title: Pivotal preclinical trial of the spheroid reservoir bioartificial liver.
abstract: OBJECTIVE
  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 90h.
  
  
  RESULTS
  At 48h, all animals had developed encephalopathy and biochemical changes confirming ALF; extracorporeal treatment was initiated and pigs were observed up to 90h 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.
authors: Department of Surgery, Mayo Clinic, Rochester, MN, USA.
authors: Jaime M
authors: JM
authors: Glorioso
authors: Department of Surgery, Mayo Clinic, Rochester, MN, USA.
authors: Shennen A
authors: SA
authors: Mao
authors: Department of Surgery, Mayo Clinic, Rochester, MN, USA.
authors: Brian
authors: B
authors: Rodysill
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Taufic
authors: T
authors: Mounajjed
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA.
authors: Walter K
authors: WK
authors: Kremers
authors: William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA.
authors: Faysal
authors: F
authors: Elgilani
authors: William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors: Raymond D
authors: RD
authors: Hickey
authors: Department of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway.
authors: Hakon
authors: H
authors: Haugaa
authors: Hepato-Neuro Laboratory, CRCHUM, Universite de Montreal, Quebec, Canada.
authors: Christopher F
authors: CF
authors: Rose
authors: Brami Biomedical, Inc., Minneapolis, MN, USA.
authors: Bruce
authors: B
authors: Amiot
authors: Department of Surgery, Mayo Clinic, Rochester, MN, USA; William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA. Electronic address: nyberg.scott@mayo.edu.
authors: Scott L
authors: SL
authors: Nyberg
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D022781:Hepatocytes / Q000166:cytology*; D017114:Liver Failure, Acute / Q000628:therapy*; D019164:Liver, Artificial; D018874:Spheroids, Cellular; D013552:Swine; D023822:Tissue Engineering / Q000379:methods*
keywords: Bioartificial liver; D-galactosamine; Hepatocyte; Liver failure; Spheroid