CC BY-NC-ND 4.0 · Semin Liver Dis 2023; 43(01): 031-049
DOI: 10.1055/a-1981-5944
Review Article

Physiomimetic In Vitro Human Models for Viral Infection in the Liver

Dennis McDuffie
1   Department of Biomedical Engineering, University of Miami, Coral Gables, Florida
David Barr
2   Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida
Madeline Helm
1   Department of Biomedical Engineering, University of Miami, Coral Gables, Florida
Thomas Baumert
3   Inserm Research Institute for Viral and Liver Diseases, University of Strasbourg, Strasbourg, France
Ashutosh Agarwal
1   Department of Biomedical Engineering, University of Miami, Coral Gables, Florida
4   Desai Sethi Urology Institute, Miller School of Medicine, University of Miami, Miami, Florida
6   Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
Emmanuel Thomas
1   Department of Biomedical Engineering, University of Miami, Coral Gables, Florida
2   Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida
5   Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida
6   Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
› Author Affiliations
Funding This work was supported by NIH-NIGMS grant R35GM124915.


Viral hepatitis is a leading cause of liver morbidity and mortality globally. The mechanisms underlying acute infection and clearance, versus the development of chronic infection, are poorly understood. In vitro models of viral hepatitis circumvent the high costs and ethical considerations of animal models, which also translate poorly to studying the human-specific hepatitis viruses. However, significant challenges are associated with modeling long-term infection in vitro. Differentiated hepatocytes are best able to sustain chronic viral hepatitis infection, but standard two-dimensional models are limited because they fail to mimic the architecture and cellular microenvironment of the liver, and cannot maintain a differentiated hepatocyte phenotype over extended periods. Alternatively, physiomimetic models facilitate important interactions between hepatocytes and their microenvironment by incorporating liver-specific environmental factors such as three-dimensional ECM interactions and co-culture with non-parenchymal cells. These physiologically relevant interactions help maintain a functional hepatocyte phenotype that is critical for sustaining viral hepatitis infection. In this review, we provide an overview of distinct, novel, and innovative in vitro liver models and discuss their functionality and relevance in modeling viral hepatitis. These platforms may provide novel insight into mechanisms that regulate viral clearance versus progression to chronic infections that can drive subsequent liver disease.

Authors' Contribution

Paper concept, design, and drafting of the manuscript were performed by D.M., D.B., M.H., T.B., E.T., and A.A.

Publication History

Accepted Manuscript online:
19 November 2022

Article published online:
10 January 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (

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