Microengineered Liver Tissues for Drug Testing

Abstract

Drug-induced liver injury (DILI) is a leading cause of drug attrition. Significant and well-documented differences between animals and humans in liver pathways now necessitate the use of human-relevant in vitro liver models for testing new chemical entities during preclinical drug development. Consequently, several human liver models with various levels of in vivo-like complexity have been developed for assessment of drug metabolism, toxicity, and efficacy on liver diseases. Recent trends leverage engineering tools, such as those adapted from the semiconductor industry, to enable precise control over the microenvironment of liver cells and to allow for miniaturization into formats amenable for higher throughput drug screening. Integration of liver models into organs-on-a-chip devices, permitting crosstalk between tissue types, is actively being pursued to obtain a systems-level understanding of drug effects. Here, we review the major trends, challenges, and opportunities associated with development and implementation of engineered liver models created from primary cells, cell lines, and stem cell-derived hepatocyte-like cells. We also present key applications where such models are currently making an impact and highlight areas for improvement. In the future, engineered liver models will prove useful for selecting drugs that are efficacious, safer, and, in some cases, personalized for specific patient populations.

Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis

“…This is important to ensure that glucose-and insulin-regulated de novo lipogenesis is not compromised and serves as a meaningful control. Second, our system is human relevant, utilizing human primary cells versus hepatic immortalized cell lines or animal models (5). Third, our multicellular system is composed of primary human hepatocytes, HSCs, and MΦs, which are all key players in the progression of NAFL/NASH (9).…”

“…Third, our multicellular system is composed of primary human hepatocytes, HSCs, and MΦs, which are all key players in the progression of NAFL/NASH (9). Additionally, in other multicellular in vitro systems, e.g., spheroids, 3D bioprinting, liver slices, and organ-on-chips, the signals from individual cell types cannot be separated (5). Fourth, in this system, the liver microenvironment is recapitulated by applying physiologically relevant hemodynamics and biological transport, which is absent in traditional static cultures (including many multicellular systems) (5,7,8).…”

“…Additionally, in other multicellular in vitro systems, e.g., spheroids, 3D bioprinting, liver slices, and organ-on-chips, the signals from individual cell types cannot be separated (5). Fourth, in this system, the liver microenvironment is recapitulated by applying physiologically relevant hemodynamics and biological transport, which is absent in traditional static cultures (including many multicellular systems) (5,7,8). Finally, the lipotoxic state is predicated upon FFA concentrations derived from clinical plasma concentrations in NASH patients (14).…”

“…There is also limited consensus regarding the utility of animal models, as demonstrated by the array of different models (>25) currently in use. Further, in vitro liver systems typically use supraphysiologic concentrations of insulin/glucose and drug concentrations, and lack key elements of the liver microenvironment, including hemodynamics, transport, and multicellularity (5). The relevance of these models to humans is questionable because they most often essentialize isolated aspects of the human pathophysiology (6).…”

JALA Special Issue: Microengineered Cell- and Tissue-Based Assays for Drug Screening and Toxicology Applications

“…14,15 The collected primary research is supported by in a number of in-depth reviews detailing some of the most important standout technologies for advancing microengineered cell-and tissue-based assays for drug-screening applications. [16][17][18][19][20][21] We have strived to collect and present a diverse array of articles in order to provide an inclusive overview of the field that emphasizes the importance of these new technologies for valuable real-world applications. We hope you enjoy this special issue from the Journal of Laboratory Automation!…”