Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies
Open accessAbstract
Investigation of the pharmacokinetics (PK) of a compound is of significant importance during the early stages of drug development, and therefore several in vitro systems are routinely employed for this purpose. However, the need for more physiologically realistic in vitro models has recently fueled the emerging field of tissue-engineered 3D cultures, also referred to as organs-on-chips, or microphysiological systems (MPSs). We have developed a novel fluidic platform that interconnects multiple MPSs, allowing PK studies in multi-organ in vitro systems along with the collection of high-content quantitative data. This platform was employed here to integrate a gut and a liver MPS together in continuous communication, and investigate simultaneously different PK processes taking place after oral drug administration in humans (e.g., intestinal permeability, hepatic metabolism). Measurement of tissue-specific phenotypic metrics indicated that gut and liver MPSs can be fluidically coupled with circulating common medium without compromising their functionality. The PK of diclofenac and hydrocortisone was investigated under different experimental perturbations, and results illustrate the robustness of this integrated system for quantitative PK studies. Mechanistic model-based analysis of the obtained data allowed the derivation of the intrinsic parameters (e.g., permeability, metabolic clearance) associated with the PK processes taking place in each MPS. Although these processes were not substantially affected by the gut-liver interaction, our results indicate that inter-MPS communication can have a modulating effect (hepatic metabolism upregulation). We envision that our integrative approach, which combines multi-cellular tissue models, multi-MPS platforms, and quantitative mechanistic modeling, will have broad applicability in pre-clinical drug development.
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Microfluidic systems can link different organs-on-a-chip to potentially simulate the complexity of multiorgan drug metabolism and pharmacokinetics.
“Furthermore, microfluidic systems can link different organs-on-a-chip to potentially simulate the complexity of multiorgan drug metabolism and pharmacokinetics9,47,50,68–71.”
From Tumor-on-a-chip: from bioinspired design to biomedical application (2021) · cites this paper as [69]
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“Pneumatic (67, 69) or electromagnetic (42) pumps built into the multiorgan units can reduce the need for additional tubing.”
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“As reported in literature, some researchers solved the problems by using multi-organon-chip composed by independent modules and transferring the media from one organ module to the subsequent in a physiological sequence, which allows each organ module to be operated independently (Tsamandouras et al., 2017).”
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“first introduced a MOoCs system including gut-on-a-chip and liver-on–a-chip described by the PK model, and used this system to study the mechanism of drug transport (Tsamandouras et al., 2017).”
BackgroundMethodA framework for developing sex-specific engineered heart models
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Clamping strategies for organ-on-a-chip devices
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“Cirit and coworkers developed a platform that reproduced first-pass metabolism [89].”
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“The connection between the gut and liver was used for studies under inflammatory conditions, where it was reported that both gut and liver amplified responses and increased hepatic metabolism markers (Tsamandouras et al. 2017).”
BackgroundEngineering in vitro immune-competent tissue models for testing and evaluation of therapeutics
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Cancer-on-a-chip for precision cancer medicine
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Self-citationAdvances in human organs-on-chips and applications for drug screening and personalized medicine
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“Tsamandouras et al. developed a polysulfone (PSF)-based gut-liver-on-a-chip to study the PK of diclofenac (DCF) and hydrocortisone (HC), and the gut-liver crosstalk on the on-platform PK-related processes [115] .”
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Organ-on-chip applications in drug discovery: an end user perspective
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Organs-on-Chips Platforms Are Everywhere: A Zoom on Biomedical Investigation
Zommiti, M., Connil, N., Tahrioui, A., Groboillot, A., Barbey, C., Konto‐Ghiorghi, Y., Lesouhaitier, O., Chevalier, S., & Feuilloley, M. G. J. (2022) · Bioengineering · doi:10.3390/bioengineering9110646 · Cited by 39 · see citing works
“Whilst the multi-organs-on-a-chip concept remains in its premature infancy, major breakthroughs have been made, encompassing the design of two organs [276,277], three organs [173,278], four organs [184,279] and even ten organs on the microfluidic chip [280].”
Recent Advances in Gut‐ and Gut–Organ‐Axis‐on‐a‐Chip Models
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“By simulating the flow of drugs from the intestine to the liver, researchers quantified metabolic rates and clearance, providing critical data for early-stage drug development (Tsamandouras et al., 2017).”
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Recent advances in an organ-on-a-chip: biomarker analysis and applications
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“…system offers an important advancement to improve drug research while simultaneously reducing the need for experiments in laboratory animals and will serve as a springboard to the construction of integrated multi-organ systems that will recapitulate the overall disposition of drugs in humans (25).”
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Pharmacokinetics‐On‐a‐Chip: In Vitro Microphysiological Models for Emulating of Drugs ADME
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“An MPS integrated with a perfusion system mimicking a peristaltic pump has been developed as an alternative to external pumps [25,26].”
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Organoid-on-a-chip: Current challenges, trends, and future scope toward medicine
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Dynamic Physiological Culture of Ex Vivo Human Tissue: A Systematic Review
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“As illustrated in the review of Wu et al., OOC systems may vary between manufacturers and models; however, they all possess the same fundamental design concepts [47].”
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BackgroundMicrophysiological systems in absorption, distribution, metabolism, and elimination sciences
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Mimicking the Human Physiology with Microphysiological Systems (MPS)
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Tissue Chips and Microphysiological Systems for Disease Modeling and Drug Testing
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“GoC have generally been designed based on (i) the traditional transwell system [50–52], using a circular porous membrane, or (ii) a semi-permeable porous membrane separating two sides of a linear channel or tube [53,54].”
BackgroundMethodLab-on-chip technologies for exploring the gut–immune axis in metabolic disease
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Multi-organ on a chip for personalized precision medicine
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Self-citationGo with the flow: modeling unique biological flows in engineered in vitro platforms
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Background
- Authors
- Tsamandouras, N., Chen, W. L. K., Edington, C. D., Stokes, C. L., Griffith, L. G., & Cirit, M.
- Affiliations
- Massachusetts Institute of Technology (US)
- Corresponding author
- Cirit, Murat
- Venue
- The AAPS Journal
- Published
- 2017-07-27
- Volume
- 19
- Issue
- 5
- Pages
- 1499-1512
- ISSN
- 1550-7416 (ISSN-L)
- PMC
- PMC6540747
- OpenAlex
- W2741120316
- Cited by
- 222
- References
- 56
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 24 · 2023: 18 · 2022: 21 · 2021: 40 · 2020: 33 · 2019: 20 · 2018: 23 · 2017: 3
- FWCI
- 9.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The AAPS Journal (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health (UH3TR000496)
- National Center for Advancing Translational Sciences
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Engineering › Biomedical Engineering › Microfluidic and Capillary Electrophoresis Applications
- Keywords
- microphysiological systems, organ-on-a-chip, in vitro pharmacokinetics, intestinal permeability, hepatic metabolism, diclofenac, cortisol, mechanistic modeling, oral administration
- MeSH terms
- Diclofenac, Humans, Hydrocortisone, Intestinal Mucosa, Liver, In Vitro Techniques
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