Preclinical Investigation of a Bioengineered Vascular Graft

描述（由申请人提供）：在美国，由于动脉粥样硬化引起的血管阻塞是死亡和发病的主要原因之一，导致每年600，000例血管置换或血管重建手术，花费超过10亿美元。不幸的是，对于多达三分之一的患者来说，自体移植物通常不是一种选择，并且用于替换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具有高失败率。该提案将研究一种生物工程方法，以改善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价内皮祖细胞（EPC）衍生的生物工程ePTFE移植物是否适用于确诊外周动脉疾病（PAD）的患者，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，我们将研究使用吡格列酮（一种过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂）作为增加EPC集落形成和细胞增殖的新策略，因为据报道PAD患者的EPC数量减少，功能受损。在该提案的临床前试验期间，我们将开发细胞分离和细胞接种方案，这些方案可以很容易地适用于医院环境。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活细胞来源，以及2.评价生物工程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，该提案中采取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，以设计一项临床试验，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.