ORIGINAL ARTICLE

Vascularized Composite Allotransplantation

and Tissue Engineering
Ericka M. Bueno, PhD, J. Rodrigo Diaz-Siso, MD, Geoffroy C. Sisk, MD, Akash Chandawarkar, BS,
Harriet Kiwanuka, Brooke Lamparello, MA, Edward J Caterson, MD, PhD, and Bohdan Pomahac, MD
Abstract: For many living with the devastating aftermath of disfiguring facial injuries, extremity amputations, and other composite
tissues defects, conventional reconstruction offers limited relief.
Full restoration of the face or extremities with anatomic equivalents
recently became possible with decades of advancements in transplantation and regenerative medicine. Vascularized composite allotransplantation (VCA) is the transfer of anatomic equivalents from
immunologically and aesthetically compatible donors to recipients
with severe defects. The transplanted tissues are composite
because they include multiple types essential for function, for
example, skin, muscle, nerves, and blood vessels. More than 100
patients worldwide have benefited from VCA, the majority receiving hand or face transplants. Despite its demonstrated results, the
clinical practice of VCA is limited by center experience, public
awareness, donor shortage, and the risks of lifelong immune suppression. Tissue engineering (TE) is the generation of customized
tissues in the laboratory using cells, biomaterials and bioreactors.
Tissue engineering may eventually supersede VCA in the clinic,
because it bypasses donor shortage and immune suppression challenges. Billions of dollars have been invested in TE research and
development, which are expected to result in a myriad of clinical
products within the mid- to long-term. First, tissue engineers must
address challenges such as vascularization of engineered tissues and
maintenance of phenotype in culture. If these hurdles can be overcome, it is to be hoped that the lessons learned through decades of
research in both VCA and TE will act synergistically to generate
off-the-shelf composite tissues that can thrive after implantation and
in the absence of immune suppression.
Key Words: Vascularized composite allotransplantation,
composite tissue transplantation, tissue engineering
(J Craniofac Surg 2013;24: 256Y263)
From the Division of Plastic Surgery, Brigham and Womens Hospital,
Boston, Massachusetts.
Received July 27, 2012.
Accepted for publication September 11, 2012.
Address correspondence and reprint requests to Ericka M. Bueno, PhD,
Division of Plastic Surgery, Brigham and Womens Hospital, 75 Francis
St, Boston MA 02115; E-mail: ebueno@partners.org
The facial transplantation clinical trial at Brigham and Womens Hospital is
supported by US Department of Defenses Biomedical Translational
Initiative contract W911QY-09-C-0216. Drs. Bueno, Diaz-Siso, and
Pomahac receive research support from the US Department of Defense,
under the Biomedical Translational Initiative (contract W91QY-09-C-0216).
The other authors report no conflicts of interest.
Copyright * 2013 by Mutaz B. Habal, MD
ISSN: 1049-2275
DOI: 10.1097/SCS.0b013e318275f173

256

r. Joseph E. Murray1 forever changed the field of transplantation in 1954, when he completed the first successful human
kidney transplant. His work invigorated global interest in transplant
medicine2 and translated to important medical advances.3 Dr.
Murrays work also raised many ethical questions similar to those
encountered today in vascularized composite allotransplantation
(VCA). The most controversial aspect of kidney transplantation in
the 1950s was performing a nephrectomy on a healthy donor2; a
similar discussion surrounds VCA because it is used in subjects
thought of as healthy. Moreover, in the early stages of organ
transplantation and VCA, concerns were raised about funding for
these therapies.4,5 Any innovative surgery or procedure carries
initially high costs; however, increased clinical experience and scientific developments eventually reduce the costs.4
Hundreds of thousands live with massive defects of vascularized composite tissues such as limb amputation or facial disfigurement. Vascularized composite tissues are functional blocks of
multiple tissues such as skin, muscle, bone, nerves, and blood vessels that must be precisely replicated to fully restore a patient to the
preinjury state. Conventional reconstruction cannot achieve such
level of restoration, whereas VCA can provide near-normal
restoration (Figs. 1 and 2). Unfortunately, VCA carries the obligation of lifelong global immunosuppression to prevent transplant
rejection.
Although not immediately available, tissue engineering (TE)
will likely replace allotransplantation in the future. Tissue engineering promises to replace damaged tissues/organs with biologic
equivalents created in the laboratory through synergistic manipulation of cells, biologic signals, and scaffolds (Fig. 3).6 Tissue engineering has had limited translation into the clinical arena, because of
difficulties with precise control over the growth, differentiation, and
integration of target tissues. Vascularized composite allotransplantation, meanwhile, has been used in more than 100 patients. A few
programs in the United States have clinical VCA experience (Table 1),
whereas TE has no comparable current availability yet. Both VCA
and TE face conceptual and practical challenges (Table 2) hindering clinical transition. For TE, the fundamental difficulty lies in the
generation of large, complex vascularized tissue blocks and their integration without loss of target phenotype. For VCA, the largest hurdle remains the requirement for immunosuppression. We believe that
ideas can flow from both the TE and VCA camps toward the goal
of restoring complex tissues back to function. We envision a coalescence of principles into a productive strategy for off-the-shelf,
immunosuppression-free incorporation of biologic tissues.7

Tissue Engineering
The Promise
Of approximately 100,000 Americans waiting for compatible
organ donors, thousands die waiting every year.8 Those who receive
transplants endure lifelong immunosuppression with its adverse
effects of metabolic disorders,9,10 nephrotoxicity,11 and increased

The Journal of Craniofacial Surgery

& Volume 24, Number 1, January 2013

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The Journal of Craniofacial Surgery

& Volume 24, Number 1, January 2013

FIGURE 1. Aesthetic restoration of a devastating partial facial defect with

conventional reconstruction (top) and VCA (bottom). A 59-year-old man
suffered from electrical burn injuries to the central face. Multiple staged
reconstructions resulted in the aesthetic outcome observed in the top row
(A, frontal view; B, profile). In addition to the aesthetic disfiguration, there were
functional limitations with breathing, speaking, eating, drinking, and drooling,
as well as severely impacted quality of life. The patient received partial facial
allotransplantation in April 2009.133 Aesthetic restoration of the facial units is
appreciated in the 2-year postoperative photographs in the bottom row
(C, frontal view; D, profile). Functionally, the patient regained near-normal
sensory and motor function of the transplanted parts. B and D are reprinted
from Caterson et al (accepted, not published yet) with permission from the
Journal of Craniofacial Surgery.

risk of infections12,13 and malignancy.14,15 Tissue engineering

eliminates the need for donors and immune suppression. Tissue
engineering was first defined in 1988,16 when researchers first
envisioned generating tissues by controlling autologous cells, materials, and their microenvironment and delivering them into a defect.17,18 This basic premise has not changed, but implementation
has proven difficult. Today, we can mimic biologically functional
tissue at the micro level.
Early proof-of-concept reports of engineered tissues promised easily available, immunologically compatible, and selfrepairing tissue and organ substitutes. Tissue engineering was
rapidly given priority federal funding status in the late 1980s.19 A
photograph of an engineered human ear on the back of a mouse
made international headlines in 1997, prompting a myriad of

VCA and Tissue Engineering

FIGURE 3. Paradigm of TE. Cells are taken from a patient in need of tissue
restoration. The cells are seeded into a biodegradable scaffold that provides
structural support as well as a three-dimensional configuration for tissue growth.
A period of in vitro or in vivo cultivation follows, during which cells proliferate
and secrete extracellular matrix into the scaffold, in synchrony with scaffold
degradation. The resulting engineered tissue construct is then implanted into
the patient for restoration of the tissue defect.

funding from the private and public sectors.20 The up-and-coming

TE industry was estimated at $100 billion. Media reports suggested
that engineered body parts would reach market shelves within 5 to
10 years.21

From the Late 1990s Into Today

The first TE products with Food and Drug Administration
(FDA) approval were allogeneic skin dressings introduced to the
market in the late 1990s (eg, Apligraf; Novartis, East Hanover, NJ)
and later followed by an autologous epidermal substitute (Epicel;
Genzyme Biosurgery, Cambridge, MA) used under a humanitarian
device exemption and an FDA-approved therapy for focal articular
cartilage lesions (Carticel; Genzyme Biosurgery). These products
were expensive to develop and produce and required substantial
time to become established in the clinical marketplace.22 In 2002,
the National Institutes of Health awarded $25 million to stem cell
research, and the FDA established an office to coordinate the regulation of all TE products.21 By 2004, although more than $4.5
billion had been invested in TE, there were few profitable products
on the market.21,23 Slow translation was attributed to poor development, management, and business strategies and an unclear regulatory environment.22 Tissue engineering products were often
unable to provide significant and cost-effective advantage to current
clinical modalities, and/or third-party reimbursement was cumbersome. Investments of $50 to $300 million were often required to
develop a TE product into an FDA-approved device or biologic.
Nearly $2.5 billion were lost in TE ventures between 2001 and
2003.22 Today, TE companies are developing profitable products24
and progressing toward clinical translation. The global TE and

TABLE 1. List of US Centers With Clinical Experience in VCA

Institution

FIGURE 2. Schematic of 3 different VCA interventions. Top: face

transplantation, center: bilateral upper-extremity transplantation, bottom:
transplantation of multiple extremities (in this case, 1 upper and 1 lower
extremities). A recipient (left column) with a large defect such as facial
disfigurement, bilateral extremity amputation, or multiple-extremity
amputation receives a replica of the missing anatomic units from a deceased
donor (center column). There is immediate restoration of form after the
operation (right column), with improved appearance as swelling decreases and
motor function returns. Motor and sensory functions return in the months
following the operation and are dependent on nerve regeneration and
compliance with rehabilitation.

Brigham and Womens Hospital

Cleveland Clinic
Emory University
University of California Los Angeles
University of Kentucky
University of Maryland
University of Miami
University of Pittsburgh
Wilford Hall USAF Medical Center

Location

Tissues Transplanted

Boston, MA
Cleveland, OH
Atlanta, GA
Los Angeles, CA
Louisville, KY
Baltimore, MD
Miami, FL
Pittsburgh, PA
San Antonio, TX

Face, upper extremities

Face, larynx
Upper extremities
Upper extremities
Upper extremities
Face
Abdominal wall
Upper extremities
Upper extremities

Centers are listed in alphabetical order, along with the anatomic units transplanted.

* 2013 Mutaz B. Habal, MD

Copyright 2013 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.

257

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Bueno et al

TABLE 2. Current Advantages and Limitations of TE and Vascularized

Composite Tissue Allotransplantation in the Treatment of Massive Composite
Tissue Defects

Advantages

VCA (Present)

TE (Future)

m Available now
m Vascularized tissues
m Return of motor and sensory
function with nerve coaptation

m No need for donors

m No immunosuppression
m Customizable tissues can
hypothetically be made to
match perfectly
m Less rigid time constraints with
respect to surgical implantation

m No donor sites needed

m One operation
m Can restore very complex units
(eg, an entire arm)
Disadvantages
n Donor shortageVoften
requires donation of identifiable anatomic features, which
can be controversial
n Lifelong immunosuppression
n Not a perfect aesthetic or
immunologic match
n Very rigid time constraints
between allograft recovery and
transplantation
n It is currently only justifiable
for the largest and/or most
severe defects

n Not currently available

n Vascularization remains
challenging
n Return of motor and sensory
function will only be possible
with successful nerve TE
n Donor sites needed

n May need staged operations

n Can currently restore only very

small (in millimeters), simple
units (eg, a focal cartilage
defect)

regenerative medicine markets are estimated to approach $3.2 billion by 2013.25

Autologous chondrocyte implantation has nearly 2 decades
of market experience in the treatment of focal cartilage defects.26 Its
long-term outcomes appear mixed, with the main criticisms being
maintenance of chondrocytic phenotype and quality of tissue
integration.27Y33 Aside from autologous chondrocyte implantation,
there is only 1 currently FDA-approved cellular therapy: an autologous fibroblast-based product for improvement of nasolabial
folds.34 Clinicaltrials.gov shows less than 30 active studies under
the keywords tissue engineering, engineered, construct, and
scaffold. Results of these trials are not available.
Documented experiences with engineered vascular grafts,35
articular cartilage constructs,36 and periodontal TE are promising.37,38 These positive outcomes may have been facilitated by the
small size of the treated defects and the absence of vascularization
challenges. As for more complex engineered tissues, there are few
isolated case reports: successful implantation of autologous engineered airway and engineered trachea39,40 and bilateral reconstruction of the orbitozygoma using engineered bone.41 Despite these
promising clinical results, engineered tissues can presently restore
only a subset of the anatomic and functional requirements of their
native counterparts. Decades of research have generated an extensive body of data showing that individual tissues have specific
engineering requirements, but as a general rule, maintaining target
phenotype and architecture and supplying adequate means of
nutrient and waste exchange to the cells are most important.
Although there have been satisfactory outcomes with small, nonvascular tissues for reconstruction (Fig. 4), the development of a
large engineered vascularized composite tissue block to restore a
full face or a limb remains beyond our reach.42

258

& Volume 24, Number 1, January 2013

The Evolution of Vascularized Composite

Allotransplantation
Although the idea of restoring the body by transplantation is
ancient,43 only as recently as during World Wars I and II the first
reconstructive techniques involving skin grafts were reported.44
Rejection of these grafts prompted studies on transplant immunology,45,46 which suggested skin was the most immunogenic and
therefore most difficult tissue to transplant.3 In 1957, 3 years after
Dr. Murrays pioneer transplant,47,48 a digital flexor tendon
mechanism that contained multiple tissues was transplanted, and the
term composite tissue allograft was born.43,49,50 Effective
immunosuppressive drugs such as azathioprine were developed
shortly after and facilitated the first cadaveric donor transplants.51 In
1964, the first hand allotransplantation was attempted in Ecuador,
but irreversible acute rejection occurred despite azathioprine and
prednisone immunosuppression.52,53 Improved immunosuppressants further helped advance solid organ transplantation, but surgeons remained cautious of transplanting skin-containing structures
until the emergence of mycophenolate mofetil and calcineurin inhibitors. In 1998, the first successful human hand transplantation
was performed in France.54 The United States followed closely with
a case in 1999. More than 50 hands have been transplanted since,
with most patients regaining sufficient sensory and motor function
to perform daily activities and return to work.55 After the hands, the
most commonly transplanted structure is the larynx, first successfully transplanted in Cleveland in 1988, and since mastered by a
Colombian team.56,57 In the late 1990s, unsuccessful knee and
femur transplantations were performed in Germany.58 American and
Italian teams reported excellent results with abdominal wall transplantation.59,60 Others reported single-experience transplantations
of uterus, tongue, and penis.61Y63 In 2005, after extensive global
ethical debate, Dubernards team performed the worlds first face
transplantation in France.64 Interventions in China, Paris, and Cleveland soon followed.65Y67 Today, more than 20 patients have
received face transplants (Table 3), with promising cosmetic and
functional results, and less severe complications than expected.
Global experience in VCA has established technical feasibility and superiority of restoration compared with conventional
reconstruction. However, these results are countered with the risks
of lifelong immunosuppression. The future of VCA depends on
reducing or eliminating these risks.

FIGURE 4. Outcomes of restoration by TE methods in a 9-year-old girl with

microtia. Autologous chondrocytes cultured in multiple layers were injected into
the abdomen of the patient where they remained for a 6-month period. The cell/
scaffold construct developed into engineered neocartilage with
neoperichondrium within the abdominal wall and was reshaped and
transplanted to the patients ear region. A, Preoperative view. B, Neocartilage
taken from the abdomen of the patient 6 months after implantation and
sculpted into the form of an ear. C, Postoperative view 5 years after successful
transplantation of the engineered ear. Reprinted with permission from Yanaga et
al, Tissue Engineering Part A, Cell-Engineered Human Elastic Chondrocytes
Regenerate Natural Scaffold In Vitro and Neocartilage With Neoperichondrium
in the Human Body Post-Transplantation, 2012 (published online ahead
of print).

* 2013 Mutaz B. Habal, MD

Copyright 2013 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.

The Journal of Craniofacial Surgery

& Volume 24, Number 1, January 2013

TABLE 3. World Experience With Facial Allotransplantation

Recipient
Sex/Age,
Country
y

Mechanism of
Injury

Full or
Partial

Date
Performed

Reference (if
Available)

France

Animal attack

Partial

November
2005

Figliuzzi et al,129
Mercader
et al130
Chung et al71
Minas72

F/38

China
France

M/30
M/29

Animal attack
Neurofibromatosis

Partial
Partial

April 2006
January
2007
December
2008
March
2009
April 2009
April 2009

United
States
France

F/45

Gunshot

Partial

M/27

Gunshot

Partial

France
United
States
France

M/39
M/59

Burns
Electrical burns

Partial
Partial

M/33

Gunshot

Partial

Spain

M/42

Cancer

Partial

France

M/27

Explosion

Partial

Spain

M/35

Neurofibromatosis

Partial

Spain
France
United
States
United
States
France
France
United
States
Belgium

M/30
M/35
M/26

Gunshot
Neurofibromatosis
Electrical burns

Full
Full
Full

August
Galloway et al132
2009
August
*
2009
November
*
2009
January
*
2010
March 2010 Barret et al134
June 2010
*
March 2011
Robertson81

M/30

Electrical burns

Full

April 2011

Robertson81

M
M
F/57

Gunshot
Gunshot
Animal attack

Partial
Partial
Full

April 2011
April 2011
May 2011

*
*
Robertson81

Undisclosed

Partial

Turkey

M/19

Burns

unknown

Turkey

M/25

Burns

Full

Turkey
United
States
Turkey

F/20
M/37

Gunshot
Gunshot

Partial
Full

December
2011
January
2012
February
2012
March 2012
March 2012

M/27

Burns

Full

May 2012

Cooper et al131
Galloway et al132
Galloway et al132
Pomahac et al133

*
*
*
*

*Based on information gathered from scientific meeting presentation and media

releases, as well as recently published reviews.

RESEARCH FUNDING
According to the NIH Reporter,68 $6,188,125 has been
granted to 7 different VCA studies, in contrast with more than $4
billion for TE research over the last 20 years.69 Recently, the Armed
Forces Institute of Regenerative Medicine became a major sponsor
of research aimed at developing TE, regenerative medicine, and
VCA solutions for wounded warriors. The Biomedical Translational
Initiative of the Department of Defense supports the Brigham and
Womens Hospital face transplantation program (Boston, MA). The
Department of Defense, through its Congressionally Directed
Medical Research Programs, has identified VCA as one of its focus
areas for the 2012 and 2013 fiscal years.
Given the huge impact of translation of TE into the clinic, we
expect that current funding will be sustained or increased. As for
VCA, there is current and emerging interest by the US Department
of Defense, which is expected to propel important developments.

VCA and Tissue Engineering

An unprecedented rate of survival in American wounded warriors

after injury by improvised explosive devices has resulted in many
with severe craniomaxillofacial defects, limb amputations, and
genitourinary defects with limited reconstructive options who could
benefit from VCA.

COSTS
Based on the Brigham and Womens Hospital experience, the
1-year mean costs of face transplantation are $246,052 and include
(i) physician and professional visits, laboratory tests, and radiology
procedures during screening; (ii) organ acquisition; (iii) perioperative, including inpatient admission, and operating room costs; and
(iv) follow-up including immunosuppression and other medications,
physician and professional visits, treatment of acute rejection,
complications, laboratory tests, radiology procedures, and rehabilitation. Others reported these costs as $349,959 for the first year,70
and lifetime costs of bilateral hand transplantation as $529,315.71
Although there is no TE intervention comparable to face or hand
transplantation, individual TE therapies such as Carticel and Infuse
bone graft have been estimated at $17,000 to $38,00072 and
$33,860,73 per patient, respectively. If we assume the costs of
assembling multiple TE products into a large vascularized composite tissue block are additive, they may total hundreds of thousands of dollars. Nonetheless, the gains in quality of life promised
by TE and VCA clearly surpass those achievable with conventional
interventions,64,66,74,75 and costs of VCA and TE should decrease
over time.

ENABLING TECHNOLOGIES
The last decades have seen remarkable advancement in our
understanding of molecular and developmental biology and materials science that may support the leap of TE and VCA toward
widespread clinical implementation. Some are briefly described in
the following sections.

Stem Cells
A tissue-engineered construct should contain millions of
cells capable of maintaining the target cellular phenotype and
building tissue with biomimetic properties, vascularization, and
nonimmunogenicity.76 Specialized adult cells cannot accomplish
this, nor can they be obtained in millions without creating sizeable
donor site defects, but stem cells can. Various types of stem cells
have been used in TE: tissue-specific adult stem cells, embryonic
stem cells (ESCs), and induced pluripotent cells.77 Embryonic stem
cells and induced pluripotent cells may hold the most promise;
research is underway to safely and reproducibly induce their commitment to target phenotypes. Embryonic stem cells may provide
the much needed pluripotency and plasticity necessary for de novo
production of functional tissues.78 Since 2008, a growing number of
countries are actively pursuing research with human ESCs
(hESCs).79 However, the utilization and destruction of human
embryos have cloaked the subject in controversy. The crux of such
heated debate lies within the question of the time point at which life
begins: fertilization, in the womb, or at birth? And, does the
potential to cure and treat an innumerable population of patients
justify the destruction of even a single embryo?80,81
Commitment to religion remains a major influencing factor
in the status of hESC research around the world. Since Islam, Hinduism, and Judaism view the beginning of life with 3 to 5 months
gestation,82 ESC research has generally been supported in countries
where these religions are predominant. However, Islamic position
prohibits the creation of embryos for the sole purpose of research.
The Catholic Church still remains staunchly opposed to hESC
research,83 and so, in Latin American countries where Catholicism
maintains a large political influence, challenges remain in how to
regulate hESC research because of religious pressures/constraints.84

* 2013 Mutaz B. Habal, MD

Copyright 2013 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.

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Bueno et al

In the United States, the Obama administration lifted President George W. Bushs prior restriction on funding of hESC
research, but the issue has resurfaced with the upcoming 2012
election. The Republican presidential candidate has indicated plans
to reduce future federal funding for hESC research. Nonetheless, the
US public shows widespread acceptance of hESC research,85 with
62% of those polled believing hESC research is morally acceptable
and 55% believing that the federal government should fund hESC
research.86 The utilization of frozen human embryos left over from
fertility treatments remains under debate.87 In Canada, hESC
research is generally perceived as acceptable but must adhere to
strict ethical guidelines and performed for specific goals88; federal
agencies fund hESC research, but cloning of stem cells and creation of embryos specifically for hESC research are prohibited.
European countries maintain a more conservative view. In Austria,
Luxembourg, Greece, and Slovenia, the majority of the public
opposes ESC, whereas in Iceland, Norway, Sweden, and Great
Britain, the largest proportion of residents supports it.86 In 2011, the
Court of Justice of the European Communities banned patents
involving hESC lines,89 prompting fears that pharmaceutical companies will stop developing stem cell therapies and halt their utilization in medicine.90

Scaffolds
A scaffold for TE should be mechanically stable, biocompatible, and able to guide tissue-specific growth. These properties can be manipulated through materials science and engineering
principles. Cell-loaded scaffolds can be cultivated inside bioreactors
that optimize and control the growth environment.91 Diffusion of
nutrients and waste through the scaffolds must be optimized to
promote growth and viability of tissues. Diffusion limitations
through scaffolds hinder the generation of large (in centimeters)
engineered tissue blocks. Ongoing research in scaffold technology
aims to overcome these limitations.92Y96

& Volume 24, Number 1, January 2013

although apparently at a lower incidence than for solid organ

recipients.111
Donor-specific immune tolerance occurs when the recipients
immune system does not react to the allograft, thus eliminating the
need for immunosuppression. Inducing donor-specific immune
tolerance remains elusive; in a few cases, it happens spontaneously.117 Some have achieved it in preclinical solid organ transplant models, but skin remains challenging.118 Increasingly
aggressive approaches toward immune tolerance are being used,119
without success in humans.120 Some strategies can reduce, although
not eliminate, the immunosuppressive drug load.121

Tissue Engineering and Immunomodulation

Engineered tissues can also induce an immune response after
implantation, because of biomaterials, growth factors, and in some
cases allogeneic cells necessary for off the shelf availability.
Immune response can hinder integration and tissue regeneration in
TE. Immunomodulation aims to use the immune response to promote tissue regeneration in situ. Some strategies for immunomodulation involve materials engineering, localized drug delivery,
and cellular therapies.122Y125 We believe that both VCA and TE
will benefit from the localized modulation of the immune environment to minimize the immunosuppression requirement and improve
tissue regeneration.

Clinical Trial Registries

Sharing of data and clinical outcomes is critical for developing new medical technologies. A framework that allows the evaluation of clinical outcomes across multiple clinical trials can
support fast and safe clinical transition. The need for a registry of
TE clinical trials was reported in 2006,126 but it remains to be
implemented. The International Registry on Hand and Composite
Tissue Transplantation fulfills this role for VCA.55

Growth Factors
These cell-secreted molecules participate in the regulation
of cellular processes, including proliferation and/or differentiation.
For example, nerve regeneration may be facilitated by neurogenic
growth factors. However, growth factors have short biologic halflives that add significant expense to their therapeutic use.97 Engineers have sought solutions such as controlled delivery of growth
factors entrapped on scaffolds, genetic modification of the cells to
produce supraphysiological amounts of growth factors,98Y101 or plasmid DNA approaches.102Y110 Although many growth factors have
been researched in TE, findings can be contradictory depending on
experimental parameters.

Immunosuppression
Vascularized composite allotransplantation elicits immune
rejection; in particular, skin is believed to be the most immunogenic
component of a vascularized composite transplant.111Y113 Eightyfive percent of hand transplant recipients experienced acute rejection at least once in the first year after transplantation, and all were
successfully treated with immunotherapy.55 Of 4 face transplant
recipients at Brigham and Womens Hospital, 3 experienced single episodes of acute rejection in the first 6 postoperative months
and were successfully treated with medication.75 Acute rejection
in VCA can be diagnosed earlier (based in visible changes in skin),
is typically less severe, and can be treated more effectively than
in organ transplants; likely because VCA recipients tend to have a
less remarkable medical history. Vascularized composite allotransplantation recipients are on immunosuppression regimens similar to
those used in kidney transplantation.114 Unfortunately, immunosuppressive medications introduce serious adverse effects,11,12,115,116

260

CHALLENGES TO ENGINEERING A LARGE,

COMPLEX VASCULARIZED TISSUE
The challenges to vascularized composite TE are partially
rooted in the complexity of the target structures.127Y129 Vascularized
composite tissues are complex structures with interdependent
function necessitating integration and cooperation of multiple
essential tissue types within a single biologic compartment. Even
with reliable success at generating individual engineered tissues, it
is unclear whether multiple engineered tissue types would integrate
and function in vivo.
Replication of the embryological development of composite
tissues would need provision of a complex, constantly evolving
environment with multiple molecular signals. The vertebrate hind
limb demonstrates this complexity. The initial growth of the limb
bud is driven by exposure to fibroblast growth factors produced in
distal ectoderm.130 As the limb grows, the distal tissues are no
longer exposed to these proteins and begin to express their own
signaling proteins prompting differentiation into the various structures of the distal limb such as metatarsal bones.131 Meanwhile in
the proximal limb, undifferentiated mesenchyme becomes long
bones.132 The intricacies of the musculoskeletal, nervous, and vascular anatomy of the distal limb may be similarly delineated by local
molecular signaling proteins.
Developmental biology may provide the path for success in
developing fully functional engineered vascularized composite TE
blocks to restore form and function in a manner comparable to
allotransplantation. Although theoretically possible, this goal is
beyond the reach of our current science.
* 2013 Mutaz B. Habal, MD

Copyright 2013 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.

The Journal of Craniofacial Surgery

& Volume 24, Number 1, January 2013

CONCLUSIONS
Tissue engineering and VCA were born and fueled out of
the necessity of delivering functional replacements to missing or
damaged tissues. Vascularized composite allotransplantation has
provided functional restoration to more than 100 patients around the
world. The aesthetic and functional results and the relatively low
incidence of immunosuppressive-related complications have sparked
a rapid expansion of availability of VCA. However, until we are able
to bypass the immunosuppression requirement, most likely by induction of donor-specific tolerance, VCA will remain applicable
only to the most severe cases. In contrast, TE can potentially treat
smaller and less severe defects, but it is not yet available for widespread clinical use. As we begin to address the challenges faced by
TE and VCA, we propose a synergistic approach where TE tools
can be used for immunomodulation in VCA and/or where the transplantation of TE constructs benefits from the lessons learned during
VCA operations.

ACKNOWLEDGMENT
The authors thank Dr. Ebru Oral for assistance with objective
review of this manuscript.

REFERENCES
1. Murray JE, Merrill JP, Harrison JH. Renal homotransplantation in
identical twins. 1955. J Am Soc Nephrol 2001;12:201Y204
2. Murray JE. The 50th anniversary of the first successful human organ
transplant. Rev Invest Clin 2005;57:118Y119
3. Murray JE. Organ transplantation (skin, kidney, heart) and the plastic
surgeon. Plast Reconstr Surg 1971;47:425Y431
4. Moore FD. The desperate case: CARE (costs, applicability, research,
ethics). JAMA 1989;261:1483Y1484
5. Johnson SE, Corsten MJ. Facial transplantation in a new era: what are
the ethical implications? Curr Opin Otolaryngol Head Neck Surg
2009;17:274Y278
6. Caterson EJ, Nesti LJ, Albert T, et al. Application of mesenchymal stem
cells in the regeneration of musculoskeletal tissues. MedGenMed 2001;
Feb 5: E1
7. Caterson EJ, Caterson SA. Regeneration in medicine: a plastic
surgeons tail of disease, stem cells, and a possible future [published
online ahead of print December 11, 2008]. Birth Defects Res C Embryo
Today 2008;84:322Y334
8. US Department of Health and Human Services. Statistics and Facts.
Available at: http://www.organdonor.gov/aboutStatsFacts.asp.
Accessed November 29, 2011
9. Vicari-Christensen M, Repper S, Basile S, et al. Tacrolimus: review of
pharmacokinetics, pharmacodynamics, and pharmacogenetics to
facilitate practitioners understanding and offer strategies for educating
patients and promoting adherence. Prog Transplant 2009;19:277Y284
10. Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after
kidney transplantation in the United States. Am J Transplant
2003;3:178Y185
11. McKane W, Kanganas C, Preston R, et al. Treatment of calcineurin
inhibitor toxicity by dose reduction plus introduction of
mycophenolate mofetil. Transplant Proc 2001;33:1224Y1225
12. Splendiani G, Cipriani S, Tisone G, et al. Infectious complications in
renal transplant recipients. Transplant Proc 2005;37:2497Y2499
13. Parasuraman R, Yee J, Karthikeyan V, et al. Infectious complications in
renal transplant recipients. Adv Chronic Kidney Dis 2006;13:280Y294
14. Nalesnik MA. Clinicopathologic features of posttransplant
lymphoproliferative disorders. Ann Transplant 1997;2:33Y40
15. Kasiske BL, Snyder JJ, Gilbertson DT, et al. Cancer after kidney
transplantation in the United States. Am J Transplant 2004;4:905Y913
16. Tissue engineering: proceedings of a workshop held at Granlibakken,
Lake Tahoe, California, February 26Y29, 1988. In: Skalak R, Fox CF,
eds. Tissue Engineering Workshop; February 26Y29, 1988; Lake
Tahoe, California. New York: Alan Liss, 1988:xxi, 343 p

VCA and Tissue Engineering

17. Vacanti CA, Vacanti JP. The science of tissue engineering. Orthop Clin
North Am 2000;31:351Y356
18. Vacanti J, Vacanti CA. The history and scope of tissue engineering. In:
Lanza RP, Langer RS, Chick WL, eds. Principles of Tissue
Engineering. San Diego Austin: Academic Press ; R.G. Landes,
1997:3Y6
19. Nerem RM. Tissue engineering in the USA. Med Biol Eng Comput
1992;30:CE8YCE12
20. Lysaght M, Deweerd E, Jaklenec A. Principles of tissue engineering. In:
Lanza RP, Langer RS, Vacanti J, eds. Principles of Tissue Engineering.
3rd ed. Boston, MA: Elsevier/Academic Press; 2007:1265Y1270
21. Lysaght MJ, Hazlehurst AL. Tissue engineering: the end of the
beginning. Tissue Eng 2004;10:309Y320
22. Hunziker E, Spector M, Libera J, et al. Translation from research to
applications. Tissue Eng 2006;12:3341Y3364
23. Bouchie A. Tissue engineering firms go under. Nat Biotechnol
2002;20:1178Y1179
24. Ratcliffe A. The translation of product concept to bone products: a
partnership of therapeutic effectiveness and commercialization. Tissue
Eng Part B Rev 2011;17:443Y447
25. Worldwide Markets and Emerging Technologies for Tissue
Engineering and Regenerative Medicine. Huntington Beach, CA:
Life Science Intelligence; 2009
26. Brittberg M, Lindahl A, Nilsson A, et al. Treatment of deep cartilage
defects in the knee with autologous chondrocyte transplantation. N
Engl J Med 1994;331:889Y895
27. Peterson L, Brittberg M, Kiviranta I, et al. Autologous chondrocyte
transplantation. Biomechanics and long-term durability. Am J Sports
Med 2002;30:2Y12
28. Zaslav K, Cole B, Brewster R, et al. A prospective study of autologous
chondrocyte implantation in patients with failed prior treatment for
articular cartilage defect of the knee: results of the Study of the
Treatment of Articular Repair (STAR) clinical trial. Am J Sports Med
2009;37:42Y55
29. Peterson L, Vasiliadis HS, Brittberg M, et al. Autologous chondrocyte
implantation: a long-term follow-up. Am J Sports Med
2010;38:1117Y1124
30. Panagopoulos A, van Niekerk L, Triantafillopoulos I. Autologous
chondrocyte implantation for knee cartilage injuries: moderate
functional outcome and performance in patients with high-impact
activities. Orthopedics 2012;35:e6Ye14
31. Filardo G, Kon E, Di Martino A, et al. Second-generation arthroscopic
autologous chondrocyte implantation for the treatment of degenerative
cartilage lesions. Knee Surg Sports Traumatol Arthrosc
2011;20:1704Y1713
32. Kock L, van Donkelaar CC, Ito K. Tissue engineering of functional
articular cartilage: the current status. Cell Tissue Res.
2011;347:613Y617
33. Roberts S, McCall IW, Darby AJ, et al. Autologous chondrocyte
implantation for cartilage repair: monitoring its success by magnetic
resonance imaging and histology. Arthritis Res Ther 2003;5:R60YR73
34. US Food and Drug Administration. Vaccines, blood & biologics,
marketed products. Available at: http://www.fda.gov/
BiologicsBloodVaccines/CellularGeneTherapyProducts/
ApprovedProducts/default.htm. Accessed November 29, 2011
35. Matsumura G, Hibino N, Ikada Y, et al. Successful application of tissue
engineered vascular autografts: clinical experience. Biomaterials
2003;24:2303Y2308
36. Kreuz PC, Muller S, Ossendorf C, et al. Treatment of focal degenerative
cartilage defects with polymer-based autologous chondrocyte grafts:
four-year clinical results. Arthritis Res Ther 2009;11:R33
37. Nevins ML. Tissue-engineered bilayered cell therapy for the treatment
of oral mucosal defects: a case series. Int J Periodontics Restorative
Dent 2010;30:31Y39
38. Montesani L, Schulze-Spate U, Dibart S. Sinus augmentation in two
patients with severe posterior maxillary height atrophy using
tissue-engineered bone derived from autologous bone cells: a case
report. Int J Periodontics Restorative Dent 2011;31:391Y399

* 2013 Mutaz B. Habal, MD

Copyright 2013 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.

261

Bueno et al

The Journal of Craniofacial Surgery

39. Macchiarini P, Walles T, Biancosino C, et al. First human

transplantation of a bioengineered airway tissue. J Thorac Cardiovasc
Surg 2004;128:638Y641
40. Macchiarini P, Jungebluth P, Go T, et al. Clinical transplantation of a
tissue-engineered airway. Lancet 2008;372:2023Y2030
41. Taylor JA. Bilateral orbitozygomatic reconstruction with
tissue-engineered bone. J Craniofac Surg 2010;21:1612Y1614
42. OKeefe RJ, Mao J. Bone tissue engineering and regeneration: from
discovery to the clinic an overview. Tissue Eng Part B Rev.
2011;17:389Y392
43. Tobin GR, Breidenbach WC 3rd, Ildstad ST, et al. The history of human
composite tissue allotransplantation. Transplant Proc
2009;41:466Y471
44. Brown JB, McDowell F. Massive repairs of burns with thick split-skin
grafts: emergency dressings with homografts. Ann Surg
1942;115:658Y674
45. Brown JB, McDowell F. Epithelial healing and the transplantation of
skin. Ann Surg 1942;115:1166Y1181
46. Gibson T, Medawar PB. The fate of skin homografts in man. J Anat
1943;77(pt 4):299Y310
47. Harrison JH, Merrill JP, Murray JE. Renal homotransplantation in
identical twins. Surg Forum 1956;6:432Y436
48. Merrill JP, Murray JE, Harrison JH, et al. Successful
homotransplantation of the human kidney between identical twins. J
Am Med Assoc 1956;160:277Y282
49. Peacock EE Jr. Some problems in flexor tendon healing. Surgery
1959;45:415Y423
50. Peacock EE Jr. Homologous composite tissue grafts of the digital
flexor mechanism in human beings. Transplant Bull 1960;7:418Y421
51. Merrill JP, Murray JE, Takacs FJ, et al. Successful transplantation of
kidney from a human cadaver. JAMA 1963;185:347Y353
52. Gilbert R. Transplant is successful with a cadaver forearm. Med Trib
Med News 1964;5:20Y22
53. Gilbert R. Hand transplanted from cadaver is reamputated. Med Trib
Med News 1964;5:23Y25
54. Dubernard JM, Owen E, Herzberg G, et al. Human hand allograft:
report on first 6 months. Lancet 1999;353:1315Y1320
55. Petruzzo P, Lanzetta M, Dubernard JM, et al. The International Registry
on Hand and Composite Tissue Transplantation. Transplantation.
2010;90:1590Y1594
56. Strome M, Stein J, Esclamado R, et al. Laryngeal transplantation and
40-month follow-up. N Engl J Med 2001;344:1676Y1679
57. Duque E, Duque J, Nieves M, et al. Management of larynx and trachea
donors. Transplant Proc 2007;39:2076Y2078
58. Hofmann GO, Kirschner MH, Wagner FD, et al. Allogeneic
vascularized transplantation of human femoral diaphyses and total
knee jointsVfirst clinical experiences. Transplant Proc
1998;30:2754Y2761
59. Levi DM, Tzakis AG, Kato T, et al. Transplantation of the abdominal
wall [published online ahead of print July 5, 2003]. Lancet
2003;361:2173Y2176
60. Cipriani R, Contedini F, Santoli M, et al. Abdominal wall
transplantation with microsurgical technique. Am J Transplant
2007;7:1304Y1307
61. Fageeh W, Raffa H, Jabbad H, et al. Transplantation of the human
uterus. Int J Gynaecol Obstet 2002;76:245Y251
62. Birchall M. Tongue transplantation. Lancet 2004;363:1663
63. Hu W, Lu J, Zhang L, et al. A preliminary report of penile
transplantation. Eur Urol 2006;50:851Y853
64. Dubernard JM, Lengele B, Morelon E, et al. Outcomes 18 months after
the first human partial face transplantation. N Engl J Med
2007;357:2451Y2460
65. Guo S, Han Y, Zhang X, et al. Human facial allotransplantation: a
2-year follow-up study. Lancet 2008;372:631Y638
66. Lantieri L, Meningaud JP, Grimbert P, et al. Repair of the lower and
middle parts of the face by composite tissue allotransplantation in a
patient with massive plexiform neurofibroma: a 1-year follow-up
study. Lancet 2008;372:639Y645

262

& Volume 24, Number 1, January 2013

67. Siemionow M, Papay F, Alam D, et al. Near-total human face

transplantation for a severely disfigured patient in the USA. Lancet
2009;374:203Y209
68. NIH Reporter. National Institutes of Health, Research portfolio online
reporting tools (RePORT), query form. Available at: http://
projectreporter.nih.gov/reporter.cfm. Accessed November 29, 2011
69. Hollister SJ. Scaffold engineering: a bridge to where? Biofabrication
2009;1:012001. Accessed February 15, 2012
70. Siemionow M, Gatherwright J, Djohan R, et al. Cost analysis of
conventional facial reconstruction procedures followed by face
transplantation. Am J Transplant 2011;11:379Y385
71. Chung KC, Oda T, Saddawi-Konefka D, et al. An economic analysis of
hand transplantation in the United States. Plast Reconstr Surg
2010;125:589Y598
72. Minas T. Chondrocyte implantation in the repair of chondral lesions of
the knee: economics and quality of life. Am J Orthop (Belle Mead NJ)
1998;27:739Y744
73. Glassman SD, Carreon LY, Campbell MJ, et al. The perioperative cost
of Infuse bone graft in posterolateral lumbar spine fusion. Spine J
2008;8:443Y448
74. Siemionow MZ, Papay F, Djohan R, et al. First U.S. near-total human
face transplantation: a paradigm shift for massive complex injuries.
Plast Reconstr Surg 2010;125:111Y122
75. Pomahac B, Pribaz J, Eriksson E, et al. Three patients with full facial
transplantation. N Engl J Med 2012;366:715Y722
76. Vats A, Tolley NS, Polak JM, et al. Stem cells: sources and
applications. Clin Otolaryngol Allied Sci 2002;27:227Y232
77. Teo AK, Vallier L. Emerging use of stem cells in regenerative
medicine. Biochem J 2010;428:11Y23
78. Nelson TJ, Behfar A, Terzic A. Strategies for therapeutic repair: the
R(3) regenerative medicine paradigm. Clin Transl Sci
2008;1:168Y171
79. Derouen MC, McCormick JB, Owen-Smith J, et al. The race is on:
human embryonic stem cell research goes global. Stem Cell Rev 2012
[Epub ahead of print]
80. Williams C, Kitzinger J, Henderson L. Envisaging the embryo in stem
cell research: rhetorical strategies and media reporting of the ethical
debates. Sociol Health Illn 2003;25:793Y814
81. Robertson JA. Ethics and policy in embryonic stem cell research.
Kennedy Inst Ethics J 1999;9:109Y136
82. Manzar N, Manzar B, Hussain N, et al. The ethical dilemma of
embryonic stem cell research. Sci Eng Ethics 2011
[Epub ahead of print]
83. Zycinski J. Ethics in medical technologies: the Roman Catholic
viewpoint. J Clin Neurosci 2006;13:518Y523
84. Diniz D. Embryonic stem cell research: ethical challenges for
developing world bioethics. Dev World Bioethics 2008;8:iiYiv
85. Evans M, Kelley J. US attitudes toward human embryonic stem cell
research. Nat Biotechnol 2011;29:484Y488
86. Blendon RJ, Kim MK, Benson JM. The public, political parties, and
stem-cell research. N Engl J Med 2011;365:1853Y1856
87. Tully P. Researchers and firing squads: questions concerning the use of
frozen human embryos. J Med Philos 2011;36:516Y528
88. Guidelines for the conduct of human embryonic stem cell research.
Curr Protoc Stem Cell Biol. 2007; Appendix 1:Appendix 1A
89. Abbott A. Europe rules against stem-cell patents [published online
ahead of print March 18, 2011]. Nature 2011;471:280
90. Dyer C. European courts ban on stem cell patents will harm research,
say scientists. BMJ 2011;343:d6787
91. Vunjak-Novakovic G, Obradovic B, Martin I, et al. Bioreactor studies
of native and tissue engineered cartilage. Biorheology
2002;39:259Y268
92. Khademhosseini A, Langer R, Borenstein J, et al. Microscale
technologies for tissue engineering and biology. Proc Natl Acad Sci U
S A 2006;103:2480Y2487
93. Kane RS, Takayama S, Ostuni E, et al. Patterning proteins and cells
using soft lithography. Biomaterials 1999;20:2363Y2376

* 2013 Mutaz B. Habal, MD

Copyright 2013 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.

The Journal of Craniofacial Surgery

& Volume 24, Number 1, January 2013

94. Yeong WY, Chua CK, Leong KF, et al. Rapid prototyping in tissue
engineering: challenges and potential. Trends Biotechnol
2004;22:643Y652
95. Griffith LG, Wu B, Cima MJ, et al. In vitro organogenesis of liver
tissue. Ann N Y Acad Sci 1997;831:382Y397
96. Kapur TA, Shoichet MS. Immobilized concentration gradients of nerve
growth factor guide neurite outgrowth. J Biomed Mater Res A
2004;68:235Y243
97. Bueno EM, Glowacki J. Cell-free and cell-based approaches for bone
regeneration. Nat Rev Rheumatol 2009;5:685Y697
98. Jane JA Jr, Dunford BA, Kron A, et al. Ectopic osteogenesis using
adenoviral bone morphogenetic protein (BMP)-4 and BMP-6 gene
transfer. Mol Ther 2002;6:464Y470
99. Chen Y, Cheung KM, Kung HF, et al. In vivo new bone formation by
direct transfer of adenoviral-mediated bone morphogenetic protein-4
gene. Biochem Biophys Res Commun 2002;298:121Y127
100. Betz OB, Betz VM, Nazarian A, et al. Delayed administration of
adenoviral BMP-2 vector improves the formation of bone in osseous
defects. Gene Ther 2007;14:1039Y1044
101. Egermann M, Lill CA, Griesbeck K, et al. Effect of BMP-2 gene
transfer on bone healing in sheep. Gene Ther 2006;13:1290Y1299
102. Bonadio J, Smiley E, Patil P, et al. Localized, direct plasmid gene
delivery in vivo: prolonged therapy results in reproducible tissue
regeneration. Nat Med 1999;5:753Y759
103. Fang J, Zhu YY, Smiley E, et al. Stimulation of new bone formation by
direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci U S A
1996;93:5753Y5758
104. Endo M, Kuroda S, Kondo H, et al. Bone regeneration by modified
gene-activated matrix: effectiveness in segmental tibial defects in rats.
Tissue Eng 2006;12:489Y497
105. Peng L, Cheng X, Zhuo R, et al. Novel gene-activated matrix with
embedded chitosan/plasmid DNA nanoparticles encoding PDGF for
periodontal tissue engineering. J Biomed Mater Res A
2009;90:564Y576
106. Guo T, Zhao J, Chang J, et al. Porous chitosan-gelatin scaffold
containing plasmid DNA encoding transforming growth factor-beta1
for chondrocytes proliferation. Biomaterials 2006;27:1095Y1103
107. Capito RM, Spector M. Collagen scaffolds for nonviral IGF-1 gene
delivery in articular cartilage tissue engineering. Gene Ther
2007;14:721Y732
108. Grande DA, Mason J, Light E, et al. Stem cells as platforms for delivery
of genes to enhance cartilage repair. J Bone Joint Surg Am 2003;
85-A(suppl 2):111Y116
109. Jin XB, Sun YS, Zhang K, et al. Tissue engineered cartilage from hTGF
beta2 transduced human adipose derived stem cells seeded in PLGA/
alginate compound in vitro and in vivo. J Biomed Mater Res A
2008;86:1077Y1087
110. Guan Y, Ou L, Hu G, et al. Tissue engineering of urethra using human
vascular endothelial growth factor gene-modified bladder urothelial
cells. Artif Organs 2008;32:91Y99
111. Petruzzo P, Lanzetta M, Dubernard JM, et al. The international registry
on hand and composite tissue transplantation. Transplantation
2008;86:487Y492
112. Hettiaratchy S. Transplantation tolerance and chimerism: what are they
and do we need them? Plast Reconstr Surg 2004;113:2213Y2214
113. Mathes DW, Randolph MA, Solari MG, et al. Split tolerance to a
composite tissue allograft in a swine model [published online ahead of
print January 25, 2003]. Transplantation 2003;75:25Y31
114. Pomahac B, Nowinski D, Diaz-Siso JR, et al. Face transplantation. Curr
Probl Surg 2011;48:293Y357

VCA and Tissue Engineering

115. Fraser CJ, Scott Baker K. The management and outcome of chronic
graft-versus-host disease. Br J Haematol 2007;138:131Y145
116. Fangmann J, Dalchau R, Sawyer GJ, et al. T cell recognition of donor
major histocompatibility complex class I peptides during allograft
rejection. Eur J Immunol 1992;22:1525Y1530
117. Sykes M. Immune tolerance: mechanisms and application in clinical
transplantation. J Intern Med 2007;262:288Y310
118. Davis WC, McKenzie IF, Melvold RW. A comparison of skin and heart
graft rejection patterns in H-2 mutant mice. Transplantation
1980;29:189Y192
119. Kean LS, Gangappa S, Pearson TC. Transplant tolerance in non-human
primates: progress, current challenges and unmet needs. Am J
Transplant 2006;6(5 pt 1):884Y893
120. Hawksworth JS, Leeser D, Jindal RM, et al. New directions for
induction immunosuppression strategy in solid organ transplantation.
Am J Surg 2009;197:515Y524
121. Golshayan D, Pascual M. Tolerance-inducing immunosuppressive
strategies in clinical transplantation: an overview. Drugs
2008;68:2113Y2130
122. Boehler RM, Graham JG, Shea LD. Tissue engineering tools for
modulation of the immune response. Biotechniques 2011;51:239Y240,
42, 44 passim
123. Batten P, Sarathchandra P, Antoniw JW, et al. Human mesenchymal
stem cells induce T cell anergy and downregulate T cell allo-responses
via the TH2 pathway: relevance to tissue engineering human heart
valves. Tissue Eng 2006;12:2263Y2273
124. Chan G, Mooney DJ. New materials for tissue engineering: towards
greater control over the biologic response. Trends Biotechnol
2008;26:382Y392
125. Vianello F, Poznansky MC. Generation of a tissue-engineered thymic
organoid. Methods Mol Biol 2007;380:163Y170
126. Williams D. A registry for tissue engineering clinical trials. Med Device
Technol 2006;17:8Y10
127. Quint C, Arief M, Muto A, et al. Allogeneic human tissue-engineered
blood vessel. J Vasc Surg 2011;55:790Y798
128. Godier-Furnemont AF, Martens TP, Koeckert MS, et al. Composite
scaffold provides a cell delivery platform for cardiovascular repair.
Proc Natl Acad Sci U S A 2011;108:7974Y7979
129. Figliuzzi M, Plati T, Cornolti R, et al. Biocompatibility and function of
microencapsulated pancreatic islets. Acta Biomater 2006;2:221Y227
130. Mercader N, Leonardo E, Piedra ME, et al. Opposing RA and FGF
signals control proximodistal vertebrate limb development through
regulation of Meis genes. Development 2000;127:3961Y3970
131. Cooper KL, Hu JK, Ten Berge D, et al. Initiation of proximal-distal
patterning in the vertebrate limb by signals and growth. Science
2011;332:1083Y1086
132. Galloway JL, Delgado I, Ros MA, et al. A reevaluation of
X-irradiationYinduced phocomelia and proximodistal limb
patterning. Nature 2009;460:400Y404
133. Pomahac B, Pribaz J, Eriksson E, et al. Restoration of facial form and
function after severe disfigurement from burn injury by a composite
facial allograft. Am J Transplant 2011;11:386Y393
133. Pomahac B, Pribaz J, Eriksson E, et al. Restoration of facial form and
function after severe disfigurement from burn injury by a composite
facial allograft. Am J Transplant 2011;11:386Y393
134. Barret JP, Gavalda J, Bueno J, et al. Full face transplant: the first case
report. Am J Transplant 2011;254:252Y256

* 2013 Mutaz B. Habal, MD

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263