Physiomimetic In Vitro Human Models for Viral Infection in the Liver

Abstract

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 (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. Alternatively, physiomimetic models 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 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.

Human organoids-on-chips for biomedical research and applications

“…Due to species differences in animal and human biology, it is highly desirable to develop a robust, available and humanized organ model that reflects human pathological features with viral infection. Organ chips present a rapid and effective tool to explore viral infection and transmission dynamics in a realistic manner 257 , 260 , 263 , 264 . Morphological analysis of respiratory syncytial virus-infected airway organoids uncovered a wide range of impairments ranging from cytoskeletal rearrangements and apical extrusion of infected cells, to syncytia formation 265 .…”

“…Both clinical and animal findings showed that viral infection can cause a variety of diseases [257][258][259][260][261]. For example, human immunodeficiency virus (HIV) infection can result in long-term neuropsychiatric adverse effects (neurotoxicity, depression, anxiety, and mood disorders) on individuals [26,83,260,262].…”

Microfluidic strategies for biomimetic lung chip establishment and SARS-CoV2 study

“…The rapid spread, transmission, and evolution of SARS-CoV2 have increased the risks of pandemics [ 27 , 113 , 114 ]. Developing effective antiviral drugs and vaccines has become increasingly complex with the emergence of new viral strains.…”

“…Apart from lung chips, liver chips, gut chips, and blood-brain barrier chips have recently been developed independently for SARS-CoV2 research. These diverse microfluidic systems provide a platform for accurate and efficient modeling and preclinical testing, which could ultimately expedite the discovery of effective treatments to combat pandemics [ 114 , 116 , 120 , 138 ]. Another way to address the limitations of microfluidic lung chips is to include multi-organ systems in the design, presenting complicated and near-physiological organ models for host-virus interplay in vitro .…”