Extracorporeal Liver Perfusion System for Artificial Liver Support Across a Membrane

Background

An extracorporeal porcine liver perfusion (ECPLP) system circumvents the limitations of hepatocyte based bio-artificial liver, but its clinical application has been limited so far due to the potential risk of transmission of porcine endogenous retroviruses. The aim of this study was to develop an ECPLP model that can provide artificial hepatic support across a semi-permeable membrane, which has the potential to block porcine viruses due to its pore size.

Materials and Methods

Livers from white landrace pigs were perfused with normothermic oxygenated blood using Medtronic BP560 centrifugal pump (Medtronic, Inc., Minneapolis. MN). This ECPLP system was used to support a “surrogate” patient across the filter Evaclio-EC4A. Function of liver was measured by indocyanine green retention at 15 min (ICGR15). Clearance of galactose, ammonia, and para-aminobenzoic acid infused into the “surrogate” patient circulation was calculated to assess liver support across the membrane. The study was designed as test (n = 15) versus control (n = 5), with control experiments having no liver in the circuit.

Results

For the test experiments, we perfused 15 livers with mean hepatic artery pressure of 87 mm Hg and flows of 1.2 L/min. ICGR15 in test experiments was 11%. Ammonia clearance was 945 mg/min/kg, galactose metabolic rate was 111.7 mg/min/Kg, and the hippurate ratio was 91% in the test. In contrast, the control experiments did not show any significant change in the concentration of any of these compounds.

Conclusion

Our ECPLP model was able to provide hepatic support in an experimental setting across a hollow fiber filter. Further work on an anhepatic animal is needed prior to application in human trials.

Introduction

Liver transplantation is the only available successful treatment of acute liver failure (ALF) with survival rates of up to 85% [1]. The clinical progression in fulminant hepatic failure is so rapid that these patients cannot wait on the transplant lists and therefore may face a very high mortality without a transplant. However, transient hepatic support can bridge these patients to safety with the end result being either availability of donor or regeneration of native liver. Support therapies based on non-biological adsorbent systems or biological devices are a subject of intense research. A bio-artificial liver (BAL) requires a large sustainable bio-mass of hepatocytes for which advanced and expensive tissue culture techniques are essential 2, 3, 4, 5, making its widespread use difficult. BAL has also not shown any survival benefit so far in trials involving ALF patients 6, 7, 8, 9. Clinical application of isolated perfused liver for hepatic support is an alternative, especially with the recent progresses made in pediatric cardiopulmonary bypass technology. Some authors have reported on the early experience of using extracorporeal porcine liver perfusion (ECPLP) system for ALF patients 10, 11, 12, 13. The major obstacle in the further development of these systems is potential transmission of porcine endogenous retroviruses (PERVs) into the human circulation. This problem can be solved by integrating a semi-permeable membrane in the ECPLP system that would inhibit the transfer of viruses while still allowing the free movement of albumin and hepatocyte growth factors. The current study was designed with the aim to set up such an ECPLP system and test its efficacy in an experimental setting.