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

描述（由申请人提供）：我们提出一种新型且具有价格竞争力的隧道透析导管（TDC），由专有聚合物配方制成，通过长期一氧化氮（NO）释放有效减少TDC功能障碍，特别是在偶然血液透析和TDC依赖患者的AVF成熟期间。对用于制备现有商用TDC的聚合物材料的初步研究表明，拟议的设备将具有：(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，以针对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，预计该设备的保质期将远远超过前所未有的2-4个月，为37？C（已经证明），同时在体温（37℃）下保持抗tdc功能障碍特性超过3-4周。目前，超过80%（88,200）的突发血液透析（HD）患者使用TDC开始HD， TDC的总体患病率超过20%。2010年，8.3万名患者因与TDC相关的菌血症或败血症入院，每一次与中心静脉相关的血流院内感染使护理费用增加约4.7万美元，住院时间增加14.6天。目前肝素、银浸渍或抗生素包被的tdc要么昂贵，要么无效，要么长期使用后会出现机械故障。拟议的装置将在美国加工和组装，成本几乎是目前肝素或银涂层TDC的一半，并且可能对与房室瘘管或移植物相比，TDC开始HD患者死亡率增加5倍的显著临床影响。为了进一步发展我们的产品，我们建议：(1)检测双管腔11.5Fr碳纤维/聚氨酯原型双管腔导管的体外NO释放谱和生物活性，以有效预防生物膜（金黄色葡萄球菌和表皮葡萄球菌）；(2)优化聚合物配方，使其在适当灭菌后可保留3个月的保质期，同时保持抗菌和抗血栓特性；(3)获得体内“原理证明”的理解，以衡量产品在感染，血栓形成和使用猪模型减少CVS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）和具有大型动物专业知识的创新和多产的转化研究小组（Roy-Chaudhury博士的透析血管通路研究小组）将有效地将技术、业务和临床需求结合在一起，开发出解决TDC问题的创新解决方案。Biocrede公司通过密歇根大学的技术转移办公室选择了这项技术。

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.