CME

Facial Transplantation: Principles and Evolving Concepts

Rami S. Kantar, M.D., M.P.H. Learning Objectives: After studying this article, the participant should be able to: Allyson R. Alfonso, B.S., B.A. 1. Appreciate the evolution and increasing complexity of transplanted facial Gustave K. Diep, M.D. allografts over the past two decades. 2. Discuss indications and contraindications Zoe P. Berman, M.D. for facial transplantation, and donor and recipient selection criteria and con- William J. Rifkin, M.D. siderations. 3. Discuss logistical, immunologic, and cost considerations in facial J. Rodrigo Diaz-Siso, M.D. transplantation, in addition to emerging technologies used. 4. Understand sur- Michael Sosin, M.D. gical approaches and anatomical and technical nuances of the procedure. 5. Bruce E. Gelb, M.D. Describe aesthetic, functional, and psychosocial outcomes of facial transplanta- Daniel J. Ceradini, M.D. tion reported to date. Eduardo D. Rodriguez, M.D., Summary: This CME article highlights principles and evolving concepts in D.D.S. facial transplantation. The field has witnessed significant advances over the past New York, N.Y. two decades, with more than 40 face transplants reported to date. The proce- dure now occupies the highest rung on the reconstructive ladder for patients with extensive facial disfigurement who are not amenable to autologous recon- structive approaches, in pursuit of optimal functional and aesthetic outcomes. Indications, contraindications, and donor and recipient considerations for the procedure are discussed. The authors also review logistical, immunologic, and cost considerations of facial transplantation. Surgical approaches to allograft procurement and transplantation, in addition to technical and anatomical nuances of the procedure, are provided. Finally, the authors review aesthetic, functional, and psychosocial outcomes that have been reported to date. (Plast. Reconstr. Surg. 147: 1022e, 2021.)

he first face transplant in 2005 introduced injuries in the United States lies between 32.1 and a paradigm shift in craniofacial reconstruc- 58.1 per 100,000.7 These figures, combined with Ttive surgery.1 Since then, facial transplan- recent encouraging reports of face transplant cost tation has evolved into an effective solution for coverage by third-party payers, suggest a high like- patients with extensive facial disfigurement when lihood that an increasing number of patients with autologous approaches fail or are inappropriate extensive facial injuries who are not amenable in restoring optimal facial form and function.2 to conventional reconstruction will seek evalu- Growing international experience with the proce- ation and undergo facial transplantation when dure has revealed overall satisfactory results and appropriate.8 shifted the focus of the field from demonstrating Facial transplantation is complex, requires feasibility, to refining approaches, outcomes, and extensive preparation, and relies on a multidis- addressing new challenges.2,3 ciplinary approach to achieve optimal outcomes. Over the past 15 years, a total of 48 face trans- Despite the growing number of procedures per- plants have been performed in 46 patients.2,4–6 formed around the world, consensus regarding Moreover, data suggest that the annual incidence a number of perioperative considerations is lack- rate of individuals aged 20 to 64 years who suf- ing. This is further exacerbated by limited data fer from preventable nonfatal severe craniofacial regarding long-term outcomes given the recent

From the Hansjörg Wyss Department of and Disclosure: The authors have no disclosures to the Transplant Institute, New York University Langone declare in relation to the content of this article. Health. Received for publication June 15, 2020; accepted January 20, 2021. Related digital media are available in the full-text Copyright © 2021 by the American Society of Plastic Surgeons version of the article on www.PRSJournal.com. DOI: 10.1097/PRS.0000000000007932

1022e www.PRSJournal.com Volume 147, Number 6 • Facial Transplantation advent of the field. With these issues in mind, the debates and discussions regarding the appropri- goal of this CME article is to provide an overview ateness of performing the procedure in pediatric of current and evolving concepts in facial trans- patients.20 plantation, and review important preoperative, Extensive facial disfigurement involving the intraoperative, and postoperative principles. majority of the surface area of the face in associa- tion with significant damage to or loss of central SURGICAL INDICATIONS AND facial structures that are critical to facial func- tion and appearance, and that are challenging RECIPIENT SELECTION to reconstruct through autologous techniques Surgical indications and patient selection (e.g., the nose, lips, and eyelids), is the most criteria in facial transplantation are closely widely accepted indication for facial transplanta- related, and determining the appropriate candi- tion.2,17 The most common mechanism of injury date for the procedure requires rigorous evalua- in patients who have undergone facial transplan- tion. Candidate evaluation should be performed tation is trauma, including ballistic injury, , through a collaborative and multidisciplinary animal attacks, and others.2 The procedure has team-based approach between reconstructive sur- also been performed to treat benign tumors geons, psychologists, speech therapists, dentists, such as neurofibromas, and facial defects result- 9 transplant specialists, and others. Face transplant ing from oncologic resections.2,17,19,21–23 Although teams must also thoroughly assess a candidate’s immediate facial transplantation following injury social support system to ensure favorable con- has been performed successfully with encouraging ditions for the lengthy postoperative recovery, outcomes, the viability of this approach, especially adaptation to psychological repercussions, and when considering donor shortages and matching adherence to lifelong that criteria, remains to be determined.24 Table 1 high- 2,10 accompany the procedure. Psychosocial factors lights surgical and nonsurgical indications, and are particularly important in candidates who have contraindications to facial transplantation based sustained self-inflicted injuries and have a history on the experience of the senior author (E.D.R). of substance abuse or suicidality. Facial transplan- tation has been reported to be successful in these patients, but resolution of suicidal tendencies and DONOR SELECTION AND substance abuse must be ensured before perform- CONSIDERATIONS ing the procedure.2 Facial transplantation in blind Donor selection and matching in facial trans- patients remains controversial, with opponents plantation are more challenging than in solid organ suggesting that recipients will not be able to per- transplantation. The donor and recipient must be ceive the outcomes of the procedure or allograft appropriately matched based on blood type and changes that may indicate immunologic rejec- immunologic criteria in addition to demographic tion, whereas supporters argue that it is unethi- factors, hair and skin color, and cephalometric cal to exclude blind patients, especially in light of parameters.2 These considerations have made donor favorable reported aesthetic and functional out- shortages more pronounced in facial transplanta- comes.11–15 Immunologic risk factors also need to tion, and have often resulted in prolonged candi- be considered when weighing the risks and bene- date wait times before transplantation. Moreover, fits of the procedure in potential candidates. This discrepancies exist between is particularly relevant for patients with a history of organization involvement in solid organ and vas- burns and extensive transfusions that can lead to cularized composite allograft donation, including immunosensitization, human immunodeficiency facial allografts, in favor of solid .25 syndrome infection, presence of donor-specific Strong collaborations between face transplant cen- antibodies, and other immunomodulatory con- ters and organ procurement organizations can ditions that can complicate finding matching alleviate candidate wait times by expanding dona- donors and postoperative recovery.16–18 The risk of tion service areas.25 Furthermore, opt-out donation de novo malignancies associated with the manda- systems have been shown to significantly reduce tory use of lifelong immunosuppression should candidate wait time.24 Lastly, educational initiatives also be taken into consideration, especially in targeting the general public can provide insight immunosuppressed candidates and in patients into functional and aesthetic outcomes of the pro- with facial defects resulting from oncologic resec- cedure and reduce misconceptions, and have been tions.17,19 To date, facial transplantation has been shown to increase the willingness to donate facial limited to adult patients, with ongoing ethical tissue by almost 20 percent.26

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Table 1. Surgical and Nonsurgical Indications and Contraindications to Facial Transplantation Based on the Senior Author’s Experience Strong Strong Relative Considerations Indications Contraindications Contraindications Surgical Extensive defects involving the Sufficient tissue of the central face majority of the surface area subunits (upper/lower eyelids, upper/ of the face lower lips, nose) to complete autologous reconstruction Extensive damage to or loss of the Adequate autologous tissue central face subunits (upper/lower donor sites eyelids, upper/lower lips, nose) Lack of autologous reconstructive options Nonsurgical Adequate support system Inadequate support system History of malignancy No active psychiatric disorders History of poor compliance Blindness Active psychiatric disorder Immunocompromised/ immunosensitized Active malignancy End-organ dysfunction

LOGISTIC CONSIDERATIONS Close collaboration with key stakeholders in trans- Developing and implementing standardized plantation, including local organ procurement logistic processes and workflows are critical for organizations, have led to the development of patient safety, quality improvement, and obtaining elaborate algorithms for transferring face donors reproducible outcomes in complex surgical pro- to recipient institutions and concomitant procure- cedures such as facial transplantation.27 Moreover, ment of solid organs and facial allografts.8,27,32,33 the efficacy of surgical technologies and tools that Such algorithms in addition to perioperative work- will be used in the face transplant such as three- flows ensure team readiness and team dynam- dimensionally–printed cutting guides, intraopera- ics, and uphold optimal performance during a tive navigation, masks for donor facial restoration, face transplant, especially when the donor facial and indocyanine green fluorescence angiography procurement and recipient procedure are being should be tested before the procedure, and team performed concurrently (Fig. 1).27,34 Most impor- members should be familiar with their use.8,28–31 tantly, face transplant teams need to account for

Fig. 1. Setup of face transplant donor and recipient rooms. Schematic of the donor (left) and recipient (right) operating rooms, with strategic placement of multidisciplinary team members and required equipment. IV, intravenous. (From Alfonso AR, Ramly EP, Kantar RS, et al. Anesthetic considerations in facial transplantation: Experience at NYU Langone Health and systematic review. Plast Reconstr Surg Glob Open 2020;8:e2955; printed with permission and copyrights retained by Eduardo D. Rodriguez, M.D., D.D.S.)

1024e Volume 147, Number 6 • Facial Transplantation geographic challenges that may arise when trans- procurements in brain-dead donors.28,29 The appli- plant candidates need to travel long distances cation of computerized surgical planning to facial for their procedures and postoperative visits, to transplantation has perhaps been the most signifi- ensure close follow-up and prompt treatment of cant advancement in the field, introducing a para- potential complications and rejection episodes.8,35 digm shift in allograft design, and allowing face transplant teams to adopt a personalized patient- centered reconstructive approach. Similarly, the COMPUTERIZED SURGICAL PLANNING use of computer-aided design and manufacturing AND IMPLEMENTATION of patient-specific devices such as skeletal cutting Extensive surgical preparations, combined guides has allowed further refinement of allograft with the use of cutting-edge emerging technolo- design and surgical technique (Fig. 2). This is par- gies, have allowed face transplant teams to make ticularly important for allografts including skele- significant strides in the field. Simulated exer- tal segments, where the use of these technologies cises allow face transplant teams to familiarize allows more streamlined, accurate planning and themselves with the procedure and associated execution of donor and recipient osteotomies.31 logistics, and troubleshoot potential challenges [See Video 1 (online), which shows computerized that may arise.2,27 Cadaveric rehearsals allow sur- surgical planning. For allografts including skeletal gical refinement through repetition, objective segments, the use of computerized surgical plan- outcomes assessment, and real-time high-fidelity ning and computer-aided design and manufac- simulation of the planned procedure; expedited turing allows accurate, streamlined planning and allograft procurement; and decreased opera- execution of donor and recipient osteotomies. tive time and the number of required simulated (Adapted from Ramly EP, Kantar RS, Diaz-Siso exercises with subsequent transplants.2,8,15,30,31,36–39 JR, Alfonso AR, Rodriguez ED. Computerized This can be further supplemented with research approach to facial transplantation: Evolution and

Fig. 2. Computer-aided design and manufacturing of patient-specific skeletal cutting guides. These guides have refined surgical approaches in facial transplantation. Although this recipient’s facial defect did not involve skeletal segments, the allograft was designed to include skeletal subunits to augment facial projection while preserving retaining ligaments and muscular insertion sites. Donor (left) and recipient (right) planned osteotomies and customized cutting guides are shown. (From Sosin M, Ceradini DJ, Levine JP, et al. Total face, eyelids, ears, scalp, and skeletal subunit transplant: A reconstructive solu- tion for the full face and total scalp . Plast Reconstr Surg. 2016;138:205–219; printed with permission and copyrights retained by Eduardo D. Rodriguez, M.D., D.D.S.)

1025e Plastic and Reconstructive Surgery • June 2021 application in 3 consecutive face transplants. Plast inset and fixation in the recipient (Fig. 3).8,41 Reconstr Surg Glob Open 2019;7:e2379; provided Adequate allograft perfusion and viability follow- with permission from and copyrights retained by ing skeletal inset and vascular anastomoses can Eduardo D. Rodriguez, M.D., D.D.S.)] then be verified using indocyanine green fluores- These advantages can translate into improved cence angiography, which can also be performed cephalometric and occlusal relationships between before final detachment of the allograft from the donor craniomaxillofacial segments and the donor major vessels (Fig. 4).8,28,29,36,37,42,43 Lastly, recipient craniofacial skeleton.31,40 More recently, computer-aided technologies can also be used for computer-aided intraoperative surgical naviga- donor facial restoration, with recent data demon- tion has been proposed as an adjunct to these strating that three-dimensionally–printed masks tools, with benefits including the capability to based on preoperatively acquired donor digital register and overlay the predetermined surgical facial images are more accurate than traditional plan onto the patient skeletal defect and real-time silicone-based masks (Fig. 5).44 Importantly these intraoperative guidance, which can translate into three-dimensionally–printed masks offer a less improved accuracy during donor skeletal segment invasive alternative with a lower risk of iatrogenic

Fig. 3. Intraoperative navigation. Real-time intraoperative surgical navigation can be used to confirm accurate allograft skeletal inset, and compare planned (green) versus actual (gray) position of the skeletal segments. Intraoperative computed tomographic scanning and registration of scan data using a registration device (above, left and right) allow real-time surgical navigation and verification of skeletal segment positions (below, left and right). (From Kantar RS, Ceradini DJ, Gelb BE, et al. Facial transplantation for an irreparable central and lower face injury: A modernized approach to a classic challenge. Plast Reconstr Surg. 2019;144:264e–283e; printed with permission and copyrights retained by Eduardo D. Rodriguez, M.D., D.D.S.)

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Fig. 4. Indocyanine green fluorescence angiography. The use of indocyanine green fluo- rescence angiography allows face transplant teams to verify appropriate allograft arterial perfusion and venous outflow before release from the donor major vessels and following transplantation. (From Kantar RS, Ceradini DJ, Gelb BE, et al. Facial transplantation for an irreparable central and lower face injury: A modernized approach to a classic challenge. Plast Reconstr Surg. 2019;144:264e–283e; printed with permission and copyrights retained by Eduardo D. Rodriguez, M.D., D.D.S.) injury to the allograft compared to silicone-based injuries not amenable to autologous approaches masks, given that they do not require donor facial mandates developing standardized classification impressions.44 All of these innovations can be thor- schemes and nomenclature for these injuries oughly tested during simulated exercises before to improve communication between transplant implementation during a clinical face transplant, teams and strengthen collaborative efforts which can streamline the planning and execution (Fig. 7).45 of these complex procedures, overcome intraop- When designing the facial allograft and plan- erative anticipated and unexpected challenges, ning recipient tissue excision, we recommend tak- and translate into more predictable outcomes. ing into consideration functional and aesthetic facial subunits for soft-tissue components, and TECHNICAL NUANCES AND using Le Fort–type osteotomies for skeletal seg- ments. [See Video 2 (online), which shows Le CONSIDERATIONS Fort–type osteotomies. This video shows how Le Growing experience in the field and the Fort III–type skeletal osteotomies can be used technological and logistical improvements listed for donor allograft procurement, using custom- above have allowed teams to successfully navigate tailored virtually designed cutting guides that are the anatomical complexities inherent in the head preoperatively planned to match donor and recip- and neck, and transplant increasingly complex ient facial skeletons. (Adapted from Kantar RS, facial allografts including a large amount of bone Ceradini DJ, Gelb BE, et al. Facial transplantation 2 (Fig. 6). This has allowed face transplant teams to for an irreparable central and lower face injury: A provide customized patient-specific reconstructive modernized approach to a classic challenge. Plast solutions to individuals with extensive facial disfig- Reconstr Surg. 2019;144:264e–283e; provided with urement resulting from a myriad of congenital or permission and copyrights retained by Eduardo acquired conditions (Table 2). Although surgical D. Rodriguez, M.D., D.D.S.)] approaches have varied significantly between face Appropriate allograft vascular perfusion is the transplant teams around the world, the growing cornerstone to successful transplantation, and popularity of the procedure as a reconstructive numerous allograft vascular pedicles have been solution for patients affected with extensive facial described (Table 2). To ensure optimal perfusion

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Fig. 5. Donor mask for facial restoration. A high-fidelity, three-dimensionally– printed mask (right) can be created from preoperative facial three-dimensional images for optimal donor likeness. It is used to cover the facial defect following allograft procurement. The three-dimensional printing technique (right) provides superior donor likeness compared to the traditional silicone-based technique (left), which generates a mask from preoperative facial impressions. The three- dimensionally–printed mask technique is also less invasive and can be initiated as soon as three-dimensional digital images of the donor face are obtained preop- eratively; it preserves the dignity of the donor, and allows the donor family to per- form routine end-of-life rituals. (From Kantar RS, Ceradini DJ, Gelb BE, et al. Facial transplantation for an irreparable central and lower face injury: A modernized approach to a classic challenge. Plast Reconstr Surg. 2019;144:264e–283e; printed with permission and copyrights retained by Eduardo D. Rodriguez, M.D., D.D.S.) and vascular pedicle lengths, we recommend estab- provided with permission and copyrights retained lishing bilateral arterial inflow through the external by Eduardo D. Rodriguez, M.D., D.D.S.)] carotid arteries, with corresponding appropriate It is the senior author’s (E.D.R) preference to bilateral venous outflow, which requires meticulous perform all vascular anastomoses using the oper- bilateral neck dissections at the time of transplan- ating microscope to optimize anastomotic tech- tation. [See Video 3 (online), which demonstrates nique, and to perform allograft skeletal inset and neck dissection. Neck dissection involves initial fixation in the recipient before vascular anasto- elevation of the subplatysmal flap, circumferential moses to prevent kinking of the vascular pedicles. exposure of the major vessels, harvesting of lymph [See Video 4 (online), which demonstrates vascu- nodes, and excision of the submandibular gland. lar anastomoses. This video shows how the vascu- Meticulous dissection results in clear identification lar pedicles are tailored to limit vessel redundancy of critical head and neck anatomical structures, and to help prevent kinking, and how the anasto- including the internal jugular vein, facial vein, com- moses are performed using the operating micro- mon carotid artery, external and internal carotid scope. Here, the right donor external carotid arteries, occipital artery, lingual artery, facial artery, artery was anastomosed to the right recipient and the hypoglossal nerve. (Adapted from Sosin external carotid artery end-to-end. Because of a M, Ceradini DJ, Levine JP, et al. Total face, eye- donor vascular variant identified during preoper- lids, ears, scalp, and skeletal subunit transplant: A ative imaging, the donor anterior jugular vein was reconstructive solution for the full face and total anastomosed end-to-end to the recipient internal scalp burn. Plast Reconstr Surg. 2016;138:205–219; jugular vein, as opposed to the more commonly

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Fig. 6. Face transplant/head and neck anatomy with cutting guides. (Printed with permission and copyrights retained by Eduardo D. Rodriguez, M.D., D.D.S.) used donor and recipient internal jugular veins similar for both the donor and recipient opera- anastomosed end-to-side. (Adapted from Kantar tions. A skin flap is elevated in the subcutaneous RS, Ceradini DJ, Gelb BE, et al. Facial transplan- plane and continues deep to the masseteric fascia tation for an irreparable central and lower face as the nerve exits the parotid gland. The upper, injury: A modernized approach to a classic chal- middle, and lower divisions of the facial nerve are lenge. Plast Reconstr Surg. 2019;144:264e–283e; identified using intraoperative nerve stimulation. provided with permission and copyrights retained (Adapted from Dorafshar AH, Bojovic B, Christy by Eduardo D. Rodriguez, M.D., D.D.S.)] MR, et al. Total face, double jaw, and tongue trans- Moreover, it is important to mention that plantation: An evolutionary concept. Plast Reconstr our preferred preoperative vascular imaging Surg. 2013;131:241–251; provided with permission protocol consists of conventional angiography and copyrights retained by Eduardo D. Rodriguez, supplemented by computerized tomographic M.D., D.D.S.)] angiography, to visualize vessel patency and real- It is also important to mention that coapt- time vascular flow dynamics, which can signifi- ing the facial nerve branches distally in prox- cantly affect surgical planning.2,46 Despite early imity to the target muscles has been proposed debate on the inclusion of salivary glands within to reduce the risk of synkinesis.1,2,47,48 We also the allograft, we recommend excluding the recommend coapting sensory nerves when pos- parotid and remaining salivary glands to mini- sible. Preventing ocular complications includ- mize the formation of sialoceles [see Video 3 ing ectropion, lid retraction, and loss of blink (online)]. Optimal patient outcomes are highly reflex, is also critical in facial transplantation dependent on restoring appropriate sensory and and relies on meticulous dissection and preserva- motor facial functions following transplantation. tion of periorbital structures.2,48–50 [See Video 6 This relies on identification and meticulous dis- (online), which demonstrates periorbital dissec- section of the facial nerve and corresponding tion. In this video we demonstrate our periorbital branches, which can be facilitated by the use of approach in one of our face transplant recipients, intraoperative nerve stimulation. [See Video 5 where the periorbital dissection proceeds in the (online), which demonstrates facial nerve dissec- subcutaneous plane. The orbicularis oculi and tion. The approach to facial nerve dissection is underlying structures are preserved in an effort

1029e Plastic and Reconstructive Surgery • June 2021 — — Yes Yes Yes Yes No No No No No No Yes No No No No No No No No No No No No No No Chronic Rejection (Continued) — — Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Acute Rejection

TFT) Status 36 mo) (malignancy) (HCC, 10 yr) 2 mo) compliance, 27 mo) (malignancy, (malignancy, 11 yr) (COD, Alive Alive Alive Alive Alive Death (suicide, Alive Alive Alive Alive Alive Alive Death Alive Death Death (sepsis, Alive Alive Alive Death (non- Alive Alive Death Alive Alive Alive Alive

artery plus ECA plus ECA trunk facial artery artery artery artery Pedicle Vascular Vascular Allograft — ECA Facial Facial artery Facial artery ECA ECA Linguofacial ECA ECA CCA — CCA ECA ECA plus ECA ECA Facial ECA Maxillary — ECA Facial — ECA ECA —

Type Full Full Partial Partial Full Full Partial Full Full Partial Partial Full Full Full Partial Partial Partial Partial Partial Partial Partial Partial Partial Partial Partial Full Partial Allograft

Extent of Defect mandible maxilla, mandible, lips bone, lips, maxilla, mandible cheek, lips nasal bone, cheek, lips tus, zygoma, maxilla, mandible lips, chin, perioral area of mouth, mandible mandible maxilla, zygoma ears, cheek orbital floor, zygoma, maxilla orbital floor, nose, lips, cheeks maxilla, orbital wall, zygoma cheek, ears, eyes, neck tongue lips, zygoma, maxilla, mandible Nose, upper lip, teeth, maxilla, — Forehead, nose, cheeks, lips Eyes, eyelid, cheek, nose, Forehead, eyelids, eyes, nasal Forehead, eyelids, nasal bone, Nose, mandible, maxilla Nose, mandible, maxilla Forehead, eyelids, left eye, Eyelids, ears, nose, lips, oral mucosa Eyelids, nose, lips, lacrimal appara - Cheek, lips, chin, mandible Mandible, upper and lower Lower lip, tongue, floor Cheek, nose, lips, maxilla, Lower eyelid, cheek, nose, lips, Forehead, nose, eyelids, Nose, lips, maxilla, mandible Lower eyelids, nose, upper lip, Forehead, brows, eyelids, Nose, lips, eyelid, cheek, maxilla Cheek, nose, upper lip, Nose, lips, eyelids, forehead, Cheek, nose, lips, chin Forehead, eyelids, nose, cheeks, lips Lower eyelid, mandible, maxilla, Forehead, eyelids, nose, cheek,

trauma trauma attack burn trauma burn trauma malignancy trauma burn burn trauma trauma attack burn attack burn tumor trauma Indication Ballistic Burn Burn Ballistic Animal Electrical Ballistic Ballistic trauma Electrical NF Ballistic NF Ballistic trauma ORN after Ballistic Electrical Third-degree Ballistic trauma Ballistic NF Blunt Animal Chemical Animal Thermal Vascular Vascular Ballistic Sex F M M M F M M M M M M M M M M M M M F M M M F F M F M — 20 25 19 54 57 30 41 45 25 35 30 35 27 42 33 59 37 27 45 29 30 38 35 37 32 44 Age (yr) Recipient plant - Trans 03/2012 02/2012 01/2012 12/2011 05/2011 04/2011 04/2011 04/2011 03/2011 06/2010 03/2010 01/2010 11/2009 08/2009 08/2009 04/2009 04/2009 03/2009 12/2008 01/2007 04/2006 11/2005 05/2012 09/2012 03/2012 05/2013 Date of 02/2013

Transplant Location of Spain Spain Ohio Republic of China France , Ankara, Turkey Ankara, Turkey Ankara, Turkey Ghent, Belgium Boston, Mass. Boston, Mass. Paris, France Paris, France Boston, Mass. Paris, France Barcelona, Seville, Spain , Valencia, Valencia, Paris, France Boston, Mass. Paris, France Paris, France Cleveland, Paris, France Gliwice, Xi’an, People’s Xi’an, People’s Boston, Mass. Amiens, Ankara, Turkey Amiens, France Baltimore, Md. Team Surgical Facial Transplantation Worldwide as of April 2020 as of April Worldwide Transplantation Facial Dubernard Dubernard Dubernard Ozmen Nasir Ozkan Blondeel Pomahac Pomahac Lantieri Lantieri Pomahac Lantieri Barret Gomez-Cia Devauchelle, Cavadas Lantieri Pomahac Lantieri Lantieri Siemionow Lantieri Maciejewski Guo Pomahac Devauchelle, Ozkan Devauchelle, Rodriguez 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 27 2 26 1 24 25 Table 2. Table Patient 23

1030e Volume 147, Number 6 • Facial Transplantation — — — — — — No No No No No No No No No No No No No No No Chronic Rejection — — — — — — Yes Yes Yes Yes Yes Yes Yes No Yes Yes No Yes No Yes No Acute Rejection

tory failure, 11 mo) TFT) Status (COD, Alive Death (respira - Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive — Alive Alive Alive facial artery artery facial artery Pedicle ECA ECA ECA ECA plus — ECA Facial — ECA ECA ECA plus — — ECA — — — — — — ECA Vascular Vascular Allograft

Type Full Full Full Partial Full Partial Full Full Partial Full Partial Partial Full Partial Full Full Partial — Full Full Full Allograft Extent of Defect nose, cheek, mandible left eye, maxilla, mandible, tongue lips, mandible mandible eye, maxilla, cheeks lips and nose pharynx cheeks, lower face, ear, lips, neck cheeks, lower face, ear, salivary glands, lower face nose, cheeks, maxilla, mandible illa, mandible, zygoma, right orbital floor tissue 2/3 of face cheeks, lower face, lips, ears, neck, also included bilateral hands Forehead, eyelids, left eye, Scalp, forehead, eyelids, nose, Forehead, eyelids, nose, maxilla, Forehead, lips, nose, maxilla, Forehead, nose, lips, lower face Scalp, forehead, eyelids, nose, Forehead, mandible, maxilla, Lower face, neck, lips, tongue, Forehead, nose, lips Scalp, forehead, eyelids, nose, Nose, maxilla, central mandible Nose, maxilla, mandible, cheeks, Scalp, forehead, eyelids, orbit, Eyelids, nose, cheek, lips, max - — Maxilla, mandible, full face soft — Maxilla, mandible, nose, lower Lips, nose, facial skin — Scalp, forehead, eyelids, nose, trauma trauma trauma trauma trauma burn burn trauma trauma trauma trauma previous FT trauma trauma burn previous FT burn Indication Ballistic Ballistic NF Ballistic Ballistic TINI Ballistic AVM Electrical Thermal Ballistic Ballistic Ballistic Ballistic CR of Ballistic NF Ballistic Thermal CR of Thermal Sex M M F M M M M M M M M M F M M M F M M F M

26 54 28 22 39 44 31 45 22 41 34 32 21 25 43 58 49 64 68 52 22 (yr) Age Recipient plant - Trans Date of 07/2013 08/2013 12/2013 12/2013 03/2014 09/2014 10/2014 02/2015 05/2015 08/2015 02/2016 06/2016 05/2017 01/2018 01/2018 03/2018 09/2018 05/2018 07/2019 07/2020 08/2020 Turkey Turkey Turkey Poland Turkey Turkey Mass. Ohio Mass. Spain Petersburg, Russia N.Y. N.Y. Finland Minn. Ohio N.Y. N.Y. France Finland Italy Canada Mass. Transplant Location of Ankara, Ankara, Gliwice, Ankara, Boston, Cleveland, Boston, Barcelona, Saint- New York, New York, Helsinki, Rochester, Rochester, Cleveland, New York, New York, Paris, Helsinki, Rome, Montreal, Boston, Boston, Mass. New York, N.Y. New York, Team Surgical Continued Longo Ozkan Ozkan Maciejewski Ozkan Pomahac Papay Pomahac Barret Volokh Rodriguez Tornwall Mardini Papay Rodriguez Lantieri Lassus Borsuk Santanelli, Pomahac Pomahac Rodriguez 28 neurofibromatosis; ECA, external carotid artery; HCC, hepatocellular carcinoma; ORN, osteoradionecrosis; CCA, female; M, male; NF, time from transplantation; F, COD, cause of death; TFT, AVM, arteriovenous malformation; common carotid artery;necrotizing inflammation; HCC, hepatocellular carcinoma; TINI, trauma-induced TINI, trauma-induced face transplant. CR, chronic rejection; FT, 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 Table 2. Table Patient

1031e Plastic and Reconstructive Surgery • June 2021 to avoid impairment of corneal blink. (Adapted IMMUNOLOGIC CONSIDERATIONS from Dorafshar AH, Bojovic B, Christy MR, et al. AND OUTCOMES Total face, double jaw, and tongue transplanta- Immunosuppressive regimens, especially tion: An evolutionary concept. Plast Reconstr Surg. induction regimens, have varied significantly 2013;131:241–251; provided with permission and between face transplant teams. Regimens have copyrights retained by Eduardo D. Rodriguez, included tacrolimus, mycophenolate mofetil, and M.D., D.D.S.)] steroids, with humanized interleukin-2 antibody Although an extensive discussion regarding or antithymocyte globulin; steroids and anti-CD52 posttransplant revisions is beyond the scope of antibody; steroids and antithymocyte globulin; this article, it is important to highlight that they steroids, antithymocyte globulin, and anti-CD20 are commonly performed to improve functional antibody; and steroids, antithymocyte globulin, and aesthetic outcomes and to address postop- and mycophenolate mofetil.42,43,54–57 Maintenance erative complications and conditions includ- immunosuppression regimens reported by dif- ing ptosis, malocclusion, hematomas, palatal ferent teams are more homogenous and typi- fistulae, ectropion, lid retraction, facial muscle cally consist of triple therapy with a steroid taper, retraction, and contour abnormalities.2,42,48,50–53 tacrolimus, and mycophenolate mofetil, with one In patients receiving allografts that include pre- team reporting tapering steroids off completely, dominantly soft-tissue components, we believe and another team using only tacrolimus and ste- it is important to preserve and avoid disrupt- roids.55–59 Three of the four patients in whom ste- ing critical facial osteocutaneous retaining liga- roids were tapered off, however, required therapy ments by including donor skeletal segments to reintroduction because of frequent rejection minimize ptosis.42 The senior author’s (E.D.R) episodes.57 surgical approach in three face transplant recipi- The side effects and risks associated with life- ents has previously been described extensiv long immunosuppression that accompany facial ely.8,29,36,37,42,43 In this article, we include two ani- transplantation are the most significant chal- mated overviews highlighting the considerations lenges facing the field. Complications associ- discussed and representing our approach with ated with long-term immunosuppression include a patient who received an allograft containing kidney injury, increased risk of malignancy, an extensive amount of bone and a patient who metabolic abnormalities, and opportunistic infec- received an allograft containing predominantly tions.57,60 Kidney injury can progress to end-stage soft-tissue elements. [See Video 7 (online), renal failure requiring dialysis and transplanta- which displays digital animation depicting a par- tion.61 In an attempt to minimize renal toxicity, tial face and double-jaw transplant. This digital some teams have used sirolimus and belatacept animation depicts a partial face and double-jaw instead of tacrolimus, with limited success.62,63 transplant in a patient who sustained a ballistic Mycophenolate mofetil is typically associated with facial injury. (Adapted from Kantar RS, Ceradini mild gastrointestinal side effects, and metabolic DJ, Gelb BE, et al. Facial transplantation for an abnormalities can develop following facial trans- irreparable central and lower face injury: A mod- plantation because of the use of steroids. These ernized approach to a classic challenge. Plast include diabetes, hypertension, and dyslipidemia, Reconstr Surg. 2019;144:264e–283; provided with and are usually managed with lifestyle modifica- permission and copyrights retained by Eduardo tion and medications.38,60,64 Face transplant recipi- D. Rodriguez, M.D., D.D.S.) See Video 8 (online), ents should also receive appropriate prophylaxis which displays digital animation, depicting a face for opportunistic viral and bacterial infections transplant that involved predominantly soft-tis- that may arise because of chronic immunosup- sue components. This digital animation depicts pression. These infections have been reported a total face, eyelids, ears, scalp, and skeletal frequently, and should be managed swiftly when subunit transplant in a patient who sustained a they occur to minimize the risk of injury to the full facial and total scalp burn injury. (Adapted allograft.65 from Sosin M, Ceradini DJ, Levine JP, et al. Total Immunologic rejection of the allograft is a face, eyelids, ears, scalp, and skeletal subunit major concern following facial transplantation. transplant: A reconstructive solution for the Rejection is typically characterized clinically by full face and total scalp burn. Plast Reconstr Surg. allograft erythema, swelling, and redness, and is 2016;138:205–219; provided with permission and graded using the Banff classification system his- copyrights retained by Eduardo D. Rodriguez, tologically, based on epithelial involvement and M.D., D.D.S.)] inflammatory cell infiltration.66 Facial allograft

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Fig. 7. Soft-tissue and skeletal tissue defect classification system for facial transplantation. Soft-tissue defects (above) are classified as type 0, oral (includes the upper lip, lower lip, and oral commissures); type 1, oral-nasal (includes the nasal soft-tissue structures with or without type 0; type 2, oral-nasal-orbital (includes infraorbital and malar regions with or without type 1; type 3, full facial (includes the forehead, supraorbital, and preauricular regions and can include all facial soft tissues. Skeletal tissue defects (below) are classified as type A, Le Fort I–type (involves the maxilla partially or completely); type B, Le Fort III–type (includes the maxilla, inferomedial orbital, and zygomatic bones with or without nasal, vomer, and ethmoid bones); type C, monobloc advancement type (includes frontal and supraorbital bones with or without facial bones in the other types of defects); and subtype M, mandibu- lar involvement (includes the mandible partially or completely. (Adapted from Mohan R, Borsuk DE, Dorafshar AH, et al. Aesthetic and functional facial transplantation: A classification system and treatment algorithm.Plast Reconstr Surg. 2014;133:386–397; printed with permission and copyrights retained by Eduardo D. Rodriguez, M.D., D.D.S.) recipients should be closely monitored for signs date, there have been no reports of hyperacute of acute rejection, and treatment of rejection rejection or -versus-host disease. Donor- episodes, typically with pulse dose corticosteroids derived macrochimerism has been previously and adjustment of maintenance immunosuppres- reported in animal models of facial transplanta- sants if needed, must be initiated early.48 Some tion but has yet to be reported in face transplant teams have used sentinel flaps to assist with clini- recipients.73 cal monitoring, but the utility of this approach The majority of reported face transplant and the value of routine skin and mucosal sur- recipients have experienced one or several acute veillance biopsies remain unknown.67–69 Similarly, rejection episodes (Table 2). Two patients treated noninvasive imaging-based methods to monitor by our team with steroids, antithymocyte globulin, for allograft rejection remain experimental at and anti-CD20 for induction immunosuppres- this stage.2,70 Chronic immunologic rejection has sion, and steroids, tacrolimus, and mycophe- been reported in two face transplant recipients, nolate mofetil for maintenance remained free including the recipient of the first face transplant from any acute rejection episodes for more than in 2005 who required resection of part of the 5 years and 2 years, respectively, following facial allograft and autologous reconstruction.71,72 To transplantation.8,42,74 1033e Plastic and Reconstructive Surgery • June 2021

AESTHETIC, FUNCTIONAL, AND outcomes (Fig. 8).1,2,8,38,48,56,57 Recovery of motor PSYCHOSOCIAL OUTCOMES function has been reported to occur as early as Reporting outcomes in facial transplanta- 3 months, but typically occurs at 6 to 8 months 2,48,57,75 tion is challenging because of the limited num- with progressive improvement. Available ber of procedures that have been performed to outcome reports suggest that facial expression, date, and the recent advent of the field. This has speech, lip competence, and swallow demon- 2,48 contributed to the lack of standardized and vali- strate overall satisfactory recovery. Although dated assessment tools in facial transplantation, the ideal postoperative rehabilitative strategy and the paucity of long-term outcome reports.10 remains to be determined, motor recovery is cer- Nevertheless, available data suggest favorable tainly highly dependent on strict patient adher- 2,48 overall aesthetic, functional, and psychosocial ence to therapy. Recovery of sensory function

Fig. 8. Preoperative and postoperative images of three face transplant recipients, patient 1 (left), patient 2 (center), and patient 3 (right), before facial transplantation (above) and after facial transplantation and all revision procedures (below). The postoperative photographs were taken at 5 years and 1 month after transplantation for patient 1, 4 years and 1 month after transplantation for patient 2, and 1 year after transplantation for patient 3. The senior author’s experience with these three patients demonstrates the satisfactory long-term aesthetic and functional outcomes that can be achieved through facial transplantation in patients with extensive facial disfigurement, who are not amenable to autologous reconstruction. (Reprinted from Diep GK, Ramly EP, Alfonso AR, Berman ZP, Rodriguez ED. Enhancing face transplant outcomes: Fundamental principles of facial allograft revision. Plast Reconstr Surg Glob Open 2020;8:e2949; printed with permission and copyrights retained by Eduardo D. Rodriguez, M.D., D.D.S.)

1034e Volume 147, Number 6 • Facial Transplantation has been reported to occur earlier than motor necrotic tissues and reconstruction using a radial function, even when sensory nerve coaptation forearm free flap, whereas allograft failure in a full is not performed.1,2,48,57,76 Sensory recovery has face recipient was treated with excision and cover- been reported as early as 3 months, with earlier age with an anterolateral thigh flap resulting in recovery for the mental nerve compared to the significant facial disfigurement.72,84 Recently, facial trigeminal nerve.2,23,43,48,56–58 Light touch, two-point retransplantation was performed successfully in discrimination, pain sensation, and thermal sensa- a transplant recipient who suffered from chronic tion have been reported to recover later around rejection of his first allograft, demonstrating the 8 months after facial transplantation.2,48,57 Both technical feasibility of the procedure in case of motor and sensory functions have been shown allograft failure.83 Nevertheless, short- and long- to demonstrate steep significant improvements term outcomes of this salvage option in addition to in the first year after transplantation, with slower the immunologic consequences of using additional progressive recovery afterward.57 induction immunosuppression with facial retrans- Psychosocial outcomes following facial trans- plantation remain unknown. plantation are encouraging, despite early con- cerns that the procedure may compromise the recipient’s sense of identity.2,10,48,56,57,77–79 Patients COST CONSIDERATIONS receiving facial allografts have demonstrated Face transplant procedures remain costly, improved quality of life, sense of self, social inte- especially in light of the need for lifelong immu- gration, and decreased prevalence of depression, nosuppression and follow-up. However, previous with several patients returning to work following analyses have demonstrated that the long-term the procedure.2,10,48,57 Satisfactory psychosocial costs associated with conventional autologous outcomes are heavily dependent on appropri- reconstruction and face transplantation are com- ate patient selection and screening before trans- parable.85,86 To date, the majority of face trans- plantation. Rigorous candidate evaluation can plants performed have been supported through allow face transplant teams to predict noncom- institutional or grant-based funding, with signifi- pliance, detect substance abuse disorders and cant debate regarding the role of health insurance psychiatric illnesses, and determine whether the coverage.87 Recent experience with third-party candidate’s social support system is adequate for coverage of costs associated with face transplan- the lengthy recovery following transplantation tation brings the procedure one step closer to and for the extensive media exposure that these becoming standard of care in the treatment of patients usually receive.2,48 Development of col- craniofacial disfigurement.8 This holds significant laborative, multi-institutional protocols for psy- promise for patients afflicted with extensive cra- chosocial screening, evaluation, follow-up, and niomaxillofacial injuries who are not amenable treatment through initiatives such as the Chauvet to or have failed conventional autologous recon- Workgroup and the New York University/Johns struction and for the future of the field, espe- Hopkins Working group, and transparent report- cially when considering the significant number of ing of outcomes by face transplant teams, are crit- patients who are estimated to potentially benefit ical to determine the long-term impact of facial from face transplant evaluation.7 transplantation on recipients.57,80–82 CONCLUSIONS ALLOGRAFT FAILURE MANAGEMENT Almost two decades after the first face trans- STRATEGIES plant, the procedure has emerged from the exper- Risks of facial allograft failure, including signif- imental realm to occupy the highest rung on the icant morbidity, mortality, and disfigurement, need reconstructive ladder for patients with extensive to be discussed with candidates extensively preop- facial disfigurement who are not amenable to eratively. Surgical teams need to weigh the poten- autologous reconstructive approaches, in pursuit tial aesthetic benefits of including additional tissue of optimal functional and aesthetic outcomes. in the transplanted allograft against limiting their Combining lessons learned from growing experi- autologous reconstructive options. To date, contin- ence in the field over the past two decades with gency plans in case of allograft failure remain team- emerging technologies, innovative immunologic and patient-specific, with no clear consensus within approaches, and strong international collabora- the field.83 Partial allograft failure in the first face tions will certainly allow face transplant teams to transplant recipient was managed with excision of make greater strides in the years to come.

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Eduardo D. Rodriguez, M.D., D.D.S. 11. Carty MJ, Bueno EM, Lehmann LS, Pomahac B. A position Hansjörg Wyss Department of Plastic Surgery New York paper in support of face transplantation in the blind. Plast University Langone Health Reconstr Surg. 2012;130:319–324. 222 East 41st Street, 6th Floor 12. Hendrickx H, Blondeel PN, Van Parys H, et al. Facing a new New York, N.Y. 10017 face: An interpretative phenomenological analysis of the [email protected] experiences of a blind face transplant patient and his part- Instagram: @dr_eduardo_d_rodriguez_nyc ner. J Craniofac Surg. 2018;29:826–831. 13. Lemmens GM, Poppe C, Hendrickx H, et al. Facial trans- plantation in a blind patient: Psychologic, marital, and PATIENT CONSENT family outcomes at 15 months follow-up. Psychosomatics 2015;56:362–370. Patients provided written consent for the use of their 14. Van Lierde KM, De Letter M, Vermeersch H, et al. images. Longitudinal progress of overall intelligibility, voice, reso- nance, articulation and oromyofunctional behavior during the first 21 months after Belgian facial transplantation.J ACKNOWLEDGMENTS Commun Disord. 2015;53:42–56. 15. Roche NA, Vermeersch HF, Stillaert FB, et al. Complex The authors would like to acknowledge the donor facial reconstruction by vascularized composite allotrans- patients and families for selflessly donating the gift of plantation: The first Belgian case.J Plast Reconstr Aesthet Surg. life, and the recipient patients and families. They would 2015;68:362–371. also like to recognize the diligent efforts of LiveOnNY, 16. Chandraker A, Arscott R, Murphy GF, et al. The manage- New York University Langone Health and School of ment of antibody-mediated rejection in the first presensi- tized recipient of a full-face allotransplant. Am J Transplant. Medicine, LaGuardia Studio–New York University, 2014;14:1446–1452. Materialise, DePuy Synthes CMF, Brainlab, LifeCell, 17. Cavadas PC, Ibáñez J, Thione A. Surgical aspects of a lower and Checkpoint Surgical. The authors would also like to face, mandible, and tongue . J Reconstr thank Elie Ramly for contribution with Video 1. Microsurg. 2012;28:43–47. 18. Bharadia D, Sinha I, Pomahac B. Role of facial vascularized composite allotransplantation in burn patients. Clin Plast Surg. 2017;44:857–864. REFERENCES 19. Diaz-Siso JR, Sosin M, Plana NM, Rodriguez ED. Face trans- 1. Dubernard JM, Lengelé B, Morelon E, et al. Outcomes 18 plantation: Complications, implications, and an update for months after the first human partial face transplantation.N the oncologic surgeon. J Surg Oncol. 2016;113:971–975. Engl J Med. 2007;357:2451–2460. 20. Benghiac AG, Garrett JR, Carter BS. Ethical issues in pediat- 2. Rifkin WJ, David JA, Plana NM, et al. Achievements and chal- ric face transplantation. Pediatr Transplant. 2017;21. lenges in facial transplantation. Ann Surg. 2018;268:260–270. 21. Sosin M, Rodriguez ED. The face transplantation update: 3. Kollar B, Pomahac B. Facial restoration by transplantation. 2016. Plast Reconstr Surg. 2016;137:1841–1850. Surgeon 2018;16:245–249. 22. Gomez-Cia T, Sicilia-Castro D, Infante-Cossio P, et al. Second 4. Steinbuch Y. This is the first man to have three faces. human facial allotransplantation to restore a severe defect New York Post April 17, 2018. Available at: https://nypost. following radical resection of bilateral massive plexiform com/2018/04/17/this-is-the-first-man-to-have-three-faces/. neurofibromas.Plast Reconstr Surg. 2011;127:995–996. Accessed March 1, 2020. 23. Lantieri L, Meningaud JP, Grimbert P, et al. Repair of the 5. Rosenberg E. His face was severely damaged on a hunt. Now lower and middle parts of the face by composite tissue allo- he’s the world’s oldest face transplant recipient. Washington transplantation in a patient with massive plexiform neurofi- Post September 14, 2018. 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30. Lindford AJ, Mäkisalo H, Jalanko H, et al. The Helsinki 50. Greenfield JA, Kantar RS, Rifkin WJ, et al. Ocular consider- approach to face transplantation. J Plast Reconstr Aesthet Surg. ations in face transplantation: Report of 2 cases and review of 2019;72:173–180. the literature. Ophthalmic Plast Reconstr Surg. 2019;35:218–226. 31. Ramly EP, Kantar RS, Diaz-Siso JR, Alfonso AR, Rodriguez 51. Bassiri Gharb B, Frautschi RS, Halasa BC, et al. Watershed ED. Computerized approach to facial transplantation: areas in face transplantation. Plast Reconstr Surg. Evolution and application in 3 consecutive face transplants. 2017;139:711–721. Plast Reconstr Surg Glob Open 2019;7:e2379. 52. Mohan R, Fisher M, Dorafshar A, et al. Principles of face 32. Diaz-Siso JR, Plana NM, Schleich B, Irving H, Gelb BE, transplant revision: Beyond primary repair. Plast Reconstr Rodriguez ED. Novel donor transfer algorithm for multi- Surg. 2014;134:1295–1304. organ and facial allograft procurement. Am J Transplant. 53. Aycart MA, Alhefzi M, Kueckelhaus M, et al. A retrospective 2017;17:2496–2497. analysis of secondary revisions after face transplantation: 33. Brazio PS, Barth RN, Bojovic B, et al. Algorithm for total face Assessment of outcomes, safety, and feasibility. Plast Reconstr and multiorgan procurement from a brain-dead donor. Am J Surg. 2016;138:690e–701e. Transplant. 2013;13:2743–2749. 54. Guntinas-Lichius O. Outcomes 18 months after the 34. Sweeney N, Allen K, Miller B, Nolan T, Sheerin K. first human partial face transplantation.N Engl J Med. Perioperative nursing management of donor and recipi- 2008;358:2179–2180; author reply 2180. ent patients undergoing face transplantation. AORN J. 55. Guo S, Han Y, Zhang X, et al. Human facial allotransplanta- 2017;106:8–19. tion: A 2-year follow-up study. Lancet 2008;372:631–638. 35. Rifkin WJ, Manjunath A, Kimberly LL, et al. Long-distance 56. Pomahac B, Pribaz J, Eriksson E, et al. Three patients with care of face transplant recipients in the United States. J Plast full facial transplantation. N Engl J Med. 2012;366:715–722. Reconstr Aesthet Surg. 2018;71:1383–1391. 57. Tasigiorgos S, Kollar B, Turk M, et al. Five-year follow-up 36. Sosin M, Ceradini DJ, Hazen A, et al. Total face, eyelids, ears, after face transplantation. N Engl J Med. 2019;380:2579–2581. scalp, and skeletal subunit transplant cadaver simulation: 58. Siemionow M, Papay F, Alam D, et al. Near-total human face The culmination of aesthetic, craniofacial, and microsurgery transplantation for a severely disfigured patient in the USA. principles. Plast Reconstr Surg. 2016;137:1569–1581. Lancet 2009;374:203–209. 37. Brown EN, Dorafshar AH, Bojovic B, et al. Total face, double 59. Devauchelle B, Badet L, Lengelé B, et al. First human face jaw, and tongue transplant simulation: A cadaveric study allograft: Early report. Lancet 2006;368:203–209. using computer-assisted techniques. Plast Reconstr Surg. 60. Diaz-Siso JR, Bueno EM, Sisk GC, Marty FM, Pomahac B, 2012;130:815–823. Tullius SG. Vascularized composite tissue allotransplanta- 38. Lantieri L, Grimbert P, Ortonne N, et al. Face transplant: tion: State of the art. Clin Transplant. 2013;27:330–337. Long-term follow-up and results of a prospective open study. 61. Shockcor N, Buckingham B, Hassanein W, et al. End stage Lancet 2016;388:1398–1407. renal disease after face transplant. Available at: https:// 39. Meningaud JP, Benjoar MD, Hivelin M, Hermeziu O, Toure atcmeetingabstracts.com/abstract/end-stage-renal-disease- G, Lantieri L. Procurement of total human face graft for allo- after-face-transplant/. Accessed March 1, 2020. transplantation: A preclinical study and the first clinical case. 62. Petruzzo P, Testelin S, Kanitakis J, et al. First human Plast Reconstr Surg. 2010;126:1181–1190. face transplantation: 5 years outcomes. Transplantation 40. Ramly EP, Kantar RS, Diaz-Siso JR, Alfonso AR, Shetye PR, 2012;93:236–240. Rodriguez ED. Outcomes after tooth-bearing maxilloman- 63. Krezdorn N, Murakami N, Pomahac B, Riella LV. dibular facial transplantation: Insights and lessons learned. J Immunological characteristics of a patient with belatacept- Oral Maxillofac Surg. 2019;77:2085–2103. resistant acute rejection after face transplantation. Am J 41. Azarmehr I, Stokbro K, Bell RB, Thygesen T. Surgical navi- Transplant. 2016;16:3305–3307. gation: A systematic review of indications, treatments, and 64. Diaz-Siso JR, Parker M, Bueno EM, et al. Facial allotransplan- outcomes in oral and maxillofacial surgery. J Oral Maxillofac tation: A 3-year follow-up report. J Plast Reconstr Aesthet Surg. Surg. 2017;75:1987–2005. 2013;66:1458–1463. 42. Sosin M, Ceradini DJ, Levine JP, et al. Total face, eyelids, 65. Broyles JM, Alrakan M, Ensor CR, et al. Characterization, ears, scalp, and skeletal subunit transplant: A reconstructive prophylaxis, and treatment of infectious complications solution for the full face and total scalp burn. Plast Reconstr in craniomaxillofacial and upper extremity allotrans- Surg. 2016;138:205–219. plantation: A multicenter perspective. Plast Reconstr Surg. 43. Dorafshar AH, Bojovic B, Christy MR, et al. Total face, dou- 2014;133:543e–551e. ble jaw, and tongue transplantation: An evolutionary con- 66. Cendales LC, Kanitakis J, Schneeberger S, et al. The Banff cept. Plast Reconstr Surg. 2013;131:241–251. 2007 working classification of skin-containing composite tis- 44. Cammarata MJ, Wake N, Kantar RS, et al. Three-dimensional sue allograft pathology. Am J Transplant. 2008;8:1396–1400. analysis of donor masks for facial transplantation. Plast 67. Kueckelhaus M, Fischer S, Lian CG, et al. Utility of sentinel Reconstr Surg. 2019;143:1290e–1297e. flaps in assessing facial allograft rejection.Plast Reconstr Surg. 45. Mohan R, Borsuk DE, Dorafshar AH, et al. Aesthetic and 2015;135:250–258. functional facial transplantation: A classification system and 68. Kanitakis J, Badet L, Petruzzo P, et al. Clinicopathologic mon- treatment algorithm. Plast Reconstr Surg. 2014;133:386–397. itoring of the skin and oral mucosa of the first human face 46. Kantar RS, Ceradini DJ, Rodriguez ED. Unique venous anat- allograft: Report on the first eight months.Transplantation omy in a face donor. JAMA Facial Plast Surg. 2019;21:462–463. 2006;82:1610–1615. 47. Pomahac B, Pribaz JJ, Bueno EM, et al. Novel surgical 69. Chaudhry A, Sosin M, Bojovic B, Christy MR, Drachenberg technique for full face transplantation. Plast Reconstr Surg. CB, Rodriguez ED. Defining the role of skin and mucosal 2012;130:549–555. biopsy in facial allotransplantation: A 2-year review and anal- 48. 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