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.

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.

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.

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.

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.

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.

Ethics of Facial Transplantation: The Effect of Psychological Trauma Associated With Facial Disfigurement on Risk Acceptance and Decision Making.

OBJECTIVE: This study examines and contrasts the effect of risk disclosure on risk acceptance and perceived changes in quality of life (QoL) among individuals with and without facial disfigurement. SUMMARY OF BACKGROUND DATA: Psychological distress has been previously shown to alter patients' perception of certain treatments. Due to the grave risks and complications of FT, it is important to understand whether the psychological trauma associated with facial disfigurement alters their perception of FT and its associated risks. METHODS: Participants with and without facial disfigurement were recruited to complete a questionnaire about their perceived QoL, sense of identity, and willingness to proceed with FT in the context of 3 different hypothetical scenarios involving facial disfiguration. RESULTS: Four hundred nine nonfacially disfigured and 74 facially disfigured participants were included. When both healthy and facially disfigured individuals were presented with the risks and benefits of a FT, they both perceived their QoL to be as low, or significantly lower, than if they had severe facial disfigurement. Furthermore, presenting the risks of FT significantly altered the decision making and risk acceptance of healthy individuals with no facial disfigurement. However, risk disclosure did not affect the decision making among facially disfigured individuals. CONCLUSION: This study highlights that presenting the complication profile of FT decreases risk acceptance of FT in healthy individuals but has no significant effects on facially disfigured individuals. The psychological impact of facial disfigurement and its influence on accepting the significant risks of FT should be considered and warrants further investigation.

Recipient Selection Criteria for Facial Transplantation: A Systematic Review.

BACKGROUND: Recipient selection is an important determinant of surgical outcomes in facial transplantation (FT). Appropriately, each FT program develops their own guidelines for recipient selection criteria. Currently, there is no resource to simultaneously assess and identify similarities and differences between these guidelines. Such information could be useful in distinguishing areas of FT that are well understood from those that could benefit from further exploration. METHODS: We performed a systematic review of the scientific literature from inception to June 18, 2021, using Pubmed, Embase, Cochrane Library, and Scopus to identify articles pertaining to recipient selection criteria. Clinical trials were identified through the Clinicaltrials.gov registry. United States and international program websites were reviewed for patient-facing information. RESULTS: Our systematic review yielded 90 suitable articles, 8 clinical trials, and 7 program websites containing the recipient selection criteria of 24 different FT programs. The most reported on recipient criteria were age, positive human immunodeficiency viral status (HIV+), positive hepatitis C viral status, psychosocial stability, and medical compliance. Other criteria were rarely addressed, such as blindness and recipient immune status. CONCLUSIONS: Guidelines among different face transplant programs are changing over time. We found consensus on certain recipient selection criteria, but the majority remain program or surgeon dependent, emphasizing that FT is still an evolving procedure. Although most programs reported on their recipient selection criteria, the rationale was often missing. Further discussion about recipient selection criteria and the reasoning behind employing or changing them will help advance the field.

The Second Helsinki Face Transplantation and the World Experience of Revision Surgery During the First Posttransplantation Year.

INTRODUCTION: We conducted a review of all surgical interventions performed during the first postoperative year in published face transplantation (FT) cases. In addition, we herein present our second FT patient, a full-face composite FT with an emphasis on surgical revisions after transplantation. MATERIALS AND METHODS: A literature review was conducted and resulted in 376 publications of which 33 included reference to surgical interventions during the first post-FT year. For our second FT patient, a thorough review of all medical records was performed. RESULTS: Among the first 41 FTs, 32 FT patients had reports with reference to corrective surgery during the first year (22 composite and 10 soft-tissue FTs). Soft-tissue FTs had a median of 2 procedures (range, 1-8 procedures), and composite FTs, 3 procedures per patient (range, 1-9 procedures). Nearly all early interventions (<1 month) were performed in composite FT patients (anastomotic occlusion, hematoma, sialocele, palatinal dehiscence). The most common late interventions were scar corrections, tissue suspensions, periorbital corrections, osseal and dental procedures, and interventions for palatinal dehiscence and sialocele. Our second FT patient has recovered well and has undergone 3 surgical interventions during the first year. CONCLUSIONS: Surgical interventions are very common during the first postoperative year after FT, and composite FTs are more prone to complications necessitating surgical intervention than soft-tissue FTs. There is a wide variety of complications reflecting the heterogeneity of FT allografts. Corrective surgery in FT patients appears safe with only a few reported complications.

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.

Special Considerations in Face Transplantation: A Systematic Review.

ABSTRACT: Vascularized composite allotransplantation of the face is an exceedingly complex procedure, requiring extensive planning and surgical precision in order to successfully manage patients with facial disfigurements. This review aims to present an overview of the salient anatomic considerations in facial transplantation, as well as give attention to unique patient populations and special considerations.A literature review was performed in search of articles pertaining to considerations in facial transplantation using the databases PubMed, Web of Science, and Cochrane. Articles selected for further review included full-text articles with an emphasis on specific anatomic defects and how they were addressed in the transplant process, as well as management of special patient populations undergoing facial transplantation. In total, 19 articles were deemed appropriate for inclusion.The use of computer-assisted technologies for the planning portion of the procedure, as well as intraoperative efficiency, has yielded favorable results and can be considered as part of the operative plan. The ultimate outcome is dependent upon the synchronization of subunits of the allograft and the desired functional outcomes, including osseous, ocular, oral, and otologic considerations. Management of specific pathology and subgroups of patients are critical aspects. Although pediatric face transplantation has not yet been performed, it is a likely a future step in the evolution of this procedure.When performing a face transplantation, many components must be considered pre-, intra-, and post-operatively. This systematic review presents specific anatomic considerations, as well as information about special patient populations within this crosssection of multidisciplinary microsurgery, psychiatry, and transplant immunology.

Personality, Success, and Beyond: The Layperson's Perception of Patients With Facial Transplantation.

BACKGROUND: While the goal of facial vascularized composite allotransplantation (FVCA) is to provide patients with improved physical and social function, no study has evaluated layperson perception of social acceptance and perceived career success of patients with FVCA. The purpose of this study was to determine how FVCA changes social acceptance and perceived career success of patients with facial disfiguration. METHODS: Eight hundred fifteen laypersons were surveyed through Mechanical Turk to evaluate their perceptions of patients with FVCA. Respondents were shown facial photographs of patients pre-FVCA, post-FVCA, and matched controls and evaluated these photos on 26 items of perceived social acceptance and career success. Responses were analyzed using descriptive statistics and the Wilcoxon signed-rank test. RESULTS: Both male and female post-FVCA photos were perceived as significantly more socially accepted and professionally successful than their pre-FVCA photos in at least 21 out of 26 items (P < 0.001 for all), but the posttransplant patients scored lower than their control in at least 25 out of 26 items (P < 0.001 for all). Additionally, there were discrepancies in findings based on patient gender. CONCLUSIONS: This study suggests that while FVCA has a significantly positive impact on social acceptance and perceived professional success, it does not fully reinstate these qualities. Furthermore, varying surgical outcomes and/or cognitive biases (such as gender) may impact perceptions of the individual by the public. Our findings suggest a need to standardize practices to better predict and improve outcomes and encourage surgeons to consider patient factors such as gender when planning these procedures.

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.

Face Autotransplantation After an Accident.

ABSTRACT: Microsurgical replantation is considered the best method to treat avulsion or amputation injuries of unique head parts, including the scalp, eyelid, nose, ear, lip, and tongue. However, there is currently no report on microsurgical replantation of substi-tutable facial tissues in the literature. This report presents a patient with avulsed facial composite tissue composed of the skin and subcutaneous layers treated by microsurgical replantation. The present case shows that microsurgical replantation of small facial composite tissues is feasible. The authors suggest that the indication spectrum for microsurgical replantation should be expanded beyond current clinical practice.

Software-based Detection of Acute Rejection Changes in Face Transplant.

BACKGROUND: An objective, non-invasive method for redness detection during acute allograft rejection in face transplantation (FT) is lacking. METHODS: A retrospective cohort study was performed with 688 images of 7 patients with face transplant (range, 1 to 108 months post-transplant). Healthy controls were matched to donor age, sex, and had no prior facial procedures. Rejection state was confirmed via tissue biopsy. An image-analysis software developed alongside VicarVision (Amsterdam, Netherlands) was used to produce R, a measure of differences between detectable color and absolute red. R is inversely proportional to redness, where lower R values correspond to increased redness. Linear mixed models were used to study fixed effect of rejection state on R values. Estimated marginal means of fitted models were calculated for pairwise comparisons. RESULTS: Of 688 images, 175, 170, 202, and 141 images were attributable to Banff Grade 0,1,2, and 3, respectively. Estimated change in R value of facial allografts decreased with increasing Banff Grade (p = 0.0001). The mean R value of clinical rejection (Banff Grade ⅔) (16.67, 95% Confidence Interval [CI] 14.79-18.58) was lower (p = 0.005) than non-rejection (Banff Grade 0/1) (19.38, 95%CI 17.43-21.33). Both clinical and non-rejection mean R values were lower (p = 0.0001) than healthy controls (24.12, 95%CI 20.96-27.28). CONCLUSION: This proof-of-concept study demonstrates that software-based analysis can detect and monitor acute rejection changes in FT. Future studies should expand on this tool's potential application in telehealth and as a screening tool for allograft rejection.

'A Procedure Without a Problem', or the face transplant that didn't happen. The Royal Free, the Royal College of Surgeons and the challenge of surgical firsts.

Face transplants are an innovative and unusual form of modern surgery. There have been 47 face transplants around the world to date, but none as yet in the UK. Yet in 2003, the UK was poised to undertake the first face transplant in the world. The reasons why it didn't take place are not straightforward, but largely unexplored by historians. The Royal College of Surgeons, concerned about the media attention given to face transplants and the ethical and surgical issues involved, held a working party and concluded that it could not give approval for face transplants, effectively bringing to a halt the UK's momentum in the field. This extraordinary episode in medical history has been anecdotally influential in shaping the course of British surgical history. This article explores and explains the lack of a face transplant in the UK and draws attention to the complex emotional, institutional and international issues involved. Its findings have implications beyond the theme of face transplants, into the cultural contexts and practices in which surgical innovation takes place.

Face transplantation: A longitudinal histological study focusing on chronic active and mucosal rejection in a series with long-term follow-up.

The 2007 Banff working classification of skin-containing Tissue Allograft Pathology addressed only acute T cell-mediated rejection in skin. We report the longitudinal long-term histological follow-up of six face transplant recipients, focusing on chronic and mucosal rejection. We identified three patterns suggestive of chronic rejection (lichen planus-like, vitiligo-like and scleroderma-like). Four patients presented lichen planus-like and vitiligo-like chronic rejection at 52 ± 17 months posttransplant with severe concomitant acute T cell-mediated rejection. After lichen planus-like rejection, two patients developed scleroderma-like alterations. Graft vasculopathy with C4d deposits and de novo DSA led to subsequent graft loss in one patient. Chronic active rejection was frequent and similar patterns were noted in mucosae. Concordance between 124 paired skin and mucosal biopsies acute rejection grades was low (κ = 0.2, p = .005) but most grade 0/I mucosal rejections were associated with grade 0/I skin rejections. We defined discordant (grade≥II mucosal rejection and grade 0/I skin rejection) (n = 55 [70%]) and concordant (grade≥II rejection in both biopsies) groups. Mucosal biopsies of the discordant group displayed lower intra-epithelial GranzymeB/FoxP3 ratios suggesting a less aggressive phenotype (p = .08). The grading system for acute rejection in mucosa may require phenotyping. Whether discordant infiltrates reflect a latent allo-immune reaction leading to chronic rejection remains an open question.

Mixed Reality and 3D Printed Models for Planning and Execution of Face Transplantation.

OBJECTIVE: The aim of this study was to evaluate a novel holographic craniofacial surgical planning application and its implementation throughout the planning and operative stages of facial transplantation by performing a critical analysis of comparative utility, cost, and limitations of MR and 3D printing. SUMMARY OF BACKGROUND DATA: Face transplantation is a highly complex form of craniofacial reconstruction requiring significant planning, knowledge of patient-specific spatial relationships, and time-sensitive decision making. Computer-aided 3D modeling has improved efficiency and outcomes of complex craniofacial reconstruction by enabling virtual surgical planning and 3D printed model generation. MR technology can enhance surgical planning, improve visualization, and allow manipulation of virtual craniofacial biomodels within the operative field. METHODS: Accounting for the time-sensitive nature of face transplantation, a unique, highly coordinated workflow for image acquisition and processing was designed to facilitate rapid holographic rendering and 3D printing. During recent face transplantation, both holographic and 3D printed models were utilized, and the time and cost of fabrication were compared. RESULTS: Holographic models required less time and cost for fabrication. They provided both comprehensive visualization of 3D spatial relationships and novel means to perform VSP and virtual face transplantation by interacting with and manipulating patient-specific, anatomic holograms. CONCLUSION: Time efficiency, low-cost biomodel production, provision of unlimited preoperative surgical rehearsal, and potential for intraoperative surgical guidance makes holographic VSP and MR highly promising technology for use in complex craniofacial surgery.

First human facial retransplantation: 30-month follow-up.

BACKGROUND: Since the first successful facial transplantation in 2005, the benefits of this procedure in terms of aesthetics, functionality, and quality of life have been firmly established. However, despite immunosuppressive treatment, long-term survival of the allograft might be compromised by chronic antibody-mediated rejection (CAMR), leading to irreversible necrosis of the tissue. In the absence of therapeutic options, this complication is inevitably life-threatening. METHODS: We report facial retransplantation in a man, 8 years after his first facial transplantation because of extensive disfigurement from type 1 neurofibromatosis and 6 weeks after complete loss of his allograft due to severe CAMR. We describe the chronology of immune-related problems that culminated in allograft necrosis and the eventual loss of the facial transplant, the desensitisation protocol used for this highly immunosensitised recipient, the surgical technicalities of the procedure, the specific psychological management of this patient, and the results from follow-up at 30 months. FINDINGS: Although the patient had a complicated postoperative course with numerous immunological, infectious, cardiorespiratory, and psychological events, he was discharged after a hospital stay of almost 1 year. He has since been able to re-integrate into his community with acceptable restoration of his quality of life. INTERPRETATION: This clinical report of the first documented human facial retransplantation is proof-of-concept that the loss of a facial transplant after CAMR can be mitigated successfully by retransplantation combined with an aggressive desensitisation process. FUNDING: Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris.