Abstract
Drug-induced liver injury (DILI) is a major cause of drug attrition. Testing drugs on human liver models is essential to mitigate the risk of clinical DILI since animal studies do not always suffice due to species-specific differences in liver pathways. While primary human hepatocytes (PHHs) can be cultured on extracellular matrix proteins, a rapid decline in functions leads to low sensitivity (<50%) in DILI prediction. Semiconductor-driven engineering tools now allow precise control over the hepatocyte microenvironment to enhance and stabilize phenotypic functions. The latest platforms coculture PHHs with stromal cells to achieve hepatic stability and enable crosstalk between the various liver cell types towards capturing complex cellular mechanisms in DILI. The recent introduction of induced pluripotent stem cell-derived human hepatocyte-like cells can potentially allow a better understanding of interindividual differences in idiosyncratic DILI. Liver models are also being coupled to other tissue models via microfluidic perfusion to study the intertissue crosstalk upon drug exposure as in a live organism. Here, we review the major advances being made in the engineering of liver models and readouts as they pertain to DILI investigations. We anticipate that engineered human liver models will reduce drug attrition, animal usage, and cases of DILI in humans.
Highlights
Drug-induced liver injury (DILI) is a leading cause of pharmaceutical attrition and acute liver failures in the US [1]
These results suggest that induced pluripotent stem cells (iPSCs)-HH-based micropatterned cocultures (MPCCs) may be ready for an initial drug toxicity screen during drug development; mechanistic inquiries into DILI outcomes will require further probing of active pathways within iPSC-HHs relative to primary human hepatocytes (PHHs)
While the development of human liver models was initiated many decades ago with the isolation and culture of PHHs on extracellular matrix (ECM), the rapid functional decline of these cells outside of their native liver microenvironment limits the prediction of clinical DILI outcomes [12, 14]
Summary
Drug-induced liver injury (DILI) is a leading cause of pharmaceutical attrition and acute liver failures in the US [1]. BioMed Research International on drug behavior [4] These include microsomes, cancerous/immortalized cell lines, isolated primary human liver cells, liver slices, and humanized rodents. While these models have already been used in some instances to mitigate the risk of DILI during drug development, there remains a need for model systems that are better predictive of clinical outcomes, with respect to the type and severity of DILI, and can be used to elucidate interindividual variability in drug outcomes. We highlight key published studies that demonstrate the different types of model systems and data sets generated for detection of DILI, while referring the reader to other review articles that provide more comprehensive information on specific technologies and/or methodologies
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