Codominant Role of Interferon-γ- and Interleukin-17-Producing T Cells During Rejection in Full Facial Transplant Recipients.

Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean follow-up of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectively, and a detailed characterization of their immune response (51 time points) was performed, defining 47 immune cell subsets, 24 serum cytokines, anti-HLA antibodies, and donor alloreactivity on each sample, producing 4269 data points. In a nonrejecting state, patients had a predominant T helper 2 cell phenotype in the blood. All patients developed at least one episode of acute cellular rejection, which was characterized by increases in interferon-γ/interleukin-17-producing cells in peripheral blood and in the allograft's skin. Serum monocyte chemotactic protein-1 level was significantly increased during rejection compared with prerejection time points. None of the patients developed de novo donor-specific antibodies, despite a fourfold expansion in T follicular helper cells at 1 year posttransplantation. In sum, facial transplantation is frequently complicated by a codominant interferon-γ/interleukin-17-mediated acute cellular rejection process. Despite that, medium-term outcomes are promising with no evidence of de novo donor-specific antibody development.

Intraoral features and considerations in face transplantation.

Face transplantation (FT) is a unique and novel addition to the field of reconstructive surgery, which offers new hope to facially disfigured individuals. This review provides an overview of FT, including clinical indications, immunological principles, and functional outcomes, as well as an in-depth characterization of the intraoral hard and soft tissue findings in the six patients transplanted to date at Brigham and Women's Hospital in Boston, MA, USA. Six FT recipients underwent comprehensive clinical and radiographic evaluation to assess their intraoral status, function, and overall health. The extra- and intraoral soft tissue was assessed via quantitative sensory testing. The vitality of the transplanted dental hard tissue was evaluated with clinically available testing methods. Native teeth and prostheses were also assessed. Sensation of transplanted oral mucosa varied based on time elapsed from FT, ranging from minimal at 3 months post-FT, to nearly complete recovery by approximately 24 months. There was mixed success with the integration of donor teeth (Patients 1, 4 and 6), including associated occlusal discrepancies. Mucosal complications included constriction at the donor/recipient interface (Patients 2 and 5) and solitary episodes of mucosal rejection presenting as lichenoid inflammation (Patients 2 and 4). Face transplantation represents a pivotal moment in the history of reconstructive surgery and transplant medicine, providing new optimism to patients with gross facial deformities. This report highlights the successes of FT, but also the challenges of transplanting hard and soft tissues to restore complex stomatognathic function. Further attention directed toward comprehensive oral rehabilitation in FT will contribute to improved outcomes, with the ultimate goal of restoring and optimizing patient quality of life.

Early postoperative imaging and image-guided procedures on patients with face transplants.

Face transplantation is being performed with increasing frequency. Facial edema, fluid collections, and lymphadenopathy are common postoperative findings and may be due to various etiologies, some of which are particular to face transplantation. The purpose of this study was to demonstrate how postoperative imaging and image-guided minimally invasive procedures can assist in diagnosing and treating complications arising from face transplantation. Retrospective evaluation of 6 consecutive cases of face transplantation performed at Brigham and Women's Hospital between April 2009 and March 2014 was performed with assessment of postoperative imaging and image-guided procedures, including aspiration of postoperative fluid collection, lymph node biopsy, and treatment of salivary gland leak. Through these cases, we demonstrate that early postoperative imaging and image-guided procedures are key components for the management of complications following face transplantation.

The management of antibody-mediated rejection in the first presensitized recipient of a full-face allotransplant.

We report on the management of the first full-face transplantation in a sensitized recipient with a positive preoperative crossmatch and subsequent antibody-mediated rejection (AMR). The recipient is a 45-year-old female who sustained extensive chemical burns, with residual poor function and high levels of circulating anti-HLA antibodies. With a clear immunosuppression plan and salvage options in place, a full-face allotransplant was performed using a crossmatch positive donor. Despite plasmapheresis alongside a standard induction regimen, clinical signs of rejection were noted on postoperative day 5 (POD5). Donor-specific antibody (DSA) titers rose with evidence of C4d deposits on biopsy. By POD19, biopsies showed Banff Grade III rejection. Combination therapy consisting of plasmapheresis, eculizumab, bortezomib and alemtuzumab decreased DSA levels, improved clinical exam, and by 6 months postop she had no histological signs of rejection. This case is the first to demonstrate evidence and management of AMR in face allotransplantation. Our findings lend support to the call for an update to the Banff classification of rejection in vascularized composite tissue allotransplantation (VCA) to include AMR, and for further studies to better classify the histology and mechanism of action of AMR in VCA.

Vascular communications between donor and recipient tissues after successful full face transplantation.

The vascular reorganization after facial transplantation has important implications on future surgical planning. The purpose of this study was to evaluate blood flow (BF) after full face transplantation using wide area-detector computed tomography (CT) techniques. Three subjects with severe craniofacial injury who underwent full face transplantation were included. All subjects underwent a single anastomosis bilaterally of the artery and vein, and the recipient tongue was preserved. Before and after surgery, dynamic volume CT studies were analyzed for vascular anatomy and blood perfusion. Postsurgical CT showed extensive vascular reorganization for external carotid artery (ECA) angiosome; collateral flows from vertebral, ascending pharyngeal or maxillary arteries supplied the branches from the recipient ECAs distal to the ligation. While allograft tissue was slightly less perfused when the facial artery was the only donor artery when compared to an ECA-ECA anastomosis (4.4 ± 0.4% vs. 5.7 ± 0.7%), allograft perfusion was higher than the recipient normal neck tissue. BF for the recipient tongue was maintained from contralateral/donor arteries when the lingual artery was sacrificed. Venous drainage was adequate for all subjects, even when the recipient internal jugular vein was anastomosed in end-to-end fashion on one side. In conclusion, dynamic CT identified adequate BF for facial allografts via extensive vascular reorganization.

Abdominal wall reconstruction using a non-cross-linked porcine dermal scaffold: a follow-up study.

PURPOSE: In a previous study, we have shown that non-cross-linked porcine dermal scaffolds (NCPDS) are a safe and effective alternative to prosthetic mesh in the reconstruction of complicated abdominal wall defects. Here, we report the long-term outcomes of abdominal wall reconstruction using NCPDS in a larger patient population. METHODS: Patients who underwent abdominal wall reconstruction with NCPDS between May 2006 and December 2010 were retrospectively reviewed. Analysis of demographics, indications for NCPDS placement, surgical technique, complications, and follow-up data was performed. RESULTS: NCPDS was used for abdominal wall repair in 40 patients. In all patients, NCPDS was positioned using an intraperitoneal technique. At a mean follow-up time of 40.1 months, most patients had successful outcomes. Complications included seroma (21 %), recurrence (7.9 %), and infection (5.2 %); these rates are comparable to our initial report. Two patients died from multi-organ failure unrelated to NCPDS placement. CONCLUSIONS: This study shows that complex abdominal wall defects can be successfully reconstructed using NCPDS with a low rate of recurrence and complications.

Evolution of indications for facial transplantation.

Face transplantation has the unique potential to restore facial form and function in patients with severe facial defects. Current indications for face transplantation remain limited by unknown long-term outcomes and the requirements for lifelong immunosuppression and substantial plans for reconstruction in case of failure. We initially obtained Institutional Review Board approval for partial face transplantation in patients with defects comprising 25% of the face and/or loss of one or more major facial features. We launched an outcome-oriented face transplantation study and screened 13 potential patients between February 2008 and January 2011. Experience gained during screening motivated the expansion of indications to include full facial defects and the consideration of patient-specific complex issues on a case-by-case basis. Although our programme focuses on restoring absent or severely compromised motor and sensory functions, we recognise aesthetic appearance as a crucial facial function. Patients are extensively educated on the risks and benefits of facial transplantation and then allowed to play the main role in the decision-making process, as long as no absolute exclusion criteria are present. As we learn more about the long-term outcomes of face transplantation and safe reduction of immunosuppression, face-transplant indications may expand from major unreconstructable defects towards potentially minor defects.

A multidisciplinary protocol for face transplantation at Brigham and Women's Hospital.

Face transplantation introduces an unprecedented potential to restore form and function in patients with severe facial disfigurement. A successful face transplantation programme requires a sound research protocol, a solid infrastructure, expert personnel and adequate funding. There are only a few active face transplant programmes in the world and interest in the development of new such programmes continues to grow. After 2 years of working on the development of the face transplant programme, in 2009 the team at Brigham and Women's Hospital (BWH) performed the 2nd face transplant in the United States. Since then, the team has continued to evaluate several possible face transplant candidates and performed three additional facial transplants. These experiences have helped refine a highly effective multidisciplinary protocol that carries a patient through recruitment, informed consent, screening, preoperative planning, face transplantation surgery and postoperative long-term follow-up. The members of the BWH face transplantation team responsible for carrying out this protocol include a team leader, a programme manager/coordinator, clinical and rehabilitation specialists, social workers, bioethicists, nurses and administrative staff. The roles of each team member during the various stages of the face transplant process are presented here. Additional insight into the interaction between the face transplant team, the Institutional Review Board and the regional Organ Procurement Organization is given. The BWH team's experience has shown that true collaboration, creativity and a unique approach to each candidate translate into the optimal care of the face transplant patient both before and after surgery.

Restoration of facial form and function after severe disfigurement from burn injury by a composite facial allograft.

Composite facial allotransplantation is emerging as a treatment option for severe facial disfigurements. The technical feasibility of facial transplantation has been demonstrated, and the initial clinical outcomes have been encouraging. We report an excellent functional and anatomical restoration 1 year after face transplantation. A 59-year-old male with severe disfigurement from electrical burn injury was treated with a facial allograft composed of bone and soft tissues to restore midfacial form and function. An initial potent antirejection treatment was tapered to minimal dose of immunosuppression. There were no surgical complications. The patient demonstrated facial redness during the initial postoperative months. One acute rejection episode was reversed with a brief methylprednisolone bolus treatment. Pathological analysis and the donor's medical history suggested that rosacea transferred from the donor caused the erythema, successfully treated with topical metronidazol. Significant restoration of nasal breathing, speech, feeding, sensation and animation was achieved. The patient was highly satisfied with the esthetic result, and regained much of his capacity for normal social life. Composite facial allotransplantation, along with minimal and well-tolerated immunosuppression, was successfully utilized to restore facial form and function in a patient with severe disfigurement of the midface.

Accelerated healing of full-thickness skin wounds in a wet environment.

Full-thickness skin wounds are preferably allowed to heal under controlled hydration dressings such as hydrocolloids. It was hypothesized that a wet (liquid) environment rather than a dry or moist one would accelerate the wound healing process. We compared skin repair by secondary intention in full-thickness skin wounds in wet (saline), moist (hydrocolloid), and dry (gauze) conditions in an established porcine wound healing model. The study included three animals with a total of 70 wounds layered in a standardized fashion on the back of young Yorkshire pigs. Twelve days after wounding, 0 percent of dry, 20 percent of moist, and 86 percent of saline-treated wounds were completely reepithelialized (p values = 0.0046 and 0.027 for saline wounds compared with dry and moist wounds, respectively). The accelerated healing was caused at least in part by faster contraction in wet wounds (p value < 0.005 compared with that of other groups 9 and 12 days after wounding). Development of granulation tissue was faster in moist conditions than it was for dry and wet wounds. The thickness and number of cell layers of the newly formed epidermis were greater in dry and wet wounds than in moist ones. It was concluded that these full-thickness porcine skin wounds healed faster in a wet environment than in a moist one. Dry wounds healed more slowly than moist wounds. The basic mechanisms of skin wound repair were influenced by the treatment modality as demonstrated by the observed differences in granulation tissue formation, reepithelialization, and rate of wound contraction.

Dermatan sulfate released after injury is a potent promoter of fibroblast growth factor-2 function.

Proteoglycans have been shown in vitro to bind multiple components of the cellular microenvironment that function during wound healing. To study the composition and function of these molecules when derived from an in vivo source, soluble proteoglycans released into human wound fluid were characterized and evaluated for influence on fibroblast growth factor-2 activity. Immunoblot analysis of wound fluid revealed the presence of syndecan-1, syndecan-4, glypican, decorin, perlecan, and versican. Sulfated glycosaminoglycan concentrations ranged from 15 to 65 microgram/ml, and treatment with chondroitinase B showed that a large proportion of the glycosaminoglycan was dermatan sulfate. The total glycosaminoglycan mixture present in wound fluid supported the ability of fibroblast growth factor-2 to signal cell proliferation. Dermatan sulfate, and not heparan sulfate, was the major contributor to this activity, and dermatan sulfate bound FGF-2 with Kd = 2.48 microM. These data demonstrate that proteoglycans released during wound repair are functionally active and provide the first evidence that dermatan sulfate is a potent mediator of fibroblast growth factor-2 responsiveness.

Tissue engineering of skin.

The skin plays a crucial role in protecting the integrity of the body's internal milieu. The loss of this largest organ is incompatible with sustained life. In reconstructive surgery or burn management, substitution of the skin is often necessary. In addition to traditional approaches such as split- or full-thickness skin grafts, tissue flaps and free-tissue transfers, skin bioengineering in vitro or in vivo has been developing over the past decades. It applies the principles and methods of both engineering and life sciences toward the development of substitutes to restore and maintain skin structure and function. Currently, these methods are valuable alternatives or complements to other techniques in reconstructive surgery. This review article deals with the evolution and current approaches to the development of in vitro and in vivo epidermis and dermis.