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; 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（由适用提供）：当前的药物洗脱支架非常容易受到血块形成（晚支架血栓形成）的影响，从而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于使用抗增殖药物会损害内皮化的抗增殖药物，从而使血液暴露于血栓形成支架上。此外，尽管存在这些问题，但用于促进药物释放的聚合物也可能引起，研究人员继续研究抗增殖药物从可降解和不可降解的支架中的递送。鉴于当前药物洗脱支架的死亡风险增加，因此需要开发一种新型的可生物降解支架，以抑制 再狭窄以及当前的药物洗脱支架，但也抑制血栓形成，加速重新内皮化并完全降解，以完全预防凝块。该提案的目的是使用具有血液相容的聚合物来捏造和表征可生物降解的纳米复合药物支架，可以抑制血栓形成，并可以提供自然存在的分子，该分子已被证明可以抑制再生一倍数的同时促进内皮化。该项目的第一部分是制造和表征纳米复合药物洗脱支架。将弹性聚合物与刚性纳米纤维聚合物组合在一起，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支架来制作支架。药物释放动力学将通过高性能液相色谱法测量。机械性能将通过压缩测试和支架压力折叠来表征。降解特性将通过测量磷酸盐缓冲盐水浸泡后的质量变化来评估。我们还将通过检查血小板粘附，全血液凝结时间和流动下的血栓形成来评估这些支架的血流相容性。释放药物对血管细胞增殖，迁移，蛋白质表达和 在流下的保留将被表征。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。新型支架的开发将是重要的，因为它将是第一个可生物降解的药物支架支架，可以特异性地抑制新的再狭窄，而不会抑制重新内皮化，因此可以显着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干预的数量，降低死亡率并大大降低医疗费用。此外，本提案中获得的信息也可用于开发改进的血管装置，这些器件也容易受到阻塞和凝块形成。