Abstract
Drug-induced liver injury (DILI) is a leading cause of drug attrition, which is partly due to differences between preclinical animals and humans in metabolic pathways. Therefore, in vitro human liver models are utilized in biopharmaceutical practice to mitigate DILI risk and assess related mechanisms of drug transport and metabolism. However, liver cells lose phenotypic functions within 1–3 days in two-dimensional monocultures on collagen-coated polystyrene/glass, which precludes their use to model the chronic effects of drugs and disease stimuli. To mitigate such a limitation, bioengineers have adapted tools from the semiconductor industry and additive manufacturing to precisely control the microenvironment of liver cells. Such tools have led to the fabrication of advanced two-dimensional and three-dimensional human liver platforms for different throughput needs and assay endpoints (e.g., micropatterned cocultures, spheroids, organoids, bioprinted tissues, and microfluidic devices); such platforms have significantly enhanced liver functions closer to physiologic levels and improved functional lifetime to >4 weeks, which has translated to higher sensitivity for predicting drug outcomes and enabling modeling of diseased phenotypes for novel drug discovery. Here, we focus on commercialized engineered liver platforms and case studies from the biopharmaceutical industry showcasing their impact on drug development. We also discuss emerging multi-organ microfluidic devices containing a liver compartment that allow modeling of inter-tissue crosstalk following drug exposure. Finally, we end with key requirements for engineered liver platforms to become routine fixtures in the biopharmaceutical industry toward reducing animal usage and providing patients with safe and efficacious drugs with unprecedented speed and reduced cost.
Highlights
The process of drug development takes 12–15 years and $3–5 billion to bring a single drug to the market.[1,2] the withdrawal of a drug from the marketplace comes with a tremendous cost to the pharmaceutical/biotech industry and the economy; more importantly, drug withdrawal deprives patients of potentially life-saving therapies for chronic diseases
When using induced-pluripotent stem cell (iPSC)-derived human hepatocyte-like cells in Micropatterned cocultures (MPCCs), sensitivity for Drug-induced liver injury (DILI) detection was found to be 65% vs 70% for MPCCs with primary human hepatocytes (PHHs), while specificity was 100% for both models;[65] these results suggest that MPCCs with iHeps can provide a potential path for precision drug testing with a large number of iPSC lines to elucidate the role of genetics in DILI
We showed that MPCCs augmented with activated hepatic stellate cells (HSCs) displayed the early stages of nonalcoholic fatty liver disease (NAFLD) with steatosis in PHHs, downregulation of cytochrome P450 (CYP) enzymes and transporters, and collagen-I deposition by HSCs; this model system was shown to be amenable to screening of clinically relevant compounds and their combinations on alleviating the hepatic dysfunctions in NAFLD.[36]
Summary
Khetani COLLECTIONS Paper published as part of the special topic on Bioengineering of the Liver.
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