HELical Biodegradable Photochemical(HELP)Stents for AVF Maturation

摘要 虽然动静脉瘘（AVF）是透析血管通路的首选模式，但超过50%的患者无法实现 “成熟”，因为它们没有形成足够的血流或直径来支持血液透析。这导致 在临床发病率和经济成本方面非常显著。在发病水平上，AVF成熟失败是由于 到（a）小血管（B）“不良”非层流血流动力学特征，可能导致更具攻击性 狭窄，由于内皮细胞功能障碍和（c）异常基线血管生物学由于尿毒症和 氧化应激 这个建议的中心假设是，放置一个螺旋生物降解光化学 AVF创建时的蚀刻（HELP）支架将（a）扩张小静脉（B）创建“良好”血流动力学 通过产生螺旋层流（c）具有未来优化“局部尿毒症血管”的潜力， 通过选定的涂层（药物、细胞或化学品），“生物学”，从而“帮助”AVF成熟。 我们计划通过一系列具体的目标来解决这个中心假设，这些目标集中在（a）制造 HELP支架具有优化的体外流动剖面（具体目标1 =工程目标）（B）证明 体内降解和毒性特征（具体目标2 =生物相容性和毒性目标）（c）体内证明 记录治疗效果的原理实验（流量和直径;具体目标3 =治疗 Aim）。 总之，对于促进AVF成熟的新疗法，显然存在巨大且未满足的临床需求 （目前还没有有效的治疗方法）。此外，创新的光化学技术 本建议书中所描述的方法适合于大规模生产和随后的规模经济。结果我们 我坚信HELP支架是一种重要的平台技术，可以改善患者的 以降低的成本获得更好的结果，从而为血液透析患者的护理增加整体价值。

ABSTRACT Although arteriovenous fistulae (AVFs) are the preferred mode of dialysis vascular access, over 50% fail to “mature”, in that they do not develop an adequate blood flow or diameter to support hemodialysis. This results in a very significant clinical morbidity and economic cost. At a pathogenetic level, AVF maturation failure is due to (a) small vessels (b) “bad” non-laminar hemodynamic profiles that likely result in a more aggressive stenosis, due to endothelial cell dysfunction and (c) abnormal baseline vascular biology due to uremia and oxidative stress. The central hypothesis for this proposal is that the placement of a HELical biodegradable Photochemically etched (HELP) stent at the time of AVF creation will (a) dilate small veins (b) create “good” hemodynamics through the generation of spiral laminar flow (c) have the future potential to optimize “local uremic vascular biology” through selected coatings (drugs, cells or chemicals), and so “help” with AVF maturation. We plan to address this central hypothesis through a series of specific aims that focus on (a) fabrication of HELP stents that have an optimized flow profile in-vitro (Specific Aim 1 = Engineering Aim) (b) demonstration of in-vivo degradation and toxicity profiles (Specific Aim 2 = Biocompatibility and Toxicity Aim) (c) in-vivo proof of principle experiments to document therapeutic efficacy (flow and diameter; Specific Aim 3 = Therapeutic Aim). In summary, there is clearly a huge and unmet clinical need for novel therapies to enhance AVF maturation (there are currently no effective therapies for this). In addition, the innovative photochemical technology described in this proposal lends itself to mass production and subsequent economies of scale. As a result we strongly believe that the HELP stent is an important platform technology that could deliver improved patient outcomes at reduced cost, thus adding overall value to the care of hemodialysis patients.