Randomized Trial of Spheroid Reservoir Bioartificial Liver in Porcine Model of Posthepatectomy Liver Failure

Harvey S. Chen, Dong Jin Joo, Mohammed Shaheen, Yi Li, Yujia Wang, Jian Yang, Clara T. Nicolas, Kelly Predmore, Bruce Amiot, Gregory Michalak, Taofic Mounajjed, Jeff Fidler, Walter K Kremers, Scott Nyberg

Research output: Contribution to journalArticle

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Abstract

Acute liver failure (ALF) is a catastrophic condition that can occur after major liver resection. The aim of this study was to determine the effects of the spheroid reservoir bio-artificial liver (SRBAL) on survival, serum chemistry, and liver regeneration in posthepatectomy ALF pigs. Wild-type large white swine (20 kg-30 kg) underwent intracranial pressure (ICP) probe placement followed by 85% hepatectomy. Computed tomography (CT) volumetrics were performed to measure the extent of resection, and at 48 hours following hepatectomy to assess regeneration of the remnant liver. Animals were randomized into three groups based on treatment delivered 24-48 hours after hepatectomy: Group1—standard medical therapy (SMT, n = 6); Group2—SMT plus bio-artificial liver treatment using no hepatocytes (0 g, n = 6); and Group3—SMT plus SRBAL treatment using 200 g of primary porcine hepatocyte spheroids (200 g, n = 6). The primary endpoint was survival to 90 hours following hepatectomy. Death equivalent was defined as unresponsive grade 4 hepatic encephalopathy or ICP greater than 20 mmHg with clinical evidence of brain herniation. All animals in both (SMT and 0 g) control groups met the death equivalent before 51 hours following hepatectomy. Five of 6 animals in the 200-g group survived to 90 hours (P < 0.01). The mean ammonia, ICP, and international normalized ratio values were significantly lower in the 200-g group. CT volumetrics demonstrated increased volume regeneration at 48 hours following hepatectomy in the 200-g group compared with the SMT (P < 0.01) and 0-g (P < 0.01) groups. Ki-67 staining showed increased positive staining at 48 hours following hepatectomy (P < 0.01). Conclusion: The SRBAL improved survival, reduced ammonia, and accelerated liver regeneration in posthepatectomy ALF. Improved survival was associated with a neuroprotective benefit of SRBAL therapy. These favorable results warrant further clinical testing of the SRBAL.

Original languageEnglish (US)
Pages (from-to)329-342
Number of pages14
JournalHepatology
Volume69
Issue number1
DOIs
StatePublished - Jan 1 2019

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Artificial Liver
Liver Failure
Hepatectomy
Swine
Liver Regeneration
Acute Liver Failure
Cone-Beam Computed Tomography
Ammonia
Hepatocytes
Staining and Labeling
International Normalized Ratio
Hepatic Encephalopathy
Regeneration
Pressure
Control Groups
Liver
Brain
Therapeutics
Serum

ASJC Scopus subject areas

  • Hepatology

Cite this

Randomized Trial of Spheroid Reservoir Bioartificial Liver in Porcine Model of Posthepatectomy Liver Failure. / Chen, Harvey S.; Joo, Dong Jin; Shaheen, Mohammed; Li, Yi; Wang, Yujia; Yang, Jian; Nicolas, Clara T.; Predmore, Kelly; Amiot, Bruce; Michalak, Gregory; Mounajjed, Taofic; Fidler, Jeff; Kremers, Walter K; Nyberg, Scott.

In: Hepatology, Vol. 69, No. 1, 01.01.2019, p. 329-342.

Research output: Contribution to journalArticle

Chen, HS, Joo, DJ, Shaheen, M, Li, Y, Wang, Y, Yang, J, Nicolas, CT, Predmore, K, Amiot, B, Michalak, G, Mounajjed, T, Fidler, J, Kremers, WK & Nyberg, S 2019, 'Randomized Trial of Spheroid Reservoir Bioartificial Liver in Porcine Model of Posthepatectomy Liver Failure', Hepatology, vol. 69, no. 1, pp. 329-342. https://doi.org/10.1002/hep.30184
Chen, Harvey S. ; Joo, Dong Jin ; Shaheen, Mohammed ; Li, Yi ; Wang, Yujia ; Yang, Jian ; Nicolas, Clara T. ; Predmore, Kelly ; Amiot, Bruce ; Michalak, Gregory ; Mounajjed, Taofic ; Fidler, Jeff ; Kremers, Walter K ; Nyberg, Scott. / Randomized Trial of Spheroid Reservoir Bioartificial Liver in Porcine Model of Posthepatectomy Liver Failure. In: Hepatology. 2019 ; Vol. 69, No. 1. pp. 329-342.
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abstract = "Acute liver failure (ALF) is a catastrophic condition that can occur after major liver resection. The aim of this study was to determine the effects of the spheroid reservoir bio-artificial liver (SRBAL) on survival, serum chemistry, and liver regeneration in posthepatectomy ALF pigs. Wild-type large white swine (20 kg-30 kg) underwent intracranial pressure (ICP) probe placement followed by 85{\%} hepatectomy. Computed tomography (CT) volumetrics were performed to measure the extent of resection, and at 48 hours following hepatectomy to assess regeneration of the remnant liver. Animals were randomized into three groups based on treatment delivered 24-48 hours after hepatectomy: Group1—standard medical therapy (SMT, n = 6); Group2—SMT plus bio-artificial liver treatment using no hepatocytes (0 g, n = 6); and Group3—SMT plus SRBAL treatment using 200 g of primary porcine hepatocyte spheroids (200 g, n = 6). The primary endpoint was survival to 90 hours following hepatectomy. Death equivalent was defined as unresponsive grade 4 hepatic encephalopathy or ICP greater than 20 mmHg with clinical evidence of brain herniation. All animals in both (SMT and 0 g) control groups met the death equivalent before 51 hours following hepatectomy. Five of 6 animals in the 200-g group survived to 90 hours (P < 0.01). The mean ammonia, ICP, and international normalized ratio values were significantly lower in the 200-g group. CT volumetrics demonstrated increased volume regeneration at 48 hours following hepatectomy in the 200-g group compared with the SMT (P < 0.01) and 0-g (P < 0.01) groups. Ki-67 staining showed increased positive staining at 48 hours following hepatectomy (P < 0.01). Conclusion: The SRBAL improved survival, reduced ammonia, and accelerated liver regeneration in posthepatectomy ALF. Improved survival was associated with a neuroprotective benefit of SRBAL therapy. These favorable results warrant further clinical testing of the SRBAL.",
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AU - Wang, Yujia

AU - Yang, Jian

AU - Nicolas, Clara T.

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AU - Michalak, Gregory

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