The clinical augmentation of bone currently involves the use of autogenous or allogeneic bone grafts and synthetic materials, all of which are associated with limitations. Research on the safe enhancement of bone formation concerns the potential value of scaffolds, stem cells, gene therapy, and chemical and mechanical signals. Optimal scaffolds are engineered to provide mechanical stability while supporting osteogenesis, osteoconduction and/or osteoinduction. Scaffold materials include natural or synthetic polymers, ceramics, and composites. The resorption, mechanical strength and efficacy of these materials can be manipulated through structural and chemical design parameters. Cell-seeded scaffolds contain stem cells or progenitor cells, such as culture-expanded marrow stromal cells and multipotent skeletal progenitor cells sourced from other tissues. Despite extensive evidence from proof-of-principle studies, bone tissue engineering has not translated to clinical practice. Much of the research involves in vitro and animal models that do not replicate potential clinical applications. Problem areas include cell sources and numbers, over-reliance on existing scaffold materials, optimum delivery of factors, control of transgene expression, vascularization, integration with host bone, and the capacity to form bone and marrow structures in vivo. Current thinking re-emphasizes the potential of biomimetic materials to stimulate, enhance, or control bone's innate regenerative capacity at the implantation site.
y Both authors contributed equally.We report on the management of the first full-face transplantation in a sensitized recipient with a positive preoperative crossmatch and subsequent antibodymediated 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.
The advent of more potent immunosuppressants led to the first successful human upper extremity transplantation in 1998. At this time, > than 100 upper extremity transplants, 30 face transplants and a variety of other vascularized composite allotransplantation (VCA) procedures have been performed around the world. VCA recipients present unique challenges for transplantation. The incidence of acute rejection exceeds 80% in hand and face transplantation and is well documented, whereas reports about antibody-mediated rejection and chronic rejection remain scarce. Immunosuppression protocols commonly used at US centers are derived from solid organ transplantation protocols. Novel approaches to minimize rejections in VCA may include improved HLA matching and considerations towards cytomegalovirus infection status. New graft preservation techniques may decrease immunogenicity prior to transplant. Novel monitoring methods such as valid biomarkers, ultrasound biomicroscopy and sentinel flaps may enable earlier diagnosis of rejection. Cell-based therapies are being explored in order to achieve immunosuppressive regimen minimization or even tolerance induction. The efficacy of local immunosuppression in clinical VCA remains controversial. In conclusion, although immunosuppressive strategies adapted from SOT have demonstrated good mid-term results, focusing on the unique features of VCA grafts may enable additional, more specific treatment strategies in the future and improved long-term graft outcomes.
In this study we provide a compilation of functional impairments before and improvements after face transplantation (FT) of five FT recipients of our institution and all FTs reported in current literature. Functional outcome included the ability to smell, breath, eat, speak, grimace and facial sensation. Before FT, all our patients revealed compromised ability to breath, eat, speak, grimace and experience facial sensation. The ability to smell was compromised in two of our five patients. Two patients were dependent on tracheostomy and one on gastrostomy tubes. After FT, all abilities were significantly improved and all patients were independent from artificial air airways and feeding tubes. Including data given in current literature about the other 24 FT recipients in the world, the abilities to smell, eat and feel were enhanced in 100% of cases, while the abilities of breathing, speaking and facial expressions were ameliorated in 93%, 71% and 76% of cases, respectively. All patients that required gastrostomy and 91% of patients depending on tracheostomy were decannulated after FT. Unfortunately, outcomes remain unreported in all other cases and therefore we are unable to comment on improvements.
This series of 113 sequential biopsies of full facial transplants provides findings of potential translational significance as well as biological insights that could prompt reexamination of conventional paradigms of effector pathways in skin allograft rejection. Serial biopsies before, during, and after rejection episodes were evaluated for clinicopathological assessment that in selected cases included specific biomarkers for donorversus-recipient T cells. Histologic evidence of rejection included lymphocyte-associated injury to epidermal rete ridges, follicular infundibula, and dermal microvessels. Surprisingly, during active rejection, immune cells spatially associated with target cell injury consisted abundantly or predominantly of lymphocytes of donor origin with an immunophenotype typical of the resident memory T-cell subset. Current dogma assumes that skin allograft rejection is mediated by recipient T cells that attack epidermal targets, and the association of donor T cells with sites of target cell injury raises questions regarding the potential complexity of immune cell interactions in the rejection process. A more histopathologically refined and immune-based biomarker approach to assessment of rejection of facial transplants is now indicated. Modern Pathology (2014) 27, 788-799; doi:10.1038/modpathol.2013.249; published online 17 January 2014Keywords: donor T cell; facial transplant; graft-versus-host disease; skin allograft; T resident memory cells; vascularized composite allotransplantation Recent reports emphasizing the critical therapeutic importance of accurate diagnosis of transplant rejection 1 have stressed the imminent need for more precise clinicopathologic criteria and complementary application of relevant biomarkers. 2 The first systematic studies of any form of human allograft rejection were reported by Gibson and Medawar 3 in their classic description of skin rejection involving wartime aviators. 4 Early clues regarding the immunologic basis of skin graft rejection came from studies by Dvorak et al 5 and Bhan et al 6 that implicated both CD4 þ and CD8 þ T cells. These T-cell populations were presumed to be of recipient origin and considered to be primary effectors of epidermal and dermal microvascular target cell injury. With the recent advent of fullfacial transplantation, 7 detailed and sequential histopathologic surveillance for rejection in a manner seldom feasible for conventional skin allografts has become a necessity. However, existing schemas 8 for histologic recognition and grading of rejection in vascular composite allotransplantation are based primarily on allografts that may express relevant structural and immunological differences from facial tissues, eg, extremities (hand) and
The authors demonstrated the feasibility and superiority of ex vivo hypothermic oxygenated machine perfusion for preservation of amputated limbs over conventional static cold storage and herewith a substantial extension of the allowable ischemia time for replantation after traumatic amputation. This approach could also be applied to the field of transplantation, expanding the potential pool of viable donor vascularized composite allografts.
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