Polymers For Medical and Tissue Engineering Applications: Review

Review
Received: 20 May 2014
Revised: 24 July 2014
Accepted article published: 4 August 2014
Published online in Wiley Online Library: 3 September 2014
(wileyonlinelibrary.com) DOI 10.1002/jctb.4505
Polymers for medical and tissue engineering

applications
Deniz Ozdila and Halil Murat Aydina,b*
Abstract
Recent decades have seen great advancements in medical research into materials, both natural and synthetic, that facilitate the
repair and regeneration of compromised tissues through the delivery and support of cells and/or biomolecules. Biocompatible
polymeric materials have become the most heavily investigated materials used for such purposes. Naturally-occurring and
synthetic polymers, including their various composites and blends, have been successful in a range of medical applications,
proving to be particularly suitable for tissue engineering (TE) approaches. The increasing advances in polymeric biomaterial
research combined with the developments in manufacturing techniques have expanded capabilities in tissue engineering
and other medical applications of these materials. This review will present an overview of the major classes of polymeric
biomaterials, highlight their key properties, advantages, limitations and discuss their applications.
2014 Society of Chemical Industry
Keywords: polymers; tissues and organs; scaolds; tissue engineering
INTRODUCTION
NATURALLY-OCCURRING POLYMERS
Regenerative medicine has seen great advancements over the

past decade with progress in polymer science oering new materials and strategies for the elds of tissue engineering, drug delivery,
and cosmetic surgery. For tissue engineering research, the primary
focus has been on developing substitutes for the natural extracellular matrix (ECM) scaolds capable of acting as temporary
three-dimensional support structures that promote and guide correct tissue pattern formation. Polymers, both naturally-occurring
and synthetic, have become the natural choice of biomaterial
for such applications for a number of reasons including their
availability as a resource and ability to be easily reproduced,
their versatility in the range of applications for which they can be
adapted, their generally tuneable properties for function-specic
use and the biodegradable nature of most of them. As polymeric scaolds are generally subjected to in vivo conditions
they are also generally required to possess good cell adhesiveness, promote cellbiomaterial interactions, exhibit structural
and mechanical integrity, and have a microstructure suitable
for tissue integration and the exchange of factors critical to cell
survival.
Scaold design parameters and manufacturing methods for
multi-faceted polymer systems ultimately rely on the fundamental chemical nature of the polymer. For example, while
collagen is degradable and highly suitable as temporary scaolding material for repair at defect sites, the mechanical strength
and non-degradability of polyurethanes are sought for load
bearing applications. Polymers used as biomaterials in biomedical applications can be separated into two broad categories:
naturally-occurring polymers and synthetic polymers. As biomedical polymers are usually combined with other materials for
maximized performance and targeted tissue response, this
review will discuss each type of polymer separately under the
aforementioned categories.
The rst polymers to be used in biomedical applications,

naturally-occurring polymers,1 far out-date the use of synthetic polymers which rst appeared around the 1960s.
Frequently-utilized, naturally-occurring polymers can be divided
into the following three groups: proteins (e.g. silk, collagen, soy,
brin gels), polysaccharides (e.g. chitin/chitosan, alginate and
hyaluronic acid derivatives) and polynucleotides (e.g. DNA and
RNA).2 The main advantage of natural polymers is their high
degree of scaoldtissue compatibility due to the positive biological recognition of their chemical make-up. However, the use of
these polymers also carries the potential for inciting an immune
response due to any impurities in the material gained during
processing. Clinical applications require the use of medical grade
materials and, in any instances where immunogenic fragments
are detected within the material, it is imperative that they are
removed.
Correspondence to: Halil Murat Aydin, Environmental Engineering Department

and Bioengineering Division, Hacettepe University, 06800, Ankara, Turkey.
E-mail: hmaydin@hacettepe.edu.tr
a BMT Calsis Co., Hacettepe University Technopolis, 06800, Beytepe, Ankara,

Turkey
b Environmental Engineering Department & Bioengineering Division and Center
for Bioengineering, Hacettepe University, 06800, Ankara, Turkey
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J Chem Technol Biotechnol 2014; 89: 17931810
Hyaluronic acid
A ubiquitous proteoglycan, and one that is often incorporated
into tissue regenerative scaolds, is the linear, anionic polymer,
hyaluronic acid. This co-polymer of D-glucuronic acid and Nacetyl-D-glucosamine can be found in several body tissues including connective, epithelial and neural tissue and synovial uid.3
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Hyaluronic acid not only has a key role in ensuring joint lubrication
but is also known to promote cell motility and proliferation which
are properties critical for tissue regeneration. These features,
alongside the enzymatic degradability, bioresorbability and the
ability to add further functionality via its side chains has led to the
development of hyaluronic-based scaolds of all forms including
hydrogels for wound healing applications,4 sponges for cartilage
repair,5 and meshes for bone tissue engineering.6 It is perhaps the
more specic features of hyaluronic acid such as its ability to organize and retain aggrecan and sulphated glycosaminoglycans,7
its ability to adhere chondrocytes through cell surface receptors
which then leads to the production of signals for cell migration,
proliferation and dierentiation,8,9 and its ability to stimulate proteoglycan synthesis10,11 that has made it so popular in cartilage
tissue.
Hyaluronic acid is also known to take part in the stimulation of
a local inammatory response which is particularly useful for the
conduction of local tissue repair and remodelling.12 In addition,
the angiogenic eects13 of hyaluronic acid have been documented
and add further appeal to the natural biomaterial as local angiogenesis is considered critical for tissue formation and survival. In
recent years chemical modications to hyaluronic acid have been
explored to chemically enhance its physical qualities, rheological
qualities and tissuematerial interactive qualities. Such upgrades
will continue to inspire future research into the use hyaluronic acid
in tissue engineering applications.
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Collagen
Collagens are extra cellular matrix proteins. Type I collagen, a
brillar, rod-shaped molecule,14 is the most abundant of the 27
dierent types of collagen. Type I collagen can be puried from
a number of tissues including tendon, ligament, bone, skin and
cornea via relatively simple biochemical processing methods.15
The high content of collagen Type I in the extracellular matrix has
been a key reason why it has become one of the most investigated
proteins for use in medical applications.16 As it normally provides
the structural framework and tensile strength in body tissues17 it
is considered an excellent biological resource for the construction
of tissue engineering scaolds.
The mechanical performance of collagen relies heavily on
the fundamental crystalline assembly of the protein which has
a helical quaternary structure.18 At the nanoscale, the helical
self-assembly of tropocollagen subunits form the collagen brils that are cross-linked at the microscale to give the ECM and
tissues its tensile strength. The interactions of these brils with
other proteins and extracellular matrix components also play a
role in dening the engineered tissue matrix. At this level, bril
diameter, length, density and orientation can all be modied to
enhance the biological and mechanical activity of the scaold.
The covalent bonding between brils to form larger brils or bre
bundles can be attained through various fabrication methods,
including electro-spinning modules and moulding. The application of mechanical stimulation such as tensile strain19 and
cyclic circumferential strain20,21 on collagen Type I-based scaolds
have proven to assist with the control of collagen deposition by
the recruited cells and therefore serves as a tool for directing the
structural formation of the scaold.
Collagen carries the advantage of having simulative chemical
characteristics, such as integrin receptors, required for adequate
cell attachment and proper tissue formation.22,23 Furthermore, the
types of cells that are attracted to and attach to this biomaterial
not only secrete specic enzymes that degrade the collagen
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D Ozdil, HM Aydin
without creating cytotoxic degradation products, but they are

also the chief synthesizers of new collagen that is deposited in to
the extracellular space. This gives collagen scaolds behavioural
characteristics that are ideal and capable of closely following the
bone remodelling process that governs bone tissue engineering
applications. Collagen can be forged to exhibit the physical and
morphological features required for local connective tissue regeneration, combined with other materials (for example -tricalcium
phosphate for bone tissue engineering) to form composites and
prepared in many dierent physical forms (beads, membranes,
shaped objects, etc.).24,25 Currently, the main issue with collagen
use from a regulatory perspective is the challenges that are associated with ensuring the safety with using such animal-derived
materials (in particular the risk of transmitting prions and BSE).
Co-polymerization capabilities with other biomaterials raise
even more options for customizing scaold properties.
Chitin/Chitosan
The second most abundant polymer in nature is chitosan, a linear cationic polysaccharide that is attained from the deacetylation of chitin (a linear polysaccharide built from -1,4 linked
N-acetylglucosamine units). Owing to the insolubility of chitin in
common solvents and the diculties this poses for processing,
deacetylation is necessitated and chitosan becomes the usable
product. Chitosan is a promising degradable polymer that is one
of the only two non-human origin natural polymers (along with
alginic acid) used in biomedical engineering. Its base unit, chitin,
has characteristics, such as wound healing capacity,26 that are particularly favourable in tissue engineering cases. The crystallinity
and molecular weight of the chitosan polymer depends on the
degree of deacetylation.27 The degradation of chitosan is also
primarily inuenced by the degree of acetylation.28 The alternative method for controlling degradation proles is by altering the
side-groups of the polymer such that extensive hydrogen bonding is prevented via the attachment of bulky side groups.29 In vitro
degradation of chitosan is performed by several enzymes including chitosanase, lysozyme and papain30 with lysozyme being the
physiologically relevant enzyme for in vivo degradation.
The poor mechanical strength of chitosan and its high degree
of hydrophilicity has traditionally been resolved by cross-linking
it to other polymers such as collagen,31,32 poly(lactic acid) (PLA),33
poly(lactic-co-glycolic acid) (PLGA),33,34 polyethylene glycol PEG35
and alginate.36 The various cross-linked forms of chitosan with
other polymers include semi- or full-interpenetrating polymer
networks, chitosanchitosan networks and hybrid polymer
networks.37,38 The structural stability of chitosan-based scaolds
can thus be varied through these cross-links.
This cationic polymer is able to form electrostatic interactions
with negatively charged cell surfaces and, depending on its conguration, it can also display great hydrophilicity and cell proliferation eects.39,40 The ability of this bioactive polymer to interact
with glycosaminoglycans (GAGs) in particular give scaolds based
on chitosan a direct inuence on the modulation of cytokines
and growth factors41 and thus local tissue regeneration activities.
Furthermore, chitosanDNA complexes have also been explored
as a means of facilitating the regeneration process via scaolds
with amplied bioactivity at the molecular level.42
The biodegradability, biocompatibility, bio-adhesiveness, and
non-toxicity of chitosan41,43 account for the popularity of this
biomaterial in medicine. This is topped by the possibility of
processing chitosan and chitosan-composites into numerous
Polymers for medical and tissue engineering applications

shapes; membranes, sponges, bres, microspheres and hydrogels. Some recent research into chitosan-based scaolds are
aimed at further improving surface characteristics of scaolds for
hard tissue regeneration,44 exploring its anti-bacterial qualities
when combined with other polymers and anti-bacterial agents,45
increasing stability of chitosan-based cartilage repair scaolds
by co-polymerization with other natural polymers,46 and introducing chitosan microspheres embedded in calcium sulphate as
point-of-care drug delivery systems.47 Bovine derived collagen,
much like the innovative uptake of fungi-derived chitosan, can be
used as an example by which solutions for the abovementioned
issues can be found, paving the way for the safe and eective
future use of this material.
Alginate
The other non-human derived natural polymer used to fabricate tissue engineering scaolds is the linear copolymer of
-D-manuronic acid and -L-glucuronic acid linked by a 14 glycosidic bond, alginate. Commonly sourced from the cell wall of
brown algae, extraction of the polysaccharide is through the use
of a basic solution followed by acidic precipitation. The molecular
weight of the polysaccharide can reach up to 500 kDa.
The simplicity of creating alginate hydrogels with the polymer undergoing spontaneous gelation in the presence of divalent cations and carboxylate side groups makes it an attractive
and promising biomaterial with tissue engineering application
potential. Traditionally, along with drug delivery and cell delivery
scaolds,48 alginate has also been used in wound dressings.
Most research and development in hydrogel based systems
have been centred on composite constructs that incorporate
dierent materials such as collagen49,50 PLGA,51,52 Poly-L-lysine
(PLL),53,54 PCL,55 polyethers,56 and chitosan,57,58 mainly for support
of alginates mechanical weakness. Scaold designs are as varied
as the types of body tissues that are aimed to be restored from
gels,59,60,50 porous networks,61,62 and sponges63 to lms64 and
microspheres.65,49,54,53 Along with its design exibility is the ability
to transform the responsiveness of alginate biomaterials toward
pH and cell adhesion through alterations to its carboxylate acid
side group.66,67
Among these advantages, however, stand alginates natural poor
cell adhesion and poor in vivo degradation performance. This
necessitates either the gamma irradiation or periodates oxidation
of alginate biomaterials. Several types of alginate-based scaolds
have been used in tissue regeneration attempts of dierent body
tissues including bone and cartilage,61,59,63,60 nerve,54 and connective tissue.50
indirectly by binding extracellular matrix proteins in the blood.69,70

The polymer also binds growth factors that further promote cell
proliferation and dierentiation.71 Furthermore, the angiogenic
eects of brin-based materials have also been established.72 This
bioactivity gives brin signicant appeal and use in medicine as
sealants or heamostatic agents, which are perhaps the more commonly known applications of the biopolymer. However, brin has
also shown success as a biomaterial with tissue engineering applicability. Orthopaedic, cardiovascular and skin tissue engineering
are key examples of areas with brin-based scaold use.73 78
The main impediment to the use of brin as scaolding material is its morphological deconguration (shrinkage) and rapid
degradation in physiological conditions.73,74 Fibrin-only cell
carriers79 are weak mechanically and thus require combinations
with strength enhancers, e.g. hyaluronic acid,80 PLGA81 and
PCL/polyurethane.82 Like all successful 3D scaolds for tissue
engineering, brin-based scaolds can exhibit interconnected
pores that allow cell inltration, the exchange of nutrients and
wastes and that support vascularization.83 Fibrinogen concentration is the fundamental determining factor of pore structure
where a low concentration creates appropriately dense matrices
that can mediate the aforementioned points critical for scaold
performance.84 86
Albumin
Albumin, a protein that contributes 50% to the total mass of
blood plasma has been investigated for use in drug delivery
applications. The role of this water-soluble protein in the blood
is to carry hydrophobic fatty acids as well as maintain the pH
balance. Since albumin is ubiquitous in the human body, almost
all body tissues can enzymatically degrade the protein. This high
degree of biocompatibility and biodegradability gives albumin
high potential as a biomaterial. Albumin is particularly successful
as a tissue engineering constructs with drug delivery capabilities
and is usually preferred in studies determining protein and growth
factor release kinetics.
The weak mechanical properties of albumin has narrowed its
use to drug delivery,87 coatings,88,89 and suturing90,91 applications.
The protein can be processed into several dierent forms including
nanoparticles,87,92 microparticles,93 and bres.94,95
Chondrotin sulphate
Chondrotin sulphate (CS) has shown great promise as a biomaterial. This sulphated glycosaminoglycan has a structure very similar
to HA. Found predominantly in articular cartilage, CS plays a role
in the matrices produced by broblasts in wound healing.96 It has
been shown to have anti-inammatory eects and is a binding
factor for extracellular matrix components.97 Chondrotin sulphate
can be commonly encountered particularly in cartilage tissue
engineering combined with other cartilage ECM components to
form multi-layered scaold Its natural role in chondrogenic activities has led to its investigation in cartilage tissue engineering98
both alone99 and featuring in composite materials that also
contain poly(-caprolactone) (PCL),100 PEG,101,102 collagen,100,103
hyaluronic acid,104 and chitosan.105
Naturally-occurring poly(amino acids)
Poly(amino acids) used in biomedical applications are branched
into two groups: natural poly(amino acids) and synthetic
poly(amino acids) (discussed later).
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Fibrin
Fibrinogen, the building block of brin, is a large (340 kD) glycoprotein that has three pairs of polypeptide chains, namely A, B, and
which are bound by disulphide bridges. A unique polymerisation process involving thrombin and activated factor XIII converts
brinogen into brin and forms a brin network. This polypeptide
is commonly known for its physiological role as a haemostatic
plug in tissue injuries. The options for cross-linking are one way
in which diverse microstructural and mechanical features of brin
networks can be achieved. In addition, autologous scaolds can
be manufactured by using brin made from a patients own blood.
Injectable brin hydrogels are the most frequently utilized forms
of the polypeptide as tissue regeneration support biomaterial68
Fibrin can adhere cells both directly via integrin receptors and
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Natural poly(amino acids) are biodegradable and, unlike proteins, are composed of only one type of amino acid bonded by
amide linkages. Poly(-glutamic acid) and poly(L-lysine) are the
most commonly utilized polymers within the natural poly(amino
acid) category.
Poly(-glutamic acid) (-PGA) is a polyamide that is composed of
D- and L-glutamic acid enantomeric units. It is soluble in water and
with a reactive carboxylate group, there exists a wide variety of
options for further development with dierent functional group
attachments. Previously, -PGA has been coupled with chemotherapeutic agents,106 antibiotics,107 DNA,108 and proteins107 to aid
tissue healing and recovery. As scaold material, however, the
-PGA homopolymer is not preferred as it does not have adequate
physical properties. It has seen some application in soft tissue engineering within cross-linked hydrogels.109 Attempts to equip this
polyamide with characteristics suited to tissue engineering have
been based on blending with natural (collagen110 and chitosan111 )
and synthetic polymers (PLA,112 PLGA,113 and PCL114 ) however,
research has been limited due to the low availability of -PGA.
Poly(L-lysine) research has revealed antibacterial,115 and antitumor activity116 eects that this polymer carries. This particular
ionic polymer, however, has also been found to have high toxicity
owing to its extremely high positive charge and therefore is limited, with in vivo use such as that with tissue engineering scaolds.
Attempts to appropriate it for use as a biomaterial have been
through blending it with -PGA117 and other polymers118 120
although poly(L-lysine) remains a blending option that still
requires further research and development before clinical uptake.
SYNTHETIC POLYMERS AS BIOMATERIALS

Synthetic polymeric biomaterials may not always come as a
cheaper alternative to biological polymers due to less availability,
however, they are much more easily reproducible and have a
longer shelf-life and therefore are often more viable sources of
polymeric biomaterials. Uniformity of microstructure, degradation rate and mechanical structure with large-scale production
are the key advantages of these polymers. The most extensively used synthetic biomedical polymers is the family of linear
aliphatic polyesters: polyvinyl alcohol (PVA), (PCL), poly(lactic
acid), poly(glycolic acid), poly(hydroxybutyrate) (PHB).121 124
Numerous combination options of these polymers, both with
each other and/or various other elements, generate a great assortment of composite scaolds with varying chemical, structural and
mechanical properties that can be suited to specic tissues and
tasks.
Regulatory bodies have presented armative guidance documents for the use of synthetic polymeric biomaterials and as such,
in terms of product validity, have supported the more ecient utilization of such synthetic materials. The future will thus continue
to see synthetic polymers as indispensable tools for medical and
tissue engineering applications.
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Polyetheretherketone (PEEK)
One of biomedical engineerings most frequently utilized polymers is polyetheretherketone (PEEK). This linear, aliphatic,31 semi
crystalline polymer is a high performance polymer with a high
melting point of 334 C and a high resistance to wear. PEEK has
a maximum tensile strength of 100 MPa, a maximum elongation
of 50150% and a Youngs Modulus of about 3.7 GPa.125 With
its mechanical properties, chemical resistance and radiolucency
closely matching those of natural bone,126 the popularity of PEEK
in orthopaedic biomedical applications can be understood.
D Ozdil, HM Aydin
The biocompatibility of PEEK and PEEK composites127 has

been conrmed through numerous in vitro cytotoxicity128 130
and mutagenecity131 studies as well as in vivo studies that have
shown that the biomaterial triggers a minimal inammatory
response.132 134 Adding to the benets of using PEEK is its MRI
compatibility. These excellent chemical, mechanical and thermal properties make PEEK an obvious choice for load-bearing
orthopaedic devices including uses in knee joints,135 spinal
fusion,136 and craniofacial repair137 which have been the initial
and traditional uses for it. Recent research,138,139 however, is
seeking to transform PEEK-based biomaterials so that further
functionality such as stimulation and integration of local tissue
can be achieved with it.
Due to the chemical intertness of PEEK, it has a limited ability
to form strong attachments to native tissues.140 Attempts to overcome this in orthopaedic applications introduced the inclusion
of osteoinductive or osteoconductive factors, such as hydroxyapatite. Such additives, however, have not provided a complete solution as the mechanical strength of the polymeric material is quickly
compromised owing to the additional lack of binding between
PEEK and reinforcement/ller elements.141 143 For the purposes of
orthopaedic tissue engineering scaold design, eorts have been
focused on developing certain manufacturing methods for PEEK
scaolds such as knitting and braiding,144,145 acid-etching, alkali
treatment, anionic oxidation, shot-blasting,146 and sulfonation147
for some modication of its mechanical properties to produce
more exible, deformable, and matrix-like structures suitable for
tissue ingrowth and local mechanics. Tissue anchorage with PEEK
materials have been largely achieved through interconnected
porous scaold designs146 that allow tissue integration in the
matrix. It has been shown that pore sizes of 200300 m141 and
a porosity value of 75%148 have been considered successful parametrical values for attaining sucient bone tissue xation.
Poly(hydroxyalkanoates)
Polyhyrdroxyalkanoates are another large class of naturallyoccurring aliphatic polyesters. In terms of both availability and suitability to tissue engineering research, however, poly 3-hydroxybutyrate (PHB), 3-hydroxybutyrate and
3-hydroxyvalerate (PHBV) co-polymers, poly 4-hydroxybutyrate
(P4HB), 3-hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx)
co-polymers and poly 3-hydroxyoctanoate (PHO) have been the
main members of interest.
The simplest and most widely investigated of this family of
thermoplastics is poly(hydroxybutyrate), which has been explored
mainly in the construction of nerve149 and bone150 tissue engineering scaolds. The biocompatibility of this biomaterial found
naturally in the body151 is quite high, with its completely non-toxic
degradation products150 that are absorbable via natural metabolic
pathways.
The main properties of PHB that limit its use are its brittleness,
tendency to acquire a high degree of crystallinity,150 poor stiness
and hydrophobic character and, compared with similar biomedically utilized polymers, its slow degradation rate.152
The diculties that these properties pose have been shown
to be overcome with various scaold fabrication methods, surface property modication procedures and other techniques. A
primary example of such attempts includes the functionalization of PHB matrices by blending it with co-polymers such as
hydroxyvalerate (PHV).153 The incorporation of hydroxyapatite
particles in PHB-based scaolds have also highlighted the contribution of such factors in enhancing the success of these scaolds
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in tissue engineering approaches by the ability of hydroxyapatite to not only attract osteoblastic activity but also modify
the microarchitecture for a more porous material. Similarly, the
porosity achievable with use of aqueous emulsions have also
been shown to positively impact PHB scaold performance.154
Another example is the use of polyethylene glycol, which has been
shown to enhance the hydrophilic properties of PHB nano-brillar
scaolds.155 Polyhydroxyalkonoates will continue to maintain
signicance in the eld of medical polymers with the continuing progress in recombinant, purication and modication
technologies.
Figure 1. Degradation time of PLGA with varying lactic acid and glycolic
acid ratio. Adapted from Ref. (179) By John Wiley & Sons, Inc. Reprinted with
permission.
composition is the main determinant of the chemical, mechanical

and structural variations that can be achieved. Figure 1 depicts
the inuence of the co-polymer ratio on degradation rates. While
increasing the amount of the slower degrading PLA increases
degradation time, counteractively increasing the amount of PGA
will slow down this process. Degradation times, for example, can
be from 12 months, 45 months and 56 months, for 50:50,
75:25 and 85:15 co-polymer ratios of PLGA, respectively.169 The
bulk erosion of PLGA makes controlled release of therapeutic
and other factors dicult. Therefore PLGA microspheres,170 173
microcapsules,174,175 nano-spheres,176 and nano-bres177,178 are
often used.
Poly(-caprolactone)
Another aliphatic polyester used as scaold material in tissue
engineering is the semi-crystalline polymer, poly(-caprolactone)
(PCL).180,181 With great organic solvent solubility, a melting temperature of about 5560 C, and glass transition temperature of
54 C182 this polymer is easily processed into tissue regeneration
support structures.
Degradation proles of the polymer make it suitable for use in
tissues that have a longer regeneration process. In particular PCL
has been shown to carry a similar rate of degradation to the rate of
new bone formation.183,184,185 Compared with its family members
PLA and PGA, PCL takes much longer to degrade186 via the same
non-enzymatic cleavage of ester linkages.189 191 This is the main
reason why PCL is usually adopted for long-term in vivo systems
rather than short-term systems.192 Enzymatic degradation of PCL
is known to occur to some extent as well, although this is not the
primary breakdown mechanism of the polymer.193
The innate biological inactivity of PCL makes it a promising
biomaterial for safe and controlled in vivo applications. The in
vivo performance of PCL scaolds have been commended for
their particular success in carrying chondrogenic additives that
successfully induce chondrogenesis in mesenchymal stem cells.194
The method by which such an inert polyester is functionalized
and activated to produce desired eects is primarily through
surface modication methods that focus on creating negatively
charged hydrophobic surfaces that promote cell attachment via
proteins such as bronectin and vitronectin.195
Furthermore, blending and copolymerization196 with other
polymers are methods by which scaold characteristics can be
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Poly(-hydroxyacids) (Poly(glycolic acid), Poly(lactic acid)

and their co-polymers)
Perhaps the most heavily researched category of synthetic
biopolymers is the linear aliphatic polyester family which includes
poly(lactic acid), poly(glycolic acid), their co-polymers poly(lactic
acid-co-glycolic acid), poly(-caprolactone), poly(propylene
fumarate) and poly(hydroxy butyrate) (the last three will
be discussed separately later).156 As the most widely used,
FDA-approved materials with long-term clinical data from a
wide range of clinical indications for which they have been utilized, this category of synthetic polymers are usually the rst to
come to mind as synthetic biomaterials.
The poly(-hydroxy acids), poly(glycolic acid) (PGA), poly(lactic
acid) (PLA) and their copolymer poly(lactic-co-glycolic acid)
(PLGA), are broken down to their monomeric units lactic acid and
glycolic acid through hydrolysis of the ester bonds in the backbone of their chains. These breakdown products are then simply
cleared by natural metabolic pathways. In order to maintain the
hydrolytic stability of the ester bond, the length of the aliphatic
chains must be limited. This is also important for keeping the
degradability characteristics of the polymer.
The highly crystalline thermoplastic, PGA, has impressive properties such as a melting temperature >200 C and a tensile strength
of about 12.5 GPa.157 These properties have led to the use of
PGA predominantly as suture material. As scaold material PGA
has some unique and signicant shortcomings. Its high molecular weight form has poor solubility in most organic solvents while
its low molecular weight forms are more soluble. The more soluble forms of PGA, however, lack sucient mechanical integrity in
vivo with signicant decline in its performance observed at 24
weeks158 161 this may not be sucient time for adequate regeneration of certain body tissues such as bone. Although glycolic
acid is a natural metabolite, high levels are known to stimulate an
excessive inammatory response.162,163 Also, because of its high
hydrolytic sensitivity, processing of PGA materials must be carried
out in carefully controlled conditions.
Poly(lactic acid) chains are assembled from chiral molecules and
may thus exist as poly(L-lactic acid) (PLLA), poly(D-lactic acid)
(PDLA), poly(D,L-lactic acid) (PDLLA) and meso-poly(lactic acid).
It is the optical impurities that exist between these enantiomers
in the PLA chain, rather than the molecular weight, that determine the ultimate properties of PLA-based materials. It is more
hydrophobic than PGA which means that degradation rates are
much slower, making it highly suitable for both in vitro and in vivo
applications164 167 where long-term mechanical integrity is critical. The general values for Youngs Modulus, tensile strength and
impact strength for PLA are around 3 GPa, 1.52.7 GPa and 50-70
MPa,168 respectively.
PLGA, on the other hand, presents a combined, myriad of property advantages over its polymeric counterparts. The copolymer
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controlled even further for desired outcomes. Owing to this
exibility, the pore sizes achievable with PCL scaolds and the
relatively inexpensive manufacturing methods with this material,
PCL serves as a viable material solution for tissue engineering
endeavours.
Poly(urethanes)
Linear aliphatic polyesters dominate the hard-tissue engineering
synthetic biomaterials category whereas the main biomaterial investigated for soft-tissue engineering purposes has been
polyurethane. A hard segment (diisocyanate), the soft segment
(poly(ethers) or poly(esters)) and chain extenders are the fundamental components of polyurethanes.197 The ratios of these
components involved in the chemical reaction that produces the
polyurethane will dene its ultimate properties.
The historical use of polyurethanes had experienced the drawbacks of the polymers toxic degradation products. To overcome
this issue, polyurethanes with diisocyanate replacements have
been developed. One example is using 1,4-diisocyanatobutane
(BDI) and a putrescine chain extender where the degradation
of BDI leads to the release of putrescine a polyamine which
encourages cell growth and proliferation.198 Another example is
polymerizing highly pure lysine diisocyanate with glucose so that
breakdown products consist of merely glucose and lysine.199
Polyurethane matrices with a wide range of porosities,
surface-to-volume ratios, and three-dimensional structures can be
made via electrospinning, water foaming and thermally-induced
phase separation methods. Tensile strength and breaking strains
can reach 13 MPa and 280%, respectively.199 Polyurethanes have
also displayed cell adhesion and proliferation qualities which also
add to their suitability for in vivo use.200 However, an important
drawback for polyurethanes in tissue engineering or drug delivery
use is that their degradation rates are found to be not suitable for
these applications. For this reason blends and combinations of
polyurethane with other biomaterials are made to assist degradation proles of polyurethane-based scaolds. Ongoing studies
are looking into chemically modifying polyurethanes to equip
them with the appropriate mechanical characteristics required
at the various stages of healing and regeneration, subsequently
followed by its biodegradation. Biodegradable polyurethanes,
therefore, continue to hold promise over highly porous scaolds
that are disadvantaged by mechanical weakness.
1798
Poly(propylene fumarate)
Poly(propylene fumarate) (PPF) is a unique, injectable, linear
polyester that contains multiple unsaturated double bonds
that are also available for covalent cross-linking in the presence of free-radical initiators using benzoyl peroxide and N
N dimethyl-p-toluidine. The biocompatibility of PFF has been
established by various studies.201,202
The cross-linking capability of the polyester means that degradation characteristics will be dependent on the cross-linking density,
the cross-linker and the molecular weight of the polymer.203
This capacity also translates to the ability of PPF-based scaffolds to assume scaold designs that may not be achievable by
non-cross-linkable biodegradable polymers. In fact, this exibility
has made PPF a common bone defect lling material.204 207
The crosslinking reaction is propagated using free-radical
polymerization.
PPF-based porous scaolds.201,208 210 and microsphereembedded scaolds211 214 have been studied in vivo or in vitro
D Ozdil, HM Aydin
extensively, and have proved to be biocompatible. The traditional

method of synthesizing porous PPF scaolds was by embedding
into the polymeric material sodium chloride crystals which are
leached out upon implantation a technique that carries the risk
of creating a hypertonic local environment and oers minimal control over interconnected porosity. Current methods are based on
initiating foaming reactions during polymerization215,216 such that
the supercritical CO2 treatment will generate the porosity essential
for the success of PPF scaolds in tissue repair and regeneration.
The inclusion of ceramics and other enhancement factors in these
scaolds mechanically strengthens them217 as well as improving
their biocompatibility and materialtissue relationships.218 220
Synthetic poly(amino acids)
Synthetic poly(amino acids) include homo-and co-poly(amino
acids), and display high crystallinity, low degradation rate,
poor mechanical properties and immunogenicity221 have been
reported for these polymers.
Poly(L-glutamic acid) (L-PGA) is a exible synthetic poly(amino
acid) that is relatively easy to fabricate into dierent
architectures.222 It is also non-immunogenic and enzymatically
degradable.223,224 It has featured as cancer drug delivery225 and
MRI contrast agents226 and as a copolymer with other polymers in
tissue engineering scaolds.
Poly(aspartic acid) (PAA) is a highly water-soluble polymer that
also exists as a hydrogel and undergoes enzymatic degradation.227
It can be copolymerized with other polymers (e.g. PLA,228 PCL229
and PEG228 ). Micellar congurations formed by these co-polymers
have seen interest for use in payload delivery.
Poly(ortho esters)
The poly(ortho ester) (POE) family of hydrophobic polymers230 are
polymers consisting of three geminal ether bonds. The unique
qualities of POEs are its surface-erosion mechanism of degradation and the sensitivity of the process to pH. Ortho-ester bonds
are stable at neutral pH but rapidly hydrolyse at about pH 5.5.
Under physiological conditions these highly hydrophobic polymers require activation of degradation via an acid.
Of the four classes of POEs, presented diagrammatically in Fig. 2,
it is the fourth group, POE IV, that has particular relevance to tissue
engineering. POE IV, modied from POE II, consists of short segments of lactic acid or glycolic acid incorporated into its backbone.
This not only speeds up degradation but makes POE IV more suitable for tissue regeneration materials than POE IIII, which possess
degradation rates much too slow for these purposes. Varying the
backbone chemistry of POEs will vary the degradation and material properties.
This new generation of POEs is an evolutionary development
of the second generation polymers232 and is recognized as
self-catalytic poly(ortho esters). In this new variation of POE, short
dimer segments of glycolic acid or lactic acid are incorporated
into the polymer backbone. Owing to the susceptibility of POE
to acid-catalysed hydrolysis, varying the concentration of the
-hydroxy acid dimer segments in the polymer backbone can
control the erosion rate of the bulk polymer. These polymers
oer signicant advantages over the second-generation POEs,
which required the addition of acidic excipients to control erosion
rate.
Poly(anhyrides)
Polyanhydrides are either aromatic, aliphatic or a mixture of the
two polymers that are constructed from two carbonyl groups
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Figure 2. The four poly(ortho ester) families. Adapted from Ref. (231) By Elsevier Science B.V. Reprinted with permission.
bound by an ether bond. Synthesis of this hydrolytically unstable polymer is via the dehydration of the diacid or mixture
of diacids by melt polycondensation produces this class of
biodegradable and biocompatible polymer. Polyanhydrides have
predominantly featured as biomaterials that are practical for
drug delivery systems. Polyanhydride-based microparticles233 235
and nanoparticles236 238 developed for these purposes can be
injected, administered orally or with aerosol delivery.
These polymers undergo surface erosion that is pH-dependent
and degradation is based on the backbone chemistry of the polymer, with the specic tuning of degradation rate. Polyanhydrides
on their own are usually not suitable for tissue engineering applications that require load bearing scaolds as their low molecular
weights limit their mechanical strength. The Youngs modulus of
poly(anhydride)s has been determined to be around 1.3 MPa239
which would not, for example, be suitable in bone tissue engineering approaches. Dimethacrylated anhydrides, however, is
one sub-class that oers a stronger polyanhydride-based material. This is due to the photo cross-linkability and variability of
monomers which allow for the attainment of higher structural
and mechanical integrity of these networks.240,241 Cross-linked
polyanhydrides have shown eective performance in bone tissue
engineering approaches as well as drug delivery materials.242
Monomer exibility also gives promise of applications in other
tissue engineering elds.
Poly(anhydrides-co-imides) have been developed as mechanically stronger brands of polyanhydride-based materials that
also undergo surface erosion.243 Compressive strengths up to
5060 MPa have been reported for poly(anhydrides-co-imides)
based on succinic acid, trimellitylimidoglycine, and
trimellitylimidoalanine.244
Poly(anhydride-esters), are particularly attractive as they combine the properties of polyesters and polyanhydrides. There are, for
example, poly(anhydride esters) that are based on salicyclic acid
that release the non-steroidal anti-inammatory (NSAID) (i.e. salicyclic acid) upon hydrolytic degradation.
The opportunity to tailor polyanhydrides in such ways make it
a versatile material that can be modelled into a diverse range of
tissue restoration systems.
1799
Poly(glycerol sebacate)
Poly(glycerol sebacate) (PGS) is a biodegradable polymer synthesized by the polycondensation of glycerol and sebacic acid. PGS
was rst used in a soft-tissue engineering applications in 2002.245
PGS is completely bioresorbable with degradation products

eliminated through natural metabolic pathways.246
The hydrophilic, partially semi-crystalline PGS polymer has thermoset elastomeric properties that can be tuned via the alteration
of curing temperature, curing time and molar ratio of glycerol to
sebacic acid.247 251
An additional level of control over these properties in
poly(glycerol sebacate acrylate) (PGSA) is through varying the
number of acrylate moieties, which translates to varying the
number of cross-links in the polymer network.252
Typical of elastomeric biomaterials, PGS has a nonlinear stress
strain behaviour and at 37 C the polymer is totally amorphous. Another interesting feature of PGS is its shapememory
behaviour. With heat, PGS materials can be stimulated to
re-conform to memorized shapes and this property is attributed
to its ability to switch from its xed three-dimensional networks
at cooler temperatures to its amorphous phase with increased
temperature.253
PGS undergoes surface erosion with the cleavage of ester linkages. This type of degradation is useful in that unlike bulk erosion, mass loss in surface erosion occurs linearly with time, so that
geometrical features supporting tissue regeneration are maintained for longer periods.245,254,255 Although PGS has an accelerated degradation rate in vivo than in vitro, the biopolymer has
shown complete biocompatibility in several studies.256 258 One
limitation to PGS use in tissue engineering applications, however,
is reported to be the acidic local environments that can be generated when the hydrolysis of the ester groups release carboxylic
acids.259
Further functionalisation of PGS has been investigated with the
use of cell migration, adhesion, dierentiation and proliferation
mediators such as laminin, bronectin, brin, collagen types I/III,
and elastin.260
To synergize the favourable characteristics of various polymers available for combination with PGS several composite
PGS-based scaolds have been explored. Bioglass/PGS membranes for cardiac tissue engineering,259 PGS with nano-tubular
halloysite (2SiO2 2Al(OH)2 ) incorporation,261 micro-structured
brous PGS-PCL scaolds for heart valve regeneration262 are some
examples of where both organic and inorganic biomaterial blends
with PGS have been studied.
It is the modication of textile manufacturing technologies
and their adaptation to production of biodegradable elastomers
that has given rise to some signicant biomedical companies of
our day. There are currently intensive research and development
www.soci.org
eorts that are producing, in particular, exible tubular structures
and woven matrices that are seen in clinical use.
Poly(phosphazenes)
Poly(phosphazenes) are a very large group of polymers that have
traditionally been produced with high molecular weights. Their
backbones are completely inorganic constructed with alternating
phosphorous and nitrogen atoms with two organic side groups
attached to each phosphorous atom. Most phosphazenes are
made by substitution reactions on a poly(dichlorophosphazene)
intermediate. The history of poly(phosphazene) use in
biomedicine only extends back to the past two decades.263
In order to functionalize the polymer further, specic side groups
can be introduced onto the primary structure such as amino acid
esters, glucosyl, lactate or imidazolyl units.264 266 This exibility
has led to >500267 types of poly(phosphazenes) produced to date
and as such initiated an exploration of these polymers as biomaterials for tissue regeneration rather than just their traditional use in
drug delivery.
The aforementioned side groups, for example, introduce
hydrolytic instability to the structure and assist with degradation
where the non-toxic breakdown products are released. Interestingly, when poly(phosphazenes) are combined with polymers, like
polyesters, that have acidic degradation products, the presence
of poly(phosphazene) breakdown products have a pH buering
eect.268 Mechanical properties are also varied in this manner too.
One study found that such modications produces signicantly
larger value ranges for glass transition temperature (Tg 035 C),
contact angle (63 107 ), tensile strength (2.47.6 MPa), and
modulus of elasticity (31.4455.9 MPa).269 Poly(phosphazenes)
do generally require blends with other polymers in this way to
improve chemical and mechanical characteristics. There has also
been some recent concern over the foreign body response270 that
poly(phosphazene)-based materials have been found to trigger,
contrary to previous research which had only found a limited
inammatory response.271
In various tissue engineering applications such as nerve
regeneration272,273 and orthopaedic applications,274,275 poly
(phosphazenes) have been used as lms,274 bres,272,275 gels,276,277
and sintered microspheres274 thanks to the ability to increase their
hydrophobicity with side group substitutions.
Poly(dioxanone)
Poly(dioxanone) (PDO) is one of the most commonly used members of the poly(ester ether) family of degradable polymers. These
polymers typically have an ether bond integrated into the backbone of a polyester with the aim of initiating hydrolytic cleavage of
the ester bond. Ring-opening polymerization of p-dioxanone produces PDO. P-dioxanone has a Tg about 10 to 0 C and a Tm of
115 C.278
PDO is considered a slow-degrading polymer that has complete
mass loss at about 612 months.157 PDO does not exhibit the
mechanical properties that tissue engineering scaolds would
generally require, with a modulus of (1.5 GPa).157 It does, however,
have good exibility and 12 months of considerable strength
maintenance which is why it has been selected for the production
of monolament sutures for decades.279
1800
Poly(ethylene glycol) Poly(ethylene oxide)

Poly(ethylene glycol) (PEG) is polyether that is polymerized from
ethylene oxide condensation. Chains of PEG that are above 10 kDa
D Ozdil, HM Aydin
are termed poly(ethylene oxide) (PEO). The hydroxyl groups at the

end of PEG chains are used for a variety of PEG macromers that
have diering properties and uses.
PEG polymers are biocompatible, biodegradable, non-toxic, and
low-immunogenic synthetic polymers that do not bind proteins or
cells.280,281 In fact, the rst interest in PEG was to use it as biomaterial surface coatings owing to its ability to prevent serum protein
adsorption, although the mechanisms by which this occurs is still
not completely understood and have been attributed to a number of factors.282,283 The mechanical properties of PEG scaolds in
tissue engineering depend on the molecular weight, cross-linking,
and polymer concentration. Decreasing the molecular weight or
increasing the concentration of the polymer has been shown to
improve the elastic modulus.284
PEG hydrogels have been studied in tissue engineering scaold
applications. Of course these scaolds have been adapted to these
purposes with the incorporation of cell adhesion RGD peptides to
enable cell adhesion and survival.285 For PEG hydrogels that may
carry proteins or cells for implantation and release, photopolymerization is preferred to thermal polymerization owing to the sensitivity of this method towards such payloads and the better eciency that it oers.286 In fact, one group has been able to demonstrate PEG photopolymerization transdermally.287 PEG is often
also preferred for its bio-inactivity toward encapsulated proteins
or cells where such interaction is not desired.285,288 291 Functionalisation is also possible where cell adhesive molecules and growth
factors used in PEG hydrogel scaolds have added to the success
of modulated tissue regeneration with these materials.292 295
As discussed, there are several synthetic polymer options that
can be used in various medical applications. The suitability of
each of these polymers for their intended use is based on their
respective chemical and physical properties and the capacity to
which they can be processed to assume the required structural
characteristics. Table 1 summarizes the key properties of the
synthetic polymers discussed for quick reference.
Hydrogels
Cross-linked polymer networks that contain 6090% water, known
as hydrogels, have become attractive materials for regenerative
medicine. Due to their remarkably tuneable properties hydrogels
are emerging as an exciting new material used in a diverse range
of applications including the development of articial cornea
implants,306 as llers for soft tissue engineering307 operations and
in cartilage repair materials,308 to name a few.
Degradable three-dimensional hydrogel matrices are made from
either hydrophilic homopolymers, copolymers, or, they can exist as
insoluble matrices via the introduction of cross-links.
Hydrogels can be fabricated from both natural polymers of
agarose, alginate, chitosan, hyaluronic acid, brin, collagen and
others, as well as synthetic polymers such as poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), and polyacrylates such as
poly(2-hydroxyethyl methacrylate) (PHEMA).309,310 Covalent and
non-covalent bonding in cross-links generate a biocompatible311
matrix with structural similarity to other macromolecules found in
the body.
Among the dierent methods of hydrogel synthesis, including
Michael (conjugate addition) and click chemistry, free-radical
polymerisation is the most appealing for tissue engineering due
to the great gelation kinetics and in situ polymerization capability
associated with this process.312 Figure 3 is a visual representation
of these chemical synthesis processes. Acrylate-based hydrogels
that have been subjected to this process contain many mechanical
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Table 1. Properties of popular synthetic polymers used in medicine

Glass
Elastic
Tensile
Melting
transition
Crystallinity
modulus
modulus
(%)
(GPa)
(GPa)
temperature
( C)
temperature
( C)
37
2.7
1.52.7
173178
Polyglycolic acid
45-55
7.0
57
Poly(caprolactone)
37
0.4
Poly-lactic-coglycolic acid
(50/50)
Amorphous
Poly(propylene
fumarate)
Polyanhydride
Polymer
Structure
Polylactic acid
Polyhphosphazene
degrade
products
(months)
6065
L-Lactic acid
1218
( 296 298)
225230
3540
Glycolic Acid
34
( 296,298)
0.40.6
5863
60
Caproic Acid
>24
( 299 301)
2.0
1.42.8
Amorphous
5055
D,L-lactic acid
and
glycolic acid
36
( 296 298)
37
23
23
3050
60
Fumaric acid,
propylene
glycol and
poly(acrylic
acid-cofumaric
acid)
Varies (>24)
( 302,303)
2527
5090
27
Carboxylic acids
0.141.4
( 304,305)
55
Phosphate,
ammonia,
corresponding
side groups
surface
( 267,274)
and structural advantages such as increased elastic modulus,313

great cellbiomaterial interactions,314 good tensile modulus,315
prevention of undesired brosis,316 enhanced mechanisms of
release of payloads embedded in polymeric material,292,294,317 and
higher compressive modulus with GAG incorporation.318 322
Mixing or blending hydrogels with micro- and nanoparticles324
which are later removed through various processes or through
natural dispersion with payload delivery allow porous scaolds
to form. Successful porous synthetic hydrogels in cornea replacements oer an example of this. Such scaolds are also known to
promote cell migration and angiogenesis and with a high water
content are capable of rapid nutrient diusion.325
Although porosity is desirable for tissue integration, the biggest
challenge yet for porous hydrogel scaolds is the poor mechanical strength that they display.326 Cross-linking density plays an
important role in appropriating mechanical compliance and
mesh size for cell encapsulation and use in tissue augmentation procedures.327 Careful control of chemical and processing
parameters can ultimately yield hydrogel scaolds with numerous
benets for tissue regeneration eorts.
STIMULI RESPONSIVE POLYMERS
Refs
polymeric systems, creating multi-functional systems.334 As

such, stimuli-responsive polymers have received great interest
over the past decade and have been taken up in a number of
medical applications from drug delivery and tissue engineering to
imaging.
Thermo-responsive polymers
To date, temperature- and pH-sensitive polymers have been the
most frequently studied type of stimuli-responsive polymer.
Thermoresponsive polymers can change their hydrophilicity/hydrophobicity, conformation or solubility due to a phase
transition reaction when prompted by elevated temperatures335
to reach a threshold temperature known as critical solution temperature (CST). Generally, a lower critical solution temperature
(LCST) polymers will reduce the solubility (increase hydrophobicity) while a higher critical solution temperature (HCST) will increase
solubility (increase hydrophilicity).336 Poly(N-isopropylacrylamide)
(PNIPAAm) in particular has been the most researched
temperature-responsive polymer where it exhibits a transition
from hydrophilicity under 32 C to a hydrophobicity above this
temperature.337 One study demonstrated the utility of the LCST
feature of PNIPAAm with a thiolated chitosan-PNIPAAm hydrogel used for wound infections that deliver ciprooxacin (an
anti-bacterial drug) to the wound site that will then swell upon
the addition of cold water for easy removal of the gel. Another
example is poly(N-vinylcaprolactam), a lactam-based polymer that
is also thermoresponsive with a LCT of about 35 C338 and holds
promise in tissue engineering applications as it thermoresponsivity allows for the formation of a macroporous architecture a
common limitation for hydrogels intended for use in tissue engineering applications. Other temperature-responsive polymers
used in biomedical applications include poly(N-vinylcaprolactam)
1801
Smart or intelligent polymers are those which can alter their

physio-chemical properties in response to stimuli (pH, temperature, redox, enzymes, light, magnetic, ultrasound) such that a particular functional output of the polymeric system occurs. Among
some property changes that can occur as a response to stimuli are
changes in surface wettability,328 membrane permeability,329,330
swelling capability (hydrogels),331 aggregation behaviour,332
and sol-gel transition.333 Stimuli-responsive polymers are produced by introducing specic polymeric modalities to traditional
Time to
Degradation
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D Ozdil, HM Aydin
Figure 3. Common methods of hydrogel synthesis A) Free-radical polymerisation of diacrylate macromer. B) Conjugate addition of a thiol and acrylate
group. C) Click bonding of a pendant alkyne and azide via 1,2,3-triazole group. Adapted from Ref. (323) by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Reprinted with permission.
(PVCL) which has increasing hydrophobicity and insolubility from

2535 C,339 poly(ethylene glycol) (PEG) or poly(ethylene oxide)
(PEO) which becomes insoluble above 80 C and poly(propylene
oxide) (PPO) which, when in co-polymer form,340,341 can exhibit a
wide range of solubility and phase transition temperatures.
properties, for example, increased surface adhesion when in

protonated form, have also inspired interest for their use in drug
delivery systems.
CONCLUDING REMARKS
1802
pH-responsive polymers
pH-responsive polymers respond to changes in pH, co-solvent,
and electrolytes such that changes in their solubility, volume,
and chain conformation can be observed. The pH-responsiveness
of polymers can be tuned by the incorporation of ionizable
monomer units in to their polymeric backbones. Chitosancarrageenan-based polyelectrolyte complexes have been
explored as porous biomaterials that can maintain stability
at physiological conditions while dissociating upon implantation due to chitosan reacting under the lowered pH levels
caused by local inammation associated with implantation.342
Another study343 was able to show how electrospun polyelectrolyte hydrogel nanobres were able to display reversible
swelling/contracting with varying pH, highlighting their potential
as articial muscles, interactive tissue engineering scaolds or
drug delivery systems. Materials based on poly(acrylic acid) (PAAc)
and poly(methacrylic acid) (PMAc) are common polymers used
in pH-responsive systems and can also exhibit reversible swelling
when pH is varied.344,345 Such acrylic polymers and their unique
Currently, the number of donors required for organ and soft tissue replacement are well below those numbers that are actually in
demand. For this reason, research and development of synthetic
materials capable of combining cellular components for both the
in vitro and in vivo regeneration of tissues are continuing to proceed at a signicant pace. The range of dierent chemical natures
of dierent polymers, the ability to fabricate them such that they
replicate tissue or organ morphologies, their ability to biodegrade
without adverse eects, and their biocompatibility has created a
great area of use in the eld of tissue engineering. The modication and enhancement of several processing methods such as
3D printing, electrospinning, bre processing, and foaming for the
production of tissue scaolds seen in recent years, the fall of prices
associated with medical grade products and the improvements in
conditions of manufacturing these products in small-scale clean
environments have all been factors leading to the uptake of polymers in eorts to regenerate bone, cartilage, tendon, skin, cornea,
and other tissues that constitute dierent morphological and
mechanical properties. The advancements in growth factor-cell

studies and stem cell studies that have progressed parallel to
these eorts combined with the widespread use of bioreactors, all
within the regulative standards of special organizations such as the
advanced technological medicinal products (ATMP), provide foresight into the utilization of polymers in multi-component complex
systems that are developed in tissue engineering studies and subsequently taken up in clinical use.
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Polymers For Medical and Tissue Engineering Applications: Review

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Review

Received: 20 May 2014

Revised: 24 July 2014

Accepted article published: 4 August 2014

Published online in Wiley Online Library: 3 September 2014

(wileyonlinelibrary.com) DOI 10.1002/jctb.4505

Polymers for medical and tissue engineering

Regenerative medicine has seen great advancements over the

The rst polymers to be used in biomedical applications,

Correspondence to: Halil Murat Aydin, Environmental Engineering Department

a BMT Calsis Co., Hacettepe University Technopolis, 06800, Beytepe, Ankara,

2014 Society of Chemical Industry

J Chem Technol Biotechnol 2014; 89: 17931810

without creating cytotoxic degradation products, but they are

2014 Society of Chemical Industry

J Chem Technol Biotechnol 2014; 89: 17931810

Polymers for medical and tissue engineering applications

J Chem Technol Biotechnol 2014; 89: 17931810

indirectly by binding extracellular matrix proteins in the blood.69,70

2014 Society of Chemical Industry

SYNTHETIC POLYMERS AS BIOMATERIALS

The biocompatibility of PEEK and PEEK composites127 has

2014 Society of Chemical Industry

J Chem Technol Biotechnol 2014; 89: 17931810

Polymers for medical and tissue engineering applications

J Chem Technol Biotechnol 2014; 89: 17931810

composition is the main determinant of the chemical, mechanical

2014 Society of Chemical Industry

Poly(-hydroxyacids) (Poly(glycolic acid), Poly(lactic acid)

extensively, and have proved to be biocompatible. The traditional

2014 Society of Chemical Industry

J Chem Technol Biotechnol 2014; 89: 17931810

Polymers for medical and tissue engineering applications

J Chem Technol Biotechnol 2014; 89: 17931810

2014 Society of Chemical Industry

PGS is completely bioresorbable with degradation products

Poly(ethylene glycol) Poly(ethylene oxide)

are termed poly(ethylene oxide) (PEO). The hydroxyl groups at the

2014 Society of Chemical Industry

J Chem Technol Biotechnol 2014; 89: 17931810

Polymers for medical and tissue engineering applications

Table 1. Properties of popular synthetic polymers used in medicine

and structural advantages such as increased elastic modulus,313

STIMULI RESPONSIVE POLYMERS

polymeric systems, creating multi-functional systems.334 As

2014 Society of Chemical Industry

Smart or intelligent polymers are those which can alter their

(PVCL) which has increasing hydrophobicity and insolubility from

properties, for example, increased surface adhesion when in

2014 Society of Chemical Industry

J Chem Technol Biotechnol 2014; 89: 17931810

Polymers for medical and tissue engineering applications

J Chem Technol Biotechnol 2014; 89: 17931810

21 Isenberg BC and Tranquillo RT, Long-term cyclic distention enhances

2014 Society of Chemical Industry

1 Lakshmi SN, Laurencin CT, Biodegradable polymers as biomaterials.

potential application in tissue engineering scaolds. Designed

67 Yamada Y, Hozumi K, Katagiri F, Kikkawa Y and Nomizu M, Biological

2014 Society of Chemical Industry

J Chem Technol Biotechnol 2014; 89: 17931810

Polymers for medical and tissue engineering applications

J Chem Technol Biotechnol 2014; 89: 17931810

111 Colonna C, Conti B, Perugini P, Pavanetto F, Modena T, Dorati R, et al.,