Hepatocyte spheroid culture on fibrous scaffolds with grafted functional ligands as an in vitro model for predicting drug metabolism and hepatotoxicity

[Display omitted] The identification of a biologic substrate for maintaining hepatocyte functions is essential to provide reliable and predictable models for in vitro drug screening. In the current study, a three-dimensional culture of hepatocytes was established on highly porous fibrous scaffolds w...

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Bibliographic Details
Published in:Acta biomaterialia 2015-12, Vol.28, p.138-148
Main Authors: Yan, Shili, Wei, Jiaojun, Liu, Yaowen, Zhang, Hong, Chen, Jianmei, Li, Xiaohong
Format: Article
Language:English
Subjects:
Animals
Biocompatibility
Cells, Cultured
Density
Drug hepatotoxicity
Drug metabolism
Drug–drug interaction
Enzymes
Fibrous scaffold
Functional ligand
Hepatocyte spheroid
Hepatocytes - cytology
Hepatocytes - drug effects
Hepatocytes - metabolism
In Vitro Techniques
In vitro testing
Ligands
Mathematical models
Metabolism
Microscopy, Electron, Scanning
Rats
Rats, Sprague-Dawley
Scaffolds
Spheroids
Tissue Scaffolds
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Summary:[Display omitted] The identification of a biologic substrate for maintaining hepatocyte functions is essential to provide reliable and predictable models for in vitro drug screening. In the current study, a three-dimensional culture of hepatocytes was established on highly porous fibrous scaffolds with grafted galactose and RGD to afford extensive cell–cell and cell–scaffold interactions spatially. The pore size and ligand densities indicated significant effects on the formation of hepatocyte spheroids in balancing the cell retention, adhesion, and migration on fibrous scaffolds. Fibrous scaffolds with an average pore size of 60μm and surface grafting densities of galactose at 5.9nmol/cm2 and RGD at 6.9pmol/cm2 provided optimal microenvironments for hepatocyte infiltration and multicellular spheroid formation. Significant promotions were also demonstrated in the syntheses of albumin and urea and the activities of phase I (CYP 3A11 and CYP 2C9) and phase II enzymes. The in vitro metabolism tests on testosterone and acetaminophen by hepatocytes on the optimal scaffolds indicated the predicated clearance rates of 50.7 and 22.6ml/min/kg, respectively, which were comparable to the in vivo values of rats. The in vitro hepatotoxicity tests on amiodarone hydrochloride and acetaminophen predicted the half maximal effective concentrations (EC50) to reflect the in vivo toxic plasma concentrations in human. In addition, the enzyme activities, predicted clearance rates and hepatotoxicity values of hepatocytes on the optimal scaffolds experienced sensitive responsiveness to specific inducers or inhibitors of CYP 3A11 and phase II enzymes, exhibiting in vivo–in vitro correlations to a certain extent. These results demonstrate the feasibility of hepatocyte spheroid culture on fibrous scaffolds as an potential in vitro testing model to predict the in vivo drug metabolism, hepatotoxicity, and drug–drug interactions.
ISSN:1742-7061
1878-7568
DOI:10.1016/j.actbio.2015.09.027