Nelson Victoria L, Stumbras Aron R, Palumbo R Noelle, Riesgraf Shawn A, Balboa Marie S, Hannah Zachary A, Bergstrom Isaac J, Fecteau Christopher J, Lake John R, Barry John J, Ross Jeff J
Miromatrix Medical Inc., Eden Prairie, MN 55344, USA.
Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN 55455, USA.
Bioengineering (Basel). 2023 Oct 16;10(10):1201. doi: 10.3390/bioengineering10101201.
Acute Liver Failure (ALF) is a life-threatening illness characterized by the rapid onset of abnormal liver biochemistries, coagulopathy, and the development of hepatic encephalopathy. Extracorporeal bioengineered liver (BEL) grafts could offer a bridge therapy to transplant or recovery. The present study describes the manufacture of clinical scale BELs created from decellularized porcine-derived liver extracellular matrix seeded entirely with human cells: human umbilical vein endothelial cells (HUVECs) and primary human liver cells (PHLCs). Decellularized scaffolds seeded entirely with human cells were shown to adhere to stringent sterility and safety guidelines and demonstrated increased functionality when compared to grafts seeded with primary porcine liver cells (PPLCs). BELs with PHLCs were able to clear more ammonia than PPLCs and demonstrated lower perfusion pressures during patency testing. Additionally, to determine the full therapeutic potential of BELs seeded with PHLCs, longer culture periods were assessed to address the logistical constraints associated with manufacturing and transporting a product to a patient. The fully humanized BELs were able to retain their function after cold storage simulating a product transport period. Therefore, this study demonstrates the manufacture of bioengineered liver grafts and their potential in the clinical setting as a treatment for ALF.
急性肝衰竭（ALF）是一种危及生命的疾病，其特征为肝脏生化指标异常、凝血功能障碍迅速出现以及肝性脑病的发生。体外生物工程肝（BEL）移植物可为移植或恢复提供桥接治疗。本研究描述了临床规模BEL的制造过程，该BEL由完全接种人细胞的脱细胞猪源肝细胞外基质制成：人脐静脉内皮细胞（HUVECs）和原代人肝细胞（PHLCs）。完全接种人细胞的脱细胞支架显示符合严格的无菌和安全指南，并且与接种原代猪肝细胞（PPLCs）的移植物相比，功能有所增强。含有PHLCs的BEL比PPLCs能清除更多的氨，并且在通畅性测试期间显示出更低的灌注压力。此外，为了确定接种PHLCs的BEL的全部治疗潜力，评估了更长的培养期以解决与制造产品并将其运送给患者相关的后勤限制问题。在模拟产品运输期的冷藏后，完全人源化的BEL能够保持其功能。因此，本研究证明了生物工程肝移植物的制造及其在临床环境中作为ALF治疗方法的潜力。
