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Biomaterials and Culture Systems for Development of Organoid and Organ-on-a-Chip Models

Abstract

The development of novel 3D tissue culture systems has enabled the in vitro study of in vivo processes, thereby overcoming many of the limitations of previous 2D tissue culture systems. Advances in biomaterials, including the discovery of novel synthetic polymers has allowed for the generation of physiologically relevant in vitro 3D culture models. A large number of 3D culture systems, aided by novel organ-on-a-chip and bioreactor technologies have been developed to improve reproducibility and scalability of in vitro organ models. The discovery of induced pluripotent stem cells (iPSCs) and the increasing number of protocols to generate iPSC-derived cell types has allowed for the generation of novel 3D models with minimal ethical limitations. The production of iPSC-derived 3D cultures has revolutionized the field of developmental biology and in particular, the study of fetal brain development. Furthermore, physiologically relevant 3D cultures generated from PSCs or adult stem cells (ASCs) have greatly advanced in vitro disease modelling and drug discovery. This review focuses on advances in 3D culture systems over the past years to model fetal development, disease pathology and support drug discovery in vitro, with a specific focus on the enabling role of biomaterials.

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References

  1. Adriani, G., D. Ma, A. Pavesi, R. D. Kamm, and E. L. Goh. A 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood-brain barrier. Lab Chip 17:448–459, 2017. https://doi.org/10.1039/c6lc00638h.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Ahadian, S., et al. Organ-on-a-chip platforms: a convergence of advanced materials, cells, and microscale technologies. Adv. Healthc. Mater. 2018. https://doi.org/10.1002/adhm.201800734.

    Article  PubMed  Google Scholar 

  3. Akay, M., et al. Drug screening of human GBM spheroids in brain cancer chip. Sci. Rep. 8:15423, 2018. https://doi.org/10.1038/s41598-018-33641-2.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Akhtar, A. The flaws and human harms of animal experimentation. Camb. Q. Healthc. Ethics 24:407–419, 2015. https://doi.org/10.1017/s0963180115000079.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Arora, P. D., N. Narani, and C. A. McCulloch. The compliance of collagen gels regulates transforming growth factor-beta induction of alpha-smooth muscle actin in fibroblasts. Am. J. Pathol. 154:871–882, 1999.

    CAS  Article  Google Scholar 

  6. Assawachananont, J., et al. Transplantation of embryonic and induced pluripotent stem cell-derived 3D retinal sheets into retinal degenerative mice. Stem Cell Rep. 2:662–674, 2014. https://doi.org/10.1016/j.stemcr.2014.03.011.

    Article  Google Scholar 

  7. Bagley, J. A., D. Reumann, S. Bian, J. Levi-Strauss, and J. A. Knoblich. Fused cerebral organoids model interactions between brain regions. Nat. Methods 14:743–751, 2017. https://doi.org/10.1038/nmeth.4304.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Barak, H., et al. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev. Cell 22:1191–1207, 2012.

    CAS  Article  Google Scholar 

  9. Barker, N., et al. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6:25–36, 2010. https://doi.org/10.1016/j.stem.2009.11.013.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Bartfeld, S., and H. Clevers. Organoids as model for infectious diseases: culture of human and murine stomach organoids and microinjection of helicobacter pylori. J. Vis. Exp. 2015. https://doi.org/10.3791/53359.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Batalov, I., and A. W. Feinberg. Differentiation of cardiomyocytes from human pluripotent stem cells using monolayer culture. Biomark Insights 10:71–76, 2015.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Bean, J., et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Mol. Cancer Ther. 6:3333s–3334s, 2007.

    Google Scholar 

  13. Bein, A., et al. Microfluidic organ-on-a-chip models of human intestine. Cell. Mol. Gastroenterol. Hepatol. 5:659–668, 2018.

    Article  Google Scholar 

  14. Bell, C. C., et al. Comparison of hepatic 2D sandwich cultures and 3D spheroids for long-term toxicity applications: a multicenter study. Toxicol. Sci. 162:655–666, 2018.

    CAS  Article  Google Scholar 

  15. Belloni, D., et al. Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment. Haematologica 103(4):703–716, 2018.

    Article  Google Scholar 

  16. Benam, K. H., et al. Engineered in vitro disease models. Annu. Rev. Pathol. Mech. 10:195–262, 2015. https://doi.org/10.1146/annurev-pathol-012414-040418.

    CAS  Article  Google Scholar 

  17. Benton, G., I. Arnaoutova, J. George, H. K. Kleinman, and J. Koblinski. Matrigel: from discovery and ECM mimicry to assays and models for cancer research. Adv. Drug Deliv. Rev. 79–80:3–18, 2014. https://doi.org/10.1016/j.addr.2014.06.005.

    CAS  Article  PubMed  Google Scholar 

  18. Bergmann, O., et al. Evidence for cardiomyocyte renewal in humans. Science 324:98, 2009. https://doi.org/10.1126/science.1164680.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Berthier, E., E. W. Young, and D. Beebe. Engineers are from PDMS-land, Biologists are from Polystyrenia. Lab. Chip 12:1224–1237, 2012. https://doi.org/10.1039/c2lc20982a.

    CAS  Article  PubMed  Google Scholar 

  20. Bhatia, S. N., and D. E. Ingber. Microfluidic organs-on-chips. Nat. Biotechnol. 32:760–772, 2014. https://doi.org/10.1038/nbt.2989.

    CAS  Article  PubMed  Google Scholar 

  21. Birey, F., et al. Assembly of functionally integrated human forebrain spheroids. Nature 545:54–59, 2017. https://doi.org/10.1038/nature22330.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Blondel, D., and M. P. Lutolf. Bioinspired hydrogels for 3D organoid culture. Chimia (Aarau) 73:81–85, 2019. https://doi.org/10.2533/chimia.2019.81.

    CAS  Article  Google Scholar 

  23. Boj, S. F., et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160:324–338, 2015. https://doi.org/10.1016/j.cell.2014.12.021.

    CAS  Article  PubMed  Google Scholar 

  24. Briscoe, J., and P. P. Therond. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol. 14:416–429, 2013. https://doi.org/10.1038/nrm3598.

    CAS  Article  PubMed  Google Scholar 

  25. 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. https://doi.org/10.1038/nprot.2016.097.

    CAS  Article  PubMed  Google Scholar 

  26. Broutier, L., et al. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat. Med. 23:1424–1435, 2017. https://doi.org/10.1038/nm.4438.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Camp, J. G., et al. Multilineage communication regulates human liver bud development from pluripotency. Nature 546:533–538, 2017. https://doi.org/10.1038/nature22796.

    CAS  Article  PubMed  Google Scholar 

  28. Campisi, M., et al. 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials 180:117–129, 2018. https://doi.org/10.1016/j.biomaterials.2018.07.014.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Cavo, M., et al. A new cell-laden 3D Alginate-Matrigel hydrogel resembles human breast cancer cell malignant morphology, spread and invasion capability observed “in vivo”. Sci. Rep. 8:5333, 2018. https://doi.org/10.1038/s41598-018-23250-4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Chen, H. Y., K. D. Kaya, L. Dong, and A. Swaroop. Three-dimensional retinal organoids from mouse pluripotent stem cells mimic in vivo development with enhanced stratification and rod photoreceptor differentiation. Mol. Vis. 22:1077–1094, 2016.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Choe, A., S. K. Ha, I. Choi, N. Choi, and J. H. Sung. Microfluidic Gut-liver chip for reproducing the first pass metabolism. Biomed. Microdev. 19:4, 2017. https://doi.org/10.1007/s10544-016-0143-2.

    CAS  Article  Google Scholar 

  32. Choi, S. H., et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515:274–278, 2014. https://doi.org/10.1038/nature13800.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Chwalek, K., et al. Providing the right cues in nerve guidance conduits: Biofunctionalization versus fiber profile to facilitate oriented neuronal outgrowth. Mater. Sci. Eng. C 61:466–472, 2016. https://doi.org/10.1016/j.msec.2015.12.059.

    CAS  Article  Google Scholar 

  34. Clevers, H. Modeling development and disease with organoids. Cell 165:1586–1597, 2016. https://doi.org/10.1016/j.cell.2016.05.082.

    CAS  Article  Google Scholar 

  35. Conant, G., S. Ahadian, Y. Zhao, and M. Radisic. Kinase inhibitor screening using artificial neural networks and engineered cardiac biowires. Sci. Rep. 7:11807, 2017. https://doi.org/10.1038/s41598-017-12048-5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. D’Amour, K. A., et al. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat. Biotechnol. 23:1534–1541, 2005. https://doi.org/10.1038/nbt1163.

    CAS  Article  PubMed  Google Scholar 

  37. Davidson, A. J., P. Lewis, A. Przepiorski, and V. Sander. Turning mesoderm into kidney. Semin. Cell Dev. Biol. 91:86–93, 2019. https://doi.org/10.1016/j.semcdb.2018.08.016.

    Article  PubMed  Google Scholar 

  38. Davis, R. P., et al. Cardiomyocytes derived from pluripotent stem cells recapitulate electrophysiological characteristics of an overlap syndrome of cardiac sodium channel disease. Circulation 125:3079–3091, 2012. https://doi.org/10.1161/circulationaha.111.066092.

    Article  PubMed  Google Scholar 

  39. Debnath, J., S. K. Muthuswamy, and J. S. Brugge. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30:256–268, 2003.

    CAS  Article  Google Scholar 

  40. des Rieux, A., A. Shikanov, and L. D. Shea. Fibrin hydrogels for non-viral vector delivery in vitro. J. Control Release 136:148–154, 2009.

    Article  Google Scholar 

  41. Desplantez, T., et al. Connexin43 ablation in foetal atrial myocytes decreases electrical coupling, partner connexins, and sodium current. Cardiovasc. Res. 94:58–65, 2012. https://doi.org/10.1093/cvr/cvs025.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Devalla, H. D., and R. Passier. Cardiac differentiation of pluripotent stem cells and implications for modeling the heart in health and disease. Sci. Transl. Med. 2018. https://doi.org/10.1126/scitranslmed.aah5457.

    Article  PubMed  Google Scholar 

  43. Devarasetty, M., A. R. Mazzocchi, and A. Skardal. Applications of bioengineered 3D tissue and tumor organoids in drug development and precision medicine: current and future. BioDrugs 32:53–68, 2018. https://doi.org/10.1007/s40259-017-0258-x.

    CAS  Article  PubMed  Google Scholar 

  44. DiStefano, T., et al. Accelerated and improved differentiation of retinal organoids from pluripotent stem cells in rotating-wall vessel bioreactors. Stem Cell Rep 10:300–313, 2018. https://doi.org/10.1016/j.stemcr.2017.11.001.

    CAS  Article  Google Scholar 

  45. Domansky, K., et al. Clear castable polyurethane elastomer for fabrication of microfluidic devices. Lab. Chip 13:3956–3964, 2013. https://doi.org/10.1039/c3lc50558h.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Dutta, D., I. Heo, and H. Clevers. Disease modeling in stem cell-derived 3D organoid systems. Trends Mol. Med. 23:393–410, 2017. https://doi.org/10.1016/j.molmed.2017.02.007.

    CAS  Article  PubMed  Google Scholar 

  47. Dye, B. R., et al. In vitro generation of human pluripotent stem cell derived lung organoids. Elife 2015. https://doi.org/10.7554/elife.05098.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Eicke, D., et al. Large-scale production of megakaryocytes in microcarrier-supported stirred suspension bioreactors. Sci. Rep. 2018. https://doi.org/10.1038/s41598-018-28459-x.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Eiraku, M., and Y. Sasai. Self-formation of layered neural structures in three-dimensional culture of ES cells. Curr. Opin. Neurobiol. 22:768–777, 2012. https://doi.org/10.1016/j.conb.2012.02.005.

    CAS  Article  PubMed  Google Scholar 

  50. Eiraku, M., et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3:519–532, 2008.

    CAS  Article  Google Scholar 

  51. Eiraku, M., et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472:51–56, 2011. https://doi.org/10.1038/nature09941.

    CAS  Article  PubMed  Google Scholar 

  52. Esch, M. B., and G. J. Mahler. Microfluidic Cell Culture Systems. Amsterdam: Elsevier, pp. 323–350, 2019.

    Book  Google Scholar 

  53. Eschenhagen, T., et al. Three-dimensional reconstitution of embryonic cardiomyocytes in a collagen matrix: a new heart muscle model system. FASEB J. 11:683–694, 1997. https://doi.org/10.1096/fasebj.11.8.9240969.

    CAS  Article  PubMed  Google Scholar 

  54. Fan, Y., D. T. Nguyen, Y. Akay, F. Xu, and M. Akay. Engineering a brain cancer chip for high-throughput drug screening. Sci. Rep. 6:25062, 2016. https://doi.org/10.1038/srep25062.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Fennema, E., N. Rivron, J. Rouwkema, C. van Blitterswijk, and J. de Boer. Spheroid culture as a tool for creating 3D complex tissues. Trends Biotechnol. 31:108–115, 2013. https://doi.org/10.1016/j.tibtech.2012.12.003.

    CAS  Article  PubMed  Google Scholar 

  56. Finnberg, N. K., et al. Application of 3D tumoroid systems to define immune and cytotoxic therapeutic responses based on tumoroid and tissue slice culture molecular signatures. Oncotarget 8:66747–66757, 2017. https://doi.org/10.18632/oncotarget.19965.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Fiorotto, R., et al. Liver diseases in the dish: iPSC and organoids as a new approach to modeling liver diseases. Biochim. Biophys. Acta Mol. Basis Dis. 920–928:2019, 1865. https://doi.org/10.1016/j.bbadis.2018.08.038.

    CAS  Article  Google Scholar 

  58. Fischer, B., et al. A complete workflow for the differentiation and the dissociation of hiPSC-derived cardiospheres. Stem Cell Res. 32:65–72, 2018. https://doi.org/10.1016/j.scr.2018.08.015.

    CAS  Article  PubMed  Google Scholar 

  59. Forbes, T. A., et al. Patient-iPSC-derived kidney organoids show functional validation of a ciliopathic renal phenotype and reveal underlying pathogenetic mechanisms. Am. J. Hum. Genet. 102:816–831, 2018. https://doi.org/10.1016/j.ajhg.2018.03.014.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Freedman, B. S., et al. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat. Commun. 6:8715, 2015. https://doi.org/10.1038/ncomms9715.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. Freund-Levi, Y., et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch. Neurol. 63:1402–1408, 2006. https://doi.org/10.1001/archneur.63.10.1402.

    Article  PubMed  Google Scholar 

  62. Fuhrmann, S. Eye morphogenesis and patterning of the optic vesicle. Curr. Top. Dev. Biol. 93:61–84, 2010. https://doi.org/10.1016/b978-0-12-385044-7.00003-5.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Fujii, M., et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 18:827–838, 2016. https://doi.org/10.1016/j.stem.2016.04.003.

    CAS  Article  PubMed  Google Scholar 

  64. Garnier, D., et al. Expansion of human primary hepatocytes in vitro through their amplification as liver progenitors in a 3D organoid system. Sci. Rep. 8:8222, 2018.

    Article  Google Scholar 

  65. Godugu, C., et al. AlgiMatrix based 3D cell culture system as an in-vitro tumor model for anticancer studies. PLoS ONE 8:e53708, 2013. https://doi.org/10.1371/journal.pone.0053708.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Greggio, C., et al. Artificial three-dimensional niches deconstruct pancreas development in vitro. Development 140:4452–4462, 2013. https://doi.org/10.1242/dev.096628.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Grinnell, F. Fibroblast biology in three-dimensional collagen matrices. Trends Cell Biol. 13:264–269, 2003. https://doi.org/10.1016/s0962-8924(03)00057-6.

    CAS  Article  PubMed  Google Scholar 

  68. Hassell, B. A., et al. Human organ chip models recapitulate orthotopic lung cancer growth, therapeutic responses, and tumor dormancy in vitro. Cell Rep. 21:508–516, 2017. https://doi.org/10.1016/j.celrep.2017.09.043.

    CAS  Article  PubMed  Google Scholar 

  69. Hersel, U., C. Dahmen, and H. Kessler. RGD modified polymers: biomaterials for stimulated cell adhesion and beyond. Biomaterials 24:4385–4415, 2003.

    CAS  Article  Google Scholar 

  70. Hinson, J. T., et al. HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science 349:982–986, 2015.

    CAS  Article  Google Scholar 

  71. Ho, B. X., N. M. Q. Pek, and B. S. Soh. Disease modeling using 3D organoids derived from human induced pluripotent stem cells. Int. J. Mol. Sci. 2018. https://doi.org/10.3390/ijms19040936.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Hofrichter, M., et al. Comparative performance analysis of human iPSC-derived and primary neural progenitor cells (NPC) grown as neurospheres in vitro. Stem Cell Res. 25:72–82, 2017. https://doi.org/10.1016/j.scr.2017.10.013.

    CAS  Article  PubMed  Google Scholar 

  73. Hohwieler, M., et al. Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling. Gut 66:473–486, 2017.

    CAS  Article  Google Scholar 

  74. Huang, S. X., et al. Efficient generation of lung and airway epithelial cells from human pluripotent stem cells. Nat. Biotechnol. 32:84–91, 2014. https://doi.org/10.1038/nbt.2754.

    CAS  Article  PubMed  Google Scholar 

  75. Huang, L., et al. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat. Med. 21:1364–1371, 2015. https://doi.org/10.1038/nm.3973.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Huch, M., et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494:247–250, 2013. https://doi.org/10.1038/nature11826.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Huch, M., et al. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J. 32:2708–2721, 2013. https://doi.org/10.1038/emboj.2013.204.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Hughes, C. S., L. M. Postovit, and G. A. Lajoie. Matrigel: a complex protein mixture required for optimal growth of cell culture. Proteomics 10:1886–1890, 2010. https://doi.org/10.1002/pmic.200900758.

    CAS  Article  PubMed  Google Scholar 

  79. 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. https://doi.org/10.1126/scitranslmed.3004249.

    CAS  Article  PubMed  Google Scholar 

  80. Hunt, N. C., et al. 3D culture of human pluripotent stem cells in RGD-alginate hydrogel improves retinal tissue development. Acta Biomater. 49:329–343, 2017. https://doi.org/10.1016/j.actbio.2016.11.016.

    CAS  Article  PubMed  Google Scholar 

  81. In, J. G., et al. Human mini-guts: new insights into intestinal physiology and host-pathogen interactions. Nat. Rev. Gastroenterol. Hepatol. 13:633–642, 2016. https://doi.org/10.1038/nrgastro.2016.142.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. Ingram, J. L., et al. Airway fibroblasts in asthma manifest an invasive phenotype. Am. J. Respir. Crit. Care Med. 183:1625–1632, 2011. https://doi.org/10.1164/rccm.201009-1452oc.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Inzana, J. A., et al. 3D printing of composite calcium phosphate and collagen scaffolds for bone regeneration. Biomaterials 35:4026–4034, 2014.

    CAS  Article  Google Scholar 

  84. Ishikawa, S., K. Ishimori, and S. Ito. A 3D epithelial-mesenchymal co-culture model of human bronchial tissue recapitulates multiple features of airway tissue remodeling by TGF-beta1 treatment. Respir. Res. 18:195, 2017. https://doi.org/10.1186/s12931-017-0680-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. Jalili-Firoozinezhad, S., et al. Modeling radiation injury-induced cell death and countermeasure drug responses in a human Gut-on-a-Chip. Cell Death Dis. 9:223, 2018. https://doi.org/10.1038/s41419-018-0304-8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. Jo, J., et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 19:248–257, 2016. https://doi.org/10.1016/j.stem.2016.07.005.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. Kale, S., et al. Three-dimensional cellular development is essential for ex vivo formation of human bone. Nat. Biotechnol. 18:954–958, 2000. https://doi.org/10.1038/79439.

    CAS  Article  PubMed  Google Scholar 

  88. Karthaus, W. R., et al. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell 159:163–175, 2014. https://doi.org/10.1016/j.cell.2014.08.017.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Kawada, J., et al. Generation of a motor nerve organoid with human stem cell-derived neurons. Stem Cell Rep 9:1441–1449, 2017. https://doi.org/10.1016/j.stemcr.2017.09.021.

    Article  Google Scholar 

  90. Kelava, I., and M. A. Lancaster. Dishing out mini-brains: current progress and future prospects in brain organoid research. Dev. Biol. 420:199–209, 2016. https://doi.org/10.1016/j.ydbio.2016.06.037.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. Kessler, M., et al. The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids. Nat. Commun. 6:8989, 2015. https://doi.org/10.1038/ncomms9989.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Khadpekar, A. J., M. Khan, A. Sose, and A. Majumder. Low Cost and Lithography-free stamp fabrication for Microcontact printing. Sci. Rep. 9:1024, 2019.

    Article  Google Scholar 

  93. Khurshid, M., A. Mulet-Sierra, A. Adesida, and A. Sen. Osteoarthritic human chondrocytes proliferate in 3D co-culture with mesenchymal stem cells in suspension bioreactors. J. Tissue Eng. Regen. Med. 12:e1418–e1432, 2018. https://doi.org/10.1002/term.2531.

    CAS  Article  PubMed  Google Scholar 

  94. Kleinman, H. K., and G. R. Martin. Matrigel: basement membrane matrix with biological activity. Semin. Cancer Biol. 15:378–386, 2005. https://doi.org/10.1016/j.semcancer.2005.05.004.

    CAS  Article  PubMed  Google Scholar 

  95. Kondo, T., et al. Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12:487–496, 2013. https://doi.org/10.1016/j.stem.2013.01.009.

    CAS  Article  PubMed  Google Scholar 

  96. Kretzschmar, K., and H. Clevers. Organoids: modeling development and the stem cell niche in a dish. Dev. Cell 38:590–600, 2016. https://doi.org/10.1016/j.devcel.2016.08.014.

    CAS  Article  PubMed  Google Scholar 

  97. Kretzschmar, K., et al. Profiling proliferative cells and their progeny in damaged murine hearts. Proc. Natl. Acad. Sci. U.S.A. 115:E12245, 2018. https://doi.org/10.1073/pnas.1805829115.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. Lancaster, M. A., and J. A. Knoblich. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345:1247125, 2014. https://doi.org/10.1126/science.1247125.

    CAS  Article  PubMed  Google Scholar 

  99. Lancaster, M. A., et al. Cerebral organoids model human brain development and microcephaly. Nature 501:373, 2013.

    CAS  Article  Google Scholar 

  100. Lancaster, M. A., et al. Guided self-organization and cortical plate formation in human brain organoids. Nat. Biotechnol. 35:659–666, 2017. https://doi.org/10.1038/nbt.3906.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. Langer, R., and J. Vacanti. Advances in tissue engineering. J. Pediatr. Surg. 51:8–12, 2016.

    Article  Google Scholar 

  102. Laschke, M. W., and M. D. Menger. Life is 3D: boosting spheroid function for tissue engineering. Trends Biotechnol. 35:133–144, 2017. https://doi.org/10.1016/j.tibtech.2016.08.004.

    CAS  Article  PubMed  Google Scholar 

  103. Li, M. L., et al. Influence of a reconstituted basement membrane and its components on casein gene expression and secretion in mouse mammary epithelial cells. Proc. Natl. Acad. Sci. U.S.A. 84:136–140, 1987. https://doi.org/10.1073/pnas.84.1.136.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. Lian, X., J. Xu, J. Li, and K. R. Chien. Next-generation models of human cardiogenesis via genome editing. Cold Spring Harb. Perspect. Med. 4:a013920, 2014. https://doi.org/10.1101/cshperspect.a013920.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. Lu, H. F., et al. Engineering a functional three-dimensional human cardiac tissue model for drug toxicity screening. Biofabrication 9:025011, 2017.

    Article  Google Scholar 

  106. Lutolf, M. P., and J. A. Hubbell. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat. Biotechnol. 23:47–55, 2005. https://doi.org/10.1038/nbt1055.

    CAS  Article  PubMed  Google Scholar 

  107. Lutolf, M. P., et al. Repair of bone defects using synthetic mimetics of collagenous extracellular matrices. Nat. Biotechnol. 21:513–518, 2003. https://doi.org/10.1038/nbt818.

    CAS  Article  PubMed  Google Scholar 

  108. Mallon, B. S., K.-Y. Park, K. G. Chen, R. S. Hamilton, and R. D. McKay. Toward xeno-free culture of human embryonic stem cells. Int. J. Biochem. Cell Biol. 38:1063–1075, 2006.

    CAS  Article  Google Scholar 

  109. Mariani, J., et al. Modeling human cortical development in vitro using induced pluripotent stem cells. Proc. Natl. Acad. Sci. U.S.A. 109:12770–12775, 2012.

    CAS  Article  Google Scholar 

  110. 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. https://doi.org/10.1039/c5lc00392j.

    CAS  Article  PubMed  Google Scholar 

  111. McCauley, H. A., and J. M. Wells. Pluripotent stem cell-derived organoids: using principles of developmental biology to grow human tissues in a dish. Development 144:958–962, 2017. https://doi.org/10.1242/dev.140731.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. McCracken, K. W., J. C. Howell, J. M. Wells, and J. R. Spence. Generating human intestinal tissue from pluripotent stem cells in vitro. Nat. Protoc. 6:1920–1928, 2011. https://doi.org/10.1038/nprot.2011.410.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. McCracken, K. W., et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516:400–404, 2014. https://doi.org/10.1038/nature13863.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. Meinhardt, A., et al. 3D reconstitution of the patterned neural tube from embryonic stem cells. Stem Cell Rep. 3:987–999, 2014. https://doi.org/10.1016/j.stemcr.2014.09.020.

    Article  Google Scholar 

  115. Mellough, C. B., E. Sernagor, I. Moreno-Gimeno, D. H. Steel, and M. Lako. Efficient stage-specific differentiation of human pluripotent stem cells toward retinal photoreceptor cells. Stem Cells 30:673–686, 2012. https://doi.org/10.1002/stem.1037.

    CAS  Article  PubMed  Google Scholar 

  116. Miao, Y., Y. B. Sun, B. C. Liu, J. D. Jiang, and Z. Q. Hu. Controllable production of transplantable adult human high-passage dermal papilla spheroids using 3D matrigel culture. Tissue Eng. Part A 20:2329–2338, 2014.

    CAS  Article  Google Scholar 

  117. Michl, P., and T. M. Gress. Current concepts and novel targets in advanced pancreatic cancer. Gut 62:317–326, 2013. https://doi.org/10.1136/gutjnl-2012-303588.

    CAS  Article  PubMed  Google Scholar 

  118. Mihara, Y., et al. Production of pancreatic progenitor cells from human induced pluripotent stem cells using a three-dimensional suspension bioreactor system. J. Tissue Eng. Regen. Med. 11:3193–3201, 2017. https://doi.org/10.1002/term.2228.

    CAS  Article  PubMed  Google Scholar 

  119. Mills, R. J., et al. Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. Proc. Natl. Acad. Sci. U.S.A. 114:E8372–E8381, 2017. https://doi.org/10.1073/pnas.1707316114.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. Monzel, A. S., et al. Derivation of Human Midbrain-Specific Organoids from Neuroepithelial Stem Cells. Stem Cell Rep 8:1144–1154, 2017. https://doi.org/10.1016/j.stemcr.2017.03.010.

    CAS  Article  Google Scholar 

  121. Muller, S., et al. Human adipose stromal-vascular fraction self-organizes to form vascularized adipose tissue in 3D cultures. Sci. Rep. 9:7250, 2019. https://doi.org/10.1038/s41598-019-43624-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. Nakano, T., et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10:771–785, 2012. https://doi.org/10.1016/j.stem.2012.05.009.

    CAS  Article  PubMed  Google Scholar 

  123. Nascimento, J. M., et al. Human cerebral organoids and fetal brain tissue share proteomic similarities. Front. Cell Dev. Biol. 7:303, 2019. https://doi.org/10.3389/fcell.2019.00303.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Nguyen, M., and H. Arnheiter. Signaling and transcriptional regulation in early mammalian eye development: a link between FGF and MITF. Development 127:3581–3591, 2000.

    CAS  PubMed  Google Scholar 

  125. Nugraha, B., et al. Monitoring and manipulating cellular crosstalk during kidney fibrosis inside a 3D in vitro co-culture. Sci. Rep. 7:14490, 2017. https://doi.org/10.1038/s41598-017-12683-y.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. Nunes, S. S., et al. Biowire: a platform for maturation of human pluripotent stem cell–derived cardiomyocytes. Nat. Methods 10:781, 2013. https://doi.org/10.1038/nmeth.2524.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. Ohlemacher, S. K., et al. Stepwise differentiation of retinal ganglion cells from human pluripotent stem cells enables analysis of glaucomatous neurodegeneration. Stem Cells 34:1553–1562, 2016. https://doi.org/10.1002/stem.2356.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. Oleaga, C., et al. Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci. Rep. 6:20030, 2016. https://doi.org/10.1038/srep20030.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. Ortega-Prieto, A. M., et al. 3D microfluidic liver cultures as a physiological preclinical tool for hepatitis B virus infection. Nat. Commun. 9:682, 2018. https://doi.org/10.1038/s41467-018-02969-8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. Pabst, A., T. Ziebart, M. Ackermann, M. Konerding, and C. Walter. Bisphosphonates’ antiangiogenic potency in the development of bisphosphonate-associated osteonecrosis of the jaws: influence on microvessel sprouting in an in vivo 3D Matrigel assay. Clin. Oral Invest. 18:1015–1022, 2014.

    CAS  Article  Google Scholar 

  131. Pampaloni, F., E. G. Reynaud, and E. H. Stelzer. The third dimension bridges the gap between cell culture and live tissue. Nat. Rev. Mol. Cell Biol. 8:839, 2007.

    CAS  Article  Google Scholar 

  132. Perry, G., A. D. Cash, and M. A. Smith. Alzheimer disease and oxidative stress. J. Biomed. Biotechnol. 2:120–123, 2002. https://doi.org/10.1155/s1110724302203010.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Perry, G., et al. Comparative biology and pathology of oxidative stress in Alzheimer and other neurodegenerative diseases: beyond damage and response. Comp. Biochem. Physiol. C: Toxicol. Pharmacol. 133:507–513, 2002. https://doi.org/10.1016/s1532-0456(02)00119-9.

    Article  Google Scholar 

  134. Perry, G., et al. Reactive oxygen: its sources and significance in Alzheimer disease. J. Neural Transm. Suppl. 2002. https://doi.org/10.1007/978-3-7091-6139-5_7.

    Article  PubMed  Google Scholar 

  135. Poincloux, R., et al. Contractility of the cell rear drives invasion of breast tumor cells in 3D Matrigel. Proc. Natl. Acad. Sci. U.S.A. 108:1943–1948, 2011.

    CAS  Article  Google Scholar 

  136. Przepiorski, A., et al. A simple bioreactor-based method to generate kidney organoids from pluripotent stem cells. Stem Cell Rep. 11:470–484, 2018. https://doi.org/10.1016/j.stemcr.2018.06.018.

    CAS  Article  Google Scholar 

  137. Qian, X., et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165:1238–1254, 2016. https://doi.org/10.1016/j.cell.2016.04.032.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. Qian, X., et al. Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat. Protoc. 13:565–580, 2018. https://doi.org/10.1038/nprot.2017.152.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. Quadrato, G., J. Brown, and P. Arlotta. The promises and challenges of human brain organoids as models of neuropsychiatric disease. Nat. Med. 22:1220–1228, 2016. https://doi.org/10.1038/nm.4214.

    CAS  Article  PubMed  Google Scholar 

  140. Quinn, J. F., et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA 304:1903–1911, 2010. https://doi.org/10.1001/jama.2010.1510.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. Rathnayake, N., et al. Salivary biomarkers for detection of systemic diseases. PLoS ONE 8:e61356, 2013. https://doi.org/10.1371/journal.pone.0061356.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. Ravi, M., V. Paramesh, S. R. Kaviya, E. Anuradha, and F. D. Solomon. 3D cell culture systems: advantages and applications. J. Cell. Physiol. 230:16–26, 2015. https://doi.org/10.1002/jcp.24683.

    CAS  Article  PubMed  Google Scholar 

  143. Ronaldson-Bouchard, K., et al. Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature 556:239–243, 2018. https://doi.org/10.1038/s41586-018-0016-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. Sachs, N., et al. A living Biobank of breast cancer organoids captures disease heterogeneity. Cell 172:373–386S, 2018. https://doi.org/10.1016/j.cell.2017.11.010.

    CAS  Article  Google Scholar 

  145. Sade, H., et al. A human blood-brain barrier transcytosis assay reveals antibody transcytosis influenced by pH-dependent receptor binding. PLoS ONE 9:e96340, 2014. https://doi.org/10.1371/journal.pone.0096340.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. Sato, T., et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459:262–265, 2009. https://doi.org/10.1038/nature07935.

    CAS  Article  Google Scholar 

  147. Sato, T., et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141:1762–1772, 2011. https://doi.org/10.1053/j.gastro.2011.07.050.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  148. Seliktar, D., A. H. Zisch, M. P. Lutolf, J. L. Wrana, and J. A. Hubbell. MMP-2 sensitive, VEGF-bearing bioactive hydrogels for promotion of vascular healing. J. Biomed. Mater. Res. A 68:704–716, 2004. https://doi.org/10.1002/jbm.a.20091.

    CAS  Article  PubMed  Google Scholar 

  149. Sequist, L. V., et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N. Engl. J. Med. 372:1700–1709, 2015. https://doi.org/10.1056/nejmoa1413654.

    Article  PubMed  Google Scholar 

  150. Shelper, T. B., C. J. Lovitt, and V. M. Avery. Assessing drug efficacy in a miniaturized pancreatic cancer in vitro 3D cell culture model. Assay Drug Dev. Technol. 14:367–380, 2016. https://doi.org/10.1089/adt.2016.737.

    CAS  Article  PubMed  Google Scholar 

  151. Shen, M. M. Nodal signaling: developmental roles and regulation. Development 134:1023–1034, 2007. https://doi.org/10.1242/dev.000166.

    CAS  Article  PubMed  Google Scholar 

  152. Siebel, C., and U. Lendahl. Notch signaling in development, tissue homeostasis, and disease. Physiol. Rev. 97:1235–1294, 2017. https://doi.org/10.1152/physrev.00005.2017.

    CAS  Article  PubMed  Google Scholar 

  153. Skardal, A., T. Shupe, and A. Atala. Principles of Regenerative Medicine. Amsterdam: Elsevier, pp. 769–786, 2019.

    Book  Google Scholar 

  154. Sloan, S. A., et al. Human astrocyte maturation captured in 3D cerebral cortical spheroids derived from pluripotent stem cells. Neuron 95:779–790, 2017. https://doi.org/10.1016/j.neuron.2017.07.035.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. Spence, J. R., et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470:105–109, 2011. https://doi.org/10.1038/nature09691.

    CAS  Article  PubMed  Google Scholar 

  156. Staton, C. A., et al. Current methods for assaying angiogenesis in vitro and in vivo. Int. J. Exp. Pathol. 85:233–248, 2004.

    CAS  Article  Google Scholar 

  157. Steinhart, Z., and S. Angers. Wnt signaling in development and tissue homeostasis. Development 2018. https://doi.org/10.1242/dev.146589.

    Article  PubMed  Google Scholar 

  158. Sumi, T., N. Tsuneyoshi, N. Nakatsuji, and H. Suemori. Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/beta-catenin, Activin/Nodal and BMP signaling. Development 135:2969–2979, 2008. https://doi.org/10.1242/dev.021121.

    CAS  Article  PubMed  Google Scholar 

  159. Sun, T., et al. Expression and functional significance of Twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry. Hepatology 51:545–556, 2010.

    CAS  Article  Google Scholar 

  160. Suntharalingam, G., et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355:1018–1028, 2006. https://doi.org/10.1056/nejmoa063842.

    CAS  Article  PubMed  Google Scholar 

  161. Szot, C. S., C. F. Buchanan, J. W. Freeman, and M. N. Rylander. 3D in vitro bioengineered tumors based on collagen I hydrogels. Biomaterials 32:7905–7912, 2011.

    CAS  Article  Google Scholar 

  162. Tae, G., M. Scatena, P. S. Stayton, and A. S. Hoffman. PEG-cross-linked heparin is an affinity hydrogel for sustained release of vascular endothelial growth factor. J. Biomater. Sci. Polym. Ed. 17:187–197, 2006.

    CAS  Article  Google Scholar 

  163. Taguchi, A., and R. Nishinakamura. Higher-order kidney organogenesis from pluripotent stem cells. Cell Stem Cell 21:730–746, 2017. https://doi.org/10.1016/j.stem.2017.10.011.

    CAS  Article  PubMed  Google Scholar 

  164. Takasato, M., X. E. Pei, H. S. Chiu, and M. H. Little. Generation of kidney organoids from human pluripotent stem cells. Nat. Protoc. 11:1681, 2016.

    CAS  Article  Google Scholar 

  165. Takasato, M., et al. Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney. Nat. Cell Biol. 16:118, 2014.

    CAS  Article  Google Scholar 

  166. Takasato, M., et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526:564–568, 2015. https://doi.org/10.1038/nature15695.

    CAS  Article  PubMed  Google Scholar 

  167. Terasaki, P. I. Transplant antigens: a brief history of HLA. Textbook Org Transplantation 2014. https://doi.org/10.1002/9781118873434.

    Article  Google Scholar 

  168. Tibbitt, M. W., and K. S. Anseth. Hydrogels as extracellular matrix mimics for 3D cell culture. Biotechnol. Bioeng. 103:655–663, 2009.

    CAS  Article  Google Scholar 

  169. Tiburcy, M., et al. Defined engineered human myocardium with advanced maturation for applications in heart failure modeling and repair. Circulation 135:1832–1847, 2017. https://doi.org/10.1161/circulationaha.116.024145.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  170. Tillman, B. W., et al. The in vivo stability of electrospun polycaprolactone-collagen scaffolds in vascular reconstruction. Biomaterials 30:583–588, 2009. https://doi.org/10.1016/j.biomaterials.2008.10.006.

    CAS  Article  PubMed  Google Scholar 

  171. Torrejon, K. Y., et al. Bioengineered glaucomatous 3D human trabecular meshwork as an in vitro disease model. Biotechnol. Bioeng. 113:1357–1368, 2016. https://doi.org/10.1002/bit.25899.

    CAS  Article  PubMed  Google Scholar 

  172. Tucker, B. A., et al. Patient-specific iPSC-derived photoreceptor precursor cells as a means to investigate retinitis pigmentosa. Elife 2:e00824, 2013.

    Article  Google Scholar 

  173. van de Wetering, M., et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161:933–945, 2015. https://doi.org/10.1016/j.cell.2015.03.053.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  174. Vis, D. J., et al. Multilevel models improve precision and speed of IC50 estimates. Pharmacogenomics 17:691–700, 2016. https://doi.org/10.2217/pgs.16.15.

    CAS  Article  PubMed  Google Scholar 

  175. Vukicevic, S., et al. Identification of multiple active growth factors in basement membrane Matrigel suggests caution in interpretation of cellular activity related to extracellular matrix components. Exp. Cell Res. 202:1–8, 1992. https://doi.org/10.1016/0014-4827(92)90397-q.

    CAS  Article  PubMed  Google Scholar 

  176. Wahlin, K. J., et al. Photoreceptor outer segment-like structures in long-term 3D retinas from human pluripotent stem cells. Sci. Rep. 2017. https://doi.org/10.1038/s41598-017-00774-9.

    Article  PubMed  PubMed Central  Google Scholar 

  177. Wang, Y. I., H. E. Abaci, and M. L. Shuler. Microfluidic blood-brain barrier model provides in vivo-like barrier properties for drug permeability screening. Biotechnol. Bioeng. 114:184–194, 2017. https://doi.org/10.1002/bit.26045.

    CAS  Article  PubMed  Google Scholar 

  178. Wang, S., S. Cang, and D. Liu. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J. Hematol. Oncol. 9:34, 2016. https://doi.org/10.1186/s13045-016-0268-z.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  179. Wang, Y. I., C. Carmona, J. J. Hickman, and M. L. Shuler. Multiorgan microphysiological systems for drug development: strategies, advances, and challenges. Adv. Healthc. Mater. 2018. https://doi.org/10.1002/adhm.201701000.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Wang, Y. L., et al. A microengineered collagen scaffold for generating a polarized crypt-villus architecture of human small intestinal epithelium. Biomaterials 128:44–55, 2017. https://doi.org/10.1016/j.biomaterials.2017.03.005.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  181. Weeber, F., S. N. Ooft, K. K. Dijkstra, and E. E. Voest. Tumor organoids as a pre-clinical cancer model for drug discovery. Cell Chem. Biol. 24:1092–1100, 2017. https://doi.org/10.1016/j.chembiol.2017.06.012.

    CAS  Article  PubMed  Google Scholar 

  182. Wevers, N. R., et al. A perfused human blood-brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport. Fluids Barriers CNS 15:23, 2018. https://doi.org/10.1186/s12987-018-0108-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  183. Wolf, K., et al. Collagen-based cell migration models in vitro and in vivo. Semin. Cell Dev. Biol. 20:931–941, 2009. https://doi.org/10.1016/j.semcdb.2009.08.005.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  184. Wu, M. Y., and C. S. Hill. Tgf-beta superfamily signaling in embryonic development and homeostasis. Dev. Cell 16:329–343, 2009. https://doi.org/10.1016/j.devcel.2009.02.012.

    CAS  Article  PubMed  Google Scholar 

  185. Wu, S., R. Xu, B. Duan, and P. Jiang. Three-dimensional hyaluronic acid hydrogel-based models for in vitro human iPSC-derived NPC culture and differentiation. J Mater Chem B 5:3870–3878, 2017. https://doi.org/10.1039/c7tb00721c.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  186. Xia, Y., et al. Directed differentiation of human pluripotent cells to ureteric bud kidney progenitor-like cells. Nat. Cell Biol. 15:1507–1515, 2013. https://doi.org/10.1038/ncb2872.

    CAS  Article  PubMed  Google Scholar 

  187. Xiang, Y., et al. Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell 21:383–398, 2017. https://doi.org/10.1016/j.stem.2017.07.007.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  188. Xinaris, C., V. Brizi, and G. Remuzzi. Organoid models and applications in biomedical research. Nephron 130:191–199, 2015. https://doi.org/10.1159/000433566.

    Article  PubMed  Google Scholar 

  189. Yang, S., J. Graham, J. W. Kahn, E. A. Schwartz, and M. E. Gerritsen. Functional roles for PECAM-1 (CD31) and VE-cadherin (CD144) in tube assembly and lumen formation in three-dimensional collagen gels. Am. J. Pathol. 155:887–895, 1999. https://doi.org/10.1016/s0002-9440(10)65188-7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  190. Yang, K., et al. Recapitulation of in vivo-like paracrine signals of human mesenchymal stem cells for functional neuronal differentiation of human neural stem cells in a 3D microfluidic system. Biomaterials 63:177–188, 2015. https://doi.org/10.1016/j.biomaterials.2015.06.011.

    CAS  Article  PubMed  Google Scholar 

  191. Yang, X., et al. Nanofiber membrane supported lung-on-a-chip microdevice for anti-cancer drug testing. Lab Chip 18:486–495, 2018.

    CAS  Article  Google Scholar 

  192. Yin, X., et al. Engineering stem cell organoids. Cell Stem Cell 18:25–38, 2016. https://doi.org/10.1016/j.stem.2015.12.005.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  193. Yoon, S. J., et al. Reliability of human cortical organoid generation. Nat. Methods 16:75–78, 2019. https://doi.org/10.1038/s41592-018-0255-0.

    CAS  Article  PubMed  Google Scholar 

  194. Zacharias, W. J., et al. Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature 555:251–255, 2018. https://doi.org/10.1038/nature25786.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  195. Zhang, S. C., M. Wernig, I. D. Duncan, O. Brustle, and J. A. Thomson. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat. Biotechnol. 19:1129–1133, 2001. https://doi.org/10.1038/nbt1201-1129.

    CAS  Article  PubMed  Google Scholar 

  196. Zhang, B., et al. Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis. Nat. Mater. 15:669, 2016. https://doi.org/10.1038/nmat4570.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  197. Zhang, B., et al. Microfabrication of AngioChip, a biodegradable polymer scaffold with microfluidic vasculature. Nat. Protoc. 13:1793–1813, 2018. https://doi.org/10.1038/s41596-018-0015-8.

    CAS  Article  PubMed  Google Scholar 

  198. Zhao, Y., A. Korolj, N. Feric, and M. Radisic. Human pluripotent stem cell-derived cardiomyocyte based models for cardiotoxicity and drug discovery. Expert Opin. Drug Saf. 15:1455–1458, 2016. https://doi.org/10.1080/14740338.2016.1223624.

    Article  PubMed  Google Scholar 

  199. Zhao, Y., et al. A platform for generation of chamber-specific cardiac tissues and disease modeling. Cell 176:913–927, 2019.

    CAS  Article  Google Scholar 

  200. Zhao, Y., et al. A multimaterial microphysiological platform enabled by rapid casting of elastic microwires. Adv. Healthc. Mater. 2019. https://doi.org/10.1002/adhm.201801187.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Zhao, Y., et al. Engineering microenvironment for human cardiac tissue assembly in heart-on-a-chip platform. Matrix Biol. 2019. https://doi.org/10.1016/j.matbio.2019.04.001.

    Article  PubMed  Google Scholar 

  202. Zhao, Y., et al. Towards chamber specific heart-on-a-chip for drug testing applications. Adv. Drug Deliv. Rev. 2020. https://doi.org/10.1016/j.addr.2019.12.002.

    Article  PubMed  Google Scholar 

  203. Zhong, X., et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat. Commun. 5:4047, 2014. https://doi.org/10.1038/ncomms5047.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  204. 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. https://doi.org/10.1038/srep31771.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  205. Zhou, J., et al. Differentiated human airway organoids to assess infectivity of emerging influenza virus. Proc. Natl. Acad. Sci. U.S.A. 115:6822–6827, 2018. https://doi.org/10.1073/pnas.1806308115.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We wish to thank Dr. Penney Gilbert for providing us with guidance in the preparation of this review. Radisic lab is supported by the Canadian Institutes of Health Research (CIHR) Operating Grants (MOP-126027 and MOP-137107), Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant (RGPIN 326982-10), NSERC-CIHR Collaborative Health Research Grant (CHRP 493737-16) and National Institutes of Health Grant 2R01 HL076485.

Authors contributions

KD, MK, AL, AM, YZ wrote and edited the manuscript. MR supervised the work and edited the manuscript.

Competing interests

Yimu Zhao and Milica Radisic are co-founders of TARA Biosystems Inc, and hold equity in the company.

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D’Costa, K., Kosic, M., Lam, A. et al. Biomaterials and Culture Systems for Development of Organoid and Organ-on-a-Chip Models. Ann Biomed Eng 48, 2002–2027 (2020). https://doi.org/10.1007/s10439-020-02498-w

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  • DOI: https://doi.org/10.1007/s10439-020-02498-w