Novel high-throughput polymer biocompatibility screening designed for SAR (structure-activity relationship): application for evaluating polymer coatings for cardiovascular drug-eluting stents.

The development of stents has been a major advancement over balloon angioplasty, improving vessel revascularization in obstructive coronary artery disease. The development of drug-eluting stents (DES) was the next breakthrough, designed to prevent the development of neointimal hyperplasia (restenosis) following percutaneous coronary interventions (PCI). Several DES are currently in various stages of clinical development; these DES use different stent platforms, different antiproliferative drugs and different polymeric coatings that carry the drugs and control their delivery kinetics. Following DES implantation, when the entire drug is released, the polymeric coating is still retained on the stent and can influence subsequent tissue response and vascular healing. Therefore, the biocompatibility of the polymeric coatings is an important component of DES safety and needs to be thoroughly evaluated. Here we describe the development of a high-throughput screening platform for the evaluation of polymer biocompatibility, assaying whether a polymeric coating triggers inflammation in vascular cells. The data generated by these assays provides a structure-activity relationship (SAR) that can guide polymer chemists in polymer design. We have also applied this methodology to evaluate the components of a novel polymer system (BioLinx polymer system) designed in-house. In addition, we assayed other polymeric coatings similar to those currently used on various DES. The results of this evaluation reveal a remarkable correlation between polymer hydrophobicity and its ability to provoke inflammatory response.

Impact of polymer hydrophilicity on biocompatibility: implication for DES polymer design.

Polymer coatings are essential for local delivery of drug from the stent platform. In designing a DES, it is critical to balance the hydrophilic and hydrophobic components of the polymer system to obtain optimal biocompatibility, while maintaining controlled drug elution. This study investigates the impact of polymer composition of the BioLinx polymer blend on in vitro biocompatibility, as measured by monocytic adhesion. Comparable evaluation was performed with polymers similar to those utilized in various DES that are currently being marketed. Relative hydrophilicities of polymer surfaces were determined through contact angle measurements and surface analyses. Polymer biocompatibility was evaluated in a novel in vitro assay system in which activated monocyte cells were exposed to polymer coated on 96-well plates. Enhanced monocyte adhesion was observed with polymers of a more hydrophobic nature, whereas those which were more hydrophilic did not induce activated monocyte adhesion. Our data supports the hypothesis that polymer composition is a feature that dictates in vitro biocompatibility as measured by monocyte driven inflammation. Monocyte adhesion has been shown to induce local inflammation as well as promote vascular cell proliferation factors contributing to in stent restenosis (Rogers et al., Arterioscler Thromb Vasc Biol 1996;16:1312-1318). Observed results suggest hydrophobic but not hydrophilic polymer surfaces support adhesion of activated monocytes to the polymer scaffold. The proprietary DES polymer blend BioLinx has a hydrophilic surface architecture and does not induce an inflammatory response as measured by these in vitro assays.

Development of a novel biocompatible polymer system for extended drug release in a next-generation drug-eluting stent.

Drug-eluting stents have proven superior to bare metal stents with lower restenosis rates. Local delivery of drugs from these stents is achieved in most cases with the help of biostable polymer coatings. However, since the polymer coating remains in the body well after all the drug is released, patients can potentially develop hypersensitivity to these polymers--leading to complications such as late-stent thrombosis. It is therefore important that the polymers are designed to be biocompatible and well tolerated by the body. The polymer coatings are also expected to be robust and provide good control over elution of the desired drug. This paper describes the development of a unique, proprietary polymer blend system, specially designed to meet these requirements. Mutually compatible, free-radical-initiated elastomeric polymers were designed to provide a robust coating and offer a steady, sustained release of the highly hydrophobic drug zotarolimus over an extended period. The polymer blend system is also well tolerated by the hydrophilic environment in vivo, as demonstrated through porcine studies.