Preclinical Investigation of a Bioengineered Vascular Graft

描述（由申请人提供）：动脉粥样硬化引起的血管阻塞是美国死亡率和发病率的主要原因之一，每年导致60万例血管置换或血管重建术，费用超过10亿美元。不幸的是，多达三分之一的患者往往不能选择自体移植物，而用于替代小直径血管的合成移植物由于血栓形成和新生内膜增生而失败率很高。本提案将研究一种生物工程方法来提高合成移植物的功能和安全性，特别是膨胀聚四氟乙烯（ePTFE）。本提案的总体目标是评估内皮祖细胞（EPC）衍生的生物工程ePTFE移植物是否适用于确诊的外周动脉疾病（PAD）患者，并在大型动物模型中研究生物工程移植物的安全性和有效性。特别是，我们将研究吡格列酮，一种过氧化物酶体增殖物激活受体γ (PPAR-γ)激动剂，作为一种增加EPC集落形成和细胞增殖的新策略，因为有报道称PAD患者的EPC数量减少并功能受损。在该建议的临床前试验期间，我们将开发细胞分离和细胞播种方案，可以很容易地适应在医院环境中使用。具体目标是：1。评估来自PAD患者的循环EPCs是否是基于细胞的生物工程血管移植物的可行细胞来源；评估生物工程ePTFE移植物在动脉粥样硬化猪颈动脉ePTFE旁路模型中的安全性和有效性。鉴于动脉粥样硬化和外周动脉疾病的广泛性，该提案中采用的创新方法有望直接改善数百万美国人的患者护理。这项建议将使我们能够收集必要的专业知识和数据来设计临床试验，以评估生物工程移植物的早期疗效。

DESCRIPTION (provided by applicant): Blockage of blood vessels due to atherosclerosis is one of the main causes of mortality and morbidity in the United States resulting in 600,000 blood vessel replacement or revascularization procedures each year at a cost of over 1 billion dollars. Unfortunately, autologous grafts are often not an option for as many as one third of patients and synthetic grafts used to replace small-diameter blood vessels have high rates of failure due to thrombosis and neointimal hyperplasia. This proposal will investigate a bioengineering approach to improve the function and safety of synthetic grafts, specifically expanded polytetrafluoroethylene (ePTFE). The overall goal of this proposal is to evaluate whether an endothelial progenitor cells (EPC)-derived bioengineered ePTFE graft is feasible for patients with confirmed peripheral arterial disease (PAD) and to investigate the safety and efficacy of bioengineered grafts in a large animal model. In particular, we will investigate the use of pioglitazone, a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, as a novel strategy to increase EPC colony formation and cell proliferation as patients with PAD have been reported to have reduced EPC numbers with impaired function. During the pre-clinical trials of this proposal we will develop cell isolation and cell-seeding protocols that can be readily adapted for use in the hospital setting. The specific aims are to: 1. assess whether circulating EPCs from patients with PAD are a viable cell source for a cell-based bioengineered vascular graft, and 2. evaluate the safety and efficacy of the bioengineered ePTFE grafts in an atherosclerotic swine carotid artery ePTFE bypass model. Given the widespread nature of atherosclerosis and peripheral artery disease, the innovative approach taken in this proposal is expected to directly improve patient care of millions of Americans. This proposal will allow us to gather the necessary expertise and data to design a clinical trial to assess early stage efficacy of the bioengineered grafts.