Engineered materials for organoid systems

Abstract

Organoids are 3D cell culture systems that mimic some of the structural and functional characteristics of an organ. Organoid cultures provide the opportunity to study organ-level biology in models that mimic human physiology more closely than 2D cell culture systems or non-primate animal models. Many organoid cultures rely on decellularized extracellular matrices as scaffolds, which are often poorly chemically defined and allow only limited tunability and reproducibility. By contrast, the biochemical and biophysical properties of engineered matrices can be tuned and optimized to support the development and maturation of organoid cultures. In this Review, we highlight how key cell–matrix interactions guiding stem-cell decisions can inform the design of biomaterials for the reproducible generation and control of organoid cultures. We survey natural, synthetic and protein-engineered hydrogels for their applicability to different organoid systems and discuss biochemical and mechanical material properties relevant for organoid formation. Finally, dynamic and cell-responsive material systems are investigated for their future use in organoid research.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2: Organoid cell sources and types.
Fig. 3: Cell–matrix interactions.
Fig. 4: Dynamic organoid niches.

References

  1. 1.

    Harrison, R. G., Greenman, M. J., Mall, F. P. & Jackson, C. M. Observations of the living developing nerve fiber. Anat. Rec. 1, 116–128 (1907).

    Google Scholar 

  2. 2.

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

    CAS  Google Scholar 

  3. 3.

    Ishii, K. Reconstruction of dissociated chick brain cells in rotation-mediated culture. Cytologia (Tokyo) 31, 89–98 (1966).

    CAS  Google Scholar 

  4. 4.

    Edington, C. D. et al. Interconnected microphysiological systems for quantitative biology and pharmacology studies. Sci. Rep. 8, 4530 (2018).

    Google Scholar 

  5. 5.

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

    CAS  Google Scholar 

  6. 6.

    Stelzner, M. et al. A nomenclature for intestinal in vitro cultures. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1359–G1363 (2012).

    CAS  Google Scholar 

  7. 7.

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

    CAS  Google Scholar 

  8. 8.

    HogenEsch, H. & Nikitin, A. Y. Challenges in pre-clinical testing of anti-cancer drugs in cell culture and in animal models. J. Control. Release 164, 183–186 (2012).

    CAS  Google Scholar 

  9. 9.

    Horrobin, D. F. Modern biomedical research: an internally self-consistent universe with little contact with medical reality? Nat. Rev. Drug Discov. 2, 151–154 (2003).

    CAS  Google Scholar 

  10. 10.

    Pasca, S. P. Assembling human brain organoids. Science 363, 126–127 (2019).

    CAS  Google Scholar 

  11. 11.

    Mak, I. W., Evaniew, N. & Ghert, M. Lost in translation: animal models and clinical trials in cancer treatment. Am. J. Transl. Res. 6, 114–118 (2014).

    Google Scholar 

  12. 12.

    Pound, P. & Ritskes-Hoitinga, M. Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail. J. Transl. Med. 16, 304 (2018).

    Google Scholar 

  13. 13.

    Co, J. Y. et al. Controlling epithelial polarity: a human enteroid model for host-pathogen interactions. Cell Rep. 26, 2509–2520.e4 (2019).

    CAS  Google Scholar 

  14. 14.

    Dang, J. et al. Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Cell Stem Cell 19, 258–265 (2016).

    CAS  Google Scholar 

  15. 15.

    Forbes, T. A. et al. Patient-iPSC-derived kidney organoids show functional validation of a ciliopathic renal phenotype and reveal underlying pathogenetic mechanisms. Am. J. Hum. Genet. 102, 816–831 (2018).

    CAS  Google Scholar 

  16. 16.

    Zhang, B. Y., Korolj, A., Lai, B. F. L. & Radisic, M. Advances in organ-on-a-chip engineering. Nat. Rev. Mat. 3, 257–278 (2018).

    Google Scholar 

  17. 17.

    Ahadian, S. et al. Organ-on-a-chip platforms: a convergence of advanced materials, cells, and microscale technologies. Adv. Healthc. Mater. 7, 1700506 (2018).

    Google Scholar 

  18. 18.

    Bhise, N. S. et al. A liver-on-a-chip platform with bioprinted hepatic spheroids. Biofabrication 8, 014101 (2016).

    Google Scholar 

  19. 19.

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

    CAS  Google Scholar 

  20. 20.

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

    CAS  Google Scholar 

  21. 21.

    Kasendra, M. et al. Development of a primary human small intestine-on-a-chip using biopsy-derived organoids. Sci. Rep. 8, 2871 (2018).

    Google Scholar 

  22. 22.

    Rossi, G., Manfrin, A. & Lutolf, M. P. Progress and potential in organoid research. Nat. Rev. Genet. 19, 671–687 (2018).

    CAS  Google Scholar 

  23. 23.

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

    Google Scholar 

  24. 24.

    Czerniecki, S. M. et al. High-throughput screening enhances kidney organoid differentiation from human pluripotent stem cells and enables automated multidimensional phenotyping. Cell Stem Cell 22, 929–940.e4 (2018).

    CAS  Google Scholar 

  25. 25.

    van de Wetering, M. et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015).

    Google Scholar 

  26. 26.

    Ranga, A. et al. Neural tube morphogenesis in synthetic 3D microenvironments. Proc. Natl. Acad. Sci. USA 113, E6831–E6839 (2016).

    CAS  Google Scholar 

  27. 27.

    Lu, P., Takai, K., Weaver, V. M. & Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. 3, a005058 (2011).

    Google Scholar 

  28. 28.

    Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    CAS  Google Scholar 

  29. 29.

    Simao, D. et al. Recapitulation of human neural microenvironment signatures in iPSC-derived NPC 3D differentiation. Stem Cell Rep. 11, 552–564 (2018).

    CAS  Google Scholar 

  30. 30.

    Sasai, Y., Eiraku, M. & Suga, H. In vitro organogenesis in three dimensions: self-organising stem cells. Development 139, 4111–4121 (2012).

    CAS  Google Scholar 

  31. 31.

    Eiraku, M. et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472, 51–56 (2011).

    CAS  Google Scholar 

  32. 32.

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

    CAS  Google Scholar 

  33. 33.

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

    CAS  Google Scholar 

  34. 34.

    Ootani, A. et al. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat. Med. 15, 701–706 (2009).

    CAS  Google Scholar 

  35. 35.

    Taguchi, A. & Nishinakamura, R. Higher-order kidney organogenesis from pluripotent stem cells. Cell Stem Cell 21, 730–746.e6 (2017).

    CAS  Google Scholar 

  36. 36.

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

    CAS  Google Scholar 

  37. 37.

    Dye, B. R. et al. In vitro generation of human pluripotent stem cell derived lung organoids. Elife 4, e05098 (2015).

    Google Scholar 

  38. 38.

    Dorrell, C. et al. The organoid-initiating cells in mouse pancreas and liver are phenotypically and functionally similar. Stem Cell Res. 13, 275–283 (2014).

    CAS  Google Scholar 

  39. 39.

    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).

    CAS  Google Scholar 

  40. 40.

    Poznansky, M. C. et al. Efficient generation of human T cells from a tissue-engineered thymic organoid. Nat. Biotechnol. 18, 729–734 (2000).

    CAS  Google Scholar 

  41. 41.

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

    CAS  Google Scholar 

  42. 42.

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

    CAS  Google Scholar 

  43. 43.

    Kadoshima, T. et al. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc. Natl. Acad. Sci. USA 110, 20284–20289 (2013).

    CAS  Google Scholar 

  44. 44.

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

    CAS  Google Scholar 

  45. 45.

    Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    CAS  Google Scholar 

  46. 46.

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

    CAS  Google Scholar 

  47. 47.

    McCracken, K. W. et al. Wnt/beta-catenin promotes gastric fundus specification in mice and humans. Nature 541, 182–187 (2017).

    CAS  Google Scholar 

  48. 48.

    Munera, J. O. et al. Differentiation of human pluripotent stem cells into colonic organoids via transient activation of bmp signaling. Cell Stem Cell 21, 51–64.e6 (2017).

    CAS  Google Scholar 

  49. 49.

    Rankin, S. A. et al. Timing is everything: reiterative Wnt, BMP and RA signaling regulate developmental competence during endoderm organogenesis. Dev. Biol. 434, 121–132 (2018).

    CAS  Google Scholar 

  50. 50.

    Carcamo-Orive, I. et al. Analysis of transcriptional variability in a large human iPSC library reveals genetic and non-genetic determinants of heterogeneity. Cell Stem Cell 20, 518–532.e9 (2017).

    CAS  Google Scholar 

  51. 51.

    Graf, T. & Stadtfeld, M. Heterogeneity of embryonic and adult stem cells. Cell Stem Cell 3, 480–483 (2008).

    CAS  Google Scholar 

  52. 52.

    Narsinh, K. H. et al. Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells. J. Clin. Invest. 121, 1217–1221 (2011).

    CAS  Google Scholar 

  53. 53.

    Wu, H. et al. Comparative analysis and refinement of human PSC-derived kidney organoid differentiation with single-cell transcriptomics. Cell Stem Cell 23, 869–881.e8 (2018).

    CAS  Google Scholar 

  54. 54.

    Spence, J. R. et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470, 105–109 (2011).

    Google Scholar 

  55. 55.

    McCracken, K. W. et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516, 400–404 (2014).

    CAS  Google Scholar 

  56. 56.

    Yoon, S. J. et al. Reliability of human cortical organoid generation. Nat. Methods 16, 75–78 (2019).

    CAS  Google Scholar 

  57. 57.

    Sloan, S. A. et al. Human astrocyte maturation captured in 3D cerebral cortical spheroids derived from pluripotent stem cells. Neuron 95, 779–790.e6 (2017).

    CAS  Google Scholar 

  58. 58.

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

    CAS  Google Scholar 

  59. 59.

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

    CAS  Google Scholar 

  60. 60.

    Watanabe, K. et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat. Neurosci. 8, 288–296 (2005).

    CAS  Google Scholar 

  61. 61.

    Qian, X. et al. Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat. Protoc. 13, 565–580 (2018).

    CAS  Google Scholar 

  62. 62.

    Kleinman, H. K. et al. Isolation and characterization of type IV procollagen, laminin, and heparan sulfate proteoglycan from the EHS sarcoma. Biochemistry 21, 6188–6193 (1982).

    CAS  Google Scholar 

  63. 63.

    Huang, G. et al. Functional and biomimetic materials for engineering of the three-dimensional cell microenvironment. Chem. Rev. 117, 12764–12850 (2017).

    CAS  Google Scholar 

  64. 64.

    Darnell, M. et al. Material microenvironmental properties couple to induce distinct transcriptional programs in mammalian stem cells. Proc. Natl. Acad. Sci. USA 115, E8368–E8377 (2018).

    CAS  Google Scholar 

  65. 65.

    Caplan, A. I. Mesenchymal stem cells: time to change the name! Stem Cells Transl. Med. 6, 1445–1451 (2017).

    Google Scholar 

  66. 66.

    Gjorevski, N. et al. Designer matrices for intestinal stem cell and organoid culture. Nature 539, 560–564 (2016).

    CAS  Google Scholar 

  67. 67.

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

    CAS  Google Scholar 

  68. 68.

    Parsons, J. T., Horwitz, A. R. & Schwartz, M. A. Cell adhesion: integrating cytoskeletal dynamics and cellular tension. Nat. Rev. Mol. Cell Biol. 11, 633–643 (2010).

    CAS  Google Scholar 

  69. 69.

    Hynes, R. O. The extracellular matrix: not just pretty fibrils. Science 326, 1216–1219 (2009).

    CAS  Google Scholar 

  70. 70.

    Huttenlocher, A. & Horwitz, A. R. Integrins in cell migration. Cold Spring Harb. Perspect. Biol. 3, a005074 (2011).

    Google Scholar 

  71. 71.

    Vicente-Manzanares, M., Choi, C. K. & Horwitz, A. R. Integrins in cell migration—the actin connection. J. Cell Sci. 122, 199–206 (2009).

    CAS  Google Scholar 

  72. 72.

    Kim, S. H., Turnbull, J. & Guimond, S. Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J. Endocrinol. 209, 139–151 (2011).

    CAS  Google Scholar 

  73. 73.

    Schwartz, M. A. Integrins and extracellular matrix in mechanotransduction. Cold Spring Harb. Perspect. Biol. 2, a005066 (2010).

    CAS  Google Scholar 

  74. 74.

    Maheshwari, G., Brown, G., Lauffenburger, D. A., Wells, A. & Griffith, L. G. Cell adhesion and motility depend on nanoscale RGD clustering. J. Cell Sci. 113 (10), 1677–1686 (2000).

    CAS  Google Scholar 

  75. 75.

    Chaudhuri, O. et al. Substrate stress relaxation regulates cell spreading. Nat. Commun. 6, 6364 (2015).

    Google Scholar 

  76. 76.

    Chaudhuri, O. et al. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat. Mater. 15, 326–334 (2016).

    CAS  Google Scholar 

  77. 77.

    Benitez, P. L., Mascharak, S., Proctor, A. C. & Heilshorn, S. C. Use of protein-engineered fabrics to identify design rules for integrin ligand clustering in biomaterials. Integr. Biol. (Camb.) 8, 50–61 (2016).

    Google Scholar 

  78. 78.

    Kong, H. J., Polte, T. R., Alsberg, E. & Mooney, D. J. FRET measurements of cell-traction forces and nano-scale clustering of adhesion ligands varied by substrate stiffness. Proc. Natl. Acad. Sci. USA 102, 4300–4305 (2005).

    CAS  Google Scholar 

  79. 79.

    Pierschbacher, M. D. & Ruoslahti, E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature 309, 30–33 (1984).

    CAS  Google Scholar 

  80. 80.

    Knight, C. G. et al. The collagen-binding A-domains of integrins alpha(1)beta(1) and alpha(2)beta(1) recognize the same specific amino acid sequence, GFOGER, in native (triple-helical) collagens. J. Biol. Chem. 275, 35–40 (2000).

    CAS  Google Scholar 

  81. 81.

    Tashiro, K. et al. A synthetic peptide containing the IKVAV sequence from the A chain of laminin mediates cell attachment, migration, and neurite outgrowth. J. Biol. Chem. 264, 16174–16182 (1989).

    CAS  Google Scholar 

  82. 82.

    Graf, J. et al. Identification of an amino acid sequence in laminin mediating cell attachment, chemotaxis, and receptor binding. Cell 48, 989–996 (1987).

    CAS  Google Scholar 

  83. 83.

    Le Saux, G., Magenau, A., Bocking, T., Gaus, K. & Gooding, J. J. The relative importance of topography and RGD ligand density for endothelial cell adhesion. PLOS ONE 6, e21869 (2011).

    Google Scholar 

  84. 84.

    Oria, R. et al. Force loading explains spatial sensing of ligands by cells. Nature 552, 219–224 (2017).

    CAS  Google Scholar 

  85. 85.

    Ye, K. et al. Matrix stiffness and nanoscale spatial organization of cell-adhesive ligands direct stem cell fate. Nano Lett. 15, 4720–4729 (2015).

    CAS  Google Scholar 

  86. 86.

    Wang, X. et al. Effect of RGD nanospacing on differentiation of stem cells. Biomaterials 34, 2865–2874 (2013).

    CAS  Google Scholar 

  87. 87.

    Salinas, C. N. & Anseth, K. S. The influence of the RGD peptide motif and its contextual presentation in PEG gels on human mesenchymal stem cell viability. J. Tissue Eng. Regen. Med. 2, 296–304 (2008).

    CAS  Google Scholar 

  88. 88.

    Koivunen, E., Wang, B. & Ruoslahti, E. Phage libraries displaying cyclic peptides with different ring sizes: ligand specificities of the RGD-directed integrins. Biotechnology (N. Y.) 13, 265–270 (1995).

    CAS  Google Scholar 

  89. 89.

    Wade, R. J., Bassin, E. J., Gramlich, W. M. & Burdick, J. A. Nanofibrous hydrogels with spatially patterned biochemical signals to control cell behavior. Adv. Mater. 27, 1356–1362 (2015).

    CAS  Google Scholar 

  90. 90.

    Arnold, M. et al. Activation of integrin function by nanopatterned adhesive interfaces. ChemPhysChem 5, 383–388 (2004).

    CAS  Google Scholar 

  91. 91.

    Cavalcanti-Adam, E. A. et al. Cell spreading and focal adhesion dynamics are regulated by spacing of integrin ligands. Biophys. J. 92, 2964–2974 (2007).

    CAS  Google Scholar 

  92. 92.

    Kloxin, A. M., Kasko, A. M., Salinas, C. N. & Anseth, K. S. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science 324, 59–63 (2009).

    CAS  Google Scholar 

  93. 93.

    Campbell, I. D. & Humphries, M. J. Integrin structure, activation, and interactions. Cold Spring Harb. Perspect. Biol. 3, a004994 (2011).

    Google Scholar 

  94. 94.

    Li, S. et al. Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability. Nat. Mater. 16, 953–961 (2017).

    CAS  Google Scholar 

  95. 95.

    Lam, J., Carmichael, S. T., Lowry, W. E. & Segura, T. Hydrogel design of experiments methodology to optimize hydrogel for iPSC-NPC culture. Adv. Healthc. Mater. 4, 534–539 (2015).

    CAS  Google Scholar 

  96. 96.

    Ali, S., Saik, J. E., Gould, D. J., Dickinson, M. E. & West, J. L. Immobilization of cell-adhesive laminin peptides in degradable PEGDA hydrogels influences endothelial cell tubulogenesis. BioRes. Open Access 2, 241–249 (2013).

    CAS  Google Scholar 

  97. 97.

    Moshayedi, P. et al. Systematic optimization of an engineered hydrogel allows for selective control of human neural stem cell survival and differentiation after transplantation in the stroke brain. Biomaterials 105, 145–155 (2016).

    CAS  Google Scholar 

  98. 98.

    Lee, J. W. & Lee, K. Y. Dual peptide-presenting hydrogels for controlling the phenotype of PC12 cells. Colloids Surf. B Biointerfaces 152, 36–41 (2017).

    CAS  Google Scholar 

  99. 99.

    Huettner, N., Dargaville, T. R. & Forget, A. Discovering cell-adhesion peptides in tissue engineering: beyond RGD. Trends Biotechnol. 36, 372–383 (2018).

    CAS  Google Scholar 

  100. 100.

    Seidlits, S. K. et al. Peptide-modified, hyaluronic acid-based hydrogels as a 3D culture platform for neural stem/progenitor cell engineering. J. Biomed. Mater. Res. A 107, 704–718 (2019).

    CAS  Google Scholar 

  101. 101.

    Müller, C., Müller, A. & Pompe, T. Dissipative interactions in cell–matrix adhesion. Soft Matter 9, 6207–6216 (2013).

    Google Scholar 

  102. 102.

    Eyckmans, J., Boudou, T., Yu, X. & Chen, C. S. A hitchhiker’s guide to mechanobiology. Dev. Cell 21, 35–47 (2011).

    CAS  Google Scholar 

  103. 103.

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

    CAS  Google Scholar 

  104. 104.

    Butcher, D. T., Alliston, T. & Weaver, V. M. A tense situation: forcing tumour progression. Nat. Rev. Cancer 9, 108–122 (2009).

    CAS  Google Scholar 

  105. 105.

    Sherratt, M. J. Tissue elasticity and the ageing elastic fibre. Age 31, 305–325 (2009).

    CAS  Google Scholar 

  106. 106.

    Handorf, A. M., Zhou, Y., Halanski, M. A. & Li, W. J. Tissue stiffness dictates development, homeostasis, and disease progression. Organogenesis 11, 1–15 (2015).

    Google Scholar 

  107. 107.

    Lampi, M. C. & Reinhart-King, C. A. Targeting extracellular matrix stiffness to attenuate disease: From molecular mechanisms to clinical trials. Sci. Transl. Med. 10, eaao0475 (2018).

    Google Scholar 

  108. 108.

    Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).

    CAS  Google Scholar 

  109. 109.

    Saha, K. et al. Substrate modulus directs neural stem cell behavior. Biophys. J. 95, 4426–4438 (2008).

    CAS  Google Scholar 

  110. 110.

    Leipzig, N. D. & Shoichet, M. S. The effect of substrate stiffness on adult neural stem cell behavior. Biomaterials 30, 6867–6878 (2009).

    CAS  Google Scholar 

  111. 111.

    Gilbert, P. M., Havenstrite, K. L., Magnusson, K. & Blau, H. M. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329, 1078–1081 (2010).

    CAS  Google Scholar 

  112. 112.

    Huebsch, N. et al. Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat. Mater. 9, 518–526 (2010).

    CAS  Google Scholar 

  113. 113.

    Evans, N. D. et al. Substrate stiffness affects early differentiation events in embryonic stem cells. Eur. Cell. Mater. 18, 1–13; discussion 13–14 (2009).

    CAS  Google Scholar 

  114. 114.

    Hadden, W. J. et al. Stem cell migration and mechanotransduction on linear stiffness gradient hydrogels. Proc. Natl. Acad. Sci. USA 114, 5647–5652 (2017).

    CAS  Google Scholar 

  115. 115.

    Lee, D. A., Knight, M. M., Campbell, J. J. & Bader, D. L. Stem cell mechanobiology. J. Cell. Biochem. 112, 1–9 (2011).

    CAS  Google Scholar 

  116. 116.

    Vining, K. H. & Mooney, D. J. Mechanical forces direct stem cell behaviour in development and regeneration. Nat. Rev. Mol. Cell Biol. 18, 728–742 (2017).

    CAS  Google Scholar 

  117. 117.

    Wang, N. Review of cellular mechanotransduction. J. Phys. D Appl. Phys. 50, 233002 (2017).

    Google Scholar 

  118. 118.

    Cameron, A. R., Frith, J. E. & Cooper-White, J. J. The influence of substrate creep on mesenchymal stem cell behaviour and phenotype. Biomaterials 32, 5979–5993 (2011).

    CAS  Google Scholar 

  119. 119.

    Cameron, A. R., Frith, J. E., Gomez, G. A., Yap, A. S. & Cooper-White, J. J. The effect of time-dependent deformation of viscoelastic hydrogels on myogenic induction and Rac1 activity in mesenchymal stem cells. Biomaterials 35, 1857–1868 (2014).

    CAS  Google Scholar 

  120. 120.

    Nam, S., Stowers, R., Lou, J., Xia, Y. & Chaudhuri, O. Varying PEG density to control stress relaxation in alginate-PEG hydrogels for 3D cell culture studies. Biomaterials 200, 15–24 (2019).

    CAS  Google Scholar 

  121. 121.

    Rudnicki, M. S. et al. Nonlinear strain stiffening is not sufficient to explain how far cells can feel on fibrous protein gels. Biophys. J. 105, 11–20 (2013).

    CAS  Google Scholar 

  122. 122.

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

    CAS  Google Scholar 

  123. 123.

    Jaspers, M. et al. Ultra-responsive soft matter from strain-stiffening hydrogels. Nat. Commun. 5, 5808 (2014).

    Google Scholar 

  124. 124.

    Das, R. K., Gocheva, V., Hammink, R., Zouani, O. F. & Rowan, A. E. Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels. Nat. Mater. 15, 318–325 (2016).

    CAS  Google Scholar 

  125. 125.

    de Almeida, P. et al. Cytoskeletal stiffening in synthetic hydrogels. Nat. Commun. 10, 609 (2019).

    Google Scholar 

  126. 126.

    Kouwer, P. H. et al. Responsive biomimetic networks from polyisocyanopeptide hydrogels. Nature 493, 651–655 (2013).

    CAS  Google Scholar 

  127. 127.

    Yin, Z. et al. The regulation of tendon stem cell differentiation by the alignment of nanofibers. Biomaterials 31, 2163–2175 (2010).

    CAS  Google Scholar 

  128. 128.

    Cardwell, R. D., Dahlgren, L. A. & Goldstein, A. S. Electrospun fibre diameter, not alignment, affects mesenchymal stem cell differentiation into the tendon/ligament lineage. J. Tissue Eng. Regen. Med. 8, 937–945 (2014).

    CAS  Google Scholar 

  129. 129.

    Silantyeva, E. A. et al. Accelerated neural differentiation of mouse embryonic stem cells on aligned GYIGSR-functionalized nanofibers. Acta Biomater. 75, 129–139 (2018).

    CAS  Google Scholar 

  130. 130.

    Christopherson, G. T., Song, H. & Mao, H. Q. The influence of fiber diameter of electrospun substrates on neural stem cell differentiation and proliferation. Biomaterials 30, 556–564 (2009).

    CAS  Google Scholar 

  131. 131.

    Lutolf, M. P. et al. Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: engineering cell-invasion characteristics. Proc. Natl. Acad. Sci. USA 100, 5413–5418 (2003).

    CAS  Google Scholar 

  132. 132.

    Han, L. H., Lai, J. H., Yu, S. & Yang, F. Dynamic tissue engineering scaffolds with stimuli-responsive macroporosity formation. Biomaterials 34, 4251–4258 (2013).

    CAS  Google Scholar 

  133. 133.

    Nih, L. R., Sideris, E., Carmichael, S. T. & Segura, T. Injection of microporous annealing particle (MAP) hydrogels in the stroke cavity reduces gliosis and inflammation and promotes NPC migration to the lesion. Adv. Mater. 29, 1606471 (2017).

    Google Scholar 

  134. 134.

    Han, L. H., Tong, X. & Yang, F. Photo-crosslinkable PEG-based microribbons for forming 3D macroporous scaffolds with decoupled niche properties. Adv. Mater. 26, 1757–1762 (2014).

    CAS  Google Scholar 

  135. 135.

    Darling, N. J., Hung, Y. S., Sharma, S. & Segura, T. Controlling the kinetics of thiol-maleimide Michael-type addition gelation kinetics for the generation of homogenous poly(ethylene glycol) hydrogels. Biomaterials 101, 199–206 (2016).

    CAS  Google Scholar 

  136. 136.

    Wang, H., Cai, L., Paul, A., Enejder, A. & Heilshorn, S. C. Hybrid elastin-like polypeptide-polyethylene glycol (ELP-PEG) hydrogels with improved transparency and independent control of matrix mechanics and cell ligand density. Biomacromolecules 15, 3421–3428 (2014).

    CAS  Google Scholar 

  137. 137.

    Zhao, H. et al. Microengineered in vitro model of cardiac fibrosis through modulating myofibroblast mechanotransduction. Biofabrication 6, 045009 (2014).

    Google Scholar 

  138. 138.

    Tse, J. R. & Engler, A. J. Stiffness gradients mimicking in vivo tissue variation regulate mesenchymal stem cell fate. PLOS ONE 6, e15978 (2011).

    CAS  Google Scholar 

  139. 139.

    Kharkar, P. M., Kiick, K. L. & Kloxin, A. M. Designing degradable hydrogels for orthogonal control of cell microenvironments. Chem. Soc. Rev. 42, 7335–7372 (2013).

    CAS  Google Scholar 

  140. 140.

    Giambernardi, T. A. et al. Overview of matrix metalloproteinase expression in cultured human cells. Matrix Biology 16, 483–496 (1998).

    CAS  Google Scholar 

  141. 141.

    Girish, K. S. & Kemparaju, K. The magic glue hyaluronan and its eraser hyaluronidase: a biological overview. Life Sci. 80, 1921–1943 (2007).

    CAS  Google Scholar 

  142. 142.

    Lee, K. Y. & Mooney, D. J. Alginate: properties and biomedical applications. Prog. Polym. Sci. 37, 106–126 (2012).

    CAS  Google Scholar 

  143. 143.

    Kong, H. J., Smith, M. K. & Mooney, D. J. Designing alginate hydrogels to maintain viability of immobilized cells. Biomaterials 24, 4023–4029 (2003).

    CAS  Google Scholar 

  144. 144.

    Parmar, P. A. et al. Temporally degradable collagen-mimetic hydrogels tuned to chondrogenesis of human mesenchymal stem cells. Biomaterials 99, 56–71 (2016).

    CAS  Google Scholar 

  145. 145.

    Stern, R., Asari, A. A. & Sugahara, K. N. Hyaluronan fragments: an information-rich system. Eur. J. Cell Biol. 85, 699–715 (2006).

    CAS  Google Scholar 

  146. 146.

    Lampe, K. J., Bjugstad, K. B. & Mahoney, M. J. Impact of degradable macromer content in a poly(ethylene glycol) hydrogel on neural cell metabolic activity, redox state, proliferation, and differentiation. Tissue Eng. Part A 16, 1857–1866 (2010).

    CAS  Google Scholar 

  147. 147.

    Khetan, S. et al. Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels. Nat. Mater. 12, 458–465 (2013).

    CAS  Google Scholar 

  148. 148.

    Salinas, C. N. & Anseth, K. S. The enhancement of chondrogenic differentiation of human mesenchymal stem cells by enzymatically regulated RGD functionalities. Biomaterials 29, 2370–2377 (2008).

    CAS  Google Scholar 

  149. 149.

    Ehrbar, M. et al. Elucidating the role of matrix stiffness in 3D cell migration and remodeling. Biophys. J. 100, 284–293 (2011).

    CAS  Google Scholar 

  150. 150.

    Khetan, S. & Burdick, J. A. Patterning network structure to spatially control cellular remodeling and stem cell fate within 3-dimensional hydrogels. Biomaterials 31, 8228–8234 (2010).

    CAS  Google Scholar 

  151. 151.

    Kloxin, A. M. et al. Responsive culture platform to examine the influence of microenvironmental geometry on cell function in 3D. Integr. Biol. (Camb.) 4, 1540–1549 (2012).

    CAS  Google Scholar 

  152. 152.

    Anderson, S. B., Lin, C. C., Kuntzler, D. V. & Anseth, K. S. The performance of human mesenchymal stem cells encapsulated in cell-degradable polymer-peptide hydrogels. Biomaterials 32, 3564–3574 (2011).

    CAS  Google Scholar 

  153. 153.

    Ashton, R. S., Banerjee, A., Punyani, S., Schaffer, D. V. & Kane, R. S. Scaffolds based on degradable alginate hydrogels and poly(lactide-co-glycolide) microspheres for stem cell culture. Biomaterials 28, 5518–5525 (2007).

    CAS  Google Scholar 

  154. 154.

    Bryant, S. J. & Anseth, K. S. Controlling the spatial distribution of ECM components in degradable PEG hydrogels for tissue engineering cartilage. J. Biomed. Mater. Res. A 64, 70–79 (2003).

    Google Scholar 

  155. 155.

    Chung, C., Beecham, M., Mauck, R. L. & Burdick, J. A. The influence of degradation characteristics of hyaluronic acid hydrogels on in vitro neocartilage formation by mesenchymal stem cells. Biomaterials 30, 4287–4296 (2009).

    CAS  Google Scholar 

  156. 156.

    Madl, C. M. et al. Maintenance of neural progenitor cell stemness in 3D hydrogels requires matrix remodelling. Nat. Mater. 16, 1233–1242 (2017).

    CAS  Google Scholar 

  157. 157.

    Purwada, A. et al. Ex vivo engineered immune organoids for controlled germinal center reactions. Biomaterials 63, 24–34 (2015).

    CAS  Google Scholar 

  158. 158.

    Purwada, A., Shah, S. B., Beguelin, W., Melnick, A. M. & Singh, A. Modular immune organoids with integrin ligand specificity differentially regulate ex vivo B cell activation. ACS Biomater. Sci. Eng. 3, 214–225 (2017).

    CAS  Google Scholar 

  159. 159.

    McGuigan, A. P. & Sefton, M. V. Vascularized organoid engineered by modular assembly enables blood perfusion. Proc. Natl. Acad. Sci. USA 103, 11461–11466 (2006).

    CAS  Google Scholar 

  160. 160.

    Weber, R. J. et al. Rapid organoid reconstitution by chemical micromolding. ACS Biomater. Sci. Eng. 2, 1851–1855 (2016).

    CAS  Google Scholar 

  161. 161.

    Jabaji, Z. et al. Type I collagen as an extracellular matrix for the in vitro growth of human small intestinal epithelium. PLOS ONE 9, e107814 (2014).

    Google Scholar 

  162. 162.

    DiMarco, R. L. et al. Engineering of three-dimensional microenvironments to promote contractile behavior in primary intestinal organoids. Integr. Biol. (Camb.) 6, 127–142 (2014).

    CAS  Google Scholar 

  163. 163.

    Takezawa, T., Ozaki, K., Nitani, A., Takabayashi, C. & Shimo-Oka, T. Collagen vitrigel: a novel scaffold that can facilitate a three-dimensional culture for reconstructing organoids. Cell Transplant. 13, 463–473 (2004).

    Google Scholar 

  164. 164.

    Lindborg, B. A. et al. Rapid induction of cerebral organoids from human induced pluripotent stem cells using a chemically defined hydrogel and defined cell culture medium. Stem Cells Transl. Med. 5, 970–979 (2016).

    CAS  Google Scholar 

  165. 165.

    Wilkinson, D. C. et al. Development of a three-dimensional bioengineering technology to generate lung tissue for personalized disease modeling. Stem Cells Transl. Med. 6, 622–633 (2017).

    Google Scholar 

  166. 166.

    Wolf, K. J. & Kumar, S. Hyaluronic acid: incorporating the bio into the material. ACS Biomater. Sci. Eng. https://doi.org/10.1021/acsbiomaterials.8b01268 (2019).

    CAS  Google Scholar 

  167. 167.

    Antoine, E. E., Vlachos, P. P. & Rylander, M. N. Review of collagen I hydrogels for bioengineered tissue microenvironments: characterization of mechanics, structure, and transport. Tissue Eng. Part B Rev. 20, 683–696 (2014).

    CAS  Google Scholar 

  168. 168.

    Hughes, C. S., Postovit, L. M. & Lajoie, G. A. Matrigel: a complex protein mixture required for optimal growth of cell culture. Proteomics 10, 1886–1890 (2010).

    CAS  Google Scholar 

  169. 169.

    Li, X. et al. Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. Nat. Med. 20, 769–777 (2014).

    CAS  Google Scholar 

  170. 170.

    Neal, J. T. et al. Organoid modeling of the tumor immune microenvironment. Cell 175, 1972–1988.e16 (2018).

    CAS  Google Scholar 

  171. 171.

    Giandomenico, S. L. et al. Cerebral organoids at the air–liquid interface generate diverse nerve tracts with functional output. Nat. Neurosci. 22, 669–679 (2019).

    CAS  Google Scholar 

  172. 172.

    Capeling, M. M. et al. Nonadhesive alginate hydrogels support growth of pluripotent stem cell-derived intestinal organoids. Stem Cell Rep. 12, 381–394 (2019).

    CAS  Google Scholar 

  173. 173.

    Chen, Y., Zhou, W., Roh, T., Estes, M. K. & Kaplan, D. L. In vitro enteroid-derived three-dimensional tissue model of human small intestinal epithelium with innate immune responses. PLOS ONE 12, e0187880 (2017).

    Google Scholar 

  174. 174.

    Banerjee, I., Pangule, R. C. & Kane, R. S. Antifouling coatings: recent developments in the design of surfaces that prevent fouling by proteins, bacteria, and marine organisms. Adv. Mater. 23, 690–718 (2011).

    CAS  Google Scholar 

  175. 175.

    Zhu, J. Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering. Biomaterials 31, 4639–4656 (2010).

    CAS  Google Scholar 

  176. 176.

    Enemchukwu, N. O. et al. Synthetic matrices reveal contributions of ECM biophysical and biochemical properties to epithelial morphogenesis. J. Cell Biol. 212, 113–124 (2016).

    CAS  Google Scholar 

  177. 177.

    Sengupta, D. & Heilshorn, S. C. Protein-engineered biomaterials: highly tunable tissue engineering scaffolds. Tissue Eng. Part B Rev. 16, 285–293 (2010).

    CAS  Google Scholar 

  178. 178.

    DiMarco, R. L., Dewi, R. E., Bernal, G., Kuo, C. & Heilshorn, S. C. Protein-engineered scaffolds for in vitro 3D culture of primary adult intestinal organoids. Biomater. Sci. 3, 1376–1385 (2015).

    CAS  Google Scholar 

  179. 179.

    Candiello, J. et al. 3D heterogeneous islet organoid generation from human embryonic stem cells using a novel engineered hydrogel platform. Biomaterials 177, 27–39 (2018).

    CAS  Google Scholar 

  180. 180.

    Sasai, Y. Cytosystems dynamics in self-organization of tissue architecture. Nature 493, 318–326 (2013).

    CAS  Google Scholar 

  181. 181.

    Li, J. & Mooney, D. J. Designing hydrogels for controlled drug delivery. Nat. Rev. Mater. 1, 16071 (2016).

    CAS  Google Scholar 

  182. 182.

    Liang, Y. & Kiick, K. L. Heparin-functionalized polymeric biomaterials in tissue engineering and drug delivery applications. Acta Biomater. 10, 1588–1600 (2014).

    CAS  Google Scholar 

  183. 183.

    Sakiyama-Elbert, S. E. Incorporation of heparin into biomaterials. Acta Biomater. 10, 1581–1587 (2014).

    CAS  Google Scholar 

  184. 184.

    Vulic, K. & Shoichet, M. S. Affinity-based drug delivery systems for tissue repair and regeneration. Biomacromolecules 15, 3867–3880 (2014).

    CAS  Google Scholar 

  185. 185.

    Willerth, S. M., Rader, A. & Sakiyama-Elbert, S. E. The effect of controlled growth factor delivery on embryonic stem cell differentiation inside fibrin scaffolds. Stem Cell Res. 1, 205–218 (2008).

    CAS  Google Scholar 

  186. 186.

    Guo, C. et al. Bio-orthogonal conjugation and enzymatically triggered release of proteins within multi-layered hydrogels. Acta Biomater. 56, 80–90 (2017).

    CAS  Google Scholar 

  187. 187.

    Straley, K. S. & Heilshorn, S. C. Independent tuning of multiple biomaterial properties using protein engineering. Soft Matter 5, 114–124 (2009).

    CAS  Google Scholar 

  188. 188.

    Patterson, J. & Hubbell, J. A. Enhanced proteolytic degradation of molecularly engineered PEG hydrogels in response to MMP-1 and MMP-2. Biomaterials 31, 7836–7845 (2010).

    CAS  Google Scholar 

  189. 189.

    Kukreja, M. et al. High-throughput multiplexed peptide-centric profiling illustrates both substrate cleavage redundancy and specificity in the MMP family. Chem. Biol. 22, 1122–1133 (2015).

    CAS  Google Scholar 

  190. 190.

    Kwon, M. Y. et al. Dose and timing of N-cadherin mimetic peptides regulate MSC chondrogenesis within hydrogels. Adv. Healthc. Mater. 7, 1701199 (2018).

    Google Scholar 

  191. 191.

    Ruskowitz, E. R. & DeForest, C. A. Photoresponsive biomaterials for targeted drug delivery and 4D cell culture. Nat. Rev. Mater. 3, 17087–17017 (2018).

    CAS  Google Scholar 

  192. 192.

    Wylie, R. G. et al. Spatially controlled simultaneous patterning of multiple growth factors in three-dimensional hydrogels. Nat. Mater. 10, 799–806 (2011).

    CAS  Google Scholar 

  193. 193.

    DeForest, C. A. & Tirrell, D. A. A photoreversible protein-patterning approach for guiding stem cell fate in three-dimensional gels. Nat. Mater. 14, 523–531 (2015).

    CAS  Google Scholar 

  194. 194.

    Grim, J. C. et al. A reversible and repeatable thiol–ene bioconjugation for dynamic patterning of signaling proteins in hydrogels. ACS Cent. Sci. 4, 909–916 (2018).

    CAS  Google Scholar 

  195. 195.

    Jeon, O., Lee, K. & Alsberg, E. Spatial micropatterning of growth factors in 3D hydrogels for location-specific regulation of cellular behaviors. Small 14, 1800579 (2018).

    Google Scholar 

  196. 196.

    Hoffmann, J. C. & West, J. L. Three-dimensional photolithographic patterning of multiple bioactive ligands in poly(ethylene glycol) hydrogels. Soft Matter 6, 5056–5063 (2010).

    CAS  Google Scholar 

  197. 197.

    Shadish, J. A., Benuska, G. M. & DeForest, C. A. Bioactive site-specifically modified proteins for 4D patterning of gel biomaterials. Nat. Mater. https://doi.org/10.1038/s41563-019-0367-7 (2019).

    CAS  Google Scholar 

  198. 198.

    Attayek, P. J. et al. In vitro polarization of colonoids to create an intestinal stem cell compartment. PLOS ONE 11, e0153795 (2016).

    Google Scholar 

  199. 199.

    Thorne, C. A. et al. Enteroid monolayers reveal an autonomous WNT and BMP circuit controlling intestinal epithelial growth and organization. Dev. Cell 44, 624–633.e4 (2018).

    CAS  Google Scholar 

  200. 200.

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

    CAS  Google Scholar 

  201. 201.

    Nguyen, E. H., Schwartz, M. P. & Murphy, W. L. Biomimetic approaches to control soluble concentration gradients in biomaterials. Macromol. Biosci. 11, 483–492 (2011).

    CAS  Google Scholar 

  202. 202.

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

    CAS  Google Scholar 

  203. 203.

    Brodland, G. W. The differential interfacial tension hypothesis (DITH): a comprehensive theory for the self-rearrangement of embryonic cells and tissues. J. Biomech. Eng. 124, 188–197 (2002).

    Google Scholar 

  204. 204.

    Fagotto, F. The cellular basis of tissue separation. Development 141, 3303–3318 (2014).

    CAS  Google Scholar 

  205. 205.

    Canty, L., Zarour, E., Kashkooli, L., Francois, P. & Fagotto, F. Sorting at embryonic boundaries requires high heterotypic interfacial tension. Nat. Commun. 8, 157 (2017).

    Google Scholar 

  206. 206.

    Knight, G. T. et al. Engineering induction of singular neural rosette emergence within hPSC-derived tissues. Elife 7, e37549 (2018).

    Google Scholar 

  207. 207.

    Knight, G. T., Sha, J. & Ashton, R. S. Micropatterned, clickable culture substrates enable in situ spatiotemporal control of human PSC-derived neural tissue morphology. Chem. Commun. 51, 5238–5241 (2015).

    CAS  Google Scholar 

  208. 208.

    Cerchiari, A. E. et al. A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity. Proc. Natl. Acad. Sci. USA 112, 2287–2292 (2015).

    CAS  Google Scholar 

  209. 209.

    DeForest, C. A., Polizzotti, B. D. & Anseth, K. S. Sequential click reactions for synthesizing and patterning three-dimensional cell microenvironments. Nat. Mater. 8, 659–664 (2009).

    CAS  Google Scholar 

  210. 210.

    Pedron, S. et al. Patterning three-dimensional hydrogel microenvironments using hyperbranched polyglycerols for independent control of mesh size and stiffness. Biomacromolecules 18, 1393–1400 (2017).

    CAS  Google Scholar 

  211. 211.

    Luo, Y. & Shoichet, M. S. A photolabile hydrogel for guided three-dimensional cell growth and migration. Nat. Mater. 3, 249–253 (2004).

    CAS  Google Scholar 

  212. 212.

    Lee, S. H., Moon, J. J. & West, J. L. Three-dimensional micropatterning of bioactive hydrogels via two-photon laser scanning photolithography for guided 3D cell migration. Biomaterials 29, 2962–2968 (2008).

    CAS  Google Scholar 

  213. 213.

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

    Google Scholar 

  214. 214.

    Marklein, R. A. & Burdick, J. A. Spatially controlled hydrogel mechanics to modulate stem cell interactions. Soft Matter 6, 136–143 (2010).

    CAS  Google Scholar 

  215. 215.

    Doyle, A. D., Wang, F. W., Matsumoto, K. & Yamada, K. M. One-dimensional topography underlies three-dimensional fibrillar cell migration. J. Cell Biol. 184, 481–490 (2009).

    CAS  Google Scholar 

  216. 216.

    Plotnikov, S. V., Pasapera, A. M., Sabass, B. & Waterman, C. M. Force fluctuations within focal adhesions mediate ECM-rigidity sensing to guide directed cell migration. Cell 151, 1513–1527 (2012).

    CAS  Google Scholar 

  217. 217.

    Brown, T. E. et al. Photopolymerized dynamic hydrogels with tunable viscoelastic properties through thioester exchange. Biomaterials 178, 496–503 (2018).

    CAS  Google Scholar 

  218. 218.

    Shao, Y. et al. Self-organized amniogenesis by human pluripotent stem cells in a biomimetic implantation-like niche. Nat. Mater. 16, 419–425 (2017).

    CAS  Google Scholar 

  219. 219.

    Shao, Y. et al. A pluripotent stem cell-based model for post-implantation human amniotic sac development. Nat. Commun. 8, 208 (2017).

    Google Scholar 

  220. 220.

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

    CAS  Google Scholar 

  221. 221.

    Madl, C. M., Katz, L. M. & Heilshorn, S. C. Tuning bulk hydrogel degradation by simultaneous control of proteolytic cleavage kinetics and hydrogel network architecture. ACS Macro. Lett. 7, 1302–1307 (2018).

    CAS  Google Scholar 

  222. 222.

    Mori, H., Gjorevski, N., Inman, J. L., Bissell, M. J. & Nelson, C. M. Self-organization of engineered epithelial tubules by differential cellular motility. Proc. Natl. Acad. Sci. USA 106, 14890–14895 (2009).

    CAS  Google Scholar 

  223. 223.

    Sarig-Nadir, O., Livnat, N., Zajdman, R., Shoham, S. & Seliktar, D. Laser photoablation of guidance microchannels into hydrogels directs cell growth in three dimensions. Biophys. J. 96, 4743–4752 (2009).

    CAS  Google Scholar 

  224. 224.

    McKinnon, D. D., Brown, T. E., Kyburz, K. A., Kiyotake, E. & Anseth, K. S. Design and characterization of a synthetically accessible, photodegradable hydrogel for user-directed formation of neural networks. Biomacromolecules 15, 2808–2816 (2014).

    CAS  Google Scholar 

  225. 225.

    Badeau, B. A., Comerford, M. P., Arakawa, C. K., Shadish, J. A. & DeForest, C. A. Engineered modular biomaterial logic gates for environmentally triggered therapeutic delivery. Nat. Chem. 10, 251–258 (2018).

    CAS  Google Scholar 

  226. 226.

    Moroni, L. et al. Biofabrication strategies for 3D in vitro models and regenerative medicine. Nat. Rev. Mater. 3, 21–37 (2018).

    CAS  Google Scholar 

  227. 227.

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

    CAS  Google Scholar 

  228. 228.

    Xiang, Y. et al. hESC-derived thalamic organoids form reciprocal projections when fused with cortical organoids. Cell Stem Cell 24, 487–497.e7 (2019).

    CAS  Google Scholar 

  229. 229.

    Du, Y., Lo, E., Ali, S. & Khademhosseini, A. Directed assembly of cell-laden microgels for fabrication of 3D tissue constructs. Proc. Natl. Acad. Sci. USA 105, 9522–9527 (2008).

    CAS  Google Scholar 

  230. 230.

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

    CAS  Google Scholar 

  231. 231.

    Groll, J. et al. A definition of bioinks and their distinction from biomaterial inks. Biofabrication 11, 013001 (2018).

    CAS  Google Scholar 

  232. 232.

    Jia, W. et al. Direct 3D bioprinting of perfusable vascular constructs using a blend bioink. Biomaterials 106, 58–68 (2016).

    CAS  Google Scholar 

  233. 233.

    Zhang, Y. S. et al. Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. Biomaterials 110, 45–59 (2016).

    CAS  Google Scholar 

  234. 234.

    Mironov, V. et al. Organ printing: tissue spheroids as building blocks. Biomaterials 30, 2164–2174 (2009).

    CAS  Google Scholar 

  235. 235.

    Yu, Y. et al. Three-dimensional bioprinting using self-assembling scalable scaffold-free “tissue strands” as a new bioink. Sci. Rep. 6, 28714 (2016).

    CAS  Google Scholar 

  236. 236.

    Laronda, M. M. et al. A bioprosthetic ovary created using 3D printed microporous scaffolds restores ovarian function in sterilized mice. Nat. Commun. 8, 15261 (2017).

    CAS  Google Scholar 

  237. 237.

    Chen, H. J., Miller, P. & Shuler, M. L. A pumpless body-on-a-chip model using a primary culture of human intestinal cells and a 3D culture of liver cells. Lab Chip 18, 2036–2046 (2018).

    CAS  Google Scholar 

  238. 238.

    Chen, W. L. K. et al. Integrated gut/liver microphysiological systems elucidates inflammatory inter-tissue crosstalk. Biotechnol. Bioeng. 114, 2648–2659 (2017).

    CAS  Google Scholar 

  239. 239.

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

    CAS  Google Scholar 

  240. 240.

    Benam, K. H. et al. Matched-comparative modeling of normal and diseased human airway responses using a microengineered breathing lung chip. Cell Systems 3, 456–466.e4 (2016).

    CAS  Google Scholar 

  241. 241.

    Barrile, R. et al. Organ-on-chip recapitulates thrombosis induced by an anti-CD154 monoclonal antibody: translational potential of advanced microengineered systems. Clin. Pharmacol. Ther. 104, 1240–1248 (2018).

    CAS  Google Scholar 

  242. 242.

    Figtree, G. A., Bubb, K. J., Tang, O., Kizana, E. & Gentile, C. Vascularized cardiac spheroids as novel 3D in vitro models to study cardiac fibrosis. Cells Tissues Organs 204, 191–198 (2017).

    CAS  Google Scholar 

  243. 243.

    Nguyen, E. H. et al. Versatile synthetic alternatives to Matrigel for vascular toxicity screening and stem cell expansion. Nat. Biomed. Eng. 1, 0096 (2017).

    Google Scholar 

  244. 244.

    Soofi, S. S., Last, J. A., Liliensiek, S. J., Nealey, P. F. & Murphy, C. J. The elastic modulus of Matrigel as determined by atomic force microscopy. J. Struct. Biol. 167, 216–219 (2009).

    CAS  Google Scholar 

  245. 245.

    Chaudhuri, O. et al. Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium. Nat. Mater. 13, 970–978 (2014).

    CAS  Google Scholar 

  246. 246.

    Villa-Diaz, L. G., Ross, A. M., Lahann, J. & Krebsbach, P. H. Concise review: the evolution of human pluripotent stem cell culture: from feeder cells to synthetic coatings. Stem Cells 31, 1–7 (2012).

    Google Scholar 

  247. 247.

    Halbleib, J. M. & Nelson, W. J. Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev. 20, 3199–3214 (2006).

    CAS  Google Scholar 

  248. 248.

    Takeichi, M. Cadherins: a molecular family important in selective cell-cell adhesion. Annu. Rev. Biochem. 59, 237–252 (1990).

    CAS  Google Scholar 

  249. 249.

    Steinberg, M. S. & McNutt, P. M. Cadherins and their connections: adhesion junctions have broader functions. Curr. Opin. Cell Biol. 11, 554–560 (1999).

    CAS  Google Scholar 

  250. 250.

    Katsamba, P. et al. Linking molecular affinity and cellular specificity in cadherin-mediated adhesion. Proc. Natl. Acad. Sci. USA 106, 11594–11599 (2009).

    CAS  Google Scholar 

  251. 251.

    Vendome, J. et al. Structural and energetic determinants of adhesive binding specificity in type I cadherins. Proc. Natl. Acad. Sci. USA 111, E4175–E4184 (2014).

    CAS  Google Scholar 

  252. 252.

    le Duc, Q. et al. Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II-dependent manner. J. Cell Biol. 189, 1107–1115 (2010).

    Google Scholar 

  253. 253.

    Leckband, D. E., le Duc, Q., Wang, N. & de Rooij, J. Mechanotransduction at cadherin-mediated adhesions. Curr. Opin. Cell Biol. 23, 523–530 (2011).

    CAS  Google Scholar 

  254. 254.

    Cosgrove, B. D. et al. N-cadherin adhesive interactions modulate matrix mechanosensing and fate commitment of mesenchymal stem cells. Nat. Mater. 15, 1297–1306 (2016).

    CAS  Google Scholar 

  255. 255.

    Bian, L., Guvendiren, M., Mauck, R. L. & Burdick, J. A. Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis. Proc. Natl. Acad. Sci. USA 110, 10117–10122 (2013).

    CAS  Google Scholar 

  256. 256.

    Karthaus, W. R. et al. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell 159, 163–175 (2014).

    CAS  Google Scholar 

  257. 257.

    Jo, J. et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 19, 248–257 (2016).

    CAS  Google Scholar 

  258. 258.

    Miller, A. J. et al. Generation of lung organoids from human pluripotent stem cells in vitro. Nat. Protoc. 14, 518–540 (2019).

    CAS  Google Scholar 

  259. 259.

    Baptista, P. M. et al. The use of whole organ decellularization for the generation of a vascularized liver organoid. Hepatology 53, 604–617 (2011).

    CAS  Google Scholar 

  260. 260.

    Finkbeiner, S. R. et al. Generation of tissue-engineered small intestine using embryonic stem cell-derived human intestinal organoids. Biol. Open 4, 1462–1472 (2015).

    CAS  Google Scholar 

  261. 261.

    Astashkina, A. I., Mann, B. K., Prestwich, G. D. & Grainger, D. W. A 3-D organoid kidney culture model engineered for high-throughput nephrotoxicity assays. Biomaterials 33, 4700–4711 (2012).

    CAS  Google Scholar 

  262. 262.

    Broguiere, N. et al. Growth of epithelial organoids in a defined hydrogel. Adv. Mater. 30, 1801621 (2018).

    Google Scholar 

  263. 263.

    Greggio, C. et al. Artificial three-dimensional niches deconstruct pancreas development in vitro. Development 140, 4452–4462 (2013).

    CAS  Google Scholar 

  264. 264.

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

  265. 265.

    Drumheller, P. D. & Hubbell, J. A. Densely crosslinked polymer networks of poly(ethylene glycol) in trimethylolpropane triacrylate for cell-adhesion-resistant surfaces. J. Biomed. Mater. Res. 29, 207–215 (1995).

    CAS  Google Scholar 

  266. 266.

    Rheinwald, J. G. & Green, H. Formation of a keratinizing epithelium in culture by a cloned cell line derived from a teratoma. Cell 6, 317–330 (1975).

    CAS  Google Scholar 

  267. 267.

    Martin, G. R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl. Acad. Sci. USA 78, 7634–7638 (1981).

    CAS  Google Scholar 

  268. 268.

    Li, M. L. et al. Influence of a reconstituted basement membrane and its components on casein gene expression and secretion in mouse mammary epithelial cells. Proc. Natl. Acad. Sci. USA 84, 136–140 (1987).

    CAS  Google Scholar 

  269. 269.

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

    CAS  Google Scholar 

  270. 270.

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

    CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge financial support from the National Institutes of Health (R21HL138042, R01HL142718, R01EB027666 (S.C.H.), U01DK085527 (C.J.K.), U19AI116484 (S.C.H., C.J.K.)), the National Science Foundation (DMR 1808415 (S.C.H.)), the Human Brain Organogenesis Program funded by the Wu Tsai Neurosciences Institute (S.C.H., S.P.P.), New York Stem Cell Foundation (NYSCF) Robertson Stem Cell Investigator Award (S.P.P.) and the Chan Zuckerberg Initiative (CZI) Ben Barres Award (S.P.P.). The authors thank D. Hunt, B. LaSavage, L. Marquardt and J. Roth for their helpful discussions.

Author information

Affiliations

Authors

Contributions

M.J.K., A.J.S., T.L.L., S.P.P., C.J.K. and S.C.H. wrote, edited and reviewed the manuscript. All authors contributed to the discussion of the content.

Corresponding author

Correspondence to Sarah C. Heilshorn.

Ethics declarations

Competing interests

The authors declare no competing 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

Verify currency and authenticity via CrossMark

Cite this article

Kratochvil, M.J., Seymour, A.J., Li, T.L. et al. Engineered materials for organoid systems. Nat Rev Mater 4, 606–622 (2019). https://doi.org/10.1038/s41578-019-0129-9

Download citation

Further reading

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