BIOARTIFICIAL RENAL TUBULE FOR RENAL FAILURE THERAPY

一种生物人工肾小管辅助装置的组织工程是 制造移位电流的可植入装置的第一步 慢性肾功能衰竭患者的血液透析治疗 优化当前患者肾脏替代疗法的关键步骤 患有急性肾功能衰竭。该项目的第一阶段组件包括 通过以下方法成功地制造出了功能性生物人工肾小管 结合哺乳动物肾小管祖细胞、细胞外基质 组件和聚合物合成中空纤维。这一成功使 二期工程建设生物人工肾的阶段 膜表面积在0.5和1.0M2之间的小管装置 在体外和体外测试其功能性能和耐用性。 活着。该第二阶段提案有三个具体目标：1)设计一个 利用数学模型制作生物人工肾小管原型 氧气传输和流体流动力学，以实现最佳性能 和功能，2)扩大规模并在体外测试该设备 转运、代谢和合成肾小管细胞功能。运输 测量将包括体积、电解质、葡萄糖、氨基酸、 尿素。合成功能测量将包括谷胱甘肽， 谷胱甘肽过氧化物酶、肿瘤坏死因子-α和白介素6 作为寄主防御的重要参数。代谢参数将 包括胰岛素样生长因子-1合成、糖异生和 氨化作用--伤口愈合和营养的重要因素 平衡：3)在正常和尿毒症大鼠体内测试这些功能 有体外血液循环的动物。圆满完成 这一第二阶段的成分将允许启动人类临床 评估该设备在重症监护室患者中的实用性的试验 患有急性肾功能衰竭(ARF)的护理病房。ARF影响超过 美国每年20万名患者，花费25亿美元 每年，死亡率超过50%。潜在的 ARF的发病机制是肾小管细胞坏死，不仅导致 在过滤失败的同时，还会失去体内平衡、代谢和 肾脏的综合功能。添加了生物人工 肾小管装置作为细胞治疗的一种形式，将取代这些 危重肾功能不能被目前的透析液或 滤过性治疗将优化患者的治疗方法 饱受这一毁灭性疾病过程的折磨。 建议的商业应用：该设备可能被证明是有用的 优化40万名患有以下疾病的美国患者的治疗 急性或慢性肾衰竭。这台设备不仅可以优化 目前对这些患者的治疗效果不佳，但可能会节省成本 用于治疗这些患者的费用高达数十亿美元。

Tissue engineering of a bioartificial renal tubule assist device is the first step to produce an implantable device to displace current hemodialysis therapy of patients with chronic renal failure and a critical step to optimize current renal replacement therapy in patients with acute renal failure. The Phase I component of this project has been successful in producing a functional bioartificial renal tubule by combining mammalian renal tubule progenitor cells, extracellular matrix components, and polymeric synthetic hollow fibers. This success sets the stage for this Phase II project to construct a bioartificial renal tubule device having a membrane surface area between 0.5 and 1.0 M2 and to test its functional performance and durability both in vitro and in vivo. This Phase II proposal has three specific aims: 1) To design a prototype bioartificial renal tubule, by utilizing mathematical modeling of oxygen transport and fluid flow mechanics, for optimal performance and function, 2) To scale up and test this device ex vivo for important transport, metabolic, and synthetic renal tubucell functions. Transport measurements will include volume, electrolytes, glucose, amino acids, urea. Synthetic function measurements will include glutathione, glutathione peroxidase, tumor necrosis factor-alpha, and interleukin-6 as important parameters in host defense. Metabolic parameters will include insulin-like growth factor-1 synthesis, gluconeogenesis, and ammoniagenesis, factors important in wound healing and nutritional balance: 3) To test these functions in vivo in normal and uremic large animals with an extracorporeal blood circuit. The successful completion of this Phase II component will allow the initiation of human clinical trials to assess the utility of this device in patients in the intensive care unit who suffer from acute renal failure (ARF). ARF affects over 200,000 patients in the U.S. each year at a cost of $2.5 billion annually, with a mortality rate greater than 50%. The underlying pathogenesis of ARF is renal tubule cell necrosis, resulting not only in filtration failure but also loss of homeostatic, metabolic, and synthetic functions of the kidney. The addition of the bioartificial renal tubule device, as a form of cell therapy, will replace these critical renal functions not substituted for with current dialytic or filtration therapy and will optimize the therapeutic approach to patient suffering from this devastating disease process. PROPOSED COMMERCIAL APPLICATION: This device may prove useful to optimize the treatment of the 400,000 U.S. patients who have either acute or chronic renal failure. Not only may this device optimize current suboptimal care for these patients, but may provide cost savings for the treatment of these patients in the billions of dollars.