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Novel Bioartificial Liver Support System: Preclinical Evaluation

Authors

  • JOHN F. PATZER II,

    1. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213-2582, USA
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  • GEORGE V. MAZARIEGOS,

    1. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213-2582, USA
    2. Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
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  • ROBERTO LOPEZ,

    1. Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
    2. Department of Surgery, Universidad de Monterrey, Monterrey, NL, Mexico
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  • ERNESTO MOLMENTI,

    1. Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
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  • DAVID GERBER,

    1. Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
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  • FRIDTJOV RIDDERVOLD,

    1. Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
    2. Department of Anesthesiology, Rikshospitalet, University of Oslo, National University Hospital of Norway, N-0027 Oslo 1, Norway
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  • AJAI KHANNA,

    1. Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
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  • WEN-YAO YIN,

    1. Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
    2. Tzu-Chi General Hospital, Hualien, Taiwan, ROC
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  • YONG CHEN,

    1. Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
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  • VICTOR L. SCOTT,

    1. Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
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  • SHUSHMA AGGARWAL,

    1. Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
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  • DAVID J KRAMER,

    1. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213-2582, USA
    2. Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
    3. Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
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  • ROBERT A. WAGNER,

    1. Central Animal Facility, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
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  • YUE ZHU,

    1. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213-2582, USA
    2. Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
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  • MELISSA L. FULMER,

    1. Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213–2582, USA
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  • GEOFFREY D. BLOCK,

    1. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213-2582, USA
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  • BRUCE P AMIOT

    1. Excorp Medical, Inc., Suite 235, 7200 Hudson Boulevard, Oakdale, Minnesota 55128, USA
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Author for correspondence: Departments of Surgery and Chemical Engineering, 1249 Benedum Hall, University of Pittsburgh, Pittsburgh, PA 15261; 412-624-9819 (voice); 412-624-9639 (fax); patzer+@pitt.edu (e-mail)

Abstract

ABSTRACT: Preclinical safety and efficacy evaluation of a novel bioartificial liver support system (BLSS) was conducted using a d-galactosamine canine liver failure model. The BLSS houses a suspension of porcine hepatocytes in a hollow fiber cartridge with the hepatocytes on one side of the membrane and whole blood flowing on the other. Porcine hepatocytes harvested by a collagenase digestion technique were infused into the hollow fiber cartridge and incubated for 16 to 24 hours prior to use. Fifteen purpose-bred male hounds, 1–3 years old, 25–30 kg, were administered a lethal dose, 1.5 g/kg, of d-galactosamine. The animals were divided into three treatment groups: (1b) no BLSS treatment (

n = 6

); (2b) BLSS treatment starting at 24–26 h post d-galactosamine (

n = 5

); and (2c) BLSS treatment starting at 16–18 h post d-galactosamine (

n = 4

). While maintained under isoflurane anesthesia, canine supportive care was guided by electrolyte and invasive physiologic monitoring consisting of arterial pressure, central venous pressure, extradural intracranial pressure (ICP), pulmonary artery pressure, urinary catheter, and end-tidal CO2. All animals were treated until death or death-equivalent (inability to sustain systolic blood pressure > 80 mmHg for 20 minutes despite massive fluid resuscitation and/or dopamine administration), or euthanized at 60 hours. All animals developed evidence of liver failure at 12–24 hours as evidenced by blood pressure lability, elevated ICP, marked hepatocellular enzyme elevation with microscopic massive hepatocyte necrosis and cerebral edema, elevated prothrombin time, and metabolic acidosis. Groups 2b and 2c marginally prolong survival compared with Group 1b (pairwise log rank censored survival time analysis,

p= 0.096

and

p= 0.064

, respectively). Since survival times for Groups 2b and 2c are not significantly different (

p= 0.694

), the groups were combined for further statistical analysis. Survival times for the combined active treatment Groups 2b and 2c are significantly prolonged versus Group 1b (

p= 0.047

). These results suggest the novel BLSS reported here can have a significant impact on the course of liver failure in the d-galactosamine canine liver failure model. The BLSS is ready for Phase I safety evaluation in a clinical setting.

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