Cellular Composite Device for Combination Therapy of Acute Liver Failure

用于急性肝衰竭联合治疗的细胞复合装置

• 批准号: 8063890
• 负责人: Martin L Yarmush
• 金额: $ 26.25万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-20 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063890
• 关键词: Acute Liver Failure; Affect; American; Amino Acids; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Artificial Liver; Bioreactors; Blood Circulation; Cause of Death; Cell physiology; Cell secretion; Cells; Cessation of life; Chemicals; Chronic; Cirrhosis; Coculture Techniques; Combined Modality Therapy; Cytoprotection; Devices; Dialysis procedure; Effectiveness; Engineering; Equipment Malfunction; Etiology; Family suidae; Foundations; Functional disorder; Galactosamine; Glucagon; Goals; Gold; Growth; Hepatic; Hepatocyte; Hospitals; Hour; Human; Immune system; Immunosuppression; In Vitro; Inflammation; Inflammatory Response; Insulin; Life; Liver; Liver Failure; Liver diseases; Malignant neoplasm of liver; Measures; Mesenchymal Stem Cells; Metabolic; Metabolism; Modeling; Onset of illness; Organ; Organ Donor; Organ failure; Pathologic Processes; Patients; Pattern; Phase; Plasma; Population Growth; Property; Protocols documentation; Rattus; Regulation; Research Design; Rodent; Rodent Model; Scheme; Seeds; Sepsis; Serological; Serum; Simulate; Staging; Supplementation; Technology; Testing; Therapeutic; Therapy Clinical Trials; Time; Transplantation; United Network for Organ Sharing; United States; Validation; Waiting Lists; base; cell type; cohort; cost; design; effective therapy; hepatotoxin; in vivo; liver transplantation; mathematical model; operation; prevent; prototype; public health relevance; scale up

DESCRIPTION (provided by applicant): Liver failure is the 7th leading cause of death and is responsible for 50,000 deaths per year in the United States. Orthotopic liver transplantation is the only proven effective treatment of acute liver failure (ALF), but its use is limited due to organ donor shortage, associated high costs, and the requirement of lifelong immunosuppression. The present and expected growth of the population that is affected by liver failure is ever rising and a life-saving alternative to transplantation is needed to support patients. Bioartificial liver devices are a rational approach to support ALF patients as a bridge to transplantation. Five cell- based devices have been tested in humans and pigs and appear safe, but none have shown a survival benefit. The failure of devices to-date suggests an ineffective mechanism of action. End-stage liver failure leads to systemic dysfunction that is occurring simultaneously with an inflammatory response. We hypothesize that a combination approach to therapy that provides hepatocellular support along with cytoprotection, anti-inflammatory, and trophic support will cover the broad spectrum of pathological processes that can stabilize a patient. In proof-of-principle therapeutic trials, we have demonstrated that human mesenchymal stem cell (MSCs) naturally secrete bioactive molecules that have immunomodulatory properties. We have developed MSC-based devices that are operated outside the body and connect to a subject's circulation to provide long-term support, and have shown that when connected to one of these devices for 10 hours, rats undergoing ALF have a 5-fold increase in survival from less than 15% to over 70%. The overall goal of this Phase I project is to develop a composite cellular bioreactor for the treatment of ALF that integrates both hepatocyte and MSC metabolism and secretion in a single unit, and evaluate the added benefit of this two-cell device over and above the effectiveness of the MSC devices. The project specific aims are: (1) To optimize the in vitro coculture of MSCs and hepatocytes and simulate the effect of liver failure serum on the function of the coculture; and (2) To incorporate MSCs and hepatocytes into flat-plate devices and initiate therapeutic testing of bioreactor treatments in rodent models. Upon successful completion of this project, the deliverable will be a prototype cell-laden dialysis cartridge that can be readily scaled up and tested in large animals. PUBLIC HEALTH RELEVANCE: We propose to develop an extracorporeal bioartificial liver device that offers unparalleled support to patients undergoing liver failure. The device will contain hepatocytes and mesenchymal stem cells (MSCs). The addition of MSCs is unique to our technology and is designed to enhance the metabolic functions of hepatocytes exposed to plasma and restore the regulation of the dysfunctional immune system in patients undergoing liver failure by active MSC secretion anti-inflammatory and trophic molecules. This two-pronged approach distinguishes this device from current prototypes. Our objectives are to perform in vitro optimization of the coculture using metabolic engineering of the coculture and in vivo testing of a microfabricated coculture device in two rat models of liver failure. These studies will determine if the combination therapeutic approach can be indicated for a broad range of liver disease etiologies and will motivate testing in large animal models of liver failure, and ultimately in human patients.

描述（由申请人提供）：肝衰竭是第七大死因，在美国每年导致 50,000 人死亡。原位肝移植是唯一被证明有效的治疗急性肝衰竭（ALF）的方法，但由于器官供体短缺、相关费用高昂以及需要终生免疫抑制，其使用受到限制。目前和预期的受肝衰竭影响的人口数量不断增加，需要一种替代移植的救生替代方案来支持患者。生物人工肝装置是支持 ALF 患者作为移植桥梁的合理方法。五种基于细胞的设备已经在人类和猪身上进行了测试，看起来很安全，但没有一个显示出对生存的益处。迄今为止设备的故障表明作用机制无效。终末期肝衰竭会导致与炎症反应同时发生的全身功能障碍。我们假设提供肝细胞支持以及细胞保护、抗炎和营养支持的组合治疗方法将涵盖可以稳定患者病情的广泛病理过程。在原理验证治疗试验中，我们证明人类间充质干细胞（MSC）自然分泌具有免疫调节特性的生物活性分子。我们开发了基于 MSC 的设备，可以在体外操作并连接到受试者的循环系统以提供长期支持，并且已经表明，当连接到其中一个设备 10 小时时，经历 ALF 的大鼠的 ALF 增加了 5 倍生存率从不足 15% 提高到超过 70%。该一期项目的总体目标是开发一种用于治疗 ALF 的复合细胞生物反应器，将肝细胞和 MSC 的代谢和分泌集成在一个单元中，并评估这种双细胞装置除有效性之外的额外益处MSC 设备。该项目的具体目标是：（1）优化间充质干细胞与肝细胞的体外共培养，模拟肝衰竭血清对共培养功能的影响； (2) 将间充质干细胞和肝细胞整合到平板装置中，并在啮齿动物模型中启动生物反应器治疗的治疗测试。该项目成功完成后，交付成果将是一个充满细胞的透析盒原型，可以轻松扩大规模并在大型动物中进行测试。 公共健康相关性：我们建议开发一种体外生物人工肝装置，为肝衰竭患者提供无与伦比的支持。该装置将含有肝细胞和间充质干细胞（MSC）。 MSC的添加是我们技术独有的，旨在增强暴露于血浆的肝细胞的代谢功能，并通过活跃的MSC分泌抗炎和营养分子来恢复肝衰竭患者功能失调的免疫系统的调节。这种双管齐下的方法使该设备有别于当前的原型。我们的目标是利用共培养的代谢工程对共培养进行体外优化，并在两种肝衰竭大鼠模型中对微型共培养装置进行体内测试。这些研究将确定联合治疗方法是否适用于广泛的肝病病因，并将推动在大型肝衰竭动物模型中进行测试，并最终在人类患者中进行测试。