Bactericidal, Nonthrombogenic Intravascular Catheters

杀菌、不形成血栓的血管内导管

• 批准号: 9316710
• 负责人: Robert H. Bartlett
• 金额: $ 71.78万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316710
• 关键词: Adhesions; Adverse effects; Animal Experiments; Animal Model; Animal Testing; Anti-Bacterial Agents; Antisepsis; Antiviral Agents; Applications Grants; Bacterial Infections; Biomedical Engineering; Blood Platelets; Blood-Borne Pathogens; Catheters; Chemistry; Chronic; Clinical; Clinical Trials; Coagulation Process; Development; Devices; Effectiveness; Endothelium; Ethylene Oxide; Evaluation; Extracorporeal Circulation; Generations; Goals; Grant; Hour; In Vitro; Infection; Infection prevention; Klebsiella pneumonia bacterium; Laboratories; Laboratory Animals; Measures; Medical; Methods; Microbe; Microbial Biofilms; Microbiology; Modeling; N-acetylpenicillamine; Nitric Oxide; Nitric Oxide Donors; Oryctolagus cuniculus; Patients; Physiological; Polymers; Polyurethanes; Preparation; Prevention; Problem Solving; Progress Reports; Property; Pseudomonas aeruginosa; Public Health Schools; Research; Research Project Grants; S-Nitrosothiols; S-nitro-N-acetylpenicillamine; Sheep; Silicones; Sinus; Solvents; Staphylococcus aureus; Staphylococcus epidermidis; Sterilization; Surface; Swelling; Technology; Temperature; Testing; Thrombosis; Time; Toxic effect; antimicrobial; antimicrobial drug; bactericide; base; clinical application; clinical development; clinical translation; commercial application; cost; diazeniumdiolate; experimental study; implanted sensor; in vivo; killings; macrophage; natural antimicrobial; neutrophil; novel; novel strategies; physical property; prevent; public health relevance; screening

 DESCRIPTION: Infection and thrombosis on intravascular catheters are major, expensive problems in medical practice. Over the last ten years we have demonstrated that surface nitric oxide (NO) release can solve these problems, using various NO donor molecules (e.g., diazeniumdiolates, S-nitrosothiols (RSNOs)) incorporated into polymeric catheter tubing. This technology is based on the fact that NO released within the sinus cavities and by neutrophils and macrophages functions as a potent natural antimicrobial and antiviral agent. Further, NO secretion by the normal endothelium prevents clotting by preventing platelet adhesion and activation. We have developed polymers that continuously produce NO to prevent biofilm formation, platelet adhesion, and thrombosis in relevant animal models of intravascular catheters. Although effective, the cost, toxicity, and preparation of the donor molecules used to date have prevented clinical application. We have recently discovered that all of the positive effects of NO release can be achieved with the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP). In contrast to earlier NO release materials, polymers that are doped/impregnated with SNAP are easy to fabricate, nontoxic, inexpensive, and very stable. We will develop new methods of fabricating NO release catheters with polymer stabilized SNAP (e.g., solvent impregnation, NO releasing multilumen catheters, etc.). The chemistry laboratory directed by Dr. Meyerhoff will create and evaluate combinations of SNAP loaded into polyurethane and silicone catheters, optimize NO release rates for 21 d, reduce leaching rates, enhance durability, and demonstrate the ability to sterilize without significant loss in NO loading Dr. Bull, a bioengineer, will model NO release from certain multi-lumen catheter configurations and also oversee testing of the physical properties of the catheters (e.g., durometer, surface roughness, etc.), in terms of potential changes in such parameters as a result of SNAP impregnation. Dr. Xi's laboratory in the School of Public Health, will examine the antimicrobial/antibiofilm activity of the new NO release catheters against several microbes known to be associated with infections caused by intravascular catheters in hospitalized patients. The large animal laboratory, directed by Dr. Bartlett, will evaluate the optimized NO secreting catheters in chronic animal testing to evaluate effect on biofilm and thrombosis formation. This bioengineering research grant (BRG) combines new basic chemistry of RSNO-based NO release agents in biomedical polymers, the bioengineering to use this chemistry to make practical devices, the microbiological studies to prove effectiveness against targeted bacterial strains, and biologic evaluation in animal models, all leading to clinical translation in four years.

 描述：血管内导管上的感染和血栓形成是医学实践中的主要昂贵问题。在过去的十年中，我们证明了表面一氧化氮（NO）释放可以解决这些问题，使用各种无供体分子（例如，二氮二醇盐，S-硝基硫醇（RSNOS））掺入聚合物导管管中。这项技术基于以下事实：鼻窦腔内没有释放，中性粒细胞和巨噬细胞起着潜在的天然抗菌和抗病毒剂的作用。此外，正常森林的分泌不会通过防止血小板粘合剂和激活来防止衣服。我们已经开发了不断产生的聚合物，以防止血管内导管相关动物模型中的生物膜形成，血小板粘合剂和血栓形成。尽管有效，但迄今为止，供体分子的成本，毒性和制备阻碍了临床应用。我们最近发现，没有供体分子s-硝基-N-乙酰苯胺（SNAP）可以实现无释放的所有积极作用。与较早的释放材料相比，用快照掺杂/浸渍的聚合物易于制造，无毒，廉价且非常稳定。我们将开发新的方法，用于制造具有聚合物稳定快照的释放导管（例如，溶剂浸没，无释放的多粉状导管等）。 Meyerhoff博士指导的化学实验室将创建和评估负载到聚氨酯和硅酮导管的SNAP的组合，优化不释放速率，降低步行率，提高耐用性，并证明在没有大量损失的情况下，可以释放某些多属性，并表现出某些多属性的构图，并证明没有大量损失的多属性，并且会导致多型的构图，并模仿过度的导管。 （例如，持久性，表面粗糙度等），从浸渍导致此类参数的潜在变化方面。 XI博士在公共卫生学院的实验室将检查新的无释放导管的抗菌/抗生素活性，以针对几种与住院患者中血管内导管引起的感染有关的几种微生物。由Bartlett博士执导的大型动物实验室将评估慢性动物测试中未进行优化的分泌导管，以评估对生物膜和血栓形成的影响。这项生物工程研究补助金（BRG）结合了生物医学聚合物中基于RSNO的NO释放剂的新基本化学反应，这是使用该化学作用的生物工程学来制造实用设备，这是对靶向细菌菌株的有效性，以及在动物模型中的生物学评估，所有这些都可以在动物模型中进行生物学评估。 四年。