Dual action nanomatrix coated stent evaluation using engineered artery sheets with atherosclerotic features

使用具有动脉粥样硬化特征的工程动脉片材进行双作用纳米基质涂层支架评估

基本信息

批准号：
10591611
负责人：
Ho-Wook Jun
金额：
$ 59.55万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591611
关键词：
Address Adolescent Adverse effects Animal Model Apoptosis Arteries Atherosclerosis Biochemical Pathway Biological Bioreactors Blood Vessels Cardiovascular Diseases Cardiovascular system Cell Proliferation Cell physiology Cells Chemicals Clinical Development Dose Encapsulated Endothelial Cells Endothelium Engineering Environment Evaluation Exhibits Fibroblasts Foam Cells Formulation Goals High Fat Diet Hyperplasia Immunosuppressive Agents Impairment Implant In Vitro Industry Inflammation Inflammatory Response Injury Legal patent Liposomes Metals Modeling Nitric Oxide Oryctolagus cuniculus Outcome Patients Performance Pharmaceutical Preparations Physiological Polymers Proliferating Property Protocols documentation Safety Sirolimus Smooth Muscle Smooth Muscle Myocytes Stents Structure Study models analog antiproliferative agents cell motility clinical effect efficacy evaluation endothelial dysfunction healing high risk human model iliac artery implantable device implantation improved in vitro Model in vivo in vivo Model injured innovation migration nano novel novel strategies peptide amphiphiles porcine model pre-clinical public health relevance response restenosis stent thrombosis targeted agent vascular injury

项目摘要

Abstract Stents are implanted during the percutaneous treatment of narrowed arteries. However, limitations and unresolved questions remain how to achieve optimal stent patency and safety. Bare metal stent (BMS) deployment remains limited by neointimal hyperplasia caused by vascular injury during stent implantation, leading to in-stent restenosis. To reduce restenosis, a drug-eluting stents (DES), coated with anti-proliferative and/or immuno-suppressive agents targeting neointimal hyperplasia, have been developed. However, recent studies have revealed that the clinically used dose of sirolimus and its analogues for DES cause serious adverse effects including 1) damage to the endothelium that delays re-endothelialization with impaired functions, and 2) inflammation in response to the polymer coating that delivers sirolimus. Another major issue in the stent industry is that outcomes from healthy animal model studies with or without balloon injury do not adequately predict problems found when stents are used in a large number of patients. Thus, there is a critical need to develop an innovative strategy for stent coating and stent evaluation in an atherosclerosis model in order to address 1) adverse effects of clinical dose of sirolimus and 2) “overly optimistic” findings when evaluating stents in a healthy rabbit model. We have successfully developed the nitric oxide (NO) releasing prohealing multifunctional endothelium- mimicking nanomatrix stent coating capable of providing the chemical and biological properties of the native endothelium as demonstrated in vitro, ex vivo, and in a balloon injury healthy rabbit iliac artery model. Notably, we recently found that NO has significant potential to salvage endothelial cell proliferation and migration from the adverse effects of sirolimus while synergistically suppressing smooth muscle cell proliferation. Therefore, we will develop the dual action NO and low-dose liposome-encapsulated sirolimus releasing prohealing nanomatrix in Specific Aim 1. We will also develop novel Engineered Artery Sheets with Atherosclerotic features (eASA) in Specific Aim 2. The efficacy of the dual action NO and sirolimus releasing prohealing nanomatrix compared with commercial BMS and DES will be evaluated under atherosclerotic conditions using the eASA in Specific Aim 2 and in a high fat diet rabbit model in Specific Aim 3. If successful, this novel strategy, combining the unique features of NO and sirolimus will advance the field by overcoming the current limitations of BMS and DES, and with the development of improved in vitro and in vivo models for stent evaluation.

抽象的在狭窄动脉的经皮治疗过程中植入支架然而，其局限性和局限性。未解决的问题仍然是如何实现最佳的支架通畅性和安全性。支架植入期间血管损伤引起的新内膜增生仍然限制部署，导致支架内再狭窄为了减少再狭窄，采用了涂有抗增殖药物的药物洗脱支架 (DES)。然而，最近已经开发出针对新内膜增生的免疫抑制剂。研究表明西罗莫司及其类似物用于DES的临床使用剂量会造成严重的不良反应影响包括 1) 内皮损伤，延迟再内皮化并导致功能受损，以及 2) 递送西罗莫司的聚合物涂层引起的炎症。支架行业的另一个主要问题是健康动物模型研究的结果，有或没有球囊损伤并不能充分预测在大量患者中使用支架时发现的问题。因此，迫切需要开发一种创新的支架涂层和支架评估策略动脉粥样硬化模型，以解决 1) 西罗莫司临床剂量的不良影响和 2) “过于乐观” 在健康兔子模型中评估支架时的发现。我们成功开发了释放一氧化氮（NO）的促愈合多功能内皮细胞- 模仿纳米基质支架涂层，能够提供天然的化学和生物特性值得注意的是，体外、离体和球囊损伤健康兔髂动脉模型中的内皮细胞。我们最近发现NO具有挽救内皮细胞增殖和迁移的巨大潜力西罗莫司的副作用，同时协同抑制平滑肌细胞增殖。因此，我们将开发双重作用的NO和低剂量脂质体包裹的西罗莫司释放剂具体目标 1 中的促愈合纳米基质。我们还将开发新型工程动脉片具体目标 2 中的动脉粥样硬化特征 (eASA)。双重作用 NO 和西罗莫司释放的功效将在动脉粥样硬化下评估促愈合纳米基质与商业 BMS 和 DES 的比较在特定目标 2 中使用 eASA 的条件以及在特定目标 3 中使用高脂肪饮食兔子模型的条件。如果成功，这一新颖的策略结合了 NO 和西罗莫司的独特功能，将推动该领域的发展克服了BMS和DES目前的局限性，并随着体外和体内改进的发展支架评估模型。