Biocompatibility of Implantable Renal Replacement Devices

描述（由申请人提供）：终末期肾病（ESRD）患者通过肾移植治疗受到供体器官短缺的严重限制，而透析昂贵，不方便，并具有显著的发病率和死亡率。美国有近40万人依赖每周三次的中心血液透析，总的来说，这些人每年在医疗保险支付的医疗保健上花费超过200亿美元。ESRD的患病率以每年5%的速度增长，绝大多数患者不太可能接受移植。我们最近着手开发一种植入式生物人工肾脏，它结合了由硅纳米孔膜（SNM）构建的血液过滤器和人类肾小管细胞的生物反应器来模拟肾脏功能。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，选择性地将大部分盐和水输送回血液中，从而维持体积稳态和电解质平衡。由NIH/ nibib资助的量子基金（1R01EB008049）支持的初步试点研究使我们的团队能够建立基本概念的可行性，包括高性能SNM过滤器的开发，抗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式血液过滤以及羊的可穿戴细胞治疗。我们还确定了成功开发植入式生物人工肾脏的一些关键障碍。其中，一个关键的挑战是血液过滤器在血栓形成和膜污染方面的长期血液相容性。拟议的R01项目将试图更好地理解跨越解剖、组织学和分子长度尺度的血液装置相互作用及其对血液过滤器生物相容性的影响。更具体地说，我们将进行输运表征实验、计算流体动力学（CFD）模拟、体外放射成像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器械血栓形成中的作用。除了立即应用于植入式生物人工肾脏之外，这项工作还将建立一种新型的人工肾

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.