Abstract

Animal models such as rats and primates provide body-wide information for drug and metabolite responses, including organ-specific toxicity and any unforeseen side effects on other organs. While effective in the drug screening process, their translatability to humans is limited due to the lack of high concordance and correlation between enzymatic mechanisms, cellular mechanisms and resulting toxicities. A significant mode of failure for safety prediction in drug screening is hepatotoxicity, resulting in ~30% of all safety-related drug failures and withdrawals from the market. The liver is a multi-functional organ with diverse metabolic, secretory and inflammatory response roles and is essential for maintaining key body functions. Conventional cell culture platforms (such as multi-well plate cultures) and metabolic enzyme (microsomes, CYP450 enzyme) systems have been routinely utilized to assess drug pharmacokinetics and metabolism. However, current in vitro models often fail to recapitulate the complexity and dynamic nature of human tissues, imposing a heavy reliance on in vivo testing using preclinical species that have metabolic processes, disease mechanisms and modes of toxicity distinct from humans. Recently, microphysiological systems (MPS) have gained attention as powerful tools with the potential to generate human-relevant information that can supplant and fill the gap of knowledge between preclinical animal models and simpler, conventional in vitro cell culture systems. Developments in microfabrication technologies for generating complex microfluidic systems, along with the ability to generate and maintain multi-cellular models to capture dynamic, human-relevant behavior, have provided new avenues to generate such physiologically-relevant systems. These MPS platforms, when designed and developed with in vivo-derived design parameters, have the potential to capture key aspects and better mimic organ functionality. In this review, we discuss developments in microtechnologies for fabricating, establishing and maintaining hepatic cell culture systems, with a specific focus on models that aim to capture in vivo physiology in vitro. By designing microscale systems to impart specific in vivo physiological parameters, it is possible to create a dynamic system that can capture multiple aspects of the hepatic microenvironment, bringing us closer to a comprehensive in vitro testing platform for hepatic responses and toxicities.