Nanocomposite drug eluting stents for inhibition of restenosis and thrombosis

 描述（由申请人提供）：目前的药物洗脱支架极易形成血凝块（晚期支架血栓形成），导致心脏病发作和死亡风险显著增加。晚期支架血栓形成的风险增加是由于使用抗增殖药物损害内皮化，使血液暴露于血栓形成的支架支柱。此外，用于促进药物释放的聚合物也可导致延迟愈合、支架支柱内皮化受损和可导致支架血栓形成的超敏反应。使用不可降解支架材料也会增加血栓形成，导致慢性炎症局部反应和长期内皮功能障碍。尽管存在这些问题，研究人员继续研究从可降解和不可降解支架中递送抗增殖药物。考虑到目前药物洗脱支架死亡风险的增加，迫切需要开发一种新型的可生物降解支架， 再狭窄以及目前的药物洗脱支架，而且还抑制血栓形成，加速再内皮化，并完全生物降解以持久防止血栓形成。本提案的目的是使用血液相容性聚合物制造和表征可生物降解的纳米复合材料药物洗脱支架，该聚合物可抑制血栓形成，并可递送已显示可抑制再狭窄同时促进内皮化的天然分子。本项目的第一部分是制备和表征纳米复合药物洗脱支架。支架将通过将弹性体聚合物与刚性纳米纤维聚合物组合来制造，以制造具有与现有聚合物支架相似的机械性能的纳米复合材料支架。将通过高效液相色谱法测量药物释放动力学。将通过压缩试验和支架塌陷压力表征机械性能。将通过测量在磷酸盐缓冲盐水中浸泡后的质量变化来评估降解特性。我们还将通过检查血小板粘附、全血凝固时间和血流下血栓形成来评估这些支架的血液相容性。释放的药物对血管细胞增殖、迁移、蛋白质表达和细胞增殖的影响。 将表征流动下的保留。在目标2和3中，将在猪动物模型中对支架进行试验。该项目的成功完成将证明我们的概念的可行性。新型支架的开发将是重要的，因为它将是第一种可生物降解的药物洗脱支架，其可以特异性地抑制由于新生内膜增生引起的再狭窄，而不抑制再内皮化，因此显著降低或消除支架血栓形成、心脏病发作和死亡的风险。这种支架的开发有可能减少重复血管介入的次数，降低死亡率，并显着降低医疗成本。此外，在该提案中获得的信息也可用于开发改进的血管装置，这些血管装置也容易发生闭塞和凝块形成。

 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.