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Rethinking organoid technology through bioengineering

Abstract

In recent years considerable progress has been made in the development of faithful procedures for the differentiation of human pluripotent stem cells (hPSCs). An important step in this direction has also been the derivation of organoids. This technology generally relies on traditional three-dimensional culture techniques that exploit cell-autonomous self-organization responses of hPSCs with minimal control over the external inputs supplied to the system. The convergence of stem cell biology and bioengineering offers the possibility to provide these stimuli in a controlled fashion, resulting in the development of naturally inspired approaches to overcome major limitations of this nascent technology. Based on the current developments, we emphasize the achievements and ongoing challenges of bringing together hPSC organoid differentiation, bioengineering and ethics. This Review underlines the need for providing engineering solutions to gain control of self-organization and functionality of hPSC-derived organoids. We expect that this knowledge will guide the community to generate higher-grade hPSC-derived organoids for further applications in developmental biology, drug screening, disease modelling and personalized medicine.

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Fig. 1: Advances in engineering hPSC-derived organoids.
Fig. 2: Engineering approaches to guide hPSC-derived organoids self-organization.
Fig. 3: Integrating emergent technologies for understanding tissue morphogenesis.
Fig. 4: Strategies for engineering hPSC-derived organoids vascularization.
Fig. 5: Approaches for engineering tissue–tissue interactions.

References

  1. 1.

    Rudnick, D. Regulation and localization in the hind limb bud of the chick embryo. Anat. Rec. 94, 492 (1946).

    CAS  Google Scholar 

  2. 2.

    Saunders, J. W. An experimental study of the distribution, orientation, and tract specificity of feather germs in the wing of the chick embryo. Anat. Rec. 99, 647 (1947).

    Google Scholar 

  3. 3.

    Moscona, A. & Moscona, H. The dissociation and aggregation of cells from organ rudiments of the early chick embryo. J. Anat. 86, 287–301 (1952).

    CAS  Google Scholar 

  4. 4.

    Weiss P, T. A. Reconstitution of complete organs from single-cell suspensions of chick embryos in advanced stages of differentiation. Proc. Natl Acad. Sci. USA 46, 1177–1185 (1960).

    Google Scholar 

  5. 5.

    Auerbach, R. & Grobstein, C. Inductive interaction of embryonic tissues after dissociation and reaggregation. Exp. Cell Res. 15, 384–397 (1958).

    CAS  Google Scholar 

  6. 6.

    Simian, M. & Bissell, M. J. Organoids: a historical perspective of thinking in three dimensions. J. Cell Biol. 216, 31–40 (2017).

    CAS  Google Scholar 

  7. 7.

    Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    CAS  Google Scholar 

  8. 8.

    Clevers, H. Modeling development and disease with organoids. Cell 165, 1586–1597 (2016).

    CAS  Google Scholar 

  9. 9.

    Xia, Y. & Izpisua Belmonte, J. C. Design approaches for generating organ constructs. Cell Stem Cell 24, 877–894 (2019).

    CAS  Google Scholar 

  10. 10.

    Thomson, Ja. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    CAS  Google Scholar 

  11. 11.

    Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    CAS  Google Scholar 

  12. 12.

    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  Google Scholar 

  13. 13.

    Nakano, T. et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10, 771–785 (2012).

    CAS  Google Scholar 

  14. 14.

    Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).

    CAS  Google Scholar 

  15. 15.

    Quadrato, G. et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545, 48–53 (2017).

    CAS  Google Scholar 

  16. 16.

    Pasca, A. M. et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat. Methods 12, 671–678 (2015).

    CAS  Google Scholar 

  17. 17.

    Sakaguchi, H. et al. Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat. Commun. 6, 8896 (2015).

    CAS  Google Scholar 

  18. 18.

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

    CAS  Google Scholar 

  19. 19.

    Spence, J. R. et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470, 105–110 (2011).

    Google Scholar 

  20. 20.

    Dye, B. R. et al. In vitro generation of human pluripotent stem cell derived lung organoids. eLife 2015, e05098 (2015).

    Google Scholar 

  21. 21.

    Koehler, K. R. et al. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat. Biotechnol. 35, 583–589 (2017).

    CAS  Google Scholar 

  22. 22.

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

    Google Scholar 

  23. 23.

    Armstrong, P. B. Cell sorting out: the self-assembly of tissues in vitro. Crit. Rev. Biochem. Mol. Biol. 24, 119–149 (1989).

    CAS  Google Scholar 

  24. 24.

    van Den Brink, S. C. et al. Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells. Develeopment 141, 4231–4242 (2014).

    CAS  Google Scholar 

  25. 25.

    Ten Berge, D. et al. Wnt signaling mediates self-organization and axis formation in embryoid bodies. Cell Stem Cell 3, 508–518 (2008).

    Google Scholar 

  26. 26.

    van den Brink, S. C. et al. Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids. Nature 582, 405–409 (2020).

    Google Scholar 

  27. 27.

    Dessaud, E., McMahon, A. P. & Briscoe, J. Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network. Development 135, 2489–2503 (2008).

    CAS  Google Scholar 

  28. 28.

    Meinhardt, A. et al. 3D reconstitution of the patterned neural tube from embryonic stem cells. Stem Cell Reports 3, 987–999 (2014).

    Google Scholar 

  29. 29.

    Renner, M. et al. Self‐organized developmental patterning and differentiation in cerebral organoids. EMBO J. 36, 1316–1329 (2017).

    CAS  Google Scholar 

  30. 30.

    Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    CAS  Google Scholar 

  31. 31.

    Rakic, P. Extrinsic cytological determinants of basket and stellate cell dendritic pattern in the cerebellar molecular layer. J. Comp. Neurol. 146, 335–354 (1972).

    CAS  Google Scholar 

  32. 32.

    Volpato, V. et al. Reproducibility of Molecular Phenotypes after Long-Term Differentiation to Human iPSC-derived neurons: a multi-site omics study. Stem Cell Reports 11, 897–911 (2018).

    CAS  Google Scholar 

  33. 33.

    Phipson, B. et al. Evaluation of variability in human kidney organoids. Nat. Methods 16, 79–87 (2019).

    CAS  Google Scholar 

  34. 34.

    Warmflash, A., Sorre, B., Etoc, F., Siggia, E. D. & Brivanlou, A. H. A method to recapitulate early embryonic spatial patterning in human embryonic stem cells. Nat. Methods 11, 847–854 (2014).

    CAS  Google Scholar 

  35. 35.

    Martyn, I., Kanno, T. Y., Ruzo, A., Siggia, E. D. & Brivanlou, A. H. Self-organization of a human organizer by combined Wnt and nodal signaling. Nature 558, 132–135 (2018).

    CAS  Google Scholar 

  36. 36.

    Ma, Z. et al. Self-organizing human cardiac microchambers mediated by geometric confinement. Nat. Commun. 6, 7413 (2015).

    CAS  Google Scholar 

  37. 37.

    Kim, H. Y. & Nelson, C. M. Extracellular matrix and cytoskeletal dynamics during branching morphogenesis. Organogenesis 8, 56–64 (2012).

    Google Scholar 

  38. 38.

    Vianello, S. & Lutolf, M. P. Understanding the mechanobiology of early mammalian development through bioengineered models. Dev. Cell 48, 751–763 (2019).

    CAS  Google Scholar 

  39. 39.

    Cruz-Acuña, R. et al. Synthetic hydrogels for human intestinal organoid generation and colonic wound repair. Nat. Cell Biol. 19, 1326–1335 (2017).

    Google Scholar 

  40. 40.

    Garreta, E. et al. Fine tuning the extracellular environment accelerates the derivation of kidney organoids from human pluripotent stem cells. Nat. Mater. 18, 397–405 (2019).

    CAS  Google Scholar 

  41. 41.

    Lancaster, M. A. et al. Guided self-organization and cortical plate formation in human brain organoids. Nat. Biotechnol. 35, 659–666 (2017).

    CAS  Google Scholar 

  42. 42.

    Storm, C., Pastore, J. J., MacKintosh, F. C., Lubensky, T. C. & Janmey, P. A. Nonlinear elasticity in biological gels. Nature 435, 191–194 (2005).

    CAS  Google Scholar 

  43. 43.

    Uzel, S. G. M. et al. Simultaneous or sequential orthogonal gradient formation in a 3D cell culture microfluidic platform. Small 12, 612–622 (2016).

    CAS  Google Scholar 

  44. 44.

    Manfrin, A. et al. Engineered signaling centers for the spatially controlled patterning of human pluripotent stem cells. Nat. Methods 16, 640–648 (2019).

    CAS  Google Scholar 

  45. 45.

    Cederquist, G. Y. et al. Specification of positional identity in forebrain organoids. Nat. Biotechnol. 37, 436–444 (2019).

    CAS  Google Scholar 

  46. 46.

    DeForest, C. A. & Anseth, K. S. Photoreversible patterning of biomolecules within click-based hydrogels. Angew. Chemie Int. Ed. 51, 1816–1819 (2012).

    CAS  Google Scholar 

  47. 47.

    Guvendiren, M. & Burdick, J. A. Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics. Nat. Commun. 3, 792 (2012).

    Google Scholar 

  48. 48.

    Vincent, L. G., Choi, Y. S., Alonso-Latorre, B., Del Álamo, J. C. & Engler, A. J. Mesenchymal stem cell durotaxis depends on substrate stiffness gradient strength. Biotechnol. J. 8, 472–484 (2013).

    CAS  Google Scholar 

  49. 49.

    Xia, B. & Yanai, I. A periodic table of cell types. Development 146, dev169854 (2019).

    CAS  Google Scholar 

  50. 50.

    Roost, M. S. et al. KeyGenes, a tool to probe tissue differentiation using a human fetal transcriptional atlas. Stem Cell Reports 4, 1112–1124 (2015).

    CAS  Google Scholar 

  51. 51.

    Nowotschin, S. et al. The emergent landscape of the mouse gut endoderm at single-cell resolution. Nature 569, 361–367 (2019).

    CAS  Google Scholar 

  52. 52.

    Pijuan-Sala, B. et al. A single-cell molecular map of mouse gastrulation and early organogenesis. Nature 566, 490–495 (2019).

    CAS  Google Scholar 

  53. 53.

    Mayr, U., Serra, D. & Liberali, P. Exploring single cells in space and time during tissue development, homeostasis and regeneration. Development 146, dev176727 (2019).

    CAS  Google Scholar 

  54. 54.

    Hannezo, E. & Heisenberg, C. P. Mechanochemical feedback loops in development and disease. Cell 178, 12–25 (2019).

    CAS  Google Scholar 

  55. 55.

    Bailles, A. et al. Genetic induction and mechanochemical propagation of a morphogenetic wave. Nature 572, 467–473 (2019).

    CAS  Google Scholar 

  56. 56.

    Alt, S., Ganguly, P. & Salbreux, G. Vertex models: from cell mechanics to tissue morphogenesis. Philos. Trans. R. Soc. B 372, 20150520 (2017).

    Google Scholar 

  57. 57.

    Latorre, E. et al. Active superelasticity in three-dimensional epithelia of controlled shape. Nature 563, 203–208 (2018).

    CAS  Google Scholar 

  58. 58.

    Okuda, S. et al. Strain-triggered mechanical feedback in self-organizing optic-cup morphogenesis. Sci. Adv. 4, eaau1354 (2018).

    CAS  Google Scholar 

  59. 59.

    Karzbrun, E., Kshirsagar, A., Cohen, S. R., Hanna, J. H. & Reiner, O. Human brain organoids on a chip reveal the physics of folding. Nat. Phys. 14, 515–522 (2018).

    CAS  Google Scholar 

  60. 60.

    Bershteyn, M. et al. Human iPSC-derived cerebral organoids model cellular features of lissencephaly and reveal prolonged mitosis of outer radial glia. Cell Stem Cell 20, 435–449 (2017).

    CAS  Google Scholar 

  61. 61.

    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).

    CAS  Google Scholar 

  62. 62.

    Freedman, B. S. et al. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat. Commun. 6, 8715 (2015).

    CAS  Google Scholar 

  63. 63.

    Bian, S. et al. Genetically engineered cerebral organoids model brain tumor formation. Nat. Methods 15, 631–639 (2018).

    CAS  Google Scholar 

  64. 64.

    Ogawa, J., Pao, G. M., Shokhirev, M. N. & Verma, I. M. Glioblastoma model using human cerebral organoids. Cell Rep. 23, 1220–1229 (2018).

    CAS  Google Scholar 

  65. 65.

    Qian, X. et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238–1254 (2016).

    CAS  Google Scholar 

  66. 66.

    Przepiorski, A. et al. A simple bioreactor-based method to generate kidney organoids from pluripotent stem cells. Stem Cell Rep. 11, 470–484 (2018).

    CAS  Google Scholar 

  67. 67.

    Wimmer, R. A. et al. Human blood vessel organoids as a model of diabetic vasculopathy. Nature 565, 505–510 (2019).

    CAS  Google Scholar 

  68. 68.

    Sabbagh, M. F. et al. Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells. eLife 7, e36187 (2018).

    Google Scholar 

  69. 69.

    Takebe, T. et al. Vascularized and complex organ buds from diverse tissues via mesenchymal cell-driven condensation. Cell Stem Cell 16, 556–565 (2015).

    CAS  Google Scholar 

  70. 70.

    Czerniecki, S. M. et al. High-throughput screening enhances kidney organoid differentiation from human pluripotent stem cells and enables automated multidimensional phenotyping. Cell Stem Cell 22, 929–940 (2018).

    CAS  Google Scholar 

  71. 71.

    Taguchi, A. & Nishinakamura, R. Higher-order kidney organogenesis from pluripotent stem cells. Cell Stem Cell 21, 730–746 (2017).

    CAS  Google Scholar 

  72. 72.

    Mansour, A. A. et al. An in vivo model of functional and vascularized human brain organoids. Nat. Biotechnol. 36, 432–441 (2018).

    CAS  Google Scholar 

  73. 73.

    Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499, 481–484 (2013).

    CAS  Google Scholar 

  74. 74.

    Takebe, T. et al. Massive and reproducible production of liver buds entirely from human pluripotent stem cells. Cell Rep. 21, 2661–2670 (2017).

    CAS  Google Scholar 

  75. 75.

    Van den Berg, C. W. et al. Renal subcapsular transplantation of PSC-derived kidney organoids induces neo-vasculogenesis and significant glomerular and tubular maturation in vivo. Stem Cell Rep. 10, 751–765 (2018).

    Google Scholar 

  76. 76.

    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).

    CAS  Google Scholar 

  77. 77.

    Shirure, V. S. et al. Tumor-on-a-chip platform to investigate progression and drug sensitivity in cell lines and patient-derived organoids. Lab Chip 18, 3687–3702 (2018).

    CAS  Google Scholar 

  78. 78.

    Song, J., Miermont, A., Lim, C. T. & Kamm, R. D. A 3D microvascular network model to study the impact of hypoxia on the extravasation potential of breast cell lines. Sci. Rep. 8, 17949 (2018).

    CAS  Google Scholar 

  79. 79.

    Homan, K. A. et al. Flow-enhanced vascularization and maturation of kidney organoids in vitro. Nat. Methods 16, 255–262 (2019).

    CAS  Google Scholar 

  80. 80.

    Mark, A. et al. Biomanufacturing of organ-specific tissues with high cellular density and embedded vascular channels. Sci. Adv. 5, eaaw2459 (2019).

    Google Scholar 

  81. 81.

    Noor, N. et al. 3D personalized thick and perfusable cardiac patches and hearts. Adv. Sci. 6, 1900344 (2019).

    Google Scholar 

  82. 82.

    Workman, M. J. et al. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat. Med. 23, 49–59 (2017).

    CAS  Google Scholar 

  83. 83.

    Birey, F. et al. Assembly of functionally integrated human forebrain spheroids. Nature 545, 54–59 (2017).

    CAS  Google Scholar 

  84. 84.

    Koike, H. et al. Modelling human hepato-biliary-pancreatic organogenesis from the foregut–midgut boundary. Nature 574, 112–116 (2019).

    CAS  Google Scholar 

  85. 85.

    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).

    CAS  Google Scholar 

  86. 86.

    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).

    Google Scholar 

  87. 87.

    Osaki, T., Uzel, S. G. M. & Kamm, R. D. Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons. Sci. Adv. 4, eaat5847 (2018).

    CAS  Google Scholar 

  88. 88.

    Achberger, K. et al. Merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human retina-on-a-chip platform. eLife 8, e46188 (2019).

    Google Scholar 

  89. 89.

    Tao, T. et al. Engineering human islet organoids from iPSCs using an organ-on-chip platform. Lab Chip 19, 948–958 (2019).

    CAS  Google Scholar 

  90. 90.

    Workman, M. J. et al. Enhanced utilization of induced pluripotent stem cell–derived human intestinal organoids using microengineered chips. Cell. Mol. Gastroenterol. Hepatol. 5, 669–677 (2018).

    Google Scholar 

  91. 91.

    Lee, K. K. et al. Human stomach-on-a-chip with luminal flow and peristaltic-like motility. Lab Chip 18, 3079–3085 (2018).

    CAS  Google Scholar 

  92. 92.

    Wang, Y. et al. In situ differentiation and generation of functional liver organoids from human iPSCs in a 3D perfusable chip system. Lab Chip 18, 3606–3616 (2018).

    CAS  Google Scholar 

  93. 93.

    Bredenoord, A. L., Clevers, H. & Knoblich, J. A. Human tissues in a dish: the research and ethical implications of organoid technology. Science 355, eaaf9414 (2017).

    Google Scholar 

  94. 94.

    Munsie, M., Hyun, I. & Sugarman, J. Ethical issues in human organoid and gastruloid research. Development 144, 942–945 (2017).

    CAS  Google Scholar 

  95. 95.

    Hyun, I. Engineering ethics and self-organizing models of human development: opportunities and challenges. Cell Stem Cell 21, 718–720 (2017).

    CAS  Google Scholar 

  96. 96.

    Van de Poel, I. & van Gorp, A. C. The need for ethical reflection in engineering design. Sci. Technol. Hum. Values 31, 333–360 (2006).

    Google Scholar 

  97. 97.

    Sample, M. et al. Multi-cellular engineered living systems: building a community around responsible research on emergence. Biofabrication 11, 043001 (2019).

    Google Scholar 

  98. 98.

    Chuva de Sousa Lopes, S. M. Accelerating maturation of kidney organoids. Nat. Mater. 18, 303–304 (2019).

    CAS  Google Scholar 

  99. 99.

    Miura, Y. & Pașca, S. P. Polarizing brain organoids. Nat. Biotechnol. 37, 377–378 (2019).

    CAS  Google Scholar 

  100. 100.

    Wilson, H. V. On some phenomena of coalescence and regeneration in sponges. J. Exp. Zool. 5, 245–258 (1907).

    Google Scholar 

  101. 101.

    Harrison, R. G. Observations on the living developing nerve fiber. Exp. Biol. Med. 4, 140–143 (1906).

    Google Scholar 

  102. 102.

    Strangeways, T. S. P. & Fell, H. B. Experimental studies on the differentiation of embryonic tissues growing in vivo and in vitro.—II. The development of the isolated early embryonic eye of the fowl when cultivated in vitro. Proc. R. Soc. B Biol. Sci. 100, 273–283 (1926).

    Google Scholar 

  103. 103.

    Trowell, O. A. A modified technique for organ culture in vitro. Exp. Cell Res. 6, 246–248 (1954).

    CAS  Google Scholar 

  104. 104.

    Streuli, C. H. & Bissell, M. J. Expression of extracellular matrix components is regulated by substratum. J. Cell Biol. 110, 1405–1415 (1990).

    CAS  Google Scholar 

  105. 105.

    Roca-Cusachs, P., Conte, V. & Trepat, X. Quantifying forces in cell biology. Nat. Cell Biol. 19, 742–751 (2017).

    CAS  Google Scholar 

  106. 106.

    Grashoff, C. et al. Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature 466, 263–266 (2010).

    CAS  Google Scholar 

  107. 107.

    Legant, W. R. et al. Measurement of mechanical tractions exerted by cells in three-dimensional matrices. Nat. Methods 7, 969–971 (2010).

    CAS  Google Scholar 

  108. 108.

    Campàs, O. et al. Quantifying cell-generated mechanical forces within living embryonic tissues. Nat. Methods 11, 183–189 (2014).

    Google Scholar 

  109. 109.

    Kumar, S. et al. Viscoelastic retraction of single living stress fibers and its impact on cell shape, cytoskeletal organization, and extracellular matrix mechanics. Biophys. J. 90, 3762–3773 (2006).

    CAS  Google Scholar 

  110. 110.

    Etournay, R. et al. TissueMiner: a multiscale analysis toolkit to quantify how cellular processes create tissue dynamics. eLife 5, e14334 (2016).

    Google Scholar 

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Acknowledgements

We thank SOLIDCAM ESTUDIO for support with figure illustrations. This work has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (StG-2014-640525_REGMAMKID to N.M., CoG-2013-616480_TensionControl to X.T., CoG-2016-725722_OVOGROWTH to S.M.C.S.L. and StG-757710 to M.A.L.). This research has been supported by the EFSD/Boehringer Ingelheim European Research Programme in Microvascular Complications of Diabetes, and EIT Health under grant ID 20366 (R2U‐Tox‐Assay) to E.G. and N.M. R.D.K. received support from the US National Science Foundation (CBET-0939511). M.A.L. received funding from the Medical Research Council (MC_UP_1201/9). R.W. received support from the NIH (R01EB024591 and R01EB025256) and the NSF (0939511 and 1446474) research grants. X.T. is also supported by the European Commission (project H2020-FETPROACT-01-2016-731957). I.H. is funded by the Greenwall Foundation’s ‘Making a Difference’ grant. This work also received funding from the Spanish Ministry of Economy and Competitiveness (MINECO)/FEDER (SAF2015-72617-EXP to N.M. and SAF2017-89782-R to N.M. and PGC2018-099645-B-I00 to X.T.), Generalitat de Catalunya and CERCA programme (2017 SGR 1306 to N.M. and SGR-2017-01602 to X.T.), Asociación Española contra el Cáncer (AECC) (LABAE16006 to N.M.). N.M. is also supported by Instituto de Salud Carlos III (Tercel, Cardiocel and ACE2ORG). The Institute for Bioengineering of Catalonia is the recipient of a ‘Centro de Excelencia Severo Ochoa’ award from the MINECO (funded by the Agencia Estatal de Investigación: SEV2014-0425 and CEX2018-000789-S) and MIT-SPAIN "la Caixa” Foundation SEED FUND project “Bioenginering Against Cancer” funded by MISTI Global Seed Funds and “la Caixa” Foundation.

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N.M. conceived the outline of the Review, and wrote and revised the manuscript. E.G. wrote and revised the manuscript. R.D.K. contributed in the section on engineering vascularization and revised the manuscript. S.M.C.S.L. contributed on the section of single-cell transcriptomics and commented on the manuscript. M.A.L. contributed to the section of understanding self-organization and symmetry breaking. R.W. commented on the manuscript. X.T. contributed to the section of probing mechanics in hPSC-organoids. I.H. wrote the section of engineering ethics and commented on the manuscript. N.M. and E.G. created the figures.

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Correspondence to Nuria Montserrat.

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R.D.K. is co-founder and has a substantial financial interest in AIM Biotech, and receives research support from Amgen, Biogen and Gore.

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Garreta, E., Kamm, R.D., Chuva de Sousa Lopes, S.M. et al. Rethinking organoid technology through bioengineering. Nat. Mater. 20, 145–155 (2021). https://doi.org/10.1038/s41563-020-00804-4

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