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

摘要 支架是在动脉狭窄的经皮治疗中植入的。然而，限制和 尚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。裸金属支架(BMS) 支架植入期间血管损伤导致的新生内膜增生仍然限制了部署， 导致支架内再狭窄。为了减少再狭窄，一种涂有抗增殖剂的药物洗脱支架(DES) 和/或针对新生内膜增生的免疫抑制药物已经开发出来。然而，最近 研究表明，临床使用的西罗莫司及其类似物治疗DES会导致严重的不良反应 影响包括：1)内皮损伤，延迟再内皮化，功能受损；2) 对提供西罗莫司的聚合物涂层的炎症反应。 支架行业的另一个主要问题是，无论有无健康动物模型研究的结果 球囊损伤不能充分预测在大量患者中使用支架时发现的问题。 因此，迫切需要开发一种用于支架涂层和支架评估的创新策略 动脉粥样硬化模型，以解决1)临床剂量西罗莫司的不良反应和2)“过于乐观” 在健康兔模型中评估支架时的发现。 我们成功地开发出释放一氧化氮(NO)的促愈合多功能内皮细胞- 模仿纳米支架涂层，能够提供天然的化学和生物学特性 血管内皮细胞在体外、体外和球囊损伤的健康兔髂动脉模型中得到证实。值得注意的是， 我们最近发现，NO具有显著的挽救内皮细胞增殖和迁移的潜力 西罗莫司协同抑制血管细胞增殖的不良反应。 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。 在特定的目标中促进纳米基质的形成1。我们还将开发新型的工程化动脉瓣， 动脉粥样硬化特征(EASA)的特异性研究2.NO和西罗莫司双重作用的疗效 修复纳米基质与商用BMS和DES的比较将在动脉粥样硬化下进行评估 条件用EASA在特定目的2和在高脂饮食兔模型中的特定目的3。 如果成功，这一新的策略，结合了NO和西罗莫司的独特功能，将通过 克服了目前BMS和DES的局限性，并随着体外和体内改进的发展 支架评估的模型。

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.