Liver organ-on-chip models for toxicity studies and risk assessment

Messelmani, Taha; Morisseau, Lisa; Sakai, Yasuyuki; Legallais, Cécile; Goff, Anne Le; Leclerc, Éric; Jellali, Rachid

doi:10.1039/d2lc00307d

Cited by 52 publications

(27 citation statements)

References 221 publications

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“…Reconstructing an in vitro liver model that mimics in vivo conditions is very challenging and aims to maintain the morphological characteristics and cellular functions of hepatocytes over long periods of culture. In past decades, different liver models based on one or more advanced technologies, such as OoC, 3D spheroids and cells embedded in hydroscaffolds, have been developed [ 17 , 20 , 61 ]. However, to our knowledge, only a few studies have focused on integrating a hydrogel/hydroscaffold into the biochip and there is no system describing a dynamic liver-on-chip model making hepatocyte cultures possible in spheroids, embedded into a hydroscaffold that closely mimics the liver’s ECM.…”

Section: Discussionmentioning

confidence: 99%

Development of Liver-on-Chip Integrating a Hydroscaffold Mimicking the Liver’s Extracellular Matrix

Messelmani

Goff

Souguir³

et al. 2022

Bioengineering

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The 3Rs guidelines recommend replacing animal testing with alternative models. One of the solutions proposed is organ-on-chip technology in which liver-on-chip is one of the most promising alternatives for drug screening and toxicological assays. The main challenge is to achieve the relevant in vivo-like functionalities of the liver tissue in an optimized cellular microenvironment. Here, we investigated the development of hepatic cells under dynamic conditions inside a 3D hydroscaffold embedded in a microfluidic device. The hydroscaffold is made of hyaluronic acid and composed of liver extracellular matrix components (galactosamine, collagen I/IV) with RGDS (Arg-Gly-Asp-Ser) sites for cell adhesion. The HepG2/C3A cell line was cultured under a flow rate of 10 µL/min for 21 days. After seeding, the cells formed aggregates and proliferated, forming 3D spheroids. The cell viability, functionality, and spheroid integrity were investigated and compared to static cultures. The results showed a 3D aggregate organization of the cells up to large spheroid formations, high viability and albumin production, and an enhancement of HepG2 cell functionalities. Overall, these results highlighted the role of the liver-on-chip model coupled with a hydroscaffold in the enhancement of cell functions and its potential for engineering a relevant liver model for drug screening and disease study.

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Section: Discussionmentioning

confidence: 99%

Development of Liver-on-Chip Integrating a Hydroscaffold Mimicking the Liver’s Extracellular Matrix

Messelmani

Goff

Souguir³

et al. 2022

Bioengineering

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“…These improvements have shown that liver-centric devices can predict clearance, toxicity, and mechanism of action of certain pharmaceutical compounds to a considerable degree [ 21 , 61 ]. Although liver microphysiological systems have shown great success in predicting the kinetics of selective drugs, their utility in predicting the kinetics of environmental compounds remains largely unexplored [ 23 , 62 , 63 ]. Compared to pharmaceuticals, environmental compounds have a much wider range of physicochemical properties, which have a direct impact on biokinetics [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Metabolism of a Defined Pesticide Mixture through Multiple In Vitro Liver Models

Valdiviezo

Kato

Baker

et al. 2022

Toxics

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The evaluation of exposure to multiple contaminants in a mixture presents a number of challenges. For example, the characterization of chemical metabolism in a mixture setting remains a research area with critical knowledge gaps. Studies of chemical metabolism typically utilize suspension cultures of primary human hepatocytes; however, this model is not suitable for studies of more extended exposures and donor-to-donor variability in a metabolic capacity is unavoidable. To address this issue, we utilized several in vitro models based on human-induced pluripotent stem cell (iPSC)-derived hepatocytes (iHep) to characterize the metabolism of an equimolar (1 or 5 µM) mixture of 20 pesticides. We used iHep suspensions and 2D sandwich cultures, and a microphysiological system OrganoPlate® 2-lane 96 (MimetasTM) that also included endothelial cells and THP-1 cell-derived macrophages. When cell culture media were evaluated using gas and liquid chromatography coupled to tandem mass spectrometry methods, we found that the parent molecule concentrations diminished, consistent with metabolic activity. This effect was most pronounced in iHep suspensions with a 1 µM mixture, and was lowest in OrganoPlate® 2-lane 96 for both mixtures. Additionally, we used ion mobility spectrometry–mass spectrometry (IMS-MS) to screen for metabolite formation in these cultures. These analyses revealed the presence of five primary metabolites that allowed for a more comprehensive evaluation of chemical metabolism in vitro. These findings suggest that iHep-based suspension assays maintain higher metabolic activity compared to 2D sandwich and OrganoPlate® 2-lane 96 model. Moreover, this study illustrates that IMS-MS can characterize in vitro metabolite formation following exposure to mixtures of environmental contaminants.

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“…In the last decades, multiple approaches based on tissue engineering and microtechnology have been used to develop relevant in vitro models for animal experiments replacement. Thanks to the progress in microfabrication, microfluidic and bioprinting, OoC technology has emerged as a promising tool to recapitulate in vitro the physiological in vivo environment of the cells or tissues [ 2 , 20 ]. Since the beginnings of microfluidics, PDMS has been the most commonly used material for microfluidics and OoC devices and is still today a widely used material in literature [ 46 , 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…The liver performs a great number of tasks to support other organs and impacts all physiological system. It is involved in several essential functions including detoxification, protein synthesis and metabolism, glycogen storage, bile secretion, as well as the removal of pathogens and exogenous antigens form the systemic circulation [ 1 , 2 ]. As the major site of xenobiotic metabolism, the liver is exposed to a wide range of exogenous substances and is often the subject of chemical-induced toxicity [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…It is involved in several essential functions including detoxification, protein synthesis and metabolism, glycogen storage, bile secretion, as well as the removal of pathogens and exogenous antigens form the systemic circulation [ 1 , 2 ]. As the major site of xenobiotic metabolism, the liver is exposed to a wide range of exogenous substances and is often the subject of chemical-induced toxicity [ 2 ]. Therefore, the investigation of drugs/chemicals hepatotoxicity is critical to their successful use.…”

Section: Introductionmentioning

confidence: 99%

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Validation of HepG2/C3A Cell Cultures in Cyclic Olefin Copolymer Based Microfluidic Bioreactors

et al. 2022

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Organ-on-chip (OoC) technology is one of the most promising in vitro tools to replace the traditional animal experiment-based paradigms of risk assessment. However, the use of OoC in drug discovery and toxicity studies remain still limited by the low capacity for high-throughput production and the incompatibility with standard laboratory equipment. Moreover, polydimethylsiloxanes, the material of choice for OoC, has several drawbacks, particularly the high absorption of drugs and chemicals. In this work, we report the development of a microfluidic device, using a process adapted for mass production, to culture liver cell line in dynamic conditions. The device, made of cyclic olefin copolymers, was manufactured by injection moulding and integrates Luer lock connectors compatible with standard medical and laboratory instruments. Then, the COC device was used for culturing HepG2/C3a cells. The functionality and behaviour of cultures were assessed by albumin secretion, cell proliferation, viability and actin cytoskeleton development. The cells in COC device proliferated well and remained functional for 9 days of culture. Furthermore, HepG2/C3a cells in the COC biochips showed similar behaviour to cells in PDMS biochips. The present study provides a proof-of-concept for the use of COC biochip in liver cells culture and illustrate their potential to develop OoC.

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Liver organ-on-chip models for toxicity studies and risk assessment

Abstract: The liver is a key organ that plays a pivotal role in metabolism and ensures a variety of functions in the body, including homeostasis, synthesis of essential components, nutrient storage,...

Cited by 52 publications

References 221 publications

Development of Liver-on-Chip Integrating a Hydroscaffold Mimicking the Liver’s Extracellular Matrix

Development of Liver-on-Chip Integrating a Hydroscaffold Mimicking the Liver’s Extracellular Matrix

Evaluation of Metabolism of a Defined Pesticide Mixture through Multiple In Vitro Liver Models

Validation of HepG2/C3A Cell Cultures in Cyclic Olefin Copolymer Based Microfluidic Bioreactors

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