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.

Pediatric vascularized composite allotransplantation.

BACKGROUND: Vascularized composite allotransplantation (VCA) has experienced a growing acceptance, which has led to a debate centered on extending the indications of the procedure to include pediatric patients. The aim of this article was to discuss such indications based on the evidence in pediatric solid organ transplantation, reconstructive surgery in children, and VCA in adult patients. METHODS: Papers published on the outcomes of pediatric solid organ transplantation, growth after replantation of extremities, vascularized autologous tissue transfer, craniofacial surgery, orthognathic procedures, facial fractures, and outcomes after repair of peripheral nerves in children were reviewed. RESULTS: Although the outcomes of solid organ transplantation in children have improved, the transplanted organs continue to have a limited lifespan. Long-term immunosuppressive therapy exposes the patients to an increased lifetime risk of infections, diabetes, hypertension, dyslipidemia, cardiovascular disease, and malignancy. Growth impairment and learning disabilities are other relevant drawbacks, which affect the pediatric recipients. Nonadherence to medication is a common cause of graft dysfunction and loss among the adolescent transplant recipients. Rejection episodes, hospitalizations, and medication adverse effects contribute negatively to the quality of life of the patients. Although normal growth after limb transplantation could be expected, pediatric facial transplant recipients may present with arrest of growth of transplanted midfacial skeleton. CONCLUSIONS: Considering the non-life-threatening nature of the conditions that lead to eligibility for VCA, it is suggested that it is premature to extend the indications of VCA to include pediatric patients under the currently available immunosuppressive protocols.

Ethics of facial transplantation revisited.

PURPOSE OF REVIEW: There have been 26 cases of facial transplantation reported, and three deaths, 11.5%. Mortality raises the issue of risk versus benefit for face transplantation, a procedure intended to improve quality of life, rather than saving life. Thus, one of the most innovative surgical procedures has opened the debate on the ethical, legal, and philosophical aspects of face transplantation. RECENT FINDINGS: Morbidity in face transplant recipients includes infections and metabolic consequences. No graft loss caused by technical failure, hyperacute, or chronic graft rejection or graft-versus-host disease has been reported. One case of posttransplant lymphoproliferative disorder, 3.45% and one case of lymphoma in an HIV-positive recipient were reported. Psychological issues in candidates can include chronic pain, mood disorders, preexisting psychotic disorders, post-traumatic stress disorder (PTSD), and substance abuse. SUMMARY: Early publications on ethical aspects of face transplantation focused mainly on informed consent. Many other ethical issues have been identified, including lack of coercion, donor family consent and confidentiality, respect for the integrity of the donor's body, and financial promotion of the recipient and transplant team, as well as the cost to society for such a highly technical procedure, requiring lifelong immunosuppression.

Face transplantation: psychological outcomes at three-year follow-up.

BACKGROUND: The advent of face transplantation has raised both ethical and psychological issues. Mortality of 18 existing face transplant recipients is 11.1% (2/18) through 2011. OBJECTIVE: Psychological outcomes are as important in face transplantation as is restoring the face physically. Little quantitative information has been published this area. METHODS: Data was systematically collected over 3 years with a face transplant recipient, including appearance self-rating, body image, mood changes, pain rating, perception of teasing, quality of life, self-esteem, and social reintegration. We identified a significant gap in rating instruments for use in the field, so we developed the Perception of Teasing-FACES, Facial Anxiety Scale-State, and the Cleveland Clinic FACES score, analogous to the model for end-stage liver disease (MELD) score for prioritizing patients for a face transplant registry. RESULTS: Appearance self-rating rose from 3/10 prior to transplantation to 7/10 now. Anxiety about body image and the Facial Anxiety score were halved by the end of the third year. Beck Depression Inventory fell from 16 (prior to transplant) to 8. Chronic daily pain was 6-7/10 prior to transplant and 0/10 by day 50. Perception of Teasing-FACES scores fell from 25 to 9 by the end of year 3. Quality of life improved on the Social Environment Domain of the psychological adjustment to illness scale-self-rated (PAIS-SR), where the score dropped from 15 to 1 by the end of year 3, indicating marked improvement in social reintegration. CONCLUSIONS: Standardized data collection may help quantify psychological outcomes with facial transplantation to determine whether the risks of immunosuppression over time are offset by improved quality of life for recipients.

Skeletal and Dental Outcomes after Facial Allotransplantation: The Cleveland Clinic Experience and Systematic Review of the Literature.

BACKGROUND: Most of the literature surrounding face transplantation focuses on technique, immunology, and psychology. Dental and skeletal outcomes remain persistently underreported. This study critically examined the worldwide face transplant experience to evaluate such outcomes. METHODS: A systematic review of all composite allografts containing midface and/or mandible was performed. Dental and skeletal complications were recorded. Formal imaging and photographs available in the literature were analyzed using skeletal measurements, soft-tissue cephalometrics, and the Angle classification. Outcomes of our face transplant patients, including condylar assessment and airway volume measurements, is also presented. RESULTS: Twenty-five patients received allografts containing midface (n = 7) or mandible (n = 2), whereas 16 contained a double-jaw. All midface-only transplants developed skeletal deformity; 57 percent developed a palatal fistula. Both partial and full arch transplantation patients developed skeletal deformity. Among double-jaw transplants, 69 percent developed palatal fistula or floor-of-mouth dehiscence, 66 percent developed malocclusion, 50 percent developed trismus, and 31 percent required corrective orthognathic surgery. In 40 percent of patients, malocclusion recurred after corrective orthognathic surgery. Forty percent of all patients developed dental cavities or periodontal disease. All of our patients received midface and/or mandible. One patient required corrective orthognathic surgery. Midfacial segments showed clockwise rotation. Airway volumes decreased over time. CONCLUSIONS: Skeletal and dental complications remain extremely common after facial allotransplantation involving either single- or double-jaw composites. Corrective orthognathic surgery and dental extraction is often necessitated. These data will aid face transplant teams during surgical planning and preoperative counseling. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Addressing religious and cultural differences in views on transplantation, including composite tissue allotransplantation.

Composite tissue allotransplantation is a rapidly developing field in plastic and reconstructive surgery and therefore imposes an obligation upon plastic and transplant surgeons to familiarize themselves with some unique aspects of this new discipline. The visible nature of extremities, and the face, presents a special hurdle when seeking the consent of the donor's family, as well as the recipient. Religious and sociocultural backgrounds of both the donor and recipient may have an important impact on the outcome of the donation and acceptance process. The purpose of this review is to present the current positions of major religious groups on allotransplantation and the cultural responses to the religious stances. In this context, we have investigated whether there are any specific religious or cultural restrictions against the practice of composite tissue allotransplantation.

Watershed Areas in Face Transplantation.

BACKGROUND: The maxillary artery has traditionally been considered the main blood supply of the facial skeleton. However, the deep and concealed location makes the harvest of facial allografts based on this artery challenging, giving preference to the facial artery. There is growing evidence that the junction between the hard and soft palate may represent a watershed area in facial artery-based allografts. The aim of this study was to review the occurrence of partial allograft necrosis and modify the available craniofacial techniques, allowing for a reliable harvest of maxillary artery-based facial allografts. METHODS: PubMed/MEDLINE databases were searched for articles presenting allograft perfusion details and the occurrence of partial flap necrosis. Next, 25 fresh cadaver heads were used: eight allografts were harvested by means of a traditional Le Fort III approach, in six the maxillary artery was injected with latex, in three cadaver heads lead oxide gel was injected in the maxillary artery, and eight full facial allografts were harvested through a modified approach. RESULTS: Seven patients developed palatal fistulas or palatal necrosis (41 percent) when allograft was perfused through the facial artery. The traditional Le Fort III approach demonstrated consistent injury to maxillary artery/branches. The modified approach allowed for preservation of the maxillary artery under direct vision. CONCLUSIONS: Current facial transplantation outcomes indicate that facial artery-based allografts containing Le Fort III bony components can experience compromised palate perfusion. The described modified Le Fort III approach allowed safe dissection of the maxillary artery, preserving the arterial blood supply to the facial skeleton. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Hand compression neuropathy: An assessment guide.

When a patient presents with pain or paresthesias of the hand and fingers, knowing what to ask, what to look for, and which tests to consider is essential.

Donor-specific tolerance in fully major histocompatibility major histocompatibility complex-mismatched limb allograft transplants under an anti-alphabeta T-cell receptor monoclonal antibody and cyclosporine A protocol.

BACKGROUND: Recent studies have demonstrated that treatment with alphabeta-T-cell receptor (TCR) monoclonal antibody and cyclosporine A (CsA) can extend survival in composite tissue allografts (CTA). The purpose of this study was to induce tolerance in fully major histocompatibility complex (MHC)-mismatched rat limb allografts under 7 days of a combined alphabeta-TCR-CsA protocol. METHODS: The authors performed 30 hind-limb allotransplantations across the MHC barrier between Brown Norway donors (BN; RT1n) and Lewis recipients (LEW; RT1l). Isograft and allograft controls received no treatment. The experimental groups received monotherapy of alphabeta-TCR and CsA or a combination of alphabeta-TCR and CsA for 7 days only. Donor-specific tolerance and immunocompetence were determined by standard skin grafting in vivo and mixed lymphocyte reaction (MLR) in vitro. The efficacy of immunosuppressive therapy and the level of donor-specific chimerism were determined by flow cytometry. RESULTS: Long-term survival (>350 days) was achieved in allograft recipients (n=6) under the 7-day protocol of combined alphabeta-TCR-CsA. Donor-specific tolerance and immunocompetence of long-term chimeras were confirmed by acceptance of skin grafts from the donors and rejection of the third-party alloantigens (AxC Irish). At day 120, MLR demonstrated unresponsiveness to the host and donor antigens but strong reactivity against third-party alloantigens. Flow cytometry confirmed the high efficacy of immunosuppressive treatment and the development of donor-specific chimerism (7.6% of CD4+-RT1n+ cells, 1.3% of CD8+-RT1n+ cells, and 16.5% of CD45RA+-RT1n+ cells) in the periphery of tolerated recipients. CONCLUSIONS: Combined therapy of alphabeta-TCR-CsA for 7 days resulted in tolerance induction in fully MHC-mismatched rat hind-limb allografts. Tolerance was directly associated with stable, donor-specific chimerism.

A new composite facial and scalp transplantation model in rats.

There are limited sources of autogenous tissue available for reconstruction of severe facial and scalp deformities caused by extensive tumor ablation, burns, or trauma. Allografts from cadaveric sources may serve as a reconstructive alternative. However, technical and immunological aspects of harvesting and transplanting face and scalp flaps limit the routine use of such procedures. For evaluation of the feasibility of composite-tissue reconstruction, an experimental model of composite face/scalp flap transplantation in rats was designed. Technical aspects of the model, survival rates, and the complications encountered during development of the model are presented. A total of 64 animals, in three experimental groups, were studied. In group I, the anatomical study group (n = 6), the anatomical features of the face and scalp region in rats were explored. Groups II and III were the transplantation groups. Isograft transplantations were performed between identical Lewis rats (RT11 to RT11), and allografts were transplanted, across major histocompatibility complex barriers, between Lewis-Brown Norway rats (RT1l/n) and Lewis rats (RT11). In group II (the control group, n = 8), transplantation of nonvascularized composite face/scalp isografts and allografts was performed. In group III (the transplantation group, n = 50), vascularized face/scalp isografts (n = 36) and allografts (n = 14) were transplanted. Complications included partial or total flap necrosis, death attributable to food aspiration, and poor general condition. To prevent acute and chronic allograft rejection, cyclosporine A (16 mg/kg per day) therapy was initiated 24 hours after transplantation; the dose was tapered to 2 mg/kg per day within 4 weeks and was maintained at that level thereafter. Long-term survival (>170 days) was achieved, without any signs of rejection, with low-dose (2 mg/kg per day) cyclosporine A therapy. This is the first report documenting successful composite face/scalp flap transplantation in the rat model.

Institutional review board-based recommendations for medical institutions pursuing protocol approval for facial transplantation.

BACKGROUND: Preliminary outcomes from the previous nine face transplants performed since 2005 have been encouraging and have therefore led to a rise in the number of medical centers interested in establishing face transplant programs worldwide. However, until now, very little literature has been published providing surgeons the necessary insight on how to (1) prepare a protocol for institutional review board approval and (2) establish a face transplant program. METHODS: The authors' face transplant team's experience with the institutional review board at the Cleveland Clinic, beginning in 2002, was critically reviewed in a detailed, retrospective manner. The purpose was to identify and define certain criteria necessary for both the institutional review board approval process and face transplant program establishment. RESULTS: In 2002, unprecedented efforts from within the authors' plastic surgery department led to the world's first institutional review board approval for face transplantation, in 2004. As a result, 4 years later, the authors' face transplant team performed the nation's first successful near-total face and maxilla transplant. CONCLUSIONS: Every surgical department hoping to establish a face transplant program must realize that this endeavor requires both tremendous financial and long-term commitments by its medical institution. These transplants should be performed only within university-based medical centers capable of orchestrating a specialized, talented, multidisciplinary team. More importantly, facial composite tissue allotransplantation possesses an unmatched level of complexity and therefore requires most centers to prepare a carefully detailed protocol using these institutional review board-based guidelines.

Face, upper extremity, and concomitant transplantation: potential concerns and challenges ahead.

From its origination involving successful rat hind-limb allograft studies using cyclosporine, face and upper extremity composite tissue allotransplantation has since developed into an exciting and promising subset of reconstructive transplant surgery. Current surgical technique involving composite tissue allotransplantation has allowed optimal outcomes in patients with massive facial and/or upper extremity defects; however, with its coexisting immunologic barrier, obligatory lifelong immunosuppression commits each patient to a daily risk of transplant-related complications with many unanswered questions. Since 1998, nearly 50 hand transplantations in 40 patients have been performed around the world at various levels ranging from wrist level to shoulder level. However, the risk-to-benefit ratio remains controversial in bilateral versus unilateral transplantation and has yet to be determined. From recent experience, the two most important determinants of the success of each patient's upper extremity transplant are patient compliance and intense rehabilitation. A total of nine face transplants have been performed since 2005. Multiple aesthetic subunits (i.e., nose, lips, eyelids) with or without underlying craniofacial skeletal defects (i.e., maxilla, mandible) have been successfully restored, thereby providing restoration of vital facial functions (i.e., smiling) in an unprecedented manner. As of today, face transplantation carries an estimated 2-year mortality of 20 percent. Concomitant composite tissue allotransplantation, which involves a variable combination of allograft subtypes, has been performed in two of the nine face transplant patients. These have included simultaneous bilateral hand transplants and tongue with mandible. Future study is warranted to investigate the potential advantages and disadvantages of using this approach versus a staged approach for reconstruction.

First U.S. near-total human face transplantation: a paradigm shift for massive complex injuries.

BACKGROUND: Severe complex facial injuries are difficult to reconstruct and require multiple surgical procedures. The potential of performing complex craniofacial reconstruction in one surgical procedure is appealing, and composite face allograft transplantation may be considered an alternative option. The authors describe establishment of the Cleveland Clinic face transplantation program that led them to perform the first U.S. near-total face transplantation. METHODS: In November of 2004, the authors received the world's first institutional review board approval to perform a face transplant in humans. In December of 2008, after a 22-hour operation, the authors performed the first near-total face transplantation in the United States, replacing 80 percent of the patient's traumatic facial deficit with a composite allograft from a brain-dead donor. This largest, and most complex, face allograft in the world included over 535 cm2 of facial skin; functional units of full nose with nasal lining and bony skeleton; lower eyelids and upper lip; underlying muscles and bones, including orbital floor, zygoma, maxilla, alveolus with teeth, hard palate, and parotid glands; and pertinent nerves, arteries, and veins. Immunosuppressive treatment consisted of thymoglobulin, tacrolimus, mycophenolate mofetil, and prednisone. RESULTS: The patient tolerated the procedure and immunosuppression well. At day 47 after transplantation, routine biopsy showed rejection of the graft mucosa without clinical evidence of skin or graft rejection. The patient's physical and psychological recovery went well. The functional outcome has been excellent, including optimal return of breathing through the nose, smelling, tasting, speaking, drinking from a cup, and eating solid foods. CONCLUSION: The functional outcome thus far at 8 months is rewarding and confirms the feasibility of performing complex reconstruction of severely disfigured patients in a single surgical procedure of facial allotransplantation.

Composite tissue allotransplantation.

Recently, composite tissue allotransplantation was introduced as a potential clinical treatment for complex reconstructive procedures, including tumor ablative operations, traumatic injuries, and extensive tissue loss secondary to burns. Composite tissue allotransplantations consist of heterogeneous tissues including skin, fat, muscle, nerves, lymph nodes, bone, cartilage, ligaments, and bone marrow, all presenting with different antigenicity. Thus, composite tissue allotransplantations are considered to elicit a stronger response compared with solid organ transplants. This article outlines different experimental models and current clinical applications of composite tissue allotransplantation.

Strategies to develop chimerism in vascularized skin allografts across MHC barrier.

In this study, we investigated the effects of 7-day-protocols of alphabeta-T-cell receptor monoclonal antibody (alphabeta-TCRmAb), cyclosporine A (CsA), and tacrolimus (FK-506) immunosuppressive monotherapies, and their combinations on the survival of vascularized skin allografts (VSA). Forty-two transplantations of VSA across a strong MHC barrier were performed between ACI (RT1a) donors and Lewis (RT1(l)) recipients in seven groups. Isograft and allograft rejection controls received no treatment. Treatment groups received a 7-day protocol of alphabeta-TCRmAb, CsA, or FK-506 monotherapy, or a combination of alphabeta-TCRmAb/CsA and alphabeta-TCRmAb/FK-506. VSA transplants were evaluated on a daily basis. Donor-specific chimerism was determined by flow cytometry (FC). The combined protocols of alphabeta-TCRmAb/FK-506 and alphabeta-TCRmAb/CsA significantly prolonged VSA survivals compared to monotherapy groups ( P < 0.005). FC analysis revealed 15.82% of donor-specific chimerism on day 7 under the alphabeta-TCRmAb/CsA protocol and a gradual chimerism decline on day 63 posttransplant. The significant extension of VSA survival achieved under 7-day protocols of combined therapies was directly associated with the presence of donor-specific chimerism.