Introduction
Vascularised facial allotransplantation is a viable option for the repair of complex craniofacial defects not amenable to autologous reconstruction with conventional reconstructive techniques. Since 2005, facial transplantation programmes have been successfully established in France, the USA, China and Spain, with a total of 12 partial and 5 full procedures reported in the literature.Reference Devauchelle, Badet, Lengelé, Morelon, Testelin and Michallet1–Reference Pomahac, Pribaz and Eriksson10 Indications for the procedures included traumatic injury, neurofibromatosis and disfigurement following resection of extensive tumours. Traumatic injuries were caused by animal attacks, gunshots, burns and falls. Several episodes of acute graft rejection occurred and were successfully managed with intensification of immunosuppression. Two recipients died at 2 months and at 27 months post-transplantation respectively: the first death in China was concluded to be due to septic multi-organ failure following voluntary cessation of immunotherapy.Reference Guo, Han, Zhang, Lu, Yi and Zhang2 In France, a patient with a concomitant facial and bilateral below-the-elbow (upper limb) composite tissue allograft suffered a cardiac arrest triggered by an obstructed tracheotomy tube.Reference Lantieri, Hivelin, Audard, Benjoar, Meringaud and Bellivier6 All remaining grafts were viable and have yielded satisfactory functional and aesthetic outcomes, with near-complete restoration of sensation. Table I summarises the main characteristics of facial transplantations performed from 2005 to 2012.Reference Devauchelle, Badet, Lengelé, Morelon, Testelin and Michallet1–Reference Pomahac, Pribaz and Eriksson10
Table I Summary of facial transplantation cases recorded in the literature
Y = years; F = female; M = male
In this report, we delineate the historical developments and future directions of facial transplantation, based on the current literature and experience of teams across the world. We wish to inform physicians of the surgical and immunological models that have been adopted, and to raise awareness of the ethics of facial transplantation, outlining the challenges of establishing a facial transplantation programme.
Materials and methods
The literature search was carried out using two electronic databases, Medline and Embase. A search of articles published from 1980 to the present with titles that included the terms ‘facial’, ‘face’, ‘transplant’ and ‘transplantation’ was conducted. Additional articles were obtained from the reference lists of identified publications.
Two independent reviewers screened 594 manuscripts. Articles with repetition or duplication of original data, animal studies, and non-English language papers were excluded. A total of 58 manuscripts were selected for the review.
Surgical outcomes
Progress in reconstructive microsurgical techniques and immunotherapy have advanced the field of composite tissue allotransplantation, which has been performed on facial and abdominal wall structures, the larynx, the tongue, and the knee.Reference Wu, Xu, Ravinda and Ildstat11 Facial composite tissue transplantation incorporates surgical techniques used in general transplantation and reconstructive surgery. The surgical act of transplantation can be broken down into graft harvesting, graft preservation, and transplant grafting with nerve and vessel anastomosis. The procedure requires meticulous tissue handling, microanastomotic skills, and appropriate graft harvesting and preserving methods.
The graft harvesting method varies according to individual surgical units, and on the amount and depth of tissue required to achieve optimal aesthetic and functional outcomes. Harvesting can commence by raising a bicoronal flap in a caudal direction to the preauricular region. Dissection is continued in a subgaleal plane towards the supraorbital region. The supraorbital and supratrochlear nerves are identified as they exit from their foramina; the bone surrounding the nerves can be trimmed using an osteotome or drill, to increase the length of nerve harvested.
If eyelids are required, dissection can proceed along the palpebral conjunctival reflection, with transection of the levator muscles, incision through the conjunctiva and dissection of the canthal ligaments at their bony insertions. This will allow detachment of the graft through the deep soft tissue layer until the inferior orbital rim is reached, allowing preservation of the upper and lower eyelids.Reference Pomahac, Pribaz, Bueno, Sisk, Diaz-Siso and Chandawarkar12 In order to harvest the nose, osteotomies can be performed to separate the nasal bone from the underlying malar eminence, allowing a full nose composite within the facial graft.Reference Pomahac, Pribaz, Bueno, Sisk, Diaz-Siso and Chandawarkar12–Reference Shanmugarajah, Hettiaratchy, Clarke and Butler14
Dissection at the preauricular incisions progresses in a lateral to medial direction on top of the parotid fascia. Facial nerve branches can be individually identified, tagged and elevated as part of the allograft.Reference Pomahac, Pribaz, Bueno, Sisk, Diaz-Siso and Chandawarkar12 Alternatively, the parotid gland, with the facial nerve dissected at its main trunk as it exits the stylomastoid foramen, can be harvested as part of the allograft.Reference Shanmugarajah, Hettiaratchy, Clarke and Butler14 Depending on the material required, either muscle alone can be harvested by continuing dissection in the subperiosteal plane, or osteotomies can be performed in order to release the zygoma and maxilla as required.Reference Wu, Xu, Ravinda and Ildstat11–Reference Shanmugarajah, Hettiaratchy, Clarke and Butler14
The graft is released up to the level of the pyriform aperture of the nose via a superior to inferior dissection, and to the level of the modiolus at the angle of the mouth via a lateral to medial dissection. Perioral tissues are then raised in a subperiosteal plane, along the gingivobuccal sulcus and inferiorly to the mandibular border, allowing for sufficient amounts of tissue harvesting for intraoral inset in the recipient.Reference Pomahac, Pribaz and Eriksson10–Reference Shanmugarajah, Hettiaratchy, Clarke and Butler14
Before releasing the lower portion of the grafts, the facial artery and vein are identified and protected. The facial artery can be identified via dissection from the carotid arteries distally. Once the facial vessels are identified and protected, the dissection can continue up to the mentum, with preservation of the mental nerve. At this point, complete dissection of the lower face will have been achieved, and the bilateral preauricular incisions can be extended inferiorly to allow neck dissections so that the sternocleidomastoid muscle, and the internal and external jugular and retromandibular veins, can be ligated and divided as required.Reference Barret, Serracanta, Collado, Garrido, Salamero and Pont8–Reference Nguyen, Naunheim, Hevelone, Diaz-Siso, Hogan and Bueno15
Once the graft has been obtained, maintaining the viability is crucial. The actual ischaemia time of facial grafts is not known; however, based on known muscle ischaemia times, authors recommend reperfusion of the graft within 4 hours of onset of cold ischaemia.Reference Pomahac, Pribaz, Bueno, Sisk, Diaz-Siso and Chandawarkar12 Alternatively, a temporary vascular anastomosis on the recipient's femoral vessels will allow reperfusion while the rest of the surgical procedures are performed.Reference Shanmugarajah, Hettiaratchy, Clarke and Butler14
Facial nerve and vessel harvesting, and eventual anastomoses, will vary depending on the recipient's needs, and on the quality of both the donor's and recipient's vessels. Vessel quality will usually be determined by computed tomography angiography and magnetic resonance imaging. Most vascular anastomoses are performed in large diameter vessels, such as external carotids and jugular veins, in order to minimise thrombosis.Reference Pomahac, Pribaz, Bueno, Sisk, Diaz-Siso and Chandawarkar12–Reference Shanmugarajah, Hettiaratchy, Clarke and Butler14 However, complete facial revascularisation can also be achieved by means of a single pedicle anastomosis of the facial vessels.Reference Barret, Serracanta, Collado, Garrido, Salamero and Pont8
Facial nerve transplantation can be achieved by either anastomosing the nerve at the main trunk, with or without the parotid gland, or by anastomosing individual branches peripherally by performing an intraparotid nerve dissection.Reference Gomez-Cia, Sicilia-Castro, Infante-Cossio, Barrera-Pulido, Gacto-Sanchez and Lagares-Borrego9, Reference Pomahac, Pribaz, Bueno, Sisk, Diaz-Siso and Chandawarkar12 Smaller calibre nerves, such as the supraorbital, infraorbital and mental nerves, can also be anastomosed.Reference Pomahac, Pribaz, Bueno, Sisk, Diaz-Siso and Chandawarkar12 The remainder of the graft containing muscle and skin can be anastomosed to underlying recipient structures in a medial to lateral, and inferior to superior, direction. Bony integration will require appropriate osteotomies and plating.
Complications are common to all surgical procedures. With respect to facial transplantation, blood loss can be particularly high.Reference Devauchelle, Badet, Lengelé, Morelon, Testelin and Michallet1–Reference Siemionow, Papay, Alam, Bernard, Djohan and Gordon4, Reference Gomez-Cia, Sicilia-Castro, Infante-Cossio, Barrera-Pulido, Gacto-Sanchez and Lagares-Borrego9 One case reported the need to transfuse 24 units.Reference Gomez-Cia, Sicilia-Castro, Infante-Cossio, Barrera-Pulido, Gacto-Sanchez and Lagares-Borrego9 In addition, in light of the prolonged surgical time, and associated immobilisation and blood loss, rhabdomyolysis is a reported complication.Reference Gomez-Cia, Sicilia-Castro, Infante-Cossio, Barrera-Pulido, Gacto-Sanchez and Lagares-Borrego9
Immunological outcomes
Despite familiarity with the immunobiology of facial transplantation, some of its fundamental characteristics remain poorly recognised. Current practice is guided by previous experience with hand composite tissue allografts and solid organ transplants. The risks of immune rejection are not established; however, a working party report from the Royal College of Surgeons of England estimates that facial composite tissue allografts carry a 10 per cent risk of acute rejection and graft failure in the first year, and a 30–50 per cent risk of chronic rejection in the second to fifth year.Reference Morris, Bradley, Doyal, Earley, Hagan and Milling16 In solid organ transplants, the risk of graft failure is proportional to the type and amount of tissue grafted, and to prior recipient sensitisation to donor major histocompatibility complex antigen.
The importance of donor–recipient immune disparity in facial transplantation is not clear, despite available documentation on the detrimental effect of human leukocyte antigen mismatch in solid organ transplants.Reference Siemionow, Papay, Alam, Bernard, Djohan and Gordon4, Reference Siemionow, Papay, Djohan, Bernard, Gordon and Alam17–Reference Dubernard, Lengelé, Morelon, Testelin, Badet and Moure19 Numerous episodes of acute rejection have occurred, none correlating with human leukocyte antigen mismatch. Chronic rejection has not been reported, despite being a principal cause of morbidity and mortality in renal and cardiothoracic transplants.Reference Weiss, Masden, Rosengard and Allan20 Regular graft biopsies and immunohistological analyses are examined for vessel obstruction with vasculopathy and neointimal hyperplasia when monitoring for chronic graft rejection in facial transplantation.Reference Leonard, Gordon, Sachs and Cetrulo21 Surgical removal and re-transplantation of the allograft may be necessary if severe rejection refractory to pharmacological therapy occurs, and this may carry a high psychological burden.
Treatment protocols utilised have universally included an anti-thymocyte globulin for induction, and tacrolimus, mycophenolate mofetil and prednisolone for maintenance.Reference Mandani, Hettiaratchy, Clarke and Butler22, Reference Siemionow and Ozturk23 With good compliance, this regimen has been effective at preventing graft loss. However, dose-dependent toxicity, opportunistic infections, and solid organ and cutaneous malignancies have occurred.
Donor bone marrow infusions, anti-interleukin-2 receptor antibodies and X-ray irradiation have been experimentally trialled; these demonstrated no significant reduction of side effects.Reference Waaga, Gasser, Laskowski and Tilney18, Reference Mathew, Garcia-Morales, Fuller, Rosen, Ciancio and Burke24 Tacrolimus has been shown to cause hypertension and nephrotoxicity characterised by interstitial fibrosis and tubular atrophy. Long-term glucocorticoids are associated with diabetes, secondary adrenal insufficiency, hypertension and osteopenia. Infections with cytomegalovirus, Epstein–Barr virus, herpes simplex virus, Pneumocystis jirovecii and opportunistic fungi have increased the risk of post-operative life-threatening sepsis.Reference Barker, Furr, Cunningham, Grossi, Vasilic and Storey25 Squamous cell cancers, cancers of the lung and colon, and cancers of viral aetiology (non-Hodgkin lymphomas, Kaposi's sarcoma and cervical cancer) have also been recorded, while lymphoproliferative disorders have not occurred.Reference Mandani, Hettiaratchy, Clarke and Butler22, Reference Siemionow and Ozturk23
There is promise that tolerance may develop after five or more years of use of the triple-therapy agents.Reference Morris, Bradley, Doyal, Earley, Hagan and Milling26 Current research is developing alternative induction protocols and immunosuppressive agents with better safety profiles. The clinical application of new drugs is limited, however, and further studies are warranted.
Ethics of facial transplantation
The face enables breathing, eating, communicating and social interacting. Furthermore, it provides information about identity, age, gender and ethnicity. Patients with severe craniofacial deformities suffer functional and aesthetic abnormalities, which are often accompanied by a sense of loss of identity. This is aggravated by the notion that a person without a face is considered ‘less human’ in some contexts.Reference Genden and Urken27 Positive and negative behavioural responses to rewarding and aversive faces respectively have been demonstrated by parametric analysis of the reward circuit in the human brain, and appear to be dopamine-mediated. This suggests that behavioural responses to ‘monstrous’ faces, such as avoidance, are subconscious in nature.Reference Liang, Zebrowitz and Zhang28
Autologous tissue transfer and reconstructive surgery have a limited application in the repair of multiple facial subunits. Facial transplantation can improve quality of life and restore social functioning in severely deformed patients. Facial transplantation is currently experimental as precise long-term outcomes are unknown, and significant morbidity and mortality may occur. The Declaration of Helsinki guidelines can aid an ethical and professional decision concerning experimental procedures on human subjects: ‘Where an intervention does not exist or has not proved effective, the physician may offer interventions with unknown outcome to patients if it can restore health or alleviate suffering, and this should be made as research in order to evaluate its efficacy’.29
The ethical and technical boundaries governing the facial transplantation debate mainly centre on the risk of life-long immunosuppression and the issue of informed consent. The notion that the procedure may be performed for aesthetic reasons or in poorly equipped centres, and the potential burden of graft failure, are also matters of concern.Reference Morris, Bradley, Doyal, Earley, Hagan and Milling26, Reference Clarke and Butler30–Reference Johnson and Corsen35 It is debated whether life-threatening risks are ethically justifiable in light of a non-life-threatening condition. In response to this, some argue that medicine often delivers care associated with risks, which are justified when outweighed by the benefits. Renal transplants are similarly undertaken on candidates who are otherwise able to remain on haemodialysis, and as facial transplant patients are younger and healthier, the risks are lower in these patients; benefit analysis findings are in favour of transplantation.Reference Wolfe, Ashby, Milford, Ojo, Ettenger and Agodoa36, Reference Vasilic, Alloway, Barker, Furr, Ashcroft and Banis37
The respect for human dignity is a pillar of contemporary research bioethics. Patients have a right to autonomy and to give informed consent. Competence, disclosure, medical literacy, understanding and voluntariness guide an informed decision-making process. In facial transplantation, this process is complicated by unknown long-term results.Reference Alexander, Alam, Gullane, Lengelé and Adamson38 In order to best understand the known risks, alternative therapies and outcomes of conventional reconstructive procedures, facial transplant patients should become an active part of the team.Reference Rumsey39 A bioethicist working closely with the patient and their family, exploring the motives for undergoing the procedure and the perception of benefits, should guide a patient-centred decision-making process.Reference Agich and Siemionow40 It is especially important that the consequences of life-long immunosuppression are explained. The patient should be aware that if chronic rejection ensues, there may be a functional and aesthetic regression from the pre-transplantation state. If these facts are fully comprehended, informed consent can be considered valid. Low socio-economic status, poor pre-operative mental and physical health, and frailty are contraindications to facial transplantation as they are associated with poor medical literacy and cognition, or low post-operative outcomes in solid organ transplant recipients.Reference Lengelé41
Physicians should disclose information as transparently as possible, and list all risks, including minor and major side effects and fatalities. The detail of disclosure should be guided by the patient's desire to learn about their illness, as both under-informing and over-informing has been linked to heightened anxiety levels and poor outcomes.Reference Wiggins, Barker, Martinez, Vossen, Maldonado and Grossi42
Establishing a facial transplantation programme
Implementing a facial transplantation programme is a complex process that presents significant logistical challenges. The American Society for Reconstructive Microsurgery and the American Society of Plastic Surgeons recommend that facial transplantation is performed on victims of severe facial disfigurement (defined as more than 25 per cent of total facial structures and including central facial units) after conventional autologous reconstruction techniques have yielded sub-optimal results.Reference Pomahac, Pribaz, Eriksson, Annino, Caterson and Sampson7 Indications are in continuous evolution, although it is generally accepted that the aim of facial transplantation is to restore functional deficits.Reference Pomahac, Diaz-Siso and Bueno43
Siemionow and colleagues, who pioneered facial transplantation in the USA, advise that the procedure be undertaken at a university-based hospital, with a designated multidisciplinary team available around the clock.Reference Siemionow and Gordon44 The team should work closely with staff at an active basic science laboratory and publish their findings transparently in order to advance the international field. Experienced craniofacial microsurgeons, maxillofacial surgeons, transplant surgeons, immunologists, infectious disease specialists, psychologists and intensivists should be recruited, together with social workers, a patient advocate, ethicists, physical and speech rehabilitation staff, institutional media, liaison and public relations personnel, and security.Reference Siemionow and Gordon44 The team leader requires prior experience with transplantation, as he or she co-ordinates and oversees all aspects of the programme, and is responsible for presenting the benefit-to-risk analysis and informed consent protocols to the independent review board.Reference Pomahac, Pribaz, Eriksson, Annino, Caterson and Sampson7 Various government agencies specific to the country where the programme is undertaken are involved. In the USA, the local organ procurement organisation evaluates and procures facial allografts, and ethical regulatory bodies approve and oversee the protocol.Reference Hobson45
Funding can dictate the feasibility of facial transplantation. In the USA, funding has been granted by institutions, awards, and private or public endowments, including military forces aiming to help soldiers with burns and blast injuries.Reference Siemionow and Gordon44 Alternative sources of funding are required if facial transplantation is to become part of routine care. The lifetime costs of one case of facial transplantation is estimated to be between $250 000 and $1500 500 per patient, which far exceeds the proposed threshold of $50 000 per quality-adjusted life year and limits the possibility of comprehensive government funding.Reference Toure, Meninguaud, Bertrand and Hervé46, Reference Chung, Oda, Saddawi-Konefka and Shauver47 Ultimately, the availability of resources that cover the cost of facial transplantation will depend on how well society perceives the procedure and how recipients re-integrate in society. Reassuringly, the first facial transplant recipient, now eight years post-operative, has demonstrated significant functional and aesthetic restoration, and 2 of the 17 recipients have returned to employment. Media coverage has enhanced awareness of facial transplantation amongst the public and the medical community, and has contributed to the increased acceptance of the procedure.
Conclusion
The controversies governing facial transplantation centre on surgical and immunological risks, and the ability to provide informed consent. Although long-term outcomes are not yet fully available, reports indicate that significant cosmetic and functional benefits, and successful social re-integration of recipients, are achieved by facial transplantation. The next challenge is to prevent immune-pathogenic responses, while diminishing the burden of life-long immunosuppression. Further understanding of the complex immune response will provide insight into effective treatment strategies and improve donor-specific tolerance. Experimental studies are ongoing; these are leading to a successful clinical translation in autoimmune disease and solid organ transplants. If novel therapeutic strategies are extended to composite tissue allografts, the field of facial transplantation may dramatically expand in both adult and paediatric surgery.
