measuring the membrane’s resistance and to determine its proton conductivity. It is a
rapid and accurate method and is quite suitable for dielectric materials such as PEMs.
The dc method has also been used [72, 94], the major advantage of this method being
the straightforward analysis of the E-j data.
Conductivity of the membrane can be measured perpendicular to the membrane’s
thickness (through-plane conductivity) or along the plane of the membrane (in-plane
conductivity). In addition, measurements can be made using either the four-probe or
103 8
Phase angle/degree
4
Impedance/Ω
–4
Impedance
Degree
102 –8
0 1 2 3 4 5
Iog frequency
Fig. 10.8. Impedance data recorded for a Nafion® 117 membrane at 100% RH. Data was acquired in
the in-plane-plane direction using a four-probe cell (reprinted with permission from [93]).
the two-probe method. In fact, there is no standard method for measuring the proton
conductivity of ionomers, and each method/cell configuration has its own advantages
and disadvantages. Figure 10.9 illustrates some of the conductivity cells reported in the
literature.
During fuel cell operation, protons move through the cross-section of the mem-
brane. Thus, measurements made in this direction are more relevant for practical ap-
plications. However, in this configuration the area of the electrodes (≈ cm2 ) is much
larger than the distance between them (given by the membrane thickness, ≈ microme-
ters), so the cell constant (l/S) is small and the contribution from the interface formed
between the membrane and the electrodes is large. On the contrary, for in-plane mea-
surements the cell constant is larger since the distance between the electrodes is of the
order of mm to cm, and the section of interest is the cross-section of the membrane.
The bulk conductivity of the membrane is the dominant element contributing to the
measurement [95]. Conductivity measurements in both directions are nevertheless im-
portant to quantify the effect of morphological anisotropy of PEMs on their proton
conductivity [95–97].
In the two-probe method, the voltage drop is measured across the same two elec-
trodes where the current flows. Accordingly, the measured impedance (or resistance)
includes the contribution of all components on the current pathway. When determin-
ing, for example, the membrane resistance from the total cell impedance, all other
contributions such as electrode resistance, lead inductance, and membrane – elec-
trode contact resistance should be subtracted from the total cell impedance [95, 98].
This is done by recording the impedance of the short-circuited and open cells [95].
With the four-probe method, only the bulk membrane resistance is measured because
two distinct pairs of electrodes are used, and current flow and voltage sensing are
done independently. The current is imposed on the external pair and the voltage drop
Teflon block Teflon block

Contact electrode
Contact electrode PEM
PEM Contact electrode
Teflon block
Teflon block
Contact electrode
(a) (b)
Membrane
Waveform generator
Galvanostat
(c)
I High impedance I
DVM
Δ Eref
Cation exchange
membrane
Glass
flange
8 cm
Saturated calomel
L reference electrode
Platinum gauze Luggin
counter electrode capillary Silicone-rubber
(1.5 cm2) gaskets
(d) 20 cm
Fig. 10.9. (a) In-plane and (b) through-plane two-probe conductivity cells; (c) In-plane and (d) four-
probe conductivity cells. (a) and (b) reprinted with permission from [94] and (d) reprinted with per-
mission from [95].
along the membrane sectional area is measured using the central pair of electrodes.
The effect of contact resistance is clearly seen in Fig. 10.10, which shows the variation
of the in-plane proton conductivity of a Nafion® 112 membrane exposed to 95% RH
and immersed in liquid water, as a function of the torque applied to the electrodes,
for a four-probe and a two-probe configuration. A lower interface resistance between
2x10–1
Four probe method at RH 95%
Two probe method at RH 95%
Four probe method in liquid water
1.5x10–1 Two probe method in liquid water
Proton conductivity (S/cm)
10–1
5x10–2
0.4 0.6 0.8 1.0 1.2 1.4 1.6

Torque (kgfcm)
Fig. 10.10. Effect of applied torque on the measured proton conductivity of Nafion® 112 by four-
probe (◼) and two-probe (∙) configurations at 95% RH and 60°C, and by four-probe (◻) and two-
probe (∘) methods in the liquid-water state at 60°C. Reprinted with permission from [98].
membrane and electrodes corresponds to a higher torque, and the influence of this ad-
ditional resistance is more important when the conductivity of the membrane is lower
(less hydrated membrane) [98].
Measurements of ion conductivity over a wide range of temperature and relative
humidity are important to determine the effect of composition and structure of the
new ionomers on the proton conduction and operational temperature. An example is
given in Fig. 10.11 which illustrates the effect of the filler content and composition on
the proton conductivity of Nafion® composite membranes containing TiO2 and propyl
sulfonic acid functionalized TiO2 nanoparticles [87]. The loading of an appropriate
amount of propylsulfonic-functionalized titania allows the preparation of Nafion® -
based composite membranes with higher conductivity and dimensional stability than
pristine Nafion® up to 140°C.
10.3.2 States of water and water mobility
Two critical parameters affecting the performance and proton conduction mechanism
of PEMs are their hydration level and water diffusion coefficient as a function of the
water content. It is therefore important to study the water sorption and diffusion be-
havior of electrolytes over a wide range of relative humidity.
140 120 100 80 60 40

–1.0
–1.2
–1.4
log (σ/S cm–1)
–1.6
–1.8 N_RC
N_5TiO2-RSO3H
N_10TiO2-RSO3H
–2.0 N_20TiO2-RSO3H
N_5TiO2
2.4 2.5 2.6 2.7 2.8 2.9 3.0 3.1 3.2 3.3
1000/T (K–1)
Fig. 10.11. Arrhenius plot of Nafion® , Nafion® -TiO2, and Nafion® propyl sulfonic acid functional-
ized TiO2 at 100% RH. The numbers in the legend indicate the wt% of filler with respect to Nafion® .
Dynamic vapor sorption

Dynamic Vapor Sorption (DVS) is a gravimetric technique which allows fast and ac-
curate determination of vapor sorption isotherms and diffusion kinetics. A simplified
scheme of the DVS apparatus is shown in Fig. 10.12(a) the samples are placed in a
weighing pan and exposed to partial pressure- and temperature-controlled environ-
ment. In order to study water management in solid electrolytes, water is used as sor-
bate and the electrolyte as sorbent. The vapor partial pressure around the sample is
controlled by mixing saturated and dry carrier gas steams using electronic mass flow
controllers. A constant temperature is maintained by enclosing the entire system in a
temperature-controlled incubator. By measuring the change in mass as a function of
time to equilibrium, a typical diagram such as that shown in Fig. 10.12(b) is obtained.
The amount of water uptake (WU) by the sample exposed to a defined partial pres-
sure can thus be obtained using equation (10.11):
m(eq)aw − mdry
WUaw = , (10.11)
mdry
where m(eq)aw is the mass of the sample at equilibrium for a defined water activity
(aw ), and mdry is the dry mass of the sample.
A sorption isotherm is the graphic representation of WU values; it describes the
relationship between the water content of the electrolyte and water activity at con-
stant temperature. Water is a small molecule and a polar adsorptive, therefore its
adsorption mechanism is influenced by water affinity to the adsorbent surface. The
Temperature Microbalance
controlled module
chamber
Humidity regulated
sample module
Flow control
generator
Dry gas
module
Vapour
module Vapour
Vapour
Sample reference
Camera option
(a)
7.25
Target aw 1.0
Water activity (aw=P/P0 )

7.00 Actual aw
0.8
6.75
M/mg
6.50 Mass 0.6
6.25 0.4
6.00
0.2
5.75
0.0
0 500 1000 1500 2000
(b) t/min
Fig. 10.12. (a) Illustration of the DVS apparatus interfaced with a personal computer (reprinted with
permission from Surface Measurements Systems), and (b) kinetics of water adsorption of a typical
Nafion® membrane at 25°C and different partial pressures.
shape of the isotherm thus also reflects the hydrophilicity/hydrophobicity of the sur-
face. IUPAC proposed a classification for water sorption isotherms as illustrated in
Fig. 10.13 [99, 100].
Each isotherm shape is related to a material with specific hydrophilic characteris-
tics. Type I is characteristic of every hydrophilic material. Type II and type IV isotherms
are characteristic of moderate hydrophilic materials. Adsorbents showing a type IV
isotherm are hydrophilic as well. Adsorbents with low hydrophilicity will give rise to
type III and type V isotherms. Type VI is typical of a hydrophilic material with mul-
tiple sorbent–water interactions and stepwise sorption, while type VII isotherms are
characteristic of very hydrophobic materials.
Hydrophilic materials
V V V V
I II IV VI
0 P/PO 0 P/PO 0 P/PO 0 P/PO
Hydrophobic materials
V V V
III V VII
0 P/PO 0 P/PO 0 P/PO
Fig. 10.13. IUPAC classification of adsorption isotherms for materials with different hydrophilicity.
Adapted with permission from [100].
Determination of the diffusion coefficient from DVS measurements

DVS measurements allow evaluation of the water diffusion coefficient through elec-
trolyte materials. Assuming that water sorption can be described by fickian behavior,
the water diffusion coefficient (D) can be calculated from the relationship between
mass variation and the time of water vapor exposure up to equilibrium [101]. This re-
lationship is obtained by combining Fick’s first law (10.12; describing the transfer of
solute atoms per unit area in a one-dimensional flow) and the conservation of mass
relationship (10.13) and expressed by Fick’s second law (10.14):
𝜕C
J = −D (10.12)
𝜕x
𝜕C 𝜕J
=− (10.13)
𝜕t 𝜕x
𝜕C 𝜕2 J
= −D 2 , (10.14)
𝜕t 𝜕x
where J is the amount of substance flowing per unit area as a function of time, C is
the concentration, and x is the position. Assuming constant diffusivity and that wa-
ter activity is constant across the membrane/vapor interface (c = c∞ at x ± d/2), solv-
ing (10.14) gives the normalized mass change as a function of the time:
Mt 4 D⋅t
= √ , (10.15)
M∞ d π
where Mt is the amount of water adsorbed at time t, M∞ is the amount of water ad-
sorbed at equilibrium, and d is the sample thickness.
D can be obtained by plotting Mt /M∞ for a sample exposed to a certain partial
pressure P/P0 (i.e., water activity) as a function of the square root of time (Fig. 10.14)
1.0
0.8
M(t)/M (∞)
0.6
0.4
Equation y = a + bx
Adj. R-Squar 0.9976
0.2 Value Standard error
Intercept –0.04147 0.01338
Slope 0.02505 0.00121
0.0
0 20 40 60 80 100 120 140

t1/2 / S1/2
Fig. 10.14. Typical plot of Mt /M∞ versus t1/2 at a given value of water activity (aw ). Adapted with
permission from [78].
and by fitting the curve to equation (10.15). This equation is valid for values of Mt /M∞ <
0.4, where the plot of Mt /M∞ against t1/2 is linear [102, 103].
Figure 10.15 shows the water diffusion coefficient of a Nafion® membrane as a
function of water activity, measured by DVS at 25°C. As shown, D increases with wa-
ter content in the membrane at low aw and reaches a maximum in the 0.3 to 0.4 aw
range. The increase in D in this aw range is due to the fact that water is less tightly as-
sociated with the sulfonic acid sites of Nafion® as water content increases. At higher
water activities, D decreases with increasing aw due to the water aggregation process
which occurs and provides kinetic limitations on the adsorption of water on the poly-
mer matrix [78].
Determination of the different states of water

It is also possible to obtain information about water mobility (and consequently
proton transport) from water sorption measurements by investigating the state of the
water in the electrolytes. In fact, specifically designed models can be applied to the
sorption isotherms in order to obtain insights into the water transport properties of
electrolytes.
For instance, conventional dual mode sorption models (Langmuir-type) are effec-
tive in describing isotherms which are concave towards the activity axis, while the
engaged species induced clustering model (Flory-type) has been highly successful in
modeling isotherms in polymers which are convex to the aw axis [104]. Multimode
sorption models (Park-type) are particularly suited to sigmoidal isotherms, which are
the most common isotherm shapes among ionomers [105].
1.75x10–7
1.50x10–7
1.25x10–7
D/cm2s–1
1.00x10–7
7.50x10–8
5.00x10–8
2.50x10–8
0.00
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
aw
Fig. 10.15. Water diffusion coefficient (D) values of a recast Nafion® membrane as a function of water
activity at 25°C. Adapted with permission from [78].
By applying the multi-mode model proposed by Park to the sorption isotherms, the
presence of three different mechanisms in the sorption process can be hypothesized:
(a) specific adsorption at low water activity, described by the Langmuir model;
(b) nonspecific adsorption, described by Henry’s law;
(c) water clustering at high water activity.
All of these contributions can be formulated in the following equation:

aL KL aW
WU = + KH aw + nKA anW , (10.16)
1 + KL aW
where aL is the specific site capacity, KL is an affinity constant, KH is Henry’s law co-
efficient, KA is the aggregation equilibrium constant, and n is the aggregate size.
A distinct population of water adsorbed in the membrane can be associated to
each adsorption mechanism: specific adsorbed water (WSA ), nonspecific adsorbed wa-
ter (WNSA ), and clustered water (WC ). Each water population is described by the terms
constituting equation (10.16) as follows:
aL KL aW
WSA = (10.17)
1 + KL aW
WNSA = KH aw (10.18)
WC = nKA anW (10.19)
Figure 10.16 depicts the typical result of the curve fitting of a polymer membrane sorp-
tion isotherm, where the adsorbed water was separated into three contributions so
that the sum of WSA , WNSA , and WC matched the experimental isotherm data.
Taking into account that each type of adsorbed water is characterized by different
mobility, we correlated the different water population to the water mobility degree in
the membrane.
Being strongly bound to specific sites, the specific adsorbed water is character-
ized by low mobility, whereas the dissolved water molecules (Henry population) have
higher mobility. The growth of water clusters then reduces the mobility of the water
aggregates. As a consequence, among the three types of water population, the non-
specific adsorbed water is characterized by the highest mobility.
The amount of each type of adsorbed water was normalized to the total water con-
tent in the membranes as follows:
W[SA]
θW [SA] = × 100 (10.20)
WTOT
W[NSA]
θW [NSA] = × 100 (10.21)
WTOT
W[C]
θW [C] = × 100 (10.22)
WTOT
As θ parameters were defined, θW [SA], θW [NSA], and θW [C] represent the “specific ad-
sorbed water degree”, “nonspecific adsorbed water degree”, and “clustered water de-
gree”, respectively. As shown in Fig. 10.16(b), specific adsorbed water dominates at
low relative humidity, nonspecific adsorbed water at intermediate values of RH, and
clustered water dominates at high relative humidity. These variations are consistent
with those found for D and shown in Fig. 10.15. The θW [NSA] parameter thus represents
the “water mobility degree” and allows comparison of different electrolytes in terms
of water mobility: the higher θW [NSA], the greater the water mobility in the electrolyte
is expected to be [72, 78].
As already mentioned, the analysis of water sorption isotherms of ionomers is
of paramount importance for the final fuel cell performance and scientific litera-
ture in this field is mainly based on adsorption properties of water on perfluorinated
polymers, in particular Nafion® , which is the state-of-the-art material [106]. Sorp-
tion isotherms of most common perfluorinated ionomers can be indeed described
by Park’s model. However, the involvement of five adjustable parameters (see equa-
tion (10.16)) makes the chemico-physical interpretation unclear for ionomers whose
microstructure is considerably different from that of Nafion® , which is the case for
polyaromatic polymers (see Fig. 10.6). The less pronounced hydrophobic/hydrophilic
separation in polyaromatic polymers compared to Nafion® makes the distinction be-
tween specific adsorbed water, nonspecific adsorbed water and clustered water (WC )
quite difficult.
As an alternative to the multimode Park’s model, the sorption behavior of the
membranes can be analyzed and interpreted on the basis of the dual mode sorption
model proposed by Feng [107]. The model is based on the Guggenheim–Anderson–
25
Equation: Adj. R-Square: 0.99828
Park model Red. Chi-Square: 0.0614
Value Standard error
20
Sample N_0_HP AL 2.89 0.418
KL 5.85 0.423
KH 9.38 0.729
WU/wt.%
15 n 10.1 0.87
KA 1.43 0.125
10 Experimental data
Curve fitting
WC
5 WNSA
WSA
0
0.0 0.2 0.4 0.6 0.8 1.0

(a) aw
70 θNSA
60
50
θSA
40
θ/%
30
20
10
θC
0
0.0 0.2 0.4 0.6 0.8 1.0

(b) aw
Fig. 10.16. (a) Typical curve fitting (Park’s model) of experimental sorption isotherm data (Nafion®
membrane at T = 25°C) and the corresponding fitting parameters, (b) variation of the three types of
water population in the membrane with the water activity. Adapted with permission from [78].
de Boer (GAB) multilayer sorption theory [108–110] and, at variance with the GAB
model which considers all sorption sites equivalent, the Feng model is based on the
assumption that the sorption sites can be divided into two different types, one be-
ing the polymer matrix region and the other the microvoid region (specific sorption
sites).
According to this model, the water content in the membranes can be described
using equation (10.23):
k󸀠 aw (A󸀠 − 1)k󸀠 aw
WU = Cp 󸀠
+ Cp , (10.23)
1 − k aw 1 + (A󸀠 − 1)k󸀠 aw
where Cp is the weighted mean value of the polymer sorption capacity, k󸀠 and A󸀠 are
temperature-dependent constants, k󸀠 provides a measure of the interaction between
water and the polymer matrix. Values lower than 1 indicate very weak interactions be-
tween water and polymer matrix. The higher the k󸀠 value, the greater the hydrophilic-
ity of the polymer. A󸀠 represents the difference between the interaction of a microvoid
and its first molecule adsorbed, and that of a microvoid and the subsequent adsorbed
molecules. Thus it provides a measure of the affinity between water and the polymer
microvoid. A󸀠 values close to 1 correspond to a polymer in a rubbery state without
microvoids; the higher A󸀠 is, the greater the dependence of sorption on microvoids
and affinity of specific sites to water.
Feng’s model requires only three parameters: Cp, the weighted mean value of the
sorption capacity of the polymer to water, k󸀠 , the affinity between water and the poly-
mer matrix (hydrophobic region), and A󸀠 , the affinity between water and the polymer
microvoid (hydrophilic domains). Rather than discriminating between the differ-
ent states of water in the membrane, the values and comparison of Feng’s parame-
ters make deep insight into chemical nature, and also into polymer microstructure
possible.
Figure 10.17 shows the water adsorption isotherms of Nafion® and sulfonated
polysulfone (SPS) with the result of a typical curve fitting Feng’s model. The figure
shows the very good match between the experimental data and the fit curves, and the
corresponding fitting parameters of all samples are summarized in the inset table.
Cp, k󸀠 , and A󸀠 parameters of the unfilled Nafion® membranes are in good agreement
with values found in previous papers. Both polymers showed low k󸀠 values, indicating
that sorption in the polymer matrix region is negligible. Hence, microvoid sorption is
predominant, as expected in the case of ionomer systems in which water associates
through the sulfonic acid groups, and Cp represents the monolayer sorption capacity
in the microvoid region (specific adsorption) [83, 111].
The comparison between the fitting parameters of unfilled Nafion® and SPS indi-
cated that Cp was higher for SPS than for Nafion® , whereas the A󸀠 parameter shows
the opposite trend. Differences in Cp and A󸀠 for Nafion® and SPS are ascribed to dif-
ferences in the microstructures of the two ionomers.
Both Nafion® and SPS phases separate in hydrophilic and hydrophobic domains.
The hydrophobic domains consist of the perfluorinated and polyaromatic backbone
of Nafion® and SPS respectively. The hydrophilic domains arise from the sulfonic acid
groups (–SO3 H) which are responsible for bonding with water molecules. Hydropho-
bic/hydrophilic separation is more pronounced in the case of Nafion® , as depicted
in Fig. 10.6. The greater tortuosity of the hydrophilic domains in SPS than in Nafion®
35
Sample Parameters Value SE
Nafion Cp 3.57 0.07
30 SPS
Reduced Chi-Sqr k' 0.88 0.03
0.04697
25 Adj. R-Square A' 15.8 1.8
0.99893
S Cp 7.46 0.37
20
Reduced Chi-Sqr k' 0.83 0.01
WU/%
0.32917
15 Adj. R-Square A' 5.32 0.42
0.99697
Nafion
10
0.0 0.2 0.4 0.6 0.8 1.0

aw
Fig. 10.17. Curve fitting of experimental adsorption isotherm data of the unfilled Nafion® and SPS
membranes at T = 25°C. SE = Standard Error. Adapted with permission from [83].
makes the water phase in SPS lower interconnected than in Nafion® , thus explaining
the higher Cp and lower A󸀠 values of SPS compared to those of Nafion® .
Differential scanning calorimetry

Differential Scanning Calorimetry (DSC) is a thermoanalytical technique which mon-
itors heat effects associated with phase transitions and chemical reactions as a func-
tion of temperature [112–114]. It consists of measuring the difference in heat flow be-
tween the sample and a reference at the same temperature, the temperature of both
sample and reference being increased at a constant rate. The heat flow difference be-
tween the sample and the reference can be either positive or negative, depending on
whether the process is endothermic or exothermic. The result of a DSC experiment is
a curve of heat flux versus temperature or time. The area enclosed between the trend
line and the base line is a direct measurement of the amount of heat, ΔH, needed for
transformation. Useful information can be obtained by DSC analysis of polymer sam-
ples, such as degree of crystallinity (from the ratio of the heat of fusion of a polymer
sample and the enthalpy of a 100% crystalline sample), specific heat, the purity of the
polymer and occurrence of oxidation, cross-linking, and chain breakage.
As far as water management of electrolytes is concerned, DSC provides informa-
tion on states of water and water mobility through the electrolyte material. Focusing
on ionomer electrolytes, three different categories of water can be discerned by record-
ing DSC thermograms at subzero temperatures:
(1) nonfreezable bound water (WNF ), strongly bound to the ionic groups present in the
polymer. This type of water is characterized by the fact that it does not crystallize
even when the swollen sample is cooled down to −100°C. These water molecules
are in close proximity to an ionic group as in hydration shells, are highly polarized,
and are unable to crystallize. WNF does not yield characteristic thermal transition
in DSC analysis.
(2) Freezable bound water, weakly polarized. This type of water crystallizes at tem-
peratures below than 0°C.
(3) Freezable unbound water, which crystallizes at 0°C.
Freezable water (WF ), being more loosely bound, has higher mobility than nonfreez-
able water and is expected to give a more significant contribution to the proton trans-
port mechanism.
By performing DSC analysis in the range between −50°C and 10°C, freezable water
can be quantified from the endothermic peak below 0°C. An example of DSC thermo-
grams obtained from two different polymer electrolyte membranes showing an en-
dothermic peak ascribed to the melting of freezable water is given in Fig. 10.18.
–1.0
–0.8
Heat flow/Wg-1
–0.6 (b)
–0.4
–0.2
ENDO Fig. 10.18. DSC thermogram of
(a) (a) an unfilled Nafion® membrane,
–0.0 and (b) a composite Nafion® /
–40 –35 –30 –25 –20 –15 –10 –5 0 5 10 zeolite membrane. Reprinted with
T/°C permission from [78].
The percentage of freezable water in the sample can obtained from the following for-
mula:
A 1
WF (%) = ( ) × 100, (10.24)
ΔHW mdry
where A is the area of the endothermic peak, ΔHw is the enthalpy of melting for bulk
water (333 J g−1 ), and mdry is the mass of the dried sample.
The degree of freezable water, θF , can be defined by normalizing the freezable
water content to the total WU, which can be measured gravimetrically (for instance
by DVS).
W
θF = F × 100 (10.25)
WU
As previously mentioned, a higher degree of mobile water corresponds to higher

proton conductivity, and since WF yields to thermal transitions similar to bulk water,
its content in the membrane can be discerned from total WU by using DSC [72, 78].
Figure 10.19 shows the variation of θF with the filler content for Nafion® –zeolite
composite membranes. Zeolites are aluminosilicates with cations relatively free to
move along the cavities of the framework. Moreover, they have a very high specific
surface area which results in a high water sorption capacity, further facilitating the ion
transport. As the zeolite content increases, qF values increase up to a maximum value
and then decrease at highest zeolite content. These findings indicate that the zeolite
likely contributes to the enhancement of the water mobility degree in the composite
membrane, which is related to its high water sorption capacity and to the introduction
of porosities at the polymer/filler interface. However, the reduction of this effect over
ca. 4 wt% zeolite content, suggests the formation of dead-end porosities which hinder
water mobility [78].
55
50
45
θF /%
40
35
30
25
0 5 10 15 20
Zeolite content/wt.%
Fig. 10.19. Variation of θF as a function of the zeolite content for Nafion® –Faujasite composite mem-
branes. Adapted with permission from [78].
10.4 Summary
Solid electrolytes are materials capable of conducting ions. They are used in many
electrochemical devices including batteries, sensors, electrolyzers, and fuel cells.
Proton exchange membrane fuel cells are considered attractive power sources for
portable applications, in-situ power generation, and for automotives. Nevertheless,
these systems still suffer from limitations which need to be addressed before they
can compete with batteries, fossil fuels, and internal combustion engines. Polymer
electrolyte membranes are one of the limiting elements of this technology. Nafion® ,
a perfluorinated sulphonic acid ionomer, is the most widely used electrolyte for both
hydrogen and liquid-fed proton exchange membrane fuel cells due to its high pro-
ton conductivity, chemical and mechanical stability. A unique feature of Nafion® is
the microphase separation between the hydrophobic backbone and the hydrated sul-
fonic acid domains, resulting in the formation of wide and well-separated water chan-
nels for proton transport. Nafion® membranes show a strong dependence of proton
conductivity on the membrane’s hydration level and are permeable to liquid fuels. In
the first case, the fuel cell system needs an expensive humidification auxiliary system
to keep the membranes hydrated. In the second, fuel cell efficiency is dramatically
reduced. Therefore the development of alternative polymer electrolyte membranes
with high proton conductivity in a wide range of temperature and hydration condi-
tions, which exhibit mechanical robustness, chemical and electrochemical stability,
low cost, and low fuel permeability remains a critical challenge for advancing fuel cell
technology.
Hydrocarbon membranes are potential candidates to replace Nafion® . Significant
efforts are being made to develop novel ionomers consisting of hydrocarbon back-
bones and pending side chains with terminal sulfonic acid groups to mimic Nafion® ’s
unique morphology. Structure–properties relationships are fundamental to learn
about the dependence of the transport properties on the membranes’ composition,
morphology, and water content, and to design better electrolytes.
Proton conductivity is a fundamental property of a proton exchange membrane.
When evaluating potential electrolytes for fuel cells, their proton conductivity is usu-
ally measured under controlled temperature and relative humidity. There is not yet
a standard method for measuring the membranes’ proton conductivity, but measure-
ments on both directions of the membrane (in-plane and through-plane) could pro-
vide valuable information on the membranes’ anisotropy. Proton conductivity of elec-
trolytes depends on their hydration level; hence it is important to study water sorption
and water diffusion over a wide range of relative humidity. The water states and water
diffusion in electrolytes can be assessed by dynamic vapor sorption and differential
scanning calorimetry. Excellent correlation has been found between proton conduc-
tivity and degree of mobile water determined by the two methods mentioned.
Advances in proton exchange membranes for fuel cells will likely contribute to the
development of other related fields including electrodialysis (water purification and
treatment) and redox flow batteries for energy conversion.
Acknowledgments
The authors would like to thank Maria J.V.R. Paulo (INRS-EMT) for helping with the
editing of this chapter.
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11 Supercritical adsorption of hydrogen on
microporous adsorbents
11.1 Introduction
Physical adsorption on microporous adsorbents is widely used in industrial physico-

chemical processes such as gas separation and purification [1, 2]. The adsorption phe-
nomena can be defined as the enrichment or depletion of a species of fluid in an inter-
facial layer between the fluid and a substrate [3]. The absorption process, in contrast,
occurs when the species is integrated into the structure of the substrate. Chemisorp-
tion typically involves both phenomena. Physisorption (or physical adsorption) is as-
sociated with weak and nonspecific interactions, typically van der Waals forces. Ph-
ysisorption does not involve the hybridization of electronic orbitals. The distinction
between physisorption and chemisorption can be subtle. Typically, adsorption pro-
cesses with a characteristic energy scale smaller than 15 kJ/mol are considered to be
physical. The adsorption process occurs within the porous structure of the adsorbent,
which is the volume of the adsorbent externally accessible to the adsorbate molecules.
The pores are formally classified by IUPAC as micropores (characteristic size < 2 nm),
mesopores (2–50 nm) and macropores (characteristic size > 50 nm) [4]. Gas storage
applications of the adsorption phenomena usually require maximizing the micropore
volume of an adsorbent.
The adsorption process can be used to store light gases at substantially lower pres-
sures, offering the possibility of safer storage conditions with respect to high pressure
compression. The storage density of gases such as hydrogen and methane can thus be
increased significantly through the interatomic and intermolecular forces between the
adsorbate molecules (adatoms) and a solid surface. Materials-based storage of gases
such as hydrogen can also be achieved through chemical binding to other elements
(chemical hydrides) or through absorption inside a solid metallic matrix (metal hy-
drides). For materials-based storage, the characteristic binding energy of hydrogen
to the material is a determining factor in the thermodynamic description of systems.
It sets the energy scale required for charging and discharging gases, regulates its ther-
mal behavior, and determines boil-off rates. Materials with binding energies smaller
than 10 kJ/mol require cryogenic operation to achieve acceptable storage densities.
Passive heat sources from the environment can then be used to thermally manage out-
gassing. Low binding energies occur when hydrogen is reversibly bound in molecular
form to a substrate through weak, nonspecific interactions. The hard-to-achieve range
of 10–20 kJ/mol is believed to be optimal for materials-based hydrogen storage appli-
cations closer to room temperature.
11.2 Fundamentals of supercritical adsorption
Weak interactions between a gas and a substrate usually result in the adsorption of
gas molecules (the adsorbate) onto the surface of the substrate (the adsorbent). The
adsorption effect corresponds to a local enhancement of the density of the adsor-
bate close to the adsorbent’s surface resulting from those interactions, in the region
where the adsorbate/adsorbent interaction potential is significant (Fig. 11.1). The to-
tal adsorbed density nt is defined as the number of adsorbate molecules present in
the porous structure of the adsorbate. The adsorbed density of the adsorbate is usu-
ally divided by the quantity of adsorbent, either volumetrically (quantity of adsorbate
molecules per unit volume of adsorbent) or gravimetrically (per unit mass of the ad-
sorbent). Both are related to one another by the density of the adsorbent.
The density profile of the gas close to the surface can be separated into 3 regions:
(1) the solid phase, (2) the interface, and (3) the gas phase with volumes Vs , Va, and Vg ,
respectively. The volume of the solid phase (Vs ) is also called the volume of the skele-
ton, as it excludes the contribution of the pores. The total volume of the adsorbate is
(a)
Interface Gas
ntot
Solid
ng
0
d
(b) Fig. 11.1. (a) Interaction potential between an ad-
sorbate molecule and the surface of an adsorbent.
ntot (b) Typical density profile of a gas close to an ad-
sorbing surface. The enhanced density in the vicinity
of the adsorbent is caused by gas-surface interac-
Solid
Gibbs surface tions. The boundary indicated on the figure depends

on the definition of a cut-off for the interaction po-
ng tential. (c) Gibbs dividing surface: the adsorbed
Gas atoms are smeared onto the solid. The dividing sur-
0 face is an ideal construct separating the adsorbent
X0 d
(c) and the adsorbate gas.
the sum of the three contributions. The adsorbate is usually described as belonging to
one of two phases: the gaseous phase (where the interaction potential is negligible)
or the adsorbed phase located in the interface.
The excess adsorbed density (na ) is defined as the number of molecules in a
porous structure in excess of the number that would be present in the same volume
under the same thermodynamic conditions in the absence of adsorbate-adsorbent
interactions. It can be defined as follows:
n a = n t − n g Vp .
The pore volume (Vp ) is defined as the sum of the volume of the gas phase in the ad-
sorbent and of the volume of the interface.
It is clear from Fig. 11.1 that the distinction between adsorbed molecules and the
bulk gas is ambiguous for long-range interaction potentials, which do not have a clear
cut-off. The boundary between the phases can be conventionally defined using a ref-
erence gas that is assumed to be nonadsorptive under ambient conditions. In Gibb’s
formulation of adsorption, this is done through the Gibbs dividing surface. The Gibbs
surface is chosen in such a way that the excess density of the reference gas (typically
helium) is zero under ambient conditions:
na (T0 , P0 ) = nt − ng Vp = 0.
This equation defines Vp and the location of the dividing surface. The pore volume
(Vp ) thus formally depends on the reference gas and the thermodynamic conditions
under which it is calculated.
In the Gibbs approach, the gas phase density is assumed to be constant and equal
to the bulk phase up to the Gibbs dividing surface [5]. The adsorbed gas molecules
(sometimes referred to as the adatoms) are assumed to be located on the surface. The
adsorbate phase has no volume (Va = 0). When considered as an interface problem,
the thermodynamic description of adsorption requires the introduction of the surface
area of the interface as a thermodynamic variable [6], coupled to a conjugate force
called the spreading pressure. It is coupled to the interfacial surface area in the free
energy equations of the system. The spreading pressure is not directly accessible and
acts as an intermediate calculation variable.
For highly microporous adsorbents (∼ 1.5 nm), the pore size is usually such that
from a microscopic point of view, an adatom is affected by adsorbent-adsorbate inter-
actions throughout the pore structure of the adsorbent. As a result, the local adsorbate
density remains larger than the free gas value in the pore volume. A macroscopic de-
scription of the adsorption process based on interface properties then becomes coun-
terintuitive, as a zero-volume interface has no simple microscopic correspondence.
From a macroscopic point of view, however, a consistent thermodynamic description
of the adsorption phenomena in microporous adsorbents based on interface thermo-
dynamic variables can still be used, as the latter are intermediate calculation variables
not directly accessible experimentally [6].
The adsorption isotherm (na (T, P)) expresses the relationship between the excess
density defined in the Gibbs sense and the pressure of the bulk gas phase with which
it is in equilibrium for a given temperature. It represents the difference between the
mass of adsorbate in the porous structure of the adsorbate and the amount that would
be present in the same volume in the absence of the adsorbate. The Gibbs adsorp-
tion isotherm is also called the excess adsorption isotherm and can be seen as the
gain in density over compression at the equilibrium pressure and temperature. The
absolute adsorption isotherm refers to the total amount of hydrogen present within
the potential field of the adsorbent. Obtaining the absolute adsorption isotherm from
the excess requires knowledge of the volume of the adsorbed phase, which is not di-
rectly accessible experimentally and depends very much on the definition of a cut-off
of the adsorbate/adsorbent interaction potential. For highly microporous adsorbents,
in which most of the volume of the pores is subject to the interaction potential, the
absolute adsorption isotherm corresponds to the total uptake of adsorbate inside the
pores. However, if macropores and mesopores are also present, adsorbate molecules
far from their surfaces should be excluded. An unambiguous definition of the abso-
lute adsorption isotherm can therefore be difficult, particularly for adsorbents with a
complex pore size distribution. The excess adsorption isotherm represents, however,
a clear and experimentally accessible concept.
The classification of adsorption isotherms by the International Union of Pure
and Applied Chemistry (IUPAC) consists of 6 categories [7]. Types I–III are reversible
isotherms which do not exhibit hysteresis. The Type I isotherm is concave with respect
to the pressure axis. It is usually associated with microporous solids (e.g., activated
carbons, molecular sieve zeolites, and certain porous oxides). The Type II isotherm
represents unrestricted monolayer-multilayer adsorption occurring in a macroporous
adsorbent. Point B in Fig. 11.2 indicates where multilayer adsorption begins to take
place. Type III isotherms are uncommon and characterized by a convex curve with re-
spect to the pressure axis. Type IV and V isotherms exhibit a hysteresis loop. Type IV
isotherms are associated with capillary condensation taking place in mesopores.
Type V isotherms are related to Type III, with a hysteresis loop as an additional
feature. Type VI isotherms are associated with stepwise multilayer adsorption on a
uniform nonporous surface. The height of each step is associated with the monolayer
capacity for each adsorbed layer.
Only adsorption processes associated with Type I isotherms will be addressed in
this chapter. We will only consider supercritical adsorption, which occurs above the
critical point of the adsorbate. We will thus limit ourselves to physical adsorption (or
physisorption) processes, associated with relatively weak adsorbate-adsorbent inter-
actions, and to the study of single component adsorbates, as the focus of this paper is
gas storage.
As discussed in the introduction, the adsorption phenomena, through gas sur-
face interactions, offers the possibility of substantially lowering the storage pressure
of gases [1, 2]. The presence of an interaction potential with a characteristic binding
energy (EA ) permeating narrow pores can substantially enhance the equilibrium den-
sities of the adsorbed gas inside the pore, compared to the far-field bulk gas, resulting
in very high local pressures in the pores of the adsorbing nanostructure. The resulting
fluid densities of the adsorbate in the pores can become comparable and sometimes
even exceed its liquid density, depending on the pressure and temperature of its bulk
phase. In addition to the characteristic energy (EA ), the surface area available for ad-
sorption processes and the bulk density of the adsorbent are important parameters for
adsorption-based applications. The specific surface is an important contributor to the
saturation density of an adsorbent, whereas the bulk density determines the weight of
the storage unit. Both parameters can be combined into the surface available to the ad-
sorbate per unit volume of the adsorbent, which should be maximized to optimize the
storage density. This quantity can be expressed in terms of adsorbate mass/adsorbent
volume, or adsorbate volume/adsorbent volume, the latter yielding the former when
multiplied by the bulk gas density at 298 K and 1 atmosphere of the adsorbate.
I II
III IV
Amount odsorbed
V VI
Fig. 11.2. Types of adsorption isotherms.

Relative pressure Reprinted with permission from [7].
11.3 Supercritical adsorption isotherms
The adsorption isotherm is the equation of the state of the adsorption process and as
such, plays a key role in its thermodynamic description. Predictive strategies involve
first principles calculations using computer simulations and numerical analysis of its
properties in specific limits. Such approaches include ab initio quantum chemistry
calculations, grand canonical Monte Carlo simulations (with or without quantum cor-
rections), the virial expansion, and to some extent classical density functional theory.
Descriptive approaches aim to describe the isotherms using adsorption models (ana-
lytic or not) appropriate for the adsorbent structure and the adsorbate-adsorbent in-
teractions. These rely on approximations which invariably limit their applicability to
specific ranges of pressure and temperature.
11.3.1 Virial expansion of the excess density in terms of pressure
In the low pressure limit, the excess adsorbed density can be expressed as a virial
series expansion in terms of pressure [8]:
p p2 p3 p4
na (p, T) = BAS + BAAS 2
+ CAAS 3
+ DAAS + ..., (11.1)
kT (kT) (kT) (kT)4
where p is the pressure of the gas phase. At the lowest order in pressure, the exces-
sadsorbed density varies linearly with pressure, which corresponds to Henry’s law as
applied to the adsorption phenomena.
The coefficient BAS , generally called the second virial coefficient, is fully deter-
mined by the interaction U (r)⃗ between a single molecule and the surface of the adsor-
bent:
1 U (r)⃗
BAS (T) = ∫ (exp (− ) − 1) dr,⃗ (11.2)
M kT
where M is the mass of the adsorbent. The virial coefficient BAS can be obtained ex-
perimentally by finding the intercept of a plot of na (p, T) kT/p as a function of the
pressure (p). The interaction potential V(r)⃗ between an adsorbate molecule and the
adsorbent atoms can be written as:
U(r)⃗ = ∑ Uαi (r ⃗ − R⃗ i ), (11.3)

i
where r ⃗ and R⃗ i are the positions of the adsorbate molecule and the ith atom of the
adsorbent, and where αi refers to the atomic species of the atom at R⃗ i . The interaction
potential U(r)⃗ is often modeled using the Lennard-Jones potential:
6 12
Uαi (r)⃗ = 4ε [(σ/r) − (σ/r) ] , (11.4)
where σ is the distance where V(r)⃗ = 0 and 𝜖 is the minimum interaction energy.
Effective adsorbate-adsorbent potentials based on the Lennard-Jones potential

have been developed to model the interaction of a crystalline adsorbent surface with
adsorbate molecules. The planar Lennard-Jones potential, for instance, represents an
averaged interaction potential resulting from smearing the atoms of a corrugated pla-
nar crystal into a uniform, continuous distribution onto an infinite two-dimensional
plane. The 10-4 Lennard-Jones planar potential is given by the:
2 1 1
V (y) = 2εs ( − ), (11.5)
5 y10 y4
where εs = πθεσ2 . The parameter θ is the surface density of a graphene plane (0.38
atoms per Å [2]). The variable (y) is dimensionless and rescaled to σ (y = z/σ) and rep-
resents the distance (z) along the normal to the plane. The parameters ε = 30.5 K and
σ = 3.19 Å represent, respectively, the Lennard-Jones energy and distance parameters
between carbon atoms and hydrogen.
The pores of an activated carbon are typically modeled using the so-called slit
pore approach, in which they consist of two parallel smeared infinite graphene lay-
ers separated by the characteristic pore size (d). The resulting interaction potential
is shown in Fig. 11.3. As a function of decreasing distance between the graphene lay-
ers, the well depth of the potential gets deeper as the overlap of the contributions
from each plane increases. Ultimately, the two minima overlap completely, resulting
in a single well. Further decreasing the distance between the planes will decrease the
depth of the well, until the interaction potential in the pores becomes positive every-
where, quenching the adsorption process in the pore.
V
є
0.5
z
–2 –1 1 2 σ
–0.5
–1.0
Fig. 11.3. The slit pore potential for activated carbons. A pore is modeled by two infinite parallel
graphene layers smeared into planes, separated by a distance assumed to be representative of
the size of the pore resulting in the above adsorbate–adsorbent interaction potential within the
slit pore.
Assuming an average noncorrugated planar interaction potential between the ad-

sorbent planes and an adsorbate molecule, the second virial coefficient is then given
by:
d∗ /2
BAS
= 2 ∫ [e kT [V(y+d /2)+V(y−d /2)] − 1] dy,
−1 ∗ ∗
(11.6)
SA σ
0
where d∗ = d/σ, y is a dimensonless integration variable, and SA is the specific surface,

which is the area of the adsorbent accessible to adsorbate molecules per unit mass of
the adsorbent. The second virial coefficient BAS for the activated carbon AX-21 is shown
in Fig. 11.4.
12
10
8
In (B AS/αZo )
–2
0 2 4 6 8 10 12 14
X = ɛs/kT
Fig. 11.4. Normalized second virial coefficient as a function of the rescaled inverse temperature. The
line shows the theoretical curve. The black and white dots show experimental data points from the
adsorption of methane and hydrogen (respectively) on the activated carbon AX-21. The normalized
curve is expected to be universal for nonpolar classical gases. Reprinted with permission from [12].
The distance (d) and the specific surface of the activated carbon are treated as ad-
justable parameters, the values d = 8.1 Å for the interlayer distance and 2 900 m2 /Å
for the specific surface area for hydrogen sorption on the activated carbon AX-21 are
obtained. Although the estimated specific surface is close to the experimentally de-
termined BET value (2 800 m2 /Å), DFT analysis of the adsorption isotherm suggests a
pore size distribution peaked around 12.5 Å.
The second virial coefficient of single-wall nanotubes has also been studied using
a cylindrical potential in the continuum approximation [9]:
21 1 10 1 4
V∗ (r∗ , R∗ ) = 3 [ ( ∗ ) M11 (r∗ /R∗ ) − ( ∗ ) M5 (r∗ /R∗ )] , (11.7)
32 R R
where r∗ = r/σ, R∗ = R/σ, and V∗ (r∗ , R∗ ) = V(r∗ σ, R∗ σ)/εs are respectively the reduced
distance from the axis, the reduced radius of the SWNT, and the reduced potential,
with
π
dφ
Mn (x) = ∫ . (11.8)
(1 + x 2 − 2x cos φ)n/2
0
The interaction potential inside a nanotube is shown in Fig. 11.5.
10
–10
V/ε
–20
–30
–40
0.0 0.2 0.4 0.6 0.8
r/R
Fig. 11.5. Potential of Stan and Cole for SWNT of various diameters R and helium, a function of
the distance from the center, divided by R. When the radius R is smaller than a critical value
Rc = 1.212 σ, the minimum is at the center. Further decreasing the radius leads to a shallower po-
tential well, and eventually a positive repulsive core [9].
Stan and Cole [9, 10] performed a study of the virial coefficient BAS for the adsorption
of rare gases on single wall nanotubes as a function of the radius using the cylin-
drical Lennard-Jones potential. The adsorbed density of Ne atoms on an SWNT was
compared to that obtained using a planar graphene sheet with the same surface area.
They found a significantly larger adsorbed density inside the SWNT compared to the
graphene sheet due to the curvature of the nanotubes. An estimate of the maximum
binding energy of adsorbate molecules in the cylindrical pore can be determined with
the cylindrical potential. The value of the potential at the centre of the tube is found
by setting normalized distance r∗ to zero in equation:
21 σ 10 σ 4
V (x = 0, R) = 3π2 θεσ2 ( ( ) − ( ) ). (11.9)
32 R R
From this expression, it can be determined that the maximum well depth is Vo =
V(r = 0, R) = −12.77 θε (or 12.5 kJ/mol for hydrogen) for a radius R0 = 1.086 σ, or
R0 = 3.43 Å for hydrogen.
The second virial coefficient, for uncapped SWNTs of length L, is given by the
following expression:
1
BAS = ∫ dr ⃗ (exp (− V (r,⃗ R)) − 1) . (11.10)
kT
V
Since the interaction potential is only a function of the normalized radius, the volume
integral can be performed using cylindrical coordinates:
2π L/2 ∞
1
BAS = ∫ dθ ∫ dz ∫ rdr (exp (− V (r∗ , R∗ )) − 1), (11.11)
kT
0 −L/2 0
which leads to
∞
BAS 1
= 2π ∫ r∗ dr∗ (exp (− ∗ V∗ (r∗ , R∗ )) − 1). (11.12)
Lσ2 T
0
Capped nanotubes do not adsorb internally, so the volume integral must exclude the
internal volume of the nanotube:
∞
BAS 1
= 2π ∫ rdr (exp (− V (r∗ , R∗ )) − 1). (11.13)
Lσ2 ∗
T
R
The behavior of the second virial coefficient as a function of the radius of the
nanotube is quite complex, and summarized in Fig. 11.6 below for hydrogen. At 77 K,
the coefficient BAS reaches its maximum value when the radius of the nanotube cor-
responds to the maximum well depth of the adsorption potential in the nanotube
(full line). The peak value of BAS is 3 orders of magnitude greater than the equiva-
lent graphene sheet. This feature, associated with a strong peak, is absent when the
nanotube is closed. The peak is quenched very quickly as a function of temperature.
At larger radii, the curves converge towards the value of an equivalent graphene sheet.
It is worthwhile to note that the smallest possible SWNT has a radius equal to that of
a C20 . These have been observed inside multi-walled carbon nanotubes as their inner-
most shells. The smallest experimentally accessible SWNTs have radii comparable to
C60 (3.5 Å). The quenching of the BAS of open SWNTs observed at higher temperatures
can be linked to the presence of repulsive and attractive regions inside the nanotube,
which at low temperature usually lead to a positive and large value of the integrant in
the expression for BAS , but which can become negative at lower temperature because
the exponential, which is sensitive to temperature, is subtracted by a temperature-
independent constant. It is then possible for the virial coefficient to become negative
and impair the adsorption process to first order in pressure. This occurs at tempera-
tures above the Boyle temperature.
107
105
103
BAS/Lσ2
10–1
10–1
10–3 C20 C60
0 1 2 3 4
R/σ
Opened SWNT, T* = 0.2089 (H2: 77.4 K)

Closed SWNT, T* = 0.2089
Opened SWNT, T* = 0.8097 (H2: 300 K)
Opened SWNT, T* = 1.000 (H2: 371 K)
Fig. 11.6. Behavior of the second virial coefficient of the adsorbed density of hydrogen on iso-
lated SWNTs as a function of its radius. The SWNT reduced radii corresponding to the C20 and
C60 fullerene cages are indicated by the vertical lines. Reprinted with permission from [11].
The behavior of the virial coefficient in bundles of SWNTs is rich, associated with the
grooves of the bundle (peripheral sites in Fig. 11.7(a)) and the interstices between the
nanotubes in the bundles (interstitial sites in Fig. 11.7(a)), which lead to additional
structures associated with the presence of additional extrema in the interaction po-
tential of the bundles (Fig. 11.7(b)).
The virial coefficient BAS is a readily physically accessible quantity which contains
a wealth of information about the energy scales of the adsorption process and in some
cases, the very structure of an adsorbent, particularly in ordered monoatomic solids
such as single wall nanotubes or other nanocrystalline carbon structures. It can be
determined experimentally from the slope of the excess adsorption isotherm at low
pressure, where the isotherm behaves according to Henry’s Law, from two pressure
measurements at a given temperature. The energy scales that can be extracted from
BAS require, however, the data from several low pressure isotherms. They can be ap-
proximately determined from a semi-logarithmic fit of BAS as a function of inverse tem-
perature.
The virial coefficient, however, does not contain much information on the high
pressure behavior of the adsorption isotherm, as it is determined in a régime where
intermolecular interactions between adatoms have not yet impacted the adsorption
phenomena, and provides little information on the eventual saturation of the adsorp-
tion isotherm. It can thus be used to determine the temperature scale of the adsorption
process, but not its saturation properties.
y
15
Tube site Peripheral site
10
–5
–10
Interstitial site
–15 x
(a) –15 –10 –5 0 5 10 15
–10
x 0
10
2
0
Vbundle
–2 Fig. 11.7. (a) Adsorption sites and
–4 (b) interaction potential of a bundle
with 19 SWNTs with R∗ = 2.038 and
–10
with a normalized lattice parame-
0 ter d∗ = 5.235 relative to hydrogen.
y
(b) 10 Reprinted with permission from [11].
11.3.2 Basic analytic models of the adsorption isotherm
The Langmuir model

The Langmuir isotherm is a local model of the absolute adsorption based on mono-
layer filling of noninteracting molecules. As such, it represents a model of supercritical
adsorption on surfaces. It predicts a monotonically increasing function of pressure,
which saturates asymptotically as a function of pressure to a value nm :
KL (T) P
n = nm , (11.14)
1 + KL (T) P
with
1
exp (ΔS0 /R) exp (−ΔH0 /RT),
KL (T) = (11.15)
P0
where ΔS0 and ΔH0 represent the entropy and enthalpy variations associated with the
adsorption process, and where P is pressure [12].
There are several strategies for deriving the Langmuir isotherm. It can be obtained
from either kinetic theory or a lattice gas approach.
The Langmuir isotherm can be put into the following form:
P 1 P
= + , (11.16)
n KL (T)nm nm
from which the parameters nm and KL (T) can be determined from experimental
isotherms. The saturation density (nm ) and the coefficient (C) can be obtained from
a simple linear fit of the experimental data. Figure 11.8 shows that even excess
adsorption data (shown as points) represented in this way yields relatively linear
curves. Note, however, that the Langmuir isotherm is not a Gibbs (excess) adsorption
isotherm. A more detailed examination of the data represented in Fig. 11.8 would
show substantial deviations from linear behavior between the low and high pressure
regions.
The excess adsorption version of the Langmuir isotherm requires knowledge of
the pore volume:
KL (T)P󸀠 P󸀠
na (P󸀠 , T) = n(P󸀠 , T) − Vp ng (P󸀠 , T) = nm 󸀠
− Vp . (11.17)
1 + KL (T)P RT
T=273 K
2.0
1.6
P/n (Mpa gr/mmol)
1.2
0.8
0.4
T=77 K
0.0
0 1 2 3 4 5 6
Pressure (Mpa)
Fig. 11.8. Expression of the excess adsorption isotherms of hydrogen on the activated carbon AX-21
as the pressure over excess density as a function of pressure. Reprinted with permission from [12].
The validity of the Langmuir model is typically limited to low pressure, high tempera-
ture adsorption of gases in the supercritical regime. As such, it is of limited usefulness
to the description of adsorption over the wide temperature and pressure ranges rele-
vant to storage applications.
The Dubinin isotherm

The adsorption isotherm of microporous adsorbents has often been modeled by the
Dubinin–Astakhov model. In this approach, the adsorption process is viewed as a vol-
umetric process in which a pore of an adsorbent is progressively filled by a subcritical
gas (T < Tc ) whose vapor phase can be described by the ideal gas law. If the con-
ditions inside a pore are such that the local pressure is greater than the saturation,
then the adsorbate is assumed to condense to a liquid state. The characteristic energy
of adsorption of the pores is also assumed to be distributed according to a Weibull
distribution. These assumptions lead to an isotherm where total adsorbed density is
expressed as:
n = n0 exp(−(A/E)m ), (11.18)
where n0 is the saturation density of the adsorbate in the pores, m is a structural het-
erogeneity parameter, E is a characteristic energy of the average gas-solid interaction
potential in the pores [13], and A is the adsorption potential:
Ps
A = RT ln ( ), (11.19)
P
where R is the universal gas constant, and Ps the saturation pressure. The parame-
ter m is fitted in such a way that the characteristic curves of nA as functions of A are
independent of temperature. The limit m = 2 reduce to the Dubinin–Raduskevitch
isotherm [14, 15].
The excess density is obtained by considering the adsorption volume Va as a fitting
parameter:
nex = na − Vp ρg , (11.20)
where ρg is the bulk gas density of hydrogen.
Surprisingly, this isotherm has been found to accurately describe the adsorption
process even in the supercritical regime. The pressure parameter Ps cannot in this
case be associated with the saturation pressure, which is undefined when T > Tc .
Amankwah and Schwarz have proposed the following equation [16] to determine Ps :
𝛾
PS = (T/TC ) PC , (11.21)
where Tc and Pc are the critical temperature and pressure of the adsorbate. This pres-
sure, however, should be interpreted as the pressure at which the adsorbed phase be-
haves like an almost incompressible fluid in the supercritical regime, leading to a very
large value of Ps when the isotherm is fitted to experimental data over wide pressure
range. Formally, at P = PS , the isotherm reaches a maximum value as a function of

pressure.
If the adsorbed phase behaves like a quasi-incompressible fluid, it can be ex-
pected that the characteristic energy also depends on temperature to reflect a limited
dependence on temperature that should be expected when P is such that the pore is
basically saturated. An analysis of the best fit of experimental isotherms of nitrogen
on activated carbon over wide ranges of pressure and temperature suggest a linear
dependence of the characteristic energy of adsorption as a function of temperature. A
modification of the Dubinin isotherm was then proposed in which the characteristic
energy of adsorption of the original model is replaced by a temperature-dependent
expression E = α + βT.
50 30 K
35 K
Excess Adsorption (mol/kg)
40 K
40
45 K
60 K
30
77 K
93 K
20
113 K
153 K
10
213 K
298 K
0
0 1 2 3 4 5 6
Pressure (Mpa)
Fig. 11.9. Modified D–A isotherm (solid lines) parameterized on the experimental excess ad-
sorption isotherms of hydrogen (shown as points) [19]. The optimal isotherm parameters are
n0 = 71.6 mol kg−1 , α = 3.08 kJ mol−1 , β = 18.9 J mol−1 K−1 , P0 = 1 470 MPa, and Vp = 1.43 l kg−1 .
The large values of P0 may be seen as coherent with the high density limit of the adsorbed gas.
Reprinted with permission from [17]
The model successfully describes the adsorption of hydrogen on several microporous

systems [17, 18], such as the activated carbon AX-21™ over the range 0–6 MPa and 30–
298 K, as shown in Fig. 11.9. The limiting density associated with complete filling of the
micropores can be estimated by dividing nmax by Vpore . A value of 50.2 mol/l is obtained
for hydrogen, which is a value close to the density of solid hydrogen (43.7 mol/l).
The model has also been used to describe the adsorption isotherms of hydrogen
on the activated carbon CNS-201™ and the metal-organic framework Cu3 (BTC)2 over
the range (0–6 MPa and 77–296 K), as well as the adsorption isotherms of nitrogen and
methane on single wall nanotubes over wide temperature and pressure ranges [19].
The Dubinin model has some issues, such as the absence of a proper Henry’s law
régime as a function of pressure. This approach should be viewed as a high density
approximation. This can lead to problematic results at low pressure, such as nega-
tive excess adsorption isotherms, for the adsorption of hydrogen on the metal organic
framework MOF 5. Its validitiy is also limited at high temperature by the fact that the
argument of the isotherm depends very little on temperature at large temperatures.
11.3.3 Self-consistent approaches
In addition to the examples of analytic isotherms described in the preceding section,

nonanalytic isotherm models have been proposed for supercritical gases over wide
pressure and temperature ranges.
Lattice gas isotherm

Aranovitch et al. proposed a set of self-consistent equations describing the adsorp-
tion process on carbon slit pores based on a lattice-gas approach [12, 20], applica-
ble in principle to the supercritical and subcritical regimes. This approach, which
can be seen as a lattice-gas version of the Langmuir isotherm, calculated assuming
a slit pore geometry, while accounting for proximity interactions between adsorbate
molecules in a molecular field approximation. It correctly yields Henry’s law in the
low pressure limit but does not, however, describe the porous structure of carbon.
The model assumes that the adsorbate molecules form N discrete layers sandwiched
by two graphene planes representing a slit pore. Adjacent molecules interact with an
Ising site potential E. Molecules adjacent to the two graphene planes are subjected
to a uniform potential EA . The coverage of the ith layer, defined by the relative den-
sity xi = ni /ns (where ns is the molar density of a completely filled adsorption layer)
is obtained from self-consistent equations with the boundary condition x1 = xN . The
excess adsorption isotherm is defined as:
N
nex = A ∑ xi − ρg Vp . (11.22)
i=1
The model has been successfully fitted to the experimental data shown in Fig. 11.10
for hydrogen on AX-21 with the following model parameters: Ea = −3.871 kJ/mol,
E = 0.519 kJ/mol and ns = 74.0 mol/l. The saturation constant (A) was fitted in the
following way:
A (T) = A0 − A1 exp (−B/T) , (11.23)
with A0 = 30.426 mol/l, A1 = 12.623 mol/l and B = 71.042 K. This isotherm leads to
a pore volume Vpore of 1.62 liter/kg [21].
50
30 K
35 K
Excess adsorbed amount [mol/kg]
45 K
40 60 K
77 K
93 K
30 113 K
133 K
153 K
20 173 K
193 K
213 K
10 233 K
253 K
273 K
295 K
0
0 1 2 3 4 5 6
Pressure [Mpa]
Fig. 11.10. Excess adsorption isotherms of hydrogen on the activated carbon AX-21. The full lines
represent a fit to the Ono-Kondo adsorption isotherm. Reprinted with permission from [21].
11.4 The thermodynamics of adsorption
Myers et al. [6] proposed a thermodynamic formulation of the adsorption process in

which the pore structure is considered to be a bulk property of the adsorbent (assum-
ing with Gibbs a zero volume adsorbed phase). This approach has the advantage of
eliminating the need for additional thermodynamic variables and their conjugated
forces.
The adsorption properties are generally referred to per unit quantity of adsorbent
(e.g., mass or volume). The adsorbed density thus represents a quantity of adsorbate
(mass, volume, moles or direct number of particles) per unit quantity of the adsorbent.
In their approach, all thermodynamic properties (Z) of the total system are con-
sidered to consist of three contributions: the adsorbate (a), the adsorbent (s) and the
gas phase (g):
Zt = Za + Zg + Zs , (11.24)
with
Zg = ng Vg zg . (11.25)
The density of the free gas (in the absence of the solid) is ng . The intensive property zg
is a thermodynamic property of the free gas which depends on temperature T, pres-
sure P and, in the case of a mixture, the set of mass fractions (yi ). The volume of the
gas phase Vg corresponds to the pore volume Vg . The properties of the solid phase
are determined through thermodynamic measurements of the solid in the absence of
the adsorbate. The properties of the adsorbed phase, on the other hand, intrinsically
depend on the interaction between the solid and the adsorbate and are obtained by
taking the difference between the thermodynamic properties of the total system and
the properties of the free gas and the solid adsorbent:
Za = Zt − Zg − Zs , (11.26)
which leads to the following expression for the adsorbed density:
na = n t − n g . (11.27)
This expression is also consistent with the excess adsorbed density defined earlier
if the system does not contain a free volume external to the porous structure of the
adsorbent, in which case Vg = Vp :
na = nt − ngaz = nt − ρg Vg = nt − ρg Vp , (11.28)
since the volume of the system is the sum of the volume of the solid and the volume
occupied by the gas in the adsorbent. At a given pressure and temperature, the ther-
modynamic properties of the adsorbed phase can be obtained by subtracting the con-
tribution of the gas phase and the adsorbent:
U a = Ut − Ug − Us = U − U s , (11.29)
Sa = St − Sg − Ss = S − Ss , (11.30)
Va = Vt − Vg − Vs = Vt − (Vg + Vs ) = 0. (11.31)
The internal energy of adsorption can be written:
Ua = U − Us = TSa + μg na + (μ − μs ) (11.32)
or:
Ua = TSa + μg na + Φ, (11.33)
with
Φ = μ − μs . (11.34)
The potential Φ is called the surface potential, defined as the difference between the
chemical potential of the adsorbent interacting with the adsorbate and its value in the
absence of such interactions, but still subjected to hydrostatic pressure P. A descrip-
tion based on the surface potential considers the adsorption process basically as a
bulk property. It is as such appropriate from a conceptual point of view to the descrip-
tion of highly microporous adsorbents such as metal organic frameworks, in which a
clear interface cannot easily be defined.
The Gibbs potential can be found using the standard Legendre transform:
Ga = Ua + PVa − TSa = Ua − TSa = μg na + Φ. (11.35)
The free energies of the adsorbed phase thus depend on the adsorption isotherms (na )
and the surface potential.
The differential forms of the thermodynamic potentials can be written:
dUa = TdSa − μg dna , (11.36)

dGa = Sa dT − μg dna , (11.37)
dΦ = −Sa dT − na dμg . (11.38)
The adsorption isotherm and the entropy of the adsorbed phase can be obtained from:
𝜕Φ 󵄨󵄨󵄨󵄨
na = − μ 󵄨 (11.39)
𝜕 g 󵄨󵄨󵄨T
and
𝜕Φ 󵄨󵄨󵄨󵄨
Sa = − 󵄨 . (11.40)
𝜕T 󵄨󵄨󵄨μg
Using the Gibbs potential it can be shown that thermodynamic equilibrium between
the adsorbed molecules and their bulk gas phase is expressed through the equality of
their temperatures and their chemical potentials:
μa = μgaz . (11.41)
11.4.1 Properties of surface potential
At constant temperature, the difference equation for surface potential becomes:
dΦ|T = −na dμg . (11.42)
Expressing chemical potential in terms of the fugacity (f):

μg
f = f0 exp . (11.43)
RT
Fugacity converges to the pressure (P) as P→0. We obtain the constant temperature
contribution to the surface potential:
f df
dΦ|T = −RTna d (ln ) = −RTna . (11.44)
f0 f
In terms of the fugacity, the differential of the surface potential becomes:
RT
dΦ = −Sa dT − na df. (11.45)
f
Note that the integrated surface potential should have the following form:
Φ(f, T) = u(f) + v(T) + w(f, T). (11.46)
When f → P → 0, however, we expect that Φ(f, T) = μ − μs = 0 because the chemi-

cal potential of the system becomes equal to the chemical potential of the adsorbent
(μ → μs ). This implies that v(T) = 0, and thus Φ(f, T) = Φ|T .
Low pressure limit

At low pressures, f ∝ P (this is exact for an ideal gas). Integrating from P󸀠 = 0 to P we
find that:
P
dP󸀠
Φ = −RT ∫ na (P󸀠 , T) . (11.47)
P󸀠
P=0
In the low pressure limit, Henry’s law states that the total adsorbed density is propor-
tional to pressure:
n(P󸀠 , T) = K(T)P󸀠 , (11.48)
where K (T) is Henry’s coefficient. The excess adsorbed density in this limit is:
P󸀠
na (P󸀠 , T) = K(T)P󸀠 − Vp ng = K(T)P󸀠 − Vp . (11.49)
RT
In the low pressure limit, the surface potential behaves as follows:
Φ = − RTK (T) P + Vp P = −RTna (P, T) + Vp P. (11.50)
The Langmuir isotherm

As an illustrative example, we consider the excess Langmuir adsorption isotherm,
which can be written in the following general form, assuming an ideal gas:
KL (T)P󸀠 P󸀠
na (P󸀠 , T) = n(P󸀠 , T) − Vp ng (P󸀠 , T) = nm 󸀠
− Vp , (11.51)
1 + KL (T)P RT
with
1
KL (T) = exp (ΔS0 /R) exp(−ΔH0 /RT), (11.52)
P0
where ΔS0 is the entropy difference relative to the reference pressure P0 (typically one
atmosphere), and ΔH0 is the enthalpy difference associated with the adsorption pro-
cess. The coefficient KL (T) corresponds to Henry’s coefficient. The corresponding sur-
face potential, for an ideal gas, is thus given by:
Φ = −RTnm ln(KL (T)P + 1) + Vp P. (11.53)
The chemical potential of the ideal gas is given by:
P
μg = RT ln ( ). (11.54)
P0
Using this expression to eliminate the pressure from the surface potential, we can ex-
press the latter in terms of its natural variables T and μ:
μg μg
Φ = −RTnm ln (KL (T)P0 exp ( ) + 1) + Vp P0 exp ( ). (11.55)
RT RT
It is easily verified that the Langmuir isotherm is recovered by the equation:

󵄨
𝜕Φ 󵄨󵄨󵄨
na = − 󵄨󵄨 . (11.56)
𝜕μg 󵄨󵄨󵄨T
Entropy, internal energy, and Helmholtz free energy can be readily obtained from the
expressions for the surface and chemical potentials of the ideal gas.
11.5 Microporous adsorbents for hydrogen storage
11.5.1 Activated carbons
Activated carbons (Fig. 11.11) have been proposed as a means of storing gases such as
natural gas at room temperature [22]. For hydrogen, storage applications require low
temperature operation and highly microporous activated carbons with high specific
surface areas due to the small value of the binding energies between carbon structures
and molecular hydrogen. Activated carbons have been widely studied for hydrogen
storage applications, because of their availability and the possibility of tailoring their
porous structures via various chemical and physical treatments. The high pressure,
low temperature adsorbed density of hydrogen on activated carbon seems to correlate
linearly with the micropore volume and the specific surface area of the adsorbent [23].
IRH-4D
Fig. 11.11. SEM image of a sample of the activated car-

bon IRH-4DD with a specific surface area of 2 000 m2 /g
showing the macroporous and mesoporous structure
18kV X1, 500 10 of the carbon [22].
The excess adsorption isotherms of hydrogen over the supercritical temperature range
of 35 K to 300 K on the activated carbon AX-21 are type I fully reversible isotherms, as
shown in Figs. 11.7 and 11.8. The specific surface and bulk density were respectively
2 800 m2 /g and 0.3 g/cm3 . The maximum excess density at 77 K was 54 g/kg at 35 bars.
This maximum occurs when the slope of the absolute adsorbed density becomes equal
to the slope of the bulk density curve multiplied by the pore volume.
The total amount of hydrogen contained in the adsorbent is the sum of the excess
density and the compressed bulk phase in the pore volume of the adsorbent. Assum-
ing that graphite corresponds to the limiting case of an activated carbon with zero pore
volume, the latter can be estimated from the ratio of the density of activated carbon to
graphite [22]:
dAC
Vpore = (1 − ) Vadsorbent , (11.57)
dgraphite
where dAC is the density of the activated carbon and dgraphite , the density of graphite
(2.2 g/cm3 ). Dividing equation (11.57) by the mass of the adsorbent yields an estimate
of the gravimetric pore volume, in this case 2.88 ml/g. The micropore volume is es-
timated to be 1.06 ml/g, or 37% of the measured total pore volume. The macropore
volume represents about 10% of the total pore volume. The remaining portion is as-
sociated with the external surface of the adsorbent (including the intergranular vol-
ume). The contribution of the compressed gravimetric density of the pore structure is
obtained by multiplying the total pore volume by the bulk gas density of the adsor-
bate, resulting in a value of 33 g/kg at 77 K and 35 bars and leading to a total gravi-
metric density of 8.7% of hydrogen in the activated carbon, most of it corresponding
to a gravimetric density of 6.6% in the micropores. The fluid phase density of hydro-
gen inside the micropores can be calculated by dividing the total density adsorbed by
the micropore volume. This yields to a value of 62 kg/m3 , suggesting that at 77 K and
35 bars, the density of hydrogen inside the micropore is already close to that of liquid
hydrogen. Similar values (from 61 to 71 mg/ml) are obtained for other activated carbon
adsorbents with different pore volumes and specific surfaces [22].
11.5.2 Single wall nanotubes
Single wall nanotubes (Fig. 11.12) were first proposed as storage media for hydrogen
by Dillon et al. [24]. They are no longer considered viable candidates in their pure
form for practical storage applications of hydrogen, due to their cost and the relatively
marginal gain they may offer over activated carbons in terms of storage capacity. The
adsorption of hydrogen on single wall nanotubes results in type I isotherms (Fig. 11.13).
The cylindrical geometry of nanotubes is conducive to deeper adsorbate-adsor-
bent interaction potential, well inside small diameter single wall nanotube. In a bun-
dle, the interstitial sites could be even more favorable due to the overlap of the molecu-
lar force fields of each SWNT. The small pore volume associated with these sites, along
with the small diameter of these pores, makes their relative contribution to the over-
all adsorbed density small. Under ambient conditions, pure SWNT adsorb less than
1 wt% hydrogen. At 77 K and 1 bar, excess adsorbed densities of up to 2.5 wt% have
been reported, depending on sample preparation [25–28]. Values of 6 wt% at 77 K and
2 bars [29] and 8 wt% at 40 bars and 80 K have been obtained [30]. The adsorption en-
thalpy is estimated to be about 4.5 kJ/mol, comparable to activated carbon adsorbents.
The adsorption of hydrogen on SWNTs is very sensitive to chemical and heat treat-
ments, as they can facilitate access to internal sites [31].
Dai18-8
140kx
100 nm
Fig. 11.12. SEM image of SWNTs [22].
3.0
2.5
Adsorption (wt%)
2.0
1.5
1.0
SWNTS-Pr.
0.5 SWNTS-700
CNI-3P
0.0
0 10 20 30 40 50
P (atm)
Fig. 11.13. Hydrogen adsorption isotherms on single wall nanotubes at 77 K [28].
11.5.3 Metal organic frameworks
Metal organic frameworks (MOFs; Fig. 11.14) are hybrid polymers made of organic and
inorganic units, bound together during isoreticular synthesis [32, 33]. They are soluble
and their configuration depends on the environmental conditions during the reaction.
The interactions that occur between metal ions and organic linkers are ionic, covalent,
and coordination bonds. There are also hydrogen and π–π bonds [34].
The synthesis conditions are dictated by the chemical properties of the or-
ganic linkers and the final desired structure. Generally, MOFs are obtained through
solvothermal synthesis, during which the organic linker and the metal salt are mixed
in a polar solvent. The temperature is then slowly increased and maintained be-
tween 50 to 150°C. The reaction is generally complete within several hours to several
Molecular complexes Extended solids
(a) Expanded framework
Fig. 11.14. Assembly of MOFs by

copolymerization of metal ions
with organic linkers to give (a) flex-
ible metal-bipyridine structures,
(b) rigid metal-carboxylate clusters
(b) Decorated-expanded framework [33].
days [35, 36]. One of the biggest advantages for MOF synthesis stems from the labile
nature of the metal-linkers bond, in the sense that if the linker is not stable, it will
dissociate by itself and take a configuration that corresponds to the minimum energy
of the final structure. Depending on the linker and the metal node geometry, ditopic
or tritopic, the building blocks will have two or three dimensions [37]; see Fig. 11.15.
MOFs are of particular interest for their adsorption properties, and can be used for
purification [38], gas storage, sensing [39, 40], catalysis or ion exchange [41–46]. It is
possible to tailor a pore distribution according to a desired application by selecting the
proper linker and metal ion. The pore size can even be changed without modifying
the global geometry of the network, by simply selecting an organic linker with the
same geometry, but with a different size (Fig. 11.16). This property is referred to as the
isoreticular principle [47]. MOFs can thus be synthesized to capture larger molecules
such as vitamin B12 and proteins [32]. MOFs are the materials with the biggest pore
openings (98 Å) and the smallest density (0.13 g/cm3 ).
Increasing the pore size generally results in a larger specific surface area and in
greater adsorption capacity at higher pressures. Physiosorption inside MOFs is the re-
sult of weak van der Waals interactions (typically less than 10 kJ/mol; [48]) between
the MOF and an adsorbate gas, which leads to a reversible increase in the gas density
Donors
0° 60° 90° 109° 120° 180°
0°
60°
Acceptors
90°
109°
120°
180°
(a)
Tritopic subunit
120°
60° 90° 109°
90°
Ditopic subunit
Trigonal Truncated
bipyramid Double square tetrahedron
109° Trigonal
bipyramid Adamantanoid Cuboctahedron
180° Fig. 11.15. (a) Ditopic building blocks gener-

ate 2D convex polygons. (b) The combina-
Tetrahedron Cube Dodecahedron tion of ditopic and tritopic building blocks
(b) results in 3D polygons [37].
inside the MOFs. A significant hydrogen adsorption capacity in MOFs is only possi-
ble for small pores (between 4.5 and 5 Å; [49–53]), which allows increased adsorbent-
adsorbate interactions due to the proximity of the structures in the unit cell, creating
overlaps of the potential energy curves [54].
Table 11.1 shows the effect of temperature on the CO2 adsorption properties of
IRMOF-1. Table 11.2 illustrates the adsorption capacity (in wt%) of three MOFs, IRMOF-1
(Zn4 O(BDC)3 ), IRMOF-11 (Zn4 O(HPDC)3 ), and MOF-177 (Zn4 (BTB)2 )¹, for H2 , CO2 , H2 S,
and CH4 at different pressure [55]. As expected, uptake decreases with temperature
but increases with pressure.
1 BDC = benzene-1,4-dicarboxylic acid; HPDC = 4,5,9,10-tetrahydropyrene–2,7-dicarboxylate;

BTB = benzene-1,3,5-tribenzoate; AM = amide
Table 11.1. Quantity of CO2 adsorbed (in mg) per gram of IRMOF-1.
IRMOF-1; CO2
Temperature (K) Pressure (Torr) wt(%) Pressure (Torr) wt%
195 74.0 11.76 751.0 148.90
208 75.0 7.62 750.2 140.55
218 75.0 3.89 750.0 123.24
233 91.5 2.73 735.8 29.87
273 91.2 0.81 748.4 6.61
The organic linkers in the MOFs open the door to postsynthetic modifications by or-
ganic reactions. Indeed, by targeting the organic part, it is possible to change the
chemical and physical properties of an MOF, basically creating a new MOF [56]. This
allows the synthesis of MOFs which would have been impossible to create directly,
because the desired functional groups would have interfered with crystal growth. The
transformation of IRMOF-3 (Zn4 O(BDC-NH2 )3 ) into IRMOF-3-AM1 is a good illustra-
tion of this principle. In this synthesis, the amine functional group from the organic
linker reacts with acetic anhydride, in CHCl3, to produce a secondary amide functional
group [57]; see Fig. 11.17.
Table 11.2. Quantity of adsorbed gas (in mg) per gram of MOF, as a function of pressure.
Temperature (K) : 77
Gas MOF Pressure (Torr) wt% Pressure (Torr) wt%
IRMOF-1 77.5 0.25 752.9 1.32
H2 IRMOF-11 75.1 0.49 753.2 1.62
MOF-177 69.1 0.17 751.0 1.25
Temperature (K): 298

IRMOF-1 920 4.73 1 556 8.10

CO2 IRMOF-11 801 7.90 1 572 13.74
MOF-177 770 3.51 1 623 7.86
IRMOF-1 708 19.86 1 458 25.00
H2 S
MOF-177 657 16.46 1 437 18.91
IRMOF-1 889 0.72 2 337 1.74
CH4 IRMOF-11 889 1.02 2 507 2.79
MOF-177 863 0.12 2 425 1.29
‒
OOC
‒
OOC
‒
OOC
N
COO‒ N N COO‒
N COO‒
‒
OOC N N
N
4,4′,4″ –(1,3,4,6,7,9,9b-
BTC (BBC)
heptaazaphenalene-
‒
OOC 2,5,8-triyl) tribenzoate
‒
(HTB) OOC
MOF-199
HKUST-1 PCN-HTB′ MOF-399
Cu3(BTC)2 Cu3(HTB)2 Cu3(BBC)2
Fig. 11.16. Molecular structures of organic linkers (top). Single crystal structures of MOF-199,
PCN-HTB0, and MOF-399 (bottom). The yellow balls indicate space in the cage [47].
O O H
NH2 N n
nO n
O
CHCl3, r.t.
n = 0 – 18
IRMOF-3 IRMOF-3-AM
Fig. 11.17. Scheme of representative postsynthetic modification reactions with IRMOF-3

and acetic anhydride [57].
Many applications of MOFs expose them to various degrees of heat and pressure. The
stability of their structure as a function of temperature and pressure is thus a crit-
ical issue which must be taken into account. Some MOFs undergo structural phase
transitions as a function of temperature and pressure due to their flexible network
[58–60]. Some, under high pressure, lose their crystallinity and become irreversibly
amorphous [61]. There may also be a reversible rearrangement of the binding between
a a
b b
(a) (b)
Fig. 11.18. Phase transition, from α-phase (a) to β-phase (b), which occurs inside ZnIm at pressure
between 0.543 GPa and 0.874 GPa [62].
the metallic centers and the linkers [62] as the pressure is increased (Fig. 11.18). This
phenomenon is called “breathing effect”.
As for all the nanostructured adsorbents discussed in this chapter, the adsorption
isotherm of hydrogen on metal organic framework nanostructures is a type I isotherm.
In 2006 Wong-Foy et al. reported hydrogen adsorption results on seven different MOFs:
IRMOF-1 (MOF-5), IRMOF-6, IRMOF-11, HKUST-1 (CuBTC), MOF-74 and MOF-177 [63].
The saturation uptake was observed to vary sharply depending on the MOF; MOF-74
exhibited the lowest adsorbed density with a saturation uptake of 2.3 wt% at 26 bar
and 3.5 wt% for IRMOF-11 at 34 bar, whereas the highest was observed on MOF-177 and
IRMOF-20, where the maximum uptake was measured at 7.5 and 6.7 wt% respectively
for pressures ranging from 70 to 80 bar. HKUST-1, IRMOF-1 and IRMOF-6 exhibited
maximum uptakes of 3.0, 4.8 and 4.5 wt% for a pressure range of 40–60 bars. The two
best adsorbents on a volumetric basis were found to be IRMOF-20 and IRMOF-177 for
a pressure range of 70–80 bar.
Recent measurements of the excess adsorption densities of hydrogen are summa-
rized in Table 11.3. It can be seen that the excess adsorbed density of hydrogen on
MOF nanostructures range from 6.5 to 9.0 (wt%). A total gravimetric density of up to
150 g/kg is possible for MOF 210, the corresponding volumetric density being 44 g/l.
MOFs are highly porous nanostructures (void space of 90% for MOF-200) with a low
density. At room temperature (295 K), reversible hydrogen uptakes of less than 1 wt%
have been obtained. The excess adsorbed density seems to correlate more or less lin-
early with the specific surface area at high pressure ([22] and references therein). This
situation seems to be reversed at very low pressure, where the trend is reversed [63],
due to the fact that gravimetric adsorption is determined by the binding energy at low
pressure and by the specific surface at high pressure, where saturation becomes an
Table 11.3. Adsorption properties of hydrogen on various metal organic frameworks at 77 K and
80 bars [65].
MOF Density BET Excess Total Total

(g/cm3 ) Surface area gravimetric gravimetric volumetric
(m2 /g) density (wt%) density (wt%) density (g/l)
MOF 5 0.59 3 800 7.1 9.6 63

MOF 177 0.43 4 500 6.8 10.4 50
MOF 200 0.22 4 530 6.9 14.0 36
MOF 205 0.38 4 460 6.5 10.7 46
MOF 210 0.25 6 240 7.9 15.0 44
UMCM-2 0.40 5 200 6.5 11.0 50
NU-100 0.29 6 143 9.0 14.1 41
issue. It is interesting to note that the adsorbed density of hydrogen, on a volumetric

basis, correlates with the crystal density of the MOF.
This is in agreement with a Grand Canonical Monte Carlo study of the effect of
the specific surface area and adsorbent density on the adsorption of hydrogen on
contrived carbon structures [64]. The contrived structures were benzene rings net-
worked in such a way as to vary density and surface area systematically, using the
same Lennard-Jones interaction parameters between the adsorbate molecules and the
adsorbent atoms. The gravimetric density of hydrogen was shown to increase as a
function of the density of the carbon nanostructure at low pressure due to narrower
pores. The trend was reversed at high pressure, at which point the specific surface of
the structures became the determining factor.
This behavior seems to be observed in metal organic frameworks. On a volumetric
basis, however, the high density materials are always found to be the best adsorbent.
A linear correlation between adsorbed density and specific surface was also observed
for these structures at 35 bars and 77 K. For physisorbed hydrogen, these results con-
firm that for a given atomic composition, maximizing the specific surface of the ad-
sorbent seems to remain the optimal strategy for the design of materials for hydrogen
storage if volumetric considerations are not critical. All contrived structures were weak
hydrogen adsorbents under ambient conditions.
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|
Part III: New trends in sustainable development
and biomedical applications
D. Mantovani, L. Levesque, G. Sabbatier, M. Leroy, D. G. Seifu,
R. Tolouei, V. Montaño, M. Cloutier, I. Bilem, C. Loy, M. Byad,
C. Paternoster, C. A. Hoesli, B. Drouin, G. Laroche
12 Advanced materials for biomedical applications
12.1 Introduction
Since 1970, biomaterials have saved or improved the lives of millions of humans
around the globe. Mostly made of polymers, metals, and ceramics, biomaterials lead
to the design, production, development and optimization of implants and prostheses
to replace, restore or reconstruct parts of diseased or damaged tissues and organs.
Research is very dynamic in all fields of biomaterials worldwide, and is mainly aimed
at improving the clinical performance of those implants and prostheses currently on
the market. It is a growing multimillion dollar industry, justified by the world’s aging
population and by humans’ desire to experience the highest quality of life even when
elderly.
The main goal of this chapter is to provide a concise and schematic overview of the
principal applications of biomaterials for the benefit of graduate and undergraduate
students as well as scientists who are curious to explore this challenging and multi-
disciplinary field. A number of more specialized books are available to those readers
interested in broadening their knowledge in the field. For example, sterilization pro-
cesses will be briefly mentioned, although these represent a potential major bottle-
neck in material design and development. Similarly, the FDA and other accreditation
processes are not addressed in this chapter, despite representing a major challenge for
the industrial development of the field. In terms of material engineering, this chap-
ter also has some limitations, as it does not address the flourishing field of surface
modifications, which are largely applied to metals, polymers, and ceramics, mainly to
modulate the interfacial properties with the surrounding (living) tissues and organs.
This chapter aims to set forth a realistic overview of the fields of implants and pros-
theses, mainly from the materials science and engineering point of view. Since bioma-
terials science and engineering is a scientific field at the frontier between medicine,
biology (life sciences), and materials science, this chapter is divided into six sections.
Each of these sections addresses a physiological system and its main pathologies, and
presents a schematic view of the leading biomaterials, implants, and prostheses used
clinically to treat these pathologies. The focus is consistently on commercially avail-
able materials used by clinicians to treat, restore, and replace diseased tissue and
organs.
Sutures are one of the oldest medical procedures. there is evidence that they have been used as long as 32 000 years ago[1]
In 1860, an The replacement
Dental implants An iron dental In 1790, Volta optometrist In 1880, artificial of maxilla and In 1894, Tetamore
were seen as implant was discovered that Since 1809, named Adolf Fick parts were used mandible by isbelieved to have
early as 600 A.D. also found electric current dentists were introduced the by Kinsgley to alloplastic implants use cellulose nitrate
in Mayan people dated 200 A.D. stimulated hearing using gold anchor glass contact reconstruct orbit, were described by to reconstruct parts
using sea shells[1]. in Europe[1] capabilities[2] to fastened tooth[1]. lenses[1] nose and palate[3] Martin in 1889[3]. of the face[3].
600 220 210 200 1790 1800 1810 1820 1830 1840 1850 1860 1870 1880 1890 1900
12.2 History of biomaterials
Sponges of Throughout, This discovery In 1953, the Between 1957 John The first fully The first The In 1960,
poly (vinyl the 1950’s to led to the heart-lung and 1958, Charnley[1, 5, 6] implantable successful development it was
alcohol) the 1980’s first prosthetic machine was Earl E. Bakken, invented the pacemaker mitral valve of the first Dr. Belding
were atrificial vascular invented by founder of first successful was developed replacement leaflet valve Scribner that
used in heart were graft made John Gibbon Madtronic, hip prosthesis. in 1959 by in human was was made in made
the implanted in Vinyon N, which made Inc., He used Teflon engineer made 1960 by routinely
1950’s as in animals textile fibers, easier developed the acetabular cup Wilson in 1960 and Warren dialysis
breast and humans, implanted cardiovascular first wearable at first in 1958. Greatbatch the valve Hancock[1]. treatment
prosthesis, but without in humans procedures[1, 4]. transistor and consisted possible.
but it had satisfactory in 1952[1]. pacemaker[1]. cardiologist of a silicone He developed
low success[1] results W. M. ball and poly a shunt which
(patients Chardack[1]. (methyl gave an easy
living up to methacrylate) and safe
620 days)[1]. cage[1]. access to
the blood[1, 4].
Cardiovascular system Kidney Skeletal system
278 | Part III New trends in sustainable development and biomedical applications
Sensorial organs Esthetical applications Others

In 1932,
In 1912, John Dr. Kazanjian In 1945, Willem J.
It is in 1912 when Jacob Abel and provided the Kolff used a rotating
Dr. Alexis Carrel his colleagues initiative for wooden drum around
developed methods developed the first maxillofacial, Plastic contact The first successful which a new membrane In 1947, Dr. Arthur
to anastomose blood functioning dialysis In 1930-31, dental, and lenses in poly(methyl dental implants was made of cellophane Voorhees noticed
vessel that vascular machine in order two groups plastic surgeons methacrylate) were made in 1937 by was wrapped to treat tissue had grown
grafting would to investigate by invented the to work together developed between Strock at Harvard successfully a 67-year-old around a silk suture
eventually see the products in rabbit portable for the improvement the years 1936 using a screw-type patient with acute kidney left inside a lab
[1] [1] [1]
day . blood[4] peacemaker[1]. of care for patient[3] to 1948 implant of Vitallium . failure[1, 4] animal[1].
1910 1920 1930 1940 1950 1960 1970 1980 1990 2000
Injections of In the 1960’s John Charnley In 1964, Dr. With hip In 1972 Stent were In 1984, In 1995, In 1998,
substances Thomas evolved to Branemark prosthesis the first design and the first Charles the first
were first Cronin and high- made the technology channel developed multichannel Vacanti tissue
used as breast Frank Gerow molecularweight unexpected was cochlear by Dr. Julio cochlear seeded a engineering
augmentation, invented a polyethylene discovery of developed implant was Palmaz to implant polymeric product was
but in the silicone shell cup in 1961 osseointe- knee introduced[7] 1978 to 1986. system was scaffold in approved
1960’s filled with to reduced gration of replacements Eventually, introduced by the shape by the FDA as
California and silicone gel[1] wear debris[1, 5] titanium. leaded by Jonhson and the Cochlear of a human living skin
Utah classified most of dental Drs. Frank Jonhson Corporation[7] ear and equivalent[8]
silicone and orthopedic Gunston and adopted the implanted it
injections as implants are John Insall project and on the back
a criminal now made of in 1968 to clinical trials of a nude
offense[1] titanium and 1972[1] were instituted mouse[8]
its alloy[1]. under the food
and drug
Administration
(FDA)[1]
|
279
12.3 Basics in material science for biomaterial applications
12.3.1 Biomaterial properties
Biomaterials present different properties according to their biological application.

Each site of implantation has its own requirements with respect to anatomy, phys-
iology, geometry, mechanical properties, and bioresponse. Mechanical properties
will vary in terms of strength, elasticity, rigidity, flexibility; durability, permeability,
and lubricity to name just a few. For example, materials used for hip replacement
need to be strong and durable; heart valve leaflets must be flexible and tough. Sim-
ilarly, bioresponses will also vary depending on the anatomical site involved and
the intended use. Biological responses can be classified into three major categories:
bioinert, bioactive, and bioresorbable. Bioinertia involves minimal interaction with
the surrounding tissues, as a fibrous capsule usually forms around the implant. In
contrast, a bioactive material will interact with the surrounding tissue, inducing
cell adhesion, proliferation, and differentiation, and leading to integration of the
biomaterial. Bioresorbable biomaterial refers to a material which will be degraded
and eliminated through the metabolic activity of the human or animal cells. The
physical or chemical behavior of a biomaterial can be tuned in order to control the
biodegradation time, for example. Tissue engineering using scaffold and drug deliv-
ery systems benefits from controlled biodegradation time, to allow the regeneration
of functional tissue or eluted drug delivery, for example. Other types of bioresponses
may be required depending on the application. For example, hemocompatibility will
be necessary for cardiovascular purposes. Furthermore, all biomaterials are required
to be non-toxic, to lead to the appropriate host reaction (immune system) and to be
sterilizable.
12.3.2 Biometals
Metals are commonly used in biomedical applications for load bearing implants and
internal fixation devices. When adequately processed, they display high tensile, fa-
tigue, and yield strength properties, as well as relatively good biocompatibility. The
properties of these metals depend on the processing method and the purity of the ma-
terial. Some important physical properties of metals are luster (shininess), good con-
ductivity of heat and electricity, high density, high melting point, ductility, and mal-
leability. Moreover, metals intended for biological applications must have well-known
chemical properties such as reactive capabilities, as well as corrosion and oxidation
behaviors. Numerous metals are used as biomaterials, however the most common are
stainless steel, cobalt chromium alloy (L-605), nickel titanium alloy, silver, titanium,
platinum, gold, tungsten, and iridium.
Metal machining and forming are the activities and processes used to give a piece
of metal a precise shape. In contrast, molding involves melting metal and pouring
it into a casting mold to create a particular product with a desired form. The way in
which these steps are carried out is very important, since heat and plastic deformation
can strongly affect the mechanical properties of metals, thus extra annealing steps are
generally required.
Corrosion is the gradual degradation of materials by electrochemicals and is
of great concern, particularly when a metallic implant is placed in the hostile elec-
trolytic environment of the human body. Implants in the human body face corrosive
environments such as blood and other constituents, body fluids, including several
components such as water, sodium, chlorine, proteins, plasma, amino acids, along
with mucin in the case of saliva. The aqueous medium in the human body consists
of various anions such as chloride, phosphate and bicarbonate ions, cations (Na+,
K+, Ca2+, Mg2+, etc.), organic substances of low molecular weight species, along
with relatively high molecular weight polymeric components, and dissolved oxygen.
Biological molecules disrupt the equilibrium of the corrosion reactions of an implant.
In spite of the fact that most of the materials used are protected from environmental
attack by surface oxide layers, there is clinical evidence for the release of metal ions
from implants, this leaching being attributed to the corrosion process.
The surface oxide film formed on metallic materials plays an important role as an
inhibitor of the release of metallic ions into the surroundings of the implant. More-
over, reactions between the surfaces of metallic materials and living tissues change
the composition of the surface oxide film. Metal ion release may also be accelerated by
means of low concentration of dissolved oxygen, inorganic ions, proteins, and cells.
The regeneration time of the surface oxide film after disruption also determines the
number of ions released. The nature of the reactions which take place during the ini-
tial stages following implantation determines tissue compatibility. Thus, the success
of the implant depends on the reactions which take place between the surface of a
metallic material and living tissues directly after the implantation procedure. There-
fore, surface oxide films present on metallic materials play a major role, not only in
corrosion resistance but also in biocompatibility.
12.3.3 Bioceramics
Polycrystalline ceramics are widely used as implant materials in the human body due
to their excellent biocompatibility [9]. Subsequently, ceramics used for this purpose
are termed “bioceramics”. Bioceramics can have structural functions as joint or hard
tissue replacements, or can be used as a coating on metal implants to enhance fixa-
tion and bonding with surrounding tissues. They can also be used in bulk, porous or
powder form providing temporary or permanent fillers. Applications of bioceramics
can be categorized in two groups: load bearing, and non-load bearing applications.
Alumina (Al2 O3 ), zirconia (ZrO2 ) and their composites are common inert, load
bearing bioceramics used in hip and knee prostheses due to their strength and good
corrosion resistance. However, these materials are usually bioinert, as they do not
form good bonds with living tissues [10].
The non-load bearing application of bioceramics can be classified into resorbable
and non-resorbable bioceramics. Non-resorbable bioceramics are bioactive materials
which encourage the formation of a biological bond between tissues and the implant
without experiencing degradation over time. On the other hand, resorbable bioce-
ramics such as calcium phosphate ceramics (CPC), hydroxyapatite (HA), tricalcium
phosphates (TCP), bioactive glasses, bioactive glass-ceramics, corals, and calcium sul-
phate degrade upon implantation and are replaced by living tissues in the host under
physiological conditions. Calcium phosphate bioceramics may be bioactive or biore-
sorbable depending on the calcium to phosphor ratio [11]. The temperature and the
presence of water, both during processing and in vivo, determine the stable phases
of calcium phosphate. Like most ceramics, calcium phosphate exhibits low strength
when compared to metals, and has a tendency towards brittle fracture.
Table 12.1. Characteristics of common ceramics biomaterials.
Material Structure Young’s Compressive Hardness Fracture Density

modulus strength (GPa) toughness (g/cm3 )
(GPa) (MPa) (MPa m1/2 )
Alumina Octahedral 300–400 2 000–4 000 20–30 5–6 3.9

Zirconia Monoclinic 150–250 2 000 10–30 4–12 6
tetragonal
cubic
HA Hexagonal 70–120 1 000–1 500 3–9 1–2 3.1
rhombic
Bioglass Amorphous 30–35 500 <1 0.7–1.2 2.5
12.3.4 Biosynthetic polymers
The term “polymer” indicates a macromolecule composed of repeating units called

monomers, linked by covalent chemical bounds. In polymer science, these materials
are classified according to their thermo-mechanical properties. Indeed, thermoplas-
tic polymers recover their properties reversibly after a heating-cooling cycle, whereas
thermosetting polymers acquire a non-reversible hardness after the same treatment.
Intrinsic physical, chemical, and mechanical properties of polymers are deter-
mined by their composition, conformation, and tacticity, which can be controlled by
polymerization parameters.
Table 12.2. Some mechanical and physical properties of the most common synthetic polymers used
in biomaterial applications [12, 13].
Polymer Water Tensile Tensile Elongation Tg (∘C) Tm (∘C)

absorption modulus strength (%)
(%) (GPa) (MPa)
Poly(acrylonitrile) 3–6 250–425 10–30 97–125 320–330

Poly(amide) 1.5 1.2–2.9 62–68 60–300 45–75 200–270
Poly(dimethyl 0.02 0.2–0.3 2–10 100–600 −120–123 −35–45
siloxane) (×10−3 )
Poly(dioxanone) 0.3–0.4 8.5–9 5–6.5 30–50 −5–10 95–110
(×10−3 )
Poly(e-caprolactone) < 0.2 0.28–0.6 20–25 80–700 −58–60 55–60
Poly(ether ether 2.5–6 65–140 15–120 130–140 220–360
ketone)
Poly(ethylene glycol) 0.98–2.4 0.1–2.2 −35–20 65–70
Poly(ethylene 0.1–0.2 2.8–4.1 30–72 50–500 69–115 265–270
terephtalate)
Poly(glycolic acid) 28 3.9–14 338–647 15–35 36–45 187–233
Poly(hydroxybutirate) 0.7–4 20–60 6–130 −6–8 47–180
Poly(imide) 0.32 3–4 75–90 4–8 400 None
Poly(lactic acid) 0.5–1.5 1.2–3 28–50 2–6 50–60 145–190
Poly(methyl 0.3–0.4 3–4.8 38–80 2.5–6 106–115 160
metacrylate)
Poly(propylene) 0.01–0.035 1.1–2.5 21–40 100–700 −30–0 160-180
Poly(sulfone) 0.2–0.4 2.4–2.7 50–70.3 40–100 170–185 180–190
Poly(tetrafloro- 0 1–2 7–28 250–550 −80–126 314–345
ethylene)
Poly(urethane) 2.5 1.5–2 28–40 36 22–30 200–225
Poly(vinilidene 0.02–0.05 4–5 35–50 20–50 −30–40 170–180
fluoride)
Poly(vinyl chloride) 0.04–0.75 3–4 10–75 10–400 −20–90 None
Structure
A chiral molecule is a monomer that cannot be superimposed with its mirror image.
Consequently, the molecule is arranged as two different forms named enantiomers,
which can be considered as two distinct monomers since they display very different
behaviors. In contrast, achiral molecules are isomorphous. Monomers can be assem-
bled homogeneously or alternatively in blocks or randomly to synthesize a great vari-
ety of macromolecules with diversified properties.
Moreover, these molecules are organized following various chain architectures

which could be linear, branched, cross-linked or networked. Polymer chains can be
weakly bonded by dipole-dipole interactions. The frequency and the force of these
bonds depend on the stereochemical state of the polymer chain and lead to various
conformations. Polymers are either amorphous or semicrystalline. Macromolecular
chains can be organized in a helix or as dispersed lattice sheets inside an amorphous
domain.
Thermo-mechanical properties
Chain entanglement enables freedom of movement in amorphous domains, which in-
creases polymer elasticity; in addition this movement can give the polymer a possible
viscoelastic behavior. In contrast, the crystallinity level has an impact on stiffness and
fatigue resistance.
When a semicrystalline polymer is heated from a glassy solid state to a liquid
state it goes through various transition phases. The first transition occurs between
a glass state and a rubber-like state and is called glass transition (Tg). Tg is a complex
thermodynamic phenomenon which characterizes the amorphous phase of a polymer.
Above Tg, polymer elongation properties are enhanced due to high chain mobility and
the polymer is thus able to reorganize during a phase transition called crystallization.
If the polymer is further heated, polymer crystals become liquid once they reach melt-
ing point. Elastomeric polymers do not exhibit crystallization or melting transitions;
however, these types of polymers liquefy upon heating.
12.3.5 Natural polymers
Natural polymers are produced by living organisms. They can be classified into three
categories: polysaccharides, polypeptides and polynucleotides. Polysaccharides are
composed of monosaccharides linked by glycosidic bonds. Carbon, hydrogen and
oxygen form the monosaccharide units. Polypeptides are chains of amino acids and
polynucleotides are formed by multiple nucleotide monomers, composed of a nucle-
obase, pentose, and phosphate.
Natural polymers have several advantages, one of them being particularly unique:
they can be recognized as biological materials by the organism and metabolically pro-
cessed by either enzymatic or hydrolytic degradation. This process can be very ben-
eficial when timed biological resorption is desired, for example in drug delivery sys-
tems or for the regeneration of functional tissues. However, natural polymers have
a few drawbacks, including immunogenicity, lot-to-lot variability, structural complex-
ity, and often inadequate biomechanical properties [1]. Nevertheless, recent devel-
opments have targeted the improvement of these disadvantages. The immunogenic
effects can be reduced by either chemical modification or decellularization [14]. Bac-
Table 12.3. General properties and applications of the most common natural polymers.
Natural Sources General properties Application

polymers
Alginate Algae (Kelp) Anionic polysaccharide, limited Wound dressing

degradation unless modified, forms (e.g., Phytacare™ )
hydrogels
Chitosan Crustacean Positively charged, enzymatic Hemostats / wound
exoskeletons degradation, can form hydrogels dressings
(e.g., HemCon™ )
Silk Synthesized by Physiological function as a protective Sutures
arthropods (spider cocoon, strong, can be woven, (e.g., Ethicon Silk
or silk worm) slow or minimal degradation, Sutures)
reported biocompatibility issues
Elastin Animal tissues Structural ECM protein found in Surgical Mesh
connective tissues, low solubility, (e.g., Collamend™ )
reversible deformation, soluble
precursor is tropoelastin
Elastin-like Synthetically Synthetic mimic of elastin based on Mostly used for
peptides produced highly repetitive amino acid motifs, research purposes
reversible thermal phase transition
Collagen Animal tissues / cell Abundant ECM protein, triple helix Dermal filler
culture / bacterial structure, provides cell attachment (e.g., Cosmo-
fermentation sites, well documented Derm™ )
Gelatin Denatured collagen Inexpensive form of collagen, Sterile sponge
used for cell attachment in culture (e.g., GelFoam™ )
Fibrin/ Animal tissues / Fibrin results from polymerization Fibrin sealant
Fibrinogen plasma of fibrinogen with thrombin, crucial (e.g., Evicel™ )
component for clot formation
Hyaluronic Animal tissues / Lubricating polymer only non-sulfated Dermal fillers /
acid bacterial GAG, negatively charged, can form wound dressings
fermentation hydrogels (e.g., Restylane™ )
Heparin Animal tissues / Strongly negatively charged GAG, Stent and catheter
plasma binds to numerous GFs, anti-coagulant coatings
activity, used for coating stents (e.g., TyCo™ )
Chondroitin Animal tissues Negatively charged GAG, major Nutritional
sulfate (commonly shark component of cartilage supplements/
cartilage) wound dressings
(gels) (e.g., Applied
Nutritionals)
Decellularized Animal tissues Complex mixture of proteins / GAGs Decellularized
tissue which retains the ECM composition pulmonary artery
and tissue structure; residual cellular patch
components can cause immune reactions (e.g., Allograft™ )
terial recombinants can be used to produce natural polymers in bacteria in order to re-
duce lot-to-lot variability, and chemical modifications or cross linking can contribute
to better control of the mechanical properties of the material. Since different methods
are used in order to improve the properties of natural polymers, it is very difficult to
list mechanical and physical properties of those biomaterials. However, some of their
general properties and applications are listed in Table 12.3.
12.4 Biomedical applications
12.4.1 Cardiovascular system
Anatomy and physiology
Superior Aortic
Branches
vena cava arch
of right Branches of
pulmonary left pulmonary
arteries lntima
arteries
(endothelial cells)
Aortic Pulmonary
semilunar trunk Elastic membrane
valve (Elastin)
Pulmonary
Pulmonary veins Media
veins (smooth
1 Left atrium
Right atrium 2 muscle
3
Bicuspid valve cells)
Tricuspid valve 4 4
Pulmonary
Papillary 5 Adventitia
semilunar valve
muscles
5
(conjunctive
Left ventricle fibrous tissue)
Right ventricle
Interventricular
Inferior vena vava Apex Artery
septum
1 Sinoatrial (SA) node 4 Left and right bundle branches

2 Atrioventricular (AV) node 5 Purkinje fibers
3 Atrioventricular (AV) bundle
Heart physiology and electrical activity
Fig. 12.1. Anatomy and physiology of the cardiovascular system.
The main function of the heart (Fig. 12.1) is to pump blood through the vascular system
with repeated rhythmical contractions. An electrical signal is produced by the sinoa-
trial node, also known as the cardiac pacemaker, which stimulates neighboring cells
to contract, thus producing the heartbeat. The heart has four chambers: the right and
left atria are the upper chambers and the right and left ventricles are the lower cham-
bers. A muscular wall called the septum separates the two atria and the two ventricles.
The heart is surrounded by a double layered membrane (pericardium), which attaches
the heart to the surrounding tissues.
The main function of the four heart valves (Fig. 12.1) is to prevent blood reflux from
the atria to the ventricles (atrioventricular valves), and between the ventricles and
outgoing arteries (sigmoid valves). The atrioventricular valves are attached to the my-
ocardia by the papillary muscles and the fibrous cordae, consequently keeping them
closed when intraventricular pressure rises and forces the blood upwards. Similarly,
the sigmoid heart valves are opened by the ventricular pressure and normal-to-leaflets
blood pressure and are closed by the blood reflux. The main systemic function of ves-
sels (Fig. 12.1) is to transport blood, oxygen, and nutrients to the organs. Arteries are
comprised of three distinct layers which have different compositions and functions:
– The adventitia is the external layer of blood vessels. This fibrous connective tissue
is mainly composed of fibroblasts embedded in a collagen matrix and a nervous
network. The fibers of the adventitia are oriented longitudinally in order to resist
hemodynamic pressure.
– The media is essentially composed of several smooth muscle cell lamellae coax-
ially oriented. Its extracellular matrix consists of collagen and elastin fibers per-
pendicularly oriented to the blood flow. The media is responsible for the vasocon-
striction and vasodilatation phenomena.
– The intima (or endothelium) is organized as a monolayer of endothelial cells at-
tached to a type IV collagen and laminin matrix. The endothelium is responsible
for mechanotransduction, the coagulation process, and the integrity of the blood
vessels.
Cardiovascular diseases
Cardiovascular diseases are the leading cause of mortality as a result of congenital
heart malformations, sedentary and unhealthy lifestyle coupled with an aging popu-
lation [15]; atherosclerosis being the main cause of vascular diseases. This pathology
is defined as a combination of intima and media reorganization due to a local accumu-
lation of cholesterol, blood products, fibrous tissues, and calcification [16]. Atheroma
plate formation is a long process which eventually obstructs the lumen of the ves-
sel, leading to thrombosis in approximately 75% of cases. An aneurysm can also be
a consequence of atherosclerosis, due to the weakening of the vascular wall. Aortic
and mitral valve diseases are likewise responsible for cardiovascular issues, the main
problem being their calcification, leading to an increase in valve stiffness, which af-
fects the opening and closing mechanisms of the valves and leads to stenosis and/or
regurgitation [17].
Table 12.4. Materials and devices for cardiovascular system repair.
Application Material & Description Advantages Disadvantages

Devices
Arrhythmia Pacemaker – Small device implanted in the chest – Control of the heartbeat. – Unresponsive to the native nervous
or abdomen. system (demands of exercise or
– A battery, a computerized generator emotions)
and electrode sensors [18]. – Requires monitoring and mainte-
– Low-energy electrical pulses are nance
delivered by the generator through – Nonadaptive to patient growth in
electrodes placed in the heart. pediatric applications.
Tachycardia Implantable – Unlike pacemakers, low-energy and
cardioverter high-energy electrical pulses are
defibrillator provided to control heartbeat [19].
Artificial heart Artificial heart – System which recreates heart beat – Mimics ventricular movement by – Sensors, motors and electronics
(SynCardia with a pump, awaiting heart trans- air-driven pump system. located outside of the body (180kg),
Systems Inc.) plant [20, 21]. – Highest patency rate (79% after 10 but a wearable power supply is in
years) research.
– Temporary
AbioCorTM Completely implantable total artificial – Temporary
heart based on the ventricular – Relatively new technology.
mechanism.
– Hydraulic pump and ventricle im-
planted in the chest (1kg).
– Battery and electronic systems
located in the abdominal area.
Innovative power supply system based
on transcutaneous energy transmission.

Devices
Aortic and Caged-ball – Different geometries available, – Loud opening and closing sound.
mitral heart valves based on available hemodynamic – Thrombogenic
valve replace- features. – Ball or disc variability or failure with
Caged-disc
ment [17] – Implanted by sternotomy and tho- different degrees of severity
valves
racotomy surgeries, but newest – 75% survival rate of the Bjork-Shiley
Bileaflet tilting valves are stent-framed and are mechanical heart valve implant af-
disc valves increasingly implanted by percuta- ter 20 years. However, only 18%
(synthetic or neous surgery. had conserved their original im-
natural leaflets) plant. The remaining patients
mainly died of heart valve mal-
function.
Stent framed – Percutaneous implantation – Highly thrombogenic
valves
Vascular Expanded – Microporous structure – Inert surface – Currently used for medium vessel
prostheses [22] polytetrafluoro- – Implanted by open surgery diameters (10 mm > D > 6 mm)
ethylene – Used for most serious cases of – Thrombogenic
(ePTFE) vascular diseases – Non-compliant
– Patency rate: 20% with a micro-
vessel PTFE graft (diameters lower
than 6 mm) after four weeks in vivo.
Polyethylene – Woven or knitted crimped textile – Relatively good mechanical proper- – Currently used for large vessel
terephthalate structure ties (tensile stress, compliance. . . ). diameters (D > 10 mm)
(PET) – Implanted by open surgery – More thrombogenic than ePTFE
– Patency rate: 95% after 5 years in

vivo, 40–50% after 10 years for
|
lower limb bypass implantation.

289
Devices
Vascular Impregnated – Impregnation of natural gels (colla- – Improved blood permeability. – Quickly degraded
prostheses [22] PET gen, gelatin, albumin. . . ) or antibac- – Improved biocompatibility or infec-
terial agents (silver, carbon) tion resistance.
Heparin – Less thrombogenic during the first
bounded PET days after implantation.
Vascular stents Stainless steel – Tubular metallic or polymeric – Optimal elongation properties. – Thrombogenic
[22, 23] (316L) meshed device – Could cause arterial wound
– Implanted by angioplasty – Restenosis may appear in 30–40%
Drug-coated – Improved surface properties.
– Used to restore blood flow after an cases after 6 months due to arterial
316L stainless
atherosclerosis-induced constric- lesions.
steel
tion.
L-605 cobalt- – Optimal tensile and yield strengths.
chromium
alloy
Nickel-titanium – Shape-memory alloy.
alloy (Nitinol)
Drug eluding – Bioresorbable – Can cause arterial wound.
polylactic acid – Based on regenerative medicine
[24, 25] principles.
Endovascular – Polymeric fabric supported by a – Same as vascular stents.
stents stent
– Implanted by angioplasty
– Used to restore blood flow after an
aneurysm.
The main problems experienced by vascular implants are due to infections or system malfunctions, whereas failures of vascular prostheses are currently
caused by intimal hyperplasia, false anastomosis aneurysm or thrombosis of conduits [26–28].
12.4.2 Musculoskeletal system

The musculoskeletal system enables movement, weight support and protection of soft
tissues and organs from the environmental stresses and strains experienced by the hu-
man body. It consists mainly of bones, cartilage, tendons, ligaments, joints, muscles,
and teeth (Fig. 12.2).
Cellular and collagen fibre organisation of cartilage
Cellular organisation Collagen fibre architecture
Articular surface
Superficial
tangential zone
Middle zone
Perimysium
Deep zone
Calcifield zone
Subchondral bone
Collagen hierachical structure

in tendons and ligaments
Collagen fibril (100 nm)
Collagen fibre
Primary fibre bundle (subfascicle)
Secondary
fibre bundle
(20-200 μm)
Tertiary fibre bundle
Bone hierachical structure
Osteocyte Haversian system

Primary
Nutriment canal structure
(for blood vessels
and nerves into and α-chains
from marrow)
Hydroxyapatite
nanocrystals
Contains yellow
marrow Collagen
Compact fibrils
bone tissue Spongy
bone tissue Collagen
Spongy bone fibers Lamellae
tissue Compact Outer layer
bone tissue (dense connective
tissue)
Fig. 12.2. Anatomy and physiology of the musculoskeletal system.

Human teeth are composed of three primary tissues: enamel, dentin, and pulp.
Enamel forms a protective layer at the anatomical crown of the teeth and is known
as the hardest substance in the human body. Dentin is the biggest component of teeth
and is a mineralized tissue with an overall composition similar to bone. It is composed
of approximately 70 percent in weight (wt%) mineral phase (apatite form), 20 wt%
collagen, and 10 wt% water.
Bone is a high strength material which serves both as load bearing and non-load
bearing structure. In biological terms, bone is described as a connective tissue, and
in materials terms bone is a natural composite material which contains both mineral
(solid matrix) and organic (soft matrix) phases. The structure of bone biocomposite
contains around 65 wt% mineral phase (calcium phosphate as the main inorganic
component), 25 wt% collagen, and 10 wt% water. Additionally, it also contains small
amounts of organic materials such as proteins, polysaccharides, and lipids.
Hyaline articular cartilage acts as a low-friction, wear-resistant, load bearing sur-
face in synovial joints and, combined with synovial fluid, facilitates the absorption of
impact and the smooth transmission of loads from the joint to the underlying bone.
Cartilage may be considered a porous composite organic solid matrix swollen by wa-
ter. It is constituted of chondrocytes embedded in a dense extracellular matrix (ECM),
mostly composed of a collagen type II fibril network, proteoglycan and water. Their
respective concentration varies with depth.
Ligaments and tendons are tough, flexible, and highly anisotropic bands of fi-
brous connective tissue ensuring the transmission of loads between the elements
they connect: tendons link muscle to bone, while ligaments connect the extremities
of bones. Although their functions are different, the structure and composition of
tendons and ligaments are similar from an engineering standpoint. They both consist
of relatively few cells (fibroblasts make up around 20% of the total volume) and a
significant amount of extracellular matrix. Roughly 70% of this ECM is water, the rest
of the solid elements being collagen, elastin, and ground substance (proteoglycans,
glycosaminoglycans, and other glycoproteins) which stabilize the collagen organi-
zation. The viscoelastic properties of these tissues, highlighted by the creep and
stress-relaxation behavior of ligament and tendons, are mainly due to this ground
substance. The arrangement of collagen fibers in tendons and ligaments differs: they
are bound together in parallel (tendon) or nearly parallel (ligament) bundles arranged
along the central axis. In the first case, this arrangement creates a stiff (Achilles ten-
don Young’s modulus is 0.8–1.5 GPa), highly anisotropic material with high tensile
strength (50–125 MPa), but with little resistance to shear and compression. As for
the ligament, the slight misorientation, combined with the larger elastin content,
allows nonaxial loads to be carried, but also reduces their overall stiffness and tensile
strength. This hierarchical structure is also present in muscles, where the building
blocks are myofibrils (bundles of actin and myosin proteins) instead of collagen.
Table 12.5. Composition of musculoskeletal tissues (%).
Components Hard tissues Soft tissues
Bone Enamel Dentin Cartilage Ligament Tendon

Water 8–10 1–2 8–10 65–80 60–80 60–80
Solids 90–92 98–99 90–92 20–35 20–40 20–40
Collagen < 30 <2 < 30 70–85 70–80 86
Minerals (calcium > 70 > 98 > 70 – – –
phosphates)
Proteins – – –
Proteoglycan & – – – 15–30 15–25 10–12
ground substance
Elastin – – – >5 2
Musculoskeletal traumas and diseases

Musculoskeletal disorders have been identified as among the most important health
conditions which exist today, according to World Health Organization (WHO) reports.
As a result of traumatic injuries such as bone fractures, bone disorders, dislodged
teeth, or non-traumatic injury like age related degeneration, tissues may require re-
pair, replacement or reconstruction [29].
Biomaterials designed for applications in the oral and maxillofacial regions are
among the most common to have reached the clinical stage. Restorative materials can
be separated into direct devices, which can be directly placed in or on the natural
dental tissues; and indirect devices, which are produced outside the mouth and then
bonded in or onto the remaining natural tissue. In more severe conditions (i.e., miss-
ing tooth), common treatments involve the use of partial or full dentures. However,
due to their recent success, there has been a dramatic increase in the inclusion of den-
tal implants as a viable treatment option. Design and production of dental implants
have been vastly studied and commercialized; parameters such as length, implant
diameter, implant geometry, and surface characteristics are customized from case to
case [30].
Bone restoration can be achieved via transplantation or implantation. Autograft
or allograft tissues can replace damaged bone tissue, but this replacement may lead to
several problems (donor site morbidity, limited availability, transmission of diseases,
etc.). For these reasons, there is a growing need for the production of artificial bone
fixations and bone fillers [31]. Various forms of bone-graft substitutes are available and
include allograft bone preparations such as demineralized bone matrix and calcium-
based materials.
Human synovial joints, such as ankle, fingers, hip and knee, are replaced with
artificial joint implants. The most common joint replacement implants are weight-
bearing joints like the hip and knee [32]. From a materials science point of view, joint
replacements can be considered devices for bearing implants. A variety of design pa-
rameters based on many surgical factors (such as length of stem, diameter of hip head,
etc.) governs the choice of weight-bearing joint replacement implants. One of the most
important challenges in hip replacement is the need to improve load transfer to the
bone and reduce the incidence of loosening and stress shielding which can lead to
implant dislocation in long term applications.
The majority of current clinical procedures in the case of osteoarthritis (also
known as degenerative joint arthritis and involving the degradation of articular car-
tilage) involve non-biomaterial related approaches. Several therapeutic interventions
have been developed to induce cartilage healing [33]. Among the grafting procedures,
osteochondral autograft transfer (mosaicplasty) and autologous chondrocyte implan-
tation (ACI) are popular strategies used in clinical situations. While the former only
consists of the implantation of multiple osteochondral plugs (forming a mosaic pat-
tern) in the damaged joint, the latter procedure, ACI, involves a three-step procedure
of cell harvesting (from non-weight bearing sites of the knee), in vitro chondrocyte
culture and cell implantation [34]. In the first generation of ACI, in clinical use since
1987, a periosteal (outer surface of bones) cover was used to seal the wound and the
culture-expanded autologous cells were injected via an aqueous solution. However,
thanks to the technological advances of biomaterial research, new generations of ACI
have initiated the use of purpose-designed biomaterials (see Table 12.6).
The high prevalence of anterior cruciate ligament (ACL), rotator cuff, and Achilles
tendon injuries as a result of occupational and sporting injuries has become a major
economic burden for healthcare systems worldwide [35]. Tendon and ligament regen-
eration procedures have proven to be a considerable clinical challenge owing to the
high mechanical stresses placed on these tissues. Currently, the most successful strat-
egy remains grafting; autografts are the most common procedures (often referred to
as the gold standard) used when tissue defects cannot be repaired naturally [36, 37].
However, their use is limited by the availability of healthy tissues and is often accom-
panied by donor site morbidity and pain. Allografts and xenografts, on the other hand,
require intense sterilization procedures which are detrimental to the biomechanical
properties of the tissue and can lead to increased graft failure [38]. Furthermore, they
are susceptible to disease transmission from the donor, restricting the already lim-
ited availability of transplants. The use of synthetic polymers as scaffolds was also at-
tempted for tendon and ligament regeneration, with limited long-term success [35, 39].
Synthetic scaffolds all displayed adequate initial performances due to their superior
mechanical properties. However, they showed little host tissue in-growth, inadequate
fiber abrasion resistance, and their degradation products often caused important in-
flammatory responses, which ultimately led to these devices no longer being used.
Commercial biological scaffolds did not fare better in clinical applications. While they
were able to induce tissue formation, their mechanical properties were significantly
lower than native tissues, which led to multiple reported failures in clinical studies
[35, 40].
Table 12.6. Materials and devices for musculoskeletal system repair.
Application Material & Devices Description Advantages Challenges

or Trauma
Restorative Direct: Amalgam Replace diseased, discolored and – Fast – Chemical leakage from
dental resin composites, malformed orodental structures in – Cost effective the material
materials glass inomer order to improve their function, – Relatively good mechanical – Matching shade, translucency,
silicate cement. speech, comfort, esthetics and properties. and texture with surrounding
integrity. teeth
– Lower biocompatibility
– Minor tooth tissue damage
due to heat generated during
restoration.
Indirect: inlays, onlays, – Effective for large dental defects – Improving esthetics
veneer – Better esthetics – Costly
cast metals (gold) – Better wear resistance – Require multiple appointments
porcelain – Higher biocompatibility and laboratory time and produc-
composites. tion personnel.
Orthodontic Wires Braces and orthodontic treatments – Good corrosion resistance – Metal ion release
products Bracket used to correct malocclusion. – Superior properties such as – Sensitivity to metal traces
Screws rigidity flexibility, fatigue, and – Esthetic problems for metallic
Bands durability. materials
SS – Low operability, low resilience
CoCr alloy and fatigue for polymeric
NiTi alloy materials.
Plastics
Elastomers
|
295
or Trauma
Dental Pure titanium Missing teeth due to periodontal – Almost 100% survival rate for – Surface modification
implants [41] Ti-based alloys disease. Dental implants produced in metallic implants – Implant loss due to insufficient
Zirconia composites various shapes and sizes, placed in – Good mechanical properties suitable bone surface
Alumina composites the jaw bone as artificial roots to – Less damaging to the gum – Maintenance of healthy sur-
support a crown or a denture. – Higher comfort, chewing ability, rounding tissues during the first
and quality of life. year of loading.
– Osteointegration.
– Poor biocompatibility, hypersen-
sitivity
– Improving esthetics for metallic
implants
Partial or full – Mimic the optical characteristics – Loosening and cleaning
dentures/crowns of enamel and dentin – Maintenance of healthy sur-
CrCo alloys – Esthetics rounding tissues
Gold alloys – Chemical inertia – Require highly accurate clinical
Porcelain – Moderate resistance to fracture and laboratory processing
in high-load restorations – Require multiple appointments
and laboratory expertise for
production.
– Low to moderate resistance to
fracture
– Allergenic sensitivity to base
metals.
Bone fixation Ti-based alloys Fractured bones are primarily – High mechanical properties – Second operation required for
Stainless steel repaired using fixation devices removal.
CoCr alloys such as wires, nails, pins, screws,

and plates.
or Trauma
Bioresorbable – Biodegradation of the whole – Low mechanical properties

polymers [42] material. – Long term balance between me-
PLA, PLLA chanical strength and material
bioabsorption.
Bone fillers Vitroceramics Bone cements and fillers are used in – Good biocompatibility – Vascularization
Calcium phosphates the treatment of benign bone tumors, – Unlimited supply – Osetoinductivity
Demineralized injuries, and disorders as alternatives – Uniform quality – Oseteogenicity.
human bone to autografts or allografts – High mechanical properties
Ceramic collagen – Osteoconductivity
composites – Good formability.
Ceramized allografts
Bone joint Metal on plastic The femoral part comprises of stem – High durability – Low wear resistance
replacement and head; it can be in one piece or as – Less expensive. – Osteolysis (bone loss)
implants a modular design. – Concerns about long term bio-
A joint implant replacement usually compatibility due to chemical
requires the removal of a significant composition and biological re-
segment of diseased articular tissue, sponse to debris.
Metal on metal moreover subject to enormous – Better wear resistance – Few cases of device recalls
repetitive stresses from body – Largest head design: higher by FDA
movement and weight-bearing. stability and motion. – Concerns about long term bio-
compatibility due to chemical
composition and biological re-
sponse to debris.
Ceramic on polymer – Better wear resistance – Associated with adverse local

– Lower fracture rate compared to and remote tissue responses
|
ceramic on ceramic. – Failure diagnosis difficult

– High articular wear rates.
297
or Trauma
Ceramic on ceramic – High wear resistance – Brittleness
– Durability – Catastrophic fracture.
– Reliability
– Good biocompatibility.
2nd generation Chondro-gide (collagen Porcine-derived type I/III collagen – Reduced risk of hypertrophy – Three-stage procedure
ACI membrane) bilayer membranes are used to suture – No second operation site, lead- – Uneven distribution of chondro-
defect before injection of a cell ing to shorter operation time cytes
suspension. The membrane is and the absence of donor site – Cartilage damaging sutures re-
composed of a compact and a porous morbidity quired for fixation
side. The compact side prevents cells – No patient-related material qual- – Low mechanical stability.
from diffusing into the synovial fluid ity issues
while the other layer favors even cell – Easy to handle and tear-resistant
distribution and attachment.
3rd generation – Hyalograft C Before implantation the autologous – Three-dimensional cellular archi- – Three-stage procedure since cell
ACI (matrix- (hyaluronan chondrocytes are seeded on a tecture harvesting and culture are still
assisted) polymer) biomaterial carrier (i.e., –Higher mechanical stability (com- necessary
– CaRes three-dimensional scaffold/matrix or pared with 1st and 2nd generation – Ex vivo chondrocyte culture
(collagen gel) gel) upon which they are grown. The ACI) – Lack of long-term follow-up
– ArthroMatrix, biomaterials with seeded cells are –Scaffolds may act as a barrier – Few materials are FDA approved
MACI, MACT (colla- trimmed to the precise defect size and to the invasion of the graft by – The properties of healthy carti-
gen membrane) implanted without the use of a fibroblasts, which may otherwise lage tissue are still unmatched by
– Bioseed-C periosteal cover or fixing stitches induce fibrous repair any available substitute.
(polymer) (fibrin glue is often used for fixation). –Faster, less extensive procedure,
– Novocart 3D suture-free
(polymer) – Some models (especially gels)
– Cartipatch can be applied with minimal

(natural hydrogel) invasive surgery
– High biocompatibility.
or Trauma
Tendon and – Restore (porcine Derived from mammalian tissues. – No donor availability problem – Mechanical properties are signif-
ligament submuscosa) Processed through cascade steps to – Biochemical composition similar icantly lower than native tissues
injuries – GraftJacket (human isolate an acellular collagen scaffold. to tendons and ligaments – High failure rates
(biological cadaver dermis) Removal of noncollagen components – Surface chemistry and structure – Inflammatory responses and
scaffolds) – Zimmer (porcine to prevent host rejection. favorable to tissue ingrowth edema have been reported with
dermis) Used as alternative to autografts – Most are FDA-approved. the use of biomaterials derived
– TissueMend (fetal or allografts. from porcine/bovine sources.
Bovine Dermis)
– OrthADAPT
(bovine/porcine
pericardium)
Tendon and – Gore-Tex (PTFE) Synthetic fibers are woven, braided – Superior mechanical properties – Tissue ingrowth varies with the
ligament – Dacron (PET) or knitted into a high strength – Easy to handle material but is usually very in-
injuries – Stryker (PET/PP) scaffold. Used as alternative to – Effective in treating complex complete
(synthetic – Leeds-Keio liga- autografts or allografts. Several instabilities – Stress shielding of maturing
scaffolds) ment (PET) prostheses have been withdrawn – Good short-term clinical results. tissues, limiting the transfer of
– Kennedy-LAD (PP) from the market due to unsatisfactory load-bearing responsibilities
long-term results. – Wear debris can induce long-term
complications & inflammatory
responses
– Limited biocompatibility
– Mechanical failure caused by
swelling and separation of fibers.
|
299
12.4.3 Visceral organs
The digestive and excretory systems are comprised of the gastrointestinal tract, solid
organs including the liver and pancreas, and the urinary tract. The main function of
the gastrointestinal tract is to break down and absorb ingested nutrients. The liver
and pancreas participate in the breakdown of carbohydrates, proteins, and fats into
smaller molecules such as glucose, amino acids, and fatty acids by secreting digestive
enzymes into the small intestine (Fig. 12.3).
Oesophagus Pancreas
Acini
(digestive enzyme
production)
Lumen
Mucosa
Submucosa
Muscularis
propria
Islet
(hormone production)
Liver (hepatic lobule) Kidney (glomerulus)

Blood
flow
Bile flow
out Capsule
Glomerulus
Blood flow in Hepatocytes Blood flow Filtrate

(metabolic reactions out
ans detoxification)
Fig. 12.3. Anatomy and physiology of visceral organs.
In addition to their digestive functions, the liver, pancreas, and kidneys play a crucial
role in metabolic and hormonal regulation. For example, the liver stores glucose in the
form of glycogen and synthesizes proteins from amino acids. The pancreas controls
blood glucose levels by releasing hormones such as insulin which increases glucose
uptake by the muscles and decreases glucose release by the liver. Waste products pro-
duced by liver, muscles and other organs are finally removed from the blood stream by
the kidneys. The kidneys first eliminate small molecules non-selectively by size-based
filtration in the glomerulus, and then reabsorb useful nutrients and osmolytes.
In sum, each organ within the digestive and excretory systems plays a role in the
transport, filtration, and transformation of nutrients or waste products. The structural
role and the absorption and filtration capacities of these organs can be assisted by
medical devices, whereas novel cell-based therapies may be required to fully replace
their metabolic and secretory functions.
Table 12.7. Materials and devices for repair of visceral organs.
Application Material & Devices Description Advantages Disadvantages

– Palliation of malignant Esophageal self- Stents made of metals such as – Appropriate mechanical Clinical complications:
dysphagia expandable metal nitinol and stainless steel. properties to resist expan- – stent migration
– Gastroduodenal outlet stents (SEMS) They can be covered, uncovered sion – acquired tracheoe-
obstructions or partially covered with – Porosity promotes gas and sophageal fistula (TEF)
polyurethane, polyethylene, nutrient exchange – difficulty in swallowing
polytetrafluoroethylene (PTFE) – Biocompatible, allowing – inadequate expansion with
or silicone. adhesion and proliferation increased post-procedural
– Tracheoesophageal fistulas Esophageal self- Stents mainly made of polyester of cells as well. dysphagia
– Benign esophageal stric- expandable plastic or silicone. – variable throat or chest
tures stents (SEPS) pain, esophageal erosions
– Esophageal perforations with bleeding and fistuliza-
and leaks tion
– Malignant airway disease – significant reflux
– Post laryngoesophagec- Salivary bypass stent Stents made of medical-grade Soft and pliable stent allowing
tomy fistula silicone. easy delivery using the
– Palliation of advanced push-through technique.
pharyngeal and cervical
esophageal cancer
– Managing traumatic in-
juries of the cervical esoph-
agus
Pancreas failure External insulin pumps Composed of a blood glucose Compared to manual injec- Costly, requires human input
sensor, an external insulin tions, insulin pumps improve and prone to catheter-related
reservoir, an open-loop blood glucose control [43], complications

electronic controller and a which may reduce the
|
subcutaneous cannula to life-threatening complications

deliver rapid-acting insulin. of diabetes.
301
Implantable pumps Delivers insulin into the ∼ 7 year battery lifespan,
peritoneal cavity through a surgical complications, need for
polyethylene-lined silicone in-hospital insulin refills, as well
catheter. as insulin aggregation leading to
pump or catheter
obstruction [44].
Hemodialysis or Separation process: – Bioartificial kidney can – Medications are needed to
Kidney and liver failure
hemofiltration pressure-driven ultrafiltration. mimic glomerular func- control the levels of miner-
Made of polysulfone, tions [45]. als and replace hormones.
polyvinylpyrrolidone, modified – Renal function can be par- – Some patients do not have
cellulosic membranes, tially replaced by dialysis suitable blood vessels for
polyacrylonitrile. through semi-permeable establishing an access site.
Sample retains molecules of membranes with well- – A permanent abdominal
8 ∼ 60 kDa: cells and most defined porosities made catheter in the case of peri-
proteins including albumin. from natural or synthetic toneal dialysis, is required,
polymers. with the risk of peritonitis.
– Membranes can be coated – The difference in compo-
with biomolecules such as sition of dialysis fluid
heparin to reduce membrane may have deleterious
thrombogenicity, or with downstream effects and
molecules which increase metabolic abnormali-
membrane permeability, ties [47].
Single pass albumin Separation process: albumin such as extracellular matrix
dialysis (SPAD) dialysis proteins [46].
Made of acrylonitrile/ sodium – Certain liver support sys-
methallyl sulfonate copolymer. tems can reduce the inci-
Sample retains molecules of dence of brain dysfunction

35∼40 kDa: cells and most (hepatic encephalopathy)
proteins including albumin. by reducing the levels of
molecules such as ammonia.
Molecular Adsorbent Separation process: albumin
Recirculating System dialysis, charcoal and resin
(MARS) adsorption.
Made of polysulfone.
Sample retains molecules of
50 kDa: cells, large proteins,
albumin (with significant
albumin losses).
Bioartificial liver Separation process:
plasmapheresis, usually
charcoal or anion-exchange
resins. Made of cellulose acetate
or polysulfone.
100 ∼ 400 kDa: Cells,
multimeric proteins.
Fractionated plasma Separation process:
separation and 1) plasmapheresis, 2) neutral
adsorption resin, 3) anion exchange.
(PROMETHEUS) Made of polysulfone.
> 100 kDa: cells, large proteins
(e.g., antibodies).
Therapeutic plasma Separation process:
exchange plasmapheresis
Made of polypropylene
|

> 1 000 kDa: cells.
303
12.4.4 Nervous system and sensory organs
Nervous system
The human nervous system is equipped to sense and respond to continuous changes
within the body and its external environment. The fluctuations of the internal and
external environments are regulated by the nervous system to maintain homeosta-
sis (state of relative stability within the body). Homeostasis is critical for survival be-
cause the body can only survive within a narrow range of conditions. The nervous
system monitors and controls most body processes, from automatic functions (such
as breathing) to activities involving fine motor coordination, learning, and cognition
(such as playing a musical instrument). The nervous system has two major divisions:
the central nervous system (CNS), and the peripheral nervous system (PNS).
– The CNS integrates and processes information sent by nerves through the brain
and the spinal cord.
– The PNS includes nerves which carry sensory messages to the CNS and nerves
which send information from the CNS to muscles and glands. It is further divided
into the somatic system and the autonomic system.
– The somatic system consists of sensory receptors in the head and extremities,
nerves which carry sensory information to the CNS, and nerves which carry in-
structions from the CNS to the skeletal muscles.
– The autonomic system controls glandular secretions and the functioning of the
smooth and cardiac muscles.
The nervous system is composed of neurons and cells which support the neurons (glial
cells). Neurons are the basic structural and functional units of the nervous system.
They are specialized to respond to physical and chemical stimuli, to conduct electro-
chemical signals, and to release chemicals which regulate various body processes.
The activity of neurons is supported by another type of cells called glial cells. Glial
cells outnumber neurons by about 10 to 1, and they account for about half the volume
of the nervous system. Collectively, glial cells nourish neurons, remove their waste,
and defend against infection. Glial cells also provide a supporting framework for all
nervous-system tissue. Neurons share four common features: dendrites, a cell body
(soma), an axon, and branching ends.
Nervous system damage and disorders

Nervous system disorders and damage can be caused by a wide range of conditions
including infections, hypoxia, poisoning, stroke, chronic degenerative disease, and
acute trauma. Some of the most problematic forms of nervous system disorders and
damage are those related to chronic neurodegenerative disease or acute trauma
caused by injury. After injury to the nervous system, a complex cascade of events
proceeds in a spatially and temporally specific manner. The effect on the nervous
system will vary depending on the type and extent of the injury [48]. Some examples
of damage are: cell death related to lesions and Wallerian degeneration, die-back of
axons, glial scarring which inhibits axonal growth, and breakdown of native ECM
components such as hyaluronic acid [49].
Ocular system
Light waves enter the eye through the cornea and are converged by the cornea and the
crystalline lens. These waves continue through the clear vitreous humor (a gel) that
accounts for about 80% of the volume of the eye, and are focused on the retina. The
retina changes light into electrical signals which are sent through the optic nerve to
the occipital cortex at the back of the brain. The eye is comprised of three tissues sub-
ject to replacement by biomaterials: the cornea, the intraocular lens, and the retina.
Moreover, to correct focus problems, lenses in direct contact with the cornea are used.
For example, retinitis pigmentosa (RP), an inherited retinal degenerative disease
which often results in almost complete blindness, affects roughly 100,000 US citizens.
The worst-affected RP patients, can be helped by a retinal prosthesis, named Argus® II.
The system works by converting video images captured by a miniature camera
housed in the patient’s glasses into a series of small electrical pulses which are trans-
mitted wirelessly to an array of electrodes on the surface of the retina. These pulses
are intended to stimulate the retina’s remaining cells resulting in the corresponding
perception of patterns of light in the brain. The patient then learns to interpret these
visual patterns, thereby regaining some visual function. Second Sight, manufacturer
of Argus® II, gained European approval (CE Mark) for the system in 2011 and FDA
approval in 2013. This approval was given under a Humanitarian Device Exemption
intended to expedite market introduction of technologies for the treatment of smaller,
underserved patient populations. It is the first approved retinal prosthesis in the
world.
Auditory system
Humans can perceive sounds in two ways, by air and by bone conduction. Air conduc-
tion uses the ear canal, eardrum, middle ear, and the inner ear to transduce sound
waves to the CNS. In contrast, sound is transmitted via bone conduction directly
through the bones, bypassing the outer and middle ear.
People with a hearing impairment use hearing aids to amplify sound so that dam-
aged ears can detect it. Cochlear implants bypass damaged portions of the ear and
directly stimulate the auditory nerve. A microphone picks up sounds from the envi-
ronment, a speech processor selectively filters sound, splits it into channels and sends
the electrical signals to the transmitter. The processed sound signals are transmitted
across the skin by electromagnetic induction. The internal stimulator sends signals
to electrodes inserted through the cochlea, which send the impulses to the nerves in
Table 12.8. Materials and devices for nervous system repair.

Devices
Hydrocephalus CNS shunt Typically consists of a proximal catheter, These shunts relieve pressure by These shunts have high failure rate
treatment system which runs from the cerebral ventricle’s draining excess cerebrospinal fluid (40–50%) during the first 2 years
subarachnoid spaces to a valve which from the cerebral ventricles or following implantation [51].
connects to a distal catheter [50]. subarachnoid spaces into a less Complications can be due to obstruction,
Medical grade silicone is almost the constrained area of the body. mechanical failure, infection or excess
only material used to produce drainage.
CNS shunts.
Pathological Stimulating Microwire electrodes are fine wires of Used to restore hearing and alleviate The formation of glial scars around the
disorders electrodes [52] 20–50 cm in diameter made of symptoms of Parkinson’s disease. implanted electrodes hinders their
conductive metals insulated with Teflon long-term performance.
or polyimide. The tips of the wires are
not insulated and are used to record
neuronal signals [53, 54].
Silicon micromachined microprobes
have unsurpassed control over electron
size, shape, texture, and spacing, and
Recording allow for multiple recording sites to be Used to control mechanical devices for
electrodes or placed on a single electrode shank the control of, for example, prosthetic
brain computer due to their photolithographic limbs or motorized wheelchairs for
interfaces [56] processability [55]. paralyzed patients.
Devices
Systemic drug Liposomes Small vesicles in which an aqueous The blood-brain barrier (BBB) is the Systemic delivery requires large doses
delivery to the inner core is entirely enclosed by principal obstacle to delivering drugs to achieve therapeutic concentrations
CNS [57, 58] unilamellar or multilamellar into the CNS, as it forms a barrier for at the target site, which can affect
phospholipid bilayers. the entry of therapeutic agents from the non-targeted tissues and organs.
bloodstream. Systemic drug carriers Inactivation of peripheral drug and
Polymeric and Particles ranging from 10 to 1 000 nm in
have been developed to avoid the modification of carrier surface are
ceramic size, in which therapeutic drugs can be
BBB [59]. common drawbacks while in the
nanoparticles adsorbed, dissolved, entrapped,
Intravenous or intraperipheral injec- bloodstream.
encapsulated or covalently attached.
tions are used for systemic drug
Polymeric Micelles form spontaneously in the delivery, which is non-invasive.
micelles aqueous solution of amphiphilic block
copolymers, have core-shell architecture
and carry drugs in their core.
Dendrimers Repeatedly branched polymer molecules
which contain a cascade of branches
grown from one or several cores
Local drug Degradable Polymeric implants in the CNS are Local drug delivery circumvents the Local drug delivery is limited by the
delivery to the and non- commonly used in local drug delivery. difficulty of penetrating the BBB, invasive nature of surgical implants of
CNS degradable systemic side effects and toxicity, polymers and the difficulty of attaining
polymers peripheral drug inactivation, and long-term drug delivery at therapeutic
[60, 61]. modification of the carrier surface. levels.
Traumatic Methyl- Intravenous or intraperipheral injec- The only clinically used therapy. This could have adverse systemic side
spinal cord prednisolone tions [62, 63]. effects like immune suppression.
and brain
Implants at injured site using hydrogels Hydrogel scaffold ability to gel in situ As yet only in clinical trial stage.
injury
impregnated with therapeutic mole- is an important property in order to fill
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cules [64, 65]. the irregular lesion cavities.

307
Table 12.9. Materials and devices for ocular repair.

Devices
Focus image Soft contact – Silicone hydrogel. – Absorb significant amounts of water – Less optical features than gas-
on the retina lenses (40 to 75%), allowing oxygen to permeable contact lenses
[67] pass through the lens – Dryness of eyes because of hy-
– More comfortable. drophobicity
Gas-permeable – Poly(methyl methacrylate) rigid – Good oxygen permeability: – Not suitable for all patients.
contact lenses microporous structure. Dk* between 12 and 150
– Superior optical features, provide
sharper vision than soft lenses
– Chemically inert.
Hybrid contact – A rigid gas-permeable central opti- – Highly oxygen-permeability: – Dryness of eyes due to hydropho-
lenses cal zone surrounded by a peripheral Dk = 130 through the center and bicity
fitting zone made of a soft contact Dk = 84 through the border
lens material.
Corneal Poly(methyl – Used in case of transplant failure or – High rate of long-term success – Results depend on the progress of
replacements methacrylate) organ donor shortage. the disease.
[67] prosthesis
Devices
Cataracts or PMMA – Optic of 6mm diameter and intra- – Could lead to posterior capsule
myopia [68] intraocular lens ocular lens-haptics. opacification due to migration of
(IOL) lens epithelial cells
– Surgically induced and corneal
astigmatism
– Spherical aberration
– Risk of postoperative refractive
errors.
– Reading glasses required
– Presbyopia from 45 years of age
leads to reoperation.
Foldable – IOL is injected into a capsular bag – Surgical implantation has greatly – Material aging induces presbyopia
acrylate IOL through a small incision in the reduced perioperative morbidity. – Presbyopia from 45 years of age
peripheral cornea. – Disadvantages of PMMA IOL are leads to reoperation.
greatly reduced. – Reading glasses required
Multifocal IOL – Designed for several refractive, – Reading glasses no longer – Reduces the quality of vision (con-
diffractive or both foci. necessary trast, creation of halos or glare)
– Presbyopia after 45 years old leads
to reoperation.
Accommodating – Designed for enabling IOL displace- – Allow accommodation with modu- – Presbyopia from 45 years of age
IOL ments. lated dioptry. leads to reoperation.
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309
the scala tympani and to the brain through the auditory nerve. The electrode array is
usually made from silicone rubber, and the electrodes are made of highly conductive
material (e.g., platinum). The Bone Anchored Hearing Aid (BAHA) system stimulates
the cochlea by transmitting the sound waves through the bones, bypassing the outer
and middle ear [69].
12.4.5 Esthetic applications
Breast implants
Breast implantation is one of the most widespread cosmetic surgical procedures; this
surgery is used both for esthetic reasons and to correct a number of pathologies such
as asymmetry, contracture, ptosis, infection, and necrosis, which can occur subse-
quent to different kinds of diseases such as breast cancer, malformations, and treat-
ments. The number of breast implantation procedures performed in the US has dou-
bled between 1998 and 2005 [70].
The breast contains the mammary gland, which is responsible for the production
of milk for infant nutrition. It is composed of several superposed layers of tissues (glan-
dular, fatty, and fibrous). It is positioned on the pectoral muscles of the external chest
wall and attached to the chest wall by Cooper’s ligaments. The breast extends hori-
zontally from the edge of the sternum to the mid-axillary line and vertically up to the
axilla (axillary tail of Spence). A thin layer of connective tissue called fascia encircles
the internal breast tissues; the superficial layer of the fascia is situated just under the
skin, while the deep one is on the top of the pectoralis muscle. Usually an implant is
inserted into the submuscular or subglandular plane.
The glandular tissue of the breast is surrounded by a layer of fat which gives the
breast a soft consistency. The glandular tissue houses the lobes, each composed of
many milk secreting glands (lobules). Ducts are small vessels connecting lobes; they
widen toward the nipple to form small bulbs called ampullas. Ampullas gather the
milk produced by the lobules and make it available to the nipple during the lactation
period. The two most important vessels in the circulatory system of the breast are the
axillary artery (extending from the armpit and supplying the outer part of the breast)
and the internal mammary artery (extending from the neck and supplying the inner
part of the breast).
Modern breast implants are composed of an elastomer containment shell and
filler whose consistency should be close to that of the natural breast. Materials used
can be separated into 3 groups: saline implants, silicone implants [71], and alternative
composite implants.
Table 12.10. Materials and devices used in breast implants.
Material & Description Advantages Disadvantages

devices
Saline implants Liquid solution Better performance; Asymmetry,
encapsulated in a look and feels closer to removal/replacement,
room-temperature normal breasts; malposition, loss of
vulcanized shell made resistant to rupture and nipple sensation,
of a silicone elastomer. gel exposure; wrinkling,
completely harmless on palpability/visibility
rupture more evident than
silicone
Silicone implant Polydimethylsiloxane Lower rates of Silicone gel breast
polymeric compound malposition and implants cost roughly as
and gel exhibiting three asymmetry than their much as saline
degrees of saline counterparts; implants.
cohesiveness. better overall
performance than saline
implants
Alternative Soybean oil Withdrawn from market
material (Trilucent™ ) [72] in 1999.
implants
Hyaluronic acid (HA) Local non-permanent Injection site pain and
(Macrolane™ ), procedure, low risk of capsular contracture in
semi-liquid material. allergic reaction or some cases, reabsorbed
transmission of after 12 months.
infections; does not
require surgical
intervention since it is
injectable
Maxillofacial prostheses
Maxillofacial prosthetics are defined as a branch of prosthodontics concerned with
restoration and replacement of both stomatognathic and associated facial structures
by permanent or temporary artificial substitutes [73, 74].
Maxillofacial prostheses are used to correct body defects and to restore both ap-
pearance and functionality to impaired organs, leading to a relative physical and psy-
chological recovery. Maxillofacial rehabilitation consists of repair of nose, maxilla,
mandibula, oral cavity, ears, eyes and ocular orbits.
Materials used in the different stages of maxillofacial prostheses creation can
be divided into five groups: impression materials (plaster of Paris, plaster bandage,
silicone putty, alginate), construction materials (for prosthetic, pattern, mold mak-
ing, separating medium), pigmentation materials (intrinsic and extrinsic coloration),
auxiliary materials (i.e., extrinsic sealant, Aerosil® 130, Silastic® foam, macrocellular
foam, Comfeel® and materials for retention (primers, double sided adhesive tape,
magnets, implants, etc.). The following section of this chapter focuses mainly on ma-
terials and their properties. Modern techniques of maxillofacial prosthesis production
use laser to measure the defect and computer aided manufacturing for the prosthesis
realization.
12.4.6 Skin

The skin is the largest organ of the human body. It consists of three principal layers: the
hypodermis, the dermis and the epidermis (Fig. 12.4). The skin plays the role of barrier
between the organism and the environment, thanks to the stratum corneum which is
the outermost layer of the epidermis, consisting of keratinocytes displaying different
levels of differentiation through a pluristratified structure. The dermis is the mechan-
ical support of the skin and plays an important role in thermoregulation. Vascular,
nervous, and lymphatic networks are found in this layer. Fibroblasts, responsible for
the synthesis of the extracellular matrix (collagen, elastin), are the main cell found in
the dermis, although some immune cells can also be found in this layer. The hypoder-
mis is an adipose tissue which stores fat. It contributes to the plasticity of the skin and
thermoregulation [80].
Skin defects
Wounds can be described as a defect or damage to the skin and can be classified as:
– Acute: resulting from physical damage. These tissue injuries heal completely, with
minimal scarring, usually within 8–12 weeks. Examples are mechanical injuries
due to external factors (abrasions), penetrating wounds (surgical wounds, knife
and gun shot wounds, tumours), chemical injuries (radiation, electricity, corro-
sive chemicals, and thermal sources), and burns [81, 82].
– Chronic: resulting from an underlying medical or physiological condition (e.g.,
diabetes, malignancies). These tissue injuries heal slowly (more than 12 weeks)
and often recur (e.g., ulcers) [81, 82].
Wounds are also classified according to the thickness of the skin layers affected [81]:
superficial (only the epidermis is affected), partial thickness (both the epidermis and
the dermis are affected) and full thickness wounds (underlying subcutaneous fat or
deeper is affected, as well as dermis and epidermis).
Skin defects may be treated using dressings or substitutes, depending on the
severity of the wound and the surface area affected. The main reasons for closing
or covering a skin defect are to (a) provide rapid and cosmetically acceptable heal-
ing, (b) prevent infection, (c) contain exudate, (d) minimize distress to the patient,
(e) reduce pain, and (f) cover a wound for cosmetic reasons [81, 83].
Table 12.11. Materials and devices used in maxillofacial implants.
Applications Material & Description Advantages Disadvantages

devices
Resins Acrylic resins Thermoplastic or thermosetting plastic Readily available, ease of coloration, Rigidity, discomfort, high thermal
[75] materials composed of acrylic acid, adequate mechanical properties, conductivity, no possible duplication.
methacrylic acid or similar monomers. compatibility with adhesives, long
working life, color stability, easily
repaired or reshaped.
Acrylic Examples of acrylic copolymers are Soft and elastic, resembling natural Poor edge strength, degradation due to
copolymers chains of hexanediol diacrylate (HDDA), replaced tissues. sunlight, difficult processing and
[76] hexyl acrylate (HA), 2-ethyl hexyl acrylate coloration, easy stainability.
(EHA) and dodecyl acrylate (DDA)
monomers.
Polyvinyl PVC chains are composed of CH2 -chcl– Flexible, adaptable to coloration for Low chemical resistance, low mechanical
chloride (PVC), monomers, while plastisols are made suitable appearance, high glass properties, high degradation rate, short
plastisols and of PVC chains and plasticizing additives transition temperature. working life.
polyvinyl such as phtalates, phosphates or fatty Need for plasticizers, linking agents and
chloride acids; PVCA copolymers are composed metal molds, low dimensional stability.
acetate (PVCA) of polyvinyl chloride and polvinyl chloride
co-polymers acetate monomers in different amounts.
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313
Applications Material & Description Advantages Disadvantages
devices
High Q7-4720/4780 Polydimethyl vinyl siloxane copolymer – Enhanced tear resistance, possibil- Need for heat curing (at least 116°C) and
Temperature SE-4524U1 with approx. 0.5% vinyl side chains, ity of hardness control, no residues catalyzers (platinum), two components to
Vulcanized M51142 [77] 2,4-dichlorobenzoylperoxide as an because of thermal curing via addi- mix before activating with catalyzer.
silicones (HTV) initiator and a silica filler obtained from tion chemistry. High temperature curing (127–175°C),
methyl silane combustion. – High tear resistance, uniform prop- need for pigmentation to perfect final
erties with different curing agents. appearance.
– Good edge tear strength, short
work and curing time, tunable me-
chanical, rheological and adhesion
properties by specific agent addi-
tion.
Room MDX 4-42103 Siloxanes containing vinyl polymers Room temperature curing, no shrinking, Long curing time (up to 24 hours), larger
Temperature [78] and hydrides; chloroplatinic acid is no presence of byproducts and parts with thick sections could require
Vulcanized Silastic often used as a catalyst, different peroxides. longer, catalyzer and degasing procedure
silicones (RTV) Medical kinds of ethoxysilane are used as Cures at room temperature when needed.
Adhesive cross-linking agents. exposed to atmospheric moisture, Releases acetic acid vapor as a
Silicone, Type solvent-free, one-component adhesive/ byproduct.
A® (# 891)3 sealant, humidity sensitive. Time consuming, especially for low
A-21864 Translucent and pigmentable, short humidity levels; heat not accelerating
preparation and curing time. curing time
1 Momentive Performance Materials Inc. product; 2 Technovent Ltd. product; 3 Dow Corning Corporation product; 4 Factor II Inc. product
A more exhaustive list of silicone-based materials used nowadays for prosthodontics can be found in the work by Montgomery et al. [79]. Other silicone-
elastomer producers can be found in [74]. Pigments generally used are metal oxides, silicone intrinsic pigment, oil and dry earth pigments [79].
Table 12.12. Materials and devices for wound dressing applications [81, 83–86].

No exudate to low Semi-permeable – Non-absorbent dressings; Can be transparent (no need to be Too thin to be packed into deep or
exudate wounds adhesive films made from a thin sheet of removed to visualize the wound); cavity wounds; care must be taken
– Partial-thickness polyurethane coated with a conform to contours (elastic and when removing film dressings (to
wounds, donor layer of adhesive. flexible nature); do not require ensure atraumatic removal); may
sites, minor burns, – Different types of film dif- additional taping; permeable to promote periwound maceration due
pressure ulcers. fer in their moisture vapor moisture, vapor, and gases; to occlusive nature.
– As a secondary permeability, method of ap- impermeable to fluid and
dressing over pri- plication, extensibility, weight microorganisms; can stay in place
mary dressings and thickness. for up to one week; aid autolytic
(gels, alginates debridement; prevent friction
and hydrofibers) against the wound bed; keep
wound bed dry; prevent bacterial
contamination of the wound.
Low to moderate Hydrocolloid dressing – Colloidal materials (gel form- Permeable to water and air after Leave residue at the wound bed
exudate wounds ing agents) combined with application; facilitate rehydration which may be mistaken for
– Wide range of exu- other materials such as elas- and debridement of the wound; infection; cannot be used in the
date from light to tomers and adhesives; com- adhere to moist and dry sites; presence of infection; may
very heavy, granu- posed mainly of cellulose and insulate the wound bed; water- encourage the growth of anaerobic
lating, sloughing or typical gel forming agents proof and impermeable to bac- bacteria; may roll over certain body
necrotic wounds including carboxymethyl cel- teria, urine or stool; painless areas (friction)
– E.g., pressure lulose (cmc), gelatin, and removal; allow patients to shower
sores, abrasions, pectin. and bath and ideally should be left
minor burns, surgi- – Occur in the form of thin films in place for 3–5 days.
cal wounds, trau- and sheets or as composite

matic injuries, dressings in combination
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pressure ulcers, with other materials such as

leg ulcers alginates.
315
Medium to high Alginate dressings (not – Produced from calcium salts In the form of readily biodegradableAlways require a secondary
exudate wounds recommended for dry of alginic acid (polysaccha- fibers: when trapped in a wound dressing (adhesive foam dressing
– Wide range of wounds) ride), a component of brown and can be rinsed away with saline or a semipermeable film); may
wound types and – Ideal for bleed- seaweed. irrigation; do not cause pain on cause desiccation of the wound
cavities which are ing wounds; un- – Occur either in the form of removal; may be used on infected bed, as well as drying exposed
granulating, with suitable for dry freeze-dried porous sheets wounds; non-adherent; encourage tendon, capsule or bone.
small amounts of wounds or those (foams) or as flexible fibers autolytic debridement.
slough. with dry, hard, (indicated for packing cavity
– E.g., venous, dia- necrotic tissues. wounds); may be woven or
betic and pressure nonwoven.
ulcers, wounds – Have the ability to form gels
with tunneling, upon contact with wound
wounds with heavy exudates (high absorbency).
exudate. Foam dressings – Consist of porous Less apt to stick to delicate wound May require a secondary dressing;
(recommended for dry polyurethane foam or beds; non-occlusive; comfortable; may promote periwound
wounds.) polyurethane foam film, allow for less frequent dressing maceration; cannot be used on
sometimes with adhesive changes (depending on the amount wounds with eschar or wounds
borders. of exudate); maintain a moist which are not draining; some foams
– Variety of foams made from environment around the wound; may not be suitable for certain
different base materials and provide thermal insulation; highly wounds (those that are infected);
constructions which have absorbent, absorbency being sheet dressings not suitable as
similar but varying perfor- controlled by foam properties. packs for cavity wounds.
mance characteristics; avail-
able in a variety of shapes,
sizes and thicknesses.
Dry or sloughy wounds Hydrogel dressings – Insoluble, swellable hy- Absorb exudate, thereby providing Amorphous hydrogels usually
drophilic materials made a moist environment; nonadherent; require a secondary covering such
from synthetic polymers such nonreactive with biological tissue; as gauze and need to be changed
as poly(methacrylates) and permeable to metabolites and frequently;
polyvinylpyrrolidine; contains nonirritant; cool the surface of the Hydrogels have low mechanical
large amounts of water (80% wound (reduction in pain, high strength and are therefore difficult
or more) and are combined patient acceptability); leave no to handle (this has been noted to
with a range of other materi- residue; malleable; improve affect patient compliance).
als (hydrocolloid materials, reepithelialization of wounds;
alginates and starch-based control transmission of water vapor
polymers). through the dressing; sheets do not
– Can be applied either as an need a secondary dressing; can be
amorphous gel or as elastic, cut to fit around the wound due to
solid sheet or film. flexible nature
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317
Minimizes scarring
Provides scaffold
for cell growth
Forms barrier
against infection
Encourages
natural blood
clotting
Epidermis
Strenghtens
new tissue
Provides protein
for healing
Absorb fluid from
Dermis inflammation
Blocks nerve ending
to reduce pain
Hypodermis
Fig. 12.4. Anatomy and physiology of the skin and properties of an ideal wound dressing.
Medicated dressings (drug delivery)

A new generation of medicated dressings incorporates chemicals which have a ther-
apeutic effect on wound healing. The incorporated drugs can be cleansing or debrid-
ing agents (removal of necrotic tissues), antimicrobials (prevent or treat infection) or
growth factors (support tissue regeneration) which play an active role in the wound
healing process. Modern dressings used to deliver active agents to wounds include
hydrocolloids, hydrogels, alginates, polyurethane foam/films, and silicone gels [81].
Controlled delivery dressings can provide an excellent means of delivering drugs
to wound sites over long periods of time without the need for frequent dressing
changes. Bio-adhesive, synthetic, semisynthetic, and naturally derived polymeric
dressings are useful in the treatment of local infections where it may be beneficial to
have increased local concentrations of antibiotics, whilst avoiding toxic reactions due
to high doses. Moreover, they are readily biodegradable and therefore can be easily
washed off the wound surface once they have had the desired effect [81].
Bioengineered skin substitutes

Bioengineered skin substitutes (biosynthetic skin substitutes and cultured autologous
engineered skin) are available in large quantities with negligible risk of infection or im-
munologic issues, to provide temporary or permanent coverage of wounds. Although
one major disadvantage of many of these products remains cost and availability [84,
87, 88], there are advantages in specific cases: they avoid the creation of a donor site
(pain and morbidity), reduce autologous skin graft, require fewer postoperative dress-
ing changes and speed up healing [87].
The use of autologous cells in cultured skin products has the advantage of im-
munological safety [88]. These skin substitutes can be used for permanent wound clo-
sure, restoring physiological stability. However, the use of autologous cells requires
extended culture time for cells extracted from the skin biopsy [89]. Autologous skin
equivalents seem to be the best treatment for chronic wounds and deep and extensive
burns. Secretion of growth factors results in faster healing of donor sites and better es-
thetic results when compared to conventional therapeutics (Biobrane-L) [90] (Please
see Table 12.13, p. 320, 321.).
12.5 Future trends
12.5.1 Tissue engineering basic concepts
The term “tissue engineering” was first introduced about 25 years ago, but tissue en-
gineering strategies have been employed for skin substitutes since the 1970s. Tissue
engineering aims to “restore tissue and organ function by employing biological and
engineering strategies to solve clinical problems” [92]. Traditional approaches to tis-
sue engineering are:
– implant a combination of an engineered matrix with cells as a tissue replacement;
– implant an engineered matrix as a guiding template for inducing tissue regener-
ation in vivo.
12.5.2 Scaffolds
Scaffold design
Most strategies in regenerative medicine have focused on 3D mechanical support en-
hancing biological tissue growth. This degradable support, also known as scaffold,
must have tailored properties for creating a specific tissue or organ. Biocompatible
and biodegradable synthetic or natural polymers are well-suited for these applica-
tions because they offer great versatility and choice of processing and material fea-
tures for matching tissue requirements. Indeed, scaffold hydrophobicity, porosity or
crystallinity can induce various cell behaviors through signaling pathways. For ex-
ample, a pore size of 20 μm is ideal for fibroblast ingrowth, whereas bone cells need a
Table 12.13. Materials and devices for skin substitute applications [84, 87–91].

Epidermal Epicel Sheets of autologous keratinocytes FDA approved; valuable for patients Mechanical fragility (absence of an
grafts (approximately 50 cm2 , two to eight with very large burns (60% of the integrated dermal component); at
cell layers thick) attached to a body surface, with poor availability least 3 weeks required for graft
supporting petrolatum gauze backing and/or quality of donor sites); cultivation; hyperkeratosis;
(removed approximately 1 week after autologous tissue can be used as a contracture; scarring; cost; long-term
grafting); can be stored for 24 hours permanent replacement; can be used safety unknown.
at cool room temperature with a dermal substitute (Integra), in
(13 to 23°C). full-thickness burns.
Epidex Sheets of cultured autologous Improves healing of (relatively small) May not provide complete coverage
keratinocytes transplanted with a chronic leg ulcers. (small and circular grafts); multiple
supportive silicone membrane; discs grafting procedures may be required
(Ø 1 cm) placed within the wound for definitive wound closure.
margins; silicone backing removed at
first dressing change.
Dermal grafts Integra Semi-biological bi-layered dressing Immediate availability in large Risk of seroma, infection; training
Severe burns Indicated for excised composed of an inner permanent quantities; used in complex traumatic required; second procedure typically
and chronic deep partial- and dermal analogue (porous matrix of soft tissue reconstruction (over necessary; expensive.
wounds full-thickness burn cross-linked type I bovine collagen, exposed tendons, joints, bone, and
wounds. chondroitin-6-sulfate, a shark- wounds from vascular and pressure
derived glycosaminoglycan), under ulcers); inhibits wound contraction
an external temporary silicone and scar formation. Semi-permeable
membrane (epidermis-like function); silicone membrane controls water
Storage: room temperature; 2-year vapor loss, provides a flexible
shelf life; silicone sheet removed as adherent covering for the wound
wound heals; thin autograft grafted surface, increased tear strength
onto the neodermis to complete of the substitute.
wound coverage.
Biobrane Temporary biosynthetic dressing Collagen incorporated into the Minimal clinical data
Placed on a fresh, clean composed of knitted nylon mesh silicone and nylon components
wound bed, superficial bonded to a thin silicone membrane provides a flexible and adherent
and partial thickness (acts as an epidermal layer) and surface for wound coverage;
burns or as coverage coated with porcine polypeptides; semipermeable external silicone
for donor sites. immobilized with suture, tape, or membrane allows excretion of burn
other dressing material, later exudates and permeability for topical
removed after wound healing antimicrobials; controls water vapor
(7 to 14 days) or when autograft loss from the wound; showed
skin is available. improvement in reepithelialization;
Manufactured in different sizes reduced pain; decreased nursing
(13 × 13 cm, to 38 × 50 cm); No costs.
special storage conditions (at least

3 years at room temperature)
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321
pore size of 200–400 μm. Numerous properties of scaffolds can improve cell adhesion,
migration, proliferation, orientation, and protein secretion. Physiological stresses are
also crucial for organ regeneration; therefore the mechanical properties of scaffolds
must be similar to those of the tissue of interest and able to resist physiological duty
cycles [93].
Degradation aspects
A suitable degradable scaffold must provide a biomimetic matrix allowing cells to
proliferate and produce their ECM, while the scaffold gradually vanishes over an ap-
propriate time period. Consequently, understanding and controlling the degradation
mechanism of a scaffold is the key to the long-term success of resorbable implants.
Indeed, implantable degradable materials and their degradation products must be
biocompatible until the degradation process has been completed. The degradation
rate is tailored according to the application, with several processing parameters such
as composition, molecular weight, polymer chain conformation, polymer structure,
and scaffold morphology. However, polymer materials are not able to deliver all sig-
naling properties required for cells to migrate, adhere, proliferate or secrete ECM. Con-
sequently, biological molecules like peptides or growth factors may be added to the
scaffold to fulfill these specifications [93, 94].
Scaffolding materials
Hydrogel materials are widely used in biomedical applications as space-filling agents
and bioactive molecule vehicles, and also for tissue constructs. The tridimensional
architecture of hydrogels is similar to ECM, easy to manufacture, and can be doped
with molecules of interest to enhance cell proliferation and tissue growth. However,
current trends are focusing on mechanical improvements of hydrogels [95, 96].
Nanofiber scaffold strategy provides a 3D framework which mimics the fibrous
state and physical scale of the ECM components. Moreover, fibers exhibit exceptional
elasticity features. Electrospinning is a common technique used to produce nanofiber
scaffolds, but other methods such as blow spinning, air spinning, and force spinning
exist. Major challenges in the nanofiber technology field are producing scaffolds with
the desired porosity for cellularizing nanofiber scaffolds with optimum requirements
and designing complex macrostructures [96, 97].
Another very common technique for generating porous scaffold is thermal-
induced phase separation. First, a polymer is totally dissolved in a solvent. Next
the polymer solution is cooled at gelation temperature in a mold, and finally the sol-
vent is evaporated via freeze drying in a vacuum. This technique offers very complex
and suitable scaffold morphologies but cannot be used for all polymers or scaled up
to an industrial level [97, 98].
Nanofibers may also be generated by self-assembly of peptide amphiphiles. This

approach aims to create supramolecular constructs from specific peptides containing
an alkyl chain tail and an antigenic determinant head, which aggregate into fibrils
with specific conditions. This spontaneous process is driven by three forces: a hy-
drophobic attractive interaction between alkyl tails which forms the core, hydrogen
bonding which forms the shape, and repulsive electrostatic forces between peptide
heads. However, this smart but complex method of forming nanofibers is only rarely
applied [98].
Decellularized matrix is another scaffold strategy. This technique consists of re-
moving cellular material from an organ via chemical treatments. The scaffold retains
the 3D structure and most of the ECM components of the organ. Nevertheless, deter-
gents have been found to denature or eliminate some important proteins like colla-
gen. On the other hand, most common methods do not achieve decellularization, and
DNA or antigen materials remain in the scaffold, which can lead to a host immune
response [99].
12.5.3 Surface modification
Biological responses to biomaterials are greatly controlled by surface physics and

chemistry. The key concepts of the surface modification strategy are to improve bi-
ological acceptance and functionalize a medical device or scaffold by changing its
surface properties while conserving its bulk properties. Material surfaces can be mod-
ified by altering the first atomic layers (chemical modification, etching, roughening),
or by adding other components (coating, grafting, deposition). Several surface mod-
ifications are aimed at modifying blood compatibility to influence cell adhesion and
growth, to control protein adsorption, to produce a nonfouling surface, to improve
lubricity, corrosion resistance, antibacterial features, and electrical properties. The
main challenges in surface engineering lie in the stability of the treatment, control of
molecule delivery, and delamination of the surface [100].
12.5.4 Stem cells
Terminally differentiated cells are limited in their proliferative capability and are
therefore less likely to completely regenerate an organ. Because of this limitation,
the use of stem or progenitor cells has become a major driver in the field of regen-
erative medicine. Stem cells are able to self-renew, to extensively proliferate, and to
differentiate into multiple cell types, making them a promising cell source for regen-
erating tissues. Stem cells are divided into two categories: embryonic and somatic.
Embryonic stem cells (ESC) are pluripotent and proliferate very quickly, but have
great limitations. First, ethical issues must be taken into account because embryos
are destroyed to obtain ESC. Second, ESCs are allogeneic and lead to an immune re-
sponse or differentiate into malignant tissues. On the other hand, multipotent adult
stem cells are able to differentiate into several tissues and mainly come from umbilical
cord blood and bone marrow. The advantage when comparing these cells to ESC is
that adult stem cells can be obtained from patients themselves, thus limiting immune
rejections. However, adult stem cells have a much more limited proliferation poten-
tial. Recent research has found the ability to reprogram somatic stem cells to obtain
characteristics similar to embryonic stem cells. Thus, finding a better approach to
differentiate stem cells into various cell-lineages is definitely the major future trend
in this field [98].
12.5.5 Bioreactors
A bioreactor is a dynamic in vitro environment which uses both biochemical and me-
chanical signals to guide and regulate tissue development. The concept of bioreactors
is not restricted to tissue engineering, since producing proteins from the culture of mi-
crobial or mammalian cells for therapeutic or diagnostic applications is a very well-
known technique [101]. Bioreactors have been developed in response to static culture
limitations and are used to distribute cells uniformly in 3D scaffolds. They provide
the desired concentrations of gases and nutrients in the culture medium, maintain
efficient mass transfer to growing tissue, and apply a physical stimulus to improve
tissue development. Several bioreactor designs such as rotating-wall, spinner flasks,
and perfusion have been developed to engineer a variety of tissues (Fig. 12.5). In or-
der to properly simulate physiological conditions, tissue engineering requires a sys-
tem which mimics the hemodynamic forces experienced by tissues. These mechanical
forces include shear stress and stresses in the radial, circumferential, and longitudinal
directions. Initial attempts to create engineered tissues resulted in the manufacturing
of grafts with poor mechanical properties. The new generation of tissue engineered
substitutes produced using bioreactors has dramatically improved the mechanical
properties of the tissues; however, it takes several months to develop engineered tis-
sues with the desired mechanical properties. Because elastin and collagen are the two
main components of ECM which influence the biomechanical properties of tissues, dy-
namic mechanical conditioning of the construct accelerates the production of these
two proteins [102].
12.5.6 Computational models
Over the past two decades, computational modeling has emerged as a significant
research activity in biomaterials, in particular in the area of polymeric science. Its
extended importance is attributable to three factors. First, the development of high
Tissue Engineering Bioreactors
In vitro bioreactors In vivo bioreactors
The peritoneal
Dynamic systems cavity bioreactor
Static systems
Mechanically driven Hydraulically driven The bone
Petri dish bioreactor
Shaker Hollow fibre bioreactor
Multiwell plate
Shake flask
T-flask Perfusion bioreactor
Multiwell plate
Membrane flask (shaken) Pulsatile flow
bioreactor Rotating unit bioreactor
Multitray cell Rotating wall Compression applied
culture system bioreactor
Spinner flask
Culture bag Membrane flask
bioreactor
Rocker unit or
raising platform
Tensile
bioreactor
Fig. 12.5. Summary of different bioreactors used for tissue fabrication (adapted from [103]).
throughput combinatorial polymer synthesis techniques has enabled the creation of

polymer libraries of extraordinary size. For example, the tyrosine-derived library of
polyarylates consists of eight diacids and fourteen diphenols for a total of 112 polymers
developed by the Kohn lab. In comparison, a large virtual library of polymethacry-
lates recently designed in the same lab resulted in more than 40 000 polymers. The
conventional experimental approach to characterizing bioresponse and materials
properties of polymers is clearly unsuitable for such enormous libraries. Second,
modeling techniques developed in computational chemistry (e.g., drug discovery)
and computer science are readily adaptable to biomaterials science. This technology
transfer leverages longstanding research programs in these related fields to provide
new modeling capabilities in biomaterials science. Third, computational resources
have continued to expand at a dramatic rate. Cluster computing using Linux-based
servers is now both commonplace and inexpensive, and has enabled application of
detailed physical modeling (e.g., molecular dynamics (MD) simulation) to specific
problems in biomaterials science [104].
Recently, computer simulation of tissue differentiation in response to mechanical
forces has become an important element in modeling studies. It involves defining al-
gorithms for mechanoregulation of each of the following cell activities: proliferation,
apoptosis, migration, and differentiation using a stimulus based on a combination of
strain and fluid flow algorithms, which are based on lattice-modeling which also facil-
itates building algorithms for complex processes such as angiogenesis. The algorithms
are designed individually but can be processed together. They can be combined to cre-
ate a computational simulation method for tissue differentiation, using finite element
analysis to compute the mechanical stimuli even in quite complex biomechanical en-
vironments [105].
The seeding of a porous scaffold with cells is a fundamental step in engineering
sizable tissue constructs that are clinically viable. However, a key problem often en-
countered is inhomogeneous seeding of the cells, particularly when the cells are de-
livered through the thickness of the scaffold. A quantitative relationship between cell
seeding efficiency and the initial vacuum pressure in a compact perfusion seeding de-
vice which uses the effect of differential pressure induced by vacuum to seed cells on
a porous scaffold was established with the help of computational models. A transient
CFD solution of the fluid flow in the device was used to formulate a 3D computational
model which can be employed to design and optimize cell seeding techniques and the
corresponding technology [106].
12.6 Summary
This chapter briefly summarized the synthetic materials and devices available to sur-
geons for the treatment, repair or replacement of tissues or organs. It should be under-
stood that these materials and devices are the result of decades of research and devel-
opment during which strategies evolved with the improvement of our understanding
of physiology and disease, as well as our materials science and engineering capabili-
ties. Therefore, knowledge of the biomaterials field requires a historical overview.
The very first biomedical devices developed were essentially designed to repro-
duce the basic functions of the tissue or organ they were intended to replace. For ex-
ample, the first arterial prostheses were made from materials which could form tubes
with adequate mechanical properties and chemical stability to withstand the pulsatile
blood pressure for many years without failure. During this early period very few con-
cerns were raised regarding the interaction between the material and the physiological
environment.
This last issue began to be of interest when researchers realized that the body’s
response towards a synthetic implant plays a very important role in its long-term pa-
tency. This awareness led to the development of stealth materials which were intended
to be hidden from the body and to have very minimal interaction with the biologi-
cal environment. This was the beginning of the development of non-fouling coatings
made with polyethylene glycol, various carbohydrates, phospholipids, etc. Despite the
fact that this approach has been demonstrated to be successful in some instances (for
example, such coatings are used to decrease protein adsorption on contact lenses), it
turned out to be almost impossible to make an antifouling layer free of defects, which
in turn, were the sites of nucleation for protein adsorption.
Today, the common strategy is to develop materials likely to proactively interact

with the physiological environment. The number of strategies are almost limitless
and they vary from the control of material surface roughness for appropriate size
matching with cell receptors, the conjugation of signal peptides for cell recruitment,
cell/drug encapsulation, to biodegradable materials that will be replaced during
the tissue/organ healing/reconstruction process. These approaches often require the
combined properties of synthetic and biological materials to be taken advantage of.
Where do we go from here? If the trend continues, it is likely that the biomaterials
of the future will be increasingly biological. Indeed, scientists now have a better un-
derstanding of how cells interact to form tissues and organs and accordingly, how to
enable cells to form suitable tissue substitutes. Indeed, such expertise is already in use
to make skin substitutes which are highly beneficial for severely burnt patients. Very
promising experiments in the generation of bone, blood vessels, or even a compete
heart from cells are ongoing. In addition, researchers are now able to benefit from cell
functions and properties at different levels of differentiation states. Having said that, it
should be kept in mind that it took nature several thousands of years to create the hu-
man body. In this context, it is unlikely that human replacement parts with the same
level of complexity as the original ones will be available in the near future. Therefore,
synthetic biomaterials will continue to play a key role in the treatment of patients for
many years to come.
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M.-A. Fortin
13 Nanoparticles for magnetic resonance imaging
(MRI) applications in medicine
Magnetic resonance imaging (MRI) has developed at an exponential rate over the last
decades, and is now widely used as an anatomical and functional medical imaging
modality. The development of magnetic nanoparticles as contrast agents for vascu-
lar, molecular, and cellular MRI applications has followed this trend. One of the most
important direct applications of nanotechnology is nanoparticles which generate ei-
ther “positive” or “negative” contrast in MRI. The present chapter is an introduction
to the principles underlying the performance of nanoparticulate-based MRI contrast
agents. It addresses the main considerations guiding the design, synthesis and the
physicochemical characterization of magnetic nanoparticles based on the elements
iron, manganese; and gadolinium (Fe, Mn, Gd). The fundamental aspects of nano-
particle magnetism and relaxometric characterization are introduced, as well as ex-
amples of applications in biological models.
Introduction to nanoparticles for MRI applications
Nanoparticles (NPs) made of the elements iron (Fe), gadolinium (Gd) or manganese
(Mn) are currently used in many diagnostic applications performed under magnetic
resonance imaging (MRI). In fact, MRI scanners do not directly detect intrinsic signals
from magnetic nanoparticles (MNPs); instead, they reconstruct images from the elec-
tromagnetic signals generated by the stimulation and relaxation of the large pool of
hydrogen (1 H) protons found in biological tissues. MNPs influence the relaxation time
of hydrogen protons contained in small, mobile molecules such as water by interac-
tions taking place at the atomic and molecular level. Thereby, MNPs induce contrast
enhancement effects on the reconstructed MR images, either as a signal increase, or
brightening (“positive” contrast agents, CAs), or a signal decrease, or darkening (“neg-
ative” CAs).
Modern medical diagnostics now rely on hybrid imaging modalities which are
capable of merging excellent anatomical resolution (MRI, CT) with the sensitive
detection of molecular and cellular events (e.g., nuclear medicine and lumines-
cence/fluorescence techniques). In fact, MRI is one of the most reliable, high reso-
lution (75–300μm), and multi-functional imaging modalities of modern medicine. In
particular, it is the imaging modality of choice for soft tissues (brain, liver, spine).
Compared to optical imaging and echography, it allows the acquisition of in-depth,
whole-body images, from the mouse model to the human. Contrary to computer to-
mography (CT), another anatomical imaging modality, MRI does not rely on ionizing
radiation. It also enables the tracking of cells, molecules, and drug delivery vehi-
cles in the human body. These applications require the development of appropriate
biomedical imaging probes (CAs or tracers).
Such probes must allow the efficient detection of a reasonable amount of mole-
cules, or cells, in the body (nanomolar or micromolar concentration range) [1–3].
Compared to MRI, positron emission tomography (PET) and luminescence/flu-
orescence imaging do not provide anatomical images, and neither are they consid-
ered high resolution imaging modalities in general. However, both are truly efficient
“molecular” imaging modalities (nanomolar detection). Unfortunately, MRI has rela-
tively poor sensitivity compared to such techniques. In order to fully exploit the wide
range of advantages MRI has to offer in molecular and cellular imaging applications,
it has been necessary to design CAs capable of very efficient interaction with hydrogen
protons.
Contrast agents (CAs) have been developed since the inception of MRI, to selec-
tively change the longitudinal and transverse relaxation times (T1 and T2 ) of 1 H in
biological tissues. Such energy transfers mainly occur through interactions between
the magnetic elements and the spins of hydrogen protons in their vicinity. Gadolinium
has 7 unpaired electrons in its 4f orbitals, giving it a very large magnetic moment. This
translates into a relatively slow electronic relaxation rate compared to other paramag-
netic elements, which enhances its proton relaxation properties [4]. Manganese can
also be exploited in MRI applications, although its magnetic moment is weaker than
that of Gd3+ (Mn2+ has 5 unpaired electrons on its 3d orbital). Most clinically approved
CAs are based on small molecules which sequestrate the paramagnetic ion Gd3+ [5, 6].
They are mainly used as nonspecific agents to enhance the general contrast of or-
gans, thereby enabling better identification of anatomical changes occurring in the
body. They are also applied to blood-pool and blood perfusion procedures. After the
first marketing authorization of Gd-DTPA (Magnevist™ ) in the US, Europe and Japan
in 1988, other Gd-based chelates were introduced to the market: Dotarem™ , based on
the DOTA chelator, as well as Omniscan™ , Prohance™ , Optimark™ , and Gadovist™ [7].
Today, contrast media are used in approximately 30 to 40% of all MRI procedures.
Parallel to the development of paramagnetic CAs, progress also occurred in the
field of MRI CAs through the unique properties of iron oxide NPs. In contrast to para-
magnetic molecules, which produce “positive” contrast in MRI, iron oxide NPs are well
known for their signal decrease. Iron oxide NPs are generally divided into two classes:
small particles of iron oxide (SPIO) and ultra-small particles of iron oxide (USPIO).
SPIOs consist of iron oxide cores with mean diameters of between 3 and 20 nm; how-
ever they form agglomerates of hydrodynamic diameter typically greater than 50 nm.
The concept of hydrodynamic diameter (Fig. 13.1) refers to the total effective diameter
of a particle suspended in a fluid and forming a colloid. The hydrodynamic diame-
ter is generally measured by means of laser analysis (dynamic light scattering, DLS),
which is an indirect measurement of the Brownian motion of NPs in aqueous media.
USPIOs, on the other hand, refer to the class of iron oxide NPs which is made of iron
13 Nanoparticles for magnetic resonance imaging (MRI) applications in medicine | 335
Water in the
hydrodynamic
corona
Ligand or organic
coating molecule + – + –
+ –
-
Link (e.g. covalent) + –
between the
Fe2O3, particles and the + – Fe2O3,
MnO, coating molecules – MnO, –
Gd2O3, + Gd2O3, +
NaGdF4 – NaGdF4 –
Functional anchor +
(attachment of – +
+ – –
targeted molecules,
+ – – +
or imaging + –+ – +
functionalities)
rH : hydrodynamic Organic
diameter molecules
adsorbed in
the corona
(a) (b)
Fig. 13.1. Schematic representations of (a) the structure of functional magnetic nanoparticles (MNPs)
for MRI applications, and (b) a colloidal nanoparticle suspended in biological media.
oxide cores (3–20 nm diameter) surrounded by a coating of molecules that preserve

their individuality (mean diameter < 50 nm).
SPIOs and USPIOs have very different mean hydrodynamic diameters, as well as
different “relaxometric” properties. Such properties can be advantageously exploited
either in cell labeling (preferentially with SPIOs), liver cancer diagnostic (preferen-
tially with SPIOs), molecular targeted imaging (preferentially with USPIOs), or blood
pool/angiography procedures (preferentially with USPIOs). In fact, a very large frac-
tion of molecular and cellular MRI applications are based on the design and pro-
duction of MNPs consisting of (a) an inorganic nanocrystal core (e.g. Fe2 O3 /Fe3 O4 ,
Gd2 O3 , MnO, NaGdF4 ), (b) a coating made of small ligands, or biocompatible organic
molecules, and (c) a functional anchor used to graft specific molecules with comple-
mentary imaging functionalities (e.g., radioactive atoms or fluorescent molecules), or
medicinal compounds for drug delivery. Injected intravenously, SPIOs are captured
by macrophages. They end up in the Kupffer cells of the liver (part of the reticuloen-
dothelial system, RES), where they are expected to degrade. As a result, an important
shortening of the transverse relaxation time (T2 /T2∗ ) is observed in liver tissue, which
is reflected by a strong signal loss[8–10]. An example of this is provided in Fig. 13.2.
By this mechanism, iron oxide NPs “passively”, but rather homogenously accu-
mulate in the liver, where they are found to lower the MR signal. However, tumors and
t = 0 min t = 8 min t = 24 h
(a)
1,60 1,20 1,60

1,50 1,10 1,50
1,40 1,00 1,40
1,30 0,90 1,30
S1/S0
S1/S0
S1/S0
1,20 0,80 1,20

1,10 0,70 1,10
1,00 0,60 1,00
0,90 0,50 0,90
0,80 0,40 0,80
0 20 40 60 80 100 120 140 0 8 16 24 32 40 48 0 8 16 24 32 40 48
(b) Time (min) (c) Time (h) (d) Time (h)
Fig. 13.2. Intravenous injections of polymer-coated iron oxide NPs in the mouse model (unpub-
lished data, Fortin et al.). After injection (t = 24 h compared to t = 0), arrows in (a)), the liver ap-
pears darker. The presence of USPIOs in the blood enhances the vascular signal during at least
20 minutes (t = 8 in (a), and (b) blood signal-enhancement ratio): USPIOs can be used as blood-
pool agents. After injection, NPs are gradually sequestrated by the macrophages and follow the
reticuloendothelial (RES) route, mainly in the liver ((a) t = 24 h, arrow; and (c)). After several hours,
a significant signal enhancement appears in the gall bladder (d), an indication of the hepatobiliary
excretion of NPs.
metastases are void of Kupffer cells and they do not internalize iron oxide NPs. This
strategy has been used in the diagnosis of liver cancer and liver metastasis, as well as
for imaging the spleen and the lymph nodes [11, 12]. Because of their elimination by
the liver, SPIOs are not efficient in applications requiring longer blood half-lives (MR
angiography, tissue perfusion imaging, functional imaging of the brain). USPIOs are
better candidates for vascular applications, since they remain in the blood for longer.
Their relaxation properties also allow them to be used as positive CAs in T1 -weighted
imaging (see next section) and angiography [13–17]. In recent years, research into tar-
geted MRI contrast agents has focused on the development of targeted USPIOs which
could enable the efficient, sensitive and selective detection of atherosclerosis, apopto-
sis, and amyloid deposition in Alzheimer’s disease [18–25]. This concept is frequently
referred to as molecular targeted imaging.
Parallel to iron oxide NPs, a new generation of paramagnetic NPs has been de-
veloped, based on Gd- and Mn-containing inorganic nanocrystals [26, 27]. These are
based on the synthesis of Gd2 O3 [28–32], NaGdF4 [33–36], and MnO [37–39] nano-
crystals. When adequately covered with biocompatible ligands and suspended in
aqueous solutions, these are “positive” CAs in MRI. Since the core of inorganic nano-
particles is very small (< 20 nm), and because they contain hundreds or thousands
of paramagnetic atoms, they can be used as molecular or cellular probes. Thereby la-
beled molecules are then much more sensitively detected than if labeled by traditional
MRI contrast agents which contain only one paramagnetic atom per unit of contrast
agent (e.g., commercially available Gd-DTPA, or Gd-DOTA) [5, 6]. Although they are
not as sensitively detected as their “negative” CA counterparts based on iron oxide
NPs, they provide contrast enhancement effects which are largely devoid of mag-
netic susceptibility image artifacts. In addition, the detection of signal-enhancement
effects generated by “positive” CAs could enable more quantitative molecular and
cellular imaging studies. Until now, CAs based on Gd and Mn nanocrystals have been
largely constrained to pre-clinical studies due to the inherent risks associated with
the leaching of potentially toxic Mn2+ and Gd3+ ions. They nonetheless represent very
useful contrast agents for research purposes in the field of cell labeling and tracking,
as well as for molecular imaging with MRI.
This chapter first describes the general considerations which must be taken into
account in the design and preparation of MNPs for MRI in vivo applications. Synthesis
and coating procedures to prepare suspensions of MNPs of narrow particle size, appro-
priate magnetic and relaxometric properties, optimal colloidal stability, and good bio-
compatibility are presented. The contrast-enhancement characteristics of superpara-
magnetic and paramagnetic NPs are discussed, in particular their respective use either
as “negative” or “positive” CAs in T2 /T2∗ -weighted or T1 -weighted MRI sequences.
13.1 The basics of MRI in medicine
A brief introduction to the basic principles of MRI will clarify important concepts guid-
ing the design and use of MNP for MRI applications in molecular and cellular imaging.
The reader is invited to expand his knowledge on this technology by referring to a se-
lection of readings on the general topic of MRI [40, 41]. In brief, the strength of the
magnetic field in common MRI scanners ranges from 1 to 3 Tesla, which is 20 000 to
60 000 times stronger than the Earth’s magnetic field. When a patient is placed in the
gantry, the hydrogen protons (1 H) align their spins along the direction of the magnetic
field (B0 , Fig. 13.3(a)). The sum of each of the magnetic moments of these spins repre-
sents the “macroscopic magnetization vector” (M) ⃗ of the biological tissue. This vector
is globally oriented along the main magnetic field of the scanner. In their initial state,
the spins “precess” at a certain frequency (ω0 ; the Larmor frequency) and are not co-
herent in phase. Then, using a transmitter coil, a radiofrequency (RF) wave tuned to
Larmor conditions is applied to the biological tissue. This causes the excitation of 1 H
spins making them lose their preferential orientation along the main magnetic field
(Fig. 13.3(b)). After application of RF excitation, M⃗ oscillates around the main mag-
netic field (the “z” axis of the MRI scanner), and the spins are phase-coherent in the
x-y plane (Fig. 13.3(b)).
RF pulse on: RF pulse off:

– Excitation of 1H: loss of Mz – Mz recovery (according to T1 )
– Spin phase coherence in xy – Loss of Mxy phase coherence (according to T2 )
Signal
B0 z B0 z B0 z
Mz
ω0 ω0
63%
M
T1
37% T2
ω0 M
x Mxy
x x
Relaxation time
M
y y y
(a) (b) (c) (d)
Fig. 13.3. Schematic representation of the macroscopic magnetization vector generated by MR

excitation.
From this moment, the oscillation motion along the x-y plane is detected by a receiver
coil and recorded. This represents the “MRI signal”. Then the “x-y” phase coherence
(Mxy ) is gradually lost (within milliseconds) as the magnetic moments of neighboring
1
H protons exert a mutual influence on each other (Fig. 13.3(c)). The time constant
used to quantify this loss of phase coherence is called the transversal relaxation time
(T2 ; Fig. 13.3(d)). Independent of this mechanism, the excited spins progressively re-
lease their energy and recover their initial orientation along the main magnetic field
of the scanner (Mz recovery; Fig. 13.3(c)). This return to the initial macroscopic mag-
netization state occurs within a time constant that is referred to as the longitudinal
relaxation time (T1 ; Fig. 13.3(d)). Both T1 and T2 are intrinsic characteristics of any
biological tissue and, together with the density of 1 H spins in the tissue (ρ), are the
most important parameters influencing the signal. For instance, the signal recorded
for a given tissue (S), using a basic spin-echo sequence, is given by the following equa-
tion:
S = ρ (1 − e(−TR/T1 ) ) (e−TR/T2 ) , (13.1)
where TR and TE are the repetition and echo times (parameters in the spin-echo se-
quence [41]). Interactions between the paramagnetic elements Fe3+ , Gd3+ , and Mn2+
take place at the molecular level, causing T1 and T2 to decrease and, in turn, to modify
the MR signal according to equation (13.1). Such interactions accelerate the release of
energy communicated to 1 H protons during RF excitation.
13.2 Relaxivity: the performance of MRI contrast agents
MNPs made of Fe, Gd, or Mn, influence the macroscopic relaxation times (T1 and
T2 ) of 1 H contained in neighboring mobile molecules. In turn, this effect modulates
the MRI signal (equation (13.1)), which translates into contrast effects in anatomical
MR images. The efficiency of MRI CAs to decrease both T1 and T2 of hydrogen protons
contained in the solution, is referred to as the “relaxivity”. Relaxivity depends on the
concentration, as well as on the physicochemical characteristics of the CAs: hydro-
dynamic diameter, number of water binding sites at the magnetic ions, diameter of
the inner core, magnetization, high specific surface, etc. The relaxivity of water pro-
tons in CAs is also dependent on pH, temperature, and magnetic-field. Some suggested
readings on the topic of MRI CA relaxivity are [5, 6, 42–44].
In brief, the effect of CAs on the relaxation time of protons (1 H protons) is usually
measured by relaxometric analysis, which is the technical term which refers to the
measurement of T1 and T2 of mobile 1 H species in aqueous suspensions or in bio-
logical tissues. In MRI, the impact of CAs on the relaxation rate of protons, measured in
fixed conditions of magnetic strength and temperature, is described by the following
equation:
1 1
Ri = = ( ) + ri C , (13.2)
Ti Ti0
where Ri=1,2 is the relaxation rate of the aqueous solution, Ti0 is the relaxation time of
the aqueous media in the absence of the CA, ri=1,2 is the relaxivity (usually at T = 20
or 37°C, pH = 7, and B0 = 1.5 or 3.0 Tesla), and C is the CA concentration (in mM
of Gd, Fe, or Mn). The concentration of magnetic elements is measured by spectro-
scopic and spectrometric elemental analysis techniques, for example atomic absorp-
tion spectroscopy – AAS, inductively coupled plasma optical emission spectroscopy
(ICP-OES), and mass spectrometry, ICP-MS. Therefore, the relaxometric performance
of MRI CAs is assessed first by measuring their relaxation rates (1/T1 and 1/T2 ), fol-
lowed by normalizing the data to the paramagnetic elemental concentration. Relaxiv-
ity values (r1 and r2 ) are extracted from the slope of the graph given by equation (13.2).
These are often referred to as relaxivity curves, and they figure among the most funda-
mental aspects of MRI CA quantification. A more detailed explanation of CA relaxivity
mechanisms is found in Section 13.5. Finally, CAs can be divided into two categories,
based on the r2 /r1 ratio. First, CAs having a similar impact on both T1 and T2 , result in
low r2 /r1 ratios (close to 1), and a capacity to enhance the MR signal. This is in agree-
ment with equations (13.1) and (13.2). Such CAs are referred to as “positive”. On the
other hand, CAs that more preferentially decrease T2 , with r2 /r1 ratios superior to 5
and often as high as 100, are called “negative”.
13.3 Synthesis and characterization of magnetic nanoparticles
Comprehensive reviews have been written describing the different ways of synthesiz-
ing MNPs. These papers mainly report on iron oxide NPs, and most of these colloidal
synthesis routes can also be adapted to other metal ions such as Mn2+ and Gd3+ . The
most important criteria guiding the selection and optimization of a particular col-
loidal NP synthesis route, with MRI applications as an objective, is good control over
nanocrystal size, shape, and NP size distribution (as narrow as possible). A reasonable
synthesis yield is also critical: CA products must be concentrated enough to produce
efficient contrast enhancement effects in MRI procedures; the colloidal synthesis tech-
nique must also minimize the loss of paramagnetic materials and surfactants used
during the production, in order to enable industrial upscale of the process.
13.3.1 Synthesis of magnetic nanocrystals
Until now, NP cores have been made from different materials and with varying sizes,
shapes, uniformities, and magnetic properties [45–49]. Apart from MRI applications,
MNPs have been formed from iron and cobalt [50]. Procedures enabling the synthe-
sis of CoPt3 [51] and FePt [52], as well as oxides [44] such as magnetite (Fe3 O4 ) and
maghemite (𝛾-Fe2 O3 ), have been successfully developed and mastered [44, 53, 54].
Iron oxide NPs have also been doped to enhance their magnetic properties to form
MFe2 O4 structures, where M is a +2 cation such as Mn, Fe, Co or Ni [55, 56]. These
MNPs make excellent MR contrast agents; their magnetic susceptibility is relatively
high, they can also be manipulated by external magnetic fields. However, NPs con-
taining Co and Ni are relatively toxic, making them poor candidates for clinical use. To
a lesser extent, this also the case for Gd- and Mn-based nanocrystals. However, these
have their own advantages and, as preclinical CAs, can be advantageously applied to
molecular and cellular imaging in animal models. For clinical use, the biocompatibil-
ity profile of iron oxide NPs is well established, and adequately documented with a
large range of clinical studies. Iron oxide NPs injected in vivo eventually degrade to
their non-toxic iron and oxygen components, making them particularly attractive as
clinical MRI CAs [57].
The present section reports the major colloidal nanoparticle synthesis procedures
which must be selected to enable efficient, rapid, and high-yield production of small
particles of well-controlled and narrow size distributions. For both paramagnetic and
superparamagnetic nanocrystals, core size dictates both the magnetic and the relax-
ometric performance of CAs. Good control over this parameter is therefore critical in
all aspects, and bottom-up approaches using chemical colloidal synthesis techniques
are almost invariably preferred. In the interest of brevity, and because nanomaterials
made of Fe, Gd or Mn account for the huge majority of MRI NPs in pre-clinical and
clinical applications, only synthesis routes enabling the production of nanocrystals
containing these three elements are described here. A selection of references is pro-
vided for the reader who wishes to read about variants to these colloidal synthesis
techniques.
Iron oxide nanoparticles: Among the most important colloidal synthesis meth-
ods used to make iron oxide NPs figure co-precipitation, co-precipitation in con-
strained environments, thermal decomposition and/or reduction, hydrothermal syn-
thesis, and polyol synthesis [44, 49, 58–61]. Each has its own specific advantages.
The most common, the simplest and possibly the most efficient is co-precipitation.
It is based on the use of an aging stoichiometric mixture of ferrous and ferric ions
(Fe2+ /Fe3+ ) in aqueous solutions. The chemical reaction for the formation of mag-
netite (Fe3 O4 ) is:
Fe2+ + 2Fe3+ + 8OH− ⇒ Fe3 O4 + 4H2 O.
According to the thermodynamics of this reaction, complete precipitation of Fe3 O4
occurs at basic pH, with a stoichiometric ratio of 2 : 1 (Fe3+ : Fe2+ ) [62]. Therefore the
reaction takes place with the addition of base under an inert atmosphere.
In the presence of oxygen, magnetite oxidizes into maghemite, as follows:
Fe3 O4 + 2H+ ⇒ 𝛾–Fe2 O3 + Fe2+ + H2 O.
In the co-precipitation technique, NPs are formed by a nucleation and growth mecha-
nism. NPs of relatively narrow size distributions can be synthesized, provided a short
nucleation event takes place followed by a slower growth phase. The types of salts em-
ployed (e.g., chlorides, sulfates, nitrates), the ratio between ferrous and ferric ions, the
temperature, the pH, and ionic strength are all parameters which must be finely tuned
to yield NPs of the desired size and narrow distribution [49]. Although they are to-
tally appropriate for the synthesis of large amounts of MNPs, standard co-precipitation
methods do not consistently deliver the same products (size, shape, and polydisper-
sity). The presence of impurities and surface defects also affects the magnetic proper-
ties of such NPs [46].
Adaptations to the co-precipitation approach to improve the uniformity and sta-
bility of USPIOs and SPIOs have been investigated. These were made through addi-
tion of polymers or polyelectrolytes to the ferric/ferrous ion solutions, with various
improvements to size, shape, and crystallinity [46, 63–66]. The addition of chelating
organic ions (carboxylate or α hydroxyl carboxylate ions such as citric acid, gluconic,
or oleic acid) or polymer surface complexing agents (dextran, carboxydextran, starch,
or polyvinyl alcohol) during the formation of the magnetite crystals help to control
NP size. Indeed, these charged organic molecules bind at the surface of iron oxide,
and this strategy can be used to modulate nanoparticle growth. Adding polymers such
as poly (acrylic acid) directly into the synthesis solution and in various concentra-
tions, allows tuning of the particle diameter between 7 and 14 nm [67]. Alternatively,
polyethylene glycol (PEG) compounds such as PEG-g-poly(glycerol monoacrylate) are
also used to modulate the size of USPIOs [68] during the synthesis stage. Importantly,
these polymers may act as surface coatings when nucleation and growth processes are
complete. These are called in situ coating processes.
In order to achieve smaller sizes, narrower particle distributions and higher mag-
netic properties, new synthesis techniques have been developed, based on high-
temperature decomposition methods using organic iron precursors [69]. For in-
stance, a high-temperature reaction of iron (III) acetylacetonate, Fe(acac)3 , in phenyl
ether in the presence of alcohol, oleic acid, and oleylamine, yielded monodisperse,
hydrophobic magnetite NPs with tunable sizes of 4–20 nm [70]. One of the major
pre-requisites of MNPs for MRI applications is that they disperse well in aqueous sol-
vents. Therefore, an additional step must be introduced to the synthesis procedure:
the replacement of the hydrophobic coating with an amphiphilic and biocompatible
surfactant.
The polyol process is an alternative to thermal decomposition methods for the
synthesis of NPs with well-defined shapes and controlled sizes [71, 72]. Owing to their
high dielectric constants, solvents such as polyethylene glycol (PEG) are able to dis-
solve inorganic compounds in a wide range of temperatures. Polyols also serve as
stabilizers to control particle growth and prevent particle aggregation. In polyol syn-
thesis, the precursor compound is suspended in a liquid polyol, and then heated to
a given temperature. During this reaction, the solubilized metal precursor forms an
intermediate, and is then reduced into metal nuclei which lead to NP growth. Good
examples of iron oxide NP synthesis in different polyols (di-,tri-,tetra-) ethylene gly-
col, can be found in a selection of recent articles [73–75]. Overall, the nanoparticles
synthesized by polyol routes have the smallest and narrowest size distributions, high
water dispersion rates, and higher magnetization compared with particles produced
by more conventional methods.
Paramagnetic nanocrystals (Gd2 O3 and NaGdF4 ): the main advantage of para-
magnetic CAs compared to superparamagnetic NPs is the ability to generate a “pos-
itive” signal where the labeled molecules or labeled cells are accumulated. Signal
enhancement is generally easier to quantify than signal voids resulting from T2 /T2∗
(e.g., magnetic susceptibility) effects (generated by iron oxide NPs). A good example
of this is illustrated in Fig. 13.4 [76]. PEG-coated Gd2 O3 NPs are used to label differ-
ent types of cells [77–83] and, in this specific example, F98 brain cancer cells. A total
of 3 × 105 labeled F98 cells were injected into mice brains (caudoputamen), to pro-
duce a brain tumor. This animal model is frequently used in the field of brain cancer
and oncology research. The same amount of SPIO-labeled cells was injected, to en-
able comparison of the capacity of both contrast media to allow cell tracking in MRI.
Figure 13.4(a) reveals the ability to efficiently visualize the area of brain cancer cell
implantation at least 48 hours after injection. Because this is a “positive” CA scanned
with a T1 -weighted MR sequence, the anatomical information surrounding the area
of cell implantation is preserved. After one week, the tumor contours can be efficiently
delineated without the use of a CA. On the other hand, SPIO-labeled cells are much
more sensitively detected than Gd2 O3 -labeled ones (Fig. 13.4(b)). However, the sus-
ceptibility artifact characteristic of iron oxide NPs largely exceeds the exact location
of the implanted cells. Even after one week, the image artifact still obliterates impor-
tant anatomical information directly in the region of the growing tumor. This is a good
example of the potential of paramagnetic NPs to replace SPIOs and UPSIOs in niche
applications where the preservation of anatomical details is an issue (such as in cell
implantation and tracking studies).
Day 1 Day 2 Day 7

Gd Labeled
(a)
Fe Labeled
(b)
Fig. 13.4. Mice brains implanted with 300,000 brain cancer cells (F98) labeled with (a) PEG-Gd2O3
(T 1 -weighted MR imaging), and (b) SPIOs, (T 2 -weighted MR imaging). Adapted with permission
from [76].
The very high density of Gd atoms per unit of contrast agent is an advantage over
macromolecules containing Gd chelates: Gd2 O3 and NaGdF4 ultra-small nanoparticles
(2−5 nm diameter) have narrow particle size distributions, and contain hundreds of
Gd atoms per CA unit [31, 76, 84]. The production of Gd2 O3 NPs, a pre-clinical CA, has
required the development of advanced colloidal synthesis techniques in high boiling
point alcohols (e.g., di-, tri-, poly-ethylene glycol) [31, 85–88]. The surface of Gd2 O3
nanocrystals forms hydroxide in contact with water and this form is at risk of leaching
potentially toxic Gd3+ ions, as demonstrated in prolonged dialysis procedures [30].
Concerns related to the potential toxicity of Gd2 O3 nanoparticles, even for pre-clinical
applications in animal models, have led to the development of other forms of poten-
tially more stable paramagnetic nanocrystals. NaGdF4 , in particular, is an attractive
material due to its high concentration of Gd atoms in a crystalline form which is less
susceptible to degradation in water. Sodium fluoride NPs are synthesized by thermal
decomposition in oleic acid and octadecene, leading to hydrophobic surfaces which
must subsequently be transferred to aqueous suspensions by using appropriate ligand
exchange procedures [89–91]. Rare-earth fluorides doped with series of lanthanides
have very promising luminescent up-conversion properties. In particular, it has been
demonstrated that ultra-small NaGdF4 nanocrystals (3 nm diam.) doped with Tm and
Tb can be used for dual MRI and near-infra-red optical imaging, with a wide array of
applications in biomedical research [34].
Antiferromagnetic MnO nanocrystals: Although Mn2+ ions are paramagnetic,
MnO NPs express antiferromagnetic behavior [92]. They behave overall as “positive”
CAs. Thermal decomposition has been one of the most widely used and reliable meth-
ods of producing relatively large NP batches of small and narrow particle size distri-
butions [38, 93–95]. One-pot synthesis techniques have also been developed in high
boiling point solvents, enabling the production of 1–3 nm diameter MnO particles [87].
13.3.2 Nanoparticle coatings for MRI applications
NPs must form stable colloids in physiological media (blood, plasma, lymph, urine)
in order to be considered for MRI applications. They must also demonstrate good
biocompatibility and prolonged vascular retention. This is particularly critical in the
case of targeted CAs, which must provide sufficient contrast at the molecular site,
where they are expected to bind to molecular biomarkers (e.g., of atherosclerosis or
Alzheimer’s disease). The ligands and polymers used as particle coatings must effi-
ciently cover the particles and promote their individualization. They must also limit
the adsorption of plasma proteins, which is the phenomenon that is a precursor to
their retrieval from blood. Indeed, “opsonized” NPs are quickly recognized and in-
gested by macrophages. NPs must be coated with a surface ligand or a polymer which
induces either an electrostatic or a strong steric repulsion between the particles. Oth-
erwise, particles are likely to agglomerate when they are submitted to strongly ionic
conditions. Hence, any injection of magnetic nanoparticles in vivo implies their prepa-
ration in a milieu close to the osmolality conditions of biological media. In general,
small hydrophilic particles of neutral charge demonstrate long plasma half-life [96].
The selected biocompatible coatings should not influence cell viability. They must
be grafted with a functionality (e.g. carboxylates, phosphates, and sulfates) which
strongly binds to the NP surface. The coatings should also be stable under various pH
conditions. For instance, acidic functions (–COOH) can bind to metal oxide surfaces.
However, if the bonding is only monodendate, their attachment at the particle sur-
face is relatively weak and not strong enough for many applications. Citric acid is a
small and very effective ligand which binds to the surface of iron oxide NPs through
carboxylic binding [97]. In particular, this strategy was used to synthesize the com-
mercial product VSOP C184 (4 nm core size) [98]. However, citric acid causes a strong
surface degradation, which affects the magnetic properties of iron oxide NPs [99]. It
is also very rapidly and strongly diverted to the liver due to its high surface charge.
Other ligand molecules can be used for the stabilization of iron oxide NPs in aqueous
medium (e.g., gluconic acid, dimercaptosuccinic acid, phosphorylcholine, as well as
phosphate and phosphonates) [100, 101]. Unfortunately many polymer coatings result
in an unacceptable increase of the hydrodynamic diameter, which can be detrimental
to the overall performance of the contrast agent (blood retention, relaxivity). In sum-
mary, the selection and application of an appropriate coating for MNPs is a critical
step which has a large influence on the overall performance of the nanoconstructs.
n=335
8.4±0.8 nm
0 2 4 6 8 10 12 14 16
50 nm
Particle core size by TEM (nm)
(a) (b)
25
2 hours
Arbitrary units (a.u.)
20 4 days
7 days
15
10
0
1 10 100
Hydrodynamic size by DLS (nm)
(c)
Fig. 13.5. (a) Electron microscopy study of MnO nanoparticles produced by thermal decomposition,
with (b) particle-size distribution, and (c) hydrodynamic size measurements. Adapted with permis-
sion from [39].
Among the polymer coatings which most efficiently enhance the blood retention
of SPIOs and USPIOs figure dextran and (carboxy, carboxymethyl)dextran [102, 103].
In particular, commercial USPIO products such as ferumoxtran-10 (AMI-227), feru-
moxytol, and Supravist (SHU-555C), are all based on iron oxide of core diameters in
the range of 4 to 8 nm, and of hydrodynamic diameters not larger than 30 nm [104].
Dextran and starch-coated iron oxide nanoparticles have shown very good relaxo-
metric properties; however, such coatings are relatively unstable when submitted to
biological media. In order to improve colloidal stability, biocompatibility, and blood
retention, PEG is used at the surface of iron oxide nanoparticles [105–107]. Feruglose
(Clariscan) is a commercial product which was developed using a PEGylated starch
coating [108]. Such coatings are less prone to being recognized by the macrophage-
monocytic system. Paramagnetic Gd2 O3 and NaGdF4 , as well as MnO nanoparticles,
have also been coated using similar strategies (e.g., citric acid, dimercaptosuccinic
acid, glucoronic acid, PEG) [28, 30, 34, 109–112]. PEG is widely applied as coating
for paramagnetic nanoparticles, through –OH [86, 113], –COOH [31, 114], -silane [30,
109, 115], and -phosphate grafting [116]. Silane coatings, for instance, could delay the
degradation of Gd2 O3 nanoparticles submitted to acidic environments. Unfortunately,
silane coatings restrict the optimal water exchange with paramagnetic ions at the sur-
face of NPs, which is the most important relaxation mechanism of “positive” CAs (see
Section 13.5). PEG-phosphate molecules can be used instead, with the significant ad-
vantage that they are not susceptible to homocondensation such as for silane-based
products [116]. Recently, PEGylated phosphonate dendrons were successfully used to
cover MnO and iron oxide nanoparticles, and this coating strategy provided enhanced
NP excretion profiles through the urinary and gastrointestinal pathways [117, 118].
13.3.3 Physicochemical characterization
After synthesis and ligand exchange, NPs must be carefully cleaned of the residual
magnetic ions (Fe2+ , Fe3+ , Gd3+ , Mn2+ and other) which could contaminate the physic-
ochemical, magnetometric, and relaxometric measurements. This procedure can be
achieved either by dialysis in saline water (e.g., 10–154 mM NaCl), by centrifugation-
filtration cycles, or by size-exclusion chromatography. Dynamic light scattering (DLS)
measurements are performed directly after the purification process, in order to assess
the overall colloidal stability and to demonstrate the absence of large-size aggregates.
No drastic divergence should be noted between “intensity”- and “number”-weighted
results, as diverging results point to the presence of large-size agglomerates which
must be eliminated prior to further use of the particles. The NPs must then ideally
demonstrate the presence of only one major hydrodynamic diameter peak for their
magnetic and relaxometric properties to be adequately predicted and controlled.
To demonstrate the colloidal stability of the particles, a weeklong DLS assay experi-
ment is necessary, in parallel with zeta potential measurements (electrostatic charge
of NPs). The particles are then submitted to a comprehensive set of physicochemical

characterization measurements using high-resolution electron microscopy (HRTEM:
particle size, morphology, crystallographic parameters), x-ray photoelectron spec-
troscopy (XPS: surface elemental analysis), Fourier transform infrared spectroscopy
(FTIR: molecular groups at the surface of particles; molecular grafting assessment),
thermogravimetric analysis (TGA: mass ratio between inorganic cores and organic
coating), 1 H-NMR relaxometry (measurement of T1 and T2 ), and magnetometric mea-
surements, to name the most important techniques. Finally, the elemental concen-
tration (Fe, Gd, Mn) of colloidal NPs is measured with spectrometric or spectroscopic
instruments by AAS, ICP-OES, ICP-MS (mentioned in Section 13.2), after careful diges-
tion in appropriate acidic conditions.
13.4 Physical properties of magnetic nanoparticles
NPs based on SPIOs, USPIOs, Gd2 O3 , NaGdF4 , and MnO, have core diameters typi-
cally in the range of 2–20 nm. However, superparamagnetic and paramagnetic nano-
particles have very different magnetic behaviors, significantly influencing their relaxo-
metric performance. USPIOs and SPIOs are said to be superparamagnetic because they
have no remanence after being introduced into and retracted from the strong magnetic
field. Upon introduction in the scanner, the global magnetic moment of superparam-
agnetic NPs aligns in the direction of this magnetic field. As soon as the magnetic
field is set back to zero (e.g., when the patient is removed from the scanner), the mag-
netic moment of the NP also goes down to zero. This is not the same behavior as for
“bulk” ferromagnetic magnetite/maghemite, materials which clearly show a strong re-
manence. The absence of residual magnetization is a very critical and useful aspect of
superparamagnetism applied to biomedicine. Macroscopically, the magnetic behav-
ior of superparamagnetic particles is similar to paramagnetism (e.g., Gd2 O3 , NaGdF4 ),
except that they feature an exceptionally high magnetic moment per unit of CA (the
“core” of iron oxide particles). This strong magnetization is largely responsible for the
remarkable “negative” CA properties of iron oxide NPs. In fact, the absence of mag-
netic remanence for USPIOs and SPIOs is due to the return to equilibrium of the mag-
netic moments through Néel relaxation. On the other hand, paramagnetic NPs, and to
a lesser extent antiferromagnetic MnO nanocrystals, do not develop strong magneti-
zation at clinical magnetic field strengths. Instead, they generate signal enhancement
(“positive” contrast), mainly through direct interactions taking place between Gd and
Mn ions and mobile 1 H protons in their surroundings, as described in Section 13.5.
The basic differences in magnetism between superparamagnetic and paramagnetic
NPs are introduced below.
(a) Superperparamagnetic NPs are very efficient “negative” CAs in MRI [119].
Due to their strong impact on the transverse relaxation times (T2 /T2∗ ) of aqueous so-
lutions, they have been considered very useful products for molecular and cellular
MRI [103]. As mentioned previously, each superparamagnetic iron oxide NP features

a high magnetic moment, and much higher Curie constants (material-dependent
magnetic susceptibility constants) than for paramagnetic NPs. As a result, they re-
spond quickly to the application of an external magnetic field and their magnetization
quickly becomes saturated at relatively low magnetic field strengths (Fig. 13.6).
80
IONs (USPIO), 5.59 nm

60 IONs (USPIO), 5.67 nm
IONs (USPIO), 4.84 nm
Magnetization (Am2 Kg‒1 ferrite)
40
20
‒20
‒40
‒60
‒80
‒1000 ‒500 0 500 1000
Field (mT)
Fig. 13.6. Magnetometric measurements of USPIOs and Gd2O3 nanoparticles

Adapted with permission from [44, 120].
Superparamagnetism only occurs when NPs are small enough to belong to sin-
gle magnetic domains. It is worth mentioning that suspensions of iron NPs (and
not iron oxide nanoparticles) would have a much higher magnetization than mag-
netite/maghemite (about 5 times higher); however, iron NPs are very quickly oxi-
dized into iron oxide NPs in aqueous media, and until now, this potential technology
could not be applied in biomedicine. Magnetite (Fe3 O4 ) and maghemite (𝛾-Fe2 O3 )
are two relatively similar forms of iron oxide (crystal structure and magnetic prop-
erties) [121, 122]. Both are present in superparamagnetic iron oxide NPs, and it is
often difficult to distinguish between them using common x-ray diffraction analy-
sis techniques. Magnetite is typically preferred due to its superior magnetic proper-
ties [44]. Maghemite (Fe3+ [Fe2+ Fe3+ ]O4 ) often results from the oxidation of magnetite
(Fe3+ [Fe3+
5/3 V1/3 ]O4 , where V represents a cation vacancy). Bulk magnetite is ferro-
magnetic. The occurrence of an oxygen-mediated coupling mechanism aligns all
the magnetic moments of the iron ions located in the tetrahedral sites of the crystal
(8 crystallographic sites per unit structure), whereas all the magnetic moments of the
octahedral ions (16 crystallographic sites per unit structure) are aligned in the oppo-
site direction. It is assumed that the magnetic properties of magnetite are provided by
uncompensated Fe2+ ions, whereas for maghemite they are provided by Fe3+ ions [123].
The magnetic energy of iron oxide NPs depends upon the direction of their magne-
tization vector, and this vector in turn depends on the crystallographic directions (the
magneto-crystalline anisotropy field) [121]. The directions which minimize the mag-
netic energy are called anisotropy directions, or easy axes (Fig. 13.7(a), from [121]).
The resulting magnetic moment of a magnetite/maghemite crystal is preferentially
aligned along such specific directions. Magnetic energy increases with the tilt angle
between the magnetic vector of the easy directions [124]. For the sake of simplicity,
the anisotropy of magnetite particles is often assumed to be uniaxial, with a single
anisotropy axis. In fact, there are several anisotropy axes dictated by the crystallo-
graphic structure of the oxide. The anisotropy energy (the amplitude of the curve), is
given by the product of the crystal volume (V) times a constant (Ka : the anisotropy
constant):
Ea = Ka V. (13.3)
The anisotropy energy, proportional to V, determines the Néel relaxation time.
Large samples of bulk ferrimagnetic magnetite/maghemite, are divided into Weiss
domains (represented in Fig. 13.7(b)) Inside each of these volumes, the magnetic mo-
ments are aligned into one preferential direction; however, between each of these do-
mains, the magnetic moment is not oriented along the same direction. As iron oxide
nanocores (such as in USPIOs) are smaller than one of these domains, each NP is com-
posed of a single domain whose magnetic moment is oriented in a specific direction.
In these single domains, the direction of the magnetic moment can flip from one
orientation to the other. When the thermal energy, given by kT (k: Boltzman constant;
T: absolute temperature) is sufficient to overcome this anisotropy energy barrier, the
magnetization fluctuates between the different anisotropy directions, according to a
characteristic time: the Néel relaxation time (τN ) [126]. Although τN relaxation influ-
ences the hydrogen relaxation times by inducing changes to the magnetic moment of
MNPs, it is a phenomenon entirely distinct from the nuclear relaxation mechanisms
of hydrogen protons (1 H) described in Section 13.5. Néel relaxation refers to the re-
laxation of the global electronic moment of a superparamagnetic crystal constituted
by a ferri-, ferro-, or antiferromagnetic compound. For dry powders of monodomain
iron oxide NPs, τN indicates the time it takes for magnetization to return to a state
of equilibrium after being submitted to a strong magnetic field. For highly anisotropic
crystals, the crystal magnetization is “locked” in the easy axes. Néel relaxation defines
the rate of fluctuations arising from the jumps of the magnetic moment between the
different easy axes (Fig. 13.7(c)). In order to flip from one easy direction to the other,
the magnetization of an NP must jump over an anisotropy energy hump. For a super-
0.2 μm
0.012
μ
0.010
Anisotropy axis
θ
0.008
Probability
0.006
0.004
0.002
(b) Typical magnetite contrast agent

0.000
0 20 40 60 80 100 120 140 160 180
(a) θ (degrees)
Neel relaxation Brownian relaxation 1e-3
After application of a After application of a τN
Relaxation time constant, τ(s)

magnetic field B magnetic field B 1e-4
τB τB τB
1e-5
τN τ
1e-6
B B
τN τB τB 1e-7
1e-8
4 5 6 7 8 9 10 11
Particle radius, R(nm)
(c) (d)
Fig. 13.7. Magnetic behavior of iron oxide NPs (radius = 5 nm): (a) uniaxial anisotropy for mag-
netite/maghemite nanoparticles (i.e., the probability of alignment of the magnetic moment in one
direction with respect to the angle between this direction and the anisotropy axis); (b) represen-
tation of Weiss domains in a large magnetite/maghemite crystal, compared to the dimensions of
a typical NP (the small circle), much smaller than a Weiss domain; (c) schematic representation of
Néel relaxation and Brownian relaxation; (d) relaxation time values plotted as a function of mag-
netite/maghemite NP size. Reprinted with permission from [100, 121, 125].
paramagnetic NP of specific V and Ka , the Néel relaxation time (τN ) is given by an Ar-
rhenius law which is similar to the one describing the activation energy for a chemical
reaction [127]:
Ea
τN = τ0 (Ea )e kT , (13.4)
where τ0 (Ea ) is the pre-exponential factor of the Néel relaxation time expression,
which depends on factors such as volume (V), specific magnetization of the nanocrys-
tal and gyromagnetic ratio of the electron [44, 128, 129]. Whereas the pre-exponential
factor decreases as the value of anisotropy energy increases, τN increases as an ex-
ponential function of V because of the second factor of equation (13.4). For small
values of the anisotropy energy and at high temperatures, Ea ≪ kT (the exponen-

tial term tends to equal 1), and τN is mainly determined by the preexponential term.
These conditions are fulfilled, for instance, with individual ultra-small NPs of iron
oxide of r < 4 nm. On the other hand, for high anisotropy energies, when Ea ≫ kT, the
evolution of τN is mainly dictated by the exponential factor (rapid increase with Ea ).
According to equation (13.4), the flipping of the magnetic moment of magnetite/
maghemite crystals is observed only for NPs of size r < 12 nm. Indeed, for magnetite
(τ0 ≈ 10−9 s, K ≈ 13 500 J m−3 ), τN goes from ∼ 500 years for particles of r = 15 nm,
down to the ms for particles of about r = 10 nm. Practically, this means that for parti-
cles with a Néel relaxation time (τN ) longer than the measurement time, the magneti-
zation curve of the NP system is irreversible and shows a hysteresis loop. These are re-
ferred to as “frozen single domain” NPs. NPs which demonstrate Néel relaxation times
of several years or centuries, can be used in computer hard disks. Indeed, such long-
term data storage applications require as little magnetic material as possible, with a
maximal anisotropy constant (Ea ).
However, such NPs cannot be used in MRI applications. Firstly, the Néel relax-
ation of larger nanoparticles showing high Ea has no effect on the nuclear relaxation
of neighboring water protons. Indeed, the diffusive rotation time of the particles in wa-
ter, and the diffusion time of water around the particles are both much shorter than
1 ms. This is incompatible with the long Néel relaxation times of large particles.
In order for magnetic iron oxide NPs to provide efficient properties for use as MRI
CAs, the condition τN < 1 s should be respected. Then, for NPs dispersed in a liq-
uid media (a colloid), the return of magnetization to equilibrium after application of
a strong magnetic field is determined by both τN and the Brownian relaxation τB of the
particles. The latter characterizes the rotation of the particle in the fluid, and takes the
viscosity of the solvent into account (Fig. 13.7(c)). The global magnetic relaxation rate
is a sum of two processes:
1 1 1
= + , (13.5)
τ τN τB
where τ is the global magnetization time and τB is the Brownian relaxation time, given
by:
3Vη
τB = , (13.6)
kT
where η is the viscosity of the solvent. For large particles, τB < τN because the Brown-
ian component of the magnetic relaxation is proportional to the crystal volume (equa-
tion (13.6)), and the Néel relaxation is an exponential function of the volume (equa-
tion (13.4)). Therefore, in suspensions of large NPs, the viscous rotation of the particles
in the liquid becomes the dominant process determining the global magnetic relax-
ation properties (Fig. 13.7(d)). As a result, the magnetic relaxation of suspensions of
magnetic nanoparticles is much faster than for dry powders of iron oxide NPs.
In summary, superparamagnetism refers to a specific magnetic condition for
which ultra-small particles of a size well inferior to typical Weiss domains of mag-
netite/maghemite materials can be submitted to high magnetic field strengths, with-

out evidence of magnetic remanence once they are retrieved (Fig. 13.6). Macroscop-
ically, the magnetization of iron oxide NPs suspensions is described by a Langevin
function, whose shape depends on the saturation magnetization (Msat ) and the size
of the magnetite crystals:
M(B0 ) = Msat L(x), (13.7)
where Msat is the magnetization at saturation, and L(x) is the Langevin function as:
1
L(x) = [coth(x) − ] (13.8)
x
with :
Ms (T)VB0
x= . (13.9)
kT
Magnetization curves of ultra-small iron oxide NPs are perfectly reversible because
the fast magnetic relaxation allows the system to remain consistently at thermody-
namic equilibrium [130]. Finally, because iron oxide superparamagnetic NPs obey this
law, it is possible to estimate the NP core size from the fit of the magnetization curves
(Fig. 13.6).
(b) Paramagnetic nanoparticles also respond to the application of an external
magnetic field by developing a magnetization vector oriented along the direction of
this field which slightly increases the local magnetic field strength [131]. Paramagnetic
nanocrystals follow Curie’s law:
C
M = χH = H, (13.10)
T
where χ is the magnetic susceptibility, H is the applied magnetic field (e.g., that of
the MRI scanner), T is the absolute temperature, and C is a material-specific Curie
constant. Unlike ferromagnets, paramagnetic materials do not retain magnetization
in the absence of an external magnetic field, and the thermal energy is sufficient to
randomize the induced magnetization. At similar concentrations of metal elements
(Fe, Gd, or Mn), the “positive contrast effect” of paramagnetic NPs is less efficiently de-
tected than the “negative contrast” effect generated by superparamagnetic agents. The
more limited magnetization response of the rare-earth ions compared with USPIOs
and SPIOs is due to their magnetic moment, which is not saturated at magnetic field
strengths typically used in MRI [4, 132]. The difference of magnetization response
between iron oxide (USPIOs) and paramagnetic Gd2 O3 nanoparticles is shown in
Fig. 13.6.
13.5 MR relaxation properties of magnetic nanoparticles
For a given concentration of magnetic atoms, the magnetization of paramagnetic CAs

is much lower than that of superparamagnetic nanocrystals. However, Gd chelates are
still by far the most widely used CAs in routine MRI. This is mainly due to their excep-
tional relaxometric properties. Both paramagnetic and superparamagnetic CAs inter-
act with the small, hydrogen-containing mobile molecules found in biological media.
In fact, one of the most important factors influencing signal enhancement in MRI is
the binding of water molecules to paramagnetic ions. The motion of contrast agents
in the fluid also has an impact, as well as the magnetic field strength-dependent elec-
tronic relaxation of the paramagnetic elements. Finally, Gd3+ chelates are, in general,
very efficiently excreted by the kidneys, this also accounting for their widespread use
in clinical MRI. This section does not aim to provide a comprehensive explanation of
the complex relaxometric mechanisms taking place between paramagnetic – or super-
paramagnetic – CAs, and the water molecules. The reader is directed towards several
books and review articles which have extensively described this subject; see [4, 6, 44,
133–135]. A summary follows of the most important aspects to take into account when
designing optimal nanoparticulate contrast agents for MRI applications.
13.5.1 Relaxivity of paramagnetic CAs
Theories explaining the relaxivity of paramagnetic CAs have been developed since
the inception of MRI. In fact, the efficiency of CAs is linked to molecular motions of
the CA unit, as well as to the motions of small molecules containing the “spins” (1 H
protons). It is also linked to intrinsic properties of the nuclei (magnetic moment, gy-
romagnetic ratio, spin). The relaxation of paramagnetic solutions is mainly explained
by two mechanisms: the “inner sphere” (IS) and “outer sphere” (OS) contributions [4].
Using equation (13.2) it is possible to dissociate two contributions for Ti , one from the
water protons in contact with the paramagnetic elements (p), and one for the rest of
the water protons in the matrix (diamagnetic contribution, d):
1 1 1
( )=( )+( ) (13.11)
Ti, obs Ti,d Ti,p
where i = 1, 2. From the paramagnetic contribution it is possible to dissociate the IS

and OS contributions as follows:
IS OS
1 1 1
( )=( ) +( ) (13.12)
Ti,p Ti,d Ti,p
The IS relaxation relies on the exchange of energy between the spins and the electrons
of the paramagnetic elements, which is facilitated when water molecules bind to the
paramagnetic ions (Fig. 13.8). The water molecules which bind to the paramagnetic
center (Gd3+ , Mn2+ ) ions, and water molecules denoted “p” (red circles in Fig. 13.8)
rapidly leave the first coordination sphere and are immediately replaced by “fresh”
molecules from the matrix (“d” water molecules: orange circles in Fig. 13.8). Hydrogen
relaxes faster on contact with the paramagnetic ions. The water residence time in the
inner sphere (τM ) is in the order of ∼ 1 ns, which means that the relaxation effect prop-
agates very fast to the rest of the solution (to “d” protons). Each of the water protons
which relaxes energy participates in the decrease of the overall longitudinal relaxation
time of the water solvent. The IS model is described by the Solomon–Bloembergen–
Morgan theory (SBM) [136, 137].
OS
Gd3+ τM
T1,2e
τR
Fig. 13.8. Schematic representation of the

inner sphere (IS), outer sphere (OS), chemical
IS
exchange, and rotational correlation times
guiding paramagnetic relaxation.
From the inner sphere contribution, T1 in the first coordination sphere is:
1 IS 1
( ) = fq( ), (13.13)
T1 T1M + τM
where f is the relative concentration of paramagnetic complex over water molecules,
and q is the number of water molecules in the first coordination sphere. The calcula-
tion of T1M is based on a model including the amplitude of the magnetic interaction, its
temporal modulation, and the effect of the external magnetic field strength as follows:
1 2 μ0 2 2 2 2 1 7τc2 3τc1
= ( ) 𝛾H 𝛾S ℎ S(S + 1) 6 [ + ], (13.14)
T1M 15 4π r 1 + (ωS τc2 )2 1 + (ωH τc1 )2
where:
1 1 1 1
= + + (13.15)
τci τR τM τsi
1 1 1 4
= [ + ] (13.16)
τs1 5τSO 1 + ωS τV 1 + 4ω2S τ2V
2 2
1 1 5 2
= [3 + + ]. (13.17)
τs2 10τSO 1 + ω2S τ2V 1 + 4ω2S τ2V
Further, 𝛾S and 𝛾H are the gyromagnetic ratio of the electron (S) and the proton (H) re-
spectively, ωS,H is the angular frequency of the electron and the proton, r is the distance
between coordinated water protons and unpaired electron spins, τc1,2 is the correla-
tion time modulating the interaction (defined by equation (13.15)), τR is the rotational
correlation time of the hydrated complex, τs1,2 is the longitudinal and transverse re-
laxation of the electron, τS0 is the value of τs1,2 at zero field, and τv is the correlation
time characteristic of the electronic relaxation times.
The second term of equation (13.12), the outer sphere relaxation (OS), is explained
by the dipolar interaction at long-distance between the magnetic moment of the para-
magnetic substance and the nuclear spin of hydrogen protons. In fact, paramagnetic
centers influence the local magnetic field around the 1 H protons flowing in their vicin-
ity. The complete equations explaining the outer sphere contribution of the longitudi-
OS
nal relaxation rate ( T1 ) , are beyond the scope of this chapter and will not be detailed
1
here. The reader is invited to refer to the description of the OS model by Freed [44, 138].
The most important aspect to retain regarding the OS contribution in the case of para-
magnetic substances is the fact that the dipolar intermolecular mechanism is modu-
lated by the translational correlation time (τD ) which takes the relative diffusion (D)
of the paramagnetic center and the solvent molecule into account, as well as their
distance of closest approach (d) as follows[138]:
d2
τD = (13.18)
D
This expression indicates that viscous solvents and large particles lead to high trans-
lational correlation times. In summary, the equations describing IS and OS contribu-
tions to the relaxivity of paramagnetic CAs are rather complex, and a large number of
parameters influence the overall relaxometric performance of CAs: τM , q, τR , D, r, d,
τV , τS0 . Because of this high number of parameters it is often difficult to perform an
accurate theoretical estimation of the performance of MRI CAs at different magnetic
field strengths. Relaxometric measurements must be performed experimentally, us-
ing a technique called proton nuclear magnetic relaxation dispersion (NMRD). NMRD
curves characterize the efficiency of CAs at different magnetic fields. For more infor-
mation regarding the interpretation of NMRD curves, the reader is invited to read a
selection of references on the subject [4, 44, 134].
A few points which are important to know prior to the interpretation of NMRD
profiles for paramagnetic solutions are presented below.
– The rotational correlation time (τR ) characterizes the reorientation of the vector
between the paramagnetic ions and the protons of the water molecule. For a low
molecular weight complex, τR limits the relaxivity of paramagnetic CAs at mag-
netic field strengths used in clinical MRI (0.5–3 Tesla). The value of τR cannot be
measured by proton NMRD, but instead by 17 O NMR measurements (longitudinal
relaxation of the nucleus 17 O), and other methods [4].
– Electronic relaxation times (τS1 and τS2 ). Longitudinal and transverse elec-
tronic relaxation times describe the process of return to equilibrium of the mag-
netization associated with electrons which transit between electronic levels of
the paramagnetic center. These transitions produce fluctuations which allow the
relaxation of protons; τS1 and τS2 are magnetic field-dependent.
– Number of coordinated water molecules (q) strongly influences the IS contri-
bution. For small complexes such as Gd-DTPA, the number of coordinated water
molecules is equal to 1. This means that, in general, only one water molecule can
bind to the paramagnetic Gd3+ ion sequestrated in the DTPA molecule. The value
of q can be estimated either in solid phase (x-rays or neutron diffraction) or in solu-
tion (fluorescence of Eu or Yb complexes, LIS (lanthanide-induced shift) method
in 17 O-NMR).
– Proton-metal distance (r). The efficiency of the IS dipolar mechanism is propor-
tional to 1/r6 , where r is the metal-proton distance. Small changes to this distance
have a considerable impact on relaxivity.
– Coordinated water residence time (τM ). The mechanism of IS relaxation is
based on an exchange between water molecules surrounding the complex and
the water molecules coordinated to the lanthanide ion. Consequently, the ex-
change rate (kex = 1/τM ) is an essential parameter for transmitting the relaxation
effect to protons in the water matrix [4].
13.5.2 Relaxivity of superparamagnetic CAs
For superparamagnetic particles, the IS contribution to relaxation is minor and often

completely negligible compared to the dominant OS contribution. As mentioned in
the previous section, this contribution is largely dependent on the movement of wa-
ter molecules near the local magnetic field gradients generated by the superparamag-
netic nanoparticles. The relaxation of superparamagnetic NP suspensions is generally
governed by Freed’s equations when τS1 is the Néel relaxation time [139]. When τD is
much shorter than the Néel relaxation time, Freed’s equations are simplified. In fact,
the ability of a fluctuation to relax the 1H proton spins depends upon whether its corre-
lation time is longer or shorter than the precession period of the spins within the exter-
nal magnetic field B0 . If the global correlation time τC (τ−1 −1 −1
C = τD + τN ) is longer than
this period, the fluctuation is averaged by the precession and it is inefficient. Other
parameters such as electron polarization and crystal anisotropy also have a consider-
able influence on the relaxation times of water protons submitted to different magnetic
fields. As in the case of paramagnetic CAs, the theoretical models explaining the re-
laxometry of aqueous suspensions of iron oxide NPs must be validated by NMRD pro-
files (Fig. 13.9). First, it is possible to precisely measure, with NMRD, the relaxometric
potential of NP as contrast agents for MRI [140]. NMRD profile analysis then also rep-
resents a powerful tool to control the reproducibility of synthetic MNP suspensions,
as well as for optimizing the parameters of nanomagnet synthesis [141]. Finally, the
fitting of NMRD profiles to adequate theories provides information about the average
30
Theoretical fit
Magnetite (experimental points)
25 Rmax ~ C • M2s • τD
Proton relaxivity (s‒1 • mM‒1)
20 Low field relaxation

rate: depends on the
anisotropy energy ωI • τD ~ 1
15 τD = r2/D
10
Low field dispersion:
an indication of
ωi
anisotropy energy
5
0
10‒2 10‒1 100 101 102 103
Proton Larmor frequency (MHz)
Fig. 13.9. NMRD profile for magnetite particles in colloidal solution.

Reproduced with permission from [134].
radius (r) of the nanocrystals, their specific magnetization (Ms ), their anisotropy en-
ergy (Ea ), as well as their Néel relaxation time (τN ) [119].
The main information extracted from NMRD profiles for superparamagnetic NP
suspensions is as given below.
– The average radius (r): at high magnetic fields, the relaxation rate depends only
on τD and the inflection point corresponds to the condition ωI ⋅ τD ∼ 1 (Fig. 13.14).
According to equation (13.18), the determination of τD gives the crystal size r (good
complement to HRTEM measurements).
– The specific magnetization (Ms ): at high magnetic fields, Ms can be obtained
from the equation Ms ≈ [(Rmax /(C ⋅ τD )]1/2 , where C is a constant and Rmax the
maximal relaxation rate.
– The crystal anisotropy energy (Ea ): the absence or presence of an inflection
point at low magnetic field strengths (10−2 − 1) is an indication of the anisotropy
energy. For crystals characterized by a high Ea compared to the thermal agitation,
the low field dispersion disappears. This has been confirmed in previous work
with cobalt ferrites, a high anisotropy energy material [142].
– The Néel relaxation time (τN ): the relaxation rate at very low fields (R0 ) is gov-
erned by a “zero magnetic field” correlation time τc0 , which is equal to τN if
τN ≪ τD . However, this situation is often not given, and in this case τN is only
reported as qualitative information.
13.5.3 Relaxometric performance of MRI CAs at clinical magnetic field strengths
As mentioned in the previous sections, the relaxometric ratio at clinical magnetic

strengths (typically at 1.5 T) is used to classify the behavior of CAs between “posi-
tive” (i.e., r2 /r1 < 5), and “negative” ones (i.e., r2 /r1 ≫ 10). The different parameters
described in the last section indicate that, at fixed magnetic field strength, the relax-
ometric ratio depends on many factors such as the crystal core diameter (influence Ea
and τD ), the specific surface and physicochemical characteristics of NP surfaces (in-
fluence τD ; particularly critical for inner-sphere mechanisms), as well as the hydrody-
namic diameter of NPs (influence τR ). Because they have the capacity to individualize
the particles, can change both their hydrodynamic diameter and their surface charge,
and finally because they can considerably modify the accessibility of water molecules
to the nanoparticle surfaces, coatings play a major role in the modulation of r1 and r2
relaxivities.
Dextran and (carboxy, carboxymethyl)dextran figure among the polymer coat-
ings which have been successfully used to enhance both the relaxometric proper-
ties and the blood retention of USPIOs. In particular, commercial products such as
Ferumoxtran-10 (AMI-227), Ferumoxytol, and Supravist are all based on iron oxide of
core diameters in the range of 4–8 nm, and of hydrodynamic diameters not larger
than 30 nm (Table 13.1). At 1.5 Tesla, the longitudinal relaxivities (r1 ) of those par-
ticles range between 9 and 15 mM−1 s−1 [143]. The relaxometric ratio of dextran and
carboxy/carboxylmethyldextran-coated USPIOs is found between 2 and 5 (1.5 T). Fi-
nally, the blood half-lives of these products, ranging from 6 to 36 hours, figure among
the longest of all iron oxide NP systems. For such reasons, and in spite of the potential
instability of dextran grafting at their surface, Ferumoxtran, Feromoxytol, and Suprav-
ist particles have been widely applied to MR molecular imaging. Table 13.1 summarizes
the performance of a selection of commercial and pre-clinical products, based on both
superparamagnetic and paramagnetic NPs.
13.6 Biological performance of magnetic nanoparticles for MRI
MNPs for MRI applications are complex pharmaceutical constructs which must nav-
igate the body either to provide a general contrast enhancement effect, or in search
of a target. They are made of at least two, if not four or five, different components
(Fig. 13.1): a central magnetically active core, a stabilizing shell or coating, made of
one or many types of biocompatible molecules, to which targeting ligands and addi-
tional imaging modalities are anchored. Therapeutic agents can also be embedded
in the structure. MNPs must be biocompatible and should not harm the patient. The
behaviour of the nanoconstruct in vivo, as well as that of each of the different compo-
nents (blood retention, clearance kinetics, possible degradation resulting in metal ion
leaching, polymer or drug elution, etc.), must be comprehensively investigated prior
Table 13.1. Relaxometric properties of MNPs measured at clinical MRI field strengths.
Product, commercial NP core Hydrodyn. r1 r2 /r1 Blood half- Use Refs.

name, coating diam., TEM size, DLS (1.5T, life, T1/2
(nm) (nm) 37∘ C) (species)
SPIO (Ferumoxides, ∼5 120–180 10.1 12 2 h LI, CL [144,
Endorem, Feridex), (humans) 145]
(AMI-25),
dextran T10
SPIO, Resovist, ∼ 10 60 9.7 19.5 2.4–3.6 h LI, CL [146]
Ferucarbotran (humans)
(SHU-555A),
carboxydextran
USPIO, 4.5 15–30 9.9 6.57 24–36 h MLNI, [102]
Ferumoxtran-10 (humans) MI,
(AMI-227), BPA,
dextran T10 CL
USPIO, 6.7 30–35 15 5.93 10–14 h MI, [144,
Ferumoxytol-7228, (humans) BPA, 147]
carboxlymethyldextran CL
USPIO, Supravist 3–5 21 10.7 3.55 6 h BPA, [148]
(SHU-555C), (humans) CL
carboxydextran
USPIO, Feruglose 6.43 11.9 ∼ 18 n. a. 6 h BPA [17,
NC100150, (∗ at 0.5T) (humans) 149]
Clariscan,
PEGylated starch111
VSOP (iron oxide), 7 14 14 2.4 0.6–1.3 h BPA, [150]
C184 (humans) CL
citrate
ESION (iron oxide), 3 4.77 6.12 > 10 min. BPA [151]
PO-PEG (∗ at 3T) (rat)
USPIO 5.5 ±0.6 24 ±3 9.5 2.97 < 40 min. BPA [152]
bis-phosphonate- (∗ at 3T, RT) (mouse)
PEG
Gd2 O3 2 9–11 14.2 1.2 – CL [76]
PEG-diacid
NaGdF4 <5 6–9 3.37 1.18 > 90 min. BPA, [34]
citrate (mouse) MRI-OI
MnO 6–8 13.4–16.2 4.4 8.6 < 20 min. BPA [118]
bis-phosphonate- (mouse)
PEG
dendrons
* Use: LI: liver imaging; CL: cellular labeling; MLNI: metastatic lymph node imaging; MI: macrophage
imaging; BPA: blood pool agent; MRI-OI: MRI-optical imaging
to approval by the health authorities. Finally, coated and functionalized MNPs should
have their relaxometric properties preserved.
13.6.1 In vivo barriers
MNPs injected in vivo must overcome several biological barriers either to reach their
target or to remain in the blood for a prolonged period. Most MRI CAs are admin-
istered through intravascular (i.v.) injections. MNPs immediately encounter blood,
a highly ionic and heterogeneous solution containing high concentrations of organic
molecules. Chemical binding and electrostatic interactions occurring between these
molecules and the MNPs can lead to dramatic changes in their hydrodynamic dia-
meter, relaxometric properties, and colloidal stability. Agglomeration and surface
charge effects can also accelerate the sequestration of MNPs by the immune system,
resulting in stronger and more rapid uptake by the macrophages. Depending on their
molecular coating, MNP can interact more or less strongly with the extracellular
matrix and, in the case of binding, this can cause the MNPs to be taken up by cells
prematurely before they reach the targeted tissue [153].
The NPs must also overcome different anatomical size restrictions which limit
their access to target tissues (e.g., extravasation of lymph node-targeting NPs from
the blood) [154]. These size limitations are very stringent in the case of certain organs
such as the brain and kidneys [155]. For instance, only NPs of sufficiently small size
and appropriate physicochemical properties may pass the blood-brain barrier, a struc-
tural and metabolic barrier consisting of endothelial cells and reinforcing astrocyte
cells that protect the brain [156]. In addition to biological barriers present in the extra-
cellular space (blood vessels, lymphatic conducts), intracellular barriers may also
restrict the function of several biomedical NP systems. NPs which bind at the surface
of targeted cells are typically taken up by such cells through receptor-mediated en-
docytosis mechanisms. Upon ingestion by the cells, NPs are trapped and “trafficked”
through endosome compartments where they progressively degrade by acidifica-
tion. The endosomes are progressively translocated into lysosomes, compartments
in which hydrolytic and enzymatic reactions metabolize or evacuate macromolecules
and NP debris [157]. Different strategies, more or less complex or potentially cytotoxic,
have been developed to facilitate the escape of NPs from the endosomes [158]. Overall,
each of these biological obstacles illustrates the different levels of complexity which
must be addressed when designing optimal MNPs as CAs for blood pool, cell labeling
and tracking, targeted imaging, and/or drug delivery procedures.
13.6.2 Impact of nanoparticle size and surface on colloidal stability and

blood retention
The ability of MNPs to remain in the blood for prolonged periods and to pass biologi-
cal barriers is largely related to their main physicochemical characteristics: hydrody-
namic size, surface charge, and type of coating [155, 159, 160]. The retention of NPs in
the blood vessels, the mechanisms of NP clearance, and the permeability of NPs from
the vasculature all strongly depend on these three parameters [161–163]. In particular,
NP charge and hydrophobicity can affect NP biodistribution by limiting or enhancing
interactions of NPs with the adaptive immune system, plasma proteins, extracellular
matrices, and non-targeted cells [153]. Specifically, hydrophobic and strongly charged
NPs have short circulation times due to the adsorption of plasma proteins such as op-
sonins, which are responsible for the recognition of MNPs by the reticuloendothelial
system (RES). As a consequence, the macrophages recognize opsonins and remove
MNPs from the bloodstream [160]. Most particles end up in the liver and spleen, where
they eventually degrade. The sequestration of MNPs by the RES can be advantageously
used in the diagnosis of hepatic lesions (e.g., liver cancer). However, particles which
are too rapidly sequestered and removed from the blood stream cannot optimally ful-
fill applications such as targeted imaging (e.g., for cancer, atherosclerotic plaque, and
Alzheimer’s disease), and drug delivery to specific organs.
Hydrodynamic size strongly affects the clearance of NPs from vascular circula-
tion [37, 47–51]. In general, small NPs (< 20 nm) can be more efficiently excreted by
the kidneys [164–166], whereas large NPs (> 50 nm) are mostly found in the liver and
spleen. However, strongly charged particles such as citrate-capped iron oxide and
paramagnetic nanocrystals follow the RES route and are cleared in the liver [98]. As a
consequence, a minor fraction of them make their way through the urinary tract [150].
Most endothelial barriers allow nanoparticles of < 150 nm hydrodynamic diameter
to pass; however, other barriers, such as the BBB, are far more restrictive. Because
the liver can metabolize very large amounts of iron, USPIOs and SPIOs are generally
well-tolerated products. As a matter of fact, Ferumoxides, Feromoxtran, Ferucarbo-
tran, Supravist, Clariscan, and a few other iron oxide-based NP systems have either
been commercialized, or at least investigated in clinics (see Table 13.1). In the case of
paramagnetic nanoparticles not based on Gd or Mn chelates (MnO, Gd2 O3 , NaGdF4 ),
the toxicity risk represented by the massive injection of Mn and Gd-based crystals po-
tentially leaching toxic Mn2+ and Gd3+ ions greatly restricts their eventual transfer to
clinical applications. However, emerging coating strategies, in particular those based
on silane-PEG or phosphate/phosphonate-PEG (Fig. 13.10), have been shown to pro-
mote the rapid excretion of paramagnetic nanocrystals via the gastrointestinal and
urinairy routes [118, 166]. It is still too soon to predict whether these strategies might
allow the clinical use of paramagnetic nanocrystals in the future. However, they facil-
itate the development of more complex and specific “positive” CAs for molecular and
cellular pre-clinical research.
t=0 t=10 min t=1 h
(a)
(b)
(c)
Fig. 13.10. Injections of MnO NPs PEGylated with phosphonate dendrons, and scanned in MRI;
(a) strong evidence of CA elimination is found in the gall bladder (hepatobiliary way) after 1 h;
(b) blood signal-enhancement persists at least 20 minutes after injection, while evidence of
CA clearance is found in the kidneys (b), and in the urine (c). Adapted with permission from [118].
In order to be truly efficient for targeted molecular imaging applications, it is neces-

sary for the MNP CAs to reach blood half-lives of many hours (such as for Feromux-
tran, Ferumoxytol, and Feruglose; Table 13.1). In this way, CAs have more chances to
effectively bind to molecular epitopes and receptors expressed at the surface of vas-
cular cells, which the targeted CAs are designed to reach. Surface modification with
the hydrophilic molecules dextran and polyethylene glycol (PEG) have been shown to
reduce opsonization, leading to prolonged NP circulation times (Table 13.1, and [167]).
13.6.3 Directing nanoparticles in vivo
The specificity of NPs for selected tissues is critical in MRI-based diagnostic imaging
[16, 74, 75]. NPs can be engineered to have an affinity for target tissues through passive,
active, and magnetic targeting approaches. Passive targeting uses the predetermined
physicochemical properties (size and surface charge) of a given NP to specifically mi-
grate to a given tissue region. In particular, the enhanced permeation and retention ef-
fect (EPR) can be used to target solid tumour tissue [76]. In an attempt to grow rapidly,
tumor cells stimulate the production of new blood vessels (termed “neovasculature”).
Such vessels are poorly organized and have leaky fenestrations. This enables extrava-
sation of NPs out of the vasculature into the tumor tissue [77, 78]. Then, because lym-
phatic drainage is relatively inefficient in solid tumors, NPs tend to accumulate at this
site [79, 80]. However, the EPR effect is limited to specific metastatic solid tumors and
the successful implementation of CA systems relying on this effect is dependent upon
a number of factors including the degree of capillary disorder, blood flow, and lym-
phatic drainage rate. As a result, it is not possible to base a therapeutic treatment or
an MR diagnostic on the EPR effect.
Passive targeting works exclusively for very specific biomedical applications, such
as for solid tumors of leaky vasculature, since it does not guarantee their internaliza-
tion by targeted cells. In order to achieve cellular internalization it is necessary to mod-
ify NPs with molecular targeting ligands to provide an “active” approach. NPs func-
tionalized with molecules which specifically bind to molecular epitopes expressed at
the surface of cancer cells or other disease tissues allow a more efficient selective con-
centration of them in the tissue to be diagnosed or treated (81, 82). In particular, a
number of iron oxide NP systems have been developed and tested in vivo with vary-
ing success. Among targeting molecules which have been used so far to achieve active
targeting with iron oxide NPs figure small organic molecules [81, 83, 84], peptides [71,
85–88], proteins [89], antibodies [90–92], and aptamers [93–95].
In addition to engineering NPs for tissue targeting, external magnetic fields can
be used to assist the diffusion of MNPs to given organs. This strategy is referred to as
“magnetic targeting” [18, 104]. It consists of focusing high fields, high gradients, or
strong rare earth magnets on the target organ or biological site. This is a good strat-
egy to accumulate high-susceptibility MNPs at specific sites, to conduct hyperthermia
treatments [100]. This technique was successfully implemented in a clinical trial to
deliver the chemotherapeutic doxorubicin to hepatocarcinoma cells [105]. The effec-
tiveness of magnetic targeting is unfortunately limited to target tissues located close to
the surface of the body (rapid loss of magnetic field strength away from the magnets).
13.6.4 Toxicity
In order to generate significant signal-enhancement effects, NPs used as MRI CAs

must be injected at relatively high doses compared to common tracers used in nuclear
medicine (e.g., PET). Therefore NPs must be demonstrated safe for cells and differ-
ent tissues, in particular when high quantities find their way to critical organs (liver,
kidneys, spleen). The impact of MNPs on the proliferation and viability of different
cell types is always demonstrated in vitro prior to injection in vivo [32, 76, 112, 168].
Depending on the concentration, type of particle, surface charge, and class of coating
ligand, the presence of a high concentration of nanoparticles in the vicinity of cells
can have a transitory effect on their cell division cycle, and sometimes influence their
viability. Apoptosis measurements can also be performed at high doses of MNPs to
evaluate the damage induced by high concentrations of MNPs to cells. The cells se-
lected for in vitro tests should ideally represent either the tissues expected to receive
the highest concentration of MNPs, or the cells most likely to be affected by MNPs. As
an example, in order to assess the biocompatibility of ultra-small MNPs for targeted
vascular imaging, epithelial vascular, kidney, and hepatic cell lines could be used.
Finally, MNPs are not intact when they are excreted from the body. They are con-
fronted with different biological mechanisms which impact on their integrity. Validat-
ing the clinical use of nanosystems is challenging, as the toxicity of both the intact
products and their different components must be rigorously studied. For instance, the
potential leaching of metal ions from MNPs in different organs must be carefully and
comprehensively quantified. Also, the impact of different NP coatings and their degra-
dation products on specific cells and organs in which they could potentially accumu-
late is also an important aspect of the toxicity evaluation of MNPs. The nature of the
degradation by-products must also be addressed [169]. Nanotoxicology is an emerging
and expanding research area and a selection of works specifically address this topic
[155, 170, 171].
13.7 Summary
The recent advances in synthesis and characterization of MNPs as MRI CAs has al-
lowed the emergence of a variety of new biomedical applications: stem cell labeling
and tracking in vivo, imaging-assisted drug and gene delivery, molecular targeting of
chronic diseases such as atherosclerosis and cancer. Because of their very strong im-
pact on the transverse relaxivity, superparamagnetic NPs in particular have been used
in a variety of clinical applications (liver, spleen, lymph node imaging). In this chapter
the basic principles of MNPs for MRI applications were reviewed. The main parame-
ters and conditions guiding their optimal design, use, and performance in biological
applications were presented. Because the relaxometric potential of MNPs is very de-
pendent on their size, fine particles of narrow size distributions are developed and
then coated with biocompatible molecules which provide enhanced colloidal stabil-
ity in physiological environments through electrostatic and steric repulsion mecha-
nisms. The biocompatibility of nanoparticles must be assessed in vitro, after careful
measurement of their magnetic and relaxometric properties. Finally, the biological ki-
netics (blood retention, organ uptake, clearance) and contrast-enhancement effects of
each new nanoparticulate system must be carefully studied in vivo. NPs are complex
systems, and the medical regulatory authorities enforce very strict requirements on
design, production reproducibility, potential toxicity, and pharmacokinetics perfor-
mance of such injectable products. Finally, the expansion of hybrid imaging modali-
ties (MRI/PET, MRI/luminescence, MRI/SPECT, MRI/echography), calls for the devel-
opment of multifunctional and increasingly complex imaging tracers. For instance,
stem cell therapies could be conducted advantageously using MRI/PET, which would
enable more sensitive detection and quantitation of areas of implanted stem cells.
The delivery of targeted drugs through nanovectors could also be performed under
MRI/PET guidance, to provide quantitative measurements of the residual concentra-
tion of drug delivery vehicles still present in the blood, then accumulating into specific
organs.
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J. Greener
14 Microfluidics for synthesis and biological
functional materials: from device fabrication
to applications
14.1 Introduction
Microfluidics (MF) is a general term for the new science and technology relating to the
manipulation of small volumes of liquid using small channels. It is considered a green
technology due to the small volumes of liquid used, which greatly reduces material
consumption and waste, thus enhancing safety when working with toxic or exother-
mic reactions [1]. Waste and energy associated with post-synthesis fractionation of
side-products from target products are further reduced because side reactions are min-
imized in microreactors. Rapid advancement of this technology is opening up new op-
portunities in many areas of research and development. Microfluidics enables strong
control over both the physical and chemical reaction environments, thereby benefit-
ing applications involving materials synthesis. For example, control of chemical con-
centrations and their gradients within microchannels opens up new possibilities for
controlling polymer chain lengths or embedding gradients in bulk material proper-
ties. On the other hand, control of physical conditions such as channel dimensions
and shear forces enables control over material shape and size. Together, MF provides
the opportunity to create materials at the microscale and smaller with controlled size
and shape, and allows separate control of surface chemistry and internal properties.
The growth of MF as a platform for microscale materials synthesis supports a growing
range of applications such as optics, microelectromechanical systems (MEMS), bio-
materials, self-assembly, catalysis, drug delivery and more.
In this chapter we review a range of important considerations regarding the syn-
thesis of synthetic and biological functional materials at the micro- and nanoscale. It
is designed to give a post-graduate level overview of MF and applications related to
functional materials. It covers a broad range of topics, from the introduction of key
concepts in MF and reactor fabrication to its utilization in the study and synthesis of
new materials. It provides valuable information for both graduate students and pro-
fessional researchers who are new to the areas of MF and functional micro-materials.
Practical considerations such as a review of the different types of microreactors, the
materials and fabrication methods for their manufacture are summarized in Section 2.
In Section 3 we discuss the special properties of liquids flowing through microchan-
nels and how to manipulate and monitor reaction solutions. In Section 4 we discuss
how MF can be used to synthesize polymer micro particles, 1D threads, and 2D mi-
crosurfaces by shaping precursor liquids into 1-, 2-, and 3D structures. This discus-
sion includes relevant concepts in MF channel geometries, their surface properties,
and macroscopic properties of the precursor liquids. Section 5 discusses synthesis of

functional nanoparticles in microchannels. Finally, Section 6 reviews state-of-the-art
applications of MF for the synthesis and study of microscale functional biomaterials
for tissue engineering, cellular microenvironments, and biofilms (BFs). At the end of
Section 6 we provide two illustrative examples: microscale microbial fuel cells, and
devices for clinical diagnostics related to exposure to nanoparticle materials.
14.2 A practical introduction to microfluidic reactors for

material synthesis
14.2.1 Microfluidic reactor geometries
For the purpose of this chapter, we define MF channels as possessing dimensions of

1 mm or less along one of their cross-sectional axes. In general, there are three types of
MF reactor platforms: capillary tubing, planar devices and digital MF. The first two are
reviewed here, but we focus on planar devices due to their versatility and wide usage
in various applications.
Capillary tubing
Using off-the-shelf polymer capillary tubing is an attractive choice from the perspec-
tive of cost and simplicity. In addition, capillary tubing can be acquired in metal, plas-
tic and glass, which provides many opportunities to find chemical compatibility with
reaction solutions (Section 2.2). Capillary tubing is generally robust, enabling high
pressures and flow rates, as well as high temperatures, particularly for metal tubing.
Another major benefit is that their outer dimensions are highly standardized, which
has resulted in many commercially available connectors for the introduction of func-
tional elements such as junctions, mixers, filters, pressure regulators, and also for in-
terfacing with standard instrumentation for characterization and fluid delivery. Gen-
erally, metal and plastic capillary tubing is opaque, limiting optical imaging and spec-
troscopic characterization. Opacity can be addressed by introducing a window stage
between two opaque capillary tubes. Another solution is the use of capillaries with
optical cladding on their inner surface, which can guide light in internal reflection
mode, thereby enabling some forms of spectroscopic characterization [2]. Fused silica
tubing enables light transmission in the visible wavelengths, but images are generally
distorted due to optical index of refraction mismatch at the curved capillary/air and
capillary/liquid interfaces. Capillary tubing with square cross-sectional dimensions
is available for specific cases, thus addressing the problem of image distortion. The
main drawback of capillary tubing is that channel designs are limited to long, straight
channel sections. Due to the simplicity of capillary tubing-based reactors, there are
limited opportunities in MF. However, capillary tubing is particularly useful for the
14 Microfluidics for synthesis and biological functional materials | 377
emulsification of precursor materials via co-flow geometry (see Section 14.4 of this
chapter).
Planar “chips”
The majority of microfluidic research and development is conducted on planar
“chips”, which are typically two-level planar devices. The first layer is a planar sub-
strate with a patterned series of trenches on its surface, which define 3 walls of the
microchannels. Approaches to fabricating this layer from polymer materials are dis-
cussed in Section 2.3. The second layer is a sealing layer, which covers the open face
of the trenches, thereby defining the fourth wall (the ceiling) of the microchannel.
Multilevel devices and 3D fabrication techniques are currently opening the way for
more complex chip-based MF reactors [3]. Fabrication techniques are different based
on material selection (Section 2.2), but generally involve the replication of chan-
nel geometries from a computer-aided design (CAD), enabling high complexity and
reproducibility. A range of designs can be implemented to control flow profiles to syn-
thesize functional materials at and below the microscale. Fabrication of microreactors
in polymers and elastomers is generally straightforward in addition, an emerging in-
dustry providing MF in glass or hard plastic is opening the way for a wider range of
MF applications and uses.
14.2.2 Device fabrication materials
Microfluidic devices feature very large surface area to volume ratios, enhancing the
interaction between the microchannel wall and the solution environment. The con-
strained physical dimensions of microchannels often result in the need to position
optical characterization equipment outside optical microchannels. In cases where
probes and other functional elements can be interfaced directly with the microreac-
tor, the mechanical properties of the device should be robust. A review of materials
for MF manufacture and their suitability for functional material synthesis and char-
acterization is presented below.
Polymers
Polymers play a dominant role as MF device fabrication materials due to their low
cost, the wide range of formulations available, the ease of processing, and the po-
tential for mass production. For these reasons, sales of polymer MF devices currently
account for approximately 50% of the world market. Moreover, polymer materials
can be transparent, enabling optical characterization. Popular polymer materials
include thermoreactive (also known as curable) polymers, elastomers, and thermo-
plastics. One of the most commonly used plastics is an elastomeric material called
poly(dimethyl siloxane) (PDMS). Its wide use, particularly in academic research and
for developmental purposes, results from its low cost, easy demolding and its good
self-adhesive properties following surface activation using O2 plasma or UV light ex-
posure. Enhanced bonding techniques for PDMS can result in stronger bonds and
seals between layers [4], but they are still more prone to debonding and channel
deformation than devices made from more robust materials such as glass or metal.
Other major drawbacks of PDMS include its permeability to small molecules and
gases, limited chemical compatibility and its propensity to swell in some solvents. As
a result, there has been a recent focus on developing new hard plastic-based microre-
actors, which could enable operation at high pressures and allow interconnectivity
with other instrumentation.
The rise of polymer-based MF platforms has paved the way for customized MF
and thus maximized the flexibility of these systems. Micropatterning of polymer ma-
terials can be accomplished by a number of techniques such as curing, microma-
chining, laser ablation, hot embossing, and injection molding. Bonding the patterned
layer to a planar layer for chip-based devices can be accomplished using heat, epox-
ies, and surface activation techniques. With a few exceptions, most polymers are hy-
drophobic, which can present challenges in forming oil droplets in water phase (see
Section 4) due to the preference of the emulsified monomer-phase precursor liquids
which wet the channel walls over the aqueous carrier phase. Surface treatment tech-
niques can change the wetting properties of microchannel walls, making it more suit-
able for emulsification of a range of liquid precursors. For example, exposure to O2
or air plasma can add OH groups to exposed surfaces, thereby converting the wall to
hydrophilic. Chemically treated thermoplastics have also been demonstrated to alter
the wetting properties and to enhance resistance to organic solvents, as demonstrated
by a series of papers involving surface modification of polycarbonate [5–7]. Generally,
surface treatments of elastomers are less effective than for rigid polymers due to the
higher mobility of surface groups.
Glass
Glasses, quartz, and fused silica are widely used materials for MF reactors [8]. Their
advantages include excellent resistance to most chemical environments (with the no-
table exceptions of HF and other acids), high temperatures and pressures. Glass is
typically hydrophilic, making it an excellent choice for emulsifying oil in water (Sec-
tion 4), and has excellent transparency in the visible region, enabling optical obser-
vation and measurements. However, glass is extremely brittle. In addition, it is costly
and time-consuming to manufacture custom geometries as compared to plastic mate-
rials. Acid (wet) etching through a chemically resistant mask is usually used in fabri-
cation. Typically, hydrofluoric acid (HF) is used for rapid glass etching, but the etching
solution often includes a blend of acids to solubilize all by-products. Wet etching of
amorphous glass materials results in isotropic, which produces hemispherical chan-
nel cross-sections. A planar coverslip can be bonded to an etched glass device using
high temperature, pressure, or an intervening layer of adhesive. Creating through-
holes in glass is relatively difficult, requiring sandblasting, laser drilling, diamond
drill bits or deep wet etching, making interface of fluidic connections and other pe-
ripheral devices challenging. Commercially available glass-based microreactor chips
usually have standard designs, as customization adds cost and complexity. Commer-
cially available capillary tubing may help to expand utilization of glass materials and
enable different connection and interface options.
Silicon
Silicon devices have similar physical properties to glass, but suffer from the ma-
jor drawback that they are only transparent in the infrared region, making optical
characterization methods impossible without complexities such as integrated win-
dows. Silicon also has excellent temperature and corrosion resistance. Untreated
silicon surfaces are moderately hydrophilic, but can be made strongly hydrophilic or
hydrophobic using various surface treatments [9]. Patterning techniques are similar
to glass, but primarily involve dry etching techniques using reactive ions and can
achieve anisotropic etching with high aspect ratios [8].
Metal
Metal microchannels are an attractive option due to their robust chemical, thermal,
and mechanical properties. For example, metals are generally resistant to chemicals,
with the notable exception of acidic solutions. The advantages of metal materials over
glass for MF include superior thermal properties and strength, as well as easier pro-
cessing due to the possibility of direct machining. Nevertheless, metals are opaque
and sealing microfabricated metallic devices is challenging. Therefore, metallic tub-
ing and connector assemblies are widely available and more frequently used than pla-
nar metallic MF chips.
Ceramic
Ceramic based MF devices are relatively new, benefiting from high temperature syn-
thesis resistivity and a wide range of chemical compatibilities. A particularly attractive
and versatile approach involves low-temperature cofired ceramics capable of incorpo-
rating built-in electronics for control and characterization [10, 11]. The drawbacks to
using ceramic materials include its brittleness and the lack of optical transparency.
14.2.3 Fabrication of polymer-based planar microreactors and components
As the field of MF has grown, so too has the range of techniques for production of MF
devices, particularly in various polymer materials. In addition, the production of vari-
ous functional elements such as microvalves and electrical components is expanding
the functionality of MF [12–15]. This section focuses on fabrication of polymer chip-
based MF reactors largely because they constitute the fastest growing and most versa-
tile type of architecture. We will start with the different approaches for producing the
feature layer (2.3.1–2.3.5) and then discuss the bonding step (2.3.6).
Casting
Casting is the process by which a mold is coated with a liquid pre-precursor which can
be solidified by heat curing, UV exposure, chemical crosslink or some combination
thereof [16]. Figure 1 shows the three step process for casting, which includes (a) coat-
ing the mold with the precursor materials, (b) curing, and finally (c) demolding. The
molded surface is then bonded to a planar substrate to form enclosed MF channels
(Fig. 14.1). Elastomeric materials, such as PDMS, are widely used because they can
form patterned surfaces rapidly, are inexpensive and can be easily demolded. Molds
for casting MF devices can be produced by many means including machining, abla-
tion, electroforming and etching, but the most common process is photolithography.
Casting
(a)
(b)
(c) (d)
Fig. 14.1. Microfabrication by casting. (a) A liquid pre-polymer is poured on top of a mold containing
the inverse design of the desired microchannel geometry. (b) The process of solidification (curing)
occurs while precursor material is in contact with the mold. (c) The solidified polymer is removed
from the mold. (d) Model of elastomeric PDMS being peeled from a silicon wafer mold.
Photolithography
Photolithography is a widely used technique for MF development since it is rapid, in-
expensive, and can result in good spatial resolution. A photoresist is spin-coated onto
a flat substrate and hardened. Then, using a 2D photo mask, portions of the resist
are exposed to light. In negative photoresists, light selectively crosslinks exposed por-
tions through the optical mask, while in positive photoresists, the light breaks bonds.
In either case, the topography of the photoresist layer is formed following the removal
of the uncrosslinked photoresist. The heights of the mold features are defined by the
photoresist thickness. Therefore, care must be taken during the spin-coating process
to ensure that the photoresist layer has an even thickness across the entire substrate
surface, particularly in the middle and near the edges, where material buildup tends
to occur. The patterned surface can then be used to form a casting mold or embossing
imprint template for patterning target materials with the desired microreactor channel
geometry. In some cases the patterned photoresist is used directly as the MF device.
Soft-lithography
Soft lithography is defined as the use of a soft surface as an imprint template, mold,
or mask [13]. Very often, the PDMS replicas made in the casting process described
above are used as templates for subsequent molding steps when the mold needs to be
compliant, for example, to generate features on curved surfaces. In other cases, the
PDMS replicas are used as “soft stamps”, enabling good contact between the stamp
features and the target surface, and the transfer of thin layers of material from the
stamp feature to the target surface.
Nanoimprint lithography
Nanoimprint lithography (NIL), also known as hot embossing, is a promising tech-
nique for large-area topographic polymer micropatterning by transferring topograph-
ical features from an imprint template to the heated target substrate [17]. It is similar
to injection molding, as elevated temperatures are used to enable production. How-
ever, NIL is more straightforward to implement, requires shorter fabrication times and
lower temperatures. This process occurs in three steps as shown in Fig. 14.2. First the
system is heated to the embossing temperature (Te ), which is higher than the glass
transition temperature (Tg ) of the thermoplastic. Following heating, the embossing
pressure (Tp ) is applied, which forces the imprint template features to penetrate the
compliant polymer. In the third step, the thermoplastic is cooled to the de-embossing
temperature (Td ), which is lower than Tg . This results in the solidification of the
thermoplastic, thereby trapping the inverse surface topography of the imprint tem-
plate. The imprinted substrate is then removed from the imprint template and bonded
to a planar material, usually, but not necessarily the same material. Sometimes lubri-
cating layers are applied to the imprint template to facilitate the de-embossing stage.
Typically, features are an exact replication of the imprint template.
The main hurdle for the implementation of NIL as a tool for fabrication of cus-
tomized MF geometries is the imprint template. The imprint template defines the ge-
ometry, resolution, and quality of the imprinted substrate. Commercially available
imprint templates are usually produced from metals, e.g., nickel, by using mechan-
ical machining, laser ablation, or electroforming [18–20]. The disadvantages of these
methods are that they are expensive and production is slow. Moreover, imprint tem-
plates based on patterned etched silicon wafers are fragile. A method has recently
been developed to overcome these limitations by generating inexpensive and robust
masters manufactured via photolithography [12]. The addition of a metallic layer to
evenly distribute heat and functional surface groups also helps the de-embossing pro-
cess [21].
(a)
(d)
(b) (ii)
(i)
(c) (e)
Fig. 14.2. Microfabrication by embossing. (a–c) The steps for embossing a thermoplastic sheet.
(d) An image of an imprint template with the geometry of a flow focusing device. Features are high-
lighted in black. (e) An embossed device with channels highlighted in green. Critical features such
as the flow focusing emulsification point (i) and the polymerization compartment (ii) are highlighted
(d and e are reprinted with permission from [12]).
Other fabrication techniques

Other approaches to microfabrication include etching techniques (usually for glass
and silicon) [8, 22–24] and computer numeric controlled (CNC) techniques such as
micromilling [25, 26], and laser ablation [27]. Each of these has advantages and lim-
itations. For example, wet etching is expensive and unsuitable for the fabrication of
isotropic features in amorphous materials. Micromilling and laser ablation can be ap-
plied to various materials in addition to polymers; however, the generation of waste

can be problematic. Additionally, these methods are challenging to implement in the
manufacture of high aspect ratio microchannels and channel intersections, and often
result in rough surface finish. In each of these cases, prototyping of complex geome-
tries is either expensive or slow, and they are therefore not considered in detail here.
Bonding step
Following the fabrication of the microstructured layer containing the channel geome-
tries, fluidic access holes are drilled or punched into the patterned side of the device,
which is then bonded to an unpatterned planar layer to seal the channels. Usually the
bonding layer is the same material as the microfabricated layer, but in some cases it
is advantageous to bond a different material as the sealing layer, for example when
optical transparency is required. Bonding can be accomplished by heating, surface
activation, or the use of epoxies. In the case of plastics, surface activation is usually
accomplished by exposure to plasma gases or UV radiation (Fig. 14.3).
(a)
Fig. 14.3. Bonding of a microfabricated device. (a) The microfabricated

layer (blue) and the planar layer (cross-hatched) are heated, surface ac-
tivated or coated with epoxy. (b) The activated layers are brought into
(b) contact with each other and pressure applied.
14.3 Manipulating and measuring precursor reagent streams

in microchannels
In this section we look at both the fundamental concepts and practical approaches
which can affect the manipulation and measurement of precursor liquids in micro-
channels.
14.3.1 High surface area to volume ratios in microchannels
We first consider the large surface area to volume ratios in microchannels compared
to bulk reactors. Surface area (SA) to volume (V) ratios can be described by equa-
tion (14.1a) for a spherical reactor vessel, and equations (14.1b) and (14.1c) for channel-
based reactors with circular and rectangular cross-sections, respectively.
SA 4πr2 3
= = (14.1a)
VB 4/3πr3 r
SA 2πrl 2
= 2 = (14.1b)
Vcirc πr l r
SA (2h + 2w)l (2h + 2w)
= = , (14.1c)
Vrec hwl hw
where r is the radius of the spherical reactor (14.1a) or the channel radius (14.1b) and
h and w are the height and width of a channel with rectangular cross-section (14.1c),
respectively. In equations (14.1b) and (14.1c), l is the channel length. Given the differ-
ences in the radial dimensions between microreactors (hundreds of micrometers or
less) and bulk reactors (meters), SA/V in MF devices can be over 4 orders of magni-
tude greater than that for batch reactors. As discussed below, large SA/V has important
effects on the flow conditions within microreactors.
14.3.2 Rapid heat transfer
Large SA/V has a strong effect on the temperature profile of liquid in microchannels
due to large thermal flux between the liquid and the microchannel walls [28]. As a re-
sult, the liquid rapidly reaches equilibrium temperatures and thus, thermal gradients
are strongly suppressed throughout the reactor environment. This has the effect of
limiting side reactions and eliminating Arrhenius-related distribution to reaction rate
constants in the microreactor. In addition, safety is enhanced by effectively eliminat-
ing the chance of runaway exothermic reactions which can occur in batch reactors.
Since liquid temperatures quickly equilibrate after entering the microchannels, tem-
perature control of the microreactor environment is an effective way of accurately
maintaining temperature throughout the reactor [29]. Enhancing thermal flux for
faster equilibration times can be achieved by using fabrication materials with better
thermal conductivity.
14.3.3 Control of concentrations
In general, MF channels are isolated from ambient conditions, thereby preventing

chemical and biological contamination of the reaction solution. The notable excep-
tion is for those reactors fabricated in PDMS, which are sufficiently porous to allow
small molecules such as O2 and CO2 to diffuse into the reaction solution. A further
benefit of the MF approach is the ability to vary the concentration of reagents in a high-
throughput way by modulating the relative flow rates of individual reagent streams.
This enables exploration of a large parameter space, which is useful for optimization
of formulations. As an example, a study involving a multicomponent polymerization
included solutions containing a monomer (M), initiator (I), and chemical accelerator
(A) had initial concentrations CM,i , CI,i , and CA,i , respectively [30]. After introduction
into an MF reactor and mutual dilution, the reagent concentrations became
CM,d = CM,i × QM /QT (14.2a)

CI,d = CI,i × QI /QT (14.2b)
CA,d = CA,i × QA /QT , (14.2c)
where CM,d , CI,d , and CA,d are the diluted concentrations; QM , QI , QA are the flow rates
of the streams containing the monomer, initiator and accelerator, respectively; QT is
the total flow rate, which is the sum of all flow rates including a dilution stream of
water (QW ), given by QT = QM + QI + QA + QW .
(ii)
(iii)
(i)
(iv)
(v) P1
(vi)
P2
P3
Fig. 14.4. Schematic of an MF reactor for the study of free radical polymerization of a complex re-
action. Solutions of monomer, a chemical accelerator, a monomer, and water were supplied to the
MF reactor by tubing connected via inlets (i–iv). Four small wavy channels following the inlets are
used to increase hydrodynamic resistance in order to stabilize flow. Mixing of reagents occurred in a
step-wise manner before entering the large serpentine channel (reaction chamber (v)), where mixing
was enhanced and the polymerization reaction took place. The composition of the reaction mixture
was characterized by ATR-FTIR using a probe placed at point P1 . A temperature probe was located
at P2 , and a pH probe was located at P3 . The reaction solution left the MF reactor via the outlet (vi).
The scale bar is 1 cm. Reprinted with permission from [30].
Another example includes the flow-based modulation of reagent concentrations

in an acid/base titration experiment to find critical values such as the pKa , the pH
at the equivalence point (pHe ) [31]. In this work, a strong base was used as a titrant
against strong, weak, and multiprotic acids. As shown in Fig. 14.5, the concentration
of the reagents was carefully modulated by flow control of the base and acid solutions
(QB /QT ) to achieve accurate titration curves.
14.3.4 Controlling “time on chip”
Synthesis in an MF reactor occurs continuously as the reagents flow through the mi-
crochannel. Therefore, given a particular flow velocity, there is a relationship between
the time of reaction and the distance downstream from the point of initial mixing. This
relationship is given by the so-called distance-to-time transformation
t = d × A/QT , (14.3)
where d is the distance downstream following the point of initial mixing. The velocity
is given by the term A/QT , where A is the cross-sectional area of the microchannel,
and QT is the total flow rate. Therefore, changing QT enables precise timing of reaction
steps or time-delayed measurements for studies of reaction kinetics.
14.3.5 Control of hydrodynamics and mass transfer
Control over turbulence

The most fundamental difference between macro- and microflows is that there exists
no turbulence for flow through a microchannel. This is quantified by a low Reynolds
number (Re), which is given by:
ρvDh
Re = , (14.4)
μ
where ρ is the liquid density, v is the liquid velocity, Dh is the hydraulic diameter of
a channel, and μ is the dynamic viscosity. For channels with rectangular inner cross-
sections, which are typically fabricated from photolithographic master molds and im-
print templates, the hydraulic diameter is given by Dh = 2wh/(w + h), where w is
the channel width and h is the channel height. Values of Re which are below the crit-
ical threshold of 2 300 describe a laminar flow environment. A typical approach to
achieving laminar conditions in macro flow systems is to use high viscosity liquids.
However, this is usually not desirable, particularly for biological systems in aqueous
media or reaction environments for chemical synthesis of micro materials. The very
small values of Dh for microchannels naturally result in laminar flow, even for very
low viscous solutions flowing at high velocities. The lack of convective flow in a di-
rection other than collinear along the microchannel means that mass transport in the
13
12
11
10
9
8
pH
7
6
5
4
3
2
1
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
(a) QKOH/QT
14
12
10
pHe
pH
pKa
4
2
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
(b) QKOH/QT
Fig. 14.5. Flow-based control of acid and base concentrations for accurate titration experiments
in microchannels. (a) Microfluidic titration of a strong acid with a strong base. Titration curves for
[KOH]i = 0.05 M, and [HCl]i equal to 0.025 M (◼), 0.035 M (󳵳), and 0.055 M (∙). The total volumetric
flow rate was QT = 2.0 ml h−1 . The dashed lines show theoretical curves. (b) Microfluidic titration
of a weak acid with a strong base. Titration curve for [CH3 COOH] = 1.00 M, [KOH] = 1.00 M. Data
acquisition was conducted 2–3 min after changing the flow rates of the liquids. The pKa is taken
from the first inflection point (where the change in pH is minimal) and the pHe is measured from the
second inflection point (where the change in pH is maximal). Reprinted with permission from [31].
lateral direction within the microchannel is controlled strictly by diffusion, which is a

very slow process. Diffusion-dominated mass transfer has strong implications for mix-
ing. In addition, the laminar flow environment supports interesting and useful phe-
nomena, such as co-flow of miscible liquids side-by-side for long distances without
significant intermixing.
Control of mixing
In general, mixing in MF reactors is highly controllable [32]. In inefficient mixing envi-
ronments, where diffusion is the only mass transfer mechanism, very strong chemical
gradients can be established at liquid-liquid interfaces. Certain device designs have
also been demonstrated, which establish long-range chemical gradients across the
entire microchannel [33]. These devices have had a number of applications includ-
ing cell culture under continuously varying chemical environments [34, 35]. Due to
the long-term stability of laminar flow, concentration gradients are indefinitely sta-
ble. As will be discussed in Sections 4.6 and 6.1, this enables the formation of 1D mi-
crothreads and 2D membranes. In addition, we will discuss the control over chemical
gradients as a means of synthesizing materials with built-in gradients in their proper-
ties, thereby enabling further functionality. Conversely, there are a range of techniques
for achieving excellent mixing in microchannels. This can be achieved passively, that
is without any external actuation, by exploiting the control over MF channel designs
featuring chaotic mixing elements [36], two- and three-dimensional switchbacks, in-
channel obstacles [37, 38], and hydrodynamic focusing of the stream into very thin
interdigitated coflowing streams where mixing by diffusion can occur rapidly. Active
mixing is also applicable using alternate-injection or pulsed-flow, electrokinetic mix-
ing, or coflowing droplets or particles. Good mixing improves the polymer polydisper-
sity index [39, 40] and enables studies of reaction kinetics without diffusion limita-
tions [30].
Control of shear forces

Due to the non-slip condition at the microfluidic wall, there is always a gradient in
flow velocity perpendicular to the channel wall. This results in an average wall shear
stress, which is measured in N/m2 and is directed perpendicular to the channel. The
average shear stress is given by
τav = Δv/L ⋅ μ, (14.5)
where τav is the wall shear stress vector, μ is the liquid dynamic viscosity, Δv is the
difference in flow velocities between minimum velocity, which is zero at the channel
wall, and maximum velocity (vmax ), which is typically taken at the centre of the chan-
nel, and L is the distance between the wall and the perpendicular distance from the
channel wall where flow velocity is vmax (also usually the centre of the channel). The
laminar flow environment results in highly predictable shear stresses which are sta-
ble for long periods. As will be discussed shortly, this is an advantage in micromaterial
synthesis.
14.3.6 Characterization in microchannels
With the notable exception of optical microscopy, analytical techniques are tradition-
ally applied to liquid emerging from the MF device (off-chip). In the last 10 years, how-
ever, the MF community has made important advances in the implementation of in situ
characterization. This avoids potential contamination from the ambient environment
outside the MF device and enables high-throughput screening of the reaction vari-
able space, feedback control of on-chip processes, monitoring of transient species,
and kinetic studies with good time resolution [41–45]. Some characterization tech-
niques from the perspective of the development of functional materials are reviewed
in the following section.
Microscopy
Microscopy is the most well-established in situ characterization method for MF. It is
typically achieved via transmission-mode microscopy using bench-top microscopes.
In addition, a range of new compact microscopic techniques are becoming avail-
able for MF [46]. Optical imaging of the liquid phase gives nondestructive, position-
dependant measurements of color and color density with high spatial- and time-
resolution [47]. Optical microscopy is usually used for multiphase systems (liquid/
liquid emulsions and bubbles or solid particles suspended in continuous phase liq-
uids), because it is a convenient and versatile tool for measuring size and shape. In
this case, optical microscopy relies on differences in optical properties between con-
tinuous phase and the micromaterials or their precursors. It is also convenient for col-
lecting statistical information, for example to determine coefficient of variance (CV)
of precursor droplet sizes (see Section 4.3). Standard enhancements to sensitivity
can be gained using fluorescence, phase contrast or differential interference contrast
microscopy in microchannels [48–51]. For example, transparent materials such as
cells and low density hydrogels can be measured in phase contrast mode or using
fluorescent labels in fluorescent mode. Optical microscopy also enables simultane-
ous measurements throughout the entire field of view within the microreactor. Using
equation (14.3), measurements at multiple times of reaction in a single image can be
obtained.
Spectroscopy
There is currently a gap between the high level of control that MFs provides over reac-
tion conditions and the ability to accurately make in situ measurements. Implementa-
tion of on-chip spectroscopy holds much promise to fill this niche and bring MF reac-
tors closer to their potential as versatile platforms for discovery [52, 53]. The develop-
ment of in situ spectroscopic tools has enabled direct measurements of a much larger
portion of the relevant variable space for MF material synthesis. Tools include NMR
[54, 55], fluorescence [56], infrared (IR) [57, 58], UV-visible, Raman spectroscopy [59]
and surface-enhanced Raman spectroscopy (SERS) [3, 60]. In addition, multimodal
characterization has been achieved by the combination of spectroscopy with pH and
temperature probes [29]. In this work, the authors demonstrated the ability to use the
temperature probe as a feedback system for temperature control. This system was used
to study the reaction kinetics of N-isopropylacrylamide at different pH values and tem-
peratures.
Examples, including vibrational spectroscopy via Raman spectroscopy and at-
tenuated total reflection Fourier transform Infrared (ATR-FTIR) spectroscopies have
been used to characterize the degree of conversion of monomer to polymers in micro-
reactors [30, 59]. A Raman-based system with built-in SERS surfaces was used to mon-
itor the growth of BFs under well-controlled hydrodynamic conditions [3]. In Section 5
we review applications of UV-visible spectroscopy for in situ measurements of nano-
particles during synthesis, enabling real-time control of reaction conditions for opti-
mization of formulations.
A priority area for material synthesis in microchannels is spectroscopic imaging,
which will enable measurements of multiphase systems, due to the ability of the tech-
nique to resolve both chemical and spatial information at the same time [61, 62]. The
MF reactor must generally be transparent in some operational frequency window in
order to achieve light-based measurement. This usually limits the reactor materials to
glass or plastic, although silicon could be used for infrared (IR) observations, as it is
optically transparent in the IR, whereas materials that are transparent in the visible
region of the spectrum may be opaque in other regions of interest.
Other characterization modes

Many examples of characterization modes which are conducted directly at the outlet
of the MF reactor exist. These are usually destructive, such as mass spectrometry,
or disruptive, such as chromatography. These techniques have the benefit of being
in direct contact with the flow environment, therefore not placing requirements on
the fabrication material of the MF reactor to be optically transmissive, for example.
Chromatographic tools such as continuous online size exclusion chromatography,
which measures both the molecular weight and its distribution for polymers synthe-
sized by nitroxide-mediated polymerisation have proven to be effective [40]. Multi-
detection of polymer molecules via gel permission chromatography at the outlet of
a microreactor enabled characterization of linear and branched polymers by com-

bining a concentration- and mass-sensitive detection. Light scattering was also used
to characterise the onset and size distribution of multilamellar vesicles of diblock
copolymers [63]. Indeed, chromatographic techniques have been used very effectively
with MF. However, they are destructive and therefore not easily applicable to real-time
optimization of formulations and quality control.
A drawback of localized probes is their inability to address different regions on-
chip simultaneously, unlike imaging-based measurements. Innovative solutions to
this problem include internal redirection of flow from different positions on-chip to
the probe. For example, a multiplexed microreactor capable of sample fractionation
enabled the pre-concentration and elution of protein samples from individually ad-
dressable, solid phase extraction (SPE) channels at different locations without cross-
contamination between channels. The samples from different SPE channels could be
individually eluted and directed to a common outlet for electrospray ionization mass
spectroscopy (ESI-MS) [64]. Figure 6 demonstrates this technique by the sequential
flow of a fluorescent tracer from different feeder channels into the common outlet.
Other approaches to flow redirection have been achieved using physical valves which,
however, require complicated fabrication processes.
(a) (b) (c) (d)
Fig. 14.6. A device with a series of downstream channels (8), with SPE being sequentially loaded
with fluorescein isothiocyanate-labelled bovine serum albumin (BSA-FITC). Following this step, the
protein BSA-FITC sample was sequentially eluted into a common outlet, where ESI-MS was con-
ducted. Figures (a)–(d) show the sequential redirection of flow through four separate channels while
maintaining flow through one common channel. Reprinted with permission from [64].
14.4 Microfluidics for polymer microparticles
Microfluidics for polymer microparticle synthesis has become a mature field with
many methods and applications [65]. In this section we review important concepts in
microparticle synthesis using MF reactors.
14.4.1 Manipulating the shaping of liquid precursors
This section discusses various methods and factors that affect the shaping of pre-
cursor liquids. Typically MF synthesis of functional micromaterials begins with the
precursor solution, which is manipulated and geometrically confined by a sheath
flow. In cases where separate droplets are formed, the precursor solution is called
the dispersed phase and the sheath flow is called the continuous phase. A reaction
is started, which results in solidification via polymerization, gelation, or crosslinking
(Sections 4.7 and 6.2). Dimensions of microscale materials are largely determined by
the dimensions of precursor liquid droplets, which are controlled by the channel ge-
ometry, the mechanism of droplet formation, the physical properties of the precursor
liquid phase and the continuous phases, the volumetric flow rates of the continuous
and precursor phases, and the channel wall properties. These issues are discussed in
detail in Sections 4.2, 4.3, and 4.4.
14.4.2 Effect of the channel wall
There are two considerations in shaping the precursor liquid related to channel walls.
The first is their geometry downstream of the droplet formation. In addition to guid-
ing the shear forces which control emulsification, droplets which are solidified within
geometrically confined regions will retain their shape even after the confinement con-
ditions are removed [66]. The second important consideration is the channel wall hy-
drophobicity. In forming and sustaining emulsified precursor droplets, the continuous
phase must preferentially wet the channel wall, otherwise emulsions can become un-
stable, collapse or cause a phase inversion, whereby the intended continuous phase
liquid becomes emulsified into segmented droplets (discontinuous). Hydrophilic glass
devices resist the wetting of oily precursor phase droplets, whereas hydrophobic plas-
tic devices generally do not. Wetting properties can be changed using a surfactant.
Surfactants work by moving to the interface between aqueous and oil phases and cre-
ating a buffer layer which resists wetting. For example, surfactant dissolved in the
hydrophobic droplet of monomer solution surrounded by a continuous water phase
will prefer to form a layer at the water/oil interface. The hydrophilic head group faces
away from the monomer solution providing a barrier to wetting the hydrophobic wall.
Similarly, a surfactant in the aqueous continuous phase can increase its ability to wet
a hydrophobic wall. However, surfactants can block mass transfer across the liquid/
liquid or gas/liquid boundaries and can affect chemical reaction kinetics. Also, sur-
factant trapped at the interface can result in undesired properties in the final mate-
rial. It is preferable to choose the appropriate fabrication materials, thus avoiding the
need for surfactants. Polymer materials are typically hydrophobic, although some ex-
ist which are hydrophilic. In addition, there are a growing number of ways of modify-
ing the surface microchannel wall to change its hydrophobicity to suit the application.
The reader is referred to Section 2.2 where this is discussed for polymer materials.
14.4.3 Emulsification of precursor droplets
A droplet is defined as a discrete segment of liquid surrounded on all sides by the so-
called continuous phase. Usually the most important physical properties of droplets
are their size and polydispersity, otherwise known as the coefficient of variance (CV).
The CV is given by δ/dm × 100%, where δ and dm are the standard deviation and the
average droplet diameter, respectively. According to the standards of the National In-
stitute of Standards and Technology (NIST): “a particle distribution may be consid-
ered monodisperse if at least 90% of the distribution lies within 5% of the median
size” [67, 68]. Typically, the continuous phase is unreactive, although in some cases it
may contain reagents which react at the interface with the precursor phase. Droplets
which are larger than the channel cross-sectional dimensions are called plugs. Plugs
occupy the entire cross-section of the channel, thereby causing discontinuities in the
bulk flow of the continuous phase fluid. Nevertheless, the continuous phase will form
a thin layer between plug and wall due to its preference for wetting the inner surface of
the channel. Forming particles from droplets is preferable for micromaterial synthesis
because they are not in contact with the walls and can freely travel with the contin-
uous liquid phase after solidification. However, there are some applications where
plugs are desirable because their shapes can be templated by the channel dimensions
(Section 4.2). Control over the size of an emulsion can be gained by changing the rela-
tive flow rates of the precursor (Qp ) and continuous phases (Qc ). Generally, increasing
the flow rate ratio Qp /Qc results in larger droplets, but the correlation is complex and
requires calibration. In addition, increasing the viscosity of the continuous phase will
increase shear against the precursor phase, resulting in a similar effect to that of in-
creasing Qc . Increasing the viscosity of the precursor phase resists droplet breakup ne-
cessitating higher Qd . In addition, the breakup of viscous precursor phase can result
in small unwanted satellite particles. In addition, increasing the interfacial tension
between the precursor and continuous phases results in smaller droplets.
14.4.4 Channel geometries to achieve emulsified droplets
In the next sections we discuss the different channel geometries used for droplet
breakup, which include (a) flow focusing, (b) cross flow, or (c) co-flow devices [69].
Flow focusing
A flow focusing device confines the precursor phase between two continuous phase
liquid streams (Fig. 14.7(a)). Breakup of the precursor stream into discrete droplets
is caused by flow through a constriction in the channel. In the so-called “dripping
mode”, competitive flow through the constriction between the precursors and the con-
tinuous phase causes one stream to flow while the other is temporarily blocked. Pres-
sure build-up in the blocked stream results in its eventual flow through the constric-
tion, thereby temporarily blocking the other stream. In this way, the precursor phase
is periodically pinched off and forms droplets which are separated from each other
and the walls by the continuous phase liquid.
Cross flow
T-junction geometry supports the flow of the continuous phase at 90 degrees from the
flow of the precursor phase (Fig. 14.7(b)). Droplet formation of the precursor phase is
caused by shear stress being applied by the continuous phase. In a second droplet
formation mode, the precursor phase enters and fully blocks the downstream chan-
nel, resulting in plug formation. This causes a rapid increase in the pressure in the
continuous stream channel, which causes the breakup of the precursor phase.
Co-flow
A co-flow system is typically used in capillary tube MF systems, as it requires the align-
ment of an inner capillary within an outer capillary [70]. The precursor liquid flows
through the inner capillary, exiting it through a nozzle to meet the continuous liq-
uid phase, which is flowing through the outer capillary (Fig. 14.7(c)). The shear forces
applied to the precursor phase liquid by the continuous liquid phase cause droplet
breakup. The co-flow approach has the advantage of being an inherently 3D tech-
nique, confining the precursor phase on all sides, thereby limiting the precursor phase
from touching the capillary walls. In practical terms, however, alignment of the inner
and outer capillary is difficult and often the precursor phase is directed toward the
capillary wall.
(a) (b) (c)
Fig. 14.7. Geometries for microfluidic emulsification based on (a) co-flow, (b) T-junction and (c) flow
focusing devices. Reprinted with permission from [69].
14.4.5 Multiple emulsions
Multiple emulsions are emulsions within emulsions. They can be beneficial for ap-
plications requiring encapsulation, such as drug delivery. The generation of multiple
emulsions using MFis conducted via sequential emulsification [71–73]. For example in
Fig. 14.8(a), an aqueous phase is first emulsified in oil using a T-junction. In order for
the aqueous (dispersed) phase not to wet the channel walls, they must be hydropho-
bic after the first emulsification junction. The output stream of the first T-junction then
feeds into the precursor phase of the second T-junction, where the emulsions are emul-
sified by an aqueous continuous phase. This is called a water-in-oil-in-water (W/O/W)
emulsion, that is to say an oil droplet with an aqueous core. It is important for the
channel walls to be hydrophilic after the second T-junction in order to ensure that
the outer (oily) shell of the emulsion does not wet the walls. This process can be con-
tinued to synthesize triple and higher-order emulsions. Similar strategies have been
employed with flow focusing and co-flow geometries [74, 75]. Multiple cores can also
be trapped in an outer shell (Fig. 14.8(b)). Synchronizing the formation of the droplet
generation at the first and second droplet generator is important to control the fill-
ing of the second droplet. The microfluidic approach for sequential emulsions has the
dual benefit of narrow polydispersity, while offering a means of generating an arbi-
trary level of complexity in synthesis which can enable a range of new formulations.
14.4.6 Forming linear threads and two-dimensional interfaces
Templating linear threads: An area of growing interest involves continuous synthesis

of micro diameter threads, which can have applications in areas including wave-
guides, drug delivery systems, additives for suspension rheology, and cell culture
environments [76, 77]. The liquid thread phase can be formed using flow focusing
devices, co-flow systems, T-junctions and other architectures [78, 79] to confine a core
precursor phase by a sheath flow. Miscible fluids are usually used in order to suppress
the tendency to form isolated emulsified droplets as discussed previously. However,
researchers have recently demonstrated the potential of using immiscible liquids for
forming linear threads, when droplet emulsification can be prevented. Advantages
include true cylindrical confinement of the inner thread phase, low diameter threads,
and smooth surfaces. Each of these effects is a result of the strong capillary forces
between immiscible fluids, which tend to minimize the thread surface area. The use
of immiscible liquids which do not breakup into droplets is achieved by introducing
a sheath flow, which is comprised of a non-Newtonian elastic liquid phase, such as a
semi-dilute polymer solution. It has been shown that if this elasticity is greater than
the elasticity of the precursor solution, the normal forces directed against the precur-
sor thread actually stabilize the liquid thread, thereby overcoming capillary instability
which typically causes the thread phase to break up. Using this method, threads with
Qaq1
Qoil Hydrophobic
surface
Qaq2
(a)
(b)
Fig. 14.8. Multiple emulsions. (a) A two-stage T-junction emulsification device forming first water-in-
oil (W/O) emulsions in a hydrophobic channel due to the shearing action of oil flowing at flow rate
Qoil against flow of an aqueous solution Qaq1 . Next a second stream of water (Qaq2 ) applies shearing
force against the W/O emulsion to create a W/O/W double emulsion in a hydrophilic channel.
(b) An arrangement of different third order O/W/O/W emulsions with precise control over the num-
ber and ratio of co-encapsulated droplets using a complex hierarchical and scalable MF encapsula-
tion device. Scale bar is 400 μm. Fig. 14.8(b) is reprinted with permission from [73]
diameters ranging from 1–14 μm were formed. Multi-phase threads have also been
used to template hollow tubes and microfibers with controlled lengths [80–82]. For-
mation of threads of biofilm, called streamers, have been demonstrated to occur at
sharp corners due to the templating effect of counter rotating vortices which exist at
these locations [83, 84].
Templating planar materials: There are a number of ways of forming interfaces
which can serve as templates for planar 2D microstructures. For example, the liquid-
liquid interface between two co-flowing phases will persist for a long time in the diffu-
sion limited environment within a microchannel. If one of the streams is a precursor
phase (containing, for example, monomer and initiator molecules), and the other a
trigger phase containing molecular species which react with the initiator to form rad-
icals, the formation of a thin film will occur at the interface between them. Another
approach is to cause pH-triggered precipitation in the precursor phase by co-flowing
a second phase with a pH that does not support material dissolution, as discussed
in Section 6 [85]. Liquid-solid interfaces within microchannels offer another conve-
nient approach for templating materials in 2D planes. For example, biomaterials such
as biofilms can be grown on the microchannel wall and subjected to different shear
forces, temperatures or chemical concentrations (Section 6.3).
14.4.7 Converting liquid precursors into solid micro-materials
Converting the liquid precursor to a solid is typically the result of a polymerization

step which traps the liquid in its state at the time of reaction. This can result in certain
shapes or preserve concentration gradients in the droplet, leading to highly functional
Janus particles, that is, particles with different properties on opposite sides. First, we
consider a simple case where free radical polymerization is used as a method for con-
verting monomer precursor solutions into solids. The monomer solution should in-
clude initiator molecules. Initiation can be triggered by temperature, photons or an
appropriate chemical reaction. The rate of change of a typical free radical polymer
product is given by
dCP /dt = k󸀠 C1M C1/2
I , (14.6)
where k󸀠 is the effective rate constant, with contributions from rates for chain prop-
agation, decomposition, and termination, and CP , CM , and CI are the concentrations
of the product, monomer and initiator species, respectively. Photopolymerization, ini-
tiated using a photoinitiator, is typically used because relatively low thermal energy
is added to the system and dosages can be well-regulated, as well as spatially con-
strained, in order to confine the reaction to designated locations. Monomer droplets,
linear thread phases or films can be exposed to photons of the proper wavelength, re-
sulting in polymerization at the rate given by equation (14.6). Rapid polymerization
may be preferable in order to suppress coalescence due to collisions between unsolid-
ified droplets, in which case high concentrations or intense illumination is helpful. In
cases where the device is not transparent in the spectral window required for photoini-
tiation (usually in UV), other means of initiation can be undertaken such as chemical
initiators. Section 6.2 reviews examples of biomaterials for cell encapsulation which
involve particle solidification via redox polymerization and gelation.
14.4.8 Scale up: a circuit analysis of microfluidic flow in a highly

parallelized microreactor
In order to produce micromaterials at industrially relevant quantities, the throughput

of MF synthesis should be increased to kilograms per day or higher. Unlike scale-up
procedures in bulk reactors, MF reactors cannot change their dimensions. Therefore,
the preferred approach is to “number up” microreactors; that is to introduce many par-
allel reactors with a common inlet and outlet [86–88]. This approach avoids the itera-
tive process of batch reaction scale-up which requires continuous re-optimization due
to changes in reaction conditions affected by reactor volume. However, there are chal-
lenges in the numbering up approach. A set of design rules has been determined to
prevent flow redirection to neighboring reactor channels [88]. First, it is critical to en-
sure that all parallel reactor channel dimensions are identical. This minimizes differ-
ences in hydrodynamic resistance, enabling uniform flow rates in each parallel reac-
tor. We take this opportunity to introduce the electrical circuit analog to MF systems.
Consider an electrical circuit with three parallel resistors (Fig. 14.9) [89, 90]. Using
Ohm’s law (V = iR), the current through each parallel path can be determined from
the equations i1 = Vi /R1 , i2 = Vi /R2 , i3 = Vi /R3 , if the applied voltage at the branching
point (Vi ) and the electrical resistance of each parallel path (R1 , R2 , R3 ) are known. In
addition, we can invoke tools such as conservation of charge (iT = i1 + i2 + i3 ). Simi-
larly, the flow rate of a liquid through parallel MF paths can be determined using the
Hagen-Poiseuille law (dp = QRH ) to solve the flow rate through different parallel paths
given knowledge of the applied pressure at the branching point (pi ), and the hydro-
dynamic resistance of each parallel path (RH1 , RH2 , RH3 ). In addition, we can invoke
conservation of mass (QT = Q1 + Q2 + Q3 ).
The hydrodynamic resistance of a single channel is given by:
8μL
RH = (14.7a)
πR4
12μL
RH = h
, (14.7b)
wh3 (1 − 0.63 ⋅ w
)
where the dimensions of the channels are given by the radius (R) for circular chan-
nels, and w and h for rectangular channels. In either case, L is the channel length
and μ is the liquid viscosity. Since the hydrodynamic resistance is very sensitive to the
cross-sectional dimensions of the channel, the first rule to numbering up for parallel
synthesis is to ensure that all parallel microchannels are fabricated with high fidelity.
This is very difficult to achieve with micromachining techniques, and therefore repli-
cate molding is preferable.
As discussed in Section 4.4, the design of an emulsification device includes the
intersection of two or more channels, thereby increasing the complexity of modeling
and the possibility of destabilizing events. Figure 14.9(c) illustrates a paralyzed sys-
tem with T-intersection points in each parallel reactor. As discussed, the formation of
emulsions results in well-defined variations in pressure with the production of each
droplet from each emulsification compartment. This can result in repeated pressure
spikes with frequencies in the kHz range emanating from each emulsion point. This
causes “cross-talk” throughout the rest of the fluidic circuit and results in a compli-
cated superposition of pressure spikes, ultimately increasing droplet polydispersity.
Therefore, the second rule to numbering up for parallel synthesis involves decoupling
liquid streams from each other by increasing the hydrodynamic resistance of both the
monomer and continuous stream phases prior to emulsification. In Fig. 14.9(c) the
hydrodynamic resistances of the channel segment between the upstream branching
R1 i1 RH1
Q1
R2 QT RH2 QT
iT i2 iT pi po
Q2
Vi Vo
RH3
R3 i3
Q3
(a) (b)
RH1a RH1b
p1
RH2a RH2b
pi p2 po
RH3a RH3b
p3
(c)
Fig. 14.9. (a) A parallel circuit diagram modeling the fluidic circuit of a parallelized MF device. Elec-
trical current iT is supplied to the inlet side of the circuit (left) and is split into i1 , i2 , i3 over 3 parallel
branches. Current flow due to a driving voltage, which is the difference between Vi and Vo , and is
applied against resistances R1 , R2 , and R3 in each parallel arm. Conservation of charge implies that
i1 + i2 + i3 = iT , and that electrical current flowing into the circuit must flow out. Outlet voltage
(Vo ) can be calculated using iT in Ohm’s law, and by reducing the parallel resistor to a single equiv-
alent resistance using 1/Req = 1/R1 + 1/R2 + 1/R3 . (b) Fluidic circuit with three parallel arms with
hydrodynamic resistances of RH1 , RH2 , and RH3 . Total flow rate QT is supplied to the channels by an
external pressure differential (not shown) and is split into flow rates Q1 , Q2 , and Q3 , through 3 three
parallel branches due to the pressure differential between pi and po . Conservation of mass implies
that Q1 + Q2 + Q3 = QT , and that flow rate into and out of this segment of the fluidic circuit are the
same. Outlet voltage (Vo ) can be calculated using QT in Hagen-Poiseuille law and by reducing the
parallel hydraulic resistance to a single equivalent resistance using 1/Qeq = 1/Q1 + 1/Q2 + 1/Q3 .
(c) Parallel microemulsification units featuring the dispersed phase (gray) intersecting the continu-
ous phase (white) in a T-junction geometry. Not shown are the resistance values associated with the
common inlet and outlet sections in (a), (b), and (c).
point and the emulsification points in the continuous-phase streams are denoted by
RH1a , RH2a , and RH3a . Not shown, but equally important to consider, are the hydrody-
namic resistances of the segments between the branching point and the T-junction in
the monomer-phase channels.
In cases where a channel becomes blocked or its dimensions are significantly
changed due to material deposition on the channel walls, a monolithic reactor will
have to be completely de-commissioned for cleaning or replacement. Therefore, the
third rule involves a strategy to implement modular synthesis platforms so that mal-
functioning components can be removed without impacting the rest of the system.
Using pressure-driven flow, it is possible to disconnect one module while the others
continue to operate.
Figure 14.10 shows a multiple module MF (M3 ) system fabricated in PDMS [88].
Emulsification in this system is accomplished using flow focusing geometry
(Fig. 14.10(a)). Each module (Fig. 14.10(b)) contains 16 separate flow focusing devices
and the entire system is comprised of 8 separate modules. A module consists of a reac-
tor level and a manifold level. The possibility of droplet coalescence must be avoided
before the monomer droplets become sufficiently polymerized. Therefore, the fourth
design rule requires that (a) monomer emulsions be quickly polymerized after forma-
tion, and that (b) the recombination points are designed to prevent droplet/droplet
interaction. Figure 14.10(c) shows the M3 system used in photopolymerization mode,
whereby emulsified monomer droplets formed in all 8 modules are immediately irradi-
ated by UV light. Figure 14.10(d) shows that the formation of monomer droplets occurs
between them with well-defined spacing. This behavior continues into the first recom-
bination point (Fig. 14.10(e)), because the droplets and continuous-phase liquids do
not change their velocity after recombination. However, after the second (Fig. 14.10(f))
and third recombination points (Fig. 14.10(g)), the change in volume of the down-
stream channel causes a reduction in velocity and collisions can occur. This behavior
can be minimized by ensuring the sum of the cross-sectional area of all inlets and the
outlet at each recombination point is always the same. In addition, monomer droplets
should be immediately exposed to UV radiation (or another polymer initiation pro-
cess) after formation so that they are solidified before reaching convergence points,
yielding monodispersed particles (h). If solidification happens too slowly, or is initi-
ated off-chip, the particles will coalesce and be polydispersed (i).
14.5 Microfluidics for synthesis of functional nanoparticles
Nanoparticles (NPs) are an important emerging class of materials with applications in

medicine, optics, energy, electronics, sensing and consumer products. Their versatil-
ity is enhanced because of their very high surface area to volume ratio, meaning that
chemical modification of their surface can provide control over their properties. From
the perspective of drug delivery, changes to surface chemistry have been exploited to
target, prevent or control aggregation, and for drug release. NPs can also have core-
shell or porous architectures, which has been exploited as caches for drug payloads.
They are also used as sensitivity enhancement agents for vibrational spectroscopy and
for visualization using fluorescence and magnetic resonance imaging tools. One of the
reasons NPs have been slow to find commercial applications results from inconsistent
batch-to-batch properties and slow approaches to their characterization. As discussed
below, MF offer an exciting opportunity for high quality NP synthesis.
(a)
(a) (d) (e)
B
A a–1
B a–1
Droplet Polymerization
generator compartment a–2
(b)
Inlet A
(f) (g) a–1–2–3–4
Inlet B a–1–2
Outlet C
a–3–4
(c)
UV irradiation (h) (i)
Fig. 14.10. Schematics of a multiple modular MF (M3 ) reactor. (a) A single reactor comprising of flow
focusing emulsification and polymerization compartments. (b) A single module containing 16 indi-
vidual reactors described in (a) connected by liquid distribution manifolds. (c) The entire M3 reactor
consisting of 8 separate modules described in (b). (d) Monomer droplets immediately after genera-
tion from a single reactor. (e–g) Microscope images of droplets emerging from two, four, and eight
droplet generators respectively. (h) Particles are monodispersed following polymerization within
the M3 system. (i) Particles are polydispersed following polymerization off-chip. All scale bars are
500 mm. (d–i) reprinted with permission from [88].
14.5.1 Microfluidics for highly controlled nanoparticle synthesis
Synthesis of NPs with tunable, highly monodispered size distributions is critical due
to the tight correlation between NP size and function. In this respect, MF synthesis of
NPs is powerful due to the ability to precisely control reaction conditions and reaction
times [91, 92]. In addition, MF offer the opportunity for on-line characterization and
real time optimization [93]. Real-time optimization involves the control of synthesis
variables, in situ characterization, and real-time optimization algorithms. Readers are
directed to a very good overview of these concepts in the synthesis of CdSe NPs using
an automated MF system described extensively elsewhere [94]. Real-time optimiza-
tion can enable point-of-use synthesis of high quality NPs. This is a common goal in
the field because NPs are known to rapidly change their properties, leading to prob-
lems associated with centralized production/shipping models for NP manufacture.
For example, changes to surface charge can result in loss of colloidal stability and ag-
gregation. Therefore, fresh and locally synthesized NPs using a low cost MF synthesis
system would be highly advantageous. High quality inorganic NPs require rapid nu-
cleation and growth in well-specified reaction conditions. The reaction conditions in
bulk often suffer from temperature and concentration gradients, as well as from poorly
controlled reaction times compared to MF synthesis environments [95–97]. As seen in
Fig. 14.11, the stronger control of the reaction environment in MF channels can result
in NPs with well-defined sizes and absorption properties and the ability to tune their
properties by changing the reaction time [98].
In addition to addressing these problems, MF have been used to synthesize high
quality inorganic NPs and inorganic core-shell NPs (e.g., CdS, and CdS/CdSe) in an
aqueous solution by implementing on-chip quenching steps with millisecond time
resolution by the addition of reagents at different locations downstream of the initial
point of mixing [99]. This process generated NPs with well-defined optical properties.
In the same work, the authors addressed the problem of NP aggregation on micro-
channel walls by conducting synthesis in water plugs, which were shielded from the
hydrophobic PDMS walls by a thin layer of non-polar continuous-phase liquid as dis-
cussed in Section 4.3.
Disadvantages of NP synthesis in MF channels include limited solvent compatibil-
ities and temperature resistance for polymer fabrication materials. However, silicon,
glass and ceramic devices can extend the range of compatible chemical reaction en-
vironments for MF synthesis.
14.6 Biomaterials
Increasingly, microscale biomaterials are servicing sophisticated life-science and

technology applications including tissue engineering, drug delivery, and even energy
production. Microfluidic platforms have been demonstrated to be efficient for both
1.0 16
On chip 3 min
Normalized
fluorescence
Absorbance
0.8 12
Benchtop 10 min
0.6
8 20 min
0.4
0.2 4
0.0 0
250 300 350 400 450 500 420 470 520 570 620 670 720
λ(nm) λ (nm)
(a) (b)
Fig. 14.11. Improvements in NP products using MF synthesis. (a) Sharp vs. broad absorption peak, in
MF and bulk synthesis, respectively. (b) Precise timing of reaction for MF synthesis enables excel-
lent tunabilty of NP optical properties. Reprinted with permission from [98].
the synthesis and study of highly functional biomaterials. They are also natural plat-
forms for the development of miniaturized devices. With the help of MF technology
and other peripheral tools, researchers have been able to precisely determine bioma-
terial properties such as chemical composition, mechanical properties, physical di-
mensions, and porosity, to name a few. In this section we review some areas where
MF is poised to make important advances in the synthesis of functional microscale
biomaterials.
14.6.1 Tissue engineering and membranes
Tissue engineering is an area where MFs is anticipated to make important impacts.

For example, the growth of biologically relevant membranes has been demonstrated
due to the ability to form stable chemical gradients. Researchers have mixed chitosan
with a low pH aqueous solution which protonated amide groups, thereby enhancing
the polarity of the molecule, rendering it soluble (Fig. 14.12) [85]. The chitosan solution
was then passed through an “X channel”, where it co-flowed beside another aqueous
solution of high pH. The absence of turbulence in the microchannel supported a very
sharp liquid/liquid interface, where a strong pH gradient was established. The chi-
tosan molecules became insoluble after deprotonation in this region. Selective pre-
cipitation at this location caused the growth of a film. The thickness of the film grew
reproducibly from microns in size to nearly 100 μm in 10 minutes and could there-
fore be controlled. Furthermore, the semi-permeable membranes featured pore sizes
in the nm range, similar to the size of antibodies. In another study, an electrochemi-
cally generated OH− concentration near a cathode resulted in chitosan film deposition
at the cathode/solution interface within an MF device [100–102]. The device enabled
studies which resolved the electrogelling mechanism of chitosan, helped to determine
the dominant factors driving deposition, and characterized the density distribution
within the resulting hydrogel. Other work using MF-based devices for chitosan depo-
sition have investigated factors affecting chemical adhesion of chitosan and strategies
for its modification. Further studies using mass transport control in 3D tissue cultures
have been made with the MF platform giving precise control of the Péclet number (ra-
tio of convective to diffusive transport) over a range of nearly five orders of magni-
tude [103].
The ability to synthesize tissue membranes and reproduce critical functionality
using MF has resulted in a wave of advancements in tissue engineering. For example,
an MF model of the human lung was demonstrated for the study of cellular response
to foreign particles and pathogenic bacteria (Section 6.4) [104, 105]. The tissue model
consisted of a membrane formed from a synthetic elastomeric film patterned with an
array of oversized (15 μm) pores, onto which cells were cultured. The model introduced
2D pulmonary tissue stretching as an approximation of the 3D stretching motion in the
human lung. Using this model, it was determined that tissue stretching was critical in
Low pH, soluble High pH, insoluble

+
OH HO NH3 pKa=6.3 OH HO NH2
O O O O
O O + 2n H+
O O
HO +NH3 OH HO NH 2 OH
n n
(a)
Chitosan (pH=5)
Chitosan
pH=6.3 Aperture
Membrane
Buffer
Buffer (pH=10)
(b) (c)
Fig. 14.12. (a) Schematic for the conversion of chitosan from water-soluble to water-insoluble using
a pH responsive system. (b) Close-up and 3D views of the pH gradient area where the membrane is
formed. Reprinted with permission from [85].
replicating NP crossings into the blood stream observed in animal models, while en-
abling easier characterization and reducing ethical concerns regarding this type of
study. Other examples of the synthesis of in vitro tissue models with organ-level func-
tionality include blood vessels [106–108], muscles [109], bones [110], airways [111],
liver tissue [112–114], brain components [115, 116], the gut [117, 118], kidneys [119, 120],
and others [121, 122].
Complementary to tissue engineering, real biological samples can be extracted
from the body and integrated into an MF platform in order to observe their behav-
ior under precise hydrodynamic conditions. For example, an MF device was devel-
oped with vacuum microchannels for on-chip fixation of mouse arterial segments. The
samples were cultured under a well-defined chemical environment and subjected to
a drug solution for contraction-expansion measurements (Fig. 14.13) [108]. This work
featured an impressive device design, which included on-chip temperature control,
pressure channels, and fully automated acquisition of up to ten dose sequences, which
were followed with real-time microscopic inspection of the changes to the physical di-
mensions of the arterial segment.
14.6.2 Microenvironments for encapsulated cells
Typically, cell cultures are conducted on two-dimensional surfaces within Petri dishes
or in multi-well plates. However, in their native environments, the majority of cells
are exposed to three-dimensional environments. The rise of MF as a platform for the
(a) (b) (c)
Fig. 14.13. An artery on a chip. (a) Artery segment, consisting of endothelial cells on the inner side,
and smooth muscle cells on the exterior. Pressurized flow stream is directed through the artery
(green). (b) Channel geometry in the vicinity of the artery. Yellow channels are vacuum channels
used for artery fixation and red channels supply the drug solution to the exterior wall of the artery
segment. (c) The entire planar MF device which enables microscopic inspection of the artery seg-
ment. Figure reprinted with permission from [108].
synthesis of three-dimensional microenvironments has been important in providing

enhanced control over forces imposed on cells, facilitating visualization, easing com-
bination or reconfiguration of the cell-laden droplets or hydrogels, and enabling the
control over transport of oxygen, nutrients, growth factors, and waste [123]. Cell en-
capsulation by aqueous droplets in a non-polar continuous phase (usually a mineral,
vegetable, or fluorinated oil) can be achieved using one of the MF channel geometries
discussed in Section 4.4. Encapsulation in hydrogels is advantageous because it offers
the possibility of transferring to an aqueous culture phase, in addition to the ability to
vary the chemical and physical properties of the substrate to mimic the natural micro-
environment. Chemical gelation consists of crosslinking and polymerization. This is
ideally not carried out using UV photoinitiation due to the stresses it places on the
cells. Other biomaterials used for encapsulation include synthetic and biopolymers.
Redox polymerization of synthetic polymers in mild conditions is a promising alterna-
tive to UV photoinitiated reactions. For example, yeast cell-laden droplets containing
low concentrations of glycerol decaacrylate and ethylene glycol diacrylate were trans-
formed into hydrogels due to the redox initiation from ammonium persulfate [124].
Compared to other chemical gelled approaches, this method resulted in cell viability
of 30% after overnight polymerization. Alternatively, non-synthetic biopolymers such
as proteins and polysaccharides have been used for MF cell encapsulation, because
they are biocompatible and can form gels under mild conditions. For example, the
polysaccharide alginate can achieve gelation via coordination of the carboxylic acid
groups with divalent ions such as Ca2+ . This is often accomplished by introducing the
droplets containing alginate into a solution of CaCl2 via a downstream channel. The
large diffusivity of the small cations results in rapid gelation and rapid increases in vis-
cosity. In order to prevent related problems, low concentration alginate solutions must
be used, which is not ideal. A solution to this problem is internal gelation, whereby
CaCO3 NPs are added to the alginate precursor droplets, which are triggered to dis-
solve and release Ca2+ by decreasing the pH of the surrounding solution [125]. This re-
sulted in better control over gelation when compared to external gelation, and in turn
resulted in a more narrow size distribution of hydrogels. Cell viability also increased
to nearly 75%, which was attributed, in part, to the buffering effect of the carbonate
ions. Agarose is another polysaccharide which has been used for on-chip encapsu-
lation. Agarose can be triggered to gel by reducing the temperature below 20°C, but
it can maintain its gelled state even when warmed to a physiological temperature of
37°C [126, 127]. Other polysaccharides which have been used for MF cell encapsulation
include pectin and chitosan. Proteins used for gelation include gelatin, which gels via
a cold-setting mechanism but maintains is gel form at 37°C. Puramatrix™ is a mixture
of 16 peptides which gel upon exposure to solutions containing salt. The MF synthe-
sis of Puramatrix™ gels containing bovine carotid artery endothelial cells displayed
excellent cell viability, with 93% of cells demonstrating growth and movement within
the gel.
One interesting potential application of cellular microenvironments has been the
effect of the mechanical properties of extracellular matrix on cells. The elastic mod-
ulus in tissues in the human body ranges from 0.1 kPa in the brain to 40 kPa in the
osteoid matrix, which can, for example, guide the differentiation of stem cells. A proof-
of-principle MF platform was developed which enabled the high-throughput synthesis
of nearly monodispersed microgels with elastic moduli ranging from 15 Pa to 520 Pa
and the loading of the microgels with murine embryonic stem cells, studied by mi-
croscopy. The study of intercellular effects through quorum sensing is another area
where MF can play a role. By controlling the relative flow rates of the cell-laden dis-
persed phase and the continuous-phase it is possible to control both the size of the
emulsified microenvironment and the number of cells it contains. It is not possible
to fully control cell loading, as this is a stochastic process, with loading being deter-
mined by Poisson statistics. Therefore, MF encapsulation in this manner can control
the average number of cells per droplet by varying the concentration of cells in the feed
supply or the size of the droplet. However, there will always be a statistical distribu-
tion in cell loading, necessitating post encapsulation fractionation, by flow cytometry,
for example.
14.6.3 Biofilms
Here we highlight a new area of functional biomaterial development: using cultured

biofilms in microchannels. Biofilm (BF) growth occurs due to the transformation of
nutrient molecules into biopolymer building blocks which can adhere to surfaces or
form free-standing structures. Biofilms are an aggregation of microbes living within
a self-produced protective matrix of natural polymers called an extracellular poly-
meric substance (EPS), which protects from detachment and against harsh chemical
environments. Many types of bacteria form BFs, and natural BFs are usually com-
prised of a community of bacteria as well as other life forms. The typical thickness
of a BF is between 10 and 1 000 μm, thus on the same scale as MF channels them-
selves. Biofilms are initiated in a microchannel by bacterial adhesion to the wall fol-
lowed by aggregation into colonies. After this aggregation, they begin to produce EPS
until the film forms a 3D structure in which the bacteria can live. Important factors
affecting the formation and proliferation of BFs are known to include hydrodynamic
shear force, temperature, nutrient concentration, and quorum sensing signals. The
ability to apply relevant external stimuli to an MF device while supporting advanced
characterization makes MF a promising tool for the study of BFs. For example, recently
flow-templated nutrient streams enabled micropatterening of BFs on a single microflu-
idic wall. Authors were able to isolate growth to a segment of the microchannel that
experienced uniform shear stress, thereby enabling well-specified growth conditions
and highly qualifiable growth kinetic measurements [62, 128]. Tools for studying BFs
in microchannels include optical methods, electrochemical measurements, and me-
chanical techniques [129–131]. The use of MF for the formation and long-term culture
of BF has been demonstrated in studies of BF properties such as Young’s modulus,
cell morphology, adhesion and proliferation, as well as diffusivity [132]. With a better
understanding and tools to control BF properties, the door is open for applications
including energy production, water remediation and catalysis.
14.6.4 Microdevices utilizing functional biomaterials
Microbial fuel cells

In addition to being an excellent platform for the study of biomaterials, MF serve as an
ideal format for miniaturized devices. To exemplify this application, we briefly con-
sider microbial fuel cells (MFCs), which have the potential of purifying waste water
while producing energy. Typical MFCs use BFs adhered to an electrode surface to cat-
alyze the breakdown of a broad range of molecules into an oxygen-deprived solution
via an oxidative pathway. The result is the generation of electrons, which flow out of
the MFC via the electrode. For example, as seen in Fig. 14.14, a molecule of sucrose
enters the BF and is oxidised by a bacteria, resulting in the generation of protons,
CO2 and electrons. The protons will travel to the cathode where they complete the
reaction by being reduced in the presence of O2 to form water. One of the main bene-
fits of an MF-based MFC is that the proton exchange membrane, which separates the
anolyte liquid from the catholyte liquid, is not necessary, since the diffusion-limited
environment in the microchannel strongly limits mixing [133]. Moreover, the ability
to cultivate, study, and optimize BFs for MFCs has been conducted by screening bac-
terial consortia [130]. Although some evidence points to the possibility of enhancing
electrical output by tuning the shear force applied to the BF, this effect needs to be
conducted in microchannels in order to be studied more carefully [134].
48e‒
48e‒
12O2 24H2O O2 saturated solution
C12H22O11 48H+ 12CO

2
Sucrose solution
48e‒
Fig. 14.14. Schematic of the critical components of a microfluidic MFC. A biofilm (brown) is attached
to an anode (cross-hatched). A sucrose molecule enters the biofilm from the solution phase and is
oxidized by a bacterium, producing electrons (which travel through an external circuit before enter-
ing the cathode), protons (which diffuse away from the anode toward the cathode and participate
in O2 reduction), and CO2 . The laminar flow environment results in the separation of the anolyte and
catholyte solutions without the need for a proton exchange membrane, thereby reducing internal
resistance.
Clinical diagnostics
Clinical diagnostics is one of the strongest drivers for MF development. Tissue devel-
opment using MF is inspiring new diagnostic tools which are inexpensive, robust, ac-
curate, and furthermore can improve clinical phase trials for new in vitro technolo-
gies. For example, rapid development of NP technology has been accompanied by en-
hanced production and utilization of new nanomaterials by industry, with relatively
little research into the effect on humans and other life forms. Nevertheless, the rapid
expansion of NP synthesis has resulted in the unprecedented – and rapidly growing –
exposure of workers and the general public to these new materials. The effect of NPs
on human health raises several important questions related to long-term storage and
toxicity. At the same time, NPs are being purposefully introduced to the body for new
medical purposes such as drug carriers, targeting, and imaging. In any case, rapid
clinical testing techniques for NPs are needed to keep pace with their development.
The corresponding control of the hydrodynamic environment of the confined flow en-
ables more realistic pre-clinical trials of NP functionality in the human body [135–137],
and can accelerate the clinical translation of NPs [98].
Typically, in vitro pre-clinical testing is conducted on cells cultured at the bot-
tom of a culture plate. The two-dimensional environment is static and leads to
gravitationally-driven NP sedimentation, resulting in tests far from in vivo conditions.
On the other hand, new MF-based in vitro platforms lead to strong control of cell cul-
ture environments which more closely mimic physiological geometries and organ-
level functionality. For example, Figure 15 shows the functional elements of a “lung-
on-a-chip”, which replicates the mechanical and cellular properties of the tissue that
separates the alveolar air space and blood capillaries in the lungs [104]. A porous
membrane was coated with an extracellular matrix material on which epithelial cells
were cultured on the air side and endothelium cells on the blood side. The resulting
membrane model was periodically stretched using two vacuum channels on either
side to replicate the regular mechanical strain experienced in vivo during breathing.
This platform was used to model the translocation of inhaled NPs across pulmonary
Epithelium Air
Endothelium Membrane
Nanoparticles
Side chambers Flow

(a) (b)
6
10% strain
No strain
5 Transwell
Gut Porous
% translocation
4 epithelium membrane
2
Vacuum Vacuum
1 chamber chamber
0
0 1 2 3 4
Time (hr)
(c) (d)
Fig. 14.15. Organs on chips. (a) Schematic of a “lung-on-a-chip” made of elastomeric material.
A tissue model was formed by suspending a thin porous elastomeric film across the channel which
was coated in situ by epithelial cells on the air side of the lung and endothelial cells on the blood
side. Two side chambers were periodically depressurized to induce lateral stretching motion.
(b) Image of an alveolar air space surrounded by blood capillaries containing red blood cells.
(c) Introduction of NPs to the epithelial layer causes response to the cell layers and NP translocation
into the bloodstream at a higher rate than for traditional membrane suspension multiwell plates or
MF platforms with static membranes. (d) A schematic for a gut-on-a-chip device with a porous mem-
brane coated with endothelium on both sides with similar capabilities. Figures (a) and (b) reprinted
with permission from [104]. Figures (c) and (d) reprinted with permission from [118].
tissue (Fig. 14.15). The dynamic stretching motion of membranes was a key feature
which resulted in higher NP translocation into the bloodstream and a stronger inflam-
matory response due to toxins. This key feature, along with realistic blood flow, is not
possible in static culture plate in vitro and can give a more realistic assessment of haz-
ards associated with exposure to airborne NPs. A similar platform has been developed
for a ‘gut-on-a-chip’, which mimics the intestinal wall, thereby enabling uptake of in-
gested NPs [118].
14.7 Summary
In this chapter a range of important issues regarding the synthesis of synthetic and
biological functional materials at the nano- and microscale using MFs have been re-
viewed. We began Section 2 with a categorization of different types of microreactors
and the materials and fabrication methods to make microreactors. In Section 3 we
discussed the special properties of liquids flowing through microchannels and how to
manipulate and monitor reaction solutions. In Section 4 we discussed how MFs can be
used to synthesize polymer particles, 1D threads and 2D microsurfaces. This discus-
sion included relevant concepts in MF channel geometries, their surface properties
and macroscopic properties of the precursor liquids. Section 5 discussed synthesis of
NPs in microchannels. Finally, Section 6 concluded with state-of-the-art applications
of MFs in the synthesis and study of microscale functional biomaterials, such as tis-
sue engineering, cellular microenvironments, and BFs. We finished the chapter with
two illustrative examples of miniaturized devices that use MF with functional bioma-
terial components: microscale microbial fuel cells and devices for clinical diagnostics
related to exposure to NP materials. This chapter covered many MF applications, as
well as a diverse range of practical issues regarding MFs.
Acknowledgments
JG thanks Ms Nahid Babaei Aznaveh for the image in Fig. 14.1(d) and Mr Mohamed
Larbi Gharib for the image in Fig. 14.8(a).
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15 Protein- and peptide-based materials: a source of
inspiration for innovation
15.1 Introduction
It is now widely recognized that, due to its pronounced and global footprint and its
excessive use of materials and energy resources, humanity is the cause of various en-
vironmental degradations (land degradation and biodiversity loss, climate change,
ocean acidification, water shortages, chemical pollution, etc.) which have reached a
point where they affect the functioning of the planetary system itself [1–5]. This sit-
uation requires drastic transformation of our socioeconomic system and way of life.
Integration of sustainability into human activities is thus one of the main challenges
humanity faces.
Although the required transformations are essentially sociological, political,
and economic, science and technology can greatly contribute to making societies
sustainable. There is henceforth an imperative need for novel useful products and
devices with a low ecological footprint, made of renewable raw materials, produced
by eco-friendly processes and totally recyclable and/or biodegradable. Besides these
attributes, products which also combine other attractive and useful properties such
as mechanical resistance, optical or electrical characteristics or biological activity are
also desired for applications in various fields.
Because evolution has solved several environmental and technological prob-
lems which humans need to address, nature is becoming a source of inspiration for
materials scientists. Living organisms exhibit a variety of organic and hybrid mate-
rials (composites) which are self-assembled and display complex hierarchical levels
of organization and miniaturization, and possess a broad diversity of functions and
properties [6, 7]. A renowned and classic hallmark of biomimicry is the remarkable
resistance and architecture of silicic skeletons of unicellular organisms (diatoms).
A second concerns silk, a micrometer-sized nanostructured material produced by
arthropods which exhibits a combination of strength and extensibility unmatched by
any industrial material.
In this context, proteins and peptides are promising building blocks for the man-
ufacture of materials, as they encompass in nature a broad variety of functions, struc-
tures, and properties. They have the ability to self-assemble into complex architec-
tures, respond to specific environmental stimuli, bind to specific receptors and ligands
or resist mechanical stresses [8]. Potential advantages of peptide- and protein-based
materials are as follows:
(i) Raw materials may be obtained in large amounts from renewable resources, either
from the biomass (or by-products) [9], or by using biotechnology (recombinant
DNA technology). The production of recombinant proteins in bacteria or other ex-
pression organisms indeed routinely yields reasonable quantities of proteins with
high purity, precise amino acid sequence, and a virtually monodisperse molecular
weight [8].
(ii) Polypeptides (proteins and peptides) are biodegradable or bioresorbable and po-
tentially biocompatible. For example, the RGD (arginine-glycine-aspartic acid)
motif, the cell-binding domain of fibronectin [10], is indeed commonly used to
mediate cell adhesion.
(iii) The natural solvent of polypeptides is water, and the processes underlying the
production of biological systems occur in mild temperature and pressure condi-
tions, which may potentially make it possible to avoid the use of harmful and en-
vironmentally costly organic solvents and physicochemical processes.
(iv) As proteins naturally exhibit diverse and hierarchical levels of organization,
a vast array of structures organized at different length scales can be considered,
thus providing design flexibility. By optimal design of the protein sequence and
through control of the aqueous environment, protein-based systems may be self-
assembled into hierarchically organized structures, while the process may be
directed and (reversibly) triggered upon application of controlled constraints
(smart materials).
(v) Proteins and peptides are naturally subjected to conformational change and their
reversible assembly/disassembly property provides the capacity to build “molec-
ular switches”, i.e., molecular systems which can be reversibly shifted between
two or more stable states in response to stimuli such as light, temperature or pH
changes.
(vi) Another strategy is the production of artificial or chimeric proteins and peptides
which contain specific chemical groups intended to fulfil particular functions
such as molecule recognition or cell growth, or that are made of a combination
of sequences originating from two or more natural proteins in order to integrate
and combine different specific properties.
(vii)Proteins can be processed in various colloidal and physical states such as films,
capsules, gels, emulsions, foams, porous systems, fibers, and non-woven fiber
mats. Therefore, many possibilities for harnessing the advantageous character-
istics of natural protein materials and systems exist.
The potential applications are thus widespread and may contribute to various sectors
of society, although medicine seems actually to be the main domain of applications.
For example, proteinous matrices can be developed for the effective encapsulation of
drugs or bioactive molecules and their delivery at the appropriate site of action, in par-
ticular in response to a specific stimulus. They can also be used as scaffolds for 3D cel-
lular growth, migration, and differentiation. These templates may find applications
15 Protein- and peptide-based materials: a source of inspiration for innovation | 417
in tissue engineering, tissue repair, implants, and wound healing. They may also be
useful for biomineralization, the process by which organic–inorganic hybrid materials
such as bones, teeth, and shells are constructed, allowing the production of innovative
material composites. Polypeptide molecules have great potential for the development
of biosensors, in particular for more efficient diagnostics. In the food industry, they
may be interesting for new packaging or for gastrointestinal delivery systems of nutri-
ents or bioactive molecules. They may also prove to be advantageous in the areas of
membrane filters, textiles, optical fibers, and in nanotechnology in general.
As can be seen, proteins and peptides may lead to useful and efficient functional
materials in the future. This chapter is devoted to a brief description of natural and
synthetic polypeptides, from peptides to globular and fibrous proteins, for the devel-
opment of functional materials. General principles and important areas of research
regarding polypeptide-based materials will be described, as well as their benefits and
future applications with the help of several examples. Necessary knowledge regarding
some protein characteristics will first be recalled.
15.2 Basics of proteins, peptides and polypeptides
Proteins exhibit different levels of structural organization called primary, secondary,

tertiary, and quaternary structures. This intrinsic characteristic makes polypeptide
molecules potentially interesting building blocks for the production of hierarchically
organized and stimuli-responsive materials.
15.2.1 Polypeptides are sequences of amino acids
Polypeptide is a generic term for molecules formed by a succession of amino acids.

It covers short peptides to large proteins and synthetic homopolypeptides. Peptides
are formed by anything from several to ∼ 50 amino acids, for a molecular weight of
1 to 5–6 kDa (1 Da = 1 g/mol). Proteins contain hundreds to thousands of amino acids.
They can be divided into three main families: globular, membrane, and fibrous pro-
teins. The first two are constituted of about 100–700 amino acids (10–80 kDa) and fulfil
biological functions such as enzymatic activity, catalysis, recognition, and transport
of ions or larger molecules. Fibrous proteins are very large biopolymers with a ba-
sic structural role in tissues and cells. Synthetic homopolypeptides exhibit the same
diversity as polymers [11] and encompass a large range of molecular weights, up to
∼ 300 000 kDa.
20 natural amino acids exist, all with different properties, such as steric hin-
drance, polarity, charge, hydrophobicity, etc. The polypeptide backbone is constituted
of a succession of peptide bonds, each carrying a specific chemical moiety called a
residue or side-chain. The composition and linear arrangement of the residues in the
chain form the so-called primary structure or sequence. It determines the folding and
association of the proteins, although the environment also strongly contributes to
these behaviors. As a matter of fact, intramolecular and intermolecular interactions
depend on pH, temperature, ionic strength, type of salt, solvents, presence of an in-
terface, etc. The diversity of amino acids makes the physicochemical properties of
proteins highly diversified.
15.2.2 Polypeptides can adopt various conformations
The sequence partly determines the chain conformation, also called secondary struc-
ture, in physiological or other conditions. It can be described by two rotational angles
around the C–N and C–C bonds, the dihedral angles, which define the angular orienta-
tion of the plane formed by the CONH amide groups. Due to steric hindrance, certain
secondary structures are more often encountered: α-helix, β-sheet, turns, 31 helix and
310 -helix (Fig. 15.1).
(a) (b) (c)
Fig. 15.1. Representation of typical secondary structures: (a) α-helix, (b) β-strand (middle), (c) and
31 -helix or PPII helix.
The α-helix is a widespread structural element, especially in membrane proteins. This

helix is right-handed, with 3.6 amino acid residues per turn, and a rise of 1.5 Å per
residue. It is stabilized by intramolecular H-bonds along the chain between the car-
bonyl oxygen atoms of ith residues with the amide hydrogen atoms of the (i + 4)th
residues [12].
The β-strand is also a very common secondary structure [13]. It is linear with a rise
of ∼ 3.3 Å per residue [12]. It most often associates with one or many β-strands to form
β-sheets. Two types of β-sheets exist: antiparallel β-sheets, where the two neighboring
chains are aligned in opposite directions, and parallel β-sheets, where the chains are
aligned in the same direction.
The 310 -helix is right-handed. It has three residues per turn and a translation of
2.0 Å along the helical axis. The N-H group of ith amino acids form an intramolecular
hydrogen bond with the C=O group of the (i + 3)th amino acid. There are 10 atoms in
the ring formed by the hydrogen bond [12].
The 31 -helix, or polyproline II (PPII) helix, is a left-handed helix, with three
residues per turn and a rise of ∼ 3.1 Å per residue [14]. Its dihedral angles are close
to those of the β-strand. It has no intramolecular H-bonds, but forms H-bonds with
water molecules, which appears to be important for structural stabilization [15]. This
secondary structure is present for only 2% of amino acids of protein sequences. How-
ever, more than half of the proteins contain at least one region of PPII helix which is
longer than three amino acids [13].
Due to the chemical structure of their side-chain, each amino acid has particu-
lar intrinsic propensities to form the regular secondary structures. Moreover, these
propensities are context-dependent, as they are affected by the environment (pH,
ionic strength, temperature, etc.) and by neighboring amino acids. Thus, the specific
conformation adopted by a given polypeptide depends on a complex combination of
various physicochemical parameters.
Polypeptide chain segments can lack structure. Some proteins can be even al-
most entirely unordered in their native state and are thus named “intrinsically un-
structured (or disordered) proteins” (IUP or IDP) or “natively disordered proteins”
(NDP). Despite their low level of order, these proteins can exhibit biological activity
[16–18]. IDPs are generally favored by a combination of high net charge and low hydro-
phobicity [19]. It is recognized that the PPII helix is frequently observed in this type of
proteins [14, 20], suggesting that they retain a certain amount of structural order.
15.2.3 Polypeptides possess various levels of structural organization
Tertiary structure, the third level of organization, refers to the spatial arrangement of
the secondary structure elements. The organization into secondary and tertiary struc-
tures constitutes the folding of the polypeptide chain. Due to the hydrophobic effect,
proteins generally tend to expose hydrophilic residues and to segregate apolar ones
from the aqueous solvent. For example, several β-sheets can arrange themselves to
form barrels with a hydrophobic pocket in the interior. Similarly, α-helices often ex-
hibit a distinct amphiphilicity which can promote their self-association and stabilize
the helical structure. α-Helix bundles and “coiled coils” constitute two examples of
such assemblies. In the latter case, two or three α-helices are intertwined such that the
hydrophobic surfaces are hidden from the aqueous phase [21]. The so-called leucine
zipper is a well-known sequence motif which forms a coiled coil [12]. Finally, a last
level of protein organization exists, the quaternary structure, which is related to the
reversible association of proteins into oligomeric forms (dimers, trimers, etc.) [12].
A distinctive mode of association, widespread among proteins, consists of the
self-aggregation of proteins. The microstructure of these aggregates can be very di-
verse, from well-ordered filaments (protofibrils (monofilaments), straight or rod-like
fibrils, worm-like fibrils and branched fibrils) to amorphous particles [22–26]. The com-
mon point of this phenomenon is the formation of ordered intermolecular β-sheets
between polypeptide chains. This β-aggregation can be used advantageously by na-
ture to form fibers such as silk, or it may lead to pathological outcomes as seen in
neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, type II di-
abetes, etc. These neurodegenerative disorders, also called amyloidoses, are charac-
terized by the presence of fibrils which form amyloid plaques in tissues. These fibrils
are constituted of the assembly of specific proteins into cross β-sheets stacked perpen-
dicularly to the main fibril axis. It has been realized that many proteins unrelated to
amyloid pathologies, if not all proteins, can associate and form cross-β fibrils if the
conditions are appropriate. The formation of amyloid fibrils thus appears to be an in-
trinsic property of proteins and peptides [27]. Consequently, this generic and intrinsic
aggregation propensity of polypeptides can be used to produce functional materials
as will be shown below.
15.3 Functional materials from fibrous proteins
Fibrous proteins are a broad family of high molecular weight proteins which play a
major role in the organ structure of many living organisms. They are constituted of
successions of repeat sequences rich in glycine and proline residues. These repeat se-
quences are often constituted of small well-defined motifs, which make the sequences
of fibrous proteins interesting candidates for the examination of the relationship be-
tween sequence and structure. Some general rules driving protein assembly are start-
ing to emerge thanks to studies in this field. Specific sequence motifs are known to
be involved in the formation of stiff β-sheets or deformable disordered structures [28].
Moreover, the content of proline and glycine residues seems to determine the exis-
tence of elastomeric properties of biological materials and the formation of amyloid
fibrils [29].
Each protein adopts a particular architecture in vivo. Collagen, a structural con-
stituent of bones and connective tissues such as skin, tendons, and ligaments, forms
triple PPII helices which associate and form fibrils [30]. Elastin, on the other hand,
is a rubber-like polymeric protein which exhibits large extensibility under mechani-
cal stress, and almost complete recoil recovery once the stress is removed. This pro-
tein can be found in tissues requiring strong elastic behavior such as arteries, lung
parenchyma, and ligaments [31]. Similarly, keratin makes coiled coils which assem-
ble to become filaments which form stiff structures like hair, feathers, and nails [32].
A last example is that of actin fibers, an intracellular protein which constitutes the
essential component of the contractile apparatus of muscle cells [30]. The diverse ex-
amples found in nature provide instruction on how to assemble proteins to innovative
functional systems. As it exceeds the scope of this chapter to cover all fibrous proteins
and properties, the focus will be devoted mainly to resilin/abductin, byssus, and silk,
and we will review some recent applications of these proteins as functional materials.
15.3.1 Resilin & abductin
Resilin and abductin, two elastic fibrous proteins similar to elastin, are found in the
joints of arthropods and hinges of bivalve molluscs. They play an essential role in
the abductor ligaments of animals whose physiology requires high strain as well as
storage of mechanical energy and its instantaneous and total recovery (the name re-
silin comes from high resilience, the percentage of recovery after a mechanical defor-
mation). These proteins form filaments and organize as tendons which act as elastic
springs against muscle contraction. Resilin, for instance, plays a role in the outstand-
ing jumping capabilities of froghoppers and cat fleas, the wing flapping of dragonflies,
and the membrane vibration (vocalization) of cicadas [33]. Abductin allows the swim-
ming scallop Placopecten magellanicus to move in water, thanks to the propulsion
created by the rapid and repetitive opening and closing of the shell [34].
The elasticity efficiency and long-term fatigue resistance of these proteins are re-
markable. Less than 5% of energy is lost by viscous processes during organ move-
ment [35]. They can extend and relax millions of times without structure alterations,
thus constituting almost perfect elastics. The primary structure of resilin and abductin
contains repeat motifs such as GGRPSDSYGAPGGGN and FGGMG sequences, respec-
tively. Resilin in particular is rich in tyrosine residues which associate in nature to form
di- and tri-tyrosine. Like disulfide bonds in rubber, the covalent bonds seem to play
the role of crosslinks in the resilin network.
These remarkable properties have attracted the interest of scientists attempt-
ing to produce new, elastic biomaterials. For example, a resilin-like protein called
pro-resilin, constituted of 17 copies of the putative elastic repeat motif GGRPSDSY-
GAPGGGN has been expressed in E. coli. Using a photochemical cross-linking process,
this protein allows the production of solid hydrogels, i.e., tridimensional cross-linked
self-supported networks in which water is immobilized. These gels exhibit an exten-
sibility of more than 300% and resilience superior to synthetic rubbers [36].
In order to take advantage of the properties of resilin, a modular recombinant
protein made of the same repeat motif and biologically active domain has been used
to produce cross-linked hydrogels and films. These materials allowed successful ad-
hesion and proliferation of viable cells and possessed good mechanical properties
(resilience of 90%) [37]. Tensile testing methods indeed indicate excellent resilience
(higher than 90%), while studies at frequencies close to human phonation indicated
elastic modulus values within the range of experimental mechanical performances
collected on excised porcine and human vocal fold tissues [38]. These materials may
thus have high interest for future medical applications, in particular in tissue regen-
eration such as blood vessels, cardiovascular tissues, and vocal folds.
15.3.2 Byssus (mussel anchoring threads)
The mussel holdfast, also known as “byssus”, is a biological fiber which has recently
attracted the attention of researchers for the conceptualization and design of renewed
biomimetic materials. Byssal threads present a unique combination of extensibility,
stiffness, and toughness only surpassed by silk [39].
Under environmental stress such as waves and water current, a mussel produces
a series of anchoring byssal threads through what is believed to be similar to an
injection-molding process. Indeed, this mollusk uses different glands to secrete a
mixture of proteins into the groove of a retractile organ called “foot”. The process
is repeated several times and results in a bundle of 20 to 60 threads, approximately
3 cm in length and 100 μm in diameter. The fibers are attached to the stem of the foot
and glued to a substrate, such as rocks or other mussels, by the plaque located at
the other end of the thread (Fig. 15.2). Between these two regions, the fiber is com-
posed of a corrugated elastic (proximal) portion as well as a smooth and stiffer (distal)
part (Fig. 15.2). A 2 to 5 μm thick layer of proteins covers the fibrillar core. Approxi-
mately 95% (dry weight) of the byssus is made of proteins, the rest being mainly
hexoses and inorganic content [40, 41].
Stem
Plaque
Proximal Distal
Core
Sheath
(a) (b)
Fig. 15.2. (a) Mussel dangling from another mussel shell using its byssus. (b) Scheme of the dif-
ferent parts of a byssal thread. The stem is linked to the animal. The corrugated proximal part is
extensible while the smooth distal part is stiff. The plaque anchors the threads to solid surfaces.
The insert illustrates the fibrous core of the thread, which is entirely covered by a thin sheath.
It is noteworthy to mention that byssus represents a mechanical mode of protection.

Indeed, although these sessile organisms are depleted of any anatomic parts which
may allow for easy displacement around the costal reefs, they can adhere easily and
strongly to almost any surface. Once anchored, it becomes very difficult to dislodge
the animal only by the lift and drag forces of the waves and tides. The glue, which
works underwater, is made of the so-called mussel foot proteins (mfps), which are in-
trinsic components of the plaque and the cuticle of the fiber. The mfps are rich in 3,4-
dihydroxyphenylalanine (DOPA), which contributes to the adhesion properties [42]

and self-healing behaviour of the thread [43] when subjected to elongation. DOPA is
believed to form complexes using coordination metals from the sea (e.g. Cu2+ , Zn2+ ,
Fe3+ ). The resulting metal coordinate acts as a sacrificial bond, thus sparing the co-
valent bonds from collapsing when submitted to external stress and promoting the
recovery of the initial mechanical properties when regenerated [43]. In addition, radi-
cal coupling through an oxidation mechanism can lead to di-DOPA cross-linking, fur-
ther increasing the mechanical performance. The radical generation of DOPA is also
believed to be involved in the adhesion mechanism of the mfps [44].
The core of the fiber also plays an important role in the self-healing behavior
and outstanding mechanical properties of byssus [40]. It is made up of a peculiar
arrangement of block copolymer-like proteins named preCols. As shown in Fig. 15.3,
these preCols are made of a central collagenous portion flanked by either elastin-like
(preCol-P), silk-like (preCol-D), or plant cell wall-like (preCol-NG) domains at both
ends, as determined by amino acid sequence homology [45]. The flanking domains
are followed by histidine- and DOPA-rich regions. The preCols are distributed in dif-
ferent ratios along the axis of the fiber. PreCol-P is mostly abundant in the proximal
region near the stem (first third of the fiber), while preCol-D occurrence gradually in-
creases from the stem to the plaque. The concentration of preCol-NG is constant along
the entire thread [46]. An atomic force microscopy (AFM) study of the byssus from
Mytilus galloprovinciallis confirmed the presence and arrangement of the preCols in
a 6 + 1 banana-like rod-shape [47]. The banana shape arises from the kinked central
collagen, as a result of an amino acid (generally glycine) deletion or exchange in the
canonical Gly-X-Y repeats found in the primary sequence. The bent, rod-like structures
finally assemble in a head-to-head tail-to-tail array in the core of the fiber via metal
cross-linking of adjacent histidine-rich domains [47].
Considering the high complexity and organization of the different proteins found
in the byssus, determination of the molecular structure of these fibers represents a
great challenge. Using 1D solid-state (SS-) NMR, FTIR, and x-ray diffraction studies,
Hagenau et al. demonstrated conformational differences between the proximal and
distal parts of the fiber [48]. Their results suggest that the distal region is well-oriented
and rich in β-sheet structures, while the proximal section is isotropic and rich in α-
helices. Using 2D 13 C solid-state NMR and 13 C-enriched byssus as well as chemical
shift prediction, Arnold et al. identified most of the amino acids found in the primary
sequences of the byssal proteins and determined the conformation in which they were
found [49, 50]. Additionally, FTIR spectromicroscopy of a fiber split through its long
axis revealed structural differences between the core and the sheath in the distal por-
tion of the byssus. A combination of 2D 13 C NMR and FTIR confirmed the presence
of the collagen triple helix, β-sheets (parallel and anti-parallel), and of β-turns struc-
tures in the core of the fiber. Moreover, unordered structure was found to be the major
conformation in the cuticle. These studies progressively led to a more in-depth under-
standing of the molecular structure of the entire fiber assembly.
Flanking domains
Histidine-rich
domains
Collagen domain
Top View
6 + 1 preCol bundle
Side view
Fig. 15.3. Representation of preCol units and their arrangement in a 6 + 1 banana-like bundle (side
and top view). All preCols are made of a kinked collagen portion flanked by elastin-like (preCol-P),
silk-like (preCol-D) or plant cell wall-like (preCol-NG) domains and terminated by histidine-rich
regions.
Byssus is currently a waste product of the mussel farming industry. To give an idea of
the scale of the loss, about 200 tons of byssus were discarded across Canada in 2010
prior to mussel commercialization [51]. Because of the known biocompatibility and
high occurrence of collagen in mammals, materials scientists are trying to take advan-
tage of this protein for various applications. The byssus preCols constitute a new type
of collagen waiting to be exploited. Despite the potential biocompatibility associated
with the protein content and the global interest in underwater adhesives, materials
scientists have so far failed to efficiently extract any byssal protein for the preparation
of new materials. The main reason is the complexity of the protein content relative to
its high degree of cross-linking. Therefore, the ability to recycle byssus for collagen
extraction would be a commercial asset for both the biotechnological industry and
mussel farmers.
Fibers have been prepared by drawing solutions of purified rod-like preCols ex-
tracted from the mussel foot [52]. It was demonstrated that preCols tend to spon-
taneously self-assemble into higher order structures, i.e., banana rods. Since the
drawing process cannot be compared to injection-molding, it was suggested that self-
assembly might be regulated by a predisposition of the preCols to form an anisotropic
liquid-crystalline (meso)phase when submitted to stress. In that specific case, being
able to extract or produce a large amount of these block copolymer-like proteins could
be a very efficient way of preparing self-assembling and potentially biocompatible
collagen-based oriented structures.
The self-healing behavior and DOPA-related chemistry of the byssus inspired
researchers in the development of functional materials designed for coatings or adhe-
sives. For example, polyethylene glycol (PEG) based dendrimers were functionalized
using either DOPA or histidine as chain-end moieties [53–55]. The gelation properties
of the resulting materials depend on both the presence of metals and pH conditions
during chelation. Gelation of histidine-based polymers was shown to be efficient in
the presence of divalent cations (Zn2+ , Cu2+ , Co2+ , Ni2+ ) at a pH where histidines are
completely deprotonated (pH ≥ 7). The strength and self-healing properties of the
gels were linked to the relaxation rate of the bonds between the metals and the his-
tidines [55]. For the PEG-DOPA polymer, Fe3+ was specifically used as cross-linking
metal, and the mechanical properties were compared to oxidation-induced cross-
linking (covalent bonding through radical coupling). Higher pH (8 to 12) led to a more
rigid cross-linked gel, with elastic moduli nearly matching the covalently cross-linked
material. This was attributable to the formation of tris-cathecol-Fe3+ complexes, sim-
ilar to those found within the mfps, constituting the cuticle of the byssus [53]. The
major difference between the two sets of gels was the self-healing behavior. When
submitted to shear stress until physical rupture, the PEG-DOPA-Fe3+ gels recovered
their elastic modulus and cohesiveness within minutes, whereas the covalently cross-
linked gels did not.
The last application covered in this section is the production of synthetic mussel
adhesive mimicking materials. Wilker et al. synthesized different poly[(3,4-dihydroxy-
styrene-co-styrene] to better understand the relationship between the number of pen-
dant groups (i.e., catechol) and the adhesion performance of the material [56]. The
catechol-functionalized polymer was submitted to periodate (IO4 )− oxidation to pro-
duce radicals. This reaction enhanced the adhesive properties of the polymer, but also
produced cross-linking within the bulk material (between two cathecol groups). It was
found that a molar ratio of 33% catechol and 67% styrene in the presence of periodate
was optimal for adhesion. A higher content of pendant catechol groups gave rise to
too much effective cross-linking in the polymer, thus increasing cohesion within the
bulk material at the expense of surface attachment. The types of substrate to which
adhesives were applied were also investigated and benchmarked against commercial
glues. The adhesive performance of the biomimetic polymer was found to be compa-
rable and, in some cases, better than commercial products made from cyanoacrylate
or epoxy.
Even though the investigation of mussel mimicking synthetic polymers only be-
gan very recently, these studies provide good insight into how byssal thread attach-
ment and mechanical properties are modulated in their environment. Moreover, these
materials offer promising applications in wet and dry conditions where there is a need
for adhesion or tunable mechanical properties with self-healing behavior, such as ma-
terial coatings or glues.
15.3.3 Silk
Besides the fascination with spiders, the popularity of silk is mainly due to the strik-
ing tensile properties of the spider dragline fiber which is as strong as steel and five
times more resistant than Kevlar [57, 58]. These peculiar properties result from an ex-
cellent combination of high strength and extensibility. The cocoon silk of the domestic
silkworm Bombyx mori (B. mori) is also a remarkable material, although more brittle.
It is an “old” material which has been used for centuries by humans on a large scale
as a textile fiber and suture material. It has the advantage of being available in large
amounts from sericulture, while farming is not viable for spiders due to their territorial
and cannibalistic nature.
Silk actually includes a wide diversity of structures and properties. By definition,
silk is a proteinous fiber excreted by arthropods such as moths, acarids, butterflies,
bees, spiders, etc. Each type of silk is produced by specialized labial or abdominal
glands and is made of one or multiple specific protein(s). For example, orb-weaving
spiders can produce six types of silk, each with a specific biological function and
adapted properties.
The major ampullate (MA) glands produce the dragline silk which is used as life-
line, web radii, and frame. The flagelliform (Flag) glands produce the thread used to
make the spiral of the web in which prey is caught. This fiber has low tensile strength
and a very high failure strain (extensibility), so that its overall toughness is close to
that of dragline silk [58].
Another example is provided by aciniform silk, which allows spiders to wrap their
prey. This fiber exhibits an even better compromise between strength and extensibil-
ity than MA silk, providing greater toughness [59]. Overall, silk in general and spider
silk in particular, exhibits very diverse properties. Thus, from a fundamental point
of view, silk represents an attractive system to investigate structure-function relation-
ships and, from an application point of view, suggests that the mechanical proper-
ties of silk-inspired biomaterials could be tuned to be adapted to specific applications
by designing the appropriate proteins and applying adequate physicochemical pro-
cesses.
The properties of biological materials are totally determined by their structure at
all length scales. A typical model of silk fiber is shown in Fig. 15.4. This structure is rep-
resentative of a family of silk fibers, including MA silk and cocoon silk from B. mori.
It is composed of highly oriented nanocrystalline β-sheets dispersed within an amor-
phous matrix constituted of more or less disordered polypeptide chains (random seg-
ments, turns, 31 -helices). As a first approximation, the stiff β-sheets are responsible
for the strength of the fiber, whereas the unordered domains would be at the origin of
its extensibility.
The β-sheets of MA silk are formed by 4–7 amino acid-long polyalanine stretches
[60], whereas more disordered segments are constituted of small glycine-rich motifs
such as GGX (where X, Q, Y, L or R) or GPGQQ and GPGGY. For B. mori, the β-sheets
are basically formed by GAGAGS motifs, the rest of the amino acids being involved in
disordered domains [61, 62].
Other spider silk fibers do not correspond to this scheme. The wrapping silk of
the spider Nephila clavipes (N. clavipes), for example, is marked by a mixture of mod-
Nephila clavipes MaSp1 AAAAAA GGAGQ GGY GGL GGQ GAGQ GGY GGL GSQ GAGR GGL GGQ GAG
Major ampullate
(spider) MaSp2 SAAAAAAAAS GPGQQ GPGGY GPGQQ GPGGY GPGQQ GLSGPG
Bombyx mori Heavy GAGAGSGAAS(GAGAGS)n GAGAGYGAGVGAGYGAGYGAGAGAGY

(silkworm) chain
Fig. 15.4. A schematized model of the structure of the MA fiber of the spider N. clavipes and the
cocoon fiber of B. mori with the protein consensus repeat sequences. MA silk is composed of two
proteins called MaSpI and MaSpII, whereas the main component of B. mori silk is called the heavy
chain. The dark blue amino acids are involved in β-sheets, the light blue ones in disordered struc-
tures.
erately oriented β-sheets and α-helices, and distributed within more disordered re-
gions (Fig. 15.5) [63]. Finally, the core fiber of the spiral of N. clavipes is constituted
of almost randomly oriented proteins with a very heterogeneous and disordered sec-
ondary structure (Fig. 15.5), although a very low amount (about 7%) of slightly oriented
β-sheets has been detected [64].
Aciniform, piriform
Flagelliform
Fig. 15.5. Other typical models of silk structures produced by the spider N. clavipes.
However, for other spider species such as Araneus diadematus and Argiope aurentia,
Flag silk exhibits a significant amount of moderately oriented β-sheets. A relation-
ship seems to exist between the proportion of β-sheets and the failure stresses and
strains. A similar function-structure relationship appears to exist with the level of ori-
entation of these β-sheets [64]. It was found that these structural elements are made
up of a sequence segment called “spacer”, thus clarifying the role of this amino acid
segment in the organization of Flag silk [64]. Overall, the results show that the same
type of silk can exhibit differences between species, which emphasizes the potential
of biomimetic silk to fulfil desirable properties.
One of the main incentives for the use of silk is to capitalize on its mechanical
properties and ability to produce different materials with various shapes, states, and
textures. After dissolution in water or in an organic solvent, silk can indeed be repro-
cessed into various types of matrices including hydrogels, films, foams, non-woven
fiber mats, capsules, and spheres [28, 65]. Due to the complexity in the production of
large amounts of spider silk proteins, the most advanced applications are currently
based on B. mori silk proteins.
B. mori fibers still arouse interest in the textile sector, especially for new proper-
ties (dyeing and grating of polymers), and for efficient suture applications, in partic-
ular regarding biocompatibility and immunogenicity [28]. Silk protein may be mod-
ified chemically to provide biocompatible coating for the surface of these systems,
for example to impart coagulant activity or to promote cell adhesion and growth [28].
Various silk-based systems have successfully been used in vitro to support cell devel-
opment, induce biomineralization, and control drug delivery [28, 65–68].
More specific 3D microperiodic scaffolds (square lattices, web-like circular lat-
tices) have been prepared by direct ink printing (Fig. 15.6). The ink consisted of a silk
fibroin solution from B. mori deposited in layers through a fine deposition nozzle to
produce under mild ambient conditions a 3D array of filaments of 5 μm diameter. This
precisely controlled architecture allowed the adhesion and growth of bone marrow-
derived stem cells and resulted in chondrogenic differentiation, an important charac-
ter for the development of cartilage [69].
Wireless passive food sensors have been produced using B. mori silk. They con-
sist of a microfabricated antenna or an array of antennae/resonators made of gold
deposited on a silk substrate. These radio frequency identification (RFID)-like silk tag
sensors are flexible and adapt to the non-planar shape of fruits or vegetables [70].
The response of these antennae is affected by the dielectric properties of the object
to be probed. Their resonant responses were successfully tested during the ripening
process to assess the potential for monitoring changes due to food spoilage. Further
applications are envisaged for human health and environmental quality monitoring.
Silkworm silk also exhibits interesting optical properties. Thanks to surface
nanopatterning, a technology for fabricating defined structures on surfaces at a
nanometer scale, optically transparent silk protein materials have been developed
to form bioactive devices for optical diffractive applications such as diffraction grat-
ings, pattern generators, and lenses [71] via the control of β-sheet crystallinity. The
“direct ink writing” method has been used to produce optical waveguides, which
offers new possibilities for creating biophotonic elements that can be readily doped
or functionalized with biologically active agents [72]. Recently, the pristine spider
dragline silk fiber has been tested as an optical fiber [73]. In this experiment, light
is transmitted in a straight or bent filament. The fiber can also be integrated into
a photonic chip made of polymer microstructures fabricated by UV-lithography,
leading to efficient micro-optical coupling between silk and synthetic optical struc-
tures [73].
(a) (b)
200μm
(c) (d)
200μm 2μm
Fig. 15.6. (a) Schematic representation of 3D direct ink writing method using a silk fibroin solution.
Typical 3D structures obtained: (b) square lattice and (c) circular web. (d) Magnified image of direct
write silk fiber. Reprinted with permission from [69].
15.4 Functional materials from globular proteins
The production of protein-based materials can rely on two strategies: the first one con-
sists of the engineering of natural proteins and the second is based on the design of
synthetic ones.
15.4.1 Natural proteins
As discussed previously for byssus, the use of biomass constituents to make innova-
tive and functional materials may represent an interesting method of valorizing waste
by-products. For example, whey is a milk by-product of the cheese industry. Its main
component is β-lactoglobulin (β-lg), a small water-soluble protein of 164 amino acids

which exists in the dimeric form. Under particular treatments, this protein exhibits
technofunctional properties, including the ability to stabilize interfaces such as emul-
sions and foams, or a gelation capacity.
Gelation of β-lg can be achieved by heating. Increasing temperature to ∼ 75°C in-
duces the protein unfolding (denaturation), i.e., the breakage of intramolecular bonds
which stabilize the native globular structure. As a result of unfolding, hydrophobic
moieties initially buried inside the native structure are exposed, leading proteins to
aggregate, the particles or fibers formed being rich in β-structures. If the concentra-
tion is sufficiently high, a gel can be obtained.
Interestingly, β-lg can generate two types of gels depending on pH [22, 25]. Elas-
tic and transparent gels are formed near the isoelectric point of the protein, i.e., be-
tween pH 4 and 6, whereas stiff and opaque gels occur for low electrostatic repul-
sions. The former gels are constituted of fine filamentous strands (fine-stranded gels),
whereas the latter are made of coarse, roughly spherical particles and have a lower
water-holding capacity (particulate gels). These differences can be accounted for by
the different amplitude of the electrostatic interactions depending on pH.
Another procedure for forming gels consists of the application of a pre-denatura-
tion step consisting of moderate heating of a protein solution, followed by cold gela-
tion induced by the addition of a divalent cation such as Ca2+ or Fe2+ . Depending on
the cation concentration, fine-stranded or particulate gels can be generated. Capital-
izing on such matrices to develop new encapsulation materials for nutrients, the gel
structure appears to influence the extent of iron release in vitro in gastrointestinal con-
ditions [74].
Taking further advantage of this method, an emulsification-cold gelation proce-
dure has been developed to make edible beads [75] or microspheres [76], intended for
effective and selective delivery of bioactive agents such as retinol to the site of action.
According to in vitro studies, these beads are not susceptible to enzymatic attack dur-
ing rapid transit of the stomach (gastroresistant) and form good matrices to protect
fat-soluble bioactive molecules for specific absorption in the intestine.
15.4.2 Artificial proteins
Artificial proteins offer different advantages to natural ones, as they allow control of
the amino acid composition (non-natural amino acids [32], hydrophobic-hydrophilic
pattern) and secondary structure [77]. Many artificial (chimeric) proteins have been
inspired by fibrous proteins [66, 78–81], but other developments have been influenced
by globular proteins.
In nature, the function of some exogenous polypeptides is to self-assemble
into pores on biological membranes and function as transporters, toxins, ion chan-
nels, and antibiotics. Trying to mimic nature, the design of protein-based stimuli-
responsive pores in membranes is a very active field of research. The control of gating,
the ability of pores or channels to open and close in response to a stimulus, may poten-
tially lead to applications such as sensors and drug controlled release. One strategy in
this area consists of using existing pore-forming protein complexes such as α-hemo-
lysin. This protein is a 293-amino-acid which naturally forms heptameric pores in
lipid bilayers. Using genetic engineering and chemical modifications, biochemical,
chemical, and physical stresses can trigger or switch on and off α-hemolysin pore-
forming activity [82, 83]. Furthermore, activation of the pore can also be reversibly
mediated by light by grafting an azobenzene group onto the protein which undergoes
a reversible trans-cis isomerization by illumination with UV-visible light (Fig. 15.7)
[82, 84].
MAL-AZO-QA
O O
H
H N N N
N N
N O
O O
N
O 380nm
N
500nm HN
O
N
~17Å H O
N+ ~10Å
N
+
(a)
N
N
S N S
N
Out +
+
380nm K+
500nm
In
(b)
Fig. 15.7. Principle of a light-activated pore based on α-hemolysin. A mutant of the protein with a
cysteine residue at position 422 is grafted through a disulfide bond with the molecule MAL-AZO-QA.
This “gate” consists of a maleimide (MAL) group, an azobenzene (AZO) group and a quaternary am-
monium (QA) group. The azobenzene isomerizes from the trans to the cis configuration with light,
which shortens the molecule by 7 Å, opens the pore and allows ion transfer. The reverse transition
for pore closing is triggered at another wavelength. Reprinted with permission from [84].
Another strategy is based on the capacity of proteins to undergo conformational

change from folded to unfolded conformations (molecular switches). Inspired by
works on polymer brushes, IDPs have been grafted to porous polymer membranes.
When the protein is unfolded, the pores are closed due to the extended and interpen-
etrating conformation of the chains, whereas upon protein folding, the pores open.
This simple switching mechanism, induced by change in pH or ionic strength, allows
the selective transfer of molecules through the pores [8, 85, 86].
Recombinant DNA methods have also been used to create artificial proteins which
undergo reversible gelation in response to changes in pH or temperature. An exam-
ple is given by a protein composed of two terminal leucine zipper domains flanking
a central, flexible, water-soluble segment [87]. The assembly of the terminal domains
into coiled-coil structures at neutral pH leads to the formation of a three-dimensional
network, with the central segment retaining solvent and preventing complete precip-
itation of the chains. Dissociation of the coiled-coil assemblies through elevation of
pH or temperature causes the return to the solution state. The control of gel forma-
tion (near-neutral pH and near-ambient temperature) suggests that these switchable
hydrogels have potential applications in encapsulation or controlled release of bio-
active molecules.
15.5 Functional materials from synthetic peptides
Control of material organization at the nanoscale is crucial for the development of

functional materials, and peptides can be rationally designed to fulfill this aim. Short
peptides have several advantages, such as control of the self-assembly process, nu-
merous possible final structures, various textures and forms of the final materials,
ease of synthesis by solid-phase synthesis, and potential for large scale production,
as already demonstrated for aspartame [88].
Previous work has shown, for example, that binary patterning of polar and non-
polar amino acids arranged with periodicity can direct protein sequences to form fib-
rils resembling amyloids [89]. This type of patterned sequence seems to have been
disfavored by evolutionary selection [90, 91]. A strategy based on this pattern has
been used to develop peptides that self-assemble in a reversible manner [92], suggest-
ing that assembly is dictated by thermodynamic stability and not by kinetic trapping.
The same strategy with a template-directed method has been used to form left-handed
helical ribbons [93] or to direct the assembly of peptides into β-sheets with a three-fold
symmetry [94].
The propensity of polypeptides to aggregate into amyloid cross-β fibrils has been
exploited to serve as a template to generate metal nanowires [95]. The peptide is
a diphenylalanine that forms typical amyloid fibrils with a hollow tubular structure.
Upon incorporation into the solution, ionic silver settles within the tubes. After sub-
sequent reduction with citric acid to form metal silver, and after enzymatic degrada-
tion of the peptide backbone, discrete nanowires are produced with a long persistence
length. Generally speaking, the literature shows that the design of biomaterials based
on peptide amyloid fibrils appears as a widespread strategy [96, 97].
For twenty years, various peptides have been engineered to produce diverse small
building blocks which can self-assemble into hierarchical structures with potential
relevant applications, especially in the biomedical area [21, 98–100]. Pioneering works
in this field use alternation of natural L- and non-natural D-amino acid enantiomers to
form ring-shaped cyclic peptides which stack one-dimensionally, via an antiparallel
β-sheet-like arrangement, into hollow tubular structures nanometers long (Fig. 15.8)
[101, 102]. The alternation of L- and D- amino acids forces the residues to lie at the out-
side of the ring, leading to nanotubes with uniform internal diameters of typically 10 Å.
A peptide forming β-hairpin (two β-strands joined by a β-turn) has been designed
to assemble into fibrils, which ultimately forms a temperature-responsive gel [78, 103].
Interestingly, hydrogels prepared from enantiomeric mixtures of these β-hairpin pep-
tides exhibit synergistic, although unexplained, increase in rigidity compared to
gels prepared from pure peptide enantiomers [104]. In another series of studies, an
11 amino acid-long peptide has been shown to form a chiral rod-like unit as a β-sheet
nanotape. This unit can self-assemble into hierarchical organizations (Fig. 15.9) such
as helical tapes and, with increasing concentration, further associate into twisted
ribbons (double tapes), fibrils (twisted stacks of ribbons), and fibers (entwined fib-
rils) [105]. By controlling the charged amino acids in the design of this type of peptides,
transition from a nematic gel to an isotropic solution can be triggered by acidic or basic
pH conditions, or can be completely independent of pH [106].
Using peptides, one can form a vast array of structures, including nanofibers [99],
nanoropes, and nanofilaments [107]. Interestingly, surfactant-like peptides, i.e., with
two distinctive polar and apolar regions, have been shown to form nanotubes and
nanovesicles [108]. The design of peptides can also be rationalized using a library
of known sequences and functions. Using this approach, a rational combinatorial li-
brary based on the structural principles of known membrane-spanning β-sheets, has
allowed the design of a pore-forming β-sheet peptide. The chosen peptide exhibits
a pore-forming activity with a mechanism of action very similar to that of natural
pore-forming peptides. This peptide is characterized by aromatic residues at the lipid-
exposed interfacial positions and basic residues in the pore-lining portion of the se-
quence [109].
Hybrid peptide-amphiphiles can also be used to build soft materials, in partic-
ular scaffolds for cell growth. For example, peptides equipped with an alkyl chain
have been constructed to form cylindrical micelles which can be considered fibers
with lengths of up to several micrometers and nearly uniform diameters of 7–8 ±1 nm
(Fig. 15.10). Nanofiber formation transforms the liquid solution into three-dimensional
reversible gels. The amphiphile-peptide molecules also contain consecutive cysteine
residues which, when oxidized, form disulfide bonds to stabilize the self-assembled
structure. Depending on the amino acid composition, the assembly process can be
NH2 HO
O O H CH3 O O
N H
N O
D
O HN L L
NH
H3C CH3
D D
HN O
O NH
HO L L NH2
O HN O O
O NH
D D
H3C CH3
HN
L L N O
O D H
N N
Self-Assembly H
H2N O CH H O OH
3
O O
OH OH OH
HO HO HO
N N N N N N
R N R
N N N N N
O HO H HO
H OH O OH
O O O
H HO H HO H HO
N N N N N N
R R
N N N N N N
HO O H HO O H H O OH
OH OH OH
HO HO HO
N N N N N N
R N R
N N N N N
O HO HO
H OH OH OH
O O O
H HO H HO H HO
N N N N N N
R R
N N N N N N
HO O H HO OH H O OH
Fig. 15.8. Model of hierarchical assembly of a peptide based on the alternation of L- and D-amino
acid enantiomers. This peptide forms a ring-shaped structure which stacks one-dimensionally, via
an antiparallel β-sheet-like hydrogen bonded arrangement, into hollow tubules nanometers long.
triggered by a change in pH, addition of divalent cations [110], or control of electro-

static interactions between polypeptides [111].
Some functionalized moieties can also be added to the peptide. For example, the
acidic amino acids aspartic acid and phosphorylated serine (phosphoserine) were
specifically used in the above peptides since they are abundant in the proteins of min-
eralized tissues such as bones and are known to initiate hydroxyapatite (HA) crystal
growth [112]. As a matter of fact, at the lowest level of their hierarchical organiza-
tion bones are formed by the self-assembly of collagen triple helices with HA crys-
(c’) (d’) (e’) (f’)
htape hribbon hfibril
(a)
Ɛtape
Ɛfibril
Ɛfibre
Ɛribbon
Rod-like monomer
Ɛtrans
b2 a
bI
Monomer Tape Ribbon Fibril Fibre
(b) (c) (d) (e) (f)
Concentration
Fig. 15.9. Model of hierarchical assembly of a chiral rod-like β-sheet nanotape. This unit can self-
assemble into helical tape, twisted ribbons (double tapes), fibrils (twisted stacks of ribbons), and
fibers (entwined fibrils). Reprinted with permission from [105].
tals grown within these fibrils. Incorporating phosphoserine residue into the peptide
sequence allows the fiber to display a phosphorylated surface able to direct miner-
alization of HA in which the c axes of the crystals are mainly aligned with the long
axes of the fibers, similar to what is observed in collagen fibrils of bones [112]. This
biomimetic strategy was thus successful in forming a nanostructured composite, with
potential use in bone tissue engineering.
15.6 Summary
Peptide- and protein-based materials offer numerous potential advantages in various

and also possibly unanticipated application fields. Their ability to change conforma-
tion and self-assemble paves the way for the fabrication of stimuli-controlled, nano-
structured, and hierarchically organized functionalized materials. Various strategies
may be adopted: from natural proteins and peptides to artificial and de novo ones. The
polypeptide world exhibits such a diversity and richness that it undoubtedly consti-
tutes a fertile ground for innovation in the field of sustainable functional materials.
2 O
HO P OH
SH SH O
O O O O O O
H H H H H H
N N N N N N N N N N N
OH
O H O H O H O H O H O O
SH SH
NH OH
3
1 NH
H2N
(a) 5
(b)
(c)
Fig. 15.10. (a) Chemical structure of the peptide-amphiphile with its key structural features. Part 1 is
an alkyl chain which provides the molecule with a hydrophobic character, the rest of the molecule
being hydrophilic. Part 2 is a four cysteine residue motif which polymerizes through disulfide bonds
when oxidized, in order to stabilize the final self-assembled structure. Part 3 is a linker made of
three glycine residues which provides some flexibility to the hydrophilic head group. Part 4 is a sin-
gle phosphorylated serine residue whose role is to interact with calcium ions and then help mineral-
ization of hydroxyapatite. Part 5 represents the cell adhesion binding site RGD. (b) Molecular model
of the peptide-amphiphile to highlight the overall conical shape of the molecule. (c) Schematic
showing the self-assembly of PA molecules into a cylindrical micelle. Reprinted with permission
from [112].
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16 Nanocomposite coatings
16.1 Introduction
This chapter will review the techniques for synthesis and characterization of coat-
ings containing nanoparticles for various substrates (i.e., nanocoatings and bio-based
nanocoatings). The discussion will focus mainly on coatings developed for wood sub-
strates, although coatings can also be applied to other types of substrates requiring
functional surface properties. There are several terms to describe different types of
coatings: stains, varnishes, paints, lacquers, and glazes. Here we will use the general
term coating and adapt the specific terms to address specific situations. This chapter
will introduce some aspects of the chemistry and physics of coatings reinforced with
nanoparticles. There is a large variety of coatings for wood and one can categorize
them as a function of their chemical, physical, and optical properties (Figs. 16.1, 16.2).
According to the formulation, these can be water-based or solvent-borne, high solid
contents, UV-cured or even powders. Considering a particular application, they can
be designed for exterior or interior use; they can also be transparent or opaque and
can incorporate several combinations of these characteristics. The main objective of
coatings incorporating nanoparticles reinforcement is better resistance to wear, UV
degradation and water ingress, all of which must be done without affecting visual
characteristics such as brilliance, color and transparency. The starting hypothesis is
that nanoparticles, when combined with existing coating formulation, may display
improved performance when compared to a similar coating containing microparticles.
Overall, the global coatings market is estimated at 30 million tons per year and is
worth about 120 billion US dollars [1]. Any additive which makes an inroad into this
huge market and very competitive environment is thus very welcome. Moreover, tech-
nology in this field is changing rapidly due to market and environmental pressures. In
recent years there has been significant emphasis on the development of water-based
and so-called ‘green’ formulations and coatings [1]. There is, especially in Europe, a
massive shift towards waterborne coatings, as they are perceived as environmentally
friendly. This is even further encouraged by government regulations related to issues
such as volatile organic compound (VOC) emissions [2].
In the field of thermoplastic composites, nanoparticle additives have been the
subject of active research for many years, whereas this is a rather new avenue for coat-
ings. Due to their relatively low thickness (around 30 microns), paints and coatings
are not thought of as composites, even in the presence of filler microparticles such
as pigments. Pigments may reinforce the coatings, but their main intended contribu-
tions are opacity and UV-absorption functions, properties for which they are designed
in the first place.
Fig. 16.1. Parquet floor with Al2 O3 UV-cured coatings resistant to wear and scratching.
Fig. 16.2. Building with UV-resistant coatings (Maibec Inc., Québec, Canada).
Wood surface characteristics
Wood is a porous, hydrophilic, and anisotropic material which is widely used because
of its availability in a great variety of species and surface textures (grain), elegant ap-
pearance, and ease of processing. It is by far the most widely used biosourced material
in the world. It is eco-friendly, is an efficient carbon sink and comes from a renewable
resource. Most wood products, except those used for structural purposes, are coated
during processing for protection against humidity and wear. Wood is especially sensi-
tive to ultraviolet light (UV) degradation, as one of its main polymeric constituents is
lignin, an unsaturated molecule which readily absorbs light in the UV range, resulting
in its degradation. In its natural configuration, wood is shielded and protected from
such degradation by the layer of bark surrounding the soft core of the tree. When used
indoors, wood must also be protected against wear by a protective coating, especially
when used in flooring applications. Coatings are usually more hydrophobic than the
wood itself. Initial roughness of the substrate, even after careful sanding, is in the
sub-millimeter (<mm) range, while the roughness of the coating once dried, is found
in the nanometer (nm) range. The coating in a liquid state will therefore penetrate the
porous structure of wood through wicking and will reticulate upon drying, thus im-
parting adhesion of the coating to the substrate. The thickness of this boundary layer
can be variable, while the dried coating is usually about 30–60 microns (μm) thick.
Most solid additives are surface-treated to enhance dispersion and avoid aggre-
gation, and since coatings are usually hydrophobic, many additives are treated to
present hydrophilic properties. The scientific literature on nanocomposite coatings is
not very abundant, although a few interesting reports have recently been published.
Bauer and Mehnert [3] worked on UV-cured acrylate coatings incorporating nanosil-
icate reinforcement. These coatings were shown to cure through very rapid radical
polymerization initiated by UV light, and are nowadays widely used. In this study, the
surface of the nanosilicate particles was treated with trialkoxysilanes to enhance ad-
hesion in the continuous phase. With respect to neat coatings, increase in hardness,
resistance to scratch and abrasion, as well as good optical properties were reported.
Allen et al. reported on the addition of nanometric TiO2 particles to acrylic coatings,
resulting in increased UV-light stability over time [4]. Fufa et al. [5] and Weinert et al.
[6] used ZnO nanoparticles in an organic matrix to enhance weather resistance of var-
ious formulations.
Appearance of coatings
In Fig. 16.3, one can see the thickness of a coating relative to the total thickness of
a wood surface. As previously mentioned, coatings are usually 30–60 μm thick, and
some substrates may have as much as five to ten layers of coatings displaying various
properties, usually starting with a stain or primer, followed by multiple paint layers
and finished with a topcoat consisting of a tough lacquer or varnish. Several charac-
terization assays can be done on the coating, regardless of the substrate of interest.
The interpenetration zone can be found between the coating and the substrate, where
the coating, while in the liquid state, diffuses in the substrate, and where the adhesion
mechanism takes place. This interphase zone can be as thick as 30 μm for a wooden
substrate. In Fig. 16.3, the particular structure of wood consisting of cells of about
30 μm in diameter can be seen, comprising an empty space called the lumen and the
cell wall. When wood is cut and processed through a sanding step, some of these cells
are damaged. The liquid coating can thus penetrate the structure for a few μm, cure
and better adhere to the surface. It is, however, improbable that it will penetrate the
cell wall itself, which is made up of a dense array of cellulose and lignin molecules.
0009 15KV X250 100Nm WD24 0066 15KV X250 100Nm WD23
(a) (b)
Fig. 16.3. SEM micrographs (250× magnification) of (a) a pristine, and (b) an artificially aged coating
(acrylic stain without nanoparticles) [7].
16.2 Coating formulations
16.2.1 Chemical components
Generally, the chemical mixture of an uncured paint or varnish is called a formula-

tion. This formulation is comprised of multiple constituents, each contributing to the
specific properties desired for the dried coating. In order to understand the chemical
composition of a coating, a list of components for a typical UV-cured aqueous coating
formulation (excluding water) follows [2, 8, 9]:
1. The binder is the main element of a paint formulation. It gives the coating its prin-
cipal physicochemical characteristics. Once cured and dried, the binder forms a
continuous dry film which adheres to the substrate. It is often a mix of reactive
oligomers, having urethane or acrylic reactive sites.
O
CH2
O
O
H2C
O
Fig. 16.4. Example of a reactive monomer in UV-cured coatings: 1,6-hexanediol diacrylate.

2. An antifoaming agent, usually a liquid with low surface tension, insoluble in the
medium into which it is introduced and with a positive spreading coefficient.
3. A surfactant, lowering the surface tension of aqueous formulations and fostering
better spreading of the formulation onto the substrate.
4. A dispersant, used to distribute the pigment evenly (for example TiO2 , Al2 O3 and
others) and nanoparticles (nanoclays, as aluminosilicates) simultaneously.
5. A photoinitiator, an essential element for a UV-curing formulation. This chemi-
cal, which initiates the radical polymerization reaction by absorbing ultraviolet
incident light, can be a phosphine, a ketone or a benzophenone.
O
OH
C
Fig. 16.5. Example of a photoinitiator: an α-hydroxyketone
6. A rheological agent (thickener), introduced in order to adjust the viscosity of the

aqueous UV-formulation.
7. A pigment (if the coating is opaque) such as titanium oxide (TiO2 ), which is well-
known for white pigmentation. In the cured formulation called a film, it can reach
a concentration of approximately 30% (dry weight), giving an opacity of 80%
which is usually sufficient for complete opacity requirements. For outdoor appli-
cations, the role of the pigment, for example zinc oxide, is to absorb UV light,
thereby protecting the substrate and paint against wear and degradation.
8. A film strengthening agent to which various nanoparticles can be added, such as
alumina or nanocrystalline cellulose (CNC), up to 10% in weight for a dry film.
This amount is restricted for rheological reasons in order to avoid high viscosity
due to nanoparticle content.
All of these components have to be added in a definite order and quantity, and usually
require strong agitation. The formulation has to remain stable without phase separa-
tion over a reasonable period of time for obvious practical reasons.
16.2.2 Mixing techniques
For nanocomposite coatings, the final morphology is dependent on both the mixing
technique and the equipment used. High levels of shear are required, while making
sure the temperature of the formulation remains low and constant. The addition of
nanoparticles, even at concentrations as low as 1% (in final cured coating), can in-
crease viscosity noticeably [10].
2 μm 2 μm
(a) (b)
2 μm 2 μm
(c) (d)
Fig. 16.6. Transmission electron microscopy images of the formulation prepared with 10%wt of
nanoclay by (a) three-roll milling, (b) bead milling, (c) ball milling, and (d) high-speed mixing
(bar = 50 nm) [9].
Figure 16.6 shows different qualities of nanoclay dispersions, achieved with four dif-
ferent types of mixers for the same formulation. It has been shown that a three-roll
milling process, followed by bead milling, leads to the best dispersion of nanoclays
[9, 11, 12]. This can be explained by the gap between the rollers which can be opti-
mized, leading to high shear throughout the formulation. One should be aware that
it might be difficult to find appropriate equipment for laboratory scale setup, since
most mixers are designed for factory requirements. This hinders research by requir-
ing industrial size formulations, as well as problems cleaning the equipment while
switching formulations. Component mixing is usually performed following a precise
procedure, and the results obtained may vary depending on the type of mixer, which
can be a conventional paddle agitator, a high speed mixer (similar to a household
blender) or a roller mixer. While mixing, the role of the antifoaming agent is to prevent
the formation of large bubbles, which otherwise could interfere with the film forming
abilities of the coating. Once the mixing process is over, the shelf life of the solution
must be characterized to determine the time required for the insoluble components of
the formulation to precipitate.
16.2.3 Application and curing
Another factor impacting on the final result of a coating is the application technique
and equipment used. Results can vary widely for the same formulation, depending on
the technique used for application. Coatings may be sprayed if their viscosity is com-
patible with spraying equipment. This technique is especially suitable for irregular
or uneven, as well as large surfaces. Application with rollers or mechanical brushes
is usually appropriate for even and small surfaces. For example, a coating can be ap-
plied, dried, and then polymerized with high intensity UV light to tailor the properties
of the paint. As seen in Fig. 16.7, the samples are put on a conveyor belt and irradiated
with UV light in a closed chamber. For thicker coatings, this process can be repeated
several times.
Fig. 16.7. A semi-industrial UV-curing oven (AyotteTechno-gas, Québec, Canada).
16.3 Nanoparticle additives
Most paints contain microparticles, mostly to make them opaque, add color, or in the
case of transparent finishes such as those ones for flooring applications, to increase
wear resistance. Since these additives are ground prior to usage, a significant fraction
of these microparticles is actually nanoparticles. These nanoparticles may be added to
a formulation in powder form, which is often a source of problems since the aggregates
are difficult to break up. A better way to incorporate these nanoparticles is to have a
concentrated suspension or slurry of nanoparticles. Moreover, the nanoparticles can
be surface-treated to prevent such aggregation and foster better dispersion and ad-
hesion to continuous phase.
Nanoclays
Nanosize additives such as aluminosilicates, also known as nanoclays, can be exfo-

liated to generate a nanothin layer which reinforces the coating (Fig. 16.6). In order
to achieve this functionality, the surface must be treated with cationic surfactants,
which adhere to the anionic nanoclay surface to make it hydrophobic [12], and hence
more dispersable. Examples of such surfactants are hexadecyltrimethylammonium
bromide (HDTMAB) and tetramethylammonium chloride (TMAC). These compounds
can be added to a concentrated aqueous suspension of nanoclay, and subsequently
washed to remove unreacted hydrophobic cationic surfactant [13]. The use of these
materials is more widespread than one might think: for instance cationically modified
cellulose materials are widely used as conditioners in formulations such as shampoos
and detergents.
H3C CH3
N+ Br– Fig. 16.8. Example of a cationic surfactant: a tetraalkyl
H3C CH3 ammonium bromide.
Inorganic oxides: titanium, aluminum and zinc oxides
Oxides are added to coating formulations to provide either resistance to UV degra-

dation [7, 14] or mechanical resistance to abrasion in applications such as flooring
[10, 12]. Oxides used in paints and coatings are: ZnO, TiO2 , SiO2 , and CeO2 , some of
which can be modified chemically, for instance with 3-aminopropyltriméthoxysilane,
to achieve better dispersion. Alternatively, dispersants such as polyacrylates may be
added to the formulation to achieve similar results. It is also possible to use organic
compounds which will act as UV absorbers, and ultrasound may also be used to en-
courage dispersion.
Organic compounds: nanocrystalline cellulose and carbon nanotubes
Cellulose, the most abundant organic polymer in the biosphere, is the main con-
stituent of wood and is a homopolysaccharide composed of β-1-4 glucopyranose units
[15, 16]. Each repeating unit of cellulose contains three hydroxyl (–OH) groups. These
hydroxyl groups and their ability to form hydrogen bonds play a major role in di-
recting the crystal packing and also governing the physical properties of cellulose.
In cellulosic plant fiber, cellulose is present in an amorphous state, but also associates
into crystalline domains through both intermolecular and intramolecular hydrogen
bonding [17, 18]. The characteristics of cellulose, including good mechanical proper-
ties, low density, biodegradability, and availability from renewable resources, have
become increasingly important in the context of sustainable development.
One of the promising new applications for cellulose is in nanotechnology as a

reinforcing material. As cellulose has a natural nanostructure, different methods
are used to benefit from this configuration, leading to various forms of nanocellu-
lose (namely nanocrystalline cellulose or cellulose nanocrystals (CNC), or in some
publications (NCC)) and microfibrillated cellulose (MFC). Cellulose fibrils consist of
different hierarchical microstructures commonly known as nanosized microfibrils.
These nanosized fibrils are comprised of a crystalline and an amorphous part, the
crystalline region being named nanocrystalline cellulose (CNC) or nanowhisker. In
comparison with MFC, CNC has received more attention and been the focus of more
intensive research.
0 4.01 μm 0 4.01 μm
Data type Height Data type Phase
Z range 15.00 nm Z range 100.0°
Fig. 16.9. Height and phase AFM images of unmodified CNCs [19].
CNC is obtained by the acid hydrolysis of cellulose under conditions where the amor-
phous regions are selectively hydrolyzed (Fig. 16.9). For wood-based CNC, the remain-
ing crystalline regions are 3–10 nm in diameter, 100–300 nm long and retain the natu-
ral cellulose I crystalline structure [20, 21]. Among its interesting characteristics, CNC
is abundant and renewable. It also exhibits low density in comparison to mineral
fillers (around 1.566 g cm−3 ), as well as a high form factor (about 70), a high specific
area of 150 m2 /g, a length of 50–500 nm and width of about 3–5 nm [21–23]. Although
neither as resistant to UV, nor as hard as the aforementioned metal oxides, these nano-
particles have several advantages. Displaying a tensile strength of about 8 GPa and
an elastic modulus in the transverse direction of about 110 GPa, there is an interest
in incorporating CNC into various polymer matrices to produce nanocomposites [24].
CNC has been shown to lead to remarkable reinforcing properties in polymer matrices
such as styrene-acrylate latex [25], starch [26], polyhydroxybutyrate octanoate [27],

and poly(ethylene oxide) [28]. In most cases, the reinforcing effect comes from the per-
colating network of CNC, together with good interfacial compatibility between matrix
and filler.
Cellulose fibers can be classified as hydrophilic because of their high hydroxyl
content (3 per anhydroglucose unit (AGU)). Therefore, when used as reinforcing fibers
in non-polar polymer matrices, the durability and mechanical performance of the re-
sulting composites are limited by poor fiber-matrix adhesion. Many studies currently
focus on the improvement of CNC dispersibility and compatibility in different solvents
or matrices, which is essential to the production of nanocomposites. However, most
nanoparticles are difficult to disperse and modify at the surface of a solvent due to
their high specific surface.
The experiences of various groups in dispersing CNC in water based adhesives
and coatings have shown that the hydrophilic nature of CNC can cause problems, es-
pecially when working with a polar matrix. The poor dispersibility of CNC when incor-
porated in large amounts results in a high degree of agglomeration, leading to the de-
terioration of the mechanical properties of adhesives and coatings. Besides the prob-
lem of incompatibility with polymer matrices, most conventional nanocelluloses are
characterized by hydrogen bonding-induced aggregation of their nanosized rod-like
and fibrillar structures. These strong hydrogen bonds prevent cellulose from melting,
dissolving, and being easily processed.
To provide CNC with ease of processability and extend its applications in nano-
composite coatings, its surface properties could be modified to inhibit self-aggregation
and improve dispersion, as well as interfacial adhesion in various coatings. Concur-
rently, the intrinsic structure of the nanocrystals (i.e., the original crystalline struc-
ture) should not be destroyed during CNC modification. There is a growing research
focus on the modification of CNC because of its increasing potential applications in
various technologies.
Chemical functionalization of CNC has been mainly conducted to (1) introduce
stable negative or positive electrostatic charges on the surface to obtain better dis-
persion (CNC obtained after sulfuric acid hydrolysis has labile sulfate moieties which
are readily removed under mild alkaline conditions), and to (2) tune its surface en-
ergy characteristics to improve compatibility, especially when used in conjunction
with nonpolar or hydrophobic matrices in nanocomposites. The main challenge for
the chemical functionalization of CNC is to conduct the process in such a way that
it only changes the surface, while preserving the original morphology to avoid any
polymorphic conversion and to maintain the integrity of the crystal.
A quick review of the literature demonstrates that the surface of CNC can be modi-
fied by different methods. For example, the modification of CNC by hexadecyltrimethy-
lammonium (HDTMA), a quaternary ammonium hydrophobic cation, leads to the ad-
dition of –CH2 , N–C and –CH3 groups to the surface (Fig. 16.10). This is a similar pro-
cess to the one used to intercalate and exfoliate nanoclays (as mentioned in this Sec-
iv
i 105.267 C2,3,5
ii 89.150 iii
iii 75.006
iv 72.050
v 65.471
C1
i
ii
v
C4 C6
250 200 150 100 50 0

(a)
i 105.382 iv
ii 89.220 iii
iii 75.181
iv 72.008
v 65.572
vi 31.024
i CH2
ii vi
v
N―C
CH3
250 200 150 100 50 0

(b)
Fig. 16.10. Solid-state NMR spectra of (a) unmodified CNC, and (b) CNC modified by hexadecyltri-
methylammonium (HDTMA) [29].
tion, 450), since this material has hydrophilic and anionic surface characteristics. A
study of the morphology of modified and unmodified CNC, performed using atomic
force microscopy (AFM), showed interesting results. As seen previously in Fig. 16.9,
the individual crystals can be seen in unmodified CNC. On the other hand, AFM im-
ages taken from re-dispersed, modified and dry-frozen CNC in water showed highly ag-
gregated CNCs, making it difficult to differentiate individual CNC crystals (Fig. 16.11).
This high level of aggregation is thought to be caused by the lack of surface charges
and hydrogen bonds leading to strong interactions between CNC particles. Precise di-
mensional measurements of CNC revealed that the modification did not change the
size of CNC particles (Fig. 16.12).
0 5.00 μm 0 5.00 μm
Data type Height Data type Phase
Z range 50.00 nm Z range 50.00°
58.001
Fig. 16.11. Height and phase AFM images of CNCs modified by hexadecyltrimethylammonium
(HDTMA) [19].
Fig. 16.12. Transmission electron microscope

100 nm micrograph of nanocrystalline cellulose.
16.4 Coating characterization
16.4.1 Mechanical properties
A great number of methods can be used to characterize coatings, and the use of a
particular method is usually related to an application of interest. For example, coat-
ings designed for outdoor use require resistance to hostile weather conditions, wa-
ter, humidity, UV light, and fungi, which must be characterized and quantified. This
can be done either in situ in natural outdoor settings, or in special accelerated weath-
ering chambers equipped with intense UV light and humidity control. For products
intended for indoor use, such as parquet floors, resistance to wear, scratching and
hardness must be measured. There are a large number of standard ASTM tests to as-
sess these parameters. The hardness of a coating film can be measured by monitoring
the damping time of a pendulum oscillation according to ASTM D4366 “Standard Test
Methods for Hardness of Organic Coatings by Pendulum Damping Tests”. As an exam-

ple, the following measurements of abrasion resistance can be combined with gloss
measurements: as the surface is abraded with a metal wool pad, the coating becomes
matt and loses its gloss. Addition of nano- and micro- alumina and silica in different
forms has the potential to increase gloss retention dramatically (Fig. 16.13).
Nanoalumina Nanosilicon
Nanometric alumina Predispersed nanoalumina
100%
90%
80%
Gloss retention at 60 °
70%
60%
50%
40%
30%
20%
10%
0%
Reference 0% 3% 5%
Weight percentage of reinforcing agent
Fig. 16.13. Gloss retention of coatings with added micro- and nanoparticles, after abrasion with
steel wool (modified from [30]).
Abrasion resistance can be determined with a Taber Rotary Platform Abraser™ , in

which mass loss can be measured after a specific number of rotations of abrasive paper
maintained with constant pressure on the coated surface, following the ASTM D4060
standard. The adhesion of a coating can be measured according to the ASTM D4541
standard, where an aluminum stub is glued to the coating surface and is pulled off us-
ing a standard protocol. If the coating is entirely pulled off with substrate fibers from
the surface clinging to it following the test, the coating has fulfilled the cohesive fail-
ure criterion. If no fibers are left on the surface and the stub remains smooth, then
the coating fails the adhesion criterion, resulting in adhesive failure. All these tests
for coatings can be performed after exposition to accelerated weathering following
a 400–2 000 h exposure to strong UV light, combined in some cases with humidity
and/or rain. Accelerated weathering tests can be done in a special chamber where the
samples are irradiated with UV-A light, (λ = 340 nm) with irradiance intensity in the
order of 0.35 W m−2 nm−1 , according to ASTM G155 and ASTM D6695 standards. In sev-
eral cases following this treatment it was found that the Tg of the coatings actually
increased and their mechanical resistance diminished as the coatings became brittle
due to weathering.
16.4.2 Optical properties
Optical properties such as color, gloss and haze can be measured according to ASTM
standards D523 and E430, with an instrument that simultaneously determines the
gloss at three different angles (20o , 60o , and 85o ), as well as the haze.
Color
To quantify the color of a coating, the CIE L*a*b* system is used in order to provide
standard values recognized worldwide. Using this method, a color is defined by a dot
located in a 3D plot (Figure 16.14), where the luminance (L*), varies from 0 (black)
to 100 (white), and where a* and b* refer to the two series of complementary colors,
respectively red–green and blue–yellow (Fig. 16.14).
With these three coordinates, any color can be reproduced in the CIE L*a*b*
referential. The measurement is usually done with a handheld meter according to
ASTM E1347 and D2244 (Fig. 16.15).
White
L=100
Yellow
90° b*
60
180° Hue(°) 0°
0
Green Red
–a* –60 85 60 a*
Chroma
270°
–60
Blue
–b*
Black
L=0
Fig. 16.14. The CIE L*a*b* color space (BYK-Gardner).

Fig. 16.15. Colorimeter (BYK-Gardner).
If one is looking for color uniformity or changes, any point within these coordinates
can be combined in an overall color index as:
ΔE = [(ΔL*)2 + (Δa*)2 + (Δb*)2 ]1/2 (16.1)
where the Δ values correspond to the absolute difference in the color and bright-
ness parameters. One should note that a ΔE of 5 or lower cannot be detected by the
human eye.
For instance, Fig. 16.16 shows an overall color change, ΔE, following accelerated
UV aging on a coating. There is a strong initial change in color followed by a slow
drift of the values measured, while the presence of nano-TiO2 increases color stability.
A typical accelerated aging apparatus is shown in Fig. 16.17.
2.5
A
B
2.0
1.5
ΔE*
1.0
0.5
0.0
0 200 400 600 800 1000
Aging time (h)
Fig. 16.16. Overall color change (ΔE) following up to 1 000 hours of accelerated UV aging treatment
in an acrylic-based waterborne solid-color opaque coating (curve A), and with the addition of nano-
TiO2 rutile (10 nm, curve B) [7].
Fig. 16.17. An example of an accelerated

UV aging system (Atlas Inc., USA).
Atomic force microscopy and surface roughness

Once sanded, wood has a typical roughness in the micron range. When a coating is
applied, this value falls about a thousandfold to the nanometer range, even with coat-
ing thicknesses as low as 30 microns (Fig. 16.18). This is important, since excessive
surface roughness can lead to deleterious optical effects such as loss of gloss. When
adding particles to the formulation, surface roughness is bound to increase and can
lead to light dispersion effects (Fig. 16.18).
30.0 nm
50.0 nm
0.0 nm
0.0 nm
10 μm 10 μm
8 8
6 6
4 4
2 2 2
4
6 2
4
8 6
10 μm 8
10 μm
(a) (b)
Fig. 16.18. AFM images of (a) a varnish without CNC, and (b) a varnish with 1.5% CNC.
16.4.3 X-ray imaging and particle aggregation
Several types of nanoparticles can be mixed into coating formulations. These are often
clays (Fig. 16.19) or oxides, as these have desirable properties such as specific colors,
UV absorption capabilities, and increased hardness. The quality of the dispersion can
be characterized by x-ray imaging with transmission electron spectroscopy. The nano-
particles can be surface-treated in order to facilitate dispersion, since dispersion of the
particles remains problematic, especially if the material is supplied in powder form,
encouraging the formation of aggregates.
Since CNC is an organic material, it is rather difficult to obtain good contrasts for
a coating in TEM images [9].
50 nm
Fig. 16.19. Presence of clay aggregates and single clay platelets (1% weight) in a formulation pre-
pared by bead milling (bar = 50 nm) [9].
16.4.4 Weathering and artificial aging
This is an important part of testing of coatings intended for outdoor use. All of the
tests and standards mentioned so far in this chapter can be carried out before and after
weathering and compared to investigate the durability of the coating. Generally, a loss
of properties and shift in colors can be observed after weathering. However, in some
cases, values of glass transition temperature (Tg ), modulus, and hardness of coatings
can actually increase after weathering, due to cross-linking of macromolecules within
the thickness of the coating. This increase happens at the expense of resistance to
impact and scratches: in other words, as it ages, the coating becomes more fragile
and displays glass-like properties.
However, a better method of testing a coating is one which reproduces realistic
service conditions. For that scenario, the samples are usually put outside in a sunny
location for months or even years at a time. The conditions needed are described in
European standards ISO 2810, EN 927-3, and ASTM D6763-08, among others. This pro-
cess is rather lengthy and efforts are being made to come up with techniques giving
faster results. There are artificial or accelerated aging techniques where the samples
are put into an environmental chamber-like device (Fig. 16.17) and subjected to intense
solar-like UV light emitted by a xenon lamp. Samples are usually submitted to these
conditions for about 2 000 hours, often mixed with cycles of water spray. This treat-
ment severely degrades unprotected samples and provides a rapid method of grading
a series of coatings in a relative fashion in order to select the most efficient, which may
then be subjected to expensive and lengthy supplementary tests. In addition, there are
other tests to quantify the performance of coatings in special environments such as
high humidity, where biofouling by fungi can be a concern, for example in bathrooms
and humid and damp climates.
16.5 Bio-based coatings
The term ‘bio-based coatings’ is intended to describe a formulation in which the chem-
icals used originate from biological products. However, it does not necessarily mean
that these formulations are eco-friendly, ecological and the like. It is easy, especially
in the marketing field, to mix terms such as recyclable, recycled, degradable, natu-
ral basis, renewable, eco-friendly, bio-, carbon sink and other catchy terms. Each one
of these descriptive terms refers to a specific set of properties. Perhaps a more use-
ful concept would be that of ‘sustainability’, which means exactly what it states. For
wood coatings, there is a long history of formulations going back as far as thousands
of years. Indeed, small industries such as cabinetmaking and ‘lutherie’ (the making
of string instruments) have developed excellent coatings, which have lasted literally
hundreds of years, for example for the famous Stradivarius violins. These were based
on natural products: linseed oil, soy, turpentine (solvent derived from pine trees),
glycerin, shellac, beeswax, rosins, and natural gums [31]. They were thus formulated
from natural bio-based products of agricultural origin or by-products from animal
sources, as synthetic chemicals derived from petroleum, coal, and gas appeared only
in the 20th century. These traditional coatings perform well indoors, but are slow to
cure and dry, are not resistant to moisture and UV light, and reliable sources for these
reagents are hard to find, especially for large volumes. Historically, the largest vol-
ume for traditional paints and varnishes were alkyd (oil-) types, based on fatty acids
such as linseed oil and its esters, and glycerin. There were very few water-based coat-
ings. The white pigment for many opaque coatings was often based on lead oxide,
which is not used nowadays due to its toxic nature. Most of the traditional paints and
varnishes were of the siccative type (oil-drying agent), based on bio-based unsatu-
rated fatty acids (termed alkyl or oil-based paints) and alcohols, which cure via an
oxidation-based free radical mechanism. Nowadays many coatings are of a different
nature, being water-based (emulsion), UV-cured or having a high solid content. There
are currently huge efforts to replace some of the synthetic chemicals used in these
formulations with bio-based ones, although they often require major modifications.
As seen in the preceding sections, one can add bio-based materials such as CNC to
coatings, but the main ingredient remains resin, which is usually petroleum-based.
Efforts are being made to develop bio-based resins such as acrylated vegetable oils
and their derivatives, e.g., epoxidized soybean oil as shown in the work of Rengasamy
et al [32]. There is still a debate as to whether soybean-based products should be clas-
sified as eco-friendly, since if they are to be used as chemical feedstock, this will also
put pressure on food prices. There are also reports of acrylated products derived from
epoxidized linseed oil, which could be of interest for similar applications [33, 34].
O
O
OH
O O
O
OH O
Fig. 16.20. Acrylated epoxidized
O fatty methyl ester [35].
Thus, for sustainable formulations, the main component of the resin constituents
should be obtained from natural sources. However, the main resin system of UV-
cured acrylates discussed in the preceding sections is a mixture of reactive monomers
and oligomers, thus containing very little solvents and therefore, little volatile organic
compounds (VOC). It remains to be seen whether bio-based materials can achieve the
same ease of formulation as their synthetic counterparts. It is also possible to incor-
porate sugar-based polymers into basic paint chemicals. Lactide-based polymers can
be incorporated into saturated polyesters and alkyl resins, thus lowering the carbon
footprint of the raw materials by as much as 27% [35]. Many coating systems already
contain cellulose-based materials, such as cellulose ethers as thickeners and cellulose
nitrates.
16.6 Future developments
Among the present and future incentives for the development of new coatings are en-
vironmental concerns and performance. Bio-based materials will play an increasing
role in paint and coating materials. The industry, especially in Europe, is incorporating
new concepts into its production practices, such as ‘cradle-to grave design’, sustain-
ability and carbon footprint. These practices are implemented for marketing reasons
and because they can lead to improved efficiency and product design, as seen for CNC
and bio-based coatings. While governments and industries are not about to regulate
the amounts of bio-based materials in formulations and products, they are rather ac-
tive on the VOC reduction front. Some coatings such as high solid content, UV-curing
and powder coatings already emit very little VOC. The French government has devel-
oped mandatory labeling for construction and decorative materials, enforced since
January 2012, which classifies emissions according to 10 key chemicals emitted by a
given material (Fig. 16.21).
Émission dans l’air intérieur
A+
Fig. 16.21. Example of French material labelling

A+ A B C
for VOC regulations.
Other existing procedures for monitoring VOC emissions are based on the ISO 16000
series. Similarly, LEED (Leadership in Energy and Environmental Design) is a US-
based rating system for sustainable buildings. It sets limits on VOC emissions for
coatings, among other things. There are also other improvements on the horizon:
superhydrophobic coatings and self-cleaning coatings are being developed. Although
they involve nanotechnologies, they currently do not involve bio-based products
per se. There is also a large amount of concern about nanoparticles regarding toxicity
issues. While unmodified CNC is deemed safe, there is a regulatory vacuum regarding
the toxicity of other nanoparticles [36].
16.7 Summary
The technical literature is replete with thermoplastic nanocomposites, but as far as

coatings are concerned, it is a rather new field. Coatings can be improved with the use
of such technologies, but several issues will have to be addressed such as formulation
stability, dispersion, cost effectiveness, chemical safety and long term performance of
nanocoatings.
Acknowledgments
The authors acknowledge the financial support from Fonds de Recherches du Québec
en Nature et Technologies (FRQNT), Arboranano and FPInnovations.
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Index
α-NaFeO2 , 185 Biosynthetic polymers, 282

Activated carbon, 180, 182, 183 Block copolymers, 65, 67, 70, 73, 82
Additive, 443 Bones, 291, 305
Adsorption, 241 Breast implant, 311
– absolute adsorption isotherm, 244
– adatom, 241, 243 Calcination, 68, 73, 78
– adsorbate, 242 Capacitance, 173, 175, 176, 180, 183
– adsorbent, 242 Carbon, 37, 175, 180–187
– characteristic binding energy, 241 Cardiovascular applications, 278, 286
– excess adsorbed density, 243 Cell reaction, 174
– excess adsorption isotherm, 244 Cellulose nanocrystals, 451
– Gibb’s formulation of adsorption, 243 Charge storage, 172, 173, 180, 181, 183
– Gibbs adsorption isotherm, 244 Co-condensation, 78
– Gibbs dividing surface, 243 Co-surfactant, 63, 68, 76
– physisorption, 241 Coating, 323, 443
– Type I isotherm, 244 Collagen, 285, 291, 293, 312
– Type II isotherm, 244 Colloidal suspensions, 105
– Type III isotherm, 244 – electrostatic stabilization, 105
– Type IV isotherm, 244 – kinetic stability, 106
– Type VI isotherm, 244 – steric stabilization, 107
Alternating copolymer, 124 Conducting polymer, 122
– electron-poor unit, 124 Conjugated polymers, 121
– electron-rich unit, 124 – PCDTBT, 130
– push-pull architecture, 124 – poly(3,4-ethylenedioxythiophene), 123
Ampiphilic, 15, 16, 30 – poly(3-alkylthiophene)s, 122
Appearance, 445 – poly(para-phenylene), 122
Artificial organs, 278 – polyacetylene, 121
– bones, 296 – polyaniline, 122
– heart, 288 – polypyrrole, 122
– kidney, 302 – polythiophene, 122
– liver, 303 – PTB7, 130
– regioregular poly(3-hexylthiophene), 123
Battery operation, 174 Constant current, 172
BET, 64, 71 Convection, 178
Bioceramics, 281 Cooperative self-assembly, 63, 65
Biomaterials, 277–331 Critical micellar concentration, 75
Biomedical applications, 81, 82, 84, 277–331 Critical micellar temperature, 75
Biometals, 280
Biomimicry, 319, 415 Debye (Length), 27–29
– building blocks, 415 Degradation, 280, 281, 284, 322
– hierarchically organized structures, 416 Dendrite, 183
– self-assembly, 424 Differential scanning calorimetry, 218, 231
Bioreactors, 324 – freezable bound water, 232
Bioresorbable, 281 – freezable unbound water, 232
Bioresponses, 280 – freezable water, 232
466 | Index
– nonfreezable bound water, 232 Formulation, 458

– states of water, 222, 231 Fuel cell, 209
Diffusion, 178 Fullerene, 38
– layer, 175 Functionalization, 62, 78, 83
Dispersion, 9–12, 17, 18, 22, 24, 26, 31
DLVO (theory), 29 Globular protein, 429
Double layer, 175–177 – α-hemolysin, 431
– capacitance, 176, 180 – β-lactoglobulin, 430
Drag force, 178 GO, 50
Drug delivery, 61, 80, 83, 86, 87, 318 Gouy–Chapman, 175, 176
Dubinin, 254 – Stern, 175, 176
– characteristic energy, 254 Grafting, 68, 78, 89
– Dubinin–Astakhov model, 254
Graphene, 37
– Dubinin–Raduskevitch, 254
– oxide, 50
– pressure parameter, 254
Graphite, 184
DVLO Theory, 106
Dynamic vapor sorption, 218, 223
– clustered water, 227, 228 Half cell, 174
– nonspecific adsorbed water, 227, 228 Hartree–Fock
– sorption isotherm, 223, 229–231 – 6-31g, 145
– sorption model, 226, 228, 230 Helmholtz, 175, 176
– specific adsorbed water, 227, 228 Henry’s law, 246
– states of water, 222, 226, 230 Hybrid
– water diffusion coefficient, 222, 225–227 – interfaces, 65, 67
– water population, 227–229 – materials, 68, 69, 91, 92
– water uptake, 223 – sorbents, 89, 91
Hydrothermal synthesis, 67, 73
Electrochemical capacitor, 171–173, 175–183,
186, 189 Implant, 277–286
– supercapacitor, 191 – bearing, 294
Electrochemical potential range of stability, 179 – bone joint, 297
Electrochemical window, 183 – breast, 310
Electrolyte, 189, 207 – cardiac, 288
– solid, 207, 208 – cochlear, 305
– solid polymer, 208 – dental, 296
Emergence, 139, 155, 164 – heart valves, 289
Emulsion, 9, 17–23, 26, 30 – insuline pumps, 302
Energy storage device, 189 – maxillofacial, 313
External circuit, 173 – pacemaker, 288
Extraction chromatography, 80, 88, 89 Impregnation, 78, 79
Inner Helmholtz plane, 175
Faradaic process, 174, 175, 180 Interface, 243
Fibrous protein, 420 – interfacial surface area, 243
– abductin, 421 – spreading pressure, 243
– byssus, 422 Inverse micelles, 104
– resilin, 421 Ion conductivity, 207, 208
– silk, 425 – charge density, 209
Flocculant, 27, 31 – degree of solvation, 209
Flocculation, 19, 25, 31, 32 – density of mobile ions, 207
Index | 467
– ion mobility, 207 MnO2 , 181–183

– mobile ions, 208 Molten salt, 190
Ionic liquid, 189 Morphology, 80
– electroactive, 199 – (particle), 13–16, 18
– functional, 189
– task-specific, 195 Nanocasting, 61
Nanocrystalline cellulose, 447
KIT-6, 63, 69, 72, 89, 91 Nanoparticles, 101, 156, 452
– aggregation, 105
LaMer diagram, 103 – magnetic, 113
Langmuir isotherm, 252 – metallic, 110
Latex, 9, 11, 12, 17–19, 21, 28, 30, 33 – nucleation, 102
Lattice gas isotherm, 256 – polymeric, 115
– Aranovitch, 256 – stabilization, 105
Layered structure, 185 – synthesis, 101
Lennard-Jones potential, 246 Nanoporous, 61
– Lennard-Jones planar potential, 247 Natural polymers, 284
Lenses, 305, 308 Negative electrode, 174, 176, 178, 180–184
Li-ion battery, 183, 185, 193 Nucleation, 18–21
– redox shuttle, 198
– transport number, 197
Optoelectronic devices, 121
LiCoO2 , 185
Ordered mesoporous silica, 61, 62
LiFePO4 , 185
Outer Helmholtz plane, 175
Lithium ion transport, 190
Localized surface plasmon, 110
Particle diameter (dP ), 10, 31
Mass transport, 178 Particle number (Np ), 10
Materials-based storage, 241 PbO2 , 181–183
Maximum work, 174 Peptide, 417
MCM-41, 62, 63, 69 Photocatalysis, 113
MCM-48, 63, 69 Plastic electronics, 121
Mechanical performance, 452 – field-effect transistors, 121
Mesopores, 176 – light-emitting diodes, 121
Mesoporous materials, 61, 80, 88 – solar cells, 126
Mesostructure, 69, 77 Polyethylene, 156
Metallic lithium, 184 Polymer electrolyte membrane fuel cells
Micelle, 15–17, 19–21, 24, 25 (PEMFC), 154
Microemulsion, 17, 18, 24, 25 – Nafion® , 154, 155
Micropores, 176 Polymeric semiconductors, 121
Microporous adsorbents for hydrogen storage, Polymerization method, 121
261 – direct (hetero)arylation polymerization
– activated carbons, 261 (DHAP), 125
– adsorption properties of hydrogen on various – electropolymerization, 124
metal organic frameworks, 269 – Grignard metathesis method, 123
– metal organic frameworks, 263 – Kumada, 124
– single wall nanotubes, 262 – Negishi, 124
Microporous materials, 61 – oxidation, 124
Migration, 178 – ring-opening metathesis polymerization, 122
Miniemulsion, 17, 18, 22–25 – Stille, 125
468 | Index
– Suzuki, 125 – sulfonated polysulfone (SPS), 230, 231

– Ziegler–Natta, 121 – vehicle mechanism, 209, 210
Polypeptide, 417 Pseudocapacitance, 180, 181, 183
Pore
– network, 64, 65, 80 Quantum dots, 107
– size, 74 Quinone, 180
– structure, 63
– volume, 64, 91 Ragone Plot, 172
Pores, 241 Redox shuttle, 190
– macropores, 241 Reduction, 164
– mesopores, 241 Reductionism, 139
– micropores, 241 RuO2 , 180
– pore volume, 243 Ruthenium dioxide, 180
Porosity, 72
Positive electrode, 174, 177, 178, 180–183, 185, SBA-15, 69, 70, 74
186 SBA-16, 69, 70
Power density, 171, 172 Scaffold, 319
Prosthesis, 277–279 Schrödinger’s equation, 139, 142, 144, 146
– corneal, 308 – ab initio, 144
– maxillofacial, 311 – Hartree–Fock, 144, 145
– retinal, 305 – density functional theory (DFT), 144, 145, 152
– tendon and ligament, 299 Self-assembly, 15–17, 25, 26, 63
Silica
– vascular, 289
– applications, 80, 82, 84
Protein, 278, 417
– synthesis, 63
Proton conductivity, 209, 210, 212, 214–216,
Silicon, 184
218, 222
Simulation, 139, 140, 142, 147, 152, 155, 164
– ac method, 219
– atomistic, 147, 155
– dc method, 219
– force field, 147–150, 152
– electrochemical impedance spectroscopy, 219
– molecular dynamics (MD), 150
– four-probe, 219–222
– molecular, 139, 140, 142, 152, 155, 164
– in-plane, 219–221
Skin, 312
– through-plane, 219, 221
Slit pore, 247
– two-probe, 220–222
Solar energy, 121
Proton exchange membrane, 209, 213 Solid content (SC), 10, 11, 26, 28
– alternative sulfonated ionomers and Solid electrolyte interface, 184
membranes, 213 Solid electrolyte interphase, 190
– amphoteric heterocycle, 216 Specific energy, 171
– anhydrous proton-conducting electrolyte, 216 Spinel, 185
– composite membrane, 217 Stabilization
– Grotthuss mechanism, 210 – depletion, 26, 31–33
– hydration level, 212, 222 – electrostatic, 26, 27
– Nafion, 207, 210, 212, 213, 215–217, 219, 220, – steric, 26, 30
222, 223, 226–233 Stents, 278
– proton transfer, 210 – esophageal, 301
– proton transport, 209, 215, 216 – laryngeal, 301
– sulfonated poly(arylene ether ketone), 216 – tracheal, 301
– sulfonated polyarylene, 214 – valves, 289
– sulfonated polyetherketone, 215 – vascular, 290
Index | 469
Stern layer, 176 Tissue engineering, 319

Structure tailoring, 72, 73 Transition, 156
Structure-directing agents, 62, 63, 68, 70, 71 – atomistic
Supercapacitor, 191 – force field, 160
Supercritical adsorption isotherms, 246 – glass, 156, 159
Surface modification, 323 – melting, 156, 157
Surfactant, 14–16, 18–22, 24–27, 30, 33, 63, 65, Transport path, 173
66, 72 True liquid-crystal templating, 64, 65
Swelling agents, 76, 82
Synthetic peptide, 432 Ultramicropores, 176
Synthetic polymers, 121, 282
Virial expansion, 246
Tg (glass transition temperature), 11–13 – second virial coefficient, 246
Theoretical capacity, 175 – second virial coefficient of single-wall
Thermodynamics of adsorption, 257 nanotubes, 248
– Gibbs potential, 258
– internal energy of adsorption, 258 Water desalination, 91
– Myers, 257 Weathering, 455
– properties of surface potential, 259 Wound dressing, 285, 315
– surface potential, 258
– thermodynamic properties, 257 X-ray photoelectron spectroscopy, 181

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De Gruyter Graduate

Leclerc, Gauvin ∙ Functional Materials

Organic and Hybrid Solar Cells – An Introduction

Journal of the Mechanical Behavior of Materials

Library of Congress Cataloging-in-Publication Data

Bibliographic information published by the Deutsche Nationalbibliothek

© 2014 Walter de Gruyter GmbH, Berlin/Boston

September 2014 Professor Gerhard Wegner

Québec, August 2014 Mario Leclerc

Contributing authors | XVII

About the editors | XXIII

Part I: Functional materials: Synthesis and applications

A. Al Shboul, F. Pierre, and J. P. Claverie

S. Rondeau-Gagné and J.-F. Morin

3.2.1 General considerations | 38

J. Florek, R. Guillet-Nicolas, and F. Kleitz

N. Allard and M. Leclerc

Part II: Development of new materials for energy applications

S. B. Schougaard and D. Bélanger

8.5.2 Hybrid electrochemical capacitors | 181

C. de Bonis, A. D’Epifanio, B. Mecheri, S. Licoccia, and A. C. Tavares

P. Bénard, A.-M. Beaulieu, D. Durette, and R. Chahine

11.5 Microporous adsorbents for hydrogen storage | 261

Part III: New trends in sustainable development and biomedical

D. Mantovani, L. Levesque, G. Sabbatier, M. Leroy, D. G. Seifu, R. Tolouei,

13.3 Synthesis and characterization of magnetic nanoparticles | 340

14.4.6 Forming linear threads and two-dimensional interfaces | 395

T. Lefèvre, F. Byette, I. Marcotte, and M. Auger

B. Riedl, V. Vardanyan, W. N. Nkeuwa, A. Kaboorani, V. Landry, B. Poaty, M. Vlad,

16.4.2 Optical properties | 456

Maxime Cloutier Marc-André Fortin

Freddy Kleitz Lucie Levesque

Barbara Mecheri Bouddah Poaty

Steen B. Schougaard Ana C. Tavares

Robert Gauvin holds a Mechanical Engineering degree from Uni-

carbon-based materials are undoubtedly amongst the most-studied materials in both

ied as an assembly of a multitude of building blocks, and that optimization of these

introduces the basic concepts related to supercritical adsorption of hydrogen on mi-

2.2 Polymer colloids inside out

2.2.1 How many polymer chains per particle?

Let us consider a polymeric sphere of diameter (dp ) = 20 nm, constituted of poly-

Particle Outer Polymer Number of

Spherical, polystyrene 20 105 26

2.2.2 How many particles?

cannot be varied independently of one another. Simple geometrical arguments can be

Fig. 2.1. Scanning electron microscopy images of

2.2.3 Are the chains immobile within the nanoparticle?

example) can act as a plasticizer, resulting in a lower Tg . Hydroplasticization is gener-

2.2.4 Morphology of polymeric nanoparticles

S1 < 0 S1 < 0 S1 < 0

0% 10% 15% 25% 50% 100%

Fig. 2.5. Simulated TEM pictures of a single

Spherical Cylindrical ‘Polymersomes’

High Medium Low

Fig. 2.7. Self-assembly of block-copolymers

Polymeric spherical micelles, the most commonly encountered self-assembled poly-

2.3 Preparation of polymer nanoparticles

polymerization technique for obtaining polymer nanoparticles. Besides conventional

Table 2.2. Main features of heterophase polymerization.

Polymer- Emulsion Dispersion Suspension

2.3.1 Emulsion polymerization

Emulsion polymerization is a remarkably simple experiment to conduct which usu-

Emulsion polymerization presents numerous advantages: