Pivotal preclinical trial of the spheroid reservoir bioartificial liver

Jaime M. Glorioso, Shennen A. Mao, Brian Rodysill, Taofic Mounajjed, Walter K Kremers, Faysal Elgilani, Raymond Hickey, Hakon Haugaa, Christopher F. Rose, Bruce Amiot, Scott Nyberg

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)388-398
Number of pages11
JournalJournal of Hepatology
Volume63
Issue number2
DOIs
StatePublished - 2015

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Artificial Liver
Swine
Acute Liver Failure
Hepatocytes
Intracranial Pressure
Ammonia
Drug Overdose
Cell- and Tissue-Based Therapy
Equipment and Supplies
Therapeutics
Galactosamine
Central Venous Catheters
Brain Edema
Brain Diseases
Neuroprotective Agents
Group Psychotherapy
Oxygen Consumption
Cell Membrane
Serum

Keywords

  • Bioartificial liver
  • D-galactosamine
  • Hepatocyte
  • Liver failure
  • Spheroid

ASJC Scopus subject areas

  • Hepatology

Cite this

Pivotal preclinical trial of the spheroid reservoir bioartificial liver. / Glorioso, Jaime M.; Mao, Shennen A.; Rodysill, Brian; Mounajjed, Taofic; Kremers, Walter K; Elgilani, Faysal; Hickey, Raymond; Haugaa, Hakon; Rose, Christopher F.; Amiot, Bruce; Nyberg, Scott.

In: Journal of Hepatology, Vol. 63, No. 2, 2015, p. 388-398.

Research output: Contribution to journalArticle

Glorioso, Jaime M. ; Mao, Shennen A. ; Rodysill, Brian ; Mounajjed, Taofic ; Kremers, Walter K ; Elgilani, Faysal ; Hickey, Raymond ; Haugaa, Hakon ; Rose, Christopher F. ; Amiot, Bruce ; Nyberg, Scott. / Pivotal preclinical trial of the spheroid reservoir bioartificial liver. In: Journal of Hepatology. 2015 ; Vol. 63, No. 2. pp. 388-398.
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abstract = "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.",
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AU - Glorioso, Jaime M.

AU - Mao, Shennen A.

AU - Rodysill, Brian

AU - Mounajjed, Taofic

AU - Kremers, Walter K

AU - Elgilani, Faysal

AU - Hickey, Raymond

AU - Haugaa, Hakon

AU - Rose, Christopher F.

AU - Amiot, Bruce

AU - Nyberg, Scott

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AB - 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.

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