A microfluidic approach for in vitro assessment of interorgan interactions in drug metabolism using intestinal and liver slices

Midwoud, Paul M. van; Merema, Marjolijn T.; Verpoorte, Elisabeth; Groothuis, Geny M. M.

doi:10.1039/c0lc00043d

Cited by 189 publications

(168 citation statements)

References 25 publications

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“…Much encouraging effort has been made to optimize the capturing of the in vivo hepatocytes microenvironment for functional maintenance of primary hepatocytes in a micropatterned co-culture module, 2 bioreactor-based liver module, [3][4][5] microfluidic 3D chip, 6 and other innovative approaches. [7][8][9] The most encouraging reports relied on undefined extracellular matrices like Matrigel, rigid collagen, or serum supplementations, which are often problematic and unacceptable in preclinical and clinical applications. Moreover, animal-derived extracellular matrices can give rise to immunological conditions and zoonosis.…”

Section: Introductionmentioning

confidence: 99%

Nanostructured self-assembling peptides as a defined extracellular matrix for long-term functional maintenance of primary hepatocytes in a bioartificial liver modular device

Giri¹,

Braumann²,

Giri³

et al. 2013

IJN

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Much effort has been directed towards the optimization of the capture of in vivo hepatocytes from their microenvironment. Some methods of capture include an ex vivo cellular model in a bioreactor based liver module, a micropatterned module, a microfluidic 3D chip, coated plates, and other innovative approaches for the functional maintenance of primary hepatocytes. However, none of the above methods meet US Food and Drug Administration (FDA) guidelines, which recommend and encourage that the duration of a toxicity assay of a drug should be a minimum of 14 days, to a maximum of 90 days for a general toxicity assay. Existing innovative reports have used undefined extracellular matrices like matrigel, rigid collagen, or serum supplementations, which are often problematic, unacceptable in preclinical and clinical applications, and can even interfere with experimental outcomes. We have overcome these challenges by using integrated nanostructured self-assembling peptides and a special combination of growth factors and cytokines to establish a proof of concept to mimic the in vivo hepatocyte microenvironment pattern in vitro for predicting the in vivo drug hepatotoxicity in a scalable bioartificial liver module. Hepatocyte functionality (albumin, urea) was measured at days 10, 30, 60, and 90 and we observed stable albumin secretion and urea function throughout the culture period. In parallel, drug metabolizing enzyme biomarkers such as ethoxyresorufin-O-deethylase, the methylthiazol tetrazolium test, and the lactate dehydrogenase test were carried out at days 10, 30, 60, and 90. We noticed excellent mitochondrial status and membrane stability at 90 days of culture. Since alpha glutathione S-transferase (GST) is highly sensitive and a specific marker of hepatocyte injury, we observed significantly low alpha GST levels on all measured days (10, 30, 60, and 90). Finally, we performed the image analysis of mitochondria-cultured hepatocytes at day 90 in different biophysical parameters using confocal microscopy. We applied an automatic algorithm-based method for 3D visualization to show the classic representation of the mitochondrial distribution in double hepatocytes. An automated morphological measurement was conducted on the mitochondrial distribution in the cultured hepatocytes. Our proof of concept of a scalable bioartificial liver modular device meets FDA guidelines and may function as an alternative model of animal experimentation for pharmacological and toxicological studies involving drug metabolism, enzyme induction, transplantation, viral hepatitis, hepatocyte regeneration, and can also be used in other existing bioreactor modules for long-term culture for up to 90 days or more.

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Section: Introductionmentioning

confidence: 99%

Nanostructured self-assembling peptides as a defined extracellular matrix for long-term functional maintenance of primary hepatocytes in a bioartificial liver modular device

Giri¹,

Braumann²,

Giri³

et al. 2013

IJN

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“…[109][110][111][112][113][114][115][116][117] Liver and intestinal slices have also been used in microfluidic devices. 118 In each case, the complexity of the neighborhood is recreated using sliced tissues.) While it is tempting to add a single lymph node to a multiorgan MPS homunculus, it would be more realistic to have a lymph node that was specialized to each organ, as occurs in vivo.…”

Section: Mps Immunologymentioning

confidence: 99%

Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology

Watson

Hunziker

Wikswo

2017

Exp Biol Med (Maywood)

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Impact statementMicrophysiological systems (MPS), which include engineered organoids and both individual and coupled organs-on-chips and tissue chips, are a rapidly growing topic of research that addresses the known limitations of conventional cellular monoculture on flat plastic -a wellperfected set of techniques that produces reliable, statistically significant results that may not adequately represent human biology and disease. As reviewed in this article and the others in this thematic issue, MPS research has made notable progress in the past three years in both cell sourcing and characterization. As the field matures, currently identified challenges are being addressed, and new ones are being recognized. Building upon investments by the Defense Advanced Research Projects Agency, National Institutes of Health, Food and Drug Administration, Defense Threat Reduction Agency, and Environmental Protection Agency of more than $200 million since 2012 and sizable corporate spending, academic and commercial players in the MPS community are demonstrating their ability to meet the translational challenges required to apply MPS technologies to accelerate drug development and advance toxicology. AbstractMicrophysiological systems (MPS), which include engineered organoids (EOs), single organ/tissue chips (TCs), and multiple organs interconnected to create miniature in vitro models of human physiological systems, are rapidly becoming effective tools for drug development and the mechanistic understanding of tissue physiology and pathophysiology. The second MPS thematic issue of Experimental Biology and Medicine comprises 15 articles by scientists and engineers from the National Institutes of Health, the IQ Consortium, the Food and Drug Administration, and Environmental Protection Agency, an MPS company, and academia. Topics include the progress, challenges, and future of organs-on-chips, dissemination of TCs into Pharma, children's health protection, liver zonation, liver chips and their coupling to interconnected systems, gastrointestinal MPS, maturation of immature cardiomyocytes in a heart-on-a-chip, coculture of multiple cell types in a human skin construct, use of synthetic hydrogels to create EOs that form neural tissue models, the blood-brain barrier-on-a-chip, MPS models of coupled female reproductive organs, coupling MPS devices to create a body-on-a-chip, and the use of a microformulator to recapitulate endocrine circadian rhythms. While MPS hardware has been relatively stable since the last MPS thematic issue, there have been significant advances in cell sourcing, with increased reliance on human-induced pluripotent stem cells, and in characterization of the genetic and functional cell state in MPS bioreactors. There is growing appreciation of the need to minimize perfusate-to-cell-volume ratios and respect physiological scaling of coupled TCs. Questions asked by drug developers are followed by an analysis of the potential value, costs, and needs of Pharma. Of highest value and lowest switching costs may be the d...

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“…In a different approach, Van Midwoud et al created a gut-liver coculture system consisting of precision-cut intestinal slices (jejunum and ileum) and rat liver slices (from male Wistar rats) connected in series representing intestinal absorption and liver metabolism, respectively. 58 Within each chamber, the precision-cut slices were suspended between two membranes allowing perfusion of media around the tissues and transport to the next chamber. Experiments with chenodeoxycholic acid (a primary bile acid) demonstrated the upregulation of fibroblast growth factor 15, resulting in a downregulation of CYP 7A1, demonstrating the retention of function within the platform and interorgan communication.…”

Section: Macroscale Bioreactor Platformsmentioning

confidence: 99%

EmergingIn VitroLiver Technologies for Drug Metabolism and Inter-Organ Interactions

Bale

Moore

Yarmush

et al. 2016

Tissue Engineering Part B: Reviews

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In vitro liver models provide essential information for evaluating drug metabolism, metabolite formation, and hepatotoxicity. Interfacing liver models with other organ models could provide insights into the desirable as well as unintended systemic side effects of therapeutic agents and their metabolites. Such information is invaluable for drug screening processes particularly in the context of secondary organ toxicity. While interfacing of liver models with other organ models has been achieved, platforms that effectively provide human-relevant precise information are needed. In this concise review, we discuss the current state-of-the-art of liver-based multiorgan cell culture platforms primarily from a drug and metabolite perspective, and highlight the importance of mediato-cell ratio in interfacing liver models with other organ models. In addition, we briefly discuss issues related to development of optimal liver models that include recent advances in hepatic cell lines, stem cells, and challenges associated with primary hepatocyte-based liver models. Liver-based multiorgan models that achieve physiologically relevant coupling of different organ models can have a broad impact in evaluating drug efficacy and toxicity, as well as mechanistic investigation of human-relevant disease conditions.

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A microfluidic approach for in vitro assessment of interorgan interactions in drug metabolism using intestinal and liver slices

Cited by 189 publications

References 25 publications

Nanostructured self-assembling peptides as a defined extracellular matrix for long-term functional maintenance of primary hepatocytes in a bioartificial liver modular device

Nanostructured self-assembling peptides as a defined extracellular matrix for long-term functional maintenance of primary hepatocytes in a bioartificial liver modular device

Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology

EmergingIn VitroLiver Technologies for Drug Metabolism and Inter-Organ Interactions

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