Pivotal preclinical trial of the spheroid reservoir bioartificial liver

JOURNAL OF HEPATOLOGY

卷:63

Article

Glorioso, Jaime M.¹  Mao, Shennen A.¹  Rodysill, Brian¹  Mounajjed, Taufic²  Kremers, Walter K.^3,4  Elgilani, Faysal⁴  Hickey, Raymond D.^4,5  Haugaa, Hakon^6,7  Rose, Christopher F.⁸  Amiot, Bruce⁹  Nyberg, Scott L.^1,4 

[1] Mayo Clin, Dept Surg, Rochester, MN 55905 USA

[2] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA

[3] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA

[4] Mayo Clin, William J von Liebig Ctr Transplantat & Clin Rege, Rochester, MN 55905 USA

[5] Mayo Clin, Dept Mol Med, Rochester, MN 55905 USA

[6] Oslo Univ Hosp, Dept Emergencies & Crit Care, Oslo, Norway

[7] Univ Oslo, Inst Clin Med, N-0316 Oslo, Norway

[8] Univ Montreal, CRCHUM, Hepatoneuro Lab, Montreal, PQ H3C 3J7, Canada

[9] Brami Biomed Inc, Minneapolis, MN USA

关键词: Liver failure;    Bioartificial liver;    Spheroid;    Hepatocyte;    D-galactosamine;   

DOI  :  10.1016/j.jhep.2015.03.021

来源: Elsevier

【 摘 要 】

Background & Aims: The neuroprotective effect of the spheroid reservoir bioartificial liver (SRBAL) was evaluated in a porcine model of drug-overdose acute liver failure (ALF). Methods: Healthy pigs were randomized into three groups (standard therapy (ST) alone, ST + No-cell device, ST + SRBAL device) before placement of an implantable intracranial pressure (ICP) monitor and a tunneled central venous catheter. One week later, pigs received bolus infusion of the hepatotoxin D-galactosamine and were followed for up to 90 h. Results: At 48 h, all animals had developed encephalopathy and biochemical changes confirming ALF; extracorporeal treatment was initiated and pigs were observed up to 90 h after drug infusion. Pigs treated with the SRBAL, loaded with porcine hepatocyte spheroids, had improved survival (83%, n = 6) compared to ST alone (0%, n = 6, p = 0.003) and No-cell device therapy (17%, n = 6, p = 0.02). Ammonia detoxification, peak levels of serum ammonia and peak ICP, and pig survival were influenced by hepatocyte cell dose, membrane pore size and duration of SRBAL treatment. Hepatocyte spheroids remained highly functional with no decline in mean oxygen consumption from initiation to completion of treatment. Conclusions: The SRBAL improved survival in an allogeneic model of drug-overdose ALF. Survival correlated with ammonia detoxification and ICP lowering indicating that hepatocyte spheroids prevented the cerebral manifestations of ALF (brain swelling, herniation, death). Further investigation of SRBAL therapy in a clinical setting is warranted. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

Free