Analysis of reproducibility and robustness of OrganoPlate® 2-lane 96, a liver microphysiological system for studies of pharmacokinetics and toxicological assessment of drugs

Kato, Yuki; Lim, Alicia Y.; Sakolish, Courtney; Valdiviezo, Alan; Moyer, Haley L.; Hewitt, Philip; Bajaj, Preeti; Han, Gang; Rusyn, Ivan

doi:10.1016/j.tiv.2022.105464

Cited by 10 publications

(15 citation statements)

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“… 58 Although the opportunities are many, the challenges are also formidable, including the cost, complexity, and low throughput of most of the available models. 38 , 59 , 60 …”

Section: Discussionmentioning

confidence: 99%

Reanalysis of Trichloroethylene and Tetrachloroethylene Metabolism to Glutathione Conjugates Using Human, Rat, and Mouse Liver in Vitro Models to Improve Precision in Risk Characterization

Valdiviezo

Brown

Michell

et al. 2022

Environ Health Perspect

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Background: Both trichloroethylene (TCE) and tetrachloroethylene (PCE) are high-priority chemicals subject to numerous human health risk evaluations by a range of agencies. Metabolism of TCE and PCE determines their ultimate toxicity; important uncertainties exist in quantitative characterization of metabolism to genotoxic moieties through glutathione (GSH) conjugation and species differences therein. Objectives: This study aimed to address these uncertainties using novel in vitro liver models, interspecies comparison, and a sensitive assay for quantification of GSH conjugates of TCE and PCE, S -(1,2-dichlorovinyl)glutathione (DCVG) and S -(1,2,2-trichlorovinyl) glutathione (TCVG), respectively. Methods: Liver in vitro models used herein were suspension, 2-D culture, and micropatterned coculture (MPCC) with primary human, rat, and mouse hepatocytes, as well as human induced pluripotent stem cell (iPSC)-derived hepatocytes (iHep). Results: We found that, although efficiency of metabolism varied among models, consistent with known differences in their metabolic capacity, formation rates of DCVG and TCVG generally followed the patterns , and primary . Data derived from MPCC were most consistent with estimates from physiologically based pharmacokinetic models calibrated to in vivo data. Discussion: For TCE, the new data provided additional empirical support for inclusion of GSH conjugation-mediated kidney effects as critical for the derivation of noncancer toxicity values. For PCE, the data reduced previous uncertainties regarding the extent of TCVG formation in humans; this information was used to update several candidate kidney-specific noncancer toxicity values. Overall, MPCC-derived data provided physiologically relevant estimates of GSH-mediated metabolism of TCE and PCE to reduce uncertainties in interspecies extrapolation that constrained previous risk evaluations, thereby increasing the precision of risk characterizations of these high-priority toxicants. https://doi.org/10.1289/EHP12006

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“… 58 Although the opportunities are many, the challenges are also formidable, including the cost, complexity, and low throughput of most of the available models. 38 , 59 , 60 …”

Section: Discussionmentioning

confidence: 99%

Reanalysis of Trichloroethylene and Tetrachloroethylene Metabolism to Glutathione Conjugates Using Human, Rat, and Mouse Liver in Vitro Models to Improve Precision in Risk Characterization

Valdiviezo

Brown

Michell

et al. 2022

Environ Health Perspect

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“…To date, liver-on-a-chip models mainly incorporate primary hepatocytes, which can be co-cultured with non-parenchymal cell types such as LSECs, Kupffer cells (KCs) and HSCs ( Ewart et al, 2022 ; Kato et al, 2022 ). Importantly, OoC devices have resolved several limitations characteristic of 2D primary hepatocyte cultures.…”

Section: Liver-on-a-chip: Recapitulating Tissue Complexitymentioning

confidence: 99%

Human induced pluripotent stem cell–derived liver-on-a-chip for studying drug metabolism: the challenge of the cytochrome P450 family

et al. 2023

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The liver is the primary organ responsible for the detoxification and metabolism of drugs. To date, a lack of preclinical models that accurately emulate drug metabolism by the human liver presents a significant challenge in the drug development pipeline, particularly for predicting drug efficacy and toxicity. In recent years, emerging microfluidic-based organ-on-a-chip (OoC) technologies, combined with human induced pluripotent stem cell (hiPSC) technology, present a promising avenue for the complete recapitulation of human organ biology in a patient-specific manner. However, hiPSC-derived organoids and liver-on-a-chip models have so far failed to sufficiently express cytochrome P450 monooxygenase (CYP450) enzymes, the key enzymes involved in first-pass metabolism, which limits the effectiveness and translatability of these models in drug metabolism studies. This review explores the potential of innovative organoid and OoC technologies for studying drug metabolism and discusses their existing drawbacks, such as low expression of CYP450 genes. Finally, we postulate potential approaches for enhancing CYP450 expression in the hope of paving the way toward developing novel, fully representative liver drug-metabolism models.

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“…However, a number of concerns regarding the implementation of MPS in safety and efficacy testing pipelines have been expressed by many end users [21,22], leading to a concerted effort by the manufacturers, end users, and regulators to inform the scientific community of how these models should be tested to demonstrate robustness, reproducibility, and utility for certain decision contexts [11,[23][24][25]. Furthermore, several recent studies have provided clarity on the anticipated utility of liver MPS by investigating their performance with different cell sources [26][27][28]. These studies have also compared MPS to simpler culture methods, quantitatively assessing both the variability within and between studies.…”

Section: Introductionmentioning

confidence: 99%

“…It is noteworthy that recent publications by the manufacturers of several liver MPS included data that shows performance across experiments and donors for several dozen compounds [32] or compared prediction accuracy for liver injury in different study designs (i.e., one replicate per drug vs. a dose-response) for over a hundred drugs [33]. Still, independent testing of several liver MPS to establish their functionality, reproducibility, robustness, and reliability not only adds useful information on what cell types and combinations may be most functional but also provides comprehensive data on the expected variability in these complex models and the challenges that end users may face [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Reproducibility and Robustness of a Liver Microphysiological System PhysioMimix LC12 under Varying Culture Conditions and Cell Type Combinations

Lim,

Kato,

Sakolish

et al. 2023

Bioengineering

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The liver is one of the key organs for exogenous and endogenous metabolism and is often a target for drug- and chemical-driven toxicity. A wide range of experimental approaches has been established to model and characterize the mechanisms of drug- and chemical-induced hepatotoxicity. A number of microfluidics-enabled in vitro models of the liver have been developed, but the unclear translatability of these platforms has hindered their adoption by the pharmaceutical industry; to achieve wide use for drug and chemical safety evaluation, demonstration of reproducibility and robustness under various contexts of use is required. One of these commercially available platforms is the PhysioMimix LC12, a microfluidic device where cells are seeded into a 3D scaffold that is continuously perfused with recirculating cell culture media to mimic liver sinusoids. Previous studies demonstrated this model’s functionality and potential applicability to preclinical drug development. However, to gain confidence in PhysioMimix LC12’s robustness and reproducibility, supplementary characterization steps are needed, including the assessment of various human hepatocyte sources, contribution of non-parenchymal cells (NPCs), and comparison to other models. In this study, we performed replicate studies averaging 14 days with either primary human hepatocytes (PHHs) or induced pluripotent stem cell (iPSC)-derived hepatocytes, with and without NPCs. Albumin and urea secretion, lactate dehydrogenase, CYP3A4 activity, and metabolism were evaluated to assess basal function and metabolic capacity. Model performance was characterized by different cell combinations under intra- and inter-experimental replication and compared to multi-well plates and other liver platforms. PhysioMimix LC12 demonstrated the highest metabolic function with PHHs, with or without THP-1 or Kupffer cells, for up to 10–14 days. iPSC-derived hepatocytes and PHHs co-cultured with additional NPCs demonstrated sub-optimal performance. Power analyses based on replicate experiments and different contexts of use will inform future study designs due to the limited throughput and high cell demand. Overall, this study describes a workflow for independent testing of a complex microphysiological system for specific contexts of use, which may increase end-user adoption in drug development.

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Analysis of reproducibility and robustness of OrganoPlate® 2-lane 96, a liver microphysiological system for studies of pharmacokinetics and toxicological assessment of drugs

Cited by 10 publications

References 50 publications

Reanalysis of Trichloroethylene and Tetrachloroethylene Metabolism to Glutathione Conjugates Using Human, Rat, and Mouse Liver in Vitro Models to Improve Precision in Risk Characterization

Reanalysis of Trichloroethylene and Tetrachloroethylene Metabolism to Glutathione Conjugates Using Human, Rat, and Mouse Liver in Vitro Models to Improve Precision in Risk Characterization

Human induced pluripotent stem cell–derived liver-on-a-chip for studying drug metabolism: the challenge of the cytochrome P450 family

Reproducibility and Robustness of a Liver Microphysiological System PhysioMimix LC12 under Varying Culture Conditions and Cell Type Combinations

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