Biocompatibility of Implantable Renal Replacement Devices

描述(申请人提供)：肾移植治疗终末期肾病(ESRD)患者受到供体器官短缺的严重限制，而透析昂贵、不便，并具有显著的发病率和死亡率。在美国，有近40万人每周需要进行三次中心内血液透析，这些人每年在医疗保险支付的医疗保健方面总共消耗了超过200亿美元。终末期肾病的患病率正以每年5%的速度增长，绝大多数患者不太可能接受移植。我们最近开始开发一种可植入的生物人工肾，它将由硅纳米孔膜(SNM)构建的血液过滤器与人肾小管细胞的生物反应器结合起来，以模拟肾脏功能。在最终设想的实施中，血液将在循环系统压力下在血液过滤器中过滤，以去除尿毒症毒素、盐、小溶质和水。由此产生的超滤液将被生物反应器处理，以选择性地将大部分盐和水输送回血液，从而维持体积平衡和电解质平衡。由NIH/NIBIB赞助的量子拨款(1R01EB008049)支持的初步初步研究使我们的团队确立了基本的概念可行性，包括开发高性能SNM过滤器、防污染薄膜聚合物涂层、人肾小管细胞分离和扩增技术、啮齿动物和猪的短期植入性血液滤过以及绵羊的可穿戴细胞治疗。我们还确定了成功开发可植入生物人工肾的一些关键障碍。其中，一个关键的挑战是血液滤器在血栓形成和膜污染方面的长期血液相容性。建议的R01项目将试图更好地了解跨越解剖、组织和分子长度尺度的血液-设备相互作用及其对血液过滤器生物兼容性的影响。更具体地说，我们将进行传输特性实验、计算流体动力学(CFD)模拟、体外放射流图和体内动物实验，以评估膜的物理化学性质对传质特性的影响，并确定流体流动异常在设备血栓形成中的作用。除了立即应用于可植入的生物人工肾外，这项工作还将建立一种 新的可植入设备的通用测试方法，这些设备在功能上依赖于大(毫米厘米)和小(纳米微米)长度的特征。

DESCRIPTION (provided by applicant): Treatment of end stage renal disease (ESRD) patients by renal transplant is severely limited by shortage of donor organs, while dialysis is expensive, inconvenient, and confers significant morbidity and mortality. There are nearly 400,000 people in the US who rely on thrice-weekly, in-center hemodialysis, and collectively, this population consumes over $20 billion annually in Medicare-paid healthcare. The prevalence of ESRD is increasing at 5% per year, and the vast majority of patients are unlikely to ever receive a transplant. We recently embarked on the development of an implantable bioartificial kidney that combines a hemofilter constructed from silicon nanopore membranes (SNM) with a bioreactor of human renal tubule cells to mimic nephronal function. In the final envisioned implementation, blood will be filtered in the hemofilter under circulatory system pressure to remove uremic toxins, salts, small solutes, and water. The resulting ultra filtrate will then be processed by the bioreactor to selectively transport most of the salts, and water back into the blood, thereby maintaining volume homeostasis and electrolyte balance. Initial pilot studies supported by a NIH/NIBIB-sponsored Quantum Grant (1R01EB008049) allowed our team to establish fundamental concept feasibility including the development of high-performance SNM filters, anti- fouling thin-film polymer coatings, human renal tubule cell isolation and expansion techniques, and short-term implantable hemofiltration in rodents and pigs as well as wearable cell therapy in sheep. We also identified a number of critical roadblocks to successful development of implantable bioartificial kidney. Among them, a key challenge is long-term blood compatibility of the hemofilter with respect to thrombosis and membrane fouling. The proposed R01 project will attempt to better understand the blood-device interactions spanning across anatomic, histologic, and molecular length scales and their influence on hemofilter biocompatibility. More specifically, we will conduct transport characterization experiments, computational fluid dynamics (CFD) simulations, in vitro radiographic flow mapping, and in vivo animal experiments to evaluate the impact of membrane physicochemical properties on mass transfer characteristics and determine the role of fluid flow anomalies in device thrombosis. Beyond the immediate application to an implantable bioartificial kidney, this work will establish a new generalized testing methodology for implantable devices that are functionally dependent on features at both large (mm-cm) and small (nm-microns) length scales.