Maximizing bone repair and regeneration continues to be a major goal in the field of regenerative medicine. Bone regeneration presents a major challenge for the reconstruction of craniofacial bones damaged by trauma, surgery for cancer, and congenital deformities. Oral cancer is a major reason for mandibulectomy and maxillectomy; there are more than 30,000 such cases in the US annually. In addition, 30% of all major neurosurgical procedures involve craniotomy: 5% are the result of head trauma and 25% are not related to trauma. In vivo bone formation is a major goal in a variety of craniofacial procedures, such as the repair of large cranial defects and large mandibular defects due to trauma and also for nonambulatory dental procedures performed to augment existing bone. Unfortunately, autologous bone, which is usually used to treat these lesions, is not always available and its harvest requires the mutilation of another bone. Moreover, the repair achieved using this technique is not efficient. Although large structural allografts are commonly used for long bone replacement (tibia, femur, humerus), they remain necrotic, and thus are not usable for craniofacial reconstruction. Recently we have developed a novel gene therapy approach to revitalize allograft bone in vivo by freeze-drying recombinant adeno-associated virus (rAAV) on the cortical surface. By transducing bone morphogenetic protein (BMP) signals, we have demonstrated the ability to induce endochondral bone formation around the allograft, which leads to a new bone collar. By transducing angiogenic (VEGF) and osteoclastogenic (RANKL) signals, we have demonstrated the induction of remodeling of the necrotic allograft with vascular ingrowth and intramembranous bone formation that revitalizes the allograft. Based on this success there are two fundamental questions that must be addressed towards the clinical development of revitalizing craniofacial allografts: 1) what are the kinetics and biodistribution of rAAV transduction following implantation of a coated allograft? And, 2) can we induce endochondral and intramembranous bone formation on rAAV coated flat bone allografts? Here we propose to address these questions using quantitative in vivo bioluminescence in a murine calvaria model. ? ? ?
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