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

延长一氧化氮输送装置以减少/预防隧道式透析导管感染

• 批准号: 9909443
• 负责人: Alexander Keith Wolf
• 金额: $ 22.49万
• 依托单位: NOTA LABORATORIES, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909443
• 关键词: Acetylcysteine; Adhesions; Aftercare; Antibiotics; Anticoagulants; Antiviral Agents; Area; Ascorbic Acid; Bacteremia; Bacteria; Bacterial Counts; Bioreactors; Blood; Caliber; Catheters; Cell Count; Cellulose; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Chemistry; Chronic; Clinical Trials; Closure by clamp; Coagulation Process; Collaborations; Cysteine; Devices; Dialysis patients; Dialysis procedure; Diffuse; Disinfectants; Disinfection; Distal; End stage renal failure; Esters; Exhibits; Failure; Fibrin; Fibrinolytic Agents; Fistula; Fluorescent Dyes; Formulation; Frequencies; Functional disorder; Gases; General Population; Glutathione; Health; Hemodialysis; Hospitalization; Hydration status; Infection; Inhalation; Kidney Failure; Kinetics; Laboratories; Length; Measures; Medical; Michigan; Microbial Biofilms; Modeling; Molecular Weight; Nitric Oxide; Operative Surgical Procedures; Patients; Penicillamine; Permeability; Phase; Platelet Activation; Play; Polyethylene Glycols; Polymers; Polyurethanes; Polyvinyl Alcohol; Property; Pseudomonas aeruginosa; Reagent; Research; Role; S-Nitrosothiols; S-nitro-N-acetylpenicillamine; Saline; Sepsis; Shunt Device; Silicone Elastomers; Slide; Stainless Steel; Stains; Staphylococcus aureus; Stenosis; Stream; Surface; Testing; Therapeutic; Thrombosis; Thrombus; Time; Treatment Cost; Tube; United States; Variant; Vasodilation; Venous; Water; Wound Healing; Zinc Oxide; antimicrobial; aqueous; bactericide; cardiovascular infection; cardiovascular risk factor; cost; crystallinity; density; design; experimental study; follow-up; hydrophilicity; imaging modality; improved; macrophage; microbicide; mortality; natural antimicrobial; neonatal pulmonary hypertension; neurotransmission; neutrophil; particle; prevent; prospective; treatment duration

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.

抽象的 一氧化氮 (NO) 在多种身体功能中发挥着关键作用，包括血管舒张、 神经传递、伤口愈合、抑制血小板活化和调节纤毛跳动频率。 此外，吸入气相NO现在常规用于治疗新生儿肺动脉高压。在感染过程中， 中性粒细胞和巨噬细胞释放的 NO 可作为有效的抗菌/抗病毒剂，且 nM 较低 高浓度的 NO 可有效分散多种细菌菌株形成的生物膜。最近的临床试验 已证明其在治疗多种呼吸道感染方面的益处。相比之下，传统抗生素表现出 当在导管锁内使用时，对已建立的细菌菌落（即生物膜）的功效降低 它们不能缓解其他导管功能障碍问题，包括与以下相关的血栓并发症 沿导管外表面的血小板活化。因此，抗菌和抗血栓联合治疗 NO 的特性使其成为预防导管相关血流感染 (CRBSI) 和 使用隧道式透析导管（TDC）的终末期肾病（ESRD）患者的血栓并发症。 最近，研究表明，稳定形式的 NO、S-亚硝基硫醇 (RSNO) 是一种便捷的方法 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 化学来开发两种相关的一次性插入装置 与 TDC 一起使用的变体能够在 3-4 天内释放大量 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，位于夹钳（中心区域）上方 TDC，在最容易细菌侵入的导管区域提供杀菌水平的 NO。第二个 产品变体将是一个更长的插入物，它将延伸到远端并通过整个 TDC 的长度。这些装置将由适当的窄直径聚合物管组成，其中填充有 可水合基质中的RSNO。每次透析结束后，TDC 的管腔将充满盐水 锁定溶液，装置将被插入两个管腔中，它们将自发地产生 NO，直到 下一次透析疗程，通常为 3 天。如果 TDC 由 NO 渗透性材料组成，则纤维蛋白鞘 TDC 外表面上的形成也应受到抑制。第一阶段研究将重点关注三个方面 目标：1) 确定最佳 RSNO 化学物质和管道来制造该设备； 2）评估NO释放量 双腔医疗级 TDC 管内的插入件； 3) 证明抗菌活性 TDC 导管内表面和外表面上经过优化的消毒插件。