Reactive Ion Plasma Treatment of Cardiovascular Biomaterials to Understand the Effect of Nanotopography on Endothelialization

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Project Summary This project proposes to investigate the role of surface topography in endothelialization by decoupling it from surface chemistry using reactive ion plasma (RIP) of peripheral vascular graft (PVG) biomaterials, including a promising material: polyvinyl alcohol (PVA). Over half of PVGs made from synthetic materials fail within two years of implantation and therapies to reduce the factors contributing to graft failure have shown no benefit in lower extremity PVG outcomes. Because the two predominant failure modes of PVGs are thrombosis (blood clotting) and intimal hyperplasia (tissue build-up inside the graft), an ideal PVG biomaterial should be resistant to both. The primary attributes of such a material are that it 1) have comparable compliance to the native vasculature, 2) be non-thrombogenic, and 3) encourage endothelialization. RIP-treated PVA is a promising PVG material which we have shown previously 1) is easily manufactured with compliance ranging from that of venous to arterial vasculature, 2) is less thrombogenic than the current clinical standard PVG material, and 3) allows endothelial progenitor cells (EPCs) to proliferate on the surface for at least 48 hours in vitro. Progress in manufacturing endothelializable PVGs has been hampered because the approaches predominantly involve conjugation of small molecules onto the PVG material, which have limitations associated with cost, stability, reproducibility, and scalability and despite significant attention have yet to be translated into the clinic. Our project is focused on using RIP treatment, a common and scalable manufacturing process, of PVA to decouple the two surface properties known to be important in the endothelialization process: surface chemistry and topography, in order to understand the fundamental factors that promote endothelialization and to achieve our long-term goal of manufacturing an improved PVG. We have shown that RIP-treatment introduces reactive surface chemistry necessary for cell adhesion in the form of surface nitrogen, as well as nanotexture to PVA and to varying degrees for different RIP treatments. While most of the reactive surface chemistry introduced by RIP is still apparent after 230 days in storage, the surface becomes smooth and EPCs no longer adhere or proliferate after storage. We will first characterize the changes in surface chemistry and topography during storage in order to understand the nature of the material surface as the topography relaxes (Aim 1). We will then decouple the effects of surface chemistry and topography on endothelial cell (EC) and EPC attachment, proliferation, and migration (Aim 2) as well as EC and EPC function with and without exposure to fluid flow (Aim 3). This understanding will allow us to determine the effect of surface chemistry and topography on the important processes of endothelialization and engineer a rapidly endothelializable PVG which remains patent longer than current clinical materials. Our studies will afford a more detailed understanding of the factors which govern endothelialization of synthetic biomaterials, provide a platform to understand EC biology, and improve translation of PVGs which can be applied to other biomaterials to improve their biointegration.