Abstract
Viral hepatitis is a leading cause of liver morbidity and mortality globally. Symptomatic infection can occur acutely with subsequent clearance, or result in a chronic infection. The mechanisms underlying acute infection and clearance, versus the development of chronic infection, are poorly understood. The prevalence and severity of viral hepatitis necessitates research on the progression of infection to liver disease. 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, there are significant challenges associated with modeling long-term infection in vitro. For example, standard two-dimensional (2D) 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. Differentiated hepatocytes are best able to sustain chronic viral hepatitis infection; therefore, traditional 2D cultures have challenges recapitulating a hepatocyte’s physiological response to infection over weeks to months. Alternatively, microphysiological systems (MPSs) facilitate important interactions between hepatocytes and their microenvironment by incorporating liver-specific environmental factors such as three-dimensional (3D) ECM interactions and co-culture with other non-parenchymal cells. These physiologically relevant interactions help maintain a mature and functional hepatocyte phenotype, that is critical for sustaining viral hepatitis infection. We designed, built, and tested a novel MPS, specifically with the goal of modeling chronic viral hepatitis infection. We achieved this by incorporating microenvironmental factors from the hepatic acinus, including co-cultures of multiple cell types with proper orientation, requisite ECM components, and perfusion to reconstruct the liver’s biology in an in vitro platform.