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

摘要 在狭窄动脉的经皮治疗过程中植入支架。然而，局限性和 如何获得最佳的支架开放性和安全性仍然是未解决的问题。裸金属支架（BMS） 展开仍然受到支架植入过程中血管损伤引起的新生内膜增生的限制， 导致支架内再狭窄。为了减少再狭窄，药物洗脱支架（DES），涂有抗增殖剂， 和/或靶向新生内膜增生的免疫抑制剂。但最近的 研究表明，临床上用于DES的西罗莫司及其类似物的剂量引起严重的不良反应， 影响包括1）内皮损伤，延迟功能受损的再内皮化，和2） 炎症反应的聚合物涂层提供西罗莫司。 支架行业的另一个主要问题是， 球囊损伤不能充分预测支架用于大量患者时发现的问题。 因此，迫切需要开发一种用于支架涂层和支架评价的创新策略， 动脉粥样硬化模型，以解决1）西罗莫司临床剂量的副作用和2）“过于乐观” 在健康家兔模型中评价支架时的发现。 我们已经成功地开发了释放一氧化氮（NO）的促愈合多功能内皮细胞- 模拟纳米基质支架涂层能够提供天然支架的化学和生物学性质， 在体外、离体和在球囊损伤健康兔髂动脉模型中证实的内皮细胞。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， 西罗莫司的副作用，同时协同抑制平滑肌细胞增殖。 因此，我们将开发一氧化氮和小剂量西罗莫司脂质体释放的双重作用， 具体目标1中的愈合前纳米基质。我们还将开发新的工程动脉片， 具体目标2中的动脉粥样硬化特征（eASA）。一氧化氮和西罗莫司双重作用释放的效果 与市售BMS和DES相比，将在动脉粥样硬化 在特定目标2中使用eASA的条件和在特定目标3中在高脂肪饮食兔模型中的条件。 如果成功，这种结合NO和西罗莫司独特功能的新策略将通过以下方式推进该领域： 克服了BMS和DES目前的局限性，并且随着体外和体内改良的药物的发展， 支架评估模型。

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.