Development of a bioartificial liver: Properties and function of a hollow-fiber module inoculated with liver cells

Abstract

We have developed a bioartificial liver support system utilizing hollow-fiber bioreactor, plasmapheresis and microcarrier cell culture technologies. Liver cells were obtained through portal vein perfusion with ethylenediaminetetraacetate or ethylenediaminetetraacetate/collagenase. A mathematical model of mass transport in a hollow-fiber module, at various plasma flow velocities and system configurations, was developed. The bioartificial liver's ability to carry out specific differentiated metabolic liver functions was tested in vitro and in vivo. A reproducible large-animal model of acute ischemic liver failure was developed. Most major first-generation cyclosporine and 19-norterstosterone metabolites were isolated after substrate addition to the bioartificial liver in vitro. After bioartificial liver treatment for 6 hr (with dog or pig liver cells), dogs with acute liver failure had significantly lower serum ammonia and lactate levels and significantly higher serum glucose levels than did control animals treated with a bioartificial liver system inoculated with microcarriers alone. In addition, bioartificial liver-treated animals had significantly higher mean systolic blood pressures than did controls. Liver cell viability at the end of the 6-hr in vivo experiment was greater than 90%.

Bioreactor technologies to support liver function in vitro

“…Next it was found that primary rat cells cultured up to 45 days in a 7-cm long hollow fiber reactor with 520-0.3 mm diameter fibers maintained almost half the diazepam-metabolizing capacity after 10 days provided the perfusion medium was equilibrated with 30% oxygen atmosphere [102]. Not surprisingly, given the similar design features between hollow fiber cell culture reactors and blood dialysis units, liver cell culture in hollow fiber reactors soon emerged as a potentially promising approach for extracorporeal liver support to provide metabolic capacity in synthesis of urea and metabolism of toxic metabolites like bilirubin [103][102,104][105][106][107]. Detailed reviews of early work of the approximately dozen groups using various bioreactor formats for clinical extracorporeal liver support, including analysis of clinical constraints, can be found in a review by Rozga and co-workers [108], while later developments and clinical applications can be found in more recent reviews [109][110][111][112][113][114][115].…”

Prospects for Extracorporeal Liver Support

“…The biological devices, which aim to provide all of the functions of the normal liver, 3 4 are based on the use of living liver cells with either human hepatic cells as in the extracorporeal liver assist device (ELAD) device 5 or porcine hepatocytes as in the BAL device 6 and in various other European devices being developed in the Netherlands 7 and in Germany. 8 The other approach is based on detoxification functions only using membranes and adsorbents which can remove the putative toxins associated with liver failure.…”

Hybrid braided 3-D scaffold for bioartificial liver assist devices

“…In the development of an efficient BAL device, it is a great challenge to manufacture a suitable bioreactor that could ensure the accommodation and maintenance of an adequate number of viable cells [27]. The hybrid scaffold developed in this work provides a highly organized three-dimensional porous framework with welldefined pores and evenly distributed porosities that would increase the surface area of the bioreactor configuration for hepatocyte culture.…”