Elsevier

Biomaterials

Volume 23, Issue 7, April 2002, Pages 1697-1706
Biomaterials

Analysis of a phosphorylcholine-based polymer coating on a coronary stent pre- and post-implantation

https://doi.org/10.1016/S0142-9612(01)00297-6Get rights and content

Abstract

There has been a move towards surface treatments for metallic coronary stents in an effort to improve their compatibility within the body and to provide a vehicle for the delivery of therapeutics. The BiodivYsio™ range of stents is characterised by a biocompatible coating comprised of a crosslinked phosphorylcholine (PC)-based polymer. In addition to a review of some of the data collected to support safety and efficacy of this device, this paper also describes a number of techniques that have been employed to both visualise and quantify the coating on the stent. Explantation of both coated and uncoated stents from porcine coronary arteries revealed that both coated and uncoated stents were >90% endothelialised after 5 days. Typical histological analysis of stented vessel sections after 4 and 12 weeks implantation showed the presence of cell types characteristic of the inflammatory response associated with the trauma caused by stent placement, with no evidence for any additional coating-related adverse inflammatory sequelae. Finally, it was demonstrated by AFM and SEM that both the thickness and force required to remove the coating were essentially unchanged after 6 months implantation. Thus, both the long-term stability and relative biological inertness of the coating has been confirmed in vivo, supporting its use as a vehicle for local drug delivery.

Introduction

Coronary artery disease is characterised by a narrowing (stenosis) of the arteries that supply blood to the tissue of the heart. Continued restriction of blood flow manifests itself as angina and ultimately myocardial infarction (heart attack) for the patient. Heart bypass surgery was once the only treatment for this condition but over the past few decades a far less traumatic procedure has emerged as an alternative. Percutaneous transluminal coronary angioplasty (PTCA) involves steering a device known as a guidewire, from an opening usually in the femoral artery of the leg, through the vasculature and into the coronary arteries. Once the narrowing (lesion or stenosis) within the artery is located, a balloon catheter is placed over the wire and moved into position within the blockage. Pressure is applied and the balloon inflated in order to re-open the vessel and establish normal blood flow. It is generally accepted that improved results are obtained if the balloon dilatation is accompanied by the placement of an intravascular scaffolding device, known as a stent, in order to prevent vessel recoil and to hold any dissections within the artery wall (flaps of loose tissue) in place [1].

Although stents have improved both the immediate and longer-term success of such procedures, there is still a high rate of vessel re-closure resulting in the need for repeat procedure. The re-narrowing, or restenosis of the treated artery is the result of a complex series of biological events in response to the initial injury of the vessel caused by balloon expansion, and the presence of the permanent stent implant. Although the underlying mechanisms of restenosis are at best only partially understood, there is evidence to suggest that early events such as activation and adhesion of platelets can have a profound effect on cellular proliferation and long-term re-narrowing of the artery. Release of platelet derived growth factor (PDGF) from activated platelets is known to promote smooth muscle cell proliferation and migration to the injury site; similarly, these cells will organise thrombus formation which will add to the growing mass of tissue at the site of the stenosis, and the combined effect is an over-exuberant healing response known as neointimal hyperplasia.

A number of strategies have been adopted in an effort to reduce both the acute thrombogenic potential of metallic stents and the stent-induced neointimal thickening [2]. Stent-based approaches include the attachment of anti-coagulants such as heparin [3] or use of radioactive stents [4] to reduce local cell proliferation. Simply coating stents with biocompatible polymers to mask the underlying thrombotic metal surface is yet another approach. Early studies on stents coated with a variety of biodegradable and biostable polymers showed marked inflammatory responses and subsequent neointimal thickening [5]. However, the concept of an optimally designed metallic stent covered with a biocompatible outer skin and further capable of delivering active agents for controlling adverse biological events remains an active area of interest for many in the field [6].

The development of a range of biomimetic phosphorylcholine (PC)-based polymers has been the focus of attention for us and others for some years [7]. The materials have shown great promise in clinical studies on a variety of devices including thoracic drain catheters [8], vascular grafts [9] and dialysis membranes [10] and are indeed used commercially as haemocompatible coatings for coating guidewires [11] and extracorporeal circuit components (including oxygenators, heat exchangers and arterial filters) [12]. More recently we have described a cross-linkable PC polymer system with improved physical properties [13]. This material has also been shown to possess excellent haemocompatibility by a variety of both in vitro and in vivo techniques. These characteristics lend themselves to the application of this material as a biocompatible coating for stents. Furthermore, the coating can be loaded with a variety of different therapeutic agents that can be released locally at the site of the injury once the stent is implanted.

The BiodivYsio range of coronary stents are characterised by a combination of this PC-based coating with a unique stent design. This coated stent has enjoyed wide clinical acceptance with over 50,000 human implantations to date. Clinical data from these implants is supporting arguments not only for low instances of stent-related thrombosis but also improved restenosis rates, in particular for the narrow-diameter (small vessel, <3 mm) stents [14], [15], [16]. More recently, a drug-delivery version of the stent has been approved for use in Europe for active agents of up to 1.2 kDa molecular weight. Detailed mechanistic studies on the swelling kinetics and release of various entities from these coatings constitute the subject of several further articles in this series [17], [18], [19], [20]. This paper presents a review of some of the pre-clinical assessments that were performed to demonstrate the in vitro and in vivo safety and efficacy of the device. Additionally, we describe some previously unreported methods that have been used to study the stent pre- and post-implantation, in order to examine some of its effects on the surrounding tissue and to determine the stability of the PC-coating with a view to its potential to deliver actives for extended periods.

Section snippets

Materials

All stents used in this study were 15 or 28 mm BiodivYsio stents (Biocompatibles Ltd.). The stents were either bare metal (316L stainless steel, specially requested) or the standard commercial product that possesses the cross-linkable PC polymer coating.

Coating characterisation—staining procedure

A simple staining method was developed as a visual demonstration of the presence of the PC coating over the entire surface of the stent. Coated and uncoated stents were placed in a 200 ppm solution of Rhodamine 6G in water for 30 s, followed by two

Stent analysis pre-implantation

Characterisation of the cross-linked coating on the stent has proved to be challenging. The coating process involves the application of two consecutive ultrathin coatings which total less than 100 nm in thickness (see AFM results in the section on post-implantation studies). X-ray photoelectron spectroscopy (XPS) has so far proved to be of little value in the analysis of these coatings, at best only detecting an enhanced carbon content for the coated stent relative to an uncoated version (at% C

Discussion

A variety of analytical methods have shown that the BiodivYsio range of coronary stents possess a coating of phosphorylcholine-based polymer that masks the entirity of the underlying steel substrate. The staining of the coating using Rhodamine 6G is shown to be a useful and simple tool for visualising the presence of the coating on the stent; more complex surface analytical techniques such as XPS are of less value on these ultra-thin coatings, particularly for the detection of low abundance

Conclusions

The results discussed here provide evidence that the PC-coating on the BiodivYsio range of stents is biocompatible and does not compound the inflammatory reaction induced by PTCA and stent placement. For standard sized vessels of 3 mm or greater however, the bioinertness of the coating cannot in itself exert a profound influence over the complex series of biological processes that constitute restenosis.

Restenosis can be broadly divided into four phases which cover early, medium and long-term

Acknowledgments

Thanks to the Thoraxcenter, Erasmus University, Rotterdam, for endothelialisation and histology studies and the Mayo Clinic, Rochester, Minnesota for the long-term implant work. (BiodivYsio is a trademark of Biocompatibles Ltd. All rights reserved.)

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