In vivo biocompatibility of a plasma-activated, coronary stent coating

Abstract

Bare metal and drug-eluting coronary stents suffer an inherent lack of vascular cell and blood compatibility resulting in adverse patient responses. We have developed a plasma-activated coating (PAC) for metallic coronary stents that is durable, withstands crimping and expansion, has low thrombogenicity and can covalently bind proteins, linker-free. This has been shown to enhance endothelial cell interactions in vitro and has the potential to promote biointegration of stents. Using the rabbit denuded iliac artery model, we show for the first time that PAC is a feasible coating for coronary stents in vivo. The coating integrity of PAC was maintained following implantation and expansion. The rate of endothelialization, strut coverage, neointimal response and the initial immune response were equivalent to bare metal stents. Furthermore, the initial thrombogenicity caused by the PAC stents showed a reduced trend compared to bare metal stents. This work demonstrates a robust, durable, non-cytotoxic plasma-based coating technology that has the ability to covalently immobilize bioactive molecules for surface modification of coronary stents. Improvements in the clinical performance of implantable cardiovascular devices could be achieved by the immobilization of proteins or peptides that trigger desirable cellular responses.

Introduction

Metallic coronary stents now dominate in percutaneous coronary interventions [1]. However, the clinical performance of both bare metal stents (BMS) and drug eluting stents (DES) is less than ideal and causes significant adverse patient outcomes. BMS are prone to high rates of vessel renarrowing known as restenosis [2], while DES suffer from an ongoing risk of late stent thrombosis [3], polymer hypersensitivity [4], polymer delamination [5] and delayed re-endothelialization [6].

New generation DES aimed at reducing these adverse effects are being developed and although promising, reliance on dual anti-platelet therapy and safety outcomes following their cessation remain issues [7]. Additionally, polymer instability is a persistent problem, with thick polymer coatings delaminating and exposing thrombogenic bare metal stent struts to the vasculature [5]. Similarly, newly developed bioresorbable stents could potentially provide benefits by degrading over time, however these are yet to be fully developed. Their clinical applicability is likely to be limited by intrinsic problems, such as poor deliverability, flexibility and radial strength. The thicker struts required to compensate for reduced radial strength of the materials [8] are known to cause increased restenosis and thrombosis [9], [10]. There remains a need for robust, biomimetic coatings for metallic stents.

We have developed a plasma-activated coating (PAC) for surface modification of metallic alloys using plasma enhanced chemical vapour deposition [11]. PAC is smooth and strongly adheres to the underlying metal by an energetic ion stitching deposition process. The coating is wear resistant under pulsatile flow and is able to withstand crimping and expansion without delaminating in vitro [11], [12]. PAC has strikingly low thrombogenicity compared to 316L stainless steel in static adhesion and flow loops in vitro using whole human blood [12], [13]. Furthermore, PAC allows linker-free covalent immobilization of functional biomolecules to the surface with the potential to allow improved biointegration of a range of biomedical implants [11], [13].

In this proof of principle study, we have evaluated the acute response to PAC stents compared to bare metal stainless steel stents in a well-established animal model [14]. In a rabbit denuded bilateral iliac artery model we analysed the feasibility of PAC as a stent coating. We evaluated coating integrity, the rate of endothelialization, the initial immune response and thrombogenicity caused by the stent.