Text Box:  Bioactive grafts have the potential to replace diseased small-caliber vessels without the complications associated with autologous or current synthetic grafts. A major roadblock in the development of off-the-shelf vascular grafts is achieving rapid endothelialization of the scaffold while minimizing the risk of thrombosis, intimal hyperplasia, and mechanical failure. Given that platelet aggregation and smooth muscle cell proliferation may be mediated by controlling endothelial cell (EC) growth and phenotype, the development of materials that direct appropriate EC behavior would have a significant impact on small vessel repair and replacement. However, matrix properties which promote graft endothelialization may not be consistent with those appropriate to sustain the loads associated with adult vasculature. To address this limitation, we propose to fabricate multilayered hydrogel-electrospun mesh scaffolds in which a hydrogel layer provides a local microenvironment inductive of rapid endothelialization and an electrospun mesh sleeve provides bulk strength, compliance matching, and suture retention. Thus, each component can be individually tuned to achieve improved outcomes without detriment to other design goals and then bonded together into composite grafts.

Collagen IV served as a design basis for the hydrogel layer due to its putative role in regulating EC adhesion and phenotype, which occurs in part through alpha1beta1 and alpha2beta1 integrin adhesion signals it presents to cells. This collagen-mimetic design strategy will be coupled with established polymer chemistry to generate biosynthetic hydrogels. The gel composition will be tailored to systematically probe the impact of hydrogel biochemical cues on EC and endothelial progenitor cell (EPC) behavior. Gel formulations that induce desired cell behaviors will then be utilized in the fabrication of the multilayer vascular graft reinforced with polyurethane electrospun mesh sleeves designed to have mechanical properties similar to native coronary arteries. The central hypothesis is that the proposed hybrid scaffold will provide local gel environments that promote rapid endothelialization while maintaining appropriate bulk strength, compliance matching, and suture retention.