XENOGENEIC BIOARTIFICAL LIVER

异种生物人工肝

• 批准号: 7460780
• 负责人: SCOTT L NYBERG
• 金额: $ 21.8万
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460780
• 关键词: Acute; Acute Liver Failure; Address; Adverse effects; Affect; Albumins; Ammonia; Animals; Artificial Liver; Biochemical; Biomedical Engineering; Canis familiaris; Cells; Cerebral Edema; Cessation of life; Chronic; Clinical Trials; Condition; Development; Devices; Dose; Drug Metabolic Detoxication; End Point; Extrahepatic; Factor Analysis; Family suidae; Frequencies; Funding; Future; Hemodialysis; Hepatic Encephalopathy; Hepatocyte; In Vitro; Individual; Infusion procedures; Liver; Liver Failure; Liver support system; Membrane; Metabolic; Modeling; Operative Surgical Procedures; Pathogenesis; Patients; Performance; Permeability; Pre-Clinical Model; Principal Investigator; Rate; Recovery; Research; Research Design; Supportive care; Testing; Toxin; Transplantation; United States; base; biomaterial compatibility; design; end of life; improved; in vivo; liver function; novel; programs; research study; response

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（由申请人提供）：肝衰竭是一个严重的问题，每年影响数以万计的美国人。生物人工肝 (BAL) 是一种新的治疗方法，正在开发中，为肝功能衰竭患者在移植前提供解毒和合成活性，直至天然肝脏恢复，或作为长期支持治疗。 BAL 的体外操作类似于血液透析，但其独特之处在于它含有代谢活跃的肝细胞（即肝细胞），可为患者提供肝功能。我们研究计划的广泛、长期目标是开发一种基于细胞的体外 BAL，为患有急性和慢性肝衰竭的患者提供支持。暴发性肝衰竭（FHF）是一种侵袭性的、可能致命的急性肝衰竭，发生在以前健康的个体中，治疗是当前应用的重点。当前应用的具体目标是优化一种新型 BAL 设计，即球体储库 BAL，并确定其在 FHF 临床前模型中的功效。优化将包括体外和体内研究，以确定 BAL 的理想操作条件。评估 SRBAL 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（即肝细胞的解毒和合成活性）。优化实验中要考虑的变量包括 BAL 膜的渗透性和成分、BAL 介质的成分（包括白蛋白浓度）、储液器的振荡频率以及体外回路中的流速。功效研究将涉及在 FHF 临床前模型中测试优化的球体储库 BAL。 FHF 中动物的存活率及其副作用（包括肝性脑病）的逆转是用于评估疗效的终点。如本申请中所提出的，在 FHF 临床前模型中验证疗效将为未来球体储库 BAL 的临床试验提供基础。