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REVIEW
Face transplantation—current status and future
developments
Sotirios Tasigiorgos
1
, Branislav Kollar
1
, Nicco Krezdorn
2
, Ericka M. Bueno
1
, Stefan G. Tullius
3
&
Bohdan Pomahac
1
1 Division of Plastic Surgery,
Department of Surgery, Brigham
and Women’s Hospital, Harvard
Medical School, Boston, MA, USA
2 Department of Plastic, Aesthetic,
Hand and Reconstructive Surgery,
Hannover Medical School,
Hannover, Germany
3 Division of Transplant Surgery,
Department of Surgery, Brigham
and Women’s Hospital, Harvard
Medical School, Boston, MA, USA
Correspondence
Bohdan Pomahac MD, Division of
Plastic Surgery, Department of
Surgery, Brigham and Women’s
Hospital, Harvard Medical School, 75
Francis Street, Boston, MA 02115,
USA.
Tel.: (617) 732-7796;
fax: (617) 732-6387;
e-mail: bpomahac@bwh.harvard.edu
SUMMARY
More than thirty-five facial allograft transplantations (FAT) have been
reported worldwide since the pioneering case performed in France in the
year 2005. FAT has received tremendous interest by the medical field and
the general public while gaining strong support from multiple disciplines
as a solution for reconstructing complex facial defects not amenable/re-
sponsive to conventional methods. FAT has expanded the frontiers of
reconstructive microsurgery, immunology and transplantation, and estab-
lished its place in the cross section of multiple disciplines. The procedure
introduces complex scientific, ethical, and societal issues. Patients and
physicians are called to deal with a variety of—sometimes everlasting—
challenges, such as immunosuppression management and psychosocial
hurdles. This review reflects on the surgical and scientific advancements in
FAT and milestones reached in the last 12 years. It aims to encourage
active discussion regarding the current practices and techniques used in
FAT and suggest future directions that may allow transitioning into the
next phase of FAT, which we describe as safe, reliable, and accessible stan-
dard operation for selected patients.
Transplant International 2018;
Key words
face transplantation, future of face transplantation, vascularized composite allotransplantion
Received: 7 November 2017; Revision requested: 21 December 2017; Accepted: 2 February 2018
Introduction
Devastating facial injuries distort the anatomy of the
face, leading to severe functional and esthetic impair-
ments. Most patients presenting for face transplant con-
sultations are missing major components of the face
such as nose, mandible, maxilla, ears, lips, and/or parts
of the oral cavity. Motor function of the face requires
an intricate interplay of these unique three-dimensional
anatomical structures [1]. Thus, defects impair not only
appearance, but also functions such as mastication,
speech, vision, and breathing [2–5]. Furthermore, the
face provides information about the identity, age,
gender, and ethnicity of an individual and thus affects
social interactions, integration, and perception of body
image. Impairment in these social functions impacts
quality of life that can result in discrimination and
depressive symptoms [2,6–9].
Conventional reconstructive techniques for treatment
of extensive facial defects include skin grafts, local/re-
gional flaps, or free tissue transfer. These approaches
yield mostly suboptimal esthetic and functional results
as they cannot replace the anatomically refined structure
of tissues, function of missing muscles, and concerted
interplay of sensation, proprioception, and movement.
Recent advancements in microsurgery, transplantation,
ª2018 Steunstichting ESOT 1
doi:10.1111/tri.13130
Transplant International
and immunology enabled the transition of Face Allo-
graft Transplantation (FAT) into clinical reality. The
first clinical case of FAT was performed in 2005 in
France [10]. Thus far, thirty-five procedures have been
reported worldwide [11,12]. To the best of our knowl-
edge, five FAT recipients have died (three deaths were
not reported [11]) resulting into a 86% patient survival
rate [13]. Many publications list all FAT procedures
conducted to date; analysis of each case is out of the
scope of this review [4,11,12,14]. Overall, the literature
on FAT suggests a “smooth” progression from the first
partial to the most extensive FAT which included scalp,
ears and ear canals, elements of bone and oral tissues
[15]. FAT is a quality of life improving rather than a
life-saving intervention; therefore, risks and benefits
must be weighed carefully in light of post-transplant
complications brought on by lifelong immunosuppres-
sion including infections, malignancies, metabolic
imbalances, and wound healing challenges.
As detailed reporting in the field has been somewhat
scarce and of limited scope, we review outline principles
of FAT and portray future directions in the field.
Patient selection/inclusion–exclusion criteria
Selection of individuals eligible for FAT is a crucial
determinant for success. At this time, there is no general
consensus on inclusion–exclusion criteria. The American
Society of Plastic Surgeons (ASPS) and the American
Society of Reconstructive Microsurgery (ASRM) recom-
mend FAT only in patients with severe facial disfigure-
ment, only after conventional autologous reconstruction
techniques have been exhausted with unsatisfactory
results [16]. We define “severe facial disfigurement” as
loss of more than 25% of the total face and/or includ-
ing central facial units [17]. Ballistic trauma and burn
victims make up 2/3 of the current FAT recipients
worldwide [12]. Other indications include gunshot
wounds, neurofibromatosis 1, animal attacks, and can-
cer defect. The potential pool of FAT recipients is
expected to continue expanding with increased publica-
tion of favorable outcomes, and advancements in
immunosuppression [18].
Face allograft transplantation should be considered the
first reconstructive option for severely disfigured patients
that fulfill indication criteria as approved by ASRT [19],
and not as a last resort after conventional reconstruction
has yielded suboptimal results. In the early stages post-
trauma, patients should have acute wounds closed using
the simplest options and then get engaged in discussions
regarding facial allotransplantation versus conventional
reconstruction. The simplest wound closure option may
be a skin graft, local flap(s), but even free tissue trans-
fer. Management of facial allograft loss remains chal-
lenging. It is our opinion that in such cases, the
recipient should be considered for another FAT. Should
the patient or the treating team disagree on re-listing
the patient for transplant, conventional reconstruction
has to take place, stressing the importance of maintain-
ing salvage options, and preserving functional tissues
[3,20].
Brigham and Women’s Hospital team in Boston first
reported a set of inclusion and exclusion criteria for
FAT [17]. Siemionow and colleagues developed an
assessment tool to identify optimal FAT candidates
called “The Cleveland Clinic FACES Score,” which may
help predict outcomes and prognosis of the procedure
by measuring comorbidities, psychosocial status, medi-
cation adherence, etc. [21]. Psychosocial history and
previous immunological status are particularly impor-
tant [22]. Recent outcome studies report that the post-
transplantation period of FAT recipients with pre-exist-
ing mental disorders was challenged by suboptimal
adherence, difficulties in social reintegration and higher
incidence of rejection episodes, albeit overall enhance-
ment of quality of life [23].
There have been many discussions on whether burn
survivors with high Human Leukocyte Antigen (HLA)
sensitization should be considered for FAT. The initial
management of severe burns often involves potentially
sensitizing events including allogenic blood products
transfusion and cadaveric skin grafts [24,25]. Positive
T-cell CDC crossmatches are usually considered a con-
traindication for solid organ transplantation [26,27].
Some, but not all have excluded sensitized patients with
a positive crossmatch for FAT because of increased risk
for rejection and high immunosuppression requirements
[28–31]. Chandraker et al. [32] reported antibody-
mediated rejection (ABMR) in a highly sensitized FAT
recipient with a calculated panel reactive antibody of
98%. ABMR was successfully treated with a combina-
tion of plasmapheresis, eculizumab, bortezomib, and
alemtuzumab [33]. We recently reported the immuno-
logical characteristics of this patient up to 4 years fol-
lowing transplantation; the patient was controlled by an
all-encompassing immunosuppressive regimen that also
included B-cell-targeted therapies and after the ABMR
episode had three episodes of T-cell-mediated AR [33].
The patient has not presented with any clinical or
pathologic signs indicative of chronic vascular rejection
and has a functioning graft. Notably, none of the
numerous reports of acute rejection in FAT recipients
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has been shown to correlate with HLA mismatch [34].
Nonetheless, Chandraker’s single case report of manage-
able ABMR rejection does not constitute sufficient evi-
dence to reduce the current cautionary approach in
sensitized FAT recipients.
Face allograft transplantation candidates are often
partially or completely linked to the original trauma.
Inclusion of blind patients in FAT protocols remains
open to debate. There is no comparative study on FAT
outcomes in recipients with normal vision versus blind
recipients. Blindness introduces additional challenges to
the postoperative period related to physical therapy,
graft surveillance, and personal appreciation of the over-
all result [35].
Finally, emergency FAT remains widely discussed and
motivated by the surgical challenges introduced by
patients with extensive conventional reconstruction his-
tories that introduce scarring, fibrosis and others. While
emergency FAT introduces concerns about access to the
donor pool, organ donation issues, and adequate
presurgical planning [36], one team has successfully
performed such a procedure [10].
Operative details and challenges
Face allograft transplantation relies on recent advances
in reconstructive microsurgery techniques [1]. Many
studies describe the surgical stages of FAT in detail
including graft procurement, preservation, and trans-
plantation [1,34,37]. This review is limited to a brief
overview of some of the most important surgical
steps. FAT can be considered as a complex functional
(osteo)myocutaneous-free tissue transfer. Extensive sur-
gical planning involving multiple disciplines is crucial.
Radiologic assessment of the recipient with computer
tomography (CT) and/or magnetic resonance imaging
(MRI) helps to determine the amount of missing tis-
sues allowing a patient-specific design of the allograft.
Our team prefers a more conservative approach that
preserves recipient’s tissues and functional units in
order to maintain salvage options in cases of graft
failure.
Computer tomography/magnetic resonance imaging
angiography is essential for planning vascular anasto-
moses [38]. Branches of the external carotid artery can
support the entire splanchnocranium [39]; however,
fullface transplants can also be sufficiently supported by
the facial artery [40]. Furthermore, a single unilateral
facial artery can perfuse allografts comprising the lower
two-thirds of the face while maintaining bilateral venous
outflow [41–43]. Nonetheless, to maximize graft
survival, we recommend a bilateral arterial and venous
anastomosis whenever possible.
Nerve repair is central to the functional outcomes of
FAT. Motor and sensory function is a critical part for
the success of the procedure. Coaptations of the facial
nerve, at either the level of the facial nerve trunk or
more distally have been reported [28,44]. Our team pre-
fers distal coaptations as they enable targeted muscle
regeneration with decreased risks of synkinesia.
Craniofacial alignment, dental occlusion, and orthog-
nathic planning also play important roles determining
facial width, position, and function in FAT [45].
The optimal extent of FAT remains controversial,
and there is no general accepted categorization of FAT
per size and composition. Different groups use different
definitions for “partial,” “near-total,” “total,” “com-
plex,” “soft-tissue only,” “scalp-including” FAT. We
favor the conservation of vascular territories within the
head and neck and original size of the facial defects in
order to facilitate back-up solutions in case of allograft
failure that would not result into disfigurement worse
than the pretransplant state [1].
Face allograft transplantation is an extensive surgery,
and the time that the allograft spends in ischemic con-
ditions must be as short as possible, ideally within less
than 4 h. Indeed, brief ischemic times may prevent
harmful immune activation and inferior functional out-
comes, although direct evidence linking ischemia/reper-
fusion injury (IRI) and alloimmunity are missing. In
hand transplantation, some have suggested poorer graft
function because of prolonged ischemia [46,47]. How-
ever, we have not identified a relationship between facial
allografts’ prolonged ischemia, and frequency of acute
rejection episodes [48]. Extracorporeal preservation of
the facial allografts shows promise toward mitigation of
IRI, enhancement of functional outcomes FAT, and
expansion of facial donor pools, based on kidney trans-
plantation experience [49]. Early promising research
results on novel preservation methods relevant for Vas-
cularized Composite Allotransplantation (VCA) have
been reported [50,51].
Functional outcomes
Motor
Defining success and measuring outcomes are critical
for progress in the field. Facial functional outcomes are
difficult to quantify uniformly, because of the complex-
ity of facial functions, wide range of extent of injuries
across FAT recipients, and variations in protocols
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Next phase of face transplantation
among providers of FAT. However, there is consensus
that motor recovery is detectable 6–8 months after
transplant [4]. Various techniques used in general
Speech and Swallow therapy may improve motor recov-
ery, and functional motoric outcomes. These include
facial muscle reeducation, speech therapy, chewing, and
swallowing therapy, starting virtually immediately fol-
lowing the transplantation [52]. To date, motor recov-
ery outcomes of FAT have been characterized as
somewhat below the original expectations and as aver-
age for sensory recovery outcomes [12,52–56].
We believe that restoration of breathing, eating, tast-
ing, smelling, speaking, facial expressions, and sensation
largely determines the success or failure of FAT. In our
center, all seven FAT recipients showed improved func-
tionality when compared to pretransplantation impair-
ment [52]. We observed 100% improvement in the
abilities to smell and eat, and in facial sensation. All
gastrostomies were removed, and ten patients were
decannulated after FAT. There was overall 93%, 76%,
and 71% improvement in breathing, facial expressions,
and intelligible speech, respectively [52]. Similar results
are reported by other institutions. Functional outcomes
of FAT are reported in only approximately 50% of all
FAT cases worldwide. Strikingly, 25% of outcome data
are by groups not directly involved in the patients’
treatment [52], raising concern about accuracy of data.
Sensory
Sensation in the allograft returns as early as 3 months
postoperatively [40,57], with satisfactory results around
8–12 months [28,40,57,58]. Tests such as Semmes-
Weinstein, 2-point discrimination, and temperature dif-
ferentiation are used to evaluate sensory function of the
facial allograft [59]. Importantly, the immunosuppres-
sant tacrolimus, often used after FAT, has been linked
to accelerating axonal regeneration [60–64].
Different surgical techniques have been reported to
enhance sensory recovery; these include all direct end-
to-end neurorraphies of trigeminal nerve branches
[10,58], simple placement of bilateral donor mental
nerves near the mental foramen without neurorrhaphy
[57], and strikingly, even no nerve repair at all [28,65].
Our team suggests primary end-to-end neurorraphies
with nerve grafting or nerve transfer if necessary.
Psychosocial implications/quality of life
Despite encouraging motor and sensory function after
FAT, quality of life outcomes varies widely across
patients. This may be because of the implications of the
surgery on the patients’ psychological status. Most
recipients accept their transplanted faces shortly after
the surgery without any issues related to facial identity
[10,28,57,58,66–68]. This is not unexpected, as the
return of human appearance following transplant is
vastly better than prior major deformity [1]. Perhaps
another consideration is that one does not observe its
own face on a regular basis during the day. The identifi-
cation with one’s face is therefore mediated by gradual
improvement of its function over time. Reports on
quality of life-related challenges after FAT may include
drug or alcohol abuse, behavioral changes, social disin-
tegration issues, family issues, depression, and even sui-
cidal attempts [23,53,69–71]. Quantitative scales
(validated in separate individual psychological diseases)
[23,28,35,52,72–76] or qualitative methods (descriptive,
provider- or self-reported) have been introduced to
measure postoperative quality of life in FAT recipients
[10,57,58,65–67,77–81]. When assessing post-FAT qual-
ity of life, pre-existing mental disorders and risk factors
should be carefully considered. Eventful pre-FAT psy-
chological history can portend long-term follow-up risks
such as poor medication adherence, quality of life
issues, and increased incidence of rejection episodes.
Lastly, although return to work appears to be an ulti-
mate goal secondary to improvements in quality of life
after FAT, its fulfillment realistically depends on the
severity of the initial injury, other comorbidities, and
social factors. Although most FAT recipients have rein-
tegrated into their family and social environments, there
are few available data on return to work.
Immunological aspects
Immunosuppressive regimens have been largely adapted
from solid organ transplantation with good results thus
far. In most cases, immunosuppression induction treat-
ment for VCA typically includes anti-thymocyte globu-
lin (ATG), a potent T-cell depleting agent [82]. In
addition, several other drugs including humanized IL-2
receptor antibody [67,83], alemtuzumab [15], and
rituximab [84] have been reported for induction in FAT
recipients. Following transplantation, maintenance
immunosuppression usually consists of triple therapy
with tacrolimus (TAC), mycophenolic acid (MMF), and
prednisone taper [5,82,85]. Among VCA teams, TAC
target blood levels in FAT patients varied anywhere
between 3 ng/ml [74] and 24 ng/ml [67] and MMF was
administered from 0.18 g twice daily [74] to 3 g daily
[10]. Attempts to withdraw MMF [86] or prednisone
4Transplant International 2018;
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Tasigiorgos et al.
[87] were also reported. In some patients, calcineurin
inhibitors-related complications have led to conversion
of TAC to sirolimus [58,88]. Additionally, one FAT
recipient was also converted to belatacept; however,
after an episode of belatacept-resistant AR, low dose
TAC (target level 4–5 ng/ml) needed to be reintroduced
to the immunosuppression regimen [89].
Many innovative avenues of research have been
attempted to overcome the serious complications of
immunosuppression, and thus enable widespread prac-
tice of FAT. Approaches that include minimization/pro-
gressive weaning of immunosuppression lack long-term
follow-up reports [40]. Other immunosuppression min-
imizing or tolerance approaches include microchimer-
ism induction through simultaneous bone marrow
transplantation [90,91], development of anti T-cell anti-
bodies, or stem cell therapies [90,92–95]. Currently,
recipients of FAT will need lifelong immunosuppres-
sion; however, all efforts should be made to minimize
dosages safely while monitoring adverse side effects.
Immune tolerance may not be possible to achieve in a
near future for FAT recipients, because of tissue
immunogenicity, and in particular its skin component
[1]. At the same time, excessive immunosuppression
reducing protocols introduces a high risk of allograft
damage and/or loss [88,96].
Complications
Face allograft transplantation is not exempt to the com-
plications inherent to any surgical procedure, including
blood loss, wound healing challenges, graft misalign-
ment, bone nonunion, eyelid asymmetry and ptosis,
ectropion, and functional issues such as obstruction of
nasal passages and salivary glands, and necrosis of the
hard palate [5,10,52,57,67,86,97,98].
Infectious complications are not uncommon after
FAT, although tailored antibiotic prophylaxis is stan-
dard peri- and postoperative practice. In solid organ
transplantation, opportunistic cytomegalovirus (CMV)
infection plays a significant role in development of allo-
graft dysfunction and patients’ mortality and morbidity
[99]. The impact of CMV infection in FAT recipients is
not well-understood, because of the relatively small
number of FAT performed to date. More than a third
of FAT recipients presented with active CMV infections
during the postoperative follow-up. All CMV infection
episodes occurred in donor seropositive/recipient
seronegative combinations did not correlate with acute
rejection and were successfully treated with antiviral
therapy [100]. In rare cases when CMV infections did
not respond to conventional therapies, extracorporeal
photopheresis and vaccines had been sucessful [23].
More recently, multidrug-resistant CMV infections in
spite of 6 months of valganciclovir prophylaxis have
been reported after FAT and led to a rare complication
involving Guillain–Barr
e syndrome [101]. Complete
recovery of the neuropathy was achieved after adminis-
tration of intravenous immunoglobulin.
Metabolic complications after FAT are mainly attrib-
uted to immunosuppression, and entail diabetes melli-
tus, hypertension, and hypercholesterolemia. Lantieri
et al. [23] showed that diabetes mellitus, hypercholes-
terolemia, and hypertension occurred in one, four, and
three of seven patients, respectively. At our center, one
patient had been borderline diabetic prior to transplan-
tation, developed diabetes mellitus 8 months postopera-
tively and is currently successfully managed with insulin
therapy and lifestyle modifications [74]. Another team
reported earlier onset of hyperglycemia on postoperative
day 3 and insulin-dependent diabetes mellitus 3 months
after FAT [67]. Cumulative world experience in FAT
suggest that metabolic complications are common and
patients should be closely monitored, and whenever
appropriate, treated for diabetes mellitus, hyperc-
holesterinemia, or hypertension.
Chronic deterioration of recipients’ kidney function
has been reported and appears to present a growing
issue with FAT recipients approaching 10 years after
transplant. Lantieri et al. [23] reported on four of seven
FAT recipients that presented with reduced eGFR. FAT
providers have started minimizing immunosuppression,
or substituting calcineurin inhibitors with alternative
medications to prevent chronic kidney disease
[40,58,74].
There are numerous reports on secondary revisions
after FAT for esthetic and functional improvements
[55,102]. Bone and dental realignment, soft-tissue resus-
pension and contouring, full-thickness skin grafting, fat
injection and dermabrasion are examples [15,103–105],
as are Le Fort I rotation, Le Fort III advancement, coro-
nal eyebrow lift, submental lipectomy, bilateral ble-
pharoplasty, revision rhinoplasty, removal of excess
glandular tissue, and chin augmentation [57,106–108].
The benefits of these secondary interventions must out-
weigh the risks in this population of immunocompro-
mised patients.
Malignancies after FAT have been reported with
Epstein-Barr virus (EBV)- and HIV-related lymphoma,
cervical dysplasia, and lung cancer [5,13,23,71,96,109].
Αpatient has developed primary asymptomatic EBV
infection, followed by EBV+B-cell lymphoma, which
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could be successfully treated with rituximab and
chemotherapy [88]. Malignant peripheral nerve sheath
tumors can potentially occur and introduce the ques-
tion of inclusion of neurofibromatosis 1 patients in FAT
protocols [110].
Acute rejection (AR) is frequent in FAT. Early
studies predicted a 10% risk of AR within the first
year after FAT and 30–50% by the second to fifth
year [111]. More recent assessments showed that the
majority of patients (approximately 80%) have at least
one episode of AR within the first year, with skin
biopsies ranging from BANFF grade 1 to BANFF
grade 3. The vast majority of rejections have been
steroid-sensitive with a few exceptions requiring anti-
lymphocytic agents including thymoglobulin or cam-
path [4,112]. We also reported one case of acute
ABMR [32]. Treatment protocols for acute rejection
in FAT are established. Management of rejection with
BANFF grades 1–2 is usually treated with a bolus
steroid treatment, increasing TAC trough levels and
sometimes introducing topical steroid or TAC treat-
ment alone. ABMR may require the addition of
plasmapheresis, eculizumab, bortezomib in addition to
lymphocytic antibodies and/or other regimen changes
[10,66,67,80,86]. Our management of grade 1 rejec-
tions has evolved from aggressive treatment to com-
plete resolution of the rejection episode to a more
conservative approach suggesting patients to avoid sun
exposure, mechanical trauma, etc. Some groups specu-
late that aggressive treatment of grade I rejection in
the early stages of FAT may help prevent progression
to chronic rejection. Chronic rejection (CR) is a well-
established complication in solid organ transplantation
and has also been reported for FAT. The incidence of
CR in FAT was initially predicted as 30–50% within
the first 5 years however, the condition appears to
occur less frequent with only two reported pathology-
proven CR [88,92,109]. The first case was a T-cell-
mediated CR after programmed reduction of the
immunosuppression therapy because of complications
(i.e. EBV-induced lymphoma and hepatic EBV-asso-
ciated post-transplant smooth muscle tumor) [88].
The other patient developed chronic vascular rejection
(described by Morelon et al. [109] as chronic anti-
body-mediated rejection) with partial loss of the face
allograft. There are certain allograft changes that may
be relevant to potential development of CR, and in
our experience include fibrotic changes, telangiectasias,
and skin thinning. Lantieri et al. [23] comment on a
progressive lymphedematous aspect of the skin as a
possible manifestation of CR. On histological
examination, CR may entail vascular changes associ-
ated with vasculopathy in general and neointimal
hyperplasia [91].
Mortalities have also been reported. A FAT recipient
in China died 3 years after the procedure because of
medication nonadherence and lack of access to medical
care. Perioperative deaths were recorded in Paris, France
after face and bilateral upper extremity transplantation,
and in Turkey. Other deaths were attributed to a recur-
rence of malignancy in HIV+patient (Spain). Most
recently, the very first face transplant patient succumbed
to lung cancer.
Adherence
Despite successes in optimizing technical, surgical, and
follow-up protocols, FAT is unique in that it requires a
rigorous outpatient medical schedule and numerous
hospitalizations [56]. There are two cases of FAT allo-
graft loss as a result of noncompliance and thus compli-
ance is an imperative assessment of the transplant
evaluation. There are some well-understood pretrans-
plant risk factors that can predict future nonadherence
in solid organ transplantation, including previous his-
tory of nonadherence, inadequate social support, and
educational level that urge for further psychosocial eval-
uation [113]. FAT providers should stress the impor-
tance of adherence and the benefits of compliance,
rather than focusing on the harmful consequences of
nonadherence, always keeping in mind that positive
psychological outcomes will ultimately lead to adher-
ence [114].
Ethical dilemmas
Face allograft transplantation is an intervention inter-
twined with ethical dilemmas, and controversies. Over-
or under-informing FAT candidates prior to face trans-
plantation have both been linked to anxiety and poor
outcomes [115]. It remains open to debate whether
facially disfigured patients are truly in a position to give
informed consent, especially for such a complex proce-
dure and while being in a vulnerable state because of
the disfigurement [116–118].
With regard to the VCA practice in children, the lit-
erature is fairly divided [119]. The youngest FAT and
hand transplant recipients reported were, respec-
tively, 19 and 8 years old [53]. Solid arguments against
FAT in children include the lifelong risks of immuno-
suppression and the disputed informed consent
[120,121].
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Tasigiorgos et al.
Face allograft transplantation is a complex and
resource-demanding process requiring full investment of
a multidisciplinary team in the pre- and postoperative
periods [1]. FAT may be more costly than conventional
reconstruction or than solid organ transplants, with its
most expensive components being surgery and nursing
followed by anesthesia and immunosuppression
[122,123]. In Europe and the USA, it is still considered
an experimental procedure and thus not unanimously
covered by medical insurance. The majority of VCA
programs are currently funded by research grants (most
commonly from the U.S. Department of Defense) and
through institutional support challenging cost benefit
analyses of FAT over conventional reconstructive proce-
dures.
Future directions
Facial allograft procurement processes have been opti-
mized in collaboration with solid organ transplant
teams [22]. Limited allograft ischemia time continues to
dictate the maximum travel time for allograft recovery
and reduces geographical pool of donors. Currently
used allograft flush with University of Wisconsin (UW)
solution, or ILG-1 [10,66,67] combined with cold stor-
age does not extent the cold ischemia time beyond 4–
6 h. Extracorporeal tissue preservation research may
provide innovative solutions to this problem. Transla-
tional research in this area has currently been per-
formed only for extremity preservation and storage for
following replantation and/or transplantation. Extracor-
poreal perfusion devices have been used to preserve
swine limbs for 12–24 h after amputation with superior
outcomes in terms of muscle damage, ischemia reperfu-
sion injury, and animal survival following replantation
when compared to the current standard of care, which
is 4-h storage in ice [51,124,125]. Similar technology
has more recently demonstrated feasibility as a promis-
ing modality in extremity preservation through near-
normothermic ex situ perfusion for 24 h in a human
limb model [50].
Future innovations in noninvasive monitoring, diag-
nosis, and prediction of acute rejection and overall graft
health assessment in FAT are expected [126]. Although
the skin in FAT can be easily monitored and biopsied,
there are reports of allograft injury in the absence of
visible signs of rejection on the skin [127]. This raises
the concern that deeper components of the allograft,
such as the vascular endothelium may undergo subclini-
cal rejection. We must therefore develop methods of
investigating the entire allograft rather than the skin
only when investigating immune rejection [128,129].
Diagnosis of acute rejection in FAT can be challenging
with the current available methods [130,131]. It is
therefore imperative to implement quick, noninvasive,
predictive methods for diagnosis of rejection in FAT
recipients in order to avoid over- or under-immuno-
suppression and subsequent negative implications. Non-
invasive markers for assessment of the transplanted
allografts are investigated as alternatives to biopsies in
the field of solid organ transplantation. These markers
include gene-expression profiling [132,133] and pro-
teomic analysis [134,135] as biomarkers for allograft
vasculopathy, identification of donor derived cell-free
DNA in the recipient’s circulation as a marker for pre-
diction of AR [136–140] and B-cell repertoire sequenc-
ing [141] analyzed from samples acquired mainly
through blood draws. Urine samples and breath tests
have also showed feasibility as modalities in noninvasive
diagnosis of rejection [142,143]. Further studies evaluat-
ing these diagnostic markers in VCA still need to be
performed to assess the accuracy of these methods in
diagnosing AR.
Many authors find interpretation of rejection by
BANFF classification inadequate for FAT. It is impor-
tant to note that this classification is derived from hand
transplant patient experience and does not address
rejection of oral mucosa [144]. Additional concerns
include biopsy site selection bias, and inadequate sam-
pling size.
Noninvasive monitoring for CR and specifically for
chronic graft vasculopathy could constitute another
major challenge that necessitates improvement. It is
known from reported studies on hand transplantation
that intimal hyperplasia is associated with CR [127].
Assessing the individual-specific donor facial to recipi-
ent sentinel flap artery (e.g. radial artery) intima ratio
through ultrasound biomicroscopy monitoring (a high-
resolution ultrasound technique measuring the arterial
wall of smaller arteries) has proven feasibility and
reproducibility as a method and could potentially serve
as a sensitive measure to detect early changes during
chronic rejection [126].
Nerve regeneration is a vital component of functional
success of FAT and contributes to the motor and sen-
sory return of the recovery phase. However, nerve
regeneration and thus clinical outcomes differ between
centers because of the different pretransplant defects
among patients and the multiple coaptation methods
(e.g. direct nerve repair, nerve graft) tailored to each
patient [11]. There is a great interest in novel transla-
tional research strategies to enhance nerve regeneration
Transplant International 2018; 7
ª2018 Steunstichting ESOT
Next phase of face transplantation
and thus improve the functional outcomes of FAT but
also for VCA in general. The usage of TAC has been
demonstrated to accelerate nerve regeneration, decrease
muscle denervation time, and improve Schwann cell
migration, proving its neuroprotective and neurotrophic
effects [145,146]. A study from Labroo et al. [147]
showed that systematic administration of FK506 for
2 months following anastomosis of transected facial
nerve resulted in an increase in axonal diameter, myelin
thickness, and number of myelinated axons. It has also
been shown that the use of glial cell-derived neu-
rotrophic factor following facial nerve injury in a rat
model led to increased survival of injured axons and
improved functional outcomes [148]. Subcutaneous
administration of growth hormone [149], and chon-
droitinase [150–152] have also been reported to acceler-
ate axonal regeneration and enhance muscle re-
innervation in peripheral nerve rat models following
crush injuries, raising the question if these approaches
could be applied to facial nerve models. Finally, stem
cell-induced nerve regeneration is of increased research
interest. Cooney et al. [153] showed that local and sys-
tematic administration of bone marrow derived mes-
enchymal stem cells improved nerve regeneration in a
hindlimb transplantation rat model, by increasing the
number of nerve fibers distal to the repair site.
Outcomes reporting after FAT have not been univer-
sal to date. Sosin et al. [11] observed a marked discrep-
ancy between the number of FAT performed versus the
ones reported worldwide. Documentation and reporting
in the International Registry on Hand and Composite
Tissue Transplantation is voluntary, and therefore,
information and follow-up data are incomplete. We
firmly believe that consistent reporting would empower
the entire VCA research community by enriching the
knowledge available to all. Delayed, partial, and varying
disclosure creates a selection bias where groups report
only on positive results [11,53]. We encourage all face
transplant teams to publish their results in order to
avoid speculation and unjustified criticism. Ultimately,
this would help to enhance scientific knowledge, safety,
and availability of FAT.
This publication is meant to promote “analysis and
not paralysis” to aid further advancement of the field of
FAT. As with other developing fields in early stages,
FAT will continue to run into many challenges [129].
Expertise should be maintained in dedicated centers,
collection, and critical analysis of outcomes must con-
tinue, supported by research grants [53].
Conclusion
Facial allograft transplantation improves quality of life
of our most disabled patients. Providers must work
together, and agree on outcomes measures that should
be strictly adhered to, and reported. Standardization of
care and outcomes analysis among different centers will
continue to advance our field forward.
Funding
The authors have declared no funding.
Conflicts of interest
The authors have declared no conflicts of interest.
REFERENCES
1. Pomahac B, Nowinski D, Diaz-Siso JR,
et al. Face transplantation. Curr Probl
Surg 2011; 48: 293.
2. Losee JE, Fletcher DR, Gorantla VS.
Human facial allotransplantation: patient
selection and pertinent considerations. J
Craniofac Surg 2012; 23: 260.
3. Pomahac B, Bueno EM, Sisk GC,
Pribaz JJ. Current principles of facial
allotransplantation: the Brigham and
Women’s Hospital Experience. Plast
Reconstr Surg 2013; 131: 1069.
4. Shanmugarajah K, Hettiaratchy S,
Butler PEM. Facial transplantation.
Curr Opin Otolaryngol Head Neck Surg
2012; 20: 291.
5. Siemionow M, Ozturk C. Face trans-
plantation: outcomes, concerns, con-
troversies, and future directions. J
Craniofac Surg 2012; 23: 254.
6. Bonanno A, Esmaeli B, Fingeret MC,
Nelson DV, Weber RS. Social challenges
of cancer patients with orbitofacial
disfigurement. Ophthal Plast Reconstr
Surg 2010; 26: 18.
7. Gamba A, Romano M, Grosso IM,
et al. Psychosocial adjustment of
patients surgically treated for head and
neck cancer. Head Neck 1992; 14: 218.
8. Tartaglia A, McMahon BT, West SL,
Belongia L. Workplace discrimination
and disfigurement: the national EEOC
ADA research project. Work Read Mass
2005; 25: 57.
9. van der Wouden JC, Greaves-Otte JG,
Greaves J, Kruyt PM, van Leeuwen O, van
der Does E. Occupational reintegration of
long-term cancer survivors. J Occup Med
1992; 34: 1084.
10. Devauchelle B, Badet L, Lengel
eB,
et al. First human face allograft: early
report. Lancet 2006; 368: 203.
11. Sosin M, Rodriguez ED. The face
transplantation update: 2016. Plast
Reconstr Surg 2016; 137: 1841.
12. Khalifian S, Brazio PS, Mohan R, et al.
Facial transplantation: the first 9 years.
Lancet 2014; 384: 2153.
8Transplant International 2018;
ª2018 Steunstichting ESOT
Tasigiorgos et al.
13. Stokes M. A decade of facial trans-
plantation: lessons learned and what
lies ahead. Plast Surg News 2016; 1: 24.
14. Infante-Cossio P, Barrera-Pulido F,
Gomez-Cia T, et al. Facial transplan-
tation: a concise update. Med Oral Patol
Oral Cirugia Bucal 2013; 18: e263.
15. Dorafshar AH, Bojovic B, Christy MR,
et al. Total face, double jaw, and tongue
transplantation: an evolutionary concept.
Plast Reconstr Surg 2013; 131: 241.
16. ASRM/ASPS. Facial Transplantation –
ASRM/ASPS Guiding Principles
[Internet]. [Cited 2017 October 16.]
Available from: http://www.microsurg.
org/assets/1/13/ftGuidelines.pdf
17. Pomahac B, Aflaki P, Chandraker A,
Pribaz JJ. Facial transplantation and
immunosuppressed patients: a new fron-
tier in reconstructive surgery. Transplan-
tation 2008; 85: 1693.
18. Pomahac B, Diaz-Siso JR, Bueno EM.
Evolution of indications for facial
transplantation. J Plast Reconstr Aesthetic
Surg JPRAS 2011; 64: 1410.
19. American Society for Reconstructive
Transplantation. ASRT [Internet]. [Cited
2018 January 8.] Available from: http://
www.a-s-r-t.com
20. €
Ozkan
€
O,
€
Ozkan
€
O, Ubur M,
Hadimioglu N, Cengiz M, Afs
ßar
_
I. Face
allotransplantation for various types of
facial disfigurements: a series of five
cases. Microsurgery 2017; doi: 10.1002/
micr.30272. [Epub ahead of print]
21. Gordon CR, Siemionow M, Coffman
K, et al. The Cleveland Clinic FACES
Score: a preliminary assessment tool
for identifying the optimal face
transplant candidate. J Craniofac Surg
2009; 20: 1969.
22. BuenoEM,Diaz-SisoJR,PomahacB.A
multidisciplinary protocol for face trans-
plantation at Brigham and Women’s
Hospital. J Plast Reconstr Aesthetic Surg
JPRAS 2011; 64:1572.
23. Lantieri L, Grimbert P, Ortonne N, et al.
Face transplant: long-term follow-up and
results of a prospective open study.
Lancet 2016; 388: 1398.
24. Win TS, Frew Q, Taylor CJ, Peacock S,
PettigrewG,DziewulskiP.Allosen-
sitization following skin allografts in acute
burn management: are burns patients
suitable face transplant candidates? JPlast
Reconstr Aesthetic Surg JPRAS 2015; 68:
1155.
25. Klein HJ, Schanz U, Hivelin M, et al.
Sensitization and desensitization of burn
patients as potential candidates for vas-
cularized composite allotransplantation.
Burns 2016; 42:246.
26. Patel R, Terasaki PI. Significance of the
positive crossmatch test in kidney
transplantation. N Engl J Med 1969;
280: 735.
27. Tait BD, S€
usal C, Gebel HM, et al.
Consensus guidelines on the testing and
clinical management issues associated
with HLA and non-HLA antibodies in
transplantation. Transplantation 2013;
95: 19.
28. Lantieri L, Hivelin M, Audard V, et al.
Feasibility, reproducibility, risks and
benefits of face transplantation: a
prospective study of outcomes. Am J
Transplant 2011; 11: 367.
29. Duhamel P, Suberbielle C, Grimbert P,
et al. Anti-HLA sensitization in exten-
sively burned patients: extent, associated
factors, and reduction in potential access
to vascularized composite allotransplan-
tation. Transpl Int 2015; 28:582.
30. Siemionow MZ, Zor F, Gordon CR.
Face, upper extremity, and concomitant
transplantation: potential concerns and
challenges ahead. Plast Reconstr Surg
2010; 126: 308.
31. Murray JE. The establishment of
composite tissue allotransplantion as a
clinical reality [Internet]. In: Hewitt
CW, Lee WPA, Gordon CR, eds.
Transplantation of Composite Tissue
Allografts. Boston, MA: Springer, 2008:
3–12. [Cited 2017 July 25.] Available
from: https://link.springer.com/chapte
r/10.1007/978-0-387-74682-1_1
32. Chandraker A, Arscott R, Murphy GF,
et al. The management of antibody-
mediated rejection in the first
presensitized recipient of a full-face
allotransplant. Am J Transplant 2014;
14: 1446.
33. Win TS, Murakami N, Borges TJ, et al.
Longitudinal immunological characteri-
zation of the first presensitized recipient
of a face transplant. JCI Insight 2017; 2:
e93894.
34. Garrett GL, Beegun I, D’souza A. Facial
transplantation: historical developments
and future directions. JLaryngolOtol
2015; 129: 206.
35. Lemmens GMD, Poppe C, Hendrickx
H, et al. Facial transplantation in a
blind patient: psychologic, marital, and
family outcomes at 15 months follow-
up. Psychosomatics 2015; 56: 362.
36. Maciejewski A, Krakowczyk Ł, Szymczyk
C, et al. The first immediate face
transplant in the world. Ann Surg 2016;
263: e36.
37. Pomahac B, Gobble RM, Schneeberger
S. Facial and hand allotransplantation.
Cold Spring Harb Perspect Med 2014; 4:
a015651.
38. Soga S, Pomahac B, Wake N, et al. CT
angiography for surgical planning in
face transplantation candidates. Am J
Neuroradiol 2013; 34: 1873.
39. Meningaud J-P, Benjoar M-D, Hivelin
M, Hermeziu O, Toure G, Lantieri L.
Procurement of total human face graft
for allotransplantation: a preclinical
study and the first clinical case. Plast
Reconstr Surg 2010; 126: 1181.
40. Pomahac B, Pribaz J, Eriksson E, et al.
Three patients with full facial transplan-
tation. N Engl J Med 2012; 366:715.
41. Fischer S, Lee TC, Krezdorn N, et al. First
lower two-thirds osteomyocutaneous
facial allograft perfused by a unilateral
facial artery: outcomes and vasculariza-
tion at 1 year after transplantation. Plast
Reconstr Surg 2017; 139: 1175e.
42. Nguyen JT, Ashitate Y, Venugopal V,
et al. Near-infrared imaging of face
transplants: are both pedicles necessary? J
Surg Res 2013; 184:714.
43. Pomahac B, Lengele B, Ridgway EB,
et al. Vascular considerations in
composite midfacial allotransplantation.
Plast Reconstr Surg 2010; 125: 517.
44. Pomahac B, Pribaz JJ, Bueno EM, et al.
Novel surgical technique for full face
transplantation. Plast Reconstr Surg
2012; 130: 549.
45. Gordon CR, Susarla SM, Peacock ZS,
Kaban LB, Yaremchuk MJ. Le Fort-based
maxillofacial transplantation: current
state of the art and a refined technique
using orthognathic applications. J
Craniofac Surg 2012; 23:81.
46. Herzberg G, Weppe F, Masson N,
Gueffier X, Erhard L. Clinical evaluation
of two bilateral hand allotransplantations
at six and three years follow-up. Chir
Main 2008; 27:109.
47. Landin L, Cavadas PC, Garcia-Cosmes P,
Thione A, Vera-Sempere F. Perioperative
ischemic injury and fibrotic degeneration
of muscle in a forearm allograft: func-
tional follow-up at 32 months post
transplantation. Ann Plast Surg 2011; 66:
202.
48. Caterson EJ, Lopez J, Medina M,
Pomahac B, Tullius SG. Ischemia-
reperfusion injury in vascularized com-
posite allotransplantation. J Craniofac
Surg 2013; 24: 51.
49. Moers C, Pirenne J, Paul A, Ploeg RJ,
Machine Preservation Trial Study Group.
Machine perfusion or cold storage in
deceased-donor kidney transplantation.
N Engl J Med 2012; 366:770.
50. Werner NL, Alghanem F, Rakestraw SL,
et al. Ex situ perfusion of human limb
allografts for 24 hours. Transplantation
2017; 101: e68.
51. Kueckelhaus M, Dermietzel A, Alhefzi M,
et al. Acellular hypothermic extracor-
poreal perfusion extends allowable
ischemia time in a porcine whole limb
replantation model. Plast Reconstr Surg
2017; 139:922e.
52. Fischer S, Kueckelhaus M, Pauzenberger
R, Bueno EM, Pomahac B. Functional
outcomes of face transplantation. Am J
Transplant 2015; 15: 220.
Transplant International 2018; 9
ª2018 Steunstichting ESOT
Next phase of face transplantation
53. Giatsidis G, Sinha I, Pomahac B. Reflec-
tions on a decade of face transplantation.
Ann Surg 2017; 265:841.
54. Aycart MA, Perry B, Alhefzi M, et al.
Surgical optimization of motor recovery
in face transplantation. J Craniofac Surg
2016; 27:286.
55. Aycart MA, Alhefzi M, Kueckelhaus M,
Fischer S, Bueno EM, Pomahac B.
Secondary revisions after facial trans-
plantation: optimizing functional and
aesthetic outcomes. Plast Reconstr Surg
2015; 136(4 Suppl.): 152.
56. Kaufman CL, Ouseph R, Marvin MR,
Manon-Matos Y, Blair B, Kutz JE.
Monitoring and long-term outcomes in
vascularized composite allotransplanta-
tion. Curr Opin Organ Transplant 2013;
18: 652.
57. Lantieri L, Meningaud J-P, 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: 639.
58. Dubernard J-M, Lengel
eB,MorelonE,
et al. Outcomes 18 months after the first
human partial face transplantation. N
Engl J Med 2007; 357: 2451.
59. Siemionow M. The decade of face
transplant outcomes. J Mater Sci Mater
Med 2017; 28: 64.
60. Siemionow M, Gharb BB, Rampazzo
A. The face as a sensory organ. Plast
Reconstr Surg 2011; 127: 652.
61. Canan S, Asim OM, Okan B, Ozek C,
Alper M. Anatomic variations of the
infraorbital foramen. Ann Plast Surg
1999; 43: 613.
62. Aziz SR, Marchena JM, Puran A.
Anatomic characteristics of the infraor-
bital foramen: a cadaver study. JOral
Maxillofac Surg 2000; 58: 992.
63. Hu K-S, Kwak H-H, Song W-C, et al.
Branching patterns of the infraorbital
nerve and topography within the
infraorbital space. J Craniofac Surg
2006; 17: 1111.
64. Hwang K, Nam YS, Choi HG, Han
SH, Hwang SH. Cutaneous innervation
of lower eyelid. J Craniofac Surg 2008;
19: 1675.
65. 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: 111.
66. Barret JP, Gavald
a J, Bueno J, et al.
Full face transplant: the first case
report. Ann Surg 2011; 254: 252.
67. Guo S, Han Y, Zhang X, et al. Human
facial allotransplantation: a 2-year
follow-up study. Lancet 2008; 372: 631.
68. Singhal D, Pribaz JJ, Pomahac B. The
Brigham and Women’s Hospital face
transplant program: a look back. Plast
Reconstr Surg 2012; 129: 81e.
69. Coffman KL, Gordon C, Siemionow M.
Psychological outcomes with face trans-
plantation: overview and case report.
Curr Opin Organ Transplant 2010; 15:
236.
70. Coffman KL, Siemionow MZ. Ethics of
facial transplantation revisited. Curr
Opin Organ Transplant 2014; 19: 181.
71. Aycart MA, Kiwanuka H, Krezdorn N,
et al. Quality of life after face transplan-
tation: outcomes, assessment tools, and
future directions. Plast Reconstr Surg
2017; 139:194.
72. Roche NA, Blondeel PN, Vermeersch HF,
et al. Long-term multifunctional out-
come and risks of face vascularized
composite allotransplantation. JCraniofac
Surg 2015; 26: 2038.
73. Kiwanuka H, Aycart MA, Gitlin DF,
et al. The role of face transplantation
in the self-inflicted gunshot wound. J
Plast Reconstr Aesthetic Surg JPRAS
2016; 69: 1636.
74. Diaz-Siso JR, Parker M, Bueno EM,
et al. Facial allotransplantation: a 3-
year follow-up report. J Plast Reconstr
Aesthetic Surg JPRAS 2013; 66: 1458.
75. Coffman KL, Siemionow MZ. Face
transplantation: psychological outcomes
at three-year follow-up. Psychosomatics
2013; 54: 372.
76. Chang G, Pomahac B. Psychosocial
changes 6 months after face transplanta-
tion. Psychosomatics 2013; 54:367.
77. Chenggang Y, Yan H, Xudong Z, et al.
Some issues in facial transplantation.
Am J Transplant 2008; 8: 2169.
78. Krakowczyk Ł, Maciejewski A, Szymczyk
C, Ole
sK,P
ołtorak S. Face transplant in
an advanced neurofibromatosis type 1
patient. Ann Transplant 2017; 22:53.
79. Petruzzo P, Testelin S, Kanitakis J, et al.
First human face transplantation: 5 years
outcomes. Transplantation 2012; 93:236.
80. 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: 386.
81. R€
uegg EM, Hivelin M, Hemery F,
et al. Face transplantation program in
France: a cost analysis of five patients.
Transplantation 2012; 93: 1166.
82. Fischer S, Lian CG, Kueckelhaus M,
et al. Acute rejection in vascularized
composite allotransplantation. Curr Opin
Organ Transplant 2014; 19: 531.
83. Cavadas PC, Ib
a~
nez J, Thione A. Surgical
aspects of a lower face, mandible, and
tongue allotransplantation. JReconstr
Microsurg 2012; 28:43.
84. Sosin M, Ceradini DJ, Levine JP, et al.
Total face, eyelids, ears, scalp, and skele-
tal subunit transplant: a reconstructive
solution for the full face and total scalp
burn. Plast Reconstr Surg 2016; 138:205.
85. Madani H, Hettiaratchy S, Clarke A,
Butler PEM. Immunosuppression in an
emerging field of plastic reconstructive
surgery: composite tissue allotransplanta-
tion. J Plast Reconstr Aesthetic Surg
JPRAS 2008; 61:245.
86. Siemionow M, Papay F, Alam D, et al.
Near-total human face transplantation
for a severely disfigured patient in the
USA. Lancet 2009; 374: 203.
87. Diaz-Siso JR, Fischer S, Sisk GC, et al.
Initial experience of dual maintenance
immunosuppression with steroid with-
drawal in vascular composite tissue
allotransplantation. Am J Transplant
2015; 15: 1421.
88. Petruzzo P, Kanitakis J, Testelin S,
et al. Clinicopathological findings of
chronic rejection in a face grafted
patient. Transplantation 2015; 99: 2644.
89. Krezdorn N, Murakami N, Pomahac B,
Riella LV. Immunological characteristics
of a patient with belatacept-resistant
acute rejection after face transplantation.
Am J Transplant 2016; 16: 3305.
90. Lantieri L. Face transplant: a paradigm
change in facial reconstruction. J
Craniofac Surg 2012; 23: 250.
91. Leonard DA, Gordon CR, Sachs DH,
Cetrulo CL. Immunobiology of face
transplantation. J Craniofac Surg 2012;
23: 268.
92. Morris P, Bradley A, Doyal L, et al. Face
transplantation: a review of the technical,
immunological, psychological and clinical
issues with recommendations for good
practice. Transplantation 2007; 83:109.
93. Leonard DA, Kurtz JM, Cetrulo CL.
Achieving immune tolerance in hand
and face transplantation: a realistic
prospect? Immunotherapy 2014; 6: 499.
94. Horner BM, Randolph MA, Duran-
Struuck R, et al. Induction of tolerance
to an allogeneic skin flap transplant in
a preclinical large animal model.
Transplant Proc 2009; 41: 539.
95. Siemionow M, Madajka M, Cwykiel J.
Application of cell-based therapies in
facial transplantation. Ann Plast Surg
2012; 69: 575.
96. Wo L, Bueno E, Pomahac B. Facial
transplantation: worth the risks? A look
at evolution of indications over the last
decade. Curr Opin Organ Transplant
2015; 20: 615.
97. Gomez-Cia T, Sicilia-Castro D,
Infante-Cossio P, et al. Second human
facial allotransplantation to restore a
severe defect following radical resection
of bilateral massive plexiform neurofi-
bromas. Plast Reconstr Surg 2011; 127:
995.
98. Siemionow M, Ozturk C. An update on
facial transplantation cases performed
10 Transplant International 2018;
ª2018 Steunstichting ESOT
Tasigiorgos et al.
between 2005 and 2010. Plast Reconstr
Surg 2011; 128: 707e.
99. Ramanan P, Razonable RR.
Cytomegalovirus infections in solid
organ transplantation: a review. Infect
Chemother 2013; 45: 260.
100. Knoll BM, Hammond SP, Koo S, et al.
Infections following facial composite
tissue allotransplantation –single
center experience and review of the
literature. Am J Transplant 2013; 13:
770.
101. Alhefzi M, Aycart MA, Bueno EM, et al.
Guillain-Barr
e syndrome associated with
resistant cytomegalovirus infection after
face transplantation. Transpl Infect Dis
2016; 18: 288.
102. Aycart MA, Alhefzi M, Kueckelhaus M,
et al. A Retrospective analysis of sec-
ondary revisions after face transplanta-
tion: assessment of outcomes, safety, and
feasibility. Plast Reconstr Surg 2016; 138:
690e.
103. Jacobs JMS, Dec W, Levine JP, et al. Best
face forward: virtual modeling and
custom device fabrication to optimize
craniofacial vascularized composite allo-
transplantation. Plast Reconstr Surg 2013;
131:64.
104. Fisher M, Dorafshar A, Bojovic B,
Manson PN, Rodriguez ED. The
evolution of critical concepts in aesthetic
craniofacial microsurgical reconstruction.
Plast Reconstr Surg 2012; 130:389.
105. Haddock NT, Saadeh PB, Siebert JW.
Achieving aesthetic results in facial
reconstructive microsurgery: planning
and executing secondary refinements.
Plast Reconstr Surg 2012; 130: 1236.
106. Mohan R, Fisher M, Dorafshar A,
et al. Principles of face transplant
revision: beyond primary repair. Plast
Reconstr Surg 2014; 134: 1295.
107. Barret JP, Serracanta J. LeFort I
osteotomy and secondary procedures
in full-face transplant patients. J Plast
Reconstr Aesthetic Surg JPRAS 2013; 66:
723.
108. Alam DS, Chi JJ. Facial transplantation
for massive traumatic injuries. Otolaryn-
gol Clin North Am 2013; 46:883.
109. Morelon E, Petruzzo P, Kanitakis J,
et al. Face transplantation: partial graft
loss of the first case 10 years later. Am
J Transplant 2017; 17: 1935.
110. Merlo CA, Studer SM, Conte JV, Yang
SC, Sonnett J, Orens JB. The course of
neurofibromatosis type 1 on immuno-
suppression after lung transplantation:
report of 2 cases. J Heart Lung Transplant
2004; 23:774.
111. Morris PJ, Bradley JA, Doyal L, et al.
Facial transplantation: a working party
report from the Royal College of
Surgeons of England. Transplantation
2004; 77: 330.
112. Shanmugarajah K, Hettiaratchy S,
Clarke A, Butler PEM. Clinical
outcomes of facial transplantation: a
review. Int J Surg 2011; 9: 600.
113. Dobbels F, Vanhaecke J, Dupont L,
et al. Pretransplant predictors of
posttransplant adherence and clinical
outcome: an evidence base for
pretransplant psychosocial screening.
Transplantation 2009; 87: 1497.
114. Pinsky BW, Takemoto SK, Lentine KL,
Burroughs TE, Schnitzler MA, Salvalaggio
PR. Transplant outcomes and economic
costs associated with patient noncom-
pliance to immunosuppression. Am J
Transplant 2009; 9: 2597.
115. Wiggins OP, Barker JH, Martinez S,
et al. On the ethics of facial
transplantation research. Am J Bioeth
AJOB 2004; 4:1.
116. Hamdy RC. Face transplantation: a
brave or maverick surgery? South Med
J2006; 99: 410.
117. The French position: Comit
e Consultatif
National d’Ethique pour les sciences de
la vie et de la sant
e: “composite tissue
allograftransplantation of the face (total
or partial graft)”. South Med J 2006; 99:
432.
118. Diver AJ. Investigation of risk acceptance
in facial transplantation. Plast Reconstr
Surg 2007; 119: 2317; author reply 2317.
119. Marchac A, Kuschner T, Paris J, Picard
A, Vazquez MP, Lantieri L. Ethical
issues in pediatric face transplantation:
should we perform face transplantation
in children? Plast Reconstr Surg 2016;
138: 449.
120. Flynn J, Shaul RZ, Hanson MD,
Borschel GH, Zuker R. Pediatric facial
transplantation: ethical considerations.
Plast Surg Oakv Ont 2014; 22: 67.
121. Doumit G, Gharb BB, Rampazzo A,
Papay F, Siemionow MZ, Zins JE.
Pediatric vascularized composite allo-
transplantation. Ann Plast Surg 2014;
73: 445.
122. Siemionow M, Gatherwright J, Djohan
R, Papay F. Cost analysis of conventional
facial reconstruction procedures followed
by face transplantation. Am J Transplant
2011; 11:379.
123. Nguyen LL, Naunheim MR, Hevelone
ND, et al. Cost analysis of conventional
face reconstruction versus face trans-
plantation for large tissue defects. Plast
Reconstr Surg 2015; 135:260.
124. Ozer K, Rojas-Pena A, Mendias CL,
Bryner B, Toomasian C, Bartlett RH. Ex
Situ Limb perfusion system to extend
vascularized composite tissue allograft
survival in swine. Transplantation 2015;
99: 2095.
125. Ozer K, Rojas-Pena A, Mendias CL,
Bryner BS, Toomasian C, Bartlett RH.
The Effect of ex situ perfusion in a
swine limb vascularized composite
tissue allograft on survival up to
24 hours. J Hand Surg 2016; 41:3.
126. Kueckelhaus M, Imanzadeh A, Fischer
S, et al. Noninvasive monitoring of
immune rejection in face transplant
recipients. Plast Reconstr Surg 2015;
136: 1082.
127. Kaufman CL, Ouseph R, Blair B, et al.
Graft vasculopathy in clinical hand
transplantation. Am J Transplant 2012;
12: 1004.
128. Morel O, Ohlmann P, Epailly E, et al.
Endothelial cell activation contributes
to the release of procoagulant
microparticles during acute cardiac
allograft rejection. J Heart Lung
Transplant 2008; 27: 38.
129. Tasigiorgos S, Krezdorn N, Bueno E,
Pomahac B. New avenues of vascularized
composite allotransplantation and their
potential risks and benefits. Ann Surg
2017; 266:e25.
130. Kanitakis J. The challenge of der-
matopathological diagnosis of composite
tissue allograft rejection: a review. J
Cutan Pathol 2008; 35:738.
131. Sarhane KA, Tuffaha SH, Broyles JM,
et al. A critical analysis of rejection in
vascularized composite allotransplanta-
tion: clinical, cellular and molecular
aspects, current challenges, and novel
concepts. Front Immunol 2013; 4: 406.
132. Yamani MH, Taylor DO, Rodriguez
ER, et al. Transplant vasculopathy is
associated with increased AlloMap gene
expression score. J Heart Lung Transplant
2007; 26:403.
133. Pham MX, Teuteberg JJ, Kfoury AG,
et al. Gene-expression profiling for
rejection surveillance after cardiac
transplantation. N Engl J Med 2010;
362: 1890.
134. Lin D, Cohen Freue G, Hollander Z,
et al. Plasma protein biosignatures for
detection of cardiac allograft vascu-
lopathy. J Heart Lung Transplant 2013;
32:723.
135. Daly KP, Seifert ME, Chandraker A,
et al. VEGF-C, VEGF-A and related
angiogenesis factors as biomarkers of
allograft vasculopathy in cardiac trans-
plant recipients. J Heart Lung Transplant
2013; 32:120.
136. Snyder TM, Khush KK, Valantine HA,
Quake SR. Universal noninvasive detec-
tion of solid organ transplant rejection.
Proc Natl Acad Sci USA 2011; 108: 6229.
137. De Vlaminck I, Valantine HA, Snyder
TM, et al. Circulating cell-free DNA
enables noninvasive diagnosis of heart
transplant rejection. Sci Transl Med
2014; 6: 241ra77.
138. De Vlaminck I, Martin L, Kertesz M,
et al. Noninvasive monitoring of
infection and rejection after lung
Transplant International 2018; 11
ª2018 Steunstichting ESOT
Next phase of face transplantation
transplantation. Proc Natl Acad Sci
USA 2015; 112: 13336.
139. Beck J, Bierau S, Balzer S, et al. Digital
droplet PCR for rapid quantification
of donor DNA in the circulation of
transplant recipients as a potential
universal biomarker of graft injury.
Clin Chem 2013; 59: 1732.
140. Beck J, Oellerich M, Schulz U, et al.
Donor-derived cell-free DNA is a novel
universal biomarker for allograft rejec-
tion in solid organ transplantation.
Transplant Proc 2015; 47: 2400.
141. Vollmers C, De Vlaminck I, Valantine
HA, et al. Monitoring pharmacologically
induced immunosuppression by immune
repertoire sequencing to detect acute
allograft rejection in heart transplant
patients: a proof-of-concept diagnostic
accuracy study. PLoS Med 2015; 12:
e1001890.
142. Li B, Hartono C, Ding R, et al.
Noninvasive diagnosis of renal-allograft
rejection by measurement of messenger
RNA for perforin and granzyme B in
urine. N Engl J Med 2001; 344:947.
143. Phillips M, Boehmer JP, Cataneo RN,
et al. Prediction of heart transplant
rejection with a breath test for markers
of oxidative stress. Am J Cardiol 2004;
94: 1593.
144. Cendales LC, Kanitakis J, Schneeberger
S, et al. The Banff 2007 working
classification of skin-containing compos-
ite tissue allograft pathology. Am J
Transplant 2008; 8: 1396.
145. Yan Y, Wood MD, Moore AM, et al.
Robust axonal regeneration in a mouse
vascularized composite allotransplant
model undergoing delayed tissue rejec-
tion. Hand 2016; 11: 456.
146. Labroo P, Ho S, Sant H, Shea J, Gale
BK, Agarwal J. Controlled delivery of
FK506 to improve nerve regener-
ation. Shock 2016; 46(3 Suppl. 1):
154.
147. Labroo P, Shea J, Sant H, Gale B,
Agarwal J. Effect of combining FK506
and neurotrophins on neurite branching
and elongation. Muscle Nerve 2017; 55:
570.
148. Oppenheim RW, Houenou LJ, Johnson
JE, et al. Developing motor neurons
rescued from programmed and axotomy-
induced cell death by GDNF. Nature
1995; 373: 344.
149. Tuffaha SH, Budihardjo JD, Sarhane KA,
et al. Growth hormone therapy accel-
erates axonal regeneration, promotes
motor reinnervation, and reduces muscle
atrophy following peripheral nerve
injury. Plast Reconstr Surg 2016; 137:
1771.
150. Zuo J, Neubauer D, Graham J, Krekoski
CA, Ferguson TA, Muir D. Regeneration
of axons after nerve transection repair is
enhanced by degradation of chondroitin
sulfate proteoglycan. Exp Neurol 2002;
176:221.
151. Tuffaha S, Quigley M, Ng T, et al. The
effect of chondroitinase on nerve
regeneration following composite tissue
allotransplantation. J Hand Surg 2011;
36: 1447.
152. Udina E, Verd
u E, Navarro X. Effects
of the immunophilin ligand FK506 on
nerve regeneration in collagen guides
seeded with Schwann cells in rats.
Neurosci Lett 2004; 357: 99.
153. Cooney DS, Wimmers EG, Ibrahim Z,
et al. Mesenchymal stem cells enhance
nerve regeneration in a rat sciatic nerve
repair and hindlimb transplant model.
Sci Rep 2016; 6: 31306.
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