title: Scaling down of a clinical three-dimensional perfusion multicompartment hollow fiber liver bioreactor developed for extracorporeal liver support to an analytical scale device useful for hepatic pharmacological in vitro studies.
abstract: Within the scope of developing an in vitro culture model for pharmacological research on human liver functions, a three-dimensional multicompartment hollow fiber bioreactor proven to function as a clinical extracorporeal liver support system was scaled down in two steps from 800 mL to 8 mL and 2 mL bioreactors. Primary human liver cells cultured over 14 days in 800, 8, or 2 mL bioreactors exhibited comparable time-course profiles for most of the metabolic parameters in the different bioreactor size variants. Major drug-metabolizing cytochrome P450 activities analyzed in the 2 mL bioreactor were preserved over up to 23 days. Immunohistochemical studies revealed tissue-like structures of parenchymal and nonparenchymal cells in the miniaturized bioreactor, indicating physiological reorganization of the cells. Moreover, the canalicular transporters multidrug-resistance-associated protein 2, multidrug-resistance protein 1 (P-glycoprotein), and breast cancer resistance protein showed a similar distribution pattern to that found in human liver tissue. In conclusion, the down-scaled multicompartment hollow fiber technology allows stable maintenance of primary human liver cells and provides an innovative tool for pharmacological and kinetic studies of hepatic functions with small cell numbers.
authors.affiliation: Division of Experimental Surgery, Berlin Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin Berlin, Berlin, Germany. katrin.zeilinger@charite.de
authors.forename: Katrin
authors.initials: K
authors.lastname: Zeilinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Schreiter
authors.forename: Malin
authors.initials: M
authors.lastname: Darnell
authors.forename: Therese
authors.initials: T
authors.lastname: Söderdahl
authors.forename: Marc
authors.initials: M
authors.lastname: Lübberstedt
authors.forename: Birgitta
authors.initials: B
authors.lastname: Dillner
authors.forename: Daniel
authors.initials: D
authors.lastname: Knobeloch
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Nüssler
authors.forename: Jörg C
authors.initials: JC
authors.lastname: Gerlach
authors.forename: Tommy B
authors.initials: TB
authors.lastname: Andersson
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D019540:Area Under Curve; D019149:Bioreactors; D018929:Cell Culture Techniques / Q000295:instrumentation*; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D019164:Liver, Artificial; D009363:Neoplasm Proteins / Q000378:metabolism; D010477:Perfusion / Q000295:instrumentation*; D013997:Time Factors; D023822:Tissue Engineering / Q000295:instrumentation* / Q000379:methods*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D003577:Cytochrome P-450 Enzyme System; D009363:Neoplasm Proteins; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C116614:ABCG2 protein, human