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Development and in vivo testing of bioartificial liver support systems for treatmnet of acute hepatic failure

Objective

To obtain primary porcine hepatocyte cultures and determine rate equations for oxygen consumption and other metabolic reactions in various culture media and in liver failure serum.
To perform hydrodynamic optimisation and obtain macroscopic transfer models of specific bioreactors containing immobilised primary porcine hepatocytes.
To evaluate bioreactor function in vivo model of liver failure.

Engineering design techniques and mathematical analysis in conjunction with relevant cell biology and clinical experience will be employed to develop optimised hepatocyte bioreactors for treatment of fulminant hepatic failure (FHF). Primary porcine hepatocytes will be obtained and evaluated in static cultures using different culture media, normal blood plasma and FHF plasma. Cell viability will be assessed by lactate dehydrogenase release and function by cytochrome P450 content, activities of P450 isoenzymes, urea synthesis and changes in reduced glutathione content. Rate equations for several liver dependent metabolic functions will be obtained in a smallscale flow reactor seeded with porcine hepatocytes. The influence of metabolite concentrations and physical operatic;, parameters ( e.g. shear rate. cell density. pH) will be studied. A novel oxystat apparatus will be used to determine cellular oxygen consumption during the critical phase of cell attachment to selected substrata as well as in the post-attachment phase of operation. These fundamental properties will enable the development of macroscopic mass transfer models of two existing bioreactor designs. Both designs utilise fibre technology to provide integral oxygenation. Fluid dynamic optimisation of these devices will he carried out and scaling rules established for bioreactor scale-up. Long term in bitro testing of the bioreactors will be performed with different culture media, normal plasma and FHF plasma. Finally, a scaled-up design will be evaluated in an animal model of FHR. Important aspects of this latter task are the establishment of a stable model of FHF and successful integration of the bioreactor and associated plasmapheresis system in the extra-corporal circuit.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

University of Strathclyde
Address
106 Rottenrow
G4 0NW Glasgow
United Kingdom

Participants (4)

Humboldt-Universität zu Berlin
Germany
Address
1,Augustenburger Platz
13353 Berlin
National and Kapodistrian University of Athens
Greece
Address
17,Ag Thoma Street
115 27 Athens
University of Edinburgh
United Kingdom
Address
Lauriston Place
EH3 9YW Edinburgh
Università degli Studi della Calabria
Italy
Address
Via Pietro Bucci
87030 Arcavacata Di Rende