Extended Nitric Oxide Delivery Device to Reduce/Prevent Tunneled Dialysis Catheter Infections

摘要 一氧化氮(NO)在广泛的身体功能中发挥着关键作用，包括血管扩张， 神经传递、伤口愈合、抑制血小板活化和纤毛搏动频率的调节。 此外，吸入气相NO现在被常规用于治疗新生儿肺动脉高压。在感染方面， 中性粒细胞和巨噬细胞释放的NO是一种有效的抗菌/抗病毒药物，并且低NM 浓度的NO能有效分散多种细菌所形成的生物膜。最近的临床试验 已经证明了它在治疗各种呼吸道感染方面的好处。相比之下，传统的抗生素展示了 当在导管锁内使用时，对已建立的细菌菌落，即生物膜的疗效降低 解决方案它们不能缓解其他导管功能障碍问题，包括与 沿导管外表面的血小板活化。因此，抗菌剂和抗血栓药的组合 NO的特性使其成为预防导管相关血流感染(CRBSI)和 隧道透析管(TDC)治疗终末期肾病(ESRD)患者的血栓并发症。 最近，有研究表明，稳定形式的NO，S-亚硝硫醇(RSNO)是一种简便的方法 为其中一些医疗应用提供治疗水平的NO。 NOTA实验室现在提议使用RSNO化学来开发两个相关的一次性插入装置 与TDC一起使用的变种，能够在3-4天内释放显著的NO通量。一种设备变体 将是一个导管插入帽，用于沐浴体外部分，位于夹紧夹(轮毂区域)上方 TDC，在最容易受到细菌入侵的导管区域提供杀菌水平的NO。第二 产品变体将是一个更长的插入件，该插入件将延伸到远端尖端并通过整个 贸发局的长度。这些装置将由适当的窄直径聚合管组成，管内填充有 水合基质中的RSNO。每次透析后，TDC的管腔将注入生理盐水。 锁定溶液，装置将被插入两个管腔，在那里它们将自发产生NO，直到 下一次透析会议，通常为3天。如果TDC是由不透水的材料组成的，纤维蛋白鞘 也应抑制贸发局外表面的形成。第一阶段的研究将集中在三个方面 目的：1)确定制造该装置的最佳RSNO化学成分和管材；2)评估NO的释放 双腔医用TDC管内的插入物；以及3)展示了 优化了TDC导尿管内外表面的消毒嵌件。

ABSTRACT Nitric oxide (NO) plays a critical role in a wide range of bodily functions, including vasodilation, neurotransmission, wound healing, suppression of platelet activation, and modulation of ciliary beat frequency. Further, inhaled gas phase NO is now routinely used to treat neonatal pulmonary hypertension. In infection, NO released by neutrophils and macrophages functions as a potent antimicrobial/antiviral agent, and low nM concentrations of NO efficiently disperse biofilm formed by a variety of bacterial strains. Recent clinical trials have demonstrated its benefit in treating a variety of airway infections. In contrast, traditional antibiotics exhibit reduced efficacy against established bacteria colonies, i.e., biofilms, and when used within a catheter lock solution they do not mitigate other catheter dysfunction problems, including thrombotic complications related to platelet activation along the outer surface of the catheter. Thus, the combined antimicrobial and antithrombotic properties of NO make it an ideal candidate to prevent catheter-related blood stream infections (CRBSI) and thrombotic complications for end stage renal disease (ESRD) patients with tunneled dialysis catheters (TDCs). Recently, it has been shown that stabilized forms of NO, S-nitrosothiols (RSNOs), are a convenient way to deliver therapeutic levels of NO for some of these medical applications. NOTA Laboratories now proposes to use RSNO chemistry to develop two related disposable insert device variants for use with TDCs that are capable of releasing significant NO fluxes for 3-4 days. One device variant would be a catheter insert cap that bathes the extracorporeal portion, above the pinch clamp (the hub area) of a TDC, to deliver bactericidal levels of NO in the catheter region most prone to bacterial intrusion. The second product variant would be a longer insert that would extend to the distal tip and release NO through the entire length of the TDC. These devices would consist of an appropriate narrow diameter polymeric tube packed with the RSNO in a hydratable matrix. After each dialysis session the lumens of the TDC will be filled with saline lock solution and the devices will be inserted into both lumens where they will spontaneously generate NO until the next dialysis session, typically 3 days. If the TDC is composed of a NO permeable material, fibrin sheath formation on the outer surface of the TDC should also be suppressed. Phase I research will focus on three aims: 1) identifying the optimal RSNO chemistry and tubing to make the device; 2) evaluating the NO release of the inserts within dual-lumen medical-grade TDC tubing; and 3) demonstrating the antimicrobial activity of optimized disinfection inserts on the inner and outer surfaces of TDC catheter tubing.