HepaChip-MP – a twenty-four chamber microplate for a continuously perfused liver coculture model

Busche, Marius; Tomilova, Olena; Schütte, Julia; Werner, S.; Beer, Meike; Groll, Nicola; Hagmeyer, Britta; Pawlak, Michael; Jones, Peter D.; Schmees, Christian; Becker, Holger; Schnabel, Juliane; Gall, Karsten; Hemmler, Roland; Matz‐Soja, Madlen; Damm, Georg; Beuck, Simon; Klaassen, Tobias; Moer, Jana; Ullrich, Anett; Runge, Dieter; Schenke‐Layland, Katja; Gebhardt, Rolf; Stelzle, Martin

doi:10.1039/d0lc00357c

Cited by 13 publications

(14 citation statements)

References 71 publications

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“…For instance, the HepaChip ® houses 24 independent culture chambers within the footprint of a standard 96-well plate; dielectrophoresis is used to aggregate PHHs and primary human liver endothelial cells into each chamber, which is then perfused continuously and unidirectionally using a custom pump system. 106 In another study, PHH functions were supported at higher levels than static controls in a 96-microfluidic array (PREDICT-96) developed using thermoplastic materials and an ultra-low volume recirculating system. 107 Alternatively, the OrganoPlate LiverTox ™ system housed in a 384-well plate contains 96 individual 2-channel microfluidic devices allowing for iPSC-derived hepatocytes to be seeded in one (static) channel and endothelial cells and macrophages in the other (fluidic) channel [ Fig.…”

Section: Engineered Human Liver Models Validated For Drug Testingmentioning

confidence: 98%

Latest impact of engineered human liver platforms on drug development

2021

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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.

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Section: Engineered Human Liver Models Validated For Drug Testingmentioning

confidence: 98%

Latest impact of engineered human liver platforms on drug development

2021

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“…Cross-species comparisons of hepatotoxicity with human, rat and dog hepatic cells have shown speciesspecific differences in response to drug treatments that simulate non-clinical safety evaluations. The HepaChip-MP is a 24-chamber microplate that can support culture of hepatocytes [38]. The system is housed in a chamber that allows for robotic pipetting that primes fluids, assembles cells, and performs media exchanges to cells that have been arranged in the chambers by dielectrophoresis.…”

Section: Accepted Articlementioning

confidence: 99%

“…The HepaChip‐MP is a 24‐chamber microplate that can support culture of hepatocytes. 38 The system is housed in a chamber that allows for robotic pipetting that primes fluids, assembles cells, and performs media exchanges to cells that have been arranged in the chambers by dielectrophoresis. This system is continuously perfused and metabolically outperformed a head‐to‐head comparison with hepatocyte spheroids.…”

Section: Hepatic Mpsmentioning

confidence: 99%

Microphysiological systems in absorption, distribution, metabolism, and elimination sciences

Ness

Cesar

Yeung

et al. 2021

Clinical Translational Sci

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The use of microphysiological systems (MPS) to support Adsorption, Distribution, Metabolism, and Elimination (ADME) sciences has grown substantially in the last decade in part driven by regulatory demands to move away from traditional animal-based safety assessment studies and industry desires to develop methodologies to efficiently screen and characterize drugs in the development pipeline. The past decade of MPS development has yielded great user-driven technological advances with the collective fine-tuning of cell culture techniques, fluid delivery systems, materials engineering, and performance enhancing modifications.The rapid advances in MPS technology have now made it feasible to evaluate critical ADME parameters within a stand-alone organ system or through interconnected organ systems. This review surveys current MPS developed for liver, kidney, and intestinal systems as stand-alone or interconnected organ systems, and evaluates each system for specific performance criteria recommended by regulatory authorities and MPS leaders that would render each system suitable for evaluating drug ADME. While some systems are more suitable for ADME type research than others, not all system designs were intended to meet the recently published desired performance criteria and are reported as a summary of initial proof-of-concept studies. Liver-Intestinal chip Caco-2/ 383-1132  cm 2 No data CYP3A-triazolam No data Gut-liver chip Caco-2/HepaRG fluorescein Morphology: F-actin Apigeninsulfation and glucuronide conjugates No data Liver-gut MPS

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“…Recently, we have developed an easy-to-use organ-on-chip system in the SBS-standard well plate format with 24 independent cell culture chambers for permanent perfusion with culture medium - the HepaChip-MP (Busche et al, 2020[ 8 ]). In the present work, we demonstrate the non-invasive, continuous and parallelized measurement of the OC of primary human hepatocytes (PHH) after being challenged by diverse metabolic substrates and drugs.…”

Section: Introductionmentioning

confidence: 99%

Continuous, non-invasive monitoring of oxygen consumption in a parallelized microfluidic in vitro system provides novel insight into the response to nutrients and drugs of primary human hepatocytes

Busche

Rabl

Fischer

et al. 2022

EXCLI Journal; 21:Doc144; ISSN 1611-2156

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Oxygen plays a fundamental role in cellular energy metabolism, differentiation and cell biology in general. Consequently, in vitro oxygen sensing can be used to assess cell vitality and detect specific mechanisms of toxicity. In 2D in vitro models currently used, the oxygen supply provided by diffusion is generally too low, especially for cells having a high oxygen demand. In organ-on-chip systems, a more physiologic oxygen supply can be generated by establishing unidirectional perfusion. We established oxygen sensors in an easy-to-use and parallelized organ-on-chip system. We demonstrated the applicability of this system by analyzing the influence of fructose (40 mM, 80 mM), ammonium chloride (100 mM) and Na-diclofenac (50 µM, 150 µM, 450 µM, 1500 µM) on primary human hepatocytes (PHH). Fructose treatment for two hours showed an immediate drop of oxygen consumption (OC) with subsequent increase to nearly initial levels. Treatment with 80 mM glucose, 20 mM lactate or 20 mM glycerol did not result in any changes in OC which demonstrates a specific effect of fructose. Application of ammonium chloride for two hours did not show any immediate effects on OC, but qualitatively changed the cellular response to FCCP treatment. Na-diclofenac treatment for 24 hours led to a decrease of the maximal respiration and reserve capacity. We also demonstrated the stability of our system by repeatedly treating cells with 40 mM fructose, which led to similar cell responses on the same day as well as on subsequent days. In conclusion, our system enables in depth analysis of cellular respiration after substrate treatment in an unidirectional perfused organ-on-chip system.

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HepaChip-MP – a twenty-four chamber microplate for a continuously perfused liver coculture model

Abstract: HepaChip-MP: a 24-culture-chamber, automated microfluidic in vitro model of the liver sinusoid in multiwellplate format.

Cited by 13 publications

References 71 publications

Latest impact of engineered human liver platforms on drug development

Latest impact of engineered human liver platforms on drug development

Microphysiological systems in absorption, distribution, metabolism, and elimination sciences

Continuous, non-invasive monitoring of oxygen consumption in a parallelized microfluidic in vitro system provides novel insight into the response to nutrients and drugs of primary human hepatocytes

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