Revascularizing bone A genetic intervention

Segmental bone defects remain among the most difficult problems in reconstructive surgery, largely because transplanted bone often lacks sufficient vascularity to heal and integrate fully. This thesis explores whether cryopreserved bone allografts an important resource in limb-sparing surgery can be revitalized by actively restoring their blood supply. Using a large-animal tibial defect model. We investigated the concept of surgical angiogenesis by implanting an arteriovenous (AV) bundle into the intramedullary canal of the graft. This technique consistently produced new, functional vasculature throughout the previously avascular bone and led to improved healing, remodeling, and microstructural integrity while maintaining acceptable mechanical performance.
Building on these findings, we explored whether enhancing this newly established vascular network with angiogenic growth factors could further improve outcomes. After demonstrating that adeno-associated virus serotype 9 (AAV9) can be used to achieve localized gene expression within targeted arteries, we applied VEGF and PDGF gene delivery to the AV bundle. This approach markedly increased vascular volume, bone turnover, and graft incorporation. However, it also produced an unexpected and significant complication: the development of multiple benign but problematic vascular tumors. These lesions, resembling pyogenic granulomas, confirmed that while gene therapy could amplify local angiogenesis, it also carried substantial systemic risks.
Overall, this thesis demonstrates that surgical angiogenesis offers a safe and effective means of revascularizing cryopreserved bone allografts in a large animal model, whereas current viral gene therapy strategies require major refinement before clinical application.