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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Scannell, J. W., Blanckley, A., Boldon, H. & Warrington, B. Diagnosing the decline in pharmaceutical R&D efficiency. Nature Rev. Drug Discov. 11, 191–200 (2012).
Paul, S. M. et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nature Rev. Drug Discov. 9, 203–214 (2010).
Caponigro, G. & Sellers, W. R. Advances in the preclinical testing of cancer therapeutic hypotheses. Nature Rev. Drug Discov. 10, 179–187 (2011).
Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nature Rev. Drug Discov. 3, 711–715 (2004).
Bowes, J. et al. Reducing safety-related drug attrition: the use of in vitro pharmacological profiling. Nature Rev. Drug Discov. 11, 909–922 (2012).
Muller, P. Y. & Milton, M. N. The determination and interpretation of the therapeutic index in drug development. Nature Rev. Drug Discov. 11, 751–761 (2012).
Folch, A. & Toner, M. Microengineering of cellular interactions. Annu. Rev. Biomed. Eng. 2, 227–256 (2000).
Whitesides, G. M., Ostuni, E., Takayama, S., Jiang, X. Y. & Ingber, D. E. Soft lithography in biology and biochemistry. Annu. Rev. Biomed. Eng. 3, 335–373 (2001).
Beebe, D. J., Mensing, G. A. & Walker, G. M. Physics and applications of microfluidics in biology. Annu. Rev. Biomed. Eng. 4, 261–286 (2002).
Shamir, E. R. & Ewald, A. J. Three-dimensional organotypic culture: experimental models of mammalian biology and disease. Nature Rev. Mol. Cell Biol. 15, 647–664 (2014).
Huh, D., Hamilton, G. A. & Ingber, D. E. From 3D cell culture to organs-on-chips. Trends Cell Biol. 21, 745–754 (2011).
Yum, K., Hong, S. G., Healy, K. E. & Lee, L. P. Physiologically relevant organs on chips. Biotechnol. J. 9, 16–27 (2014).
Huh, D. et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010).
Inamdar, N. K. & Borenstein, J. T. Microfluidic cell culture models for tissue engineering. Curr. Opin. Biotechnol. 22, 681–689 (2011).
Huh, D. et al. A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice. Sci. Transl. Med. 4, 159ra147 (2012).
Khetani, S. R. & Bhatia, S. N. Microscale culture of human liver cells for drug development. Nature Biotech. 26, 120–126 (2007).
Bhatia, S. N., Balis, U. J., Yarmush, M. L. & Toner, M. Effect of cell–cell interactions in preservation of cellular phenotype: cocultivation of hepatocytes and nonparenchymal cells. FASEB J. 13, 1883–1900 (1999).
Huh, D., Torisawa, Y. S., Hamilton, G. A., Kim, H. J. & Ingber, D. E. Microengineered physiological biomimicry: organs-on-chips. Lab Chip 12, 2156–2164 (2012).
Ghaemmaghami, A. M., Hancock, M. J., Harrington, H., Kaji, H. & Khademhosseini, A. Biomimetic tissues on a chip for drug discovery. Drug Discov. Today 17, 173–181 (2012).
van der Meer, A. D. & van den Berg, A. Organs-on-chips: breaking the in vitro impasse. Integr. Biol. (Camb.) 4, 461–470 (2012).
Griffith, L. G. & Swartz, M. A. Capturing complex 3D tissue physiology in vitro. Nature Rev. Mol. Cell Biol. 7, 211–224 (2006).
El-Ali, J., Sorger, P. K. & Jensen, K. F. Cells on chips. Nature 442, 403–411 (2006).
Whitesides, G. M. The origins and the future of microfluidics. Nature 442, 368–373 (2006).
Sackmann, E. K., Fulton, A. L. & Beebe, D. J. The present and future role of microfluidics in biomedical research. Nature 507, 181–189 (2014).
Bhatia, S. N. & Ingber, D. E. Microfluidic organs-on-chips. Nature Biotech. 32, 760–772 (2014).
Olson, H. et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharm. 32, 56–67 (2000).
Mak, I. W., Evaniew, N. & Ghert, M. Lost in translation: animal models and clinical trials in cancer treatment. Am. J. Transl. Res. 6, 114–118 (2014).
Seok, J. et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl Acad. Sci. USA 110, 3507–3512 (2013).
Henderson, V. C., Kimmelman, J., Fergusson, D., Grimshaw, J. M. & Hackam, D. G. Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments. PLoS Med. 10, e1001489 (2013).
Li, F., Yin, Z., Jin, G., Zhao, H. & Wong, S. T. Chapter 17: bioimage informatics for systems pharmacology. PLoS Comput. Biol. 9, e1003043 (2013).
Polini, A. et al. Organs-on-a-chip: a new tool for drug discovery. Expert Opin. Drug Dis. 9, 335–352 (2014).
Song, J. W. et al. Microfluidic endothelium for studying the intravascular adhesion of metastatic breast cancer cells. PLoS ONE 4, e5756 (2009).
Bersini, S. et al. A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone. Biomaterials 35, 2454–2461 (2014).
Businaro, L. et al. Cross talk between cancer and immune cells: exploring complex dynamics in a microfluidic environment. Lab Chip 13, 229–239 (2013).
Kunze, A. et al. Astrocyte–neuron co-culture on microchips based on the model of SOD mutation to mimic ALS. Integr. Biol. (Camb.) 5, 964–975 (2013).
Wang, G. et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nature Med. 20, 616–623 (2014).
Aref, A. R. et al. Screening therapeutic EMT blocking agents in a three-dimensional microenvironment. Integr. Biol. (Camb.) 5, 381–389 (2013).
Vidi, P. A. et al. Disease-on-a-chip: mimicry of tumor growth in mammary ducts. Lab Chip 14, 172–177 (2014).
Tatosian, D. A. & Shuler, M. L. A novel system for evaluation of drug mixtures for potential efficacy in treating multidrug resistant cancers. Biotechnol. Bioeng. 103, 187–198 (2009).
Torisawa, Y. S. et al. Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro. Nature Methods 11, 663–669 (2014).
Berdichevsky, Y., Staley, K. J. & Yarmush, M. L. Building and manipulating neural pathways with microfluidics. Lab Chip 10, 999–1004 (2010).
Snouber, L. C. et al. Metabolomics-on-a-chip of hepatotoxicity induced by anticancer drug flutamide and its active metabolite hydroxyflutamide using HepG2/C3a microfluidic biochips. Toxicol. Sci. 132, 8–20 (2013).
Mao, S., Gao, D., Liu, W., Wei, H. & Lin, J.-M. Imitation of drug metabolism in human liver and cytotoxicity assay using a microfluidic device coupled to mass spectrometric detection. Lab Chip 12, 219–226 (2012).
Choucha-Snouber, L. et al. Investigation of ifosfamide nephrotoxicity induced in a liver–kidney co-culture biochip. Biotechnol. Bioeng. 110, 597–608 (2013).
Agarwal, A., Goss, J. A., Cho, A., McCain, M. L. & Parker, K. K. Microfluidic heart on a chip for higher throughput pharmacological studies. Lab Chip 13, 3599–3608 (2013).
Grosberg, A., Alford, P. W., McCain, M. L. & Parker, K. K. Ensembles of engineered cardiac tissues for physiological and pharmacological study: heart on a chip. Lab Chip 11, 4165–4173 (2011).
McCain, M. L., Sheehy, S. P., Grosberg, A., Goss, J. A. & Parker, K. K. Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip. Proc. Natl Acad. Sci. USA 110, 9770–9775 (2013).
Thavandiran, N. et al. Design and formulation of functional pluripotent stem cell-derived cardiac microtissues. Proc. Natl Acad. Sci. USA 110, E4698–E4707 (2013).
Capulli, A. K. et al. Approaching the in vitro clinical trial: engineering organs on chips. Lab Chip 14, 3181–3186 (2014).
Thorneloe, K. S. et al. An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci. Transl. Med. 4, 159ra148 (2012).
Kramer, J. A., Sagartz, J. E. & Morris, D. L. The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates. Nature Rev. Drug Discov. 6, 636–649 (2007).
LeCluyse, E. L., Witek, R. P., Andersen, M. E. & Powers, M. J. Organotypic liver culture models: meeting current challenges in toxicity testing. Crit. Rev. Toxicol. 42, 501–548 (2012).
Baudoin, R. et al. Evaluation of seven drug metabolisms and clearances by cryopreserved human primary hepatocytes cultivated in microfluidic biochips. Xenobiotica 43, 140–152 (2013).
Chao, P., Maguire, T., Novik, E., Cheng, K.-C. & Yarmush, M. Evaluation of a microfluidic based cell culture platform with primary human hepatocytes for the prediction of hepatic clearance in human. Biochem. Pharmacol. 78, 625–632 (2009).
Kim, H. J., Huh, D., Hamilton, G. & Ingber, D. E. Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. Lab Chip 12, 2165–2174 (2012).
Kim, H. J. & Ingber, D. E. Gut-on-a-chip microenvironment induces human intestinal cells to undergo villus differentiation. Integr. Biol. (Camb.) 5, 1130–1140 (2013).
Gao, D., Liu, H., Lin, J.-M., Wang, Y. & Jiang, Y. Characterization of drug permeability in Caco-2 monolayers by mass spectrometry on a membrane-based microfluidic device. Lab Chip 13, 978–985 (2013).
Lee, J. B. & Sung, J. H. Organ-on-a-chip technology and microfluidic whole-body models for pharmacokinetic drug toxicity screening. Biotechnol. J. 8, 1258–1266 (2013).
Sung, J. H. et al. Microfabricated mammalian organ systems and their integration into models of whole animals and humans. Lab Chip 13, 1201–1212 (2013).
Imura, Y., Sato, K. & Yoshimura, E. Micro total bioassay system for ingested substances: assessment of intestinal absorption, hepatic metabolism, and bioactivity. Anal. Chem. 82, 9983–9988 (2010).
Imura, Y., Yoshimura, E. & Sato, K. Micro total bioassay system for oral drugs: evaluation of gastrointestinal degradation, intestinal absorption, hepatic metabolism, and bioactivity. Anal. Sci. 28, 197–199 (2012).
Imura, Y., Yoshimura, E. & Sato, K. Microcirculation system with a dialysis part for bioassays evaluating anticancer activity and retention. Anal. Chem. 85, 1683–1688 (2013).
Wikswo, J. P. et al. Scaling and systems biology for integrating multiple organs-on-a-chip. Lab Chip 13, 3496–3511 (2013).
Sung, J. H. & Shuler, M. L. A micro cell culture analog (μCCA) with 3D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugs. Lab Chip 9, 1385–1394 (2009).
Sung, J. H., Kam, C. & Shuler, M. L. A microfluidic device for a pharmacokinetic–pharmacodynamic (PK–PD) model on a chip. Lab Chip 10, 446–455 (2010).
Zheng, W., Thorne, N. & McKew, J. C. Phenotypic screens as a renewed approach for drug discovery. Drug Discov. Today 18, 1067–1073 (2013).
Lee, J. A., Uhlik, M. T., Moxham, C. M., Tomandl, D. & Sall, D. J. Modern phenotypic drug discovery is a viable, neoclassic pharma strategy. J. Med. Chem. 55, 4527–4538 (2012).
Trietsch, S. J., Israels, G. D., Joore, J., Hankemeier, T. & Vulto, P. Microfluidic titer plate for stratified 3D cell culture. Lab Chip 13, 3548–3554 (2013).
Demonaco, H. J., Ali, A. & Hippel, E. The major role of clinicians in the discovery of off-label drug therapies. Pharmacotherapy 26, 323–332 (2006).
Swinney, D. C. & Anthony, J. How were new medicines discovered? Nature Rev. Drug Discov. 10, 507–519 (2011).
Kalchman, J. et al. A three-dimensional microfluidic tumor cell migration assay to screen the effect of anti-migratory drugs and interstitial flow. Microfluid. Nanofluid. 14, 969–981 (2013).
Melnikova, I. Rare diseases and orphan drugs. Nature Rev. Drug Discov. 11, 267–268 (2012).
van der Meer, A. D., Orlova, V. V., ten Dijke, P., van den Berg, A. & Mummery, C. L. Three-dimensional co-cultures of human endothelial cells and embryonic stem cell-derived pericytes inside a microfluidic device. Lab Chip 13, 3562–3568 (2013).
Phan, V. H. et al. An update on ethnic differences in drug metabolism and toxicity from anti-cancer drugs. Expert Opin. Drug Metab. Toxicol. 7, 1395–1410 (2011).
US Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research & Center for Devices and Radiological Health. Guidance for Industry: Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products (US FDA, 2012).
Ma, L. et al. Towards personalized medicine with a three-dimensional micro-scale perfusion-based two-chamber tissue model system. Biomaterials 33, 4353–4361 (2012).
Polimanti, R., Piacentini, S., Manfellotto, D. & Fuciarelli, M. Human genetic variation of CYP450 superfamily: analysis of functional diversity in worldwide populations. Pharmacogenomics 13, 1951–1960 (2012).
Chen, Z. et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483, 613–617 (2012).
Torchilin, V. P. Multifunctional nanocarriers. Adv. Drug Deliv. Rev. 58, 1532–1555 (2006).
Boisselier, E. & Astruc, D. Gold nanoparticles in nanomedicine: preparations, imaging, diagnostics, therapies and toxicity. Chem. Soc. Rev. 38, 1759–1782 (2009).
Kim, Y. et al. Probing nanoparticle translocation across the permeable endothelium in experimental atherosclerosis. Proc. Natl Acad. Sci. USA 111, 1078–1083 (2014).
Prabhakarpandian, B. et al. SyM-BBB: a microfluidic blood brain barrier model. Lab Chip 13, 1093–1101 (2013).
Griep, L. M. et al. BBB on chip: microfluidic platform to mechanically and biochemically modulate blood–brain barrier function. Biomed. Microdevices 15, 145–150 (2013).
Achyuta, A. K. H. et al. A modular approach to create a neurovascular unit-on-a-chip. Lab Chip 13, 542–553 (2013).
Booth, R. & Kim, H. Characterization of a microfluidic in vitro model of the blood–brain barrier (mu BBB). Lab Chip 12, 1784–1792 (2012).
Nelson, C. E. et al. Balancing cationic and hydrophobic content of PEGylated siRNA polyplexes enhances endosome escape, stability, blood circulation time, and bioactivity in vivo. ACS Nano 7, 8870–8880 (2013).
Flaim, C. J., Chien, S. & Bhatia, S. N. An extracellular matrix microarray for probing cellular differentiation. Nature Methods 2, 119–125 (2005).
Berthier, E., Young, E. W. & Beebe, D. Engineers are from PDMS-land, biologists are from polystyrenia. Lab Chip 12, 1224–1237 (2012).
Wong, I. & Ho, C.-M. Surface molecular property modifications for poly (dimethylsiloxane) (PDMS) based microfluidic devices. Microfluid. Nanofluid. 7, 291–306 (2009).
Domansky, K. et al. Clear castable polyurethane elastomer for fabrication of microfluidic devices. Lab Chip 13, 3956–3964 (2013).
van Midwoud, P. M., Janse, A., Merema, M. T., Groothuis, G. M. & Verpoorte, E. Comparison of biocompatibility and adsorption properties of different plastics for advanced microfluidic cell and tissue culture models. Anal. Chem. 84, 3938–3944 (2012).
Ghafar-Zadeh, E., Waldeisen, J. R. & Lee, L. P. Engineered approaches to the stem cell microenvironment for cardiac tissue regeneration. Lab Chip 11, 3031–3048 (2011).
Mathur, A. et al. Human induced pluripotent stem cell-based microphysiological tissue models of myocardium and liver for drug development. Stem Cell Res. Ther. 4 (Suppl. 1), S14 (2013).
Neuzil, P., Giselbrecht, S., Lange, K., Huang, T. J. & Manz, A. Revisiting lab-on-a-chip technology for drug discovery. Nature Rev. Drug Discov. 11, 620–632 (2012).
Messner, S., Agarkova, I., Moritz, W. & Kelm, J. Multi-cell type human liver microtissues for hepatotoxicity testing. Arch. Toxicol. 87, 209–213 (2013).
DesRochers, T. M., Suter, L., Roth, A. & Kaplan, D. L. Bioengineered 3D human kidney tissue, a platform for the determination of nephrotoxicity. PLoS ONE 8, e59219 (2013).
Meyvantsson, I., Warrick, J. W., Hayes, S., Skoien, A. & Beebe, D. J. Automated cell culture in high density tubeless microfluidic device arrays. Lab Chip 8, 717–724 (2008).
Bouhifd, M. et al. Mapping the human toxome by systems toxicology. Basic Clin. Pharmacol. Toxicol. 115, 24–31 (2014).
US Food and Drug Administration, Center for Drug Evaluation and Research & Center for Biologics Evaluation and Research. Guidance for Industry: Product Development Under the Animal Rule (US FDA, 2014).
Esch, M., King, T. & Shuler, M. The role of body-on-a-chip devices in drug and toxicity studies. Annu. Rev. Biomed. Eng. 13, 55–72 (2011).
Williamson, A., Singh, S., Fernekorn, U. & Schober, A. The future of the patient-specific body-on-a-chip. Lab Chip 13, 3471–3480 (2013).
Sutherland, M. L., Fabre, K. M. & Tagle, D. A. The National Institutes of Health Microphysiological Systems Program focuses on a critical challenge in the drug discovery pipeline. Stem Cell Res. Ther. 4 (Suppl. 1), I1 (2013).
Dambach, D. M. & Uppal, H. Improving risk assessment. Sci. Transl. Med. 4, 159ps22 (2012).
Jeon, J. S. et al. Generation of 3D functional microvascular networks with human mesenchymal stem cells in microfluidic systems. Integr. Biol. (Camb.) 6, 555–563 (2014).
Lee, H., Kim, S., Chung, M., Kim, J. H. & Jeon, N. L. A bioengineered array of 3D microvessels for vascular permeability assay. Microvasc. Res. 91, 90–98 (2014).
Fischbach, C. et al. Engineering tumors with 3D scaffolds. Nature Methods 4, 855–860 (2007).
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.
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:  PCT/US12/36920 filed 05/08/12;  PCT/US12/37096 filed 05/09/12;  PCT/US12/68725 filed 12/10/12; and  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.
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.
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.
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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