Nonthrombogenic, Antiseptic Nitric Oxide Releasing Catheters

描述（由申请人提供）：该提案涉及将专有的一氧化氮（NO）释放聚合物材料（NORL）纳入静脉导管中，以减少感染和凝血。正常内皮释放的低水平NO抑制血小板粘附和活化，从而防止血栓形成。此外，已经表明低剂量的NO表现出显著的杀菌活性。因此，分泌NO的导管的制备将解决危重患者护理中的两个长期存在的问题。在该SBIR的第1阶段，我们：1）开发了一种独特的NO分泌聚合物材料，其可以释放超过生理水平的NO长达21天，副产物的浸出最少; 2）测试了材料的细胞毒性和溶血性，并在绵羊模型中进行了测试，以评价血栓形成和细菌粘附。我们解决了处理和包装要求，以保持材料的有效性。根据材料成本和专门的处理要求，我们确定了一种产品，该产品将受益于材料提供的长期保护，并且具有足够高的销售价格以承受增加的处理费用。该II期申请旨在构建最有效的制造工艺，以将NORL纳入导管中，进行广泛的临床前评估，并在体内评价涂层的抗微生物和抗血小板特性。NORL的初始目标产品将是适用于成人体外膜肺氧合（ECMO）的双腔导管（DLC）。具体而言，我们将构建一种用于自动和受控制造NORL导管的器械，并对装载NORL的导管进行设计验证。我们还将与密歇根大学的合作者合作，对新的NO释放导管进行广泛的体内评估。在第二阶段结束时，我们将准备将开发的工艺和设备转让给合同制造商。这种方法在改善血管内导管的生物相容性和抗微生物特征方面是一个显著的进步，因为它利用了精确模拟我们体内内源性NO释放功能的化学，包括从内皮细胞释放NO以抑制血小板粘附/活化，以及通过各种免疫细胞（例如，巨噬细胞、嗜中性粒细胞等）杀死细菌。通过减少凝血和感染，该技术将同时增加导管寿命并降低患者发病率和成本。

DESCRIPTION (provided by applicant): This proposal involves the incorporation of a proprietary nitric oxide (NO) releasing polymer material (NORL) into a venous catheter to reduce infection and clotting. Low levels of NO released by the normal endothelium inhibit platelet adhesion and activation, thus preventing thrombus formation. Further, it has been shown that NO at low doses exhibits significant bactericidal activity. Hence, the preparation of catheters that secrete NO will solve two longstanding problems in the care of critically ill patients. In Phase 1 of this SBIR, we: 1) developed a unique NO secreting polymer material that can release NO above physiological levels for up to 21 days, with minimal leaching of byproducts; 2) tested the materials for cytotoxicity and hemolysis, and conducted testing in a sheep model to evaluate thrombogenicity and bacterial adherence. We addressed handling and packaging requirements to maintain efficacy of the materials. Based on the cost of materials and the specialized handling requirements, we identified a product that would benefit from the prolonged protection offered by the material, and that has a high enough sale price to tolerate the increased handling expenses. This Phase II application is targeted at building out the manufacturing process found to be most effective for incorporating NORL in the catheter, performing extensive preclinical assessments, and evaluating the coating in vivo for anti-microbial and anti-platelet properties. The initial target product for NORL will be a dual lumen catheter (DLC) suitable for adult extracorporeal membrane oxygenation (ECMO). Specifically, we will construct a device for automated and controlled fabrication of the NORL catheter, and conduct design verification of the NORL loaded catheter. We will also work with our collaborators, at the University of Michigan, to perform extensive in vivo evaluations of the new NO release catheter. At the conclusion of Phase II, we will be prepared to transfer the developed process and equipment to a contract manufacturer. This approach is a significant advance in improving the biocompatibility and anti-microbial features of intravascular catheters since it utilizes chemistry that exactly mimics endogenous NO release function in our bodies, including from endothelial cells to inhibit platelet adhesion/activation, and by various immune cells (e.g., macrophages, neutrophils, etc.) to kill bacteria. By decreasing both clotting and infection, this technology will simultaneously increase catheter longevity and decrease patient morbidity and costs.