Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Convergence of microengineering and cellular self-organization towards functional tissue manufacturing

Abstract

Technical progress in materials science and bioprinting has for the past few decades fostered considerable advances in medicine. More recently, the understanding of the processes of self-organization of cells into three-dimensional multicellular structures and the study of organoids have opened new perspectives for tissue engineering. Here, we review microengineering approaches for building functional tissues, and discuss recent progress in the understanding of morphogenetic processes and in the ability to steer them in vitro. On the basis of biological and technical considerations, we emphasize the achievements and remaining challenges of bringing together microengineering and morphogenesis. Our viewpoint underlines the importance of cellular self-organization for the success of tissue engineering in therapeutic applications. We reason that directed self-organization, at the convergence of microengineering and cellular self-organization, is a promising direction for the manufacturing of complex functional tissues.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Organ Donation and Transplantation Activities (Global Observatory on Donation and Transplantation, 2016); http://www.transplant-observatory.org/data-reports-2014.

  2. Murphy, S. V. & Atala, A. Organ engineering — combining stem cells, biomaterials, and bioreactors to produce bioengineered organs for transplantation. BioEssays35, 163–172 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Bajaj, P., Schweller, R. M., Khademhosseini, A., West, J. L. & Bashir, R. 3D biofabrication strategies for tissue engineering and regenerative medicine. Annu. Rev. Biomed. Eng.16, 247–276 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Advancing regenerative medicine. Nat. Med. 20, 795–795 (2014).

  5. Dimmeler, S., Ding, S., Rando, T. A. & Trounson, A. Translational strategies and challenges in regenerative medicine. Nat. Med.20, 814–821 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Gudapati, H., Dey, M. & Ozbolat, I. A. comprehensive review on droplet-based bioprinting: past, present and future. Biomaterials102, 20–42 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Harrison, R. H., St-Pierre, J.-P. & Stevens, M. M. Tissue engineering and regenerative medicine: a year in review. Tissue Eng. Part B Rev.20, 1–16 (2014).

    Article  PubMed  Google Scholar 

  9. Mao, A. S. & Mooney, D. J. Regenerative medicine: current therapies and future directions. Proc. Natl Acad. Sci. USA112, 14452–14459 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tapias, L. F. & Ott, H. C. Decellularized scaffolds as a platform for bioengineered organs. Curr. Opin. Organ Transplant.19, 145–152 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Uygun, B. E. et al. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat. Med.16, 814–20 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Goh, S. K. et al. Perfusion-decellularized pancreas as a natural 3D scaffold for pancreatic tissue and whole organ engineering. Biomaterials34, 6760–6772 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Batchelder, C. A., Martinez, M. L. & Tarantal, A. F. Natural scaffolds for renal differentiation of human embryonic stem cells for kidney tissue engineering. PLoS ONE10, e0143849 (2015).

  14. Petersen, T. H. T. et al. Tissue-engineered lungs for in vivo implantation. Science329, 538–541 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Macchiarini, P. et al. Clinical transplantation of a tissue-engineered airway. Lancet372, 2023–2030 (2008).

    Article  PubMed  Google Scholar 

  16. Nakayama, K. H., Lee, C. C. I., Batchelder, C. A. & Tarantal, A. F. Tissue specificity of decellularized rhesus monkey kidney and lung scaffolds. PLoS ONE8, e64134 (2013). 

  17. Deglincerti, A. et al. Self-organization of the in vitro attached human embryo. Nature533, 251–254 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Bedzhov, I. & Zernicka-Goetz, M. Self-organizing properties of mouse pluripotent cells initiate morphogenesis upon implantation. Cell156, 1032–1044 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shahbazi, M. N. et al. Self-organization of the human embryo in the absence of maternal tissues. Nat. Cell Biol.18, 700–708 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Clevers, H. Modeling development and disease with organoids. Cell165, 1586–1597 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Varner, V. D. & Nelson, C. M. Toward the directed self-assembly of engineered tissues. Annu. Rev. Chem. Biomol. Eng.5, 507–526 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Vignaud, T., Blanchoin, L. & Théry, M. Directed cytoskeleton self-organization. Trends Cell Biol.22, 671–682 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Jackson, E. L. & 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 

  24. Atala, A., Bauer, S. B., Soker, S., Yoo, J. J. & Retik, A. B. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet367, 1241–1246 (2006).

    Article  PubMed  Google Scholar 

  25. Théry, M. Micropatterning as a tool to decipher cell morphogenesis and functions. J. Cell Sci.123, 4201–4213 (2010).

    Article  PubMed  CAS  Google Scholar 

  26. Debnath, J. & Brugge, J. S. Modelling glandular epithelial cancers in three-dimensional cultures. Nat. Rev. Cancer5, 675–688 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Wang, Z. A., Ojakian, K. G. & Nelson, W. J. Steps in the morphogenesis of a polarized epithelium I. Uncoupling the roles of cell–cell and cell–substratum contact in establishing plasma membrane polarity in multicellular epithelial (MDCK) cysts. J. Cell Sci.95, 137–152 (1990).

  28. Dianat, N. et al. Generation of functional cholangiocyte-like cells from human pluripotent stem cells and HepaRG cells. Hepatology60, 700–714 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Gudjonsson, T. et al. Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition. J. Cell Sci.115, 39–50 (2002).

    CAS  PubMed  Google Scholar 

  30. Yu, W. et al. Beta1-integrin orients epithelial polarity via Rac1 and laminin. Mol. Biol. Cell16, 433–445 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yeaman, C., Grindstaff, K. K. & Nelson, W. J. New perspectives on mechanisms involved in generating epithelial cell polarity. Physiol. Rev.79, 73–98 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Burute, M. & Théry, M. Spatial segregation between cell-cell and cell-matrix adhesions. Curr. Opin. Cell Biol.24, 628–636 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Tseng, Q. et al. Spatial organization of the extracellular matrix regulates cell-cell junction positioning. Proc. Natl Acad. Sci. USA109, 1506–1511 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cerchiari, A. E. et al. A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity. Proc. Natl Acad. Sci. USA112, 2287–2292 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Foty, R. A. & Steinberg, M. S. The differential adhesion hypothesis: a direct evaluation. Dev. Biol.278, 255–263 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Pawlizak, S. et al. Testing the differential adhesion hypothesis across the epithelial–mesenchymal transition. New J. Phys.17, 83049 (2015).

    Article  CAS  Google Scholar 

  37. Krieg, M. et al. Tensile forces govern germ-layer organization in zebrafish. Nat. Cell Biol.10, 429–436 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Krens, S. F. G. & Heisenberg, C.-P. Cell sorting in development. Curr. Top. Dev. Biol.95, 189–213 (2011).

    Article  PubMed  Google Scholar 

  39. Maitre, J. L. et al. Adhesion functions in cell sorting by mechanically coupling the cortices of adhering cells. Science338, 253–256 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Urich, E. et al. Multicellular self-assembled spheroidal model of the blood brain barrier. Sci. Rep.3, 1500 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Shi, Q. et al. Rapid disorganization of mechanically interacting systems of mammary acini. Proc. Natl Acad. Sci. USA111, 658–663 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Guo, C.-L. et al. Long-range mechanical force enables self-assembly of epithelial tubular patterns. Proc. Natl Acad. Sci. USA109, 5576–5582 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Montesano, R., Carrozzino, F. & Soulié, P. Low concentrations of transforming growth factor-beta-1 induce tubulogenesis in cultured mammary epithelial cells. BMC Dev. Biol.7, 7 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Wang, S., Sekiguchi, R., Daley, W. P. & Yamada, K. M. Patterned cell and matrix dynamics in branching morphogenesis. J. Cell Biol.216, 559–570 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ewald, A. J., Brenot, A., Duong, M., Chan, B. S. & Werb, Z. Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis. Dev. Cell14, 570–581 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Onodera, T. et al. Btbd7 regulates epithelial cell dynamics and branching morphogenesis. Science329, 562–565 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yu, W. et al. Hepatocyte growth factor switches orientation of polarity and mode of movement during morphogenesis of multicellular epithelial structures. Mol. Biol. Cell14, 748–763 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gerhardt, H. et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J. Cell Biol.161, 1163–1177 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Schnatwinkel, C. & Niswander, L. Multiparametric image analysis of lung-branching morphogenesis. Dev. Dyn.242, 622–637 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Hsu, J. C. et al. Region-specific epithelial cell dynamics during branching morphogenesis. Dev. Dyn.242, 1066–1077 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sakai, T., Larsen, M. & Yamada, K. M. Fibronectin requirement in branching morphogenesis. Nature423, 876–881 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Harunaga, J. S., Doyle, A. D. & Yamada, K. M. Local and global dynamics of the basement membrane during branching morphogenesis require protease activity and actomyosin contractility. Dev. Biol.394, 197–205 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Burute, M. et al. Polarity reversal by centrosome repositioning primes cell scattering during epithelial-to-mesenchymal transition. Dev. Cell40, 168–184 (2017).

    Article  CAS  PubMed  Google Scholar 

  54. Gentile, C. et al. VEGF-mediated fusion in the generation of uniluminal vascular spheroids. Dev. Dyn.237, 2918–2925 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Hapach, L. A., VanderBurgh, J. A., Miller, J. P. & Reinhart-King, C. A. Manipulation of in vitro collagen matrix architecture for scaffolds of improved physiological relevance. Phys. Biol.12, 61002 (2015).

    Article  CAS  Google Scholar 

  56. Duclos, G., Garcia, S., Yevick, H. G. & Silberzan, P. Perfect nematic order in confined monolayers of spindle-shaped cells. Soft Matter10, 2346–2353 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Junkin, M., Leung, S. L., Whitman, S., Gregorio, C. C. & Wong, P. K. Cellular self-organization by autocatalytic alignment feedback. J. Cell Sci.124, 4213–4220 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Duclos, G., Erlenkämper, C., Joanny, J.-F. & Silberzan, P. Topological defects in confined populations of spindle-shaped cells. Nat. Phys.13, 58–62 (2017).

    Article  CAS  Google Scholar 

  59. Saw, T. B. et al. Topological defects in epithelia govern cell death and extrusion. Nature544, 212–216 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Nelson, C. M. et al. Emergent patterns of growth controlled by multicellular form and mechanics. Proc. Natl Acad. Sci. USA102, 11594–11599 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gomez, E. W., Chen, Q. K., Gjorevski, N. & Nelson, C. M. Tissue geometry patterns epithelial–mesenchymal transition via intercellular mechanotransduction. J. Cell. Biochem.110, 44–51 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Nelson, C. M., Vanduijn, M. M., Inman, J. L., Fletcher, D. A. & Bissell, M. J. Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures. Science314, 298–300 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gjorevski, N., Piotrowski, A. S., Varner, V. D. & Nelson, C. M. Dynamic tensile forces drive collective cell migration through three-dimensional extracellular matrices. Sci. Rep.5, 11458 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Hauser, P. V., Nishikawa, M., Kimura, H., Fujii, T. & Yanagawa, N. Controlled tubulogenesis from dispersed ureteric bud-derived cells using a micropatterned gel. J. Tissue Eng. Regen. Med.10, 762–771 (2014).

    Article  PubMed  CAS  Google Scholar 

  65. Wan, L. Q. et al. Micropatterned mammalian cells exhibit phenotype-specific left–right asymmetry. Proc. Natl Acad. Sci. USA108, 12295–12300 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Doxzen, K. et al. Guidance of collective cell migration by substrate geometry. Integr. Biol.5, 1026–1035 (2013).

    Article  CAS  Google Scholar 

  67. Ravasio, A. et al. Gap geometry dictates epithelial closure efficiency. Nat. Commun.6, 7683 (2015).

    Article  PubMed  Google Scholar 

  68. Rausch, S. et al. Polarizing cytoskeletal tension to induce leader cell formation during collective cell migration. Biointerphases8, 32 (2013).

    Article  PubMed  CAS  Google Scholar 

  69. Hakim, V. & Silberzan, P. Collective cell migration: a physics perspective. Rep. Prog. Phys.80, 076601 (2017).

    Article  PubMed  CAS  Google Scholar 

  70. Rolli, C. G. et al. Switchable adhesive substrates: revealing geometry dependence in collective cell behavior. Biomaterials33, 2409–2418 (2011).

    Article  PubMed  CAS  Google Scholar 

  71. Reffay, M. et al. Orientation and polarity in collectively migrating cell structures: statics and dynamics. Biophys. J.100, 2566–2575 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Théry, M. et al. Anisotropy of cell adhesive microenvironment governs cell internal organization and orientation of polarity. Proc. Natl Acad. Sci. USA103, 19771–19776 (2006).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  73. Pitaval, A., Tseng, Q., Bornens, M. & Théry, M. Cell shape and contractility regulate ciliogenesis in cell cycle-arrested cells. J. Cell Biol.191, 303–312 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Engl, W., Arasi, B., Yap, L. L., Thiery, J. P. & Viasnoff, V. Actin dynamics modulate mechanosensitive immobilization of E-cadherin at adherens junctions. Nat. Cell Biol.16, 584–591 (2014).

    Article  CAS  Google Scholar 

  75. Li, Q. et al. Extracellular matrix scaffolding guides lumen elongation by inducing anisotropic intercellular mechanical tension. Nat. Cell Biol.18, 311–318 (2016).

    Article  CAS  PubMed  Google Scholar 

  76. Desai, R. A., Gao, L., Raghavan, S., Liu, W. F. & Chen, C. S. Cell polarity triggered by cell–cell adhesion via E-cadherin. J. Cell Sci.122, 905–911 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Dupin, I., Camand, E. & Etienne-Manneville, S. Classical cadherins control nucleus and centrosome position and cell polarity. J. Cell Biol.185, 779–786 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Rodriguez-Fraticelli, A. E., Auzan, M., Alonso, M. A., Bornens, M. & Martin-Belmonte, F. Cell confinement controls centrosome positioning and lumen initiation during epithelial morphogenesis. J. Cell Biol.198, 1011–1023 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Deforet, M., Hakim, V., Yevick, H. G., Duclos, G. & Silberzan, P. Emergence of collective modes and tri-dimensional structures from epithelial confinement. Nat. Commun.5, 3747 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Lei, Y., Zouani, O. F., Rémy, M., Ayela, C. & Durrieu, M. C. Geometrical microfeature cues for directing tubulogenesis of endothelial cells. PLoS ONE7, e41163 (2012).

  81. Dike, L. E. et al. Geometric control of switching between growth, apoptosis, and differentiation during angiogenesis using micropatterned substrates. In Vitro Cell. Dev. Biol. Anim. 35, 2690–2699 (1999).

    Article  CAS  Google Scholar 

  82. Moon, J. J., Hahn, M. S., Kim, I., Nsiah, B. A. & West, J. L. Micropatterning of poly(ethylene glycol) diacrylate hydrogels with biomolecules to regulate and guide endothelial morphogenesis. Tissue Eng. Part A15, 579–585 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Mao, Y. & Green, J. B. A. Systems morphodynamics: understanding the development of tissue hardware. Phil. Trans. R. Soc. Lond. Ser. B372, 20160505 (2017).

    Article  Google Scholar 

  84. Simunovic, M. & Brivanlou, A. H. Embryoids, organoids and gastruloids: new approaches to understanding embryogenesis. Development144, 976–985 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bartfeld, S. & Clevers, H. Stem cell-derived organoids and their application for medical research and patient treatment. J. Mol. Med.95, 729–738 (2017).

    Article  CAS  PubMed  Google Scholar 

  86. Koo, B. & Huch, M. Organoids: a new in vitro model system for biomedical science and disease modelling and promising source for cell-based transplantation. Dev. Biol.420, 197 (2016).

    Article  CAS  Google Scholar 

  87. Keller, G. M. In vitro differentiation of embryonic stem cells. Curr. Opin. Cell Biol.7, 862–869 (1995).

    Article  CAS  PubMed  Google Scholar 

  88. Kurosawa, H. Methods for inducing embryoid body formation: in vitro differentiation system of embryonic stem cells. J. Biosci. Bioeng.103, 389–398 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Martin, G. R., Wiley, L. M. & Damjanov, I. The development of cystic embryoid bodies in vitro from clonal teratocarcinoma stem cells. Dev. Biol.61, 230–244 (1977).

    Article  CAS  PubMed  Google Scholar 

  90. Wiley, L. M., Spindle, A. I. & Pedersen, R. A. Morphology of isolated mouse inner cell masses developing in vitro. Dev. Biol.63, 1–10 (1978).

    Article  CAS  PubMed  Google Scholar 

  91. ten Berge, D. et al. Wnt signaling mediates self-organization and axis formation in embryoid bodies. Cell Stem Cell3, 508–518 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. van den Brink, S. C. et al. Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells. Development141, 4231–4242 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Marikawa, Y., Tamashiro, D. A. A., Fujita, T. C. & Alarcón, V. B. Aggregated P19 mouse embryonal carcinoma cells as a simple in vitro model to study the molecular regulations of mesoderm formation and axial elongation morphogenesis. Genesis47, 93–106 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Turner, D. A. et al. Gastruloids develop the three body axes in the absence of extraembryonic tissues and spatially localised signalling. Preprint at bioRxiv https://doi.org/10.1101/104539 (2017).

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

    Article  Google Scholar 

  96. Ranga, A. et al. Neural tube morphogenesis in synthetic 3D microenvironments. Proc. Natl Acad. Sci. USA113, E6831–E6839 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Harrison, S. E., Sozen, B., Christodoulou, N., Kyprianou, C. & Zernicka-Goetz, M. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro. Science356, eaal1810 (2017).

    Article  PubMed  CAS  Google Scholar 

  98. Poh, Y.-C. et al. Generation of organized germ layers from a single mouse embryonic stem cell. Nat. Commun.5, 4000 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Sato, T. et al. Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche. Nature459, 262–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Barker, N. et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell6, 25–36 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature469, 415–418 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Lee, J.-H. et al. Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell156, 440–455 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Eiraku, M. et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature472, 51–56 (2011).

    Article  CAS  PubMed  Google Scholar 

  104. Takasato, M. et al. Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney. Nat. Cell Biol.16, 118–126 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. Ueda, T. et al. Generation of functional gut-like organ from mouse induced pluripotent stem cells. Biochem. Biophys. Res. Commun.391, 38–42 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Suga, H. et al. Self-formation of functional adenohypophysis in three-dimensional culture. Nature480, 57–62 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. McCracken, K. W. et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature516, 400–404 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Noguchi, T. K. et al. Generation of stomach tissue from mouse embryonic stem cells. Nat. Cell Biol.17, 984–993 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature501, 373–379 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Takasato, M. et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature526, 564–568 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. Ikeda, E. et al. Fully functional bioengineered tooth replacement as an organ replacement therapy. Proc. Natl Acad. Sci. USA106, 13475–13480 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Nakao, K. et al. The development of a bioengineered organ germ method. Nat. Methods4, 227–230 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Toyoshima, K. et al. Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. Nat. Commun.3, 784 (2012).

    Article  PubMed  CAS  Google Scholar 

  114. Young, C. S. et al. Tissue engineering of complex tooth structures on biodegradable polymer scaffolds. J. Dent. Res.81, 695–700 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Vacanti, J. P., Yelick, P. C. & Cells, B. Bioengineered teeth from and seeding of rat tooth. J. Dent. Res. 83, 523–528 (2004).

  116. Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature499, 481–484 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Takebe, T. et al. Vascularized and complex organ buds from diverse tissues via mesenchymal cell-driven condensation. Cell Stem Cell16, 556–565 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. Traktuev, D. O. et al. Robust functional vascular network formation in vivo by cooperation of adipose progenitor and endothelial cells. Circ. Res.104, 1410–1420 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Kelava, I. & Lancaster, M. A. Dishing out mini-brains: current progress and future prospects in brain organoid research. Dev. Biol.420, 199–209 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dahl-Jensen, S. & Grapin-Botton, A. The physics of organoids: a biophysical approach to understanding organogenesis. Development144, 946–951 (2017).

    Article  CAS  PubMed  Google Scholar 

  121. Levchenko, A. & Nemenman, I. Cellular noise and information transmission. Curr. Opin. Biotechnol.28, 156–164 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Watt, F. M., Jordant, P. W. & Neillt, C. H. O. Cell shape controls terminal differentiation of human epidermal keratinocytes. Cell85, 5576–5580 (1988).

    CAS  Google Scholar 

  123. Wang, Y. et al. A microengineered collagen scaffold for generating a polarized crypt–villus architecture of human small intestinal epithelium. Biomaterials128, 44–55 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Nazareth, E. J. P. et al. High-throughput fingerprinting of human pluripotent stem cell fate responses and lineage bias. Nat. Methods10, 1225–1231 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 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. Methods11, 847–854 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Peerani, R. et al. Niche-mediated control of human embryonic stem cell self-renewal and differentiation. EMBO J.26, 4744–4755 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Peerani, R., Onishi, K., Mahdavi, A., Kumacheva, E. & Zandstra, P. W. Manipulation of signaling thresholds in ‘engineered stem cell niches’ identifies design criteria for pluripotent stem cell screens. PLoS ONE4, e6438 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Miyamoto, D., Ohno, K., Hara, T., Koga, H. & Nakazawa, K. Effect of separation distance on the growth and differentiation of mouse embryoid bodies in micropatterned cultures. J. Biosci. Bioeng.121, 105–110 (2016).

    Article  CAS  PubMed  Google Scholar 

  129. Bauwens, C. L. et al. Control of human embryonic stem cell colony and aggregate size heterogeneity influences differentiation trajectories. Stem Cells26, 2300–2310 (2008).

    Article  PubMed  Google Scholar 

  130. Bauwens, C. L. et al. Geometric control of cardiomyogenic induction in human pluripotent stem cells. Tissue Eng.17, 1901–1909 (2011).

    Article  CAS  Google Scholar 

  131. Etoc, F. et al. A balance between secreted inhibitors and edge sensing controls gastruloid self-organization. Dev. Cell39, 302–315 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Tewary, M., Ostblom, J. E., Shakiba, N. & Zandstra, P. W. A defined platform of human peri-gastrulation-like biological fate patterning reveals coordination between reaction-diffusion and positional-information. Preprint at bioRxiv https://doi.org/10.1101/102376 (2017).

  133. Tam, P. P. & Behringer, R. R. Mouse gastrulation: the formation of a mammalian body plan. Mech. Dev.68, 3–25 (1997).

    Article  CAS  PubMed  Google Scholar 

  134. Blin, G., Picart, C., Thery, M. & Puceat, M. Geometrical confinement guides Brachyury self-patterning in embryonic stem cells. Preprint at bioRxiv https://doi.org/10.1101/138354 (2017).

  135. Hiramatsu, R. et al. External mechanical cues trigger the establishment of the anterior–posterior axis in early mouse embryos. Dev. Cell27, 131–144 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  137. Ruiz, S. A. & Chen, C. S. Emergence of patterned stem cell differentiation within multicellular structures. Stem Cells26, 2921–2927 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Wang, W. et al. 3D spheroid culture system on micropatterned substrates for improved differentiation efficiency of multipotent mesenchymal stem cells. Biomaterials30, 2705–2715 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. McBeath, R., Pirone, D. M., Nelson, C. M., Bhadriraju, K. & Chen, C. S. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell6, 483–495 (2004).

    Article  CAS  PubMed  Google Scholar 

  140. Itskovitz-Eldor, J. et al. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol. Med.6, 88–95 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ungrin, M. D., Joshi, C., Nica, A., Bauwens, C. & Zandstra, P. W. Reproducible, ultra high-throughput formation of multicellular organization from single cell suspension-derived human embryonic stem cell aggregates. PLoS ONE3, e1565 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Bratt-leal, M., Carpenedo, R. L. & Mcdevitt, T. C. Engineering the embryoid body microenvironment to direct embryonic stem cell differentiation. Biotechnol. Prog.25, 43–51 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Sakai, Y., Yoshiura, Y. & Nakazawa, K. Embryoid body culture of mouse embryonic stem cells using microwell and micropatterned chips. J. Biosci. Bioeng.111, 85–91 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Guild, J. et al. Embryonic stem cells cultured in microfluidic chambers take control of their fate by producing endogenous signals including LIF. Stem Cells34, 1501–1512 (2016).

    Article  CAS  PubMed  Google Scholar 

  145. Nakazawa, K., Yoshiura, Y., Koga, H. & Sakai, Y. Characterization of mouse embryoid bodies cultured on microwell chips with different well sizes. J. Biosci. Bioeng.116, 628–633 (2013).

    Article  CAS  PubMed  Google Scholar 

  146. Schukur, L., Zorlutuna, P., Cha, J. M., Bae, H. & Khademhosseini, A. Directed differentiation of size-controlled embryoid bodies towards endothelial and cardiac lineages in RGD-modified poly(ethylene glycol) hydrogels. Adv. Healthc. Mater.2, 195–205 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Lancaster, M. A., Corsini, N. S., Burkard, T. R. & Knoblich, J. A. Guided self-organization recapitulates tissue architecture in a bioengineered brain organoid model. Preprint at bioRxiv https://doi.org/10.1101/049346 (2016).

  148. Alessandri, K. et al. A 3D printed microfluidic device for production of functionalized hydrogel microcapsules for culture and differentiation of human neuronal stem cells (hNSC). Lab Chip16, 1593–1604 (2016).

    Article  CAS  PubMed  Google Scholar 

  149. Greggio, C. et al. Artificial three-dimensional niches deconstruct pancreas development in vitro. Development140, 4452–4462 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Finkbeiner, S. R. et al. Generation of tissue-engineered small intestine using embryonic stem cell-derived human intestinal organoids. Biol. Open4, 1462–1472 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Costello, C. M. et al. Synthetic small intestinal scaffolds for improved studies of intestinal differentiation. Biotechnol. Bioeng.111, 1222–1232 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Gjorevski, N. et al. Designer matrices for intestinal stem cell and organoid culture. Nature539, 560–564 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. McGuigan, A. P. & Sefton, M. V. Vascularized organoid engineered by modular assembly enables blood perfusion. Proc. Natl Acad. Sci. USA103, 11461–11466 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Khan, O. F., Chamberlain, M. D. & Sefton, M. V. Vasculature: differentiation of mesenchymal stromal cells within an endothelial cell-seeded modular construct in a microfluidic flow chamber. Tissue Eng. Part A18, 744–756 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Mironov, V. et al. Organ printing: tissue spheroids as building blocks. Biomaterials30, 2164–2174 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Haraguchi, Y. et al. Fabrication of functional three-dimensional tissues by stacking cell sheets in vitro. Nat. Protoc.7, 850–858 (2012).

    Article  CAS  PubMed  Google Scholar 

  157. Wilson, W. C. & Boland, T. Cell and organ printing 1: protein and cell printers. Anat. Rec. A Discov. Mol. Cell. Evol. Biol.272, 491–496 (2003).

    Article  PubMed  Google Scholar 

  158. Xu, C., Chai, W., Huang, Y. & Markwald, R. R. Scaffold-free inkjet printing of three-dimensional zigzag cellular tubes. Biotechnol. Bioeng.109, 3152–3160 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. Nishiyama, Y. et al. Development of a three-dimensional bioprinter: construction of cell supporting structures using hydrogel and state-of-the-art inkjet technology. J. Biomech. Eng.131, 35001 (2009).

    Article  Google Scholar 

  160. Pedde, R. D. et al. Emerging biofabrication strategies for engineering complex tissue constructs. Adv. Mater.29, 1–27 (2017).

    Article  CAS  Google Scholar 

  161. Xu, T. et al. Complex heterogeneous tissue constructs containing multiple cell types prepared by inkjet printing technology. Biomaterials34, 130–139 (2013).

    Article  PubMed  CAS  Google Scholar 

  162. Tan, Y. et al. 3D printing facilitated scaffold-free tissue unit fabrication. Biofabrication6, 24111 (2014).

    Article  CAS  Google Scholar 

  163. Xu, T., Jin, J., Gregory, C., Hickman, J. J. & Boland, T. Inkjet printing of viable mammalian cells. Biomaterials26, 93–99 (2005).

    Article  PubMed  CAS  Google Scholar 

  164. Xu, C. et al. Study of droplet formation process during drop-on-demand inkjetting of living cell-laden bioink. Langmuir30, 9130–9138 (2014).

    Article  CAS  PubMed  Google Scholar 

  165. Saunders, R. E., Gough, J. E. & Derby, B. Delivery of human fibroblast cells by piezoelectric drop-on-demand inkjet printing. Biomaterials29, 193–203 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Nakamura, M. et al. Biocompatible Inkjet printing technique for designed seeding of individual living cells. Tissue Eng.11, 1658–1666 (2005).

    Article  CAS  PubMed  Google Scholar 

  167. Demirci, U. & Montesano, G. Single cell epitaxy by acoustic picolitre droplets. Lab Chip7, 1139–1145 (2007).

    Article  CAS  PubMed  Google Scholar 

  168. Ringeisen, B. R. et al. Laser printing of pluripotent embryonal carcinoma cells. Tissue Eng.10, 483–491 (2004).

    Article  CAS  PubMed  Google Scholar 

  169. Norotte, C., Marga, F. S., Niklason, L. E. & Forgacs, G. Scaffold-free vascular tissue engineering using bioprinting. Biomaterials30, 5910–5917 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Neagu, A., Jakab, K., Jamison, R. & Forgacs, G. Role of physical mechanisms in biological self-organization. Phys. Rev. Lett.95, 1–4 (2005).

    Article  CAS  Google Scholar 

  171. Yang, X., Mironov, V. & Wang, Q. Modeling fusion of cellular aggregates in biofabrication using phase field theories. J. Theor. Biol.303, 110–118 (2012).

    Article  PubMed  Google Scholar 

  172. Fleming, P. A. et al. Fusion of uniluminal vascular spheroids: a model for assembly of blood vessels. Dev. Dyn.239, 398–406 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Jang, J. et al. 3D printed complex tissue construct using stem cell-laden decellularized extracellular matrix bioinks for cardiac repair. Biomaterials112, 264–274 (2017).

    Article  CAS  PubMed  Google Scholar 

  174. Okano, T., Yamada, N., Sakai, H. & Sakurai, Y. A novel recovery system for cultured cells using plasma-treated polystyrene dishes grafted with poly(N-isopropylacrylamide). J. Biomed. Mater. Res.27, 1243–1251 (1993).

    Article  CAS  PubMed  Google Scholar 

  175. Tsuda, Y. et al. The use of patterned dual thermoresponsive surfaces for the collective recovery as co-cultured cell sheets. Biomaterials26, 1885–1893 (2005).

    Article  CAS  PubMed  Google Scholar 

  176. Miyahara, Y. et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat. Med.12, 459–465 (2006).

    Article  CAS  PubMed  Google Scholar 

  177. Tsuda, Y. et al. Cellular control of tissue architectures using a three-dimensional tissue fabrication technique. Biomaterials28, 4939–4946 (2007).

    Article  CAS  PubMed  Google Scholar 

  178. Kikuchi, T., Shimizu, T., Wada, M., Yamato, M. & Okano, T. Automatic fabrication of 3-dimensional tissues using cell sheet manipulator technique. Biomaterials35, 2428–2435 (2014).

    Article  CAS  PubMed  Google Scholar 

  179. Elloumi Hannachi, I. et al. Fabrication of transferable micropatterned-co-cultured cell sheets with microcontact printing. Biomaterials30, 5427–5432 (2009).

    Article  PubMed  CAS  Google Scholar 

  180. Takahashi, H., Nakayama, M., Shimizu, T., Yamato, M. & Okano, T. Anisotropic cell sheets for constructing three-dimensional tissue with well-organized cell orientation. Biomaterials32, 8830–8838 (2011).

    Article  CAS  PubMed  Google Scholar 

  181. Isenberg, B. C. et al. Micropatterned cell sheets with defined cell and extracellular matrix orientation exhibit anisotropic mechanical properties. J. Biomech.45, 756–761 (2012).

    Article  PubMed  Google Scholar 

  182. Lim, J. et al. Fabrication of cell sheets with anisotropically aligned myotubes using thermally expandable micropatterned hydrogels. Macromol. Res.24, 562–572 (2016).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  184. Hannachi, I. E., Yamato, M. & Okano, T. Cell sheet technology and cell patterning for biofabrication. Biofabrication1, 22002 (2009).

    Article  CAS  Google Scholar 

  185. L’Heureux, N., Pâquet, S., Labbé, R., Germain, L. & Auger, F. A. A completely biological tissue-engineered human blood vessel. FASEB J.12, 47–56 (1998).

    Article  PubMed  Google Scholar 

  186. McAllister, T. N. et al. Effectiveness of haemodialysis access with an autologous tissue-engineered vascular graft: a multicentre cohort study. Lancet373, 1440–1446 (2009).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  188. Kloxin, A. M., Kasko, A. M., Salinas, C. N. & Anseth, K. S. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science324, 59–63 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Itoga, K., Yamato, M., Kobayashi, J., Kikuchi, A. & Okano, T. Cell micropatterning using photopolymerization with a liquid crystal device commercial projector. Biomaterials25, 2047–2053 (2004).

    Article  CAS  PubMed  Google Scholar 

  190. Gauvin, R. et al. Microfabrication of complex porous tissue engineering scaffolds using 3D projection stereolithography. Biomaterials33, 3824–3834 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Lin, H. et al. Application of visible light-based projection stereolithography for live cell-scaffold fabrication with designed architecture. Biomaterials34, 331–339 (2013).

    Article  CAS  PubMed  Google Scholar 

  192. Ma, X. et al. Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting. Proc. Natl Acad. Sci. USA113, 2206–2211 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Zhu, W. et al. Direct 3D bioprinting of prevascularized tissue constructs with complex microarchitecture. Biomaterials124, 106–115 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Vishwakarma, A. et al. Engineering immunomodulatory biomaterials to tune the inflammatory response. Trends Biotechnol.34, 470–482 (2016).

    Article  CAS  PubMed  Google Scholar 

  195. Wiles, K. L., Fishman, J. M., De Coppi, P. & Birchall, M. The host immune response to tissue-engineered organs: current problems and future directions. Tissue Eng. Part B Rev.44, 1–43 (2015).

    Google Scholar 

  196. Yin, X. et al. Engineering stem cell organoids. Cell Stem Cell18, 25–38 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Murrow, L. M., Weber, R. J. & Gartner, Z. J. Dissecting the stem cell niche with organoid models: an engineering-based approach. Development144, 998–1007 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Gjorevski, N., Ranga, A. & Lutolf, M. P. Bioengineering approaches to guide stem cell-based organogenesis. Development141, 1794–1804 (2014).

    Article  CAS  PubMed  Google Scholar 

  199. Schneeberger, K. et al. Converging biofabrication and organoid technologies: the next frontier in hepatic and intestinal tissue engineering? Biofabrication9, 13001 (2017).

    Article  CAS  Google Scholar 

  200. Bhatia, S. N. & Ingber, D. E. Microfluidic organs-on-chips. Nat. Biotechnol.32, 760–772 (2014).

    Article  CAS  PubMed  Google Scholar 

  201. Skardal, A., Shupe, T. & Atala, A. Organoid-on-a-chip and body-on-a-chip systems for drug screening and disease modeling. Drug Discov. Today21, 1399–1411 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Marti-Figueroa, C. R. & Ashton, R. S. The case for applying tissue engineering methodologies to instruct human organoid morphogenesis. Acta Biomater.54, 35–44 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Matthys, O. B., Hookway, T. A. & McDevitt, T. C. Design principles for engineering of tissues from human pluripotent stem cells. Curr. Stem Cell Rep.2, 43–51 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Sasai, Y. Cytosystems dynamics in self-organization of tissue architecture. Nature493, 318–326 (2013).

    Article  CAS  PubMed  Google Scholar 

  206. Davies, J. Using synthetic biology to explore principles of development. Development144, 1146–1158 (2017).

    Article  CAS  PubMed  Google Scholar 

  207. Dekkers, J. F. et al. WS14.5 A functional CFTR assay using primary cystic fibrosis intestinal organoids. J. Cyst. Fibros.11, S32 (2012).

    Article  Google Scholar 

  208. Schwank, G. et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell13, 653–658 (2013).

    Article  CAS  PubMed  Google Scholar 

  209. Yui, S. et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med.18, 618–623 (2012).

    Article  CAS  PubMed  Google Scholar 

  210. Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology141, 1762–1772 (2011).

    Article  CAS  PubMed  Google Scholar 

  211. Freeman, S. A. et al. Applied stretch initiates directional invasion through the action of Rap1 GTPase as a tension sensor. J. Cell Sci.130, 152–163 (2017).

    Article  CAS  PubMed  Google Scholar 

  212. Spence, J. R. et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature470, 105–109 (2011).

    Article  PubMed  CAS  Google Scholar 

  213. Saito, H., Takeuchi, M., Chida, K. & Miyajima, A. Generation of glucose-responsive functional islets with a three-dimensional structure from mouse fetal pancreatic cells and iPS cells in vitro. PLoS ONE6, e28209 (2011).

  214. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Karthaus, W. R. et al. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell159, 163–175 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Eiraku, M. et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell3, 519–532 (2008).

    Article  CAS  PubMed  Google Scholar 

  217. Mariani, J. et al. Modeling human cortical development in vitro using induced pluripotent stem cells. Proc. Natl Acad. Sci. USA109, 12770–12775 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Paşca, A. M. et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat. Methods12, 671–678 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Soto-Gutierrez, A. et al. A whole-organ regenerative medicine approach for liver replacement. Tissue Eng. Part C Methods17, 677–686 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Ruprecht, V. et al. How cells respond to environmental cues — insights from bio-functionalized substrates. J. Cell Sci.130, 51–61 (2016).

    Article  PubMed  CAS  Google Scholar 

  221. Théry, M. & Piel, M. Adhesive micropatterns for cells: a microcontact printing protocol. Cold Spring Harb. Protoc.2009, pdb.prot5255 (2009).

    Article  PubMed  Google Scholar 

  222. Azioune, A., Carpi, N., Tseng, Q., Théry, M. & Piel, M. Protein micropatterns: a direct printing protocol using deep UVs. Methods Cell Biol.97, 133–146 (2010).

    Article  CAS  PubMed  Google Scholar 

  223. Strale, P. O. et al. Multiprotein printing by light-induced molecular adsorption. Adv. Mater.28, 2024–2029 (2016).

    Article  CAS  PubMed  Google Scholar 

  224. Mazzaferri, J. & Costantino, S. Laser-assisted adsorption by photobleaching. Methods Cell Biol.119, 125–140 (2014).

    Article  PubMed  CAS  Google Scholar 

  225. Yamahira, S. et al. Dynamic photochemical lipid micropatterning for manipulation of nonadherent mammalian cells. Methods Cell Biol. 120, 131–44 (2014).

  226. Piel, M. & Théry, M. (eds) Micropatterning in Cell Biology, Part A (Elsevier Science, CA, USA, 2014).

  227. Choi, Y. Y. et al. Controlled-size embryoid body formation in concave microwell arrays. Biomaterials31, 4296–4303 (2010).

    Article  CAS  PubMed  Google Scholar 

  228. Baranski, J. D. et al. Geometric control of vascular networks to enhance engineered tissue integration and function. Proc. Natl Acad. Sci. USA110, 7586–7591 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Dupin, I., Dahan, M. & Studer, V. Investigating axonal guidance with microdevice-based approaches. J. Neurosci.33, 17647–17655 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Cambier, T. et al. Design of a 2D no-flow chamber to monitor hematopoietic stem cells. Lab Chip15, 77–85 (2014).

    Article  Google Scholar 

  231. Tan, Y. C., Hettiarachchi, K., Siu, M., Pan, Y. R. & Lee, A. P. Controlled microfluidic encapsulation of cells, proteins, and microbeads in lipid vesicles. J. Am. Chem. Soc.128, 5656–5658 (2006).

    Article  CAS  PubMed  Google Scholar 

  232. Doméjean, H. et al. Controlled production of sub-millimeter liquid core hydrogel capsules for parallelized 3D cell culture. Lab Chip17, 110–119 (2017).

    Article  CAS  Google Scholar 

  233. Di Carlo, D., Wu, L. Y. & Lee, L. P. Dynamic single cell culture array. Lab Chip6, 1445–1449 (2006).

    Article  PubMed  CAS  Google Scholar 

  234. Schepers, A., Li, C., Chhabra, A., Seney, B. T. & Bhatia, S. N. Engineering a perfusable 3D human liver platform from iPS cells. Lab Chip16, 2644–2653 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Ali, S., Cuchiara, M. L. & West, J. L. Micropatterning of poly(ethylene glycol) diacrylate hydrogels. Methods Cell Biol. 121, 105–119 (2014).

  236. Brandenberg, N. & Lutolf, M. P. In situ patterning of microfluidic networks in 3D cell-laden hydrogels. Adv. Mater.28, 7450–7456 (2016).

    Article  CAS  PubMed  Google Scholar 

  237. Verhulsel, M. et al. A review of microfabrication and hydrogel engineering for micro-organs on chips. Biomaterials35, 1816–1832 (2014).

    Article  CAS  PubMed  Google Scholar 

  238. Zhu, J. & Marchant, R. E. Design properties of hydrogel tissue-engineering scaffolds. Expert Rev. Med. Devices8, 607–626 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  239. Ranga, A. et al. 3D niche microarrays for systems-level analyses of cell fate. Nat. Commun. 5, 4324 (2014).

  240. Hasan, A. et al. Microfluidic techniques for development of 3D vascularized tissue. Biomaterials35, 7308–7325 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Rouwkema, J. & Khademhosseini, A. Vascularization and angiogenesis in tissue engineering: beyond creating static networks. Trends Biotechnol.34, 733–745 (2016).

    Article  CAS  PubMed  Google Scholar 

  242. Takei, T., Sakai, S. & Yoshida, M. In vitro formation of vascular-like networks using hydrogels. J. Biosci. Bioeng.122, 519–527 (2016).

    Article  CAS  PubMed  Google Scholar 

  243. Smith, Q. & Gerecht, S. Going with the flow: microfluidic platforms in vascular tissue engineering. Curr. Opin. Chem. Eng.3, 42–50 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  244. Bersini, S. et al. Cell–microenvironment interactions and architectures in microvascular systems. Biotechnol. Adv.34, 1113–1130 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Rayner, S. G. & Zheng, Y. Engineered microvessels for the study of human disease. J. Biomech. Eng.138, 110801 (2016).

    Article  Google Scholar 

  246. Sudo, R., Chung, S., Shin, Y. & Tanishita, K. in Vascular Engineering 297–332 (Springer, Tokyo, 2016).

  247. Folkmann, J. & Haudenschild, C. Angiogenesis in vitro. Nature288, 551–556 (1980).

    Article  Google Scholar 

  248. Egginton, S. & Gerritsen, M. Lumen formation: in vivo versus in vitro observations. Microcirculation10, 45–61 (2003).

    PubMed  Google Scholar 

  249. Wu, P. K. & Ringeisen, B. R. Development of human umbilical vein endothelial cell (HUVEC) and human umbilical vein smooth muscle cell (HUVSMC) branch/stem structures on hydrogel layers via biological laser printing (BioLP). Biofabrication2, 14111 (2010).

    Article  CAS  Google Scholar 

  250. Unger, R. E. et al. Tissue-like self-assembly in cocultures of endothelial cells and osteoblasts and the formation of microcapillary-like structures on three-dimensional porous biomaterials. Biomaterials28, 3965–3976 (2007).

    Article  CAS  PubMed  Google Scholar 

  251. Dickinson, L. E., Moura, M. E. & Gerecht, S. Guiding endothelial progenitor cell tube formation using patterned fibronectin surfaces. Soft Matter6, 5109–5119 (2010).

    Article  CAS  Google Scholar 

  252. Kobayashi, A. et al. In vitro formation of capillary networks using optical lithographic techniques. Biochem. Biophys. Res. Commun.358, 692–697 (2007).

    Article  CAS  PubMed  Google Scholar 

  253. Ehrbar, M. et al. The role of actively released fibrin-conjugated VEGF for VEGF receptor 2 gene activation and the enhancement of angiogenesis. Biomaterials29, 1720–1729 (2008).

    Article  CAS  PubMed  Google Scholar 

  254. Levenberg, S. et al. Engineering vascularized skeletal muscle tissue. Nat. Biotechnol.23, 879–884 (2005).

    Article  CAS  PubMed  Google Scholar 

  255. Rochon, M.-H. et al. Normal human epithelial cells regulate the size and morphology of tissue-engineered capillaries. Tissue Eng. Part A16, 1457–1468 (2010).

    Article  CAS  PubMed  Google Scholar 

  256. Fuchs, S., Hofmann, A. & Kirkpatrick, C. J. Microvessel-like structures from outgrowth endothelial cells from human peripheral blood in 2-dimensional and 3-dimensional co-cultures with osteoblastic lineage cells. Tissue Eng.13, 2577–2588 (2007).

    Article  CAS  PubMed  Google Scholar 

  257. Miller, J. S. et al. Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Nat. Mater.11, 768–774 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Chaturvedi, R. R. et al. Patterning vascular networks in vivo for tissue engineering applications. Tissue Eng. Part C Methods5, 509–517 (2015).

    Article  CAS  Google Scholar 

  259. Kim, S., Lee, H., Chung, M. & Jeon, N. L. Engineering of functional, perfusable 3D microvascular networks on a chip. Lab Chip13, 1489–1500 (2013).

    Article  CAS  PubMed  Google Scholar 

  260. Wang, X., Phan, D. T. T., George, S. C., Hughes, C. C. W. & Lee, A. P. Engineering anastomosis between living capillary networks and endothelial cell-lined microfluidic channels. Lab Chip16, 282–290 (2015).

    Article  CAS  Google Scholar 

  261. Kinoshita, K., Iwase, M., Yamada, M., Yajima, Y. & Seki, M. Fabrication of multilayered vascular tissues using microfluidic agarose hydrogel platforms. Biotechnol. J.11, 1415–1423 (2016).

    Article  CAS  PubMed  Google Scholar 

  262. 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  PubMed  PubMed Central  CAS  Google Scholar 

  263. Hayashi, K. et al. A neo-esophagus reconstructed by cultured human esophageal epithelial cells, smooth muscle cells, fibroblasts, and collagen. ASAIO J. 50, 261–266 (2004).

    Article  CAS  PubMed  Google Scholar 

  264. Poghosyan, T. et al. Circumferential esophageal replacement using a tube-shaped tissue-engineered substitute: an experimental study in minipigs. Surgery158, 266–277 (2015).

    Article  PubMed  Google Scholar 

  265. Poghosyan, T. et al. In vitro development and characterization of a tissue-engineered conduit resembling esophageal wall using human and pig skeletal myoblast, oral epithelial cells, and biologic scaffolds. Tissue Eng. Part A19, 2242–2252 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge research grants from the French National Research Agency (ANR program ANR-10-IBHU-0002 and ANR-14-CE11-0012-01; RHU program ANR-16-RHUS-0005), from the programme ‘Coup d’élan’ of the Bettencourt Schueller Fondation, from the Fondation Schlumberger pour l’Education et la Recherche and from the Emergence programme of the City of Paris.

Author information

Authors and Affiliations

Authors

Contributions

All authors discussed and wrote the manuscript. J.L. and M.T. drew the figures.

Corresponding authors

Correspondence to Alexandra Fuchs, Jérôme Larghero or Manuel Théry.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Laurent, J., Blin, G., Chatelain, F. et al. Convergence of microengineering and cellular self-organization towards functional tissue manufacturing. Nat Biomed Eng 1, 939–956 (2017). https://doi.org/10.1038/s41551-017-0166-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-017-0166-x

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing