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

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

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

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).

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

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

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

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

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).

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

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

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).

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

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).

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

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

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). 

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

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

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

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

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

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

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).

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).

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

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

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).

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

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).

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

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

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

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

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).

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

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

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

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

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

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

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

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

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).

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).

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).

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

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).

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

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

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

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

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).

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

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

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).

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

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).

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

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

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

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).

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).

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).

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).

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

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

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

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

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

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

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

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).

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).

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).

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

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).

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

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).

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).

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).

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).

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).

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

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

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

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).

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

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

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).

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).

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

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).

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).

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).

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

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

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).

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

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

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).

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

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).

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

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).

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

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

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

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

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

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

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

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

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

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

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

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

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

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).

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

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

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

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

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

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

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).

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

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).

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).

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

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

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

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).

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

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).

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

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

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

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

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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

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

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

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

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

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).

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

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

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).

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).

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).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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).

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

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

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

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).

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

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).

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).

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

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

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

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).

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

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

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).

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).

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

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

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

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

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

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).

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

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).

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

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

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

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).

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).

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).

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

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

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

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

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).

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).

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

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).

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

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).

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).

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

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).

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

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

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

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

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

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).

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

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

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

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

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

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).

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

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

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).

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

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

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).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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).

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).

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

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

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).

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

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).

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).

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

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

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

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).

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).

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).

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).

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

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).