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Development of a Hybrid Artificial Liver for Treatment of Acute and Chronic Liver Failure Patients

开发用于治疗急性和慢性肝衰竭患者的混合人工肝

基本信息

批准号：
12305053
负责人：
FUNATSU Kazumori
金额：
$ 24.76万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12305053/
关键词：
Hybrid Artificial Liver Preclinical Study Acute Liver Failure Chronic Liver Failure Polyurethane Foam Hepatocyte Spheroid Hollow Fiber Hepatocyte Organoid 肝小葉類似構造遠心力ポリウレタン発泡体ラット実験血管網類似構造免疫反応

项目摘要

1. Development of a hybrid artificial liver for clinical trialWe developed a hybrid artificial liver (HAL) which consists of a hepatocyte culture module with multi-capillary polyurethane foam packed-bed containing 200 g primary porcine hepatocytes and an extracorporeal circulation line. Almost all of the hepatocytes in the module formed spheroids, and they maintained the liver specific functions for at least 2 weeks. As preclinical study, the HAL was applied to about 25 kg warm ischemic liver failure pigs. In the preclinical study, we demonstrated its effectiveness such functions as suppression of increase of blood ammonia, maintenance of blood glucose, stabilization of vital sign and urinary excretion, extension of survival time. The HAL was effective to stabilize the general conditions of the body in addition to supporting various liver functions. These results suggest that the HAL has a strong possibility to be used in treating acute liver failure patients.2. Development of novel hybrid artificial liver module using hepatocyte organoid cultureAs a novel artificial liver module, we developed a hollow fiber module having a liver lobule-like structure, in which the hollow fibers representing blood vessels are arranged by spacers in a micro-regular arrangement within 150 μm. Inoculated hepatocytes in the extra-fiber space were formed in a lotus root-organoid by loading appropriate centrifugal force. The novel module achieved high cell density of about 4.0 x l0^7 cells / cm^3 - module and maintained better liver function compared to previous hollow fiber modules for several month. These results suggest that this novel module will be a new HAL for treatment of both chronic and acute liver failure patients, and for long-term bridge use for liver transplantation. Now we are investigating the optimization and scale up of the module.

1.用于临床试验的混合型人工肝的研制我们研制了一种混合型人工肝，它由含有200g原代猪肝细胞的多毛细管聚氨酯泡沫填充床和一条体外循环线组成。该模块中几乎所有的肝细胞都形成了球形，它们至少维持了2周的肝脏特异性功能。作为临床前研究，HAL应用于约25公斤热缺血性肝衰竭猪。在临床前研究中，我们证实了其具有抑制血氨升高、维持血糖、稳定生命体征和尿液排泄、延长生存时间等作用。HAL除了支持各种肝功能外，还能有效地稳定身体的一般状况。这些结果提示HAL有很强的可能性用于治疗急性肝功能衰竭患者。新型混合型人工肝模块的研制作为一种新型人工肝模块，我们研制了一种具有肝小叶样结构的中空纤维组件，其中代表血管的中空纤维在150μm内以微规则的方式排列，通过加载适当的离心力在纤维外间隙内形成接种的肝细胞。与以前的中空纤维组件相比，这种新型组件的细胞密度高达约4.0×10~(-7)个/厘米~3-模块，并保持了更好的肝功能。这些结果表明，这种新的模块将是一种新的HAL，用于治疗慢性和急性肝衰竭患者，并用于肝移植的长期过渡性使用。现在我们正在研究该模块的优化和放大。