P4: Revitalizing structural allografts for traumatic bone defects

University Of Rochester, Rochester NY

Investigators

Linked publications & trials

Abstract

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