Biodegradable Magensium Stents to Enhance AV Fistula Maturation

描述（由申请人提供）：尽管动静脉内瘘（AVF）是透析血管通路的首选模式，但超过50%未能"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。这导致非常显著的临床发病率和经济成本。在发病水平上，AVF成熟失败是由于（a）小血管（B）"不良"血流动力学，不允许释放血管扩张剂分子，如一氧化氮和（c）由于尿毒症和氧化应激导致的异常血管生物学。该提案的中心假设是，在动静脉瘘形成时放置可延展、涂层（药物/细胞/基因/化学品）、可生物降解的成熟促进支架（bMES）将（a）扩张小静脉（B）优化解剖结构，以改善血液动力学和（c）由于涂层药物而改善"局部"血管生物学。我们计划通过一系列具体目标来解决这一中心假设，重点是（a）bMES的体内降解特征和毒性（B）体内原理验证实验，以记录流量和直径方面的有效性。我们认为，对于可能促进动静脉瘘成熟的新疗法存在巨大的未满足的临床需求，如果成功，bMES的概念可以显著降低与动静脉瘘成熟失败相关的巨大临床发病率和经济成本。

DESCRIPTION (provided by applicant): 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" hemodynamics that do not allow for the release of vasodilator molecules such as nitric oxide and (c) abnormal vascular biology due to uremia and oxidative stress. The central hypothesis for this proposal is that the placement of a malleable, coated (drug/cell/gene/chemical), biodegradable maturation enhancing stent (bMES) at the time of AV fistula creation will (a) dilate small veins (b) optimize anatomical configuration in order to improve hemodynamics and (c) improve upon "local" vascular biology as a result of the coated agents. We plan to address this central hypothesis through a series of specific aims that focus on (a) in-vivo degradation profile and toxicity for the bMES (b) in-vivo proof of principle experiments to document efficacy with regard to flow and diameter. We believe that there is a huge unmet clinical need for novel therapies that might enhance AV fistula maturation and that if successful, the concept of bMES could significantly reduce the huge clinical morbidity and economic cost associated with AVF maturation failure.