PEG Hydrogels to Investigate the Role of Vasa Vasorum Angiogenesis in Tissue Engineered Vascular Grafts

PROJECT SUMMARY Tissue engineered vascular grafts (TEVGs) are a promising alternative to autologous tissues, yet none have been clinically approved for small-diameter revascularization due to pathological remodeling. Our lab previously showed TEVGs made from decellularized arteries had severe calcification which was associated with vascular smooth muscle cell (VSMC) osteogenic transdifferentiation and oxidative stress. We are now developing TEVGs resistant to calcification using matrix metalloprotease - degradable polyethylene glycol hydrogels (MMP- PEG) to coat the adventitial surface of decellularized aortas. This approach enables us to manipulate various aspects of TEVG adventitia remodeling including angiogenesis, innervation, and immunomodulation. As a proof-of-concept of our novel TEVG design, this project seeks to determine the effect of vasa vasorum neoangiogenesis in TEVG remodeling and to ascertain whether promoting angiogenesis is a feasible approach to improve TEVG remodeling. We hypothesize that robust vasa vasorum angiogenesis will reduce TEVG calcification by reducing osteogenic differentiation of cells in the vascular wall. We will test this hypothesis through two Aims. In Aim 1, we will utilize IPSC technology and PEG hydrogels to study the vasculogenic potential of MSCs, one of the main cells involved in vasa vasorum angiogenesis and vascular remodeling, derived from peripheral artery disease patients in 3D. The knowledge generated in this aim will provide insight into the regenerative potential of diseased patients and guide the design of biomaterials suited to promote adventitia angiogenesis, specifically the ideal mechanical stiffness and choice of pendant peptides in our PEG hydrogels. In Aim 2, we will evaluate the impact of vasa vasorum angiogenesis using TEVGs coated with angiogenic PEG hydrogels. Apart from a new approach to improve TEVG remodeling, the findings from this project will provide new insights into the role the vasa vasorum in vascular disease and yields a new technology that can be extended to autologous grafts and periadventitial therapies. Ultimately, this project has the potential to improve healthcare and quality of life of patients with cardiovascular disease thereby fulfilling the mission of the NHLBI.