HELical Biodegradable Photochemical(HELP)Stents for AVF Maturation

摘要 尽管动静脉瘘(AVF)是透析血管通路的首选模式，但超过50%的人未能 “成熟”，因为它们不能形成足够的血流量或直径来支持血液透析。这将导致 在临床上有非常显著的发病率和经济成本。在致病水平上，aVF的成熟失败是由于 至(A)小血管(B)“不良”非层流血流动力学特征，可能导致更具侵袭性 狭窄，原因是内皮细胞功能障碍和(C)尿毒症和 氧化应激。 这一提议的中心假设是螺旋状生物可降解光化学物质的放置 在AVF创建时蚀刻的(辅助)支架将(A)扩张小血管(B)产生“良好的”血流动力学 通过产生螺旋层流(C)未来有潜力优化“局部尿毒症血管” 生物“通过选定的涂层(药物、细胞或化学品)，因此有助于AVF的成熟。 我们计划通过一系列具体目标来解决这一中心假设，这些目标集中在(A)捏造 体外流动曲线优化的HELP支架(特殊目标1=工程目标)(B)演示 体内降解和毒性特征(特定目标2=生物兼容性和毒性目标)(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 目标)。 综上所述，临床上对增强aVF成熟的新疗法的需求显然是巨大的，而且尚未得到满足。 (目前还没有有效的治疗方法。)此外，创新的光化学技术 这项提案中所描述的有助于大规模生产和随后的规模经济。因此，我们 坚信Help支架是一种重要的平台技术，可以改善患者的病情 以更低的成本获得结果，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.