Serious traumatic injuries to the skeleton that result in unrepairable destruction of structural bone must betreated with either a limb salvage procedure that replaces the bone segment, or amputation. As limbsalvage is the favorable outcome, the absence of a highly efficacious approach to replace the bone segmentthat will osteointegrate and restore normal function indefinitely remains a significant problem. Since humancortical bone is the ideal replacement material to fill segmental defects, structural allografts have been usedfor over 50 years for this purpose. Unfortunately, the absence of a vascular supply, and limited bone formingand remodeling of structural allografts is directly associated with the 25% to 35% failure rate within 3-yearsdue to infection, fracture and nonunion. For those that survive, the failure rate at 10-years has beendocumented to be as high as 60%. As a result of this poor clinical success, the use of structural allograftshas 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 isa nitrous for infection, the use of structural allografts to repair these injuries is contraindicated. To the end ofa revitalizing structural allograft that has a vascular supply for immunity against infection and the ability toremodel microcracks, we have developed a revolutionary approach that introduces angiogenic,osteoclastogenic and osteogenic signals on the cortical surface via immobilized recombinant adenoassociatevirus (rAAV). Based on our remarkable success with this approach in a murine femoral allograftmodel, here we propose to maximize its ability to reproducibly achieve unions with ideal biomechanicalproperties, and develop a minimally invasive outcome measure to prove its angiogenic and osteogenicproperties in humans.
In Aim 1 we will determine if our remodeling allograft coated with rAAV-VEGF + rAAV-RANKLis superior to our osteogenic allograft coated with rAAV-caAlk2, and if these vectors can beefficiently combined.
In Aim 2 we will determine if PTH can be use as an adjuvant to increase boneformation and connectivity of our revitalizing allografts.
In Aim 3 we will perform a clinical pilot in auto andallograft patients to evaluate a novel vascular cone beam CT outcome measure to quantify vascular andbone volume longitudinally.
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