Reduction of Tunneled Dialysis Catheter Dysfunction Via Long Term Nitric Oxide Re

通过长期一氧化氮再灌注减少隧道式透析导管功能障碍

• 批准号: 8646266
• 负责人: Hao Chen
• 金额: $ 21.9万
• 依托单位: BIOCREDE, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646266
• 关键词: Adhesions; Animals; Anti-Infective Agents; Antibiotics; Arteries; Bacteremia; Bacteria; Biocompatible Materials; Biological; Bioreactors; Blood Circulation; Blood Platelets; Blood Vessels; Body Temperature; Buffers; Businesses; Caring; Catheters; Cell Proliferation; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Trials; Clinical effectiveness; Coagulation Process; Copper; Data; Detection; Development; Devices; Dialysis procedure; Drug Formulations; Effectiveness; Elastomers; Electron Microscopy; Epidural Abscess; Epithelial Cells; Escherichia coli; Ethylene Oxide; Exhibits; Family suidae; Fibrin; Film; Fistula; Functional disorder; Hemodialysis; Heparin; Hospitals; In Vitro; Infection; Infection prevention; Infective endocarditis; Laboratories; Legal patent; Length; Length of Stay; Life; Local Anti-Infective Agents; Marketing; Mechanics; Mediating; Mercury; Michigan; Microbial Biofilms; Modeling; Muscle relaxation phase; N-acetylpenicillamine; Nitric Oxide; Nosocomial Infections; Ointments; Osteomyelitis; Patients; Phase; Polymers; Polyurethanes; Prevalence; Prevention; Price; Process; Property; Quality of life; Research; S-Nitroso-N-Acetylpenicillamine; Sepsis; Silicones; Silver; Skeletal Muscle; Smooth Muscle; Smooth Muscle Myocytes; Solutions; Staphylococcus aureus; Staphylococcus epidermidis; Stenosis; Sterilization; Study models; Surface; Survival Rate; Techniques; Technology; Temperature; Thrombosis; Translational Research; Universities; Venous; antimicrobial; antimicrobial drug; arm; bactericide; copolymer; cost; improved; in vivo; innovation; killings; macrophage; microbicide; mortality; novel; polycarbonate; polydimethylsiloxane; prevent; prototype; public health relevance; trend

DESCRIPTION (provided by applicant): We propose a novel and price competitive Tunneled Dialysis Catheter (TDC) made from a proprietary polymeric formulation to effectively reduce TDC dysfunction via long-term nitric oxide (NO) release, particularly during the period of AVF maturation in incident hemodialysis and TDC dependent patients. Preliminary studies with polymer materials used to prepare existing commercial TDCs, suggests that the proposed device will possess: (a) microbicidal (b) anti-platelet/anti-thrombosis and (c) anti-smooth-muscle cell-proliferation activities to target all the current effector arms of TDC dysfunction: infection thrombosis/fibrin sheath formation, and central venous stenosis. In addition, it is anticipated tha the device's shelf life can be extended well beyond the unprecedented 2-4 months at 37?C (already demonstrated) while maintaining anti-TDC dysfunction properties for over 3-4 weeks at body temperatures (37?C). Currently, over 80% (88,200) of incident hemodialysis (HD) patients start HD using a TDC, and the overall prevalence rate of TDCs is over 20%. In 2010, 83,000 patients were admitted to hospitals for TDC related bacteremia or sepsis, and each central line-associated bloodstream nosocomial infection adds ca. $47,000 to the cost of care and a 14.6 d increase in length of stay. Current heparin, silver impregnated, or antibiotic coated TDCs are either expensive, non-effective, or suffer from mechanical breakdown after prolonged use. The proposed device will be processed and assembled in the US at almost half the cost of current heparin or silver coated TDCs, and potentially have a significant clinical impact on the 5 fold increase in mortality in patients starting HD with a TDC as opposed to an AV fistula or graft. To continue the development of our product, we propose: (1) to examine in vitro NO release profiles and biological activity of dual lumen 11.5Fr carbosil/polyurethane prototype dual lumen catheters for effective biofilm prevention (Staphylococcus aureus, and Staphylococcus epidermidis); (2) to optimize the polymeric formulation to allow for 3 months of shelf life after proper sterilization while maintaining antimicrobial and antithrombotic properties; and (3) to obtain an in vivo "proof-of-principle" understanding to gauge the product's clinical effectiveness in terms of infection, thrombosis and CVS reduction using a pig model. This combined collaborative approach between a respected academic laboratory which is a world leader in the local delivery and release of NO (Meyerhoff laboratory) and an innovative and productive translational research group with large animal expertise (Dr. Roy-Chaudhury's Dialysis Vascular Access Research Group) will effectively bring the technology, business, and clinical needs together, to develop an innovative solution to the TDC problem. This technology has been optioned by Biocrede Inc. via the Office of Tech Transfer at the University of Michigan.

描述（由申请人提供）：我们提出了一种由专有聚合物配方制成的新型且具有价格竞争力的隧道透析导管（TDC），可通过长期一氧化氮（NO）释放有效减少TDC功能障碍，特别是在事件血液透析和TDC依赖患者的AVF成熟期间。对用于制备现有商业TDC的聚合物材料的初步研究表明，所提出的装置将具有：（a）杀微生物（B）抗血小板/抗血栓形成和（c）抗平滑肌细胞增殖活性，以靶向TDC功能障碍的所有当前效应臂：感染血栓形成/纤维蛋白鞘形成和中心静脉狭窄。此外，预计该器械的保质期可以大大延长，超过前所未有的2-4个月（37？C（已经证明），同时在体温（37？C）。目前，超过80%（88，200）的血液透析（HD）患者使用TDC开始HD，TDC的总体患病率超过20%。2010年，83，000名患者因TDC相关菌血症或脓毒症而入院，每例中心静脉导管相关血流医院感染增加约1000人。护理费用增加47，000美元，住院时间增加14.6天。目前的肝素、银浸渍或抗生素涂覆的TDC要么昂贵、无效，要么在长期使用后遭受机械损坏。申报器械将在美国进行加工和组装，成本几乎是当前肝素或银涂层TDC的一半，并且可能对使用TDC开始HD的患者的死亡率增加5倍（与AV瘘或移植物相比）产生显著的临床影响。为了继续开发我们的产品，我们提出：（1）检测11.5Fr碳硅/聚氨酯双腔原型导管的体外NO释放特性和生物活性，以有效地预防生物膜（金黄色葡萄球菌和表皮葡萄球菌）;（二）优化聚合物配方，使其在适当灭菌后具有3个月的保质期，同时保持抗菌和抗血栓形成性质;以及（3）获得体内“原理验证”理解，以使用猪模型来评估产品在感染、血栓形成和CVS减少方面的临床有效性。在NO的本地输送和释放方面处于世界领先地位的受人尊敬的学术实验室（Meyerhoff实验室）与具有大型动物专业知识的创新和富有成效的转化研究小组（Roy-Chaudhury博士的透析血管通路研究小组）之间的这种联合合作方法将有效地将技术，业务和临床需求结合在一起，以开发TDC问题的创新解决方案。该技术已被Biocrede Inc.通过密歇根大学的技术转移办公室