Reducing Tunneled Dialysis Catheter Dysfunction through Nitric Oxide Release

描述（由申请人提供）：隧道透析导管（TDC）是透析血管通路的重要模式。80%的透析患者开始血液透析时发生TDC，美国的总体患病率约为25%。不幸的是，TDC具有感染、血栓形成和中心静脉狭窄的巨大问题，这导致非常显著的发病率、死亡率和经济成本。尽管临床问题的严重性，然而，没有有效的治疗TDC功能障碍。一氧化氮（Nitric oxide，NO）是一种重要的生物介质，具有抗菌、抗血小板聚集、抗平滑肌细胞增殖等作用，可减少TDC并发症的发生。我们之前已经开发了一种新颖的创新技术，以电化学方式调节NO释放（在导管腔内）;其中嵌入亚硝酸盐溶液中的铜电极能够在长时间内产生NO（通过Cu离子和亚硝酸盐之间的相互作用）。该提议的中心假设是，从TDC内的管腔电化学调节的NO释放可以靶向与TDC使用相关的所有三种主要并发症（感染、血栓形成和中心静脉狭窄）;从而显著降低与TDC使用相关的巨大发病率、死亡率和经济成本。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）具有生物活性的电化学调节的NO释放系统的开发和验证（在TDC内腔内）（B）在猪模型中用释放NO的TDC在体内减少感染、血栓形成和中心静脉狭窄。我们认为，对于减少TDC功能障碍的新疗法存在巨大的未满足的临床需求，并且认为释放NO的TDC的概念可以显著降低与该棘手问题相关的巨大的临床发病率和经济成本。

DESCRIPTION (provided by applicant): Tunneled Dialysis Catheters (TDCs) are an important mode of dialysis vascular access. 80% of incident dialysis patients begin hemodialysis with a TDC and the overall prevalence in the US is approximately 25%. Unfortunately, TDCs have huge problems with infection, thrombosis and central venous stenosis, which results in a very significant morbidity, mortality and economic cost. Despite the magnitude of the clinical problem, however, there are no effective therapies for TDC dysfunction. Nitric oxide (NO) is an important biological mediator, which has potent anti-bacterial, anti-platelet aggregation and anti-smooth muscle cell proliferation activities, which could potentially reduce TDC complications. We have previously developed a novel and innovative technology, to electrochemically modulate NO release (within a catheter lumen); in which a copper electrode embedded in a nitrite solution is able to generate NO (through the interaction between Cu ions and nitrite) over a prolonged period of time. The central hypothesis of this proposal, is that the electrochemically modulated release of NO from a lumen within a TDC could target all three major complications associated with TDC use (infection, thrombosis and central vein stenosis); thus significantly reducing the huge morbidity, mortality and economic cost associated with TDC use. We plan to address this central hypothesis through a series of specific aims that focus on (a) the development and validation (within a TDC lumen) of an electrochemically modulated NO release system with biological activity (b) reducing infection, thrombosis and central vein stenosis with NO releasing TDCs in-vivo, in a pig model. We believe that there is a huge unmet clinical need for novel therapies that reduce TDC dysfunction and feel that the concept of NO releasing TDCs could significantly reduce the huge clinical morbidity and economic cost associated with this intractable problem.