The liver plays a critical role in the metabolism and clearance of more than 70% of marketed drugs. Furthermore, toxicity to the liver is a major reason for preclinical and clinical drug failures. Animals are not always predictive of human liver-drug interactions due to significant species-specific differences in drug metabolism and toxicity pathways. Thus, in vitro models of the human liver are now routinely utilized in pharmaceutical practice to complement animal testing; such models enable faster and cheaper drug testing and hold the promise to prevent harm to living patients. Isolated primary human liver cells are the gold standard for fabricating human liver models, but these cells rapidly lose their liver functions, including drug metabolism capacities, in conventional 2-dimensional monocultures. In contrast, semiconductor-driven microfabrication tools and co-culture with non-parenchymal cells have been used to precisely modulate the microenvironment around hepatocytes towards enhancing and stabilizing phenotypic functions for 4-6 weeks. Such engineered liver co-cultures have significantly improved the sensitivity for the detection of drug clearance, drug metabolite identification, drug-transporter interactions, and drug-induced liver toxicity. This presentation will showcase the development and validation of engineered human liver co-cultures for the above-mentioned applications; it will then discuss emerging trends in further improving the physiological relevance of the platform using liver non-parenchymal cells and determining the role of major liver diseases (e.g., non-alcoholic fatty liver disease) in changing drug outcomes.
1. The key design features necessary for building robust in vitro human liver models and
2. The various applications within the drug development pipeline where such models can be effectively utilized.