FACTORS INFLUENCING SURVIVAL OF VASCULAR BONE GRAFTS

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This proposal seeks to: 1. Evaluate prolonging vascularized bone allograft (VBA) survival by methods relatively nontoxic to the host, the material properties of orthotopically placed VBAs, and ultrastructural changes of these grafts. Having determined the roles of classic specific and nonspecific means of immunosuppression, monoclonal antibodies and the use of graft irradiation to prolong graft survival in a heterotopic model will be explored. Grafts will be placed in the orthotopic position, and the duration of classic immunosuppressive therapy regimens will be determined. The material properties of these orthotopically placed grafts will be evaluated, and ultrastructural changes in the graft will be studied in order to discern the focus of the rejection process in these composite grafts. 2 We plan to use a syngeneic vascularized bone transplantation model to study (1) the influences of gender and hormonal milieu on longitudinal skeletal growth and (2) the molecular mechanisms involved in disuse osteoporosis which is typically seen in the transplanted limbs. Limbs will be transplanted form female rats to pre- and post-pubertal male rats and to control females in an attempt to dissect the influences of chondrocyte genotype and hormonal environment on skeletal growth. Hypophysectomized rats at progressive weeks after surgery will be used as donors to evaluate the duration of growth potential and possible mechanisms involved in senescence at the growth plate. To examine disuse osteoporosis, immunohistochemical staining will be used to determine which matrix components are appropriately incorporated into bone; for those components which are not present, in situ hybridization will be used to establish whether this control is at the transcriptional or translational level. 3. Explore the reconstructive potential of the concept previously termed "molded vascularized osteoneogenesis" in which the incorporation of a vascular pedicle with nonvascularized bone grafts in a mold of predetermined size and shape will result in a viable vascularized bone graft. Experiments have been designed to determine if these grafts can be transferred as island or free grafts, the optimum timing for transfer of such grafts, the healing and material properties of these grafts, and the ability of non- host bone substances to become molded vascularized grafts.