BIOARTIFICIAL RENAL TUBULE FOR RENAL FAILURE THERAPY

生物人工肾小管辅助装置的组织工程是 第一步，生产可植入装置以转移电流 慢性肾功能衰竭患者血液透析治疗 优化患者当前肾脏替代治疗的关键步骤 急性肾衰竭 该项目第一阶段的组成部分， 已经成功地生产了功能性生物人工肾小管， 将哺乳动物肾小管祖细胞、细胞外基质 组分和聚合物合成中空纤维。 这一成功使 该二期工程的阶段是构建生物人工肾， 具有0.5 - 1.0M2的膜表面积的小管装置，和 以测试其在体外和体内的功能性能和耐久性， vivo. 第二阶段的建议有三个具体目标：1）设计一个 生物人工肾小管的数学模型 氧气输送和流体流动力学，以实现最佳性能 2）为了放大和测试该装置的体外重要功能， 运输、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和白细胞介素-6 作为宿主防御的重要参数。 代谢参数将 包括胰岛素样生长因子-1合成、胰岛素样生长因子生成， 氨生成，在伤口愈合中的重要因素和营养 平衡：3）在正常和尿毒症大细胞中测试这些功能 有体外循环血液回路的动物。 圆满完成 这一阶段的第二部分将允许启动人类临床试验， 评估该器械在密集型患者中的效用的试验 急性肾功能衰竭（ARF）患者的护理单位。 ARF影响超过 美国每年有20万名患者，花费25亿美元 死亡率超过50%。 底层 ARF的发病机制是肾小管细胞坏死，不仅导致 在过滤失败，但也失去稳态，代谢， 肾脏的合成功能。 添加生物人工 肾小管装置，作为一种细胞疗法，将取代这些 当前透析无法替代的关键肾功能，或 过滤治疗，并将优化患者的治疗方法 遭受着这种毁灭性的疾病 拟议的商业应用：该器械可用于 优化40万美国患者的治疗， 急性或慢性肾衰竭。 这个装置不仅可以优化 目前对这些患者的护理不理想，但可能节省成本 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.