Organ-on-a-chip: a new paradigm for drug screening and disease modeling

Organ-on-a-chip: a new paradigm for drug screening and disease modeling

Organ-on-a-chip: a new paradigm for drug screening and disease modeling

The drug discovery and development process has a bottleneck: the use of animal models in preclinical stages. Animal use is costly, time-consuming, and implies ethical concerns. 

Governments and regulatory agencies encourage reducing animals used for scientific purposes by approving directives such as the 2010/63/EU or the US Food and Drug Administration (FDA) Modernization Act of 2021. 

New Alternative Models (NAMs) constitute a reliable alternative to traditional animal testing for assessing the safety and efficacy of chemicals, pharmaceuticals, and other substances. In vitro cellular models, precisely organ-on-a-chip (OOC), are here to stay and promise to revolutionize the drug discovery and development process as we know it.

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Organ-on-a-chip recapitulates organ and organism-level functions

.Organ-on-a-chip are microfluidic devices that simulate the physiological responses of entire organs, or even entire organisms, outside the human body. Human cells and tissues are contained in hollow channels, under dynamic fluid flow to resemble the in vivo environment from a biochemical and physical point of view. 

OOC allows tight microenvironment control and direct observation of cell and tissue behavior. Since human cells are used, the underlying molecular and cellular mechanisms are more accurate than those found in animal models, increasing clinical relevance. 

Possibilities are endless when talking about configurations: 

    • Design and conceptualization: from top-down approaches using organ slices from biopsy or preformed organoids to bottom-up using isolated cells from primary, immortalized lines or stem cell-derived sources cultured inside an a priori empty microfluidic environment.
    • Material selection and fabrication:  common materials include silicone rubber, such as poly(dimethylsiloxane) (PDMS); glass; and thermoplastics, such as polystyrene (PS), poly(methyl methacrylate) (PMMA), or polycarbonate (PC).
    • Selection of biological components: influenced by the need for patient specificity, the need for supporting cells, proliferation capacity, or the required cell functionality to recapitulate a tissue function.
    • Supporting life inside: perfusion, incubators, mechanical stimulation, and controls and sensors may be needed to support cell survival inside the device.

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Liver-on-a-chip to shape the future of drug screening

Given the liver’s crucial biological functions, developing an organ-on-a-chip that accurately replicates these organ functions and structure offers multiple insights into drug development and disease modeling.

Ingber describes some of its milestones in a review published in Nature

    • Drug Metabolism. A microfluidic liver chip containing liver primary human hepatocytes and Kupffer cells can replicate the breakdown of anti-inflammatory drugs. The intrinsic clearance values were comparable to human data. 
    • Drug-drug interactions. A similar liver chip system was designed to model the drug-drug interaction observed in patients treated with anti-inflammatory monoclonal antibodies used to treat rheumatoid arthritis and simvastatin hydroxy acid, which was not possible using 2D static culture models. 
    • Hepatotoxicity. Liver-on-a-chip has been used to model human-specific hepatotoxicity, which is hard to reproduce in animal models. A chip containing human primary hepatocytes but separated from flow by a micro-engineered porous barrier was able to reproduce the metabolism-specific hepatotoxicity of an anti-inflammatory drug.
    • Infection. Liver chips can be used to model viral infections in vitro. Specifically, a liver-on-a-chip with human hepatocytes with hepatitis B (HBV) virus was able to reproduce all steps of the HBV life cycle.  

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BeCytes contributes to the development of organ-on-a-chip technology

Becytes expertise in primary cell isolation will be used to provide liver and lung cells to the UNLocking Data Content of Organ-On-Chips (UNLOOC) project. This project, funded by The European Union and the national funding authorities of the participating countries accounts for more than 50 international partners. 

UNLOOC aims to develop, optimize, and validate organ-on-a-chip systems for different organs to replace the need for animal and in-human testing in drug discovery, clinical testing, and validation.

To unlock organ-on-a-chip’s true potential, we need to advance in automation, reproducibility, scalability, and standardization and put them into a format that makes them accessible for broader use in industry and academia.

Our extensive portfolio also offers human primary hepatocytes, fresh or cryopreserved, and human non-parenchymal cells, including Kupffer Cellsliver endothelial cells/liver sinusoidal endothelial cells, and stellate cells for research purposes. 

No matter what your organ-on-a-chip configuration is, our cells will line it! Contact us at info@cytesbiotech.com.

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References

Carvalho MR, Yan LP, Li B, Zhang CH, He YL, Reis RL, Oliveira JM. Gastrointestinal organs and organoids-on-a-chip: advances and translation into the clinics. Biofabrication. 2023;15(4). doi: 10.1088/1758-5090/acf8fb. 

Ingber, D.E. Human organs-on-chips for disease modelling, drug development and personalized medicine. Nat Rev Genet. 2022;23, 467–491. doi.org/10.1038/s41576-022-00466-9.

Leung, C.M., de Haan, P., Ronaldson-Bouchard, K. et al. A guide to the organ-on-a-chip. Nat Rev Methods Primers. 2022; 2, 33. doi.org/10.1038/s43586-022-00118-6.

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