Nanocomposite drug eluting stents for inhibition of restenosis and thrombosis



 DESCRIPTION (provided by applicant): Current drug eluting stents are highly susceptible to blood clots forming (late stent thrombosis) leading to significantly increased risk of heart attack and death. The increased risk of late stent thrombosis is caused by the use of anti-proliferative drugs that impair endothelialization so that blood is exposed to thrombogenic stent struts. Furthermore, the polymers used to facilitate drug release can also cause delayed healing, impaired stent strut endothelialization, and hypersensitivity reaction that can culminate in stent thrombosis. Thrombosis is also increased by the use of non-degradable stent materials that results in chronic inflammatory local reactions and long-term endothelial dysfunction. Despite these problems, researchers continue to study the delivery of antiproliferative drugs from both degradable and non-degradable stents. Given the increased risk of death with current drug eluting stents, there is a critical need to develop a new type of biodegradable stent that inhibits restenosis as well as current drug eluting stents, but also inhibits thrombosis, accelerates re- endothelialization, and biodegrades completely for lasting clot prevention. The objective of this proposal is to fabricate and characterize a biodegradable nanocomposite drug eluting stent using a polymer that is hemocompatible, can inhibit thrombosis, and can deliver a naturally occurring molecule that has been shown to inhibit restenosis while promoting endothelialization. The first part of this project is to fabricate and characterize nanocomposite drug eluting stents. Stents will be made by combining an elastomeric polymer with a rigid nanofibrous polymer in order to fabricate nanocomposite stents with mechanical properties similar to existing polymeric stents. Drug release kinetics will be measured via high performance liquid chromatography. Mechanical properties will be characterized via compression testing and collapsed stent pressure. Degradation properties will be assessed by measuring the change in mass after soaking in phosphate buffered saline. We will also assess the hemocompatibility of these stents by examining platelet adhesion, whole blood clotting times, and thrombus formation under flow. The effect of the released drugs on vascular cell proliferation, migration, protein expression, and retention under flow will be characterized. In aims 2 and 3, stents will be tested in a porcine animal model. Successful completion of this project will demonstrate feasibility of our concept. Development of a new type of stent would be significant because it would be the first biodegradable drug eluting stent that can specifically inhibit restenosis due to neointimal hyperplasia without inhibiting re-endothelialization and therefore significantly reducing or eliminating the risk of stent thrombosis, heart attack, and death. Development of such a stent has the potential to reduce the number of repeat vascular interventions, decrease mortality rates, and significantly reduce healthcare costs. Furthermore, the information gained in this proposal could also be used to develop improved vascular devices that also are susceptible to occlusion and clot formation.