Molecular Heparan Sulfate Delivery in Wound Regeneration

DESCRIPTION (provided by applicant): Tissue engineering, grafting procedures, regeneration, and tissue remodeling are developing therapies with great potential medical value. None of these therapeutic modalities are yet fully effective or predictable. Glycosaminoglycan-decorated proteoglycans such as perlecan, once thought to primarily serve as structural components of extracellular matrix, are now being focused on for their role in tissue and cell regulation, particularly angiogenesis and wound healing. Perlecan's domain 1 becomes glycosylated with heparan sulfate in vivo so has the potential to effect several aspects of wound healing and is an excellent candidate for induction in an effort to modulate wound healing. This project is premised on the hypothesis that delivery of heparan sulfate via the perlecan domain 1 will improve wound healing. Agenta Biotechnologies owns IP related to nucleic acid vector presentation of perlecan in wound healing and regeneration. In phase 1 of the project we will complete two aims related to osseous regeneration. To establish replicable in vitro parameters, we will measure delivery of replication-defective adenovirus expressing perlecan domain 1 to endothelial cells and osteoblasts. To establish proof of principle in vivo, we will assess delivery of the adenovirus particles, perlecan domain 1 and heparan sulfate expression, and wound healing parameters relating to vasculogenesis and new bone formation in a mouse osseous defect model. In each aim, particle delivery, via a common bone graft substitute, hydroxyapatite crystals, will be assessed. Outcomes of this phase 1 project will be applicable to many wound healing disciplines but will be targeted first to improvement of osseous regeneration in phase 2 of this project where alternative bone graft substitutes, barrier membranes, and surgical applications will be investigated, and a more extensive biochemical analysis of loading, delivery, and expression will be performed. Molecular heparan sulfate delivery has the potential to improve osseous grafting and the usefulness of bone graft substitutes, which is the ultimate goal of this technology platform and proposed project.