Serious traumatic injuries to the skeleton that result in unrepairable destruction of structural bone must be treated with either a limb salvage procedure that replaces the bone segment, or amputation. As limb salvage is the favorable outcome, the absence of a highly efficacious approach to replace the bone segment that will osteointegrate and restore normal function indefinitely remains a significant problem. Since human cortical bone is the ideal replacement material to fill segmental defects, structural allografts have been used for over 50 years for this purpose. Unfortunately, the absence of a vascular supply, and limited bone forming and remodeling of structural allografts is directly associated with the 25% to 35% failure rate within 3-years due to infection, fracture and nonunion. For those that survive, the failure rate at 10-years has been documented to be as high as 60%. As a result of this poor clinical success, the use of structural allografts has been restricted to repair segmental defects following tumor resection in cancer patients. Furthermore, since traumatic wounds are often contaminated with compromised soft tissue coverage, and necrotic bone is a nitrous for infection, the use of structural allografts to repair these injuries is contraindicated. To the end of a revitalizing structural allograft that has a vascular supply for immunity against infection and the ability to remodel microcracks, we have developed a revolutionary approach that introduces angiogenic, osteoclastogenic and osteogenic signals on the cortical surface via immobilized recombinant adenoassociate virus (rAAV). Based on our remarkable success with this approach in a murine femoral allograft model, here we propose to maximize its ability to reproducibly achieve unions with ideal biomechanical properties, and develop a minimally invasive outcome measure to prove its angiogenic and osteogenic properties in humans.
In Aim 1 we will determine if our remodeling allograft coated with rAAV-VEGF + rAAV-RANKL is superior to our osteogenic allograft coated with rAAV-caAlk2, and if these vectors can be efficiently combined.
In Aim 2 we will determine if PTH can be use as an adjuvant to increase bone formation and connectivity of our revitalizing allografts.
In Aim 3 we will perform a clinical pilot in auto and allograft patients to evaluate a novel vascular cone beam CT outcome measure to quantify vascular and bone volume longitudinally.
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