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Advances in organ-on-a-chip engineering

Abstract

Predicting the effects of drugs before human clinical trials is at the heart of drug screening and discovery processes. The cost of drug discovery is steadily increasing owing to the limited predictability of 2D cell culture and animal models. The convergence of microfabrication and tissue engineering gave rise to organ-on-a-chip technologies, which offer an alternative to conventional preclinical models for drug screening. Organ-on-a-chip devices can replicate key aspects of human physiology crucial for the understanding of drug effects, improving preclinical safety and efficacy testing. In this Review, we discuss how organ-on-a-chip technologies can recreate functions of organs, focusing on tissue barrier properties, parenchymal tissue function and multi-organ interactions, which are three key aspects of human physiology. Specific organ-on-a-chip systems are examined in terms of cell sources, functional hallmarks and available disease models. Finally, we highlight the challenges that need to be overcome for the clinical translation of organ-on-a-chip devices regarding materials, cellular fidelity, multiplexing, sensing, scalability and validation.

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Fig. 1: Major milestones in organ-on-a-chip technology and establishment of organ-on-a-chip companies.
Fig. 2: Reproducing tissue barrier function.
Fig. 3: Reproducing elongated parenchymal tissues.
Fig. 4: Reproducing spherical parenchymal tissues.
Fig. 5: Body-on-a-chip devices.
Fig. 6: Functional scaling of body-on-a-chip devices.
Fig. 7: Modelling multi-organ interactions.

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References

  1. Shehab, N. et al. US emergency department visits for outpatient adverse drug events, 2013–2014. JAMA 316, 2115–2125 (2016).

    Article  Google Scholar 

  2. Shahrbaf, F. G. & Assadi, F. Drug-induced renal disorders. J. Renal Injury Prevention 4, 57 (2015).

    CAS  Google Scholar 

  3. Kim, S. Y. & Moon, A. Drug-induced nephrotoxicity and its biomarkers. Biomolecules Ther. 20, 268 (2012).

    Article  CAS  Google Scholar 

  4. Adams, C. P. & Brantner, V. V. Spending on new drug development1. Health Econom. 19, 130–141 (2010).

    Article  Google Scholar 

  5. Kinch, M. S. & Merkel, J. An analysis of FDA-approved drugs for inflammation and autoimmune diseases. Drug Discov. Today 20, 920–923 (2015).

    Article  CAS  Google Scholar 

  6. DiMasi, J. A., Grabowski, H. G. & Hansen, R. W. Innovation in the pharmaceutical industry: new estimates of R&D costs. J. Health Econom. 47, 20–33 (2016).

    Article  Google Scholar 

  7. Paul, S. M. et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat. Rev. Drug Discov. 9, 203–214 (2010).

    Article  CAS  Google Scholar 

  8. Ben-David, U. et al. Patient-derived xenografts undergo mouse-specific tumor evolution. Nat. Genet. 49, 1567–1575 (2017).

    Article  CAS  Google Scholar 

  9. Rohr, S., Schölly, D. M. & Kleber, A. G. Patterned growth of neonatal rat heart cells in culture. Morphological and electrophysiological characterization. Circul. Res. 68, 114–130 (1991).

    Article  CAS  Google Scholar 

  10. Fast, V. G., Rohr, S., Gillis, A. M. & Kléber, A. G. Activation of cardiac tissue by extracellular electrical shocks: formation of ‘secondary sources’ at intercellular clefts in monolayers of cultured myocytes. Circul. Res. 82, 375–385 (1998).

    Article  CAS  Google Scholar 

  11. Kucera, J. P., Kléber, A. G. & Rohr, S. Slow conduction in cardiac tissue, II: effects of branching tissue geometry. Circul. Res. 83, 795–805 (1998).

    Article  CAS  Google Scholar 

  12. Rohr, S., Kucera, J. P. & Kléber, A. G. Slow conduction in cardiac tissue, I: effects of a reduction of excitability versus a reduction of electrical coupling on microconduction. Circul. Res. 83, 781–794 (1998).

    Article  CAS  Google Scholar 

  13. Rohr, S., Kucera, J. P., Fast, V. G. & Kléber, A. G. Paradoxical improvement of impulse conduction in cardiac tissue by partial cellular uncoupling. Science 275, 841–844 (1997).

    Article  CAS  Google Scholar 

  14. Duffy, D. C., McDonald, J. C., Schueller, O. J. & Whitesides, G. M. Rapid prototyping of microfluidic systems in poly(dimethylsiloxane). Anal. Chem. 70, 4974–4984 (1998).

    Article  CAS  Google Scholar 

  15. Xia, Y. & Whitesides, G. M. Soft lithography. Annu. Rev. Mater. Sci. 28, 153–184 (1998).

    Article  CAS  Google Scholar 

  16. Whitesides, G. M. The origins and the future of microfluidics. Nature 442, 368 (2006).

    Article  CAS  Google Scholar 

  17. Sin, A. et al. The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors. Biotechnol. Progress 20, 338–345 (2004).

    Article  CAS  Google Scholar 

  18. Viravaidya, K., Sin, A. & Shuler, M. L. Development of a microscale cell culture analog to probe naphthalene toxicity. Biotechnol. Progress 20, 316–323 (2004).

    Article  CAS  Google Scholar 

  19. Song, J. W. et al. Computer-controlled microcirculatory support system for endothelial cell culture and shearing. Anal. Chem. 77, 3993–3999 (2005).

    Article  CAS  Google Scholar 

  20. Lam, M. T., Huang, Y.-C., Birla, R. K. & Takayama, S. Microfeature guided skeletal muscle tissue engineering for highly organized 3-dimensional free-standing constructs. Biomaterials 30, 1150–1155 (2009).

    Article  CAS  Google Scholar 

  21. Jang, K., Sato, K., Igawa, K., Chung, U.-i. & Kitamori, T. Development of an osteoblast-based 3D continuous-perfusion microfluidic system for drug screening. Anal. Bioanal. Chem. 390, 825–832 (2008).

    Article  CAS  Google Scholar 

  22. Huh, D. et al. Acoustically detectable cellular-level lung injury induced by fluid mechanical stresses in microfluidic airway systems. Proc. Natl Acad. Sci. USA 104, 18886–18891 (2007).

    Article  CAS  Google Scholar 

  23. Carraro, A. et al. In vitro analysis of a hepatic device with intrinsic microvascular-based channels. Biomed. Microdevices 10, 795–805 (2008).

    Article  Google Scholar 

  24. Lee, P. J., Hung, P. J. & Lee, L. P. An artificial liver sinusoid with a microfluidic endothelial-like barrier for primary hepatocyte culture. Biotechnol. Bioeng. 97, 1340–1346 (2007).

    Article  CAS  Google Scholar 

  25. Harris, S. G. & Shuler, M. L. Growth of endothelial cells on microfabricated silicon nitride membranes for an in vitro model of the blood-brain barrier. Biotechnol. Bioprocess Eng. 8, 246–251 (2003).

    Article  CAS  Google Scholar 

  26. Mahler, G. J., Esch, M. B., Glahn, R. P. & Shuler, M. L. Characterization of a gastrointestinal tract microscale cell culture analog used to predict drug toxicity. Biotechnol. Bioeng. 104, 193–205 (2009).

    Article  CAS  Google Scholar 

  27. Kimura, H., Yamamoto, T., Sakai, H., Sakai, Y. & Fujii, T. An integrated microfluidic system for long-term perfusion culture and on-line monitoring of intestinal tissue models. Lab. Chip 8, 741–746 (2008).

    Article  CAS  Google Scholar 

  28. Jang, K.-J. & Suh, K.-Y. A multi-layer microfluidic device for efficient culture and analysis of renal tubular cells. Lab. Chip 10, 36–42 (2010).

    Article  CAS  Google Scholar 

  29. Huh, D. et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010). This is a landmark study on recapitulating organ-level lung function in vitro with a microfluidic chip.

    Article  CAS  Google Scholar 

  30. Ingber, D. E. Reverse engineering human pathophysiology with organs-on-chips. Cell 164, 1105–1109 (2016).

    Article  CAS  Google Scholar 

  31. Langer, R. & Vacanti, J. P. Tissue engineering. Science 260, 920–926 (1993).

    Article  CAS  Google Scholar 

  32. El-Ali, J., Sorger, P. K. & Jensen, K. F. Cells on chips. Nature 442, 403–411 (2006).

    Article  CAS  Google Scholar 

  33. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  Google Scholar 

  34. Park, I.-H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008).

    Article  CAS  Google Scholar 

  35. Reardon, S. Organs-on-chips’ go mainstream: drug companies put in vitro systems through their paces. Nature 523, 266–267 (2015).

    Article  CAS  Google Scholar 

  36. Zhang, B. & Radisic, M. Organ-on-a-Chip devices advance to market. Lab. Chip 17, 2395–2420 (2017). This is a comprehensive review on organ-on-a-chip start-ups in the market space.

    Article  CAS  Google Scholar 

  37. Zheng, Y., Chen, J. & López, J. A. Flow-driven assembly of VWF fibres and webs in in vitro microvessels. Nat. Commun. 6, 7858 (2015).

    Article  CAS  Google Scholar 

  38. Zheng, Y. et al. In vitro microvessels for the study of angiogenesis and thrombosis. Proc. Natl Acad. Sci. USA 109, 9342–9347 (2012).

    Article  CAS  Google Scholar 

  39. Jang, K.-J. et al. Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. Integr. Biol. 5, 1119–1129 (2013).

    Article  CAS  Google Scholar 

  40. 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).

    Article  CAS  Google Scholar 

  41. Benam, K. H. et al. Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro. Nat. Methods 13, 151–157 (2016).

    Article  CAS  Google Scholar 

  42. Musah, S. et al. Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip. Nat. Biomed. Eng. 1, 0069 (2017).

    Article  Google Scholar 

  43. Adriani, G., Ma, D., Pavesi, A., Kamm, R. D. & Goh, E. L. A. 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood–brain barrier. Lab. Chip (2017).

  44. Jeon, J. S. et al. Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proc. Natl Acad. Sci. USA 112, 214–219 (2015).

    Article  CAS  Google Scholar 

  45. Trietsch, S. J. et al. Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes. Nat. Commun. 8, 262 (2017).

    Article  CAS  Google Scholar 

  46. Adler, M. et al. A quantitative approach to screen for nephrotoxic compounds in vitro. J. Am. Soc. Nephrol. 27, 1015–1028 (2016).

    Article  CAS  Google Scholar 

  47. Homan, K. A. et al. Bioprinting of 3D convoluted renal proximal tubules on perfusable chips. Sci. Rep. 6, 34845 (2016).

    Article  CAS  Google Scholar 

  48. Weber, E. J. et al. Development of a microphysiological model of human kidney proximal tubule function. Kidney Int. 90, 627–637 (2016).

    Article  Google Scholar 

  49. Shlomai, A. et al. Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems. Proc. Natl Acad. Sci. USA 111, 12193–12198 (2014).

    Article  CAS  Google Scholar 

  50. Khetani, S. R. & Bhatia, S. N. Microscale culture of human liver cells for drug development. Nat. Biotechnol. 26, 120–126 (2008).

    Article  CAS  Google Scholar 

  51. Frey, O., Misun, P. M., Fluri, D. A., Hengstler, J. G. & Hierlemann, A. Reconfigurable microfluidic hanging drop network for multi-tissue interaction and analysis. Nat. Commun. 5, 4250 (2014).

    Article  CAS  Google Scholar 

  52. Yazdi, S. R. et al. Adding the ‘heart’to hanging drop networks for microphysiological multi-tissue experiments. Lab. Chip 15, 4138–4147 (2015).

    Article  CAS  Google Scholar 

  53. Nguyen, D. G. et al. Bioprinted 3D primary liver tissues allow assessment of organ-level response to clinical drug induced toxicity in vitro. PLoS One 11, e0158674 (2016).

    Article  CAS  Google Scholar 

  54. Nunes, S. S. et al. Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat. Methods 10, 781–787 (2013). This is a study on the maturation of engineered human cardiac tissues with electrical stimulation.

    Article  CAS  Google Scholar 

  55. Mathur, A. et al. Human iPSC-based cardiac microphysiological system for drug screening applications. Sci. Rep. 5, 8883 (2015).

    Article  CAS  Google Scholar 

  56. Legant, W. R. et al. Microfabricated tissue gauges to measure and manipulate forces from 3D microtissues. Proc. Natl Acad. Sci. USA 106, 10097–10102 (2009).

    Article  CAS  Google Scholar 

  57. Jackman, C. P., Carlson, A. L. & Bursac, N. Dynamic culture yields engineered myocardium with near-adult functional output. Biomaterials 111, 66–79 (2016).

    Article  CAS  Google Scholar 

  58. Lind, J. U. et al. Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing. Nat. Mater. 16, 303–308 (2016). This study presents an entirely 3D-printed platform for the culture and analysis of engineered cardiac tissues.

    Article  CAS  Google Scholar 

  59. Sidorov, V. Y. et al. I-Wire Heart-on-a-Chip I: three-dimensional cardiac tissue constructs for physiology and pharmacology. Acta Biomaterialia 48, 68–78 (2017).

    Article  CAS  Google Scholar 

  60. Zimmermann, W.-H. et al. Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat. Med. 12, 452–458 (2006).

    Article  CAS  Google Scholar 

  61. Wittmann, K. & Fischbach, C. Contextual control of adipose-derived stem cell function: implications for engineered tumor models. ACS Biomater. Sci. Eng. 3, 1483–1493 (2016).

    Article  CAS  Google Scholar 

  62. Miller, P. G. & Shuler, M. L. Design and demonstration of a pumpless 14 compartment microphysiological system. Biotechnol. Bioeng. 113, 2213–2227 (2016). This study presents a body-on-a-chip platform integrated with 14 tissue compartments.

    Article  CAS  Google Scholar 

  63. Oleaga, C. et al. Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci. Rep. 6, 20030 (2016).

    Article  CAS  Google Scholar 

  64. Xiao, S. et al. A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nat. Commun. 8, 14584 (2017).

    Article  CAS  Google Scholar 

  65. Coppeta, J. et al. A portable and reconfigurable multi-organ platform for drug development with onboard microfluidic flow control. Lab. Chip 17, 134–144 (2017).

    Article  CAS  Google Scholar 

  66. Vernetti, L. et al. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Sci. Rep. 7, 42296 (2017). This is a study on multi-organ interaction with multiple decentralized organ-on-a-chip systems located at different sites.

    Article  CAS  Google Scholar 

  67. Maschmeyer, I. et al. A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. Lab. Chip 15, 2688–2699 (2015).

    Article  CAS  Google Scholar 

  68. Loskill, P., Marcus, S. G., Mathur, A., Reese, W. M. & Healy, K. E. μOrgano: A Lego®-like plug & play system for modular multi-organ-chips. PLoS One 10, e0139587 (2015).

    Article  CAS  Google Scholar 

  69. Zhang, Y. S. et al. Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proc. Natl Acad. Sci. USA 114, E2293–E2302 (2017).

    Article  CAS  Google Scholar 

  70. Zhang, B. et al. Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis. Nat. Mater. 15, 669–678 (2016). This study presents a biodegradable scaffold with a built-in blood vessel network that supports both organ-on-a-chip engineering and in vivo implantation.

    Article  CAS  Google Scholar 

  71. Kolesky, D. B., Homan, K. A., Skylar-Scott, M. A. & Lewis, J. A. Three-dimensional bioprinting of thick vascularized tissues. Proc. Natl Acad. Sci. USA 113, 3179–3184 (2016).

    Article  CAS  Google Scholar 

  72. Miller, J. S. et al. Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Nat. Mater. 11, 768–774 (2012). This study discusses the rapid fabrication of microfluidic networks in hydrogel matrices by 3D printing of sacrificial materials.

    Article  CAS  Google Scholar 

  73. Kang, H.-W. et al. A 3D bioprinting system to produce human-scale tissue constructs with structural integrity. Nat. Biotechnol. 34, 312–319 (2016).

    Article  CAS  Google Scholar 

  74. Takasato, M. et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526, 564–568 (2015).

    Article  CAS  Google Scholar 

  75. Takebe, T., Zhang, B. & Radisic, M. Synergistic engineering: organoids meet organs-on-a-chip. Cell Stem Cell 21, 297–300 (2017). This is a review that promotes the integration of organoids and organs-on-a-chip as a future step in the field.

    Article  CAS  Google Scholar 

  76. Berthier, E., Young, E. W. & Beebe, D. Engineers are from PDMS-land, biologists are from polystyrenia. Lab. Chip 12, 1224–1237 (2012).

    Article  CAS  Google Scholar 

  77. Junaid, A., Mashaghi, A., Hankemeier, T. & Vulto, P. An end-user perspective on Organ-on-a-Chip: assays and usability aspects. Curr. Opin. Biomed. Engineer. 1, 15–22 (2017).

    Article  Google Scholar 

  78. Maoz, B. M. et al. Organs-on-Chips with combined multi-electrode array and transepithelial electrical resistance measurement capabilities. Lab. Chip 17, 2294–2302 (2017).

    Article  CAS  Google Scholar 

  79. Ingber, D. E. Cellular mechanotransduction: putting all the pieces together again. FASEB J. 20, 811–827 (2006).

    Article  CAS  Google Scholar 

  80. 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).

    Article  CAS  Google Scholar 

  81. Huh, D. et al. Microfabrication of human organs-on-chips. Nat. Protoc. 8, 2135–2157 (2013).

    Article  CAS  Google Scholar 

  82. Benam, K. H. et al. Matched-comparative modeling of normal and diseased human airway responses using a microengineered breathing lung chip. Cell Systems 3, 416–418 (2016).

    Article  CAS  Google Scholar 

  83. Kim, H. J., Li, H., Collins, J. J. & Ingber, D. E. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip. Proc. Natl Acad. Sci. USA 113, E7–E15 (2016).

    Article  CAS  Google Scholar 

  84. Villenave, R. et al. Human Gut-on-a-Chip supports polarized infection of coxsackie B1 virus in vitro. PLoS One 12, e0169412 (2017).

    Article  CAS  Google Scholar 

  85. Kim, S. et al. Pharmacokinetic profile that reduces nephrotoxicity of gentamicin in a perfused kidney-on-a-chip. Biofabrication 8, 015021 (2016).

    Article  Google Scholar 

  86. Tavana, H., Zamankhan, P., Christensen, P. J., Grotberg, J. B. & Takayama, S. Epithelium damage and protection during reopening of occluded airways in a physiologic microfluidic pulmonary airway model. Biomed. Microdevices 13, 731–742 (2011).

    Article  Google Scholar 

  87. Tavana, H. et al. Dynamics of liquid plugs of buffer and surfactant solutions in a micro-engineered pulmonary airway model. Langmuir 26, 3744–3752 (2009).

    Article  CAS  Google Scholar 

  88. Blundell, C. et al. A microphysiological model of the human placental barrier. Lab. Chip 16, 3065–3073 (2016).

    Article  CAS  Google Scholar 

  89. Choi, Y. et al. A microengineered pathophysiological model of early-stage breast cancer. Lab. Chip 15, 3350–3357 (2015).

    Article  CAS  Google Scholar 

  90. Heles, T. Emulate expands series B to $45m. Global University Venturing http://www.globaluniversityventuring.com/article.php/5521/emulate-expands-series-b-to-45m (2016).

  91. Bouchie, A. & DeFrancesco, L. Nature Biotechnology’s academic spinouts of 2014. Nat. Biotechnol. 33, 247–255 (2015).

    Article  CAS  Google Scholar 

  92. Timmerman, L. Organ-on-a-Chip startup, Emulate, grabs $45m to shake up drug discovery. Forbes https://www.forbes.com/sites/luketimmerman/2016/10/20/organ-on-a-chip-startup-emulate-grabs-45m-to-improve-drug-discovery/#3b20b0825fcb (2016).

  93. Choi, N. W. et al. Microfluidic scaffolds for tissue engineering. Nat. Mater. 6, 908–915 (2007).

    Article  CAS  Google Scholar 

  94. Leach, J. B. & Schmidt, C. E. Characterization of protein release from photocrosslinkable hyaluronic acid-polyethylene glycol hydrogel tissue engineering scaffolds. Biomaterials 26, 125–135 (2005).

    Article  CAS  Google Scholar 

  95. Ligresti, G. et al. A novel three-dimensional human peritubular microvascular system. J. Am. Soc. Nephrol. 27, 2370–2381 (2015).

    Article  CAS  Google Scholar 

  96. Tourovskaia, A., Fauver, M., Kramer, G., Simonson, S. & Neumann, T. Tissue-engineered microenvironment systems for modeling human vasculature. Exp. Biol. Med. 239, 1264–1271 (2014).

    Article  CAS  Google Scholar 

  97. Stucki, A. O. et al. A lung-on-a-chip array with an integrated bio-inspired respiration mechanism. Lab. Chip 15, 1302–1310 (2015).

    Article  CAS  Google Scholar 

  98. Gu, Z. Integrating intelligent materials into organ on a chip system (abstract W4B.1). Proceedings International Conference on Photonics and Imaging in Biology and Medicine (2017).

  99. Moreno, E. L. et al. Differentiation of neuroepithelial stem cells into functional dopaminergic neurons in 3D microfluidic cell culture. Lab. Chip 15, 2419–2428 (2015).

    Article  CAS  Google Scholar 

  100. Trietsch, S. J., Israëls, G. D., Joore, J., Hankemeier, T. & Vulto, P. Microfluidic titer plate for stratified 3D cell culture. Lab. Chip 13, 3548–3554 (2013).

    Article  CAS  Google Scholar 

  101. Duinen, V. v. et al. 96 perfusable blood vessels to study vascular permeability in vitro. Sci. Rep. 7, 18071 (2017).

    Article  CAS  Google Scholar 

  102. Jeon, N. L. In vitro formation and characterization of a perfusable three-dimensional tubular capillary network in microfluidic devices. Lab. Chip 12, 2815–2822 (2012).

    Article  CAS  Google Scholar 

  103. Kim, S., Lee, H., Chung, M. & Jeon, N. L. Engineering of functional, perfusable 3D microvascular networks on a chip. Lab. Chip 13, 1489–1500 (2013).

    Article  CAS  Google Scholar 

  104. Shin, Y. et al. Microfluidic assay for simultaneous culture of multiple cell types on surfaces or within hydrogels. Nat. Protoc. 7, 1247–1259 (2012).

    Article  CAS  Google Scholar 

  105. Chung, S. et al. Cell migration into scaffolds under co-culture conditions in a microfluidic platform. Lab. Chip 9, 269–275 (2009).

    Article  CAS  Google Scholar 

  106. Wang, X. et al. An on-chip microfluidic pressure regulator that facilitates reproducible loading of cells and hydrogels into microphysiological system platforms. Lab. Chip 16, 868–876 (2016).

    Article  CAS  Google Scholar 

  107. Wang, X. et al. Engineering anastomosis between living capillary networks and endothelial cell-lined microfluidic channels. Lab. Chip 16, 282–290 (2016).

    Article  CAS  Google Scholar 

  108. Moya, M. L., Hsu, Y.-H., Lee, A. P., Hughes, C. C. & George, S. C. In vitro perfused human capillary networks. Tissue Eng. Part C Methods 19, 730–737 (2013).

    Article  CAS  Google Scholar 

  109. Hsu, Y.-H., Moya, M. L., Hughes, C. C., George, S. C. & Lee, A. P. A microfluidic platform for generating large-scale nearly identical human microphysiological vascularized tissue arrays. Lab. Chip 13, 2990–2998 (2013).

    Article  CAS  Google Scholar 

  110. Wiedeman, M. P. Dimensions of blood vessels from distributing artery to collecting vein. Circul. Res. 12, 375–378 (1963).

    Article  CAS  Google Scholar 

  111. Polacheck, W. J., German, A. E., Mammoto, A., Ingber, D. E. & Kamm, R. D. Mechanotransduction of fluid stresses governs 3D cell migration. Proc. Natl Acad. Sci. USA 111, 2447–2452 (2014).

    Article  CAS  Google Scholar 

  112. Aref, A. R. et al. Screening therapeutic EMT blocking agents in a three-dimensional microenvironment. Integr. Biol. 5, 381–389 (2013).

    Article  CAS  Google Scholar 

  113. Vickerman, V. & Kamm, R. D. Mechanism of a flow-gated angiogenesis switch: early signaling events at cell–matrix and cell–cell junctions. Integr. Biol. 4, 863–874 (2012).

    Article  CAS  Google Scholar 

  114. Chung, M., Kim, S., Ahn, J., Lee, S. & Jeon, N. L. Interstitial flow regulates angiogenic response and phenotype of endothelial cells in a 3D culture model. Lab. Chip 16, 4189–4199 (2016).

    Article  CAS  Google Scholar 

  115. Phan, D. T. et al. A vascularized and perfused organ-on-a-chip platform for large-scale drug screening applications. Lab. Chip 17, 511–520 (2017).

    Article  CAS  Google Scholar 

  116. LiáJeon, N. Microfluidic vascularized bone tissue model with hydroxyapatite-incorporated extracellular matrix. Lab. Chip 15, 3984–3988 (2015).

    Article  CAS  Google Scholar 

  117. Zervantonakis, I. K. et al. Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function. Proc. Natl Acad. Sci. USA 109, 13515–13520 (2012).

    Article  CAS  Google Scholar 

  118. Sobrino, A. et al. 3D microtumors in vitro supported by perfused vascular networks. Sci. Rep. 6, 31589 (2016).

    Article  CAS  Google Scholar 

  119. Oh, S. et al. “Open-top” microfluidic device for in vitro three-dimensional capillary beds. Lab. Chip 17, 3405–3414 (2017).

    Article  CAS  Google Scholar 

  120. Nashimoto, Y. et al. Integrating perfusable vascular networks with a three-dimensional tissue in a microfluidic device. Integr. Biol. 9, 506–518 (2017).

    Article  Google Scholar 

  121. Kim, S., Chung, M. & Jeon, N. L. Three-dimensional biomimetic model to reconstitute sprouting lymphangiogenesis in vitro. Biomaterials 78, 115–128 (2016).

    Article  CAS  Google Scholar 

  122. Wadman, M. Merck settles Vioxx lawsuits for $4.85 billion. Nature 450, 324 (2007).

    Article  CAS  Google Scholar 

  123. Kattman, S. J. et al. Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8, 228–240 (2011).

    Article  CAS  Google Scholar 

  124. Radisic, M. et al. Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds. Proc. Natl Acad. Sci. USA 101, 18129–18134 (2004).

    Article  CAS  Google Scholar 

  125. Tandon, N. et al. Electrical stimulation systems for cardiac tissue engineering. Nat. Protoc. 4, 155–173 (2009).

    Article  CAS  Google Scholar 

  126. Stoehr, A. et al. Spontaneous formation of extensive vessel-like structures in murine engineered heart tissue. Tissue Eng. Part A 22, 326–335 (2016).

    Article  CAS  Google Scholar 

  127. Mannhardt, I. et al. Human engineered heart tissue: analysis of contractile force. Stem Cell Rep. 7, 29–42 (2016).

    Article  CAS  Google Scholar 

  128. Eder, A., Vollert, I., Hansen, A. & Eschenhagen, T. Human engineered heart tissue as a model system for drug testing. Adv. Drug Deliv. Rev. 96, 214–224 (2016).

    Article  CAS  Google Scholar 

  129. Zimmermann, W.-H. et al. Tissue engineering of a differentiated cardiac muscle construct. Circul. Res. 90, 223–230 (2002).

    Article  CAS  Google Scholar 

  130. Bian, W., Badie, N., Himel IV, H. D. & Bursac, N. Robust T-tubulation and maturation of cardiomyocytes using tissue-engineered epicardial mimetics. Biomaterials 35, 3819–3828 (2014).

    Article  CAS  Google Scholar 

  131. Vunjak-Novakovic, G., Bhatia, S., Chen, C. & Hirschi, K. HeLiVa platform: integrated heart-liver-vascular systems for drug testing in human health and disease. Stem Cell Res. Ther. 4, S8 (2013).

    Article  Google Scholar 

  132. Wilson, K., Das, M., Wahl, K. J., Colton, R. J. & Hickman, J. Measurement of contractile stress generated by cultured rat muscle on silicon cantilevers for toxin detection and muscle performance enhancement. PLoS One 5, e11042 (2010).

    Article  CAS  Google Scholar 

  133. Schroer, A. K., Shotwell, M. S., Sidorov, V. Y., Wikswo, J. P. & Merryman, W. D. I-Wire Heart-on-a-Chip II: biomechanical analysis of contractile, three-dimensional cardiomyocyte tissue constructs. Acta Biomaterialia 48, 79–87 (2017).

    Article  CAS  Google Scholar 

  134. Watkins, P. B. et al. The clinical liver safety assessment best practices workshop: rationale, goals, accomplishments and the future. Drug Safety 37, 1–7 (2014).

    Article  Google Scholar 

  135. Lucena, M. I. et al. Trovafloxacin-induced acute hepatitis. Clin. Infect. Dis. 30, 400–401 (2000).

    Article  CAS  Google Scholar 

  136. Bhatia, S., Balis, U., Yarmush, M. & Toner, M. Effect of cell–cell interactions in preservation of cellular phenotype: cocultivation of hepatocytes and nonparenchymal cells. FASEB J. 13, 1883–1900 (1999).

    Article  CAS  Google Scholar 

  137. Hui, E. E. & Bhatia, S. N. Micromechanical control of cell–cell interactions. Proc. Natl Acad. Sci. USA 104, 5722–5726 (2007).

    Article  CAS  Google Scholar 

  138. Stevens, K. et al. InVERT molding for scalable control of tissue microarchitecture. Nat. Commun. 4, 1847 (2013).

    Article  CAS  Google Scholar 

  139. Ware, B. R., Berger, D. R. & Khetani, S. R. Prediction of drug-induced liver injury in micropatterned co-cultures containing iPSC-derived human hepatocytes. Toxicol. Sci. 145, 252–262 (2015).

    Article  CAS  Google Scholar 

  140. Ploss, A. et al. Persistent hepatitis C virus infection in microscale primary human hepatocyte cultures. Proc. Natl Acad. Sci. USA 107, 3141–3145 (2010).

    Article  CAS  Google Scholar 

  141. Khetani, S. R. et al. Use of micropatterned cocultures to detect compounds that cause drug-induced liver injury in humans. Toxicol. Sci. 132, 107–117 (2013).

    Article  CAS  Google Scholar 

  142. Xu, J. J. et al. Cellular imaging predictions of clinical drug-induced liver injury. Toxicol. Sci. 105, 97–105 (2008).

    Article  CAS  Google Scholar 

  143. Nguyen, T. V. et al. Establishment of a hepatocyte-kupffer cell coculture model for assessment of proinflammatory cytokine effects on metabolizing enzymes and drug transporters. Drug Metab. Dispos. 43, 774–785 (2015).

    Article  CAS  Google Scholar 

  144. Stevens, K. R. et al. In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease. Sci. Transl Med. 9, eaah5505 (2017).

    Article  Google Scholar 

  145. Jakab, K., Neagu, A., Mironov, V., Markwald, R. R. & Forgacs, G. Engineering biological structures of prescribed shape using self-assembling multicellular systems. Proc. Natl Acad. Sci. USA 101, 2864–2869 (2004).

    Article  CAS  Google Scholar 

  146. Norotte, C., Marga, F. S., Niklason, L. E. & Forgacs, G. Scaffold-free vascular tissue engineering using bioprinting. Biomaterials 30, 5910–5917 (2009).

    Article  CAS  Google Scholar 

  147. Jakab, K. et al. Tissue engineering by self-assembly and bio-printing of living cells. Biofabrication 2, 022001 (2010).

    Article  CAS  Google Scholar 

  148. Norona, L. M., Nguyen, D. G., Gerber, D. A., Presnell, S. C. & LeCluyse, E. L. Modeling compound-induced fibrogenesis in vitro using three-dimensional bioprinted human liver tissues. Toxicol. Sci. 154, 354–367 (2016).

    Article  CAS  Google Scholar 

  149. Rodenhizer, D. et al. A three-dimensional engineered tumour for spatial snapshot analysis of cell metabolism and phenotype in hypoxic gradients. Nat. Mater. 15, 227–234 (2016).

    Article  CAS  Google Scholar 

  150. Kelm, J. M., Timmins, N. E., Brown, C. J., Fussenegger, M. & Nielsen, L. K. Method for generation of homogeneous multicellular tumor spheroids applicable to a wide variety of cell types. Biotechnol. Bioeng. 83, 173–180 (2003).

    Article  CAS  Google Scholar 

  151. Kelm, J. M. & Fussenegger, M. Microscale tissue engineering using gravity-enforced cell assembly. Trends Biotechnol. 22, 195–202 (2004).

    Article  CAS  Google Scholar 

  152. Kim, J.-Y. et al. 3D spherical microtissues and microfluidic technology for multi-tissue experiments and analysis. J. Biotechnol. 205, 24–35 (2015).

    Article  CAS  Google Scholar 

  153. Falkenberg, N. et al. Three-dimensional microtissues essentially contribute to preclinical validations of therapeutic targets in breast cancer. Cancer Med. 5, 703–710 (2016).

    Article  CAS  Google Scholar 

  154. Horman, S. R. et al. High-content analysis of three-dimensional tumor spheroids: Investigating signaling pathways using small hairpin RNA. Nat. Methods 10, 1036 (2013).

    Article  CAS  Google Scholar 

  155. Wagner, I. et al. A dynamic multi-organ-chip for long-term cultivation and substance testing proven by 3D human liver and skin tissue co-culture. Lab. Chip 13, 3538–3547 (2013).

    Article  CAS  Google Scholar 

  156. Chung, K. et al. A microfluidic array for large-scale ordering and orientation of embryos. Nat. Methods 8, 171–176 (2011).

    Article  CAS  Google Scholar 

  157. Levario, T. J., Zhan, M., Lim, B., Shvartsman, S. Y. & Lu, H. Microfluidic trap array for massively parallel imaging of Drosophila embryos. Nat. Protoc. 8, 721 (2013).

    Article  Google Scholar 

  158. Jackson, E. & Lu, H. Three-dimensional models for studying development and disease: moving on from organisms to organs-on-a-chip and organoids. Integr. Biol. 8, 672–683 (2016).

    Article  CAS  Google Scholar 

  159. Jackson-Holmes, E., McDevitt, T. C. & Lu, H. A microfluidic trap array for longitudinal monitoring and multi-modal phenotypic analysis of individual stem cell aggregates. Lab. Chip 17, 3634–3642 (2017).

    Article  CAS  Google Scholar 

  160. Atienzar, F. A. et al. Predictivity of dog co-culture model, primary human hepatocytes and HepG2 cells for the detection of hepatotoxic drugs in humans. Toxicol. Appl. Pharmacol. 275, 44–61 (2014).

    Article  CAS  Google Scholar 

  161. Novik, E., Maguire, T. J., Chao, P., Cheng, K. & Yarmush, M. L. A microfluidic hepatic coculture platform for cell-based drug metabolism studies. Biochem. Pharmacol. 79, 1036–1044 (2010).

    Article  CAS  Google Scholar 

  162. 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).

    Article  CAS  Google Scholar 

  163. Kidambi, S. et al. Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance. Proc. Natl Acad. Sci. USA 106, 15714–15719 (2009).

    Article  CAS  Google Scholar 

  164. 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).

    Article  CAS  Google Scholar 

  165. Wikswo, J. P. et al. Scaling and systems biology for integrating multiple organs-on-a-chip. Lab. Chip 13, 3496–3511 (2013).

    Article  CAS  Google Scholar 

  166. Moraes, C. et al. On being the right size: scaling effects in designing a human-on-a-chip. Integr. Biol. 5, 1149–1161 (2013).

    Article  CAS  Google Scholar 

  167. Esch, M. B., Ueno, H., Applegate, D. R. & Shuler, M. L. Modular, pumpless body-on-a-chip platform for the co-culture of GI tract epithelium and 3D primary liver tissue. Lab. Chip 16, 2719–2729 (2016).

    Article  CAS  Google Scholar 

  168. Esch, M. B., Mahler, G. J., Stokol, T. & Shuler, M. L. Body-on-a-chip simulation with gastrointestinal tract and liver tissues suggests that ingested nanoparticles have the potential to cause liver injury. Lab. Chip 14, 3081–3092 (2014).

    Article  CAS  Google Scholar 

  169. 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).

    Article  CAS  Google Scholar 

  170. Materne, E.-M. et al. The multi-organ chip-a microfluidic platform for long-term multi-tissue coculture. J. Vis. Exp. 98, e52526 (2015).

    Google Scholar 

  171. Bauer, S. et al. Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model. Sci. Rep. 7, 14620 (2017).

    Article  CAS  Google Scholar 

  172. Loskill, P. et al. WAT-on-a-chip: a physiologically relevant microfluidic system incorporating white adipose tissue. Lab. Chip 17, 1645–1654 (2017).

    Article  CAS  Google Scholar 

  173. Yu, J. et al. Quantitative systems pharmacology approaches applied to microphysiological systems (MPS): data interpretation and multi-MPS integration. CPT Pharmacometrics Syst. Pharmacol. 4, 585–594 (2015).

    Article  CAS  Google Scholar 

  174. Wikswo, J. P. & Porter, A. P. Biology coming full circle: joining the whole and the parts. Exp. Biol. Med. 240, 3–7 (2015).

    Article  CAS  Google Scholar 

  175. Lai, B. F. L. et al. InVADE: integrated vasculature for assessing dynamic events. Adv. Funct. Mater. https://doi.org/10.1002/adfm.201703524 (2017). This study presents an organ-on-a-chip platform in the format of a multiwell plate that can model inter-organ cancer metastasis.

    Article  Google Scholar 

  176. Yarmush, M. L., Freedman, R., Del Bufalo, A., Teissier, S. & Meunier, J.-R. Immune system modeling devices and methods. Patent application number US9535056B2 (2017).

  177. Vargesson, N. Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res. C Embryo Today 105, 140–156 (2015).

    Article  CAS  Google Scholar 

  178. Therapontos, C., Erskine, L., Gardner, E. R., Figg, W. D. & Vargesson, N. Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation. Proc. Natl Acad. Sci. USA 106, 8573–8578 (2009).

    Article  CAS  Google Scholar 

  179. Nawroth, J., Rogal, J., Weiss, M., Brucker, S. Y. & Loskill, P. Organ-on-a-Chip systems for women’s health applications. Adv. Healthc. Mater. https://doi.org/10.1002/adhm.201700550 (2017).

    Article  Google Scholar 

  180. Jo, B.-H., Van Lerberghe, L. M., Motsegood, K. M. & Beebe, D. J. Three-dimensional micro-channel fabrication in polydimethylsiloxane (PDMS) elastomer. J. Microelectromechan. Systems 9, 76–81 (2000).

    Article  CAS  Google Scholar 

  181. Thorsen, T., Maerkl, S. J. & Quake, S. R. Microfluidic large-scale integration. Science 298, 580 (2002).

    Article  CAS  Google Scholar 

  182. Unger, M. A., Chou, H. P., Thorsen, T., Scherer, A. & Quake, S. R. Monolithic microfabricated valves and pumps by multilayer soft lithography. Science 288, 113–116 (2000).

    Article  CAS  Google Scholar 

  183. Woodruff, K. & Maerkl, S. J. A. High-throughput microfluidic platform for mammalian cell transfection and culturing. Sci. Rep. 6, 23937 (2016).

    Article  CAS  Google Scholar 

  184. Fidalgo, L. M. & Maerkl, S. J. A software-programmable microfluidic device for automated biology. Lab. Chip 11, 1612–1619 (2011).

    Article  CAS  Google Scholar 

  185. Piraino, F., Volpetti, F., Watson, C. & Maerkl, S. J. A. Digital–analog microfluidic platform for patient-centric multiplexed biomarker diagnostics of ultralow volume samples. ACS Nano 10, 1699–1710 (2016).

    Article  CAS  Google Scholar 

  186. Miklas, J. W. et al. Bioreactor for modulation of cardiac microtissue phenotype by combined static stretch and electrical stimulation. Biofabrication 6, 024113–024113 (2014).

    Article  Google Scholar 

  187. Borysiak, M. D. et al. Simple replica micromolding of biocompatible styrenic elastomers. Lab. Chip 13, 2773–2784 (2013).

    Article  CAS  Google Scholar 

  188. Borysiak, M. D., Yuferova, E. & Posner, J. D. Simple, low-cost styrene-ethylene/butylene-styrene microdevices for electrokinetic applications. Anal. Chem. 85, 11700–11704 (2013).

    Article  CAS  Google Scholar 

  189. Guillemette, M. D., Roy, E., Auger, F. A. & Veres, T. Rapid isothermal substrate microfabrication of a biocompatible thermoplastic elastomer for cellular contact guidance. Acta Biomaterialia 7, 2492–2498 (2011).

    Article  CAS  Google Scholar 

  190. Domansky, K. et al. Clear castable polyurethane elastomer for fabrication of microfluidic devices. Lab. Chip 13, 3956–3964 (2013).

    Article  CAS  Google Scholar 

  191. Sasaki, H., Onoe, H., Osaki, T., Kawano, R. & Takeuchi, S. Parylene-coating in PDMS microfluidic channels prevents the absorption of fluorescent dyes. Sensors Actuators B Chem. 150, 478–482 (2010).

    Article  CAS  Google Scholar 

  192. Ren, K., Zhao, Y., Su, J., Ryan, D. & Wu, H. Convenient method for modifying poly (dimethylsiloxane) to be airtight and resistive against absorption of small molecules. Anal. Chem. 82, 5965–5971 (2010).

    Article  CAS  Google Scholar 

  193. Tran, R. T. et al. Synthesis and characterization of a biodegradable elastomer featuring a dual crosslinking mechanism. Soft Matter 6, 2449–2461 (2010).

    Article  CAS  Google Scholar 

  194. Davenport Huyer, L. et al. Highly elastic and moldable polyester biomaterial for cardiac tissue engineering applications. ACS Biomater. Sci. Eng. 2, 780–788 (2016).

    Article  CAS  Google Scholar 

  195. Pan, C., Kumar, C., Bohl, S., Klingmueller, U. & Mann, M. Comparative proteomic phenotyping of cell lines and primary cells to assess preservation of cell type-specific functions. Mol. Cell. Proteom.: MCP 8, 443–450 (2009).

    Article  CAS  Google Scholar 

  196. Zhao, Y., Korolj, A., Feric, N. & Radisic, M. Human pluripotent stem cell-derived cardiomyocyte based models for cardiotoxicity and drug discovery. Expert Opin. Drug Safety 15, 1455–1458 (2016).

    Article  Google Scholar 

  197. Ahadian, S. et al. Organ-on-a-Chip platforms: a convergence of advanced materials, cells, and microscale technologies. Adv. Healthc Mater. https://doi.org/10.1002/adhm.201700506 (2017).

    Article  Google Scholar 

  198. Unger, R. E., Krump-Konvalinkova, V., Peters, K. & Kirkpatrick, C. J. In vitro expression of the endothelial phenotype: comparative study of primary isolated cells and cell lines, including the novel cell line HPMEC-ST1.6R. Microvascular Res. 64, 384–397 (2002).

    Article  CAS  Google Scholar 

  199. Baumann, K. Achieving pluripotency. Nat Rev. Mol. Cell Biol. 11, 677 (2010).

    Article  CAS  Google Scholar 

  200. Saha, K. & Jaenisch, R. Technical challenges in using human induced pluripotent stem cells to model disease. Cell Stem Cell 5, 584–595.

    Article  CAS  Google Scholar 

  201. Hanna, J. et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920 (2007).

    Article  CAS  Google Scholar 

  202. Colman, A. & Dreesen, O. Pluripotent stem cells and disease modeling. Cell Stem Cell 5, 244–247 (2009).

    Article  CAS  Google Scholar 

  203. Li, Y. Y. & Jones, S. J. M. Drug repositioning for personalized medicine. Genome Med. 4, 27–27 (2012).

    Article  CAS  Google Scholar 

  204. Evans, W. E. & Relling, M. V. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286, 487 (1999).

    Article  CAS  Google Scholar 

  205. van de Stolpe, A. & den Toonder, J. Workshop meeting report Organs-on-Chips: human disease models. Lab. Chip 13, 3449–3470 (2013).

    Article  CAS  Google Scholar 

  206. Yazawa, M. et al. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471, 230–234 (2011).

    Article  CAS  Google Scholar 

  207. Moretti, A. et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N. Engl. J. Med. 363, 1397–1409 (2010).

    Article  CAS  Google Scholar 

  208. Carvajal-Vergara, X. et al. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 465, 808–812 (2010).

    Article  CAS  Google Scholar 

  209. Wang, G. et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat. Med. 20, 616–623 (2014).

    Article  CAS  Google Scholar 

  210. Sun, N. et al. Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci. Transl Med. 4, 130ra147 (2012).

    Article  Google Scholar 

  211. Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

    Article  CAS  Google Scholar 

  212. Hsu, P. D., Lander, E. S. & Zhang, F. Development and applications of CRISPR-Cas9 for genome engineering. Cell 157, 1262–1278 (2014).

    Article  CAS  Google Scholar 

  213. Völkner, M. et al. Retinal organoids from pluripotent stem cells efficiently recapitulate retinogenesis. Stem Cell Rep. 6, 525–538 (2016).

    Article  CAS  Google Scholar 

  214. Foster, J. W. et al. Cornea organoids from human induced pluripotent stem cells. Sci. Rep. 7, 41286 (2017).

    Article  CAS  Google Scholar 

  215. Broutier, L. et al. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat. Med. 23, 1424 (2017).

    Article  CAS  Google Scholar 

  216. Broutier, L. et al. Culture and establishment of self-renewing human and mouse adult liver and pancreas 3D organoids and their genetic manipulation. Nat. Protoc. 11, 1724–1743 (2016).

    Article  CAS  Google Scholar 

  217. Boj, Sylvia, F. et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338.

    Article  CAS  Google Scholar 

  218. Dedhia, P. H., Bertaux-Skeirik, N., Zavros, Y. & Spence, J. R. Organoid models of human gastrointestinal development and disease. Gastroenterology 150, 1098–1112 (2016).

    Article  Google Scholar 

  219. Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373 (2013).

    Article  CAS  Google Scholar 

  220. Chen, Y.-W. et al. A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat. Cell Biol. 19, 542 (2017).

    Article  CAS  Google Scholar 

  221. Lancaster, M. A. & Knoblich, J. A. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345, 1247125 (2014).

    Article  CAS  Google Scholar 

  222. Byun, C. K., Abi-Samra, K., Cho, Y. K. & Takayama, S. Pumps for microfluidic cell culture. Electrophoresis 35, 245–257 (2014).

    Article  CAS  Google Scholar 

  223. Li, X., Brooks, J. C., Hu, J., Ford, K. I. & Easley, C. J. 3D-templated, fully automated microfluidic input/output multiplexer for endocrine tissue culture and secretion sampling. Lab. Chip 17, 341–349 (2017).

    Article  CAS  Google Scholar 

  224. Huh, D., Hamilton, G. A. & Ingber, D. E. From 3D cell culture to organs-on-chips. Trends Cell Biol. 21, 745–754 (2011).

    Article  CAS  Google Scholar 

  225. Wevers, N. R. et al. High-throughput compound evaluation on 3D networks of neurons and glia in a microfluidic platform. Sci. Rep. 6, 38856 (2016).

    Article  CAS  Google Scholar 

  226. Theberge, A. B. et al. Microfluidic multiculture assay to analyze biomolecular signaling in angiogenesis. Anal. Chem. 87, 3239–3246 (2015).

    Article  CAS  Google Scholar 

  227. Kim, S., Chung, M., Ahn, J., Lee, S. & Jeon, N. L. Interstitial flow regulates the angiogenic response and phenotype of endothelial cells in a 3D culture model. Lab. Chip 16, 4189–4199 (2016).

    Article  CAS  Google Scholar 

  228. Osaki, T., Sivathanu, V. & Kamm, R. D. Crosstalk between developing vasculature and optogenetically engineered skeletal muscle improves muscle contraction and angiogenesis. Biomaterials 156, 65–76 (2018).

    Article  CAS  Google Scholar 

  229. Uzel, S. G. et al. Microfluidic device for the formation of optically excitable, three-dimensional, compartmentalized motor units. Sci. Adv. 2, e1501429 (2016).

    Article  Google Scholar 

  230. Patra, B., Peng, C.-C., Liao, W.-H., Lee, C.-H. & Tung, Y.-C. Drug testing and flow cytometry analysis on a large number of uniform sized tumor spheroids using a microfluidic device. Sci. Rep. 6, 21061 (2016).

    Article  CAS  Google Scholar 

  231. Gruber, P., Marques, M. P., Szita, N. & Mayr, T. Integration and application of optical chemical sensors in microbioreactors. Lab. Chip 17, 2693–2712 (2017).

    Article  CAS  Google Scholar 

  232. Choi, J.-r., Song, H., Sung, J. H., Kim, D. & Kim, K. Microfluidic assay-based optical measurement techniques for cell analysis: a review of recent progress. Biosensors Bioelectron. 77, 227–236 (2016).

    Article  CAS  Google Scholar 

  233. Xiao, F., Wang, L. & Duan, H. Nanomaterial based electrochemical sensors for in vitro detection of small molecule metabolites. Biotechnol. Adv. 34, 234–249 (2016).

    Article  CAS  Google Scholar 

  234. Wang, L., Acosta, M. A., Leach, J. B. & Carrier, R. L. Spatially monitoring oxygen level in 3D microfabricated cell culture systems using optical oxygen sensing beads. Lab. Chip 13, 1586–1592 (2013).

    Article  CAS  Google Scholar 

  235. Suzuki, H., Hirakawa, T., Watanabe, I. & Kikuchi, Y. Determination of blood pO 2 using a micromachined Clark-type oxygen electrode. Anal. Chim. Acta 431, 249–259 (2001).

    Article  CAS  Google Scholar 

  236. Bellin, D. L. et al. Integrated circuit-based electrochemical sensor for spatially resolved detection of redox-active metabolites in biofilms. Nat. Commun. 5, 3256 (2014).

    Article  CAS  Google Scholar 

  237. Wu, M.-H., Lin, J.-L., Wang, J., Cui, Z. & Cui, Z. Development of high throughput optical sensor array for on-line pH monitoring in micro-scale cell culture environment. Biomed. Microdevices 11, 265–273 (2009).

    Article  Google Scholar 

  238. Eklund, S. E. et al. Modification of the Cytosensor Microphysiometer to simultaneously measure extracellular acidification and oxygen consumption rates. Anal. Chim. Acta 496, 93–101 (2003).

    Article  CAS  Google Scholar 

  239. Lin, Z., Cherng-Wen, T., Roy, P. & Trau, D. In-situ measurement of cellular microenvironments in a microfluidic device. Lab. Chip 9, 257–262 (2009).

    Article  CAS  Google Scholar 

  240. Lin, Y., Lu, F., Tu, Y. & Ren, Z. Glucose biosensors based on carbon nanotube nanoelectrode ensembles. Nano Lett. 4, 191–195 (2004).

    Article  CAS  Google Scholar 

  241. Boero, C. et al. Design, development, and validation of an in-situ biosensor array for metabolite monitoring of cell cultures. Biosensors Bioelectron. 61, 251–259 (2014).

    Article  CAS  Google Scholar 

  242. Sonker, M., Sahore, V. & Woolley, A. T. Recent advances in microfluidic sample preparation and separation techniques for molecular biomarker analysis: a critical review. Anal. Chim. Acta 986, 1–11 (2017).

    Article  CAS  Google Scholar 

  243. Xiao, Y., Lubin, A. A., Heeger, A. J. & Plaxco, K. W. Label-free electronic detection of thrombin in blood serum by using an aptamer-based sensor. Angew. Chem. Int. Ed. 44, 5456–5459 (2005).

    Article  CAS  Google Scholar 

  244. Shin, S. R. et al. Aptamer-based microfluidic electrochemical biosensor for monitoring cell-secreted trace cardiac biomarkers. Anal. Chem. 88, 10019–10027 (2016).

    Article  CAS  Google Scholar 

  245. Shin, S. R. et al. Label-free and regenerative electrochemical microfluidic biosensors for continual monitoring of cell secretomes. Adv. Sci. 4, 1600522 (2017).

    Article  CAS  Google Scholar 

  246. Xie, Y. et al. A novel electrochemical microfluidic chip combined with multiple biomarkers for early diagnosis of gastric cancer. Nanoscale Res. Lett. 10, 477 (2015).

    Article  CAS  Google Scholar 

  247. Henry, O. et al. Organs-on-Chips with integrated electrodes for Trans-Epithelial Electrical Resistance (TEER) measurements of human epithelial barrier function. Lab. Chip 17, 2264–2271 (2017).

    Article  CAS  Google Scholar 

  248. ávan der Meer, A. D., JungáKim, H., ávan der Helm, M. W. & den Berg, A. Measuring direct current trans-epithelial electrical resistance in organ-on-a-chip microsystems. Lab. Chip 15, 745–752 (2015).

    Article  CAS  Google Scholar 

  249. Murphy, S. V. & Atala, A. 3D bioprinting of tissues and organs. Nat. Biotechnol. 32, 773–785 (2014).

    Article  CAS  Google Scholar 

  250. Waheed, S. et al. 3D printed microfluidic devices: enablers and barriers. Lab. Chip 16, 1993–2013 (2016).

    Article  CAS  Google Scholar 

  251. Zhang, Y. S. et al. 3D bioprinting for tissue and organ fabrication. Ann. Biomed. Engineer. 45, 148–163 (2017).

    Article  Google Scholar 

  252. Dehne, E.-M., Hasenberg, T. & Marx, U. The ascendance of microphysiological systems to solve the drug testing dilemma. Future Sci. OA 3, FSO0185 (2017).

    Article  CAS  Google Scholar 

  253. Sager, P. T., Gintant, G., Turner, J. R., Pettit, S. & Stockbridge, N. Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium. Am. Heart J. 167, 292–300 (2014).

    Article  Google Scholar 

  254. US Food and Drug Administration. Paving the way for personalized medicine. (FDA, 2013).

  255. Conant, G., Ahadian, S., Zhao, Y. & Radisic, M. Kinase inhibitor screening using artificial neural networks and engineered cardiac biowires. Sci. Rep. 7, 11807 (2017).

    Article  CAS  Google Scholar 

  256. Sun, X. & Nunes, S. S. Biowire platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Methods 101, 21–26 (2016).

    Article  CAS  Google Scholar 

  257. Marga, F. et al. Toward engineering functional organ modules by additive manufacturing. Biofabrication 4, 022001 (2012).

    Article  Google Scholar 

  258. Zhou, M. et al. Development of a functional glomerulus at the organ level on a chip to mimic hypertensive nephropathy. Sci. Rep. 6, 31771 (2016).

    Article  CAS  Google Scholar 

  259. Wang, L. et al. A disease model of diabetic nephropathy in a glomerulus-on-a-chip microdevice. Lab. Chip 17, 1749–1760 (2017).

    Article  CAS  Google Scholar 

  260. Lee, J. S. et al. Placenta-on-a-chip: a novel platform to study the biology of the human placenta. J. Maternal Fetal Neonatal Med. 29, 1046–1054 (2016).

    Article  CAS  Google Scholar 

  261. Booth, R. & Kim, H. Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB). Lab. Chip 12, 1784–1792 (2012).

    Article  CAS  Google Scholar 

  262. Brown, J. A. et al. Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit. J. Neuroinflamm. 13, 306 (2016).

    Article  CAS  Google Scholar 

  263. Deosarkar, S. P. et al. A novel dynamic neonatal blood-brain barrier on a chip. PLoS One 10, e0142725 (2015).

    Article  CAS  Google Scholar 

  264. Prabhakarpandian, B. et al. SyM-BBB: a microfluidic blood brain barrier model. Lab. Chip 13, 1093–1101 (2013).

    Article  CAS  Google Scholar 

  265. Chung, M. et al. Wet-AMD on a chip: modeling outer blood-retinal barrier in vitro. Adv. Healthc. Mater. https://doi.org/10.1002/adhm.201700028 (2017).

    Article  Google Scholar 

  266. Kolesky, D. B. et al. 3D bioprinting of vascularized, heterogeneous cell-laden tissue constructs. Adv. Mater. 26, 3124–3130 (2014).

    Article  CAS  Google Scholar 

  267. Tsvirkun, D., Grichine, A., Duperray, A., Misbah, C. & Bureau, L. Microvasculature on a chip: study of the endothelial surface layer and the flow structure of red blood cells. Sci. Rep. 7, 45036 (2017).

    Article  CAS  Google Scholar 

  268. Zhang, B., Peticone, C., Murthy, S. K. & Radisic, M. A standalone perfusion platform for drug testing and target validation in micro-vessel networks. Biomicrofluidics 7, 044125 (2013).

    Article  CAS  Google Scholar 

  269. Ting, L., Feghhi, S., Karchin, A., Tooley, W. & White, N. J. Clot-on-a-chip: a microfluidic device to study platelet aggregation and contractility under shear. Blood 122, 2363–2363 (2013).

    Google Scholar 

  270. Lamberti, G. et al. Adhesive interaction of functionalized particles and endothelium in idealized microvascular networks. Microvascular Res. 89, 107–114 (2013).

    Article  CAS  Google Scholar 

  271. Wang, L. et al. Patterning cells and shear flow conditions: convenient observation of endothelial cell remoulding, enhanced production of angiogenesis factors and drug response. Lab. Chip 11, 4235–4240 (2011).

    Article  CAS  Google Scholar 

  272. Srigunapalan, S., Lam, C., Wheeler, A. R. & Simmons, C. A. A microfluidic membrane device to mimic critical components of the vascular microenvironment. Biomicrofluidics 5, 13409 (2011).

    Article  CAS  Google Scholar 

  273. Zhang, Y. S. et al. Bioprinted thrombosis-on-a-chip. Lab. Chip 16, 4097–4105 (2016).

    Article  CAS  Google Scholar 

  274. Zhang, W. et al. Elastomeric free-form blood vessels for interconnecting organs on chip systems. Lab. Chip 16, 1579–1586 (2016).

    Article  CAS  Google Scholar 

  275. Yasotharan, S., Pinto, S., Sled, J. G., Bolz, S.-S. & Günther, A. Artery-on-a-chip platform for automated, multimodal assessment of cerebral blood vessel structure and function. Lab. Chip 15, 2660–2669 (2015).

    Article  CAS  Google Scholar 

  276. Günther, A. et al. A microfluidic platform for probing small artery structure and function. Lab. Chip 10, 2341–2349 (2010).

    Article  CAS  Google Scholar 

  277. Price, G. M., Chrobak, K. M. & Tien, J. Effect of cyclic AMP on barrier function of human lymphatic microvascular tubes. Microvascular Res. 76, 46–51 (2008).

    Article  CAS  Google Scholar 

  278. Schaaf, S. et al. Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology. PLoS One 6, e26397 (2011).

    Article  CAS  Google Scholar 

  279. Yang, X., Pabon, L. & Murry, C. E. Engineering adolescence maturation of human pluripotent stem cell–derived cardiomyocytes. Circul. Res. 114, 511–523 (2014).

    Article  CAS  Google Scholar 

  280. Bian, W., Jackman, C. P. & Bursac, N. Controlling the structural and functional anisotropy of engineered cardiac tissues. Biofabrication 6, 024109 (2014).

    Article  CAS  Google Scholar 

  281. Nunes, S. S. et al. Human stem cell-derived cardiac model of chronic drug exposure. ACS Biomater. Sci. Eng. 3, 1911–1921 (2017).

    Article  CAS  Google Scholar 

  282. Thavandiran, N. et al. Design and formulation of functional pluripotent stem cell-derived cardiac microtissues. Proc. Natl Acad. Sci. USA 110, E4698–E4707 (2013).

    Article  CAS  Google Scholar 

  283. Guo, X., Gonzalez, M., Stancescu, M., Vandenburgh, H. H. & Hickman, J. J. Neuromuscular junction formation between human stem cell-derived motoneurons and human skeletal muscle in a defined system. Biomaterials 32, 9602–9611 (2011).

    Article  CAS  Google Scholar 

  284. Davidson, M. D., Lehrer, M. & Khetani, S. R. Hormone and drug-mediated modulation of glucose metabolism in a microscale model of the human liver. Tissue Eng. Part C Methods 21, 716–725 (2015).

    Article  CAS  Google Scholar 

  285. Chan, T. S., Yu, H., Moore, A., Khetani, S. R. & Tweedie, D. Meeting the challenge of predicting hepatic clearance of compounds slowly metabolized by cytochrome P450 using a novel hepatocyte model, HepatoPac. Drug Metab. Dispos. 41, 2024–2032 (2013).

    Article  CAS  Google Scholar 

  286. Ballard, T. E. et al. Application of a micropatterned cocultured hepatocyte system to predict preclinical and human-specific drug metabolism. Drug Metab. Dispos. 44, 172–179 (2016).

    Article  CAS  Google Scholar 

  287. Anastasov, N. et al. A 3D-microtissue-based phenotypic screening of radiation resistant tumor cells with synchronized chemotherapeutic treatment. BMC Cancer 15, 1 (2015).

    Article  Google Scholar 

  288. Rimann, M. et al. An in vitro osteosarcoma 3D microtissue model for drug development. J. Biotechnol. 189, 129–135 (2014).

    Article  CAS  Google Scholar 

  289. Huval, R. M. et al. Microengineered peripheral nerve-on-a-chip for preclinical physiological testing. Lab. Chip 15, 2221–2232 (2015).

    Article  CAS  Google Scholar 

  290. Liazoghli, D., Roth, A. D., Thostrup, P. & Colman, D. R. Substrate micropatterning as a new in vitro cell culture system to study myelination. ACS Chem. Neurosci. 3, 90–95 (2011).

    Article  CAS  Google Scholar 

  291. Magdesian, M. H. et al. Atomic force microscopy reveals important differences in axonal resistance to injury. Biophys. J. 103, 405–414 (2012).

    Article  CAS  Google Scholar 

  292. Belkaid, W. et al. Cellular response to micropatterned growth promoting and inhibitory substrates. BMC Biotechnol. 13, 86 (2013).

    Article  CAS  Google Scholar 

  293. Magdesian, M. H. et al. Rapid mechanically controlled rewiring of neuronal circuits. J. Neurosci. 36, 979–987 (2016).

    Article  CAS  Google Scholar 

  294. Khoshakhlagh, P. & Moore, M. J. Photoreactive interpenetrating network of hyaluronic acid and Puramatrix as a selectively tunable scaffold for neurite growth. Acta Biomaterialia 16, 23–34 (2015).

    Article  CAS  Google Scholar 

  295. Peyrin, J.-M. et al. Axon diodes for the reconstruction of oriented neuronal networks in microfluidic chambers. Lab. Chip 11, 3663–3673 (2011).

    Article  CAS  Google Scholar 

  296. Deleglise, B. et al. β-Amyloid induces a dying-back process and remote trans-synaptic alterations in a microfluidic-based reconstructed neuronal network. Acta Neuropathol. Commun. 2, 145 (2014).

    Google Scholar 

  297. Taylor, A. M. et al. A microfluidic culture platform for CNS axonal injury, regeneration and transport. Nat. Methods 2, 599–605 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank M. Lecce and L. D. Huyer for helping with the editing of this manuscript. This work was made possible by the National Sciences and Engineering Research Council of Canada (NSERC) Postgraduate Scholarships-Doctoral Program awarded to B.F.L.L., Alexander Graham Bell Canada Graduate Scholarships-Doctoral Program awarded to A.K. and the Canadian Institutes of Health Research (CIHR) Banting Postdoctoral Fellowship to B.Z. This work was also funded by the CIHR Operating Grants (MOP-126027 and MOP-137107), NSERC Discovery Grant (RGPIN-2015-05952), NSERC Steacie Fellowship (SMFSU 4620), Heart and Stroke Foundation Grant-in-Aid (G-16-00012), NSERC-CIHR Collaborative Health Research Grant (CHRPJ 4937) and NSERC Strategic Grant (STPGP 5066) to M.R.

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B.Z., A.K. and B.F.L.L. wrote and edited the manuscript. M.R. supervised the work and edited the manuscript.

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Correspondence to Milica Radisic.

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B.Z. and M.R. hold equity in TARA Biosystems Inc.

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American Institute for Medical and Biological Engineering (AIMBE): http://aimbe.org

Comprehensive In Vitro Proarrhythmia Assay (CiPA): http://cipaproject.org

IQ Consortium: https://iqconsortium.org

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Zhang, B., Korolj, A., Lai, B.F.L. et al. Advances in organ-on-a-chip engineering. Nat Rev Mater 3, 257–278 (2018). https://doi.org/10.1038/s41578-018-0034-7

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