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.

摘要 一氧化氮（NO）在广泛的身体功能中起关键作用，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搏动频率。 此外，吸入气相NO现在常规用于治疗新生儿肺动脉高压。在感染中， 由中性粒细胞和巨噬细胞释放的NO作为有效的抗微生物/抗病毒剂发挥作用，并且低nM 高浓度的NO有效地分散由多种细菌菌株形成的生物膜。最近的临床试验 已经证明了它在治疗各种呼吸道感染中的益处。相比之下，传统抗生素表现出 降低了对已建立的细菌菌落的效力，即，生物膜，并且当在导管锁内使用时 它们不能缓解其他导管功能障碍问题，包括与 血小板活化沿着导管的外表面。因此，抗微生物和抗血栓的组合 NO的特性使其成为预防导管相关血流感染（CRBSI）的理想候选物， 使用隧道透析导管（TDC）的终末期肾病（ESRD）患者的血栓并发症。 最近，已经表明，稳定形式的NO，S-亚硝基硫醇（RSNO），是一种方便的方法， 为这些医学应用中的一些递送治疗水平的NO。 NOTA实验室现在建议使用RSNO化学来开发两种相关的一次性插入器械 与TDC一起使用的变体能够释放显著的NO通量3-4天。一种器械变体 将是导管插入帽，其在管夹（座区域）上方浸泡体外部分， TDC，以在最易于细菌侵入的导管区域中递送杀菌水平的NO。第二 产品变体将是更长的插入物，其将延伸至远端头端并通过整个 TDC的长度。这些装置将由适当的窄直径聚合物管组成， RSNO在水合基质中。每次透析后，TDC内腔将充满生理盐水 封闭溶液和器械将插入两个管腔中，在那里它们将自发产生NO， 下一个透析疗程，通常为3天。如果TDC由NO可渗透材料、纤维蛋白鞘 TDC的外表面上的形成也应该被抑制。第一阶段的研究将集中在三个方面 目的：1）确定最佳的RSNO化学和管道，使装置; 2）评估NO释放 双腔医用级TDC管内的插入物;以及3）证明 TDC导管管路内外表面上的优化消毒插件。