Dolph Houben

14 CHAPTER 1 Living bone and joint allotransplantation A future alternative for skeletal reconstruction may be bone and/or joint vascularized composite allotransplantation (VCA). VCA is defined as the transplantation of living allogeneic tissue from an organ donor and microvascular repair of its allogeneic vascular supply to maintain transplant viability. Living bone and joint allotransplantation combine the advantages of CBAs with the enhanced healing and remodeling potential of autologous VBGs, minimalizing the risk of late stress fractures, resorption and infection [12, 48] . Transfer of living allogenic tissue will closely match the defect size, shape and tissue type, and would eliminate donor site morbidity. Current multi- organ donor programs have the ability to identify and match the right donor and recipient. Bone is relatively ischemia-tolerant, and tissue harvest may therefore take place after critical organ harvest has been completed and bone tissue viability can be maintained for up to 5 days in cold storage [49-53] . First clinical experience In VCA and organ transplantation, rejection, morbidity, and mortality resulting from efforts to modulate the immune system are major issues. Cell-mediated and humoral responses develop in 3-5 days after VCA transplantation [54] and cause subsequent rejection if immunosuppression is not administered [55-58] . While microvascular surgery makes VCA technically feasible, to date VCA requires the use of life-long immunosuppression (IS). Internationally more than 100 upper extremity transplantations and 30 face transplants have been performed with an incidence of acute rejection exceeding 80% [59] . Before 2010 (first facial transplant), 49 hand transplantations have been performed internationally. Complications included acute rejection (85%), opportunistic infections (88%), and metabolic or drug-related problems in 70% [60] . Twenty-four percent of the hand transplantations failed, with amputation or patient death as a result. Clinical experience with bone and joint VCA is limited. In 1990 the first vascularized allogenic femoral diaphysis was transplanted in a human without the use of IS, since donor and recipient were ABO blood system and Human Leukocyte Antigen (HLA) matched [61] . Later in 1996, a congenital pseudarthrosis was treated with a vascularized allogenic fibula flap from mother to daughter using IS, constituting the first successfully-healed VCA described in the literature [62] . A German group has reported the largest cohort of clinical bone and joint VCA. They reported transplantation totals of three femoral diaphysis and five whole knees in 2000 [63] . Most of the clinical VCA reconstructions to date have eventually failed due to infection, acute rejection, or chronic allotransplant vasculopathy [63-71] . Immunology of vascularized composite allotransplantation Vascularized composite allotransplantation has revolutionized the reconstructive options for the most challenging tissue defects. For example, the clinical successes achieved in hand and face allotransplantation are based on the knowledge gained in solid organ transplantation. The immunologic reaction of the body against allogeneic tissue is the result form the interplay between the innate (non-specific) and adaptive (specific) immune response. The innate immune response is largely mediated by macrophages, dendritic cells, neutrophils, natural killer cells, and the complement system. These cells respond to ‘danger’ which can be induced by surgical trauma, infection, ischemia-reperfusion injury, mutated cells, and foreign tissues. Activated innate