XENOGENEIC BIOARTIFICAL LIVER

异种生物人工肝

• 批准号: 7146384
• 负责人: SCOTT L NYBERG
• 金额: $ 23.68万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146384
• 关键词: albumins; ammonia; animal tissue; biochemistry; bioengineering /biomedical engineering; biomaterial compatibility; biomaterial development /preparation; biomaterial evaluation; detoxification; disease /disorder model; dogs; hepatic coma /encephalopathy; liver failure; liver function; liver transplantation; membrane permeability; membrane structure; nonhuman therapy evaluation; protein metabolism; swine; tissue engineering; transplantation immunology; xenotransplantation

DESCRIPTION (provided by applicant): Liver failure is a serious problem that affects tens of thousands of people in the United States each year. A new form of therapy, the bioartificial liver (BAL), is in development to provide detoxification and synthetic activity to patients with liver failure prior to transplantation, until recovery of the native liver, or as a chronic supportive therapy. The BAL operates extracorporeally like hemodialysis, but is unique in that it contains metabolically active liver cells (i.e., hepatocytes) that provide liver functions to the patient. The broad, long term objective of our research program is to develop a cell-based extracorporeal BAL for supporting patients with acute and chronic forms of liver failure. Treatment of fulminant hepatic failure (FHF), an aggressive and potentially life-ending form of acute liver failure that occurs in previously healthy individuals, is the focus of the current application. The specific aims of the current application are to optimize a novel BAL design, the spheroid reservoir BAL, and to establish its efficacy in a preclinical model of FHF. Optimization will include both in vitro and in vivo studies to identify the ideal operating conditions for the BAL. Endpoints to assess optimization of the SRBAL include mass transfer of polar and non-polar molecules, spheroid formation, immuno-protection, biocompatibility and biochemical performance (i.e., detoxification and synthetic activity of hepatocytes). Variables to be considered in optimization experiments include permeability and composition of the BAL membrane, composition of the BAL medium including albumin concentration, oscillation frequency of the reservoir, and flow rates in the extracorporeal circuit. Efficacy studies will involve testing the optimized spheroid reservoir BAL in a pre-clinical model of FHF. Survival of animals in FHF and reversal of its side effects including hepatic encephalopathy and are the endpoints that will be used to assess efficacy. Demonstration of efficacy in a pre-clinical model of FHF, as proposed in this application, will provide a basis for future clinical trials of the spheroid reservoir BAL.

描述（申请人提供）：肝衰竭是一个严重的问题，每年影响美国成千上万的人。一种新形式的治疗形式，即生物人工肝（BAL），正在开发为肝衰竭之前的患者提供排毒和合成活性，直至恢复天然肝脏或作为长期支持治疗。 BAL像血液透析一样进行体外运行，但其独特之处在于它包含代谢活跃的肝细胞（即肝细胞），可为患者提供肝功能。我们研究计划的广泛，长期目标是开发基于细胞的体外BAL，用于支持急性和慢性肝衰竭的患者。当前应用的重点是治疗暴发性肝衰竭（FHF），这是以前健康个体中发生的一种侵略性且潜在的急性肝衰竭形式，是急性肝脏衰竭的重点。当前应用的具体目的是优化一种新型的BAL设计，球体储层BAL，并在FHF的临床前模型中确定其功效。优化将包括体外和体内研究，以确定BAL的理想工作条件。评估SRBAR优化的终点包括极性和非极性分子的传质，球体形成，免疫保护，生物相容性和生化性能（即肝细胞的排毒和合成活性）。在优化实验中要考虑的变量包括BAL膜的渗透性和组成，BAL培养基的组成，包括白蛋白浓度，储层的振荡频率以及体外电路中的流速。功效研究将涉及在FHF前临床模型中测试优化的球体储层BAL。动物在FHF中的存活以及其副作用的逆转，包括肝脑病，是用于评估功效的终点。正如本应用程序中提出的那样，在FHF的临床前模型中的功效证明将为球体储层BAL的未来临床试验提供基础。