Biocompatibility of Implantable Renal Replacement Devices

植入式肾脏替代装置的生物相容性

• 批准号: 8463847
• 负责人: SHUVO ROY
• 金额: $ 51.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463847
• 关键词: Address; Adsorption; Affect; American; Anatomy; Animal Experiments; Animal Testing; Animals; Area; Award; Back; Bioreactors; Blood; Blood Platelets; Blood flow; Cardiovascular system; Cell Separation; Cell Therapy; Cells; Characteristics; Citrates; Coagulation Process; Defect; Development; Device Designs; Devices; Dialysis procedure; Duct (organ) structure; Electrolyte Balance; End stage renal failure; Equipment Malfunction; Failure; Family suidae; Film; Fright; Future; Grant; Healthcare; Hemodialysis; Hemofiltration; Hemolysis; Histologic; Homeostasis; Human; Image; Implant; In Vitro; Kidney; Kidney Failure; Kidney Transplantation; Length; Liquid substance; Locales; Maps; Measures; Medical Device; Medicare; Membrane; Methodology; Modeling; Modification; Molecular; Morbidity - disease rate; National Institute of Biomedical Imaging and Bioengineering; Organ Donor; Patients; Performance; Permeability; Pilot Projects; Plasma; Plasma Proteins; Platelet Activation; Polymers; Population; Preparation; Prevalence; Process; Property; Proteins; Renal tubule structure; Rodent; Role; Saline; Salts; Shapes; Sheep; Silicon; Sodium Chloride; Solutions; Surface; System; Tantalum; Techniques; Technology; Testing; Thrombosis; Time; Toxin; Transmembrane Transport; Transplantation; Ultrafiltration; United States National Institutes of Health; Variant; Water; Whole Blood; Work; base; biomaterial compatibility; cost; design; flexibility; fluid flow; implantable device; implantation; improved; in vivo; mortality; nanopore; nanoscale; preclinical study; pressure; prototype; quantum; research study; shear stress; simulation; solute; success; surface coating; tool

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.

描述（由申请人提供）：通过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，而透析费用昂贵、不方便，并导致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，这一人群每年在医疗保险支付的医疗保健方面消耗超过200亿美元。ESRD的患病率每年增加5%，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，该肾将由硅纳米孔膜（SNM）构建的血液滤过器与人类肾小管细胞的生物反应器相结合，以模拟肾单位功能。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。然后，所得到的超滤液将通过生物反应器进行处理，以选择性地将大部分盐和水转运回血液中，从而保持体积稳态和电解质平衡。由NIH/NIBIB赞助的量子基金（1 R 01 EB 008049）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，包括开发高性能SNM过滤器、防污薄膜聚合物涂层、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滤过以及绵羊的可穿戴细胞治疗。我们还确定了一些关键的障碍，以成功开发植入式生物人工肾。其中，一个关键的挑战是血液滤过器在血栓形成和膜污染方面的长期血液相容性。申报的R 01项目将尝试更好地了解跨越解剖学、组织学和分子长度尺度的血液-器械相互作用及其对血液滤过器生物相容性的影响。更具体地说，我们将进行传输表征实验、计算流体动力学（CFD）模拟、体外放射学流量测绘和体内动物实验，以评价膜理化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。除了直接应用于可植入的生物人工肾，这项工作将建立一个 新的通用测试方法，用于功能上依赖于大（mm-cm）和小（nm-微米）长度尺度特征的植入式器械。