Development of the artificial liver assist device with normothermic xenoperfusion system of the whole liver

为了辅助肝脏的各种功能，本项目对异种猪肝作为肝脏辅助装置的使用进行了评估。在本研究中，我们原有的肝脏灌注系统，包括持续给药前列腺素E1，短冷缺血时间，生理调节，使猪肝脏异种灌注超过9小时，肝脏代谢能力充足。利用该系统，我们成功地对手术性肝衰竭犬进行了有效的肝辅助。这些结果于1997年在美国人工内脏器官学会和美国移植医师学会的大会上发表。然而，长期的猪肝异种灌流通过人抗猪异种抗原激活人补体系统而引起严重的体液损伤。因此，我们必须克服这种异质体液损伤，以开发更有效的肝辅助装置。在这项研究中，我们发现重组可溶性补体受体I型（sCR1）在人全血异种灌注猪肝时显著抑制体液损伤。使用sCR1，猪全肝异种灌注可持续24小时以上，肝功能良好。1997年4月，我们在京都大学医院建立了异种器官使用系统，将该系统应用于临床。现在，我们正在评估猪肝异种灌流系统的安全性，用狒狒代替人作为临床前研究。

To assist various functions of the liver, usage of the xenogeneic pig liver as a liver assist device were evaluated in this progect. In this study, our original liver perfusion system, including continuous prostaglandin E1 administration, short cold ischemic time, physiological conditioning, enabled the pig liver to be xenoperfused more than 9 hours with adequate hepatic metabolic capacity. With this system, we succeeded in effective liver assist of the surgically induced liver failure dogs. These results were presented at both congresses of the American Society of the Artificial Internal Organ and American Society of Transplantation Physician in 1997. However, long-term pig liver xenoperfusion causes severe humoral injury via activation of human complement system by human anti-porcine xenoantigen. Hence, we had to conquer this xenogeneic humoral injury to develop more potent liver assist device. In this study, we revealed that recombinant soluble Complement Receptor type I (sCR1) dramatically suppressed humoral injury during xenoperfusion of the pig liver with human whole blood. With sCR1, xenoperfusion of the pig whole liver could be continued more than 24 hours with high hepatic function. To introduce this system to the clinical field, we established the xenogeneic organ usage system in April 1997 in Kyoto University Hospital. Now, we are evaluating the safety of the pig liver xenoperfusion system with baboon instead of human as a preclinical study.