XENOGENEIC BIOARTIFICAL LIVER

描述（由申请人提供）：肝衰竭是一个严重的问题，每年影响美国成千上万的人。一种新的治疗形式，生物人工肝（BAL），正在开发中，为肝衰竭患者在移植前提供解毒和合成活性，直到天然肝脏恢复，或作为慢性支持治疗。BAL的体外操作类似于血液透析，但其独特之处在于其含有代谢活性肝细胞（即，肝细胞），其为患者提供肝功能。我们研究项目的广泛、长期目标是开发一种基于细胞的体外BAL，用于支持急性和慢性肝衰竭患者。暴发性肝衰竭（FHF）是一种侵袭性和潜在的生命终结形式的急性肝衰竭，发生在以前的健康个体中，是当前应用的重点。本申请的具体目的是优化一种新型BAL设计，即球状体储库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的理想操作条件。评估SRBAL优化的终点包括极性和非极性分子的质量转移、球状体形成、免疫保护、生物相容性和生物化学性能（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膜的渗透性和组成、BAL介质的组成（包括白蛋白浓度）、储药器的振荡频率和体外回路中的流速。疗效研究将涉及在FHF临床前模型中检测优化的球形储液器BAL。FHF中动物的存活率及其副作用（包括肝性脑病）的逆转是将用于评估疗效的终点。本申请中提出的FHF临床前模型中的疗效证明将为球形储库BAL的未来临床试验提供基础。

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.