Nonthrombogenic, Antiseptic Nitric Oxide Releasing Catheters

非血栓形成、抗菌一氧化氮释放导管

• 批准号: 8778830
• 负责人: Scott I Merz
• 金额: $ 73.55万
• 依托单位: MC3, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8778830
• 关键词: Address; Adherence; Adhesions; Adult; Aging; Bacteria; Biochemistry; Biocompatible; Biocompatible Materials; Blood; Blood Platelets; Blood Vessels; Caring; Catheters; Cells; Chemicals; Chemistry; Clinical; Coagulation Process; Contracts; Critical Illness; Development; Devices; Dose; Drug Formulations; Endothelial Cells; Endothelium; Equipment; Evaluation; Exhibits; Extracorporeal Membrane Oxygenation; Generations; Goals; Growth; Hemolysis; Histologic; Immune; Implant; Infection; Investments; Laboratories; Lead; Letters; Local Anti-Infective Agents; Longevity; Manufacturer Name; Marketing; Materials Testing; Mechanics; Methods; Michigan; Modeling; Morbidity - disease rate; Nitric Oxide; Patients; Phase; Physiological; Platelet Activation; Polymers; Preparation; Price; Process; Production; Property; Research; Resistance to infection; Risk; S-Nitrosothiols; Sales; Sheep; Side; Small Business Innovation Research Grant; Sterilization; Technology; Testing; Thrombus; Universities; Venous; Work; antimicrobial; bactericide; base; biomaterial compatibility; cost; cytotoxicity; design; falls; improved; in vivo; killings; macrophage; manufacturing process; microbial; neutrophil; next generation; novel; patient safety; pre-clinical; prevent; public health relevance

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.

描述（由申请人提供）：该提案涉及将专有的一氧化氮（NO）释放到静脉导管中，以减少感染和凝结。正常内皮释放的NO释放的低水平抑制了血小板粘附和激活，从而防止了血栓形成。此外，已经表明，低剂量的没有表现出明显的杀菌活性。因此，分泌NO的导管的准备将解决重症患者的两个长期问题。在该SBIR的第1阶段中，我们：1）开发了一种独特的分泌聚合物材料，在长达21天的时间内不得释放高于生理水平，而副产品的浸出最少； 2）测试了细胞毒性和溶血的材料，并在绵羊模型中进行了测试，以评估血栓形成性和细菌依从性。我们解决了处理和包装要求，以维持材料的功效。根据材料的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延长保护，并且具有足够高的销售价格来容忍增加的处理费用。该II期应用的目的是建立对将NORL纳入导管，进行广泛的临床前评估以及在体内评估抗微生物和抗植物特性的涂层最有效的制造过程。 NORL的最初目标产物将是适用于成人体外膜氧合（ECMO）的双管腔导管（DLC）。具体而言，我们将构建一种用于自动化和受控的Norl导管的设备，并进行Norl负载导管的设计验证。我们还将与密歇根大学的合作者合作，对新的无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过程和设备转移到合同制造商中。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项重大进步，因为它利用了化学性质，这些化学精确地模拟了内源性无释放功能，包括从内皮细胞来抑制血小板粘附/激活，以及各种免疫细胞，以及各种免疫细胞（例如，巨噬细胞，中性嗜酸群等）。通过减少凝血和感染，这项技术将同时增加导管的寿命并降低患者的发病率和成本。