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      Liver Microphysiological Systems for Predicting and Evaluating Drug Effects

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          Abstract

          Liver plays a major role in drug metabolism and is one of the main sites of drug adverse effects. Microphysiological systems (MPS), also known as organs‐on‐a‐chip, are a class of microfluidic platforms that recreate properties of tissue microenvironments. Among different properties, the liver microenvironment is three‐dimensional, fluid flows around its cells, and different cell types regulate its function. Liver MPS aim to recreate these properties and enable drug testing and measurement of functional endpoints. Tests with these systems have demonstrated their potential for predicting clinical drug effects. Properties of liver MPS that improve the physiology of cell culture are reviewed, specifically focusing on the importance of recreating a physiological microenvironment to evaluate and model drug effects. Advances in modeling hepatic function by leveraging MPS are addressed, noting the need for standardization in the use, quality control, and interpretation of data from these systems.

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          Microfluidic lab-on-a-chip platforms: requirements, characteristics and applications.

          Daniel Mark, Stefan Haeberle, Günter Roth … (2010)
          This critical review summarizes developments in microfluidic platforms that enable the miniaturization, integration, automation and parallelization of (bio-)chemical assays (see S. Haeberle and R. Zengerle, Lab Chip, 2007, 7, 1094-1110, for an earlier review). In contrast to isolated application-specific solutions, a microfluidic platform provides a set of fluidic unit operations, which are designed for easy combination within a well-defined fabrication technology. This allows the easy, fast, and cost-efficient implementation of different application-specific (bio-)chemical processes. In our review we focus on recent developments from the last decade (2000s). We start with a brief introduction into technical advances, major market segments and promising applications. We continue with a detailed characterization of different microfluidic platforms, comprising a short definition, the functional principle, microfluidic unit operations, application examples as well as strengths and limitations of every platform. The microfluidic platforms in focus are lateral flow tests, linear actuated devices, pressure driven laminar flow, microfluidic large scale integration, segmented flow microfluidics, centrifugal microfluidics, electrokinetics, electrowetting, surface acoustic waves, and dedicated systems for massively parallel analysis. This review concludes with the attempt to provide a selection scheme for microfluidic platforms which is based on their characteristics according to key requirements of different applications and market segments. Applied selection criteria comprise portability, costs of instrument and disposability, sample throughput, number of parameters per sample, reagent consumption, precision, diversity of microfluidic unit operations and the flexibility in programming different liquid handling protocols (295 references).
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            Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins

            H. Gerets, K. Tilmant, B. Gerin … (2012)
            In the pharmaceutical industry, improving the early detection of drug-induced hepatotoxicity is essential as it is one of the most important reasons for attrition of candidate drugs during the later stages of drug development. The first objective of this study was to better characterize different cellular models (i.e., HepG2, HepaRG cells, and fresh primary human hepatocytes) at the gene expression level and analyze their metabolic cytochrome P450 capabilities. The cellular models were exposed to three different CYP450 inducers; beta-naphthoflavone (BNF), phenobarbital (PB), and rifampicin (RIF). HepG2 cells responded very weakly to the different inducers at the gene expression level, and this translated generally into low CYP450 activities in the induced cells compared with the control cells. On the contrary, HepaRG cells and the three human donors were inducible after exposure to BNF, PB, and RIF according to gene expression responses and CYP450 activities. Consequently, HepaRG cells could be used in screening as a substitute and/or in complement to primary hepatocytes for CYP induction studies. The second objective was to investigate the predictivity of the different cellular models to detect hepatotoxins (16 hepatotoxic and 5 nonhepatotoxic compounds). Specificity was 100% with the different cellular models tested. Cryopreserved human hepatocytes gave the highest sensitivity, ranging from 31% to 44% (depending on the donor), followed by lower sensitivity (13%) for HepaRG and HepG2 cells (6.3%). Overall, none of the models under study gave desirable sensitivities (80–100%). Consequently, a high metabolic capacity and CYP inducibility in cell lines does not necessarily correlate with a high sensitivity for the detection of hepatotoxic drugs. Further investigations are necessary to compare different cellular models and determine those that are best suited for the detection of hepatotoxic compounds.
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              Metabolic zonation of the liver: The oxygen gradient revisited

              Thomas Kietzmann (2017)
              The liver has a multitude of functions which are necessary to maintain whole body homeostasis. This requires that various metabolic pathways can run in parallel in the most efficient manner and that futile cycles are kept to a minimum. To a large extent this is achieved due to a functional specialization of the liver parenchyma known as metabolic zonation which is often lost in liver diseases. Although this phenomenon is known for about 40 years, the underlying regulatory pathways are not yet fully elucidated. The physiologically occurring oxygen gradient was considered to be crucial for the appearance of zonation; however, a number of reports during the last decade indicating that β-catenin signaling, and the hedgehog (Hh) pathway contribute to metabolic zonation may have shifted this view. In the current review we connect these new observations with the concept that the oxygen gradient within the liver acinus is a regulator of zonation. This is underlined by a number of facts showing that the β-catenin and the Hh pathway can be modulated by the hypoxia signaling system and the hypoxia-inducible transcription factors (HIFs). Altogether, we provide a view by which the dynamic interplay between all these pathways can drive liver zonation and thus contribute to its physiological function.
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                Author and article information

                Contributors
                Alexandre J. S. Ribeiro: alexandre.ribeiro@fda.hhs.gov
                Journal
                Journal ID (nlm-ta): Clin Pharmacol Ther
                Journal ID (iso-abbrev): Clin. Pharmacol. Ther
                Journal ID (doi): 10.1002/(ISSN)1532-6535
                Journal ID (publisher-id): CPT
                Title: Clinical Pharmacology and Therapeutics
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0009-9236
                ISSN (Electronic): 1532-6535
                Publication date (Electronic): 04 June 2019
                Publication date (Print): July 2019
                Publication date PMC-release: 04 June 2019
                Volume: 106
                Issue: 1 , Real‐World Data: Real‐World Evidence ( doiID: 10.1002/cpt.2019.106.issue-1 )
                Pages: 139-147
                Affiliations
                [ 1 ] Division of Applied Regulatory Science Office of Translational Science Office of Clinical Pharmacology Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USA
                [ 2 ] Office of Clinical Pharmacology Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USA
                Author notes
                [*] [* ]Correspondence: Alexandre J. S. Ribeiro ( alexandre.ribeiro@ 123456fda.hhs.gov )
                Article
                Publisher ID: CPT1458
                DOI: 10.1002/cpt.1458
                PMC ID: 6771674
                PubMed ID: 30993668
                SO-VID: 56015c72-8574-4837-9174-45b605c3bdff
                Copyright © Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 15 January 2019
                Date accepted : 26 March 2019
                Page count
                Figures: 5, Tables: 0, Pages: 9, Words: 7060
                Funding
                Funded by: Defense Advanced Research Projects Agency
                Categories
                Subject: Review
                Subject: Reviews
                Subject: Reviews
                Custom metadata
                source-schema-version-number 2.0
                component-id cpt1458
                cover-date July 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:01.10.2019

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

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