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.
Citation
Post, Allison Davis (2018). Development of a Multilayer Vascular Graft with Targeted Cellular Interactions and Improved Mechanical Properties. Doctoral dissertation, Texas A & M University. Available electronically from https : / /hdl .handle .net /1969 .1 /174400.