Bactericidal, Nonthrombogenic Intravascular Catheters

 描述：血管内导管的感染和血栓形成是医疗实践中主要的、昂贵的问题。在过去的十年中，我们已经证明，表面一氧化氮（NO）释放可以解决这些问题，使用各种NO供体分子（例如，二醇二氮烯鎓、S-亚硝基硫醇（RSNO））。该技术基于这样的事实，即在窦腔内以及由中性粒细胞和巨噬细胞释放的NO用作有效的天然抗微生物剂和抗病毒剂。此外，正常内皮的NO分泌通过防止血小板粘附和活化来防止凝血。我们已经开发了连续产生NO的聚合物，以防止血管内导管的相关动物模型中的生物膜形成、血小板粘附和血栓形成。尽管有效，但迄今为止使用的供体分子的成本、毒性和制备阻碍了临床应用。我们最近发现，NO释放的所有积极作用都可以通过NO供体分子S-亚硝基-N-乙酰青霉胺（SNAP）实现。与早期的NO释放材料相比，用SNAP掺杂/浸渍的聚合物易于制造、无毒、便宜且非常稳定。我们将开发制造具有聚合物稳定的SNAP的NO释放导管的新方法（例如，溶剂浸渍、NO释放多腔导管等）。由Meyerhoff博士指导的化学实验室将创建和评估加载到聚氨酯和硅胶导管中的SNAP组合，优化21 d的NO释放速率，降低浸出率，增强耐久性，并证明在NO加载无显著损失的情况下灭菌的能力。将对某些多腔导管配置的NO释放进行建模，并监督导管物理性能的测试（例如，硬度计、表面粗糙度等），就SNAP浸渍导致的这些参数的潜在变化而言。公共卫生学院Xi博士的实验室将检查新型NO释放导管对已知与住院患者血管内导管引起的感染相关的几种微生物的抗菌/抗菌膜活性。由Bartlett博士指导的大型动物实验室将在慢性动物试验中评价优化的NO分泌导管，以评价对生物膜和血栓形成的影响。这项生物工程研究资助（BRG）结合了生物医学聚合物中基于RSNO的NO释放剂的新基础化学，使用这种化学物质制造实用设备的生物工程，证明对目标细菌菌株有效性的微生物学研究，以及动物模型中的生物学评估，所有这些都导致了临床转化。 四年

 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.