Organs-on-chips (OoCs), also known as microphysiological systems or ‘tissue chips’ (the terms are synonymous), have attracted substantial interest in recent years owing to their potential to be informative at multiple stages of the drug discovery and development process. These innovative devices could provide insights into normal human organ function and disease pathophysiology, as well as more accurately predict the safety and efficacy of investigational drugs in humans. Therefore, they are likely to become useful additions to traditional preclinical cell culture methods and in vivo animal studies in the near term, and in some cases replacements for them in the longer term. In the past decade, the OoC field has seen dramatic advances in the sophistication of biology and engineering, in the demonstration of physiological relevance and in the range of applications. These advances have also revealed new challenges and opportunities, and expertise from multiple biomedical and engineering fields will be needed to fully realize the promise of OoCs for fundamental and translational applications. This Review provides a snapshot of this fast-evolving technology, discusses current applications and caveats for their implementation, and offers suggestions for directions in the next decade.
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Defense Advanced Research Project Agency (DARPA) funded linked 10-organ system: https://www.darpa.mil/program/microphysiological-systems
European Union Reference Laboratory for Alternatives to Animal Testing: https://ec.europa.eu/jrc/en/eurl/ecvam
Good manufacturing practice guidelines: https://www.ecfr.gov/cgi-bin/text-idx?SID=cb7c830642b365274d824a432e118e77&mc=true&node=pt21.8.820&rgn=div5
Human Organ and Disease Model Technologies (hDMT): https://www.hdmt.technology/
IQ Consortium: https://iqconsortium.org/
National Center for Advancing Translational Sciences (NCATS) Tissue Chips in Space: https://ncats.nih.gov/tissuechip/projects/space
NIH Heal Initiative: https://heal.nih.gov
Organisation for Economic Co-operation and Development “Guidance Document on the Validation and International Acceptance of New or Updated Test Methods for Hazard Assessment”: https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecd-gd34.pdf
Organs on chips — 2017 market overview analysis by Yole Développement: http://www.yole.fr/OrgansOnChips_Market.aspx#.XIP6dVNKiV4
The Center for Advancement of Science in Space (CASIS): https://www.iss-casis.org/
The Gartner hype cycle for emerging technologies 2018: https://www.gartner.com/smarterwithgartner/5-trends-emerge-in-gartner-hype-cycle-for-emerging-technologies-2018/
Tissue Chip Drug Screening: https://ncats.nih.gov/tissuechip
Tissue Chip Testing Centers: https://ncats.nih.gov/tissuechip/projects/Centres
US National Institutes of Health (NIH), FDA and DARPA funded development of tissue chips to advance regulatory sciences: https://www.nih.gov/news-events/news-releases/nih-fda-announce-collaborative-initiative-fast-track-innovations-public
- Extracellular matrix
(ECM). Supporting network of macromolecules providing structural and biochemical support to surrounding cells. Promotes cell adhesion and cell–cell communication and produces biochemical cues for tissue growth and maintenance. The ECM is tissue specific and in animal tissues consists of fibrous elements (collagen and elastin), and links proteins (laminin and fibronectin) and other molecules.
Highly absorbent and hydrophilic biocompatible 3D polymer networks used to contain cells or drugs for tissue engineering applications. Can consist of natural (collagen, gelatin and agarose) or synthetic components and respond to environmental conditions such as pH. May have both liquid and solid properties. Other uses include wound dressings and contact lenses.
- Multi-electrode arrays
Arrays of tens to thousands of tightly spaced microelectrical sensors designed to record from single cells to networks of cells on submillisecond timescales. Can also be used to stimulate cells with precise spatial and temporal characteristics. Used in electrically excitable tissues such as cardiac, muscle and neural tissues.
- Pharmacokinetic/pharmacodynamic modelling
Integration of pharmacokinetics (movement of drugs through the body) and pharmacodynamics (the body’s biological response to drugs) into a mathematical model describing dose–concentration–response relationships. Can be used to predict effect and efficacy of drug dosing over time.
- Physiologically based pharmacokinetic modelling
Mathematical modelling of body compartments (predefined organs or tissues) combined with known parameters of concentrations, quantities and transport between compartments used to predict absorption, distribution, metabolism and excretion of synthetic or natural chemical substances within the body.
- Investigational New Drug
(IND). An application submitted to the US Food and Drug Administration to administer a novel drug to humans. The first step in the drug review process, which includes information on animal studies, manufacturing protocols and clinical and personnel protocols. Data gathered become part of the New Drug Application.
- New Drug Application
(NDA). An application submitted to the US Food and Drug Administration requesting permission to sell and market a drug in the USA. Information submitted includes data from the Investigational New Drug and is reviewed for safety and efficacy, benefit versus risks, appropriate labelling information, and manufacturing and processing methods.
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Low, L.A., Mummery, C., Berridge, B.R. et al. Organs-on-chips: into the next decade. Nat Rev Drug Discov 20, 345–361 (2021). https://doi.org/10.1038/s41573-020-0079-3
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