Development of a Multilayer Vascular Graft with Targeted Cellular Interactions and Improved Mechanical Properties

Abstract

Limited long-term patency of synthetic small diameter vascular grafts has driven considerable research to address their two main failure modes: thrombosis and re-occlusion of the vessel due to intimal hyperplasia. To address these limitations, our lab has created a multilayered graft with a hydrogel inner layer that promotes post-implantation endothelialization for initial and sustained thromboresistance and an electrospun outer layer with arterial compliance matching to limit intimal hyperplasia. In this work, we provide improvements in cellular interactions, outer layer mechanics, and hydrogel design to increase the graft’s potential for long term patency.

First, we further characterized cellular interactions with the inner layer that promote thromboresistance upon endothelialization. To optimize these interactions, we investigated specific integrin targeting utilizing designer proteins and their effect on endothelial cell hemostatic regulation. Elucidation of this relationship allows for tailoring thromboresistance of our inner layer as well as other blood contacting devices. We further improved the graft by increasing outer layer compliance matching and elucidated the intrinsic relationship between compliance mismatch and the development of intimal hyperplasia. We first fabricated grafts of increasing compliance while maintaining safe burst pressures and suture retention strength by modulating electrospinning parameters without altering graft chemistry. Grafts sutured to carotid arteries were cultured for two weeks before interrogation of early intimal hyperplasia markers. Changes in these markers were correlated to differences in wall shear stress predicted by a computational model of fluid flow changes based on dilation differences in compliance mismatch. With this relationship understanding, we created a high compliance graft that limits development of early markers for intimal hyperplasia and validated a system for rapid graft screening. Finally, we developed a suture damage resistant hydrogel formulation that enables safe graft implantation without adversely affecting bioactivity of the inner layer. We also identified properties determinant of suture damage resistance that enable development of future hydrogel formulations.

Overall, this work improves multiple aspects of a multilayered graft for long term patency. Additionally, we have elucidated fundamental material properties and biological relationships that can be used to enhance not only the multilayer vascular graft, but also biomaterial design for other cardiovascular devices.