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Microphysiological Systems (MPSs) or organs-on-chips, are microfluidic devices used to model human physiology in vitro. Polydimethylsiloxane (PDMS) is the most widely used material for organs-on-chips due to its established fabrication methods and biocompatibility properties. However, non-specific binding of small molecules limits PDMS for drug screening applications. Here, we designed a novel acrylic-based MPS to capture the physiological architecture that is observed universally in tissues across the body: the endothelial–epithelial interface (EEI). To reconstruct the EEI biology, we designed a membrane-based chip that features endothelial cells on the underside of the membrane exposed to mechanical shear from the path of media flow, and epithelial cells on the opposite side of the membrane protected from flow, as they are in vivo. We used a liver model with a hepatic progenitor cell line and human umbilical vein endothelial cells to assess the biological efficacy of the MPS. We computationally modeled the physics that govern the function of perfusion through the MPS. Empirically, efficacy was measured by comparing differentiation of the hepatic progenitor cells between the MPS and 2D culture conditions. We demonstrated that the MPS significantly improved hepatocyte differentiation, increased extracellular protein transport, and raised hepatocyte sensitivity to drug treatment. Our results strongly suggest that physiological perfusion has a profound effect on proper hepatocyte function, and the modular chip design motivates opportunities for future study of multi-organ interactions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Viral hepatitis is a leading cause of liver disease and mortality. Infection can occur acutely or chronically, but the mechanisms that govern the clearance of virus or lack thereof are poorly understood and merit further investigation. Though cures for viral hepatitis have been developed, they are expensive, not readily accessible in vulnerable populations and some patients may remain at an increased risk of developing hepatocellular carcinoma (HCC) even after viral clearance. To sustain infection in vitro, hepatocytes must be fully mature and remain in a differentiated state. However, primary hepatocytes rapidly dedifferentiate in conventional 2D in vitro platforms. Physiologically relevant or physiomimetic microsystems, are increasingly popular alternatives to traditional two-dimensional (2D) monocultures for in vitro studies. Physiomimetic systems reconstruct and incorporate elements of the native cellular microenvironment to improve biologic functionality in vitro. Multiple elements contribute to these models including ancillary tissue architecture, cell co-cultures, matrix proteins, chemical gradients and mechanical forces that contribute to increased viability, longevity and physiologic function for the tissue of interest. These microsystems are used in a wide variety of applications to study biological phenomena. Here, we explore the use of physiomimetic microsystems as tools for studying viral hepatitis infection in the liver and how the design of these platforms is tailored for enhanced investigation of the viral lifecycle when compared to conventional 2D cell culture models. Although liver-based physiomimetic microsystems are typically applied in the context of drug studies, the platforms developed for drug discovery purposes offer a solid foundation to support studies on viral hepatitis. Physiomimetic platforms may help prolong hepatocyte functionality in order to sustain chronic viral hepatitis infection in vitro for studying virus-host interactions for prolonged periods. [ABSTRACT FROM AUTHOR]