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  • Review Article
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Integrating organoids and organ-on-a-chip devices

Nature Reviews Bioengineering volume 2, pages 588–608 (2024)Cite this article

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Abstract

Organoids and organs-on-chips are two rapidly emerging 3D cell culture techniques that aim to bridge the gap between in vitro 2D cultures and animal models to enable clinically relevant drug discovery and model human diseases. Despite their similar goals, they use different approaches and exhibit varying requirements for implementation. Integrative approaches promise to provide improved cellular fidelity in the format of a device that can control the geometry of the organoid and provide flow, mechanical and electrical stimuli. In this Review, we discuss recent integrative approaches in the areas of intestine, kidney, lung, liver, pancreas, brain, retina, heart and tumour. We start by defining the two fields and describe how they emerged from the fields of tissue engineering, regenerative medicine and stem cells. We compare the scales at which the two methods operate and briefly describe their achievements, followed by studies integrating organoids and organ-on-a-chip devices. Finally, we define implementation limitations and requirements for translation of the integrated devices, including determining the differentiation stage at which an organoid should be placed into an organ-on-a-chip device, providing perfusable vasculature within the organoid and overcoming limitations of cell line and batch-to-batch variability.

Key points

  • Organoids and organs-on-chips (OoCs) aim to improve drug testing and disease modelling, but integration examples are still scarce.

  • The benefits of integration include organ-specific cellular hierarchy and structural fidelity; microscopic features from OoCs guiding tissue morphological formation; better reproducibility and scale-up capacities; and biocompatible built-in sensors for in situ functional readouts and industrially compatible culture formats.

  • A key challenge is vascularizing organoids with tissue-specific endothelial cells and aligning different cell types in organoids with appropriate flow in scalable, integrated devices.

  • In parallel, advances in computer vision and deep learning will be needed to enhance data processing and analysis. Addressing cell line variability and establishing validation criteria for OoC–organoid integrated devices is critical for commercial and translational success.

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Fig. 1: Main approaches in organoids and OoC systems.
Fig. 2: Timeline and examples of multi-well devices for integration of organoids and OoC devices.
Fig. 3: Advances and challenges in the integration of organoids and OoC systems.

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Acknowledgements

Our work is funded by Canadian Institutes of Health Research (CIHR) Foundation grant FDN-167274, Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grant (RGPIN 326982-10), NSERC-CIHR Collaborative Health Research grant (CHRP 493737-16), US National Institutes of Health grant 2R01 HL076485 and a Stem Cell Network Impact Award (IMP-C4R1-3). M.R. was supported by the Killam Fellowship and Canada Research Chair. Y.Z. was supported by a CIHR postdoctoral award. S.L. was supported by a Rothschild, Zuckerman, and EMBO (ALTF 530-2022) fellowship.

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Author notes

  1. These authors contributed equally: Yimu Zhao, Shira Landau.

Authors and Affiliations

  1. Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada

    Yimu Zhao, Shira Landau, Sargol Okhovatian, Chuan Liu, Rick Xing Ze Lu, Benjamin Fook Lun Lai, Qinghua Wu, Jennifer Kieda & Milica Radisic

  2. Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

    Yimu Zhao, Shira Landau, Sargol Okhovatian, Chuan Liu, Qinghua Wu & Milica Radisic

  3. Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada

    Krisco Cheung & Milica Radisic

  4. Department of Chemical Engineering, McMaster University, Hamilton, Ontario, Canada

    Shravanthi Rajasekar & Boyang Zhang

  5. School of Biomedical Engineering, McMaster University, Hamilton, Ontario, Canada

    Kimia Jozani & Boyang Zhang

  6. Terrence Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, Ontario, Canada

    Milica Radisic

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Contributions

Conceptualization: M.R., Y.Z., S.L. and S.O. Writing – original draft: Y.Z., S.L., S.O., C.L., R.X.Z.L., B.F.L.L., Q.W., J.K., K.C., S.R., K.J., B.Z. and M.R. Writing – review and editing: M.R., Y.Z., S.L. and S.O. Visualization: Y.Z., S.L., S.O. and K.C. Supervision: M.R. and B.Z. Project administration: M.R. Funding acquisition: M.R. and B.Z.

Corresponding author

Correspondence to Milica Radisic.

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Competing interests

M.R., Y.Z. and B.Z. are inventors on an issued US patent for Biowire technology that is licensed to Valo Health; they receive royalties for this invention. B.Z. and S.R. are co-founders and hold equity in OrganoBiotech. The remaining authors declare no competing interests.

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Nature Review Bioengineering thanks Kimberly Homan, who co-reviewed with Julien Roth; Ryuji Morizane; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Bioconvergence hub: https://bico.com/what-we-do/

Comprehensive In Vitro Pro-arrhythmia Assay (CIPA): https://cipaproject.org/

Human Cell Atlas: https://www.humancellatlas.org/

IQ consortium: https://iqconsortium.org/

United Network for Organ Sharing: https://unos.org/

Valo Health, an AI company, acquiring the heart-on-a-chip company TARA Biosystems: https://www.valohealth.com/press/valo-health-acquires-tara-biosystems-creating-first-of-its-kind-vertically-integrated-cardiovascular-platform

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Zhao, Y., Landau, S., Okhovatian, S. et al. Integrating organoids and organ-on-a-chip devices. Nat Rev Bioeng 2, 588–608 (2024). https://doi.org/10.1038/s44222-024-00207-z

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