International consensus recommendations on face transplantation: A 2-step Delphi study.

Face transplantation is a viable reconstructive approach for severe craniofacial defects. Despite the evolution witnessed in the field, ethical aspects, clinical and psychosocial implications, public perception, and economic sustainability remain the subject of debate and unanswered questions. Furthermore, poor data reporting and sharing, the absence of standardized metrics for outcome evaluation, and the lack of consensus definitions of success and failure have hampered the development of a "transplantation culture" on a global scale. We completed a 2-round online modified Delphi process with 35 international face transplant stakeholders, including surgeons, clinicians, psychologists, psychiatrists, ethicists, policymakers, and researchers, with a representation of 10 of the 19 face transplant teams that had already performed the procedure and 73% of face transplants. Themes addressed included patient assessment and selection, indications, social support networks, clinical framework, surgical considerations, data on patient progress and outcomes, definitions of success and failure, public image and perception, and financial sustainability. The presented recommendations are the product of a shared commitment of face transplant teams to foster the development of face transplantation and are aimed at providing a gold standard of practice and policy.

18 years of face transplantation: Adverse outcomes and challenges.

BACKGROUND: Since the first procedure performed in 2005, face transplantation has been debated as viable approach for the treatment of severe craniofacial defects. Despite the benefits provided, the experience in face allotransplantation has brought to light a significant risk of complications, including allograft removal or loss, and mortality. The present study is intended to provide an updated review on complications and major challenges witnessed over 18 years of experience in the field. METHODS: A systematic review of PubMed, MEDLINE, Cochrane, Google, and Google Scholar databases on face transplantation was conducted according to PRISMA guidelines up to April 2023. Articles providing details on cases of face allograft loss, removal, and patient death were included. Online articles and media reports were assessed to include information not disclosed in peer-reviewed literature. Face transplant centers were contacted to have updated follow-up information on single-face transplant cases. RESULTS: The search yielded 1006 reports, of which 28 were included. On a total of 48 procedures performed in 46 patients, adverse outcomes were gleaned in 14 cases (29%), including seven allograft losses (14.6%), and the death of ten patients (21.7%). Chronic rejection was the leading cause of allograft loss, with a median time from transplant to irreversible rejection of 90 months (IQR 88.5-102). The main causes of death were infectious complications, followed by malignancies, non-compliance to immunosuppression, and suicide. The median time to death was 48.5 months (IQR 19-122). CONCLUSIONS: To the best of our knowledge, this is the first study providing a comprehensive review of adverse outcomes in face transplantation. Considering the high rate of major complications, the heterogeneity of cases and single-center approaches, and the absence of published standards of care, the development of a consensus by face transplant teams holds the key to the field's advancement.

Insights from immunoproteomic profiling of a rejected full-face transplant.

Vascularized composite allografts (VCAs) of faces and extremities are subject to chronic rejection that is incompletely understood. Here we report on immunoproteomic evaluation of a full facial VCA removed 88 months after transplantation due to chronic rejection. CD8-positive T cells of donor (graft) origin infiltrate deep intragraft arteries in apposition to degenerating endothelium of chimeric recipient origin in association with arteriosclerotic alterations. Digital spatial proteomic profiling highlighted proteins expressed by activated cytotoxic T cells and macrophages as well as pathway components involved in atherogenic responses, including Indoleamine 2,3-Dioxygenase 1 (IDO1) and Stimulator of Interferon Response CGAMP Interactor (STING). Chronic facial VCA rejection thus involves T cell/macrophage-mediated accelerated arteriosclerosis not normally represented in punch biopsies and potentially driven by persistent graft-resident effector T cells and recipient target endothelium that chimerically repopulates graft arteries.

Comprehensive outcome analysis in two composite face transplants in Helsinki: Have we succeeded?

INTRODUCTION: There is a need to define what is success after face transplantation (FT). We have previously created a four-component criteria tool to define indications for FT. In this study, we used the same criteria to evaluate the overall outcome of our first two patients after FT. PATIENTS AND METHODS: Preoperative analysis of our two bimaxillary FT patients was compared to the results at four and six years post-transplantation. The facial deficiency impact was divided into four categories: (1) anatomical regions, (2) facial functions (mimic muscles, sensation, oral functions, speech, breathing, periorbital functions), (3) esthetics, and (4) impact on health-related quality of life (HRQoL). Immunological status and complications were also evaluated. RESULTS: For both patients, near-normal anatomical restoration of almost all the facial regions (except the periorbital and intraoral regions) was achieved. The majority of the facial function parameters improved in both patients (patient 2 to a near-normal level). The esthetic score improved from severely disfigured to impaired (patient 1) and to near to normal (patient 2). Quality of life was severely lowered prior to FT and improved after FT but was still affected. Neither patient has experienced acute rejection episodes during follow-up. CONCLUSIONS: We conclude that our patients have benefitted from FT, and we have succeeded. Time will reveal whether we have achieved long-term success.

Re-cognizing the new self: The neurocognitive plasticity of self-processing following facial transplantation.

The face is a defining feature of our individuality, crucial for our social interactions. But what happens when the face connected to the self is radically altered or replaced? We address the plasticity of self-face recognition in the context of facial transplantation. While the acquisition of a new face following facial transplantation is a medical fact, the experience of a new identity is an unexplored psychological outcome. We traced the changes in self-face recognition before and after facial transplantation to understand if and how the transplanted face gradually comes to be perceived and recognized as the recipient's own new face. Neurobehavioral evidence documents a strong representation of the pre-injury appearance pre-operatively, while following the transplantation, the recipient incorporates the new face into his self-identity. The acquisition of this new facial identity is supported by neural activity in medial frontal regions that are considered to integrate psychological and perceptual aspects of the self.

Facial Allograft Donation: An Interpretative Phenomenological Analysis of the Experiences of Family Members.

Facial allograft transplantation can be regarded as a particular and complex type of donation because of its perceptibility and the importance of the face as an identity characteristic. As research on this topic is currently lacking, the objective of this study is to explore the experiences of the family members of the donor in facial allograft donation. In-depth, semi-structured interviews were conducted separately with the donor's family members and analyzed using interpretative phenomenological analysis. Six themes were identified: (1) Contrasting facial donation to that of more commonly donated organs; (2) Consenting to facial donation; (3) Expectations towards the recipient of the facial graft; (4) Expectations and consequences of restoration of the donor's face; (5) Relationship with the medical team during the process; and (6) Media attention. The findings of our study help to better support donor families through the facial donation process and to improve facial transplantation procedures.

Facial Expression after Face Transplant: An International Face Transplant Cohort Comparison.

BACKGROUND: Assessment of motor function restoration following face transplant (FT) is difficult, as standardized, bilateral tests are lacking. This study aims to bolster support for software-based analysis through international collaboration. METHODS: FaceReader (Noldus, Wageningen, The Netherlands), a facial expression analysis software, was used to analyze posttransplant videos of eight FT patients from Boston, Massachusetts (range, 1 to 9 years after transplant), two FT patients from Helsinki, Finland (range, 3 to 4 years after transplant), and three FT patients from Antalya, Turkey (range, 6.5 to 8.5 years after transplant). Age-matched healthy controls from respective countries had no history of prior facial procedures. Videos contained patients and controls performing facial expressions evaluated by software analysis using the Facial Action Coding System. Facial movements were assigned intensity score values between 0 (absent) and 1 (fully present). Maximum values were compared with respective healthy controls to calculate percentage restoration. RESULTS: Of 13 FT patients, eight patients were full FT, five patients were partial FT, and two patients were female patients. Compared with healthy controls, the median restoration of motor function was 36.9% (interquartile range, 28.8% to 52.9%) for all patients with FT ( P = 0.151). The median restoration of smile was 37.2% (interquartile range, 31.5% to 52.7%) for all patients with FT ( P = 0.065). When facial nerve coaptation was performed at the distal branch level, average motor function restoration was 42.7% ± 3.61% compared with 27.9% ± 6.71% at the proximal trunk coaptation level ( P = 0.032). Use of interpositional nerve grafts had no influence on motor outcomes. CONCLUSIONS: Software-based analysis is suitable to assess motor function after FT. International collaboration strengthens outcome data for FT. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The Role of the Cross Face Nerve Graft in Facial Reanimation and Endoscopic Harvest of the Sural Nerve.

Cross-face nerve grafting (CFNG) allows for spontaneous, involuntary facial movement for patients with irreversible hemifacial paralysis. This technique uses an intact contralateral facial nucleus and nerve as an input and axon source, allowing donor neural input to be routed through a nerve graft across the face. The sural nerve is well equipped for use as a nerve graft due to its length and minimal donor site morbidity. Endoscopic nerve harvest techniques allow for efficient, minimally invasive dissection that improves the integrity of the harvested nerve.

The Facial Graft: A Graft of Emotions? (About the Reanimation of the Facial Allotransplantation).

Although there have been numerous scientific papers reporting on composite allotransplantation of the face, few have been about assessment and evolution of the functional benefit for patients in terms of soft tissue mobility, movement coordination, and face expressions, even fewer on the choice of the surgical procedures to restore motricity. On some videos and interviews, it is possible to analyze significative motricity. Of course that has been voluntary motricity, not emotional motricity. The data confirmed that the result on the complexity of the expression of the face is not great, providing opportunity to reflect on the question of nerve regeneration.

Low-dose interleukin-2 promotes immune regulation in face transplantation: A pilot study.

Face transplantation is a life-changing procedure for patients with severe composite facial defects. However, it is hampered by high acute rejection rates due to the immunogenicity of skin allograft and toxicity linked to high doses of immunosuppression. To reduce immunosuppression-associated complications, we, for the first time in face transplant recipients, used low-dose interleukin 2 (IL-2) therapy to expand regulatory T cells (Tregs) in vivo and to enhance immune modulation, under close immunological monitoring of peripheral blood and skin allograft. Low-dose IL-2 achieved a sustained expansion (∼4-fold to 5-fold) of circulating Tregs and a reduction (∼3.5-fold) of B cells. Post-IL-2 Tregs exhibited greater suppressive function, characterized by higher expression of TIM-3 and LAG3co-inhibitory molecules. In the skin allograft, Tregs increased after low-dose IL-2 therapy. IL-2 induced a distinct molecular signature in the allograft with reduced cytotoxicity-associated genes (granzyme B and perforin). Two complications were observed during the trial: one rejection event and an episode of autoimmune hemolytic anemia. In summary, this initial experience demonstrated that low-dose IL-2 therapy was not only able to promote immune regulation in face transplant recipients but also highlighted challenges related to its narrow therapeutic window. More specific targeted Treg expansion strategies are needed to translate this approach to the clinic.

First Composite Woman-to-Woman Facial Transplantation in Turkey: Challenges and Lessons to Be Learned.

ABSTRACT: After the first face transplantation from woman to woman we performed in our clinic, it was aimed to eliminate the lack of knowledge about the subject in the literature by transferring our experiences and long-term results to the problems we had with the patient. A 20-year-old patient underwent partial osteomyocutaneous facial transplant (22nd facial transplant), which included 2 functional units of the face. The patient had no major problems in the early period and had a good aesthetic appearance. In the postoperative period, the patient ended her social isolation and adopted the transplanted face.In the late period, secondary surgical interventions, management of the problems caused by immunosuppression, and the patient's living in a remote location to our clinic were the difficulties encountered. Six revision surgeries were performed after the transplantation. Due to immunosuppression, opportunistic infections and metabolic problems required intermittent hospitalization. The patient died at the end of 56 months because of complications secondary to immunosuppression.A successful transplant involves the management of long-term problems rather than a successful tissue transfer in the early period. In today's conditions, long-term success can be achieved with a good patient compliance, as well as each team member should take an active role in the team at the transplantation centers. More case series are needed to adapt the standard treatment and follow-up protocols for solid organ transplantations for composite tissue allotransplantations. This will be possible by sharing the results and experiences transparently in the centers where face transplantation is performed worldwide.

Cortical reintegration after facial allotransplantation.

Neural plasticity of the brain or its ability to reorganize following injury has likely coincided with the successful clinical correction of severe deformity by facial transplantation since 2005. In this study, we present the cortical reintegration outcomes following syngeneic hemifacial vascularized composite allograft (VCA) in a small animal model. Specifically, changes in the topographic organization and unit response properties of the rodent whisker-barrel somatosensory system were assessed following hemifacial VCA. Clear differences emerged in the barrel-cortex system when comparing naïve and hemiface transplanted animals. Neurons in the somatosensory cortex of transplanted rats had decreased sensitivity albeit increased directional sensitivity compared with naïve rats and evoked responses in transplanted animals were more temporally dispersed. In addition, receptive fields were often topographically mismatched with the indication that the mismatched topography reorganized within adjacent barrel (same row-arc bias following hemifacial transplant). These results suggest subcortical changes in the thalamus and/or brainstem play a role in hemifacial transplantation cortical plasticity and demonstrate the discrete and robust data that can be derived from this clinically relevant small animal VCA model for use in optimizing postsurgical outcomes.NEW & NOTEWORTHY Robust rodent hemifacial transplant model was used to record functional changes in somatosensory cortex after transplantation. Neurons in the somatosensory cortex of face transplant recipients had decreased sensitivity to stimulation of whiskers with increased directional sensitivity vs. naive rats. Transplant recipient cortical unit response was more dispersed in temporary vs. naive rats. Despite histological similarities to naive cortices, transplant recipient cortices had a mix of topographically appropriate and inappropriate whiskered at barrel cortex relationships.

Maxillary and Mandibular Healing After Facial Allotransplantation.

INTRODUCTION: Facial transplantation has emerged as a viable option in treating devastating facial injuries.Despite the high healing rate of Le Fort III and bilateral sagittal split osteotomies (BSSO) in nontransplant patients, few studies have reported assessment of maxillary and mandibular healing in face transplant patients compared with nontransplant patients. The aim of this study was to examine differences in bone healing in our patients. PATIENTS AND METHODS: A retrospective chart review was conducted of facial allotransplantation patients at the Cleveland Clinic from December 2008 to inception. Demographics such as age, date of birth, and sex were recorded. Additional variables included procedures, revisions, reoperations, medications, and bone stability and healing. Computed tomography (CT) images assessed the alignment of skeletal components, bony union quality, and stability of fixation. RESULTS: Three patients were included: 2 had Le Fort III segment transplantation, and 1 had transplantation of both a Le Fort III segment and mandibular BSSO. The Le Fort III segment in all patients exhibited mobility and fibrous union at the Le Fort III osteotomy on CT. In contrast, the BSSO healed uneventfully after transplantation and revision surgery, with bony union confirmed by both CT and histology of the fixation area between the donor and recipient mandible bilaterally. No patients with midfacial fibrous union required revision of the nonunion as they were clinically asymptomatic. CONCLUSION: Le Fort osteotomy demonstrates inferior healing in facial transplantation compared with the nontransplant population. In contrast, the successful healing in the mandible is likely owing to the high density of rich cancellous bone.

Youngest Composite Full-Face Transplant: A Model for Vascularized Composite Allograft in Younger Populations.

BACKGROUND: The field of face transplantation continues to evolve, with more complex defects being addressed, and, at the same time, increased outcome expectations. Given our unique long-term experience in this field, we consented one of the youngest patients to undergo a full-face transplant. METHODS: An 18-year-old woman presented with complete destruction of her central face and craniofacial structures. She had coexisting major injuries, including pituitary gland, visual axis, and motor control. After extensive rehabilitation and reconstruction techniques, the patient underwent face transplant on May 4, 2017, at the age of 21 years. RESULTS: The total operative time for the recipient was 26 hours. There were no major perioperative complications. Since transplant, the patient has undergone 3 revision surgeries. She is near completely independent from a daily life activity standpoint. She has had 1 episode of rejection above grade II that was successfully treated with a short-term increased in immunosuppression. CONCLUSIONS: Contrary to data in solid organ transplantation where youth is associated with increased risk of rejection, our current algorithm in immunosuppression, combined with this patient's compliance, has led to only 1 rejection episode beyond grade II. This successful transplant can serve as a model for future vascularized composite transplants in younger populations.

Measurements of motor functional outcomes in facial transplantation: A systematic review.

Although the ethical and technical feasibility of face transplant (FT) has been established, current literature lacks consensus on functional outcomes monitoring for recipients. This systematic review aims to appraise and summarize the current literature on tools used to assess motor functional outcomes in FT. This study complied with the guidelines outlined in the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). On September 15, 2020, two reviewers conducted independent electronic searches using medical literature databases, without language or time frame limitations. Eligibility criteria included studies reporting on the evaluation of motor functional outcomes in face transplant recipients. Of 451 papers found in the literature, 12 fulfilled the study inclusion criteria. The reported tools included clinical scales/examinations, electromyography, optical movement tracking devices, muscle volumetric measurement using magnetic resonance imaging, and software-based video and photo analyses. The frequency of data collection varied from every three months to every year. Publications reporting on motor functional outcomes tracking tools vary broadly and demonstrate a lack of consensus. Although quantitative measurements are desirable, adapted clinical scales are still the current standard of care.

The First Successful Combined Full Face and Bilateral Hand Transplant.

BACKGROUND: Vascularized composite allotransplantation has redefined the frontiers of plastic and reconstructive surgery. At the cutting edge of this evolving paradigm, the authors present the first successful combined full face and bilateral hand transplant. METHODS: A 21-year-old man presented for evaluation with sequelae of an 80 percent total body surface area burn injury sustained after a motor vehicle accident. The injury included full face and bilateral upper extremity composite tissue defects, resulting in reduced quality of life and loss of independence. Multidisciplinary evaluation confirmed eligibility for combined face and bilateral hand transplantation. The operative approach was validated through 11 cadaveric rehearsals utilizing computerized surgical planning. Institutional review board and organ procurement organization approvals were obtained. The recipient, his caregiver, and the donor family consented to the procedure. RESULTS: Combined full face (i.e., eyelids, ears, nose, lips, and skeletal subunits) and bilateral hand transplantation (i.e., forearm level) was performed over 23 hours on August 12 to 13, 2020. Triple induction and maintenance immunosuppressive therapy and infection prophylaxis were administered. Plasmapheresis was necessary postoperatively. Minor revisions were performed over seven subsequent operations, including five left upper extremity, seven right upper extremity, and seven facial secondary procedures. At 8 months, the patient was approaching functional independence and remained free of acute rejection. He had significantly improved range of motion, motor power, and sensation of the face and hand allografts. CONCLUSIONS: Combined face and bilateral hand transplantation is feasible. This was the most comprehensive vascularized composite allotransplantation procedure successfully performed to date, marking a new milestone in plastic and reconstructive surgery for patients with otherwise irremediable injuries.

Volumetric Effect and Patient Satisfaction after Facial Fat Grafting.

BACKGROUND: Facial fat grafts decrease in volume after transplantation. This observation is based on overall facial three-dimensional analyses, because there is sparse information on volume changes in well-defined aesthetic areas. The authors aimed to assess the overall and, more specifically, the local volumetric effects of facial fat grafting and relate these effects to patient satisfaction up to 1 year after treatment. METHODS: All consecutive adult female patients who were scheduled for facial fat grafting without additional surgical procedures were asked to participate. All patients underwent the same fat grafting method. An algorithm-based personalized aesthetic template was applied to define specific aesthetic areas on the preoperative three-dimensional image. Objective outcome parameters [i.e., three-dimensional volume differences, patient satisfaction (FACE-Q questionnaire)] were measured at baseline and at 6 weeks, 6 months, and 12 months after fat grafting. RESULTS: Of 33 female patients who underwent a facial fat graft procedure, 23 patients had complete three-dimensional data and were eligible for analysis. The highest volume gain was observed 6 weeks after grafting and was followed by a gradual loss thereafter. Overall and in the zygomatic area, a substantial gain in volume was still present 1 year after grafting, whereas this effect was lost in the lip area. FACE-Q scales Satisfaction with Facial Appearance Overall and Satisfaction with Cheeks improved too, whereas scores for Lines: Lips returned to baseline levels. The improvement in FACE-Q scales was in agreement with the objective change in volume. CONCLUSION: Gain in overall and local volumetric effects is accompanied by comparable changes in patient satisfaction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.