Graphene coated bare metal stents as an enhanced design for the treatment of coronary artery disease

Abstract

Abstract Introduction Coronary artery disease is the leading cardiovascular related death worldwide. The mainstay therapeutic intervention is either coronary artery bypass grafting or endovascular approaches, inserting a metallic scaffold to maintain the opened state of the vessel. There are many scaffolds currently available and under development, with bare metal stents being first designed followed by drug eluting stents which are now commonly used. This necessitates the use of dual anti-platelet therapy to evade thrombosis. Bare metal stents pose a significant risk of in-stent restenosis followed by late stent thrombosis risk caused by the drug eluting stent. Importantly, drug eluting stents have significantly decreased the incidence of in-stent restenosis. Consequently, there remains the need to develop a complication-free stent, and thus we propose combining the structural strength of metallic stents, bare metal stents, with the surface characteristics of graphene to promote vessel healing and prevent complications. Graphene is a mono layered sheet of hexagonal structured carbon atoms, and has been hailed as the ‘wonder’ material across many disciplines. We aim to incorporate many of the desirable qualities of graphene and graphene oxide; strong, flexible, anti-corrosive, smooth, biocompatible, antibacterial, into a coronary stent coating in order to alleviate some of the complications of currently available stents. Methods Graphene was prepared by liquid phase exfoliation using a stabilising agent known as 1-pyrene sulfonic acid sodium salt while graphene oxide was prepared by Hummer’s exfoliation method. The quality of the dispersions were characterised using a range of techniques, particularly Raman spectroscopy and atomic force microscopy. Dip-coating, with applied bias and spray coating techniques were tested to select the optimal method of graphene/graphene oxide coating of bare metal stents. The selected technique was then investigated further to optimise coating to achieve thin, uniform and maximal coverage of the stent. Human coronary artery endothelial cell growth was investigated in vitro by incubation with the coated stents for durations of one and eight days (n=3). Following this, stents coated with graphene and graphene oxide underwent ex vivo incubation on porcine aortic tissue for a period of 14 days in order to determine the formation of neointimal hyperplasia. Following 14 days, visualisation by scanning electron microscopy was performed as well as Miller’s staining and immunohistochemistry for endothelial cells. Results Spray coating was selected at a spray distance of 10cm and 400µL at 0.4 mgmL-1 concentration to spray the stents for a duration of 60-80 minutes. Enhanced human coronary artery endothelial cell growth was observed from day one to day eight, on the graphene coated stents when compared to uncoated stents and graphene oxide coated stent. Porcine coronary and aortic tissue culture demonstrated no significant difference in neointimal thickness between any of the coated/uncoated bare metal stent groups. Graphene and graphene oxide were not inferior to uncoated bare metal stents in neointimal thickness. There were no endothelial cells present after 14 days of aortic tissue culture, even though endothelial cells were present before tissue culture. Conclusion Graphene coating prototype of coronary artery bare metal stents was achieved by spray coating. Graphene coating supported enhanced viability and growth of human coronary artery endothelial cells. Ex vivo study of neointimal hyperplasia in the porcine aortic tissue revealed no benefit of graphene coating in reducing neointimal thickness.

Date of Award	1 Aug 2019
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Cathy Holt (Supervisor), Nadim Malik (Supervisor) & Cinzia Casiraghi (Supervisor)