Nanocomposite drug eluting stents for inhibition of restenosis and thrombosis

用于抑制再狭窄和血栓形成的纳米复合药物洗脱支架

• 批准号: 9217674
• 负责人: Josephine Allen
• 金额: $ 36.31万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217674
• 关键词: Adhesions; Animal Model; Blood; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Cardiovascular system; Cause of Death; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chronic; Citrates; Coagulation Process; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Development; Devices; Elastomers; Endothelial Cells; Family suidae; Goals; Health Care Costs; High Pressure Liquid Chromatography; Hyperplasia; Hypersensitivity; Impaired wound healing; Impairment; In Vitro; Inflammation; Inflammatory; Intervention; Kinetics; Lead; Measures; Mechanics; Medical Device; Modeling; Myocardial Infarction; Patient Care; Pharmaceutical Preparations; Phosphate Buffer; Physiological; Polymers; Prevention; Property; Psychological reinforcement; Rattus; Reaction; Research; Research Personnel; Risk; SDZ RAD; Safety; Saline; Sirolimus; Smooth Muscle Myocytes; Stents; Sterility; Testing; Thrombosis; Thrombus; Time; Tretinoin; United States; Vascular Diseases; Vascular Graft; Whole Blood; Work; antiproliferative drugs; base; biomaterial compatibility; cell growth; combat; elastomeric; endothelial dysfunction; expectation; flexibility; improved; mechanical properties; migration; mortality; nanocomposite; nanofiber; novel; pressure; prevent; protein expression; public health relevance; restenosis; skills; stent thrombosis; tetrafluoroethylene

 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.

 描述（由申请人提供）：目前的药物洗脱支架非常容易形成血栓（晚期支架血栓形成），导致心脏病发作和死亡的风险显着增加。晚期支架血栓形成的风险增加是由抗增殖药物的使用引起的。此外，用于促进药物释放的聚合物也会导致愈合延迟、支架支柱受损。内皮化和过敏反应最终导致支架血栓形成。使用不可降解的支架材料也会增加血栓形成，从而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，但研究人员仍在继续研究支架内血栓的传递。鉴于现有药物洗脱支架的死亡风险增加，迫切需要开发一种新型支架。可生物降解的支架可抑制 与目前的药物洗脱支架一样，它还可以抑制血栓形成，加速再内皮化，并完全生物降解以实现持久的血栓预防。本提案的目的是使用血液相容性聚合物制造并表征可生物降解的纳米复合材料药物洗脱支架。可以抑制血栓形成，并可以传递一种天然存在的分子，该分子已被证明可以抑制再狭窄，同时促进内皮化。制造和表征纳米复合材料药物洗脱支架将通过将弹性聚合物与刚性纳米纤维聚合物相结合来制造，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，并通过高效液相色谱法测量药物释放动力学。我们将通过压缩测试来表征性能，并通过测量浸泡在磷酸盐缓冲盐水中后的质量变化来评估降解性能。还通过检查血小板粘附、全血凝固时间和流动下血栓形成来评估这些支架的血液相容性，以及释放的药物对血管细胞增殖、迁移、蛋白质表达和血流的影响。 在目标 2 和 3 中，支架将在猪动物模型中进行测试，该项目的成功完成将证明我们的概念的可行性，因为它将是一种新型支架。第一个可生物降解的药物洗脱支架，可以特异性抑制内膜增生引起的再狭窄，而不抑制再内皮化，从而显着降低或消除支架血栓、心脏病和死亡的风险。这种支架的设计有可能减少重复血管介入的次数，降低死亡率，并显着降低医疗费用。此外，该提案中获得的信息还可用于开发也易于闭塞和堵塞的改进血管装置。凝块形成。