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Organs-on-chips at the frontiers of drug discovery

Abstract

Improving the effectiveness of preclinical predictions of human drug responses is critical to reducing costly failures in clinical trials. Recent advances in cell biology, microfabrication and microfluidics have enabled the development of microengineered models of the functional units of human organs — known as organs-on-chips — that could provide the basis for preclinical assays with greater predictive power. Here, we examine the new opportunities for the application of organ-on-chip technologies in a range of areas in preclinical drug discovery, such as target identification and validation, target-based screening, and phenotypic screening. We also discuss emerging drug discovery opportunities enabled by organs-on-chips, as well as important challenges in realizing the full potential of this technology.

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Figure 1: Lung-on-a-chip.
Figure 2: Organ-on-a-chip models for cancer research.
Figure 3: In vivo engineering of bone marrow.
Figure 4: Brain tissue-on-a-chip.
Figure 5: Body-on-chip systems.

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Acknowledgements

The authors thank M. Farrell, M. Mondrinos, C. Blundell, J. Mealy and M. Chen for helpful discussions. The authors are supported by the US National Institutes of Health (NIH) Director's Innovator Award to D.H. (1DP2HL127720-01), the University of Pennsylvania, USA, and the National Research Foundation of Korea (2012M3A7B4035286 and 2013R1A2A2A04013379). E.W.E. is supported by the US National Science Foundation Graduate Research Fellowship Program.

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Correspondence to Dongeun Huh.

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Competing interests

A.B. is partly paid by a Defense Advanced Research Projects Agency (DARPA) grant and an FDA Broad Agency Announcement grant, both relating to organ on chip work; A.B. is not the principal investigator for these grants. A.B. is listed on four patents regarding organs on chips: [1] PCT/US12/36920 filed 05/08/12; [2] PCT/US12/37096 filed 05/09/12; [3] PCT/US12/68725 filed 12/10/12; and [4] PCT/US12/68766 filed 12/10/12. The value of each patent is not expected to change with this publication. E.W.E. and D.H. declare no competing financial interests.

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Glossary

Biomimetic

Refers to the use of principles, mechanisms and designs derived from those naturally occurring in living organisms.

Epithelial–mesenchymal transition

(EMT). The process by which a polarized epithelial cell undergoes a series of biochemical changes to acquire characteristics of a mesenchymal cell, including increased invasive and migratory capacity, higher resistance to apoptosis and upregulated production of extracellular matrix proteins.

Microfluidics

A science and engineering discipline focusing on the development of fluidic systems with characteristic dimensions of tens to hundreds of micrometres that provide capabilities to control, manipulate and analyse small volumes of fluids (microlitres to attolitres) for a wide range of applications.

Spheroids

Three-dimensional spherical agglomerations of adherent cells generated by intercellular adhesion and aggregation.

Stratified medicine

An approach that aims to develop patient-specific therapies using biological or risk characteristics (for example, biomarkers and genetics) shared by subgroups of patient populations. This approach is also referred to as personalized or precision medicine.

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Esch, E., Bahinski, A. & Huh, D. Organs-on-chips at the frontiers of drug discovery. Nat Rev Drug Discov 14, 248–260 (2015). https://doi.org/10.1038/nrd4539

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