Angiogenesis and Long-term Bone and Joint Allotransplant Survival

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 DESCRIPTION (provided by applicant): More than 3000 limb-sparing surgeries are performed annually in the United States to reconstruct segmental loss of bone resulting from treatment of neoplasm, infection, trauma or congenital anomaly. Current limb salvage reconstructive options have significant morbidity and frequent complications including prosthetic loosening and mechanical failures, as well as late stress fracture, infection and nonunion of bone allografts. A better solution to this difficult problem is required. The ability to transplant living allogeneic one, or alternatively, to revitalize cryopreserved bone allografts (CBAs) whose shape closely matches missing bone morphology potentially provides both the immediate stability needed for limb function as well as the vascularity needed to maintain or restore osteocyte viability. The result may be the same healing and remodeling potential as autogenous living bone. We have demonstrated the use of angiogenesis from autogenous vessels to provide a neoangiogenic circulation and promote vital, remodeling of bone. This may be accomplished in bone vascularized composite allotransplants (VCA) without need for long-term immune modulation. Instead, only 2 weeks of drug immunosuppression is used, sufficient to permit generation of the neoangiogenic circulation. The same process may revitalize cryopreserved bone allografts in the same rat and rabbit models. The important next steps require the use of a large animal model if our decade of small animal study is to be successfully translated into clinical applications. We propose to use Yucatan miniature swine for this purpose, orthotopically reconstructing segmental tibial defects with allogeneic bone. We will test if bone VCA and CBA segments will demonstrate enhanced bone circulation and remodeling potential, when surgically revascularized with implanted autogenous vessels. We will investigate the interplay of angiogenesis and systemic immune responses, and ask how they influence allograft segmental revitalization, bone remodeling and biomechanics. We will further ask if vascular endothelial growth factor (VEGF) delivery provided by VEGF gene transduction of vascular endothelial cells may further improve the results in both cryopreserved bone allografts (CBA) and bone VCA reconstruction.