Skip to main content

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

  • Primer
  • Published:

Engineered hydrogels for mechanobiology

Nature Reviews Methods Primers volume 2, Article number: 98 (2022) Cite this article

Subjects

Abstract

Cells’ local mechanical environment can be as important in guiding cellular responses as many well-characterized biochemical cues. Hydrogels that mimic the native extracellular matrix can provide these mechanical cues to encapsulated cells, allowing for the study of their impact on cellular behaviours. Moreover, by harnessing cellular responses to mechanical cues, hydrogels can be used to create tissues in vitro for regenerative medicine applications and for disease modelling. This Primer outlines the importance and challenges of creating hydrogels that mimic the mechanical and biological properties of the native extracellular matrix. The design of hydrogels for mechanobiology studies is discussed, including the appropriate choice of cross-linking chemistry and strategies to tailor hydrogel mechanical cues. Techniques for characterizing hydrogels are explained, highlighting methods used to analyse cell behaviour. Example applications in regenerative medicine and for studying fundamental mechanobiological processes are provided, along with a discussion of the limitations of hydrogels as mimetics of the native extracellular matrix. The Primer ends with an outlook for the field, focusing on emerging technologies that will enable new insights into mechanobiology and its role in tissue homeostasis and disease.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Engineered hydrogels replicate ECM and mechanical cues of native tissues.
Fig. 2: Overview of different types of hydrogels.
Fig. 3: Measuring physical properties of hydrogels.
Fig. 4: Analysis of cells in hydrogels.
Fig. 5: Hydrogels for directing stem cell fate by engaging mechanotransduction pathways.
Fig. 6: Engineering hydrogel properties for applications in regenerative medicine, organoid growth, and immune cell activation.

Similar content being viewed by others

References

  1. Petzold, J. & Gentleman, E. Intrinsic mechanical cues and their impact on stem cells and embryogenesis. Front. Cell Dev. Biol. 9, 761871 (2021).

    Article  Google Scholar 

  2. Carey, E. J. Direct observations on the transformation of the mesenchyme in the thigh of the pig embryo (Sus scrofa), with especial reference to the genesis of the thigh muscles, of the knee- and hip-joints, and of the primary bone of the femur. J. Morphol. 37, 1–77 (1922).

    Article  Google Scholar 

  3. Panciera, T., Azzolin, L., Cordenonsi, M. & Piccolo, S. Mechanobiology of YAP and TAZ in physiology and disease. Nat. Rev. Mol. Cell Biol. 18, 758–770 (2017).

    Article  Google Scholar 

  4. van Helvert, S., Storm, C. & Friedl, P. Mechanoreciprocity in cell migration. Nat. Cell Biol. 20, 8–20 (2018).

    Article  Google Scholar 

  5. 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).

    Article  Google Scholar 

  6. Huse, M. Mechanical forces in the immune system. Nat. Rev. Immunol. 17, 679–690 (2017).

    Article  Google Scholar 

  7. Lei, K. et al. Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy. Nat. Biomed. Eng. 5, 1411–1425 (2021).

    Article  Google Scholar 

  8. Dupont, S. & Wickstrom, S. A. Mechanical regulation of chromatin and transcription. Nat. Rev. Genet. 23, 624–643 (2022).

    Article  Google Scholar 

  9. Foyt, D. A., Norman, M. D. A., Yu, T. T. L. & Gentleman, E. Exploiting advanced hydrogel technologies to address key challenges in regenerative medicine. Adv. Healthc. Mater. 7, e1700939 (2018).

    Article  Google Scholar 

  10. Walters, N. J. & Gentleman, E. Evolving insights in cell–matrix interactions: elucidating how non-soluble properties of the extracellular niche direct stem cell fate. Acta Biomater. 11, 3–16 (2015).

    Article  Google Scholar 

  11. Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006). Seminal work that identified a role for 2D matrix stiffness in directing hMSC differentiation.

    Article  Google Scholar 

  12. Gilbert, P. M. et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329, 1078–1081 (2010). This article reports that culturing muscle satellite cells on 2D PEG hydrogels that match the stiffness of native muscle preserves their capacity for self-renewal and to contribute to muscle regeneration.

    Article  ADS  Google Scholar 

  13. Kim, S., Uroz, M., Bays, J. L. & Chen, C. S. Harnessing mechanobiology for tissue engineering. Dev. Cell 56, 180–191 (2021).

    Article  Google Scholar 

  14. Khetan, S. et al. Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels. Nat. Mater. 12, 458–465 (2013). This article highlighted that in covalently cross-linked hydrogels, mechano-sensing in 3D was dependent on cells’ ability to degrade and thus apply traction on their surrounding matrix.

    Article  ADS  Google Scholar 

  15. Huebsch, N. Translational mechanobiology: designing synthetic hydrogel matrices for improved in vitro models and cell-based therapies. Acta Biomater. 94, 97–111 (2019).

    Article  Google Scholar 

  16. Li, L., Eyckmans, J. & Chen, C. S. Designer biomaterials for mechanobiology. Nat. Mater. 16, 1164–1168 (2017).

    Article  ADS  Google Scholar 

  17. Lee, H. P., Gu, L., Mooney, D. J., Levenston, M. E. & Chaudhuri, O. Mechanical confinement regulates cartilage matrix formation by chondrocytes. Nat. Mater. 16, 1243–1251 (2017). This article uses slow and fast relaxing alginate hydrogels to identify how mechanical confinement, which restricts cell volume changes, acts as an adhesion-independent means of 3D mechano-sensing.

    Article  ADS  Google Scholar 

  18. Below, C. R. et al. A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids. Nat. Mater. 21, 110–119 (2022).

    Article  ADS  Google Scholar 

  19. Ruiter, F. A. A. et al. Soft, dynamic hydrogel confinement improves kidney organoid lumen morphology and reduces epithelial–mesenchymal transition in culture. Adv. Sci. 9, e2200543 (2022).

    Article  Google Scholar 

  20. Jowett, G. M. et al. ILC1 drive intestinal epithelial and matrix remodelling. Nat. Mater. 20, 250–259 (2021). This article shows that immune cells co-cultured with human iPSC intestinal organoids within PEG hydrogels prompt mesenchymal cells to remodel their local microenvironment, changing its mechanical stiffness.

    Article  ADS  Google Scholar 

  21. Giobbe, G. G. et al. Extracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture. Nat. Commun. 10, 5658 (2019).

    Article  ADS  Google Scholar 

  22. Kim, S. et al. Tissue extracellular matrix hydrogels as alternatives to Matrigel for culturing gastrointestinal organoids. Nat. Commun. 13, 1692 (2022).

    Article  ADS  Google Scholar 

  23. Moura, B. S. et al. Advancing tissue decellularized hydrogels for engineering human organoids. Adv. Funct. Mater. https://doi.org/10.1002/adfm.202202825 (2022).

    Article  Google Scholar 

  24. 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).

    Article  Google Scholar 

  25. Nichol, J. W. et al. Cell-laden microengineered gelatin methacrylate hydrogels. Biomaterials 31, 5536–5544 (2010).

    Article  Google Scholar 

  26. Singh, R. K., Seliktar, D. & Putnam, A. J. Capillary morphogenesis in PEG–collagen hydrogels. Biomaterials 34, 9331–9340 (2013).

    Article  Google Scholar 

  27. Baldwin, A. D. & Kiick, K. L. Polysaccharide-modified synthetic polymeric biomaterials. Biopolymers 94, 128–140 (2010).

    Article  Google Scholar 

  28. 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).

    Article  ADS  Google Scholar 

  29. 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).

    Article  ADS  Google Scholar 

  30. Phelps, E. A. et al. Maleimide cross-linked bioactive PEG hydrogel exhibits improved reaction kinetics and cross-linking for cell encapsulation and in situ delivery. Adv. Mater. 24, 64–70 (2012).

    Article  Google Scholar 

  31. 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). This article describes using fully synthetic polyisocyanopeptide hydrogels to identify a role for stress stiffening in directing hMSC fate in 3D.

    Article  ADS  Google Scholar 

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

    Article  ADS  Google Scholar 

  33. Zimoch, J. et al. Polyisocyanopeptide hydrogels: a novel thermo-responsive hydrogel supporting pre-vascularization and the development of organotypic structures. Acta Biomater. 70, 129–139 (2018).

    Article  Google Scholar 

  34. Faroni, A., Workman, V. L., Saiani, A. & Reid, A. J. Self-assembling peptide hydrogel matrices improve the neurotrophic potential of human adipose-derived stem cells. Adv. Healthc. Mater. 8, e1900410 (2019).

    Article  Google Scholar 

  35. Kyburz, K. A. & Anseth, K. S. Synthetic mimics of the extracellular matrix: how simple is complex enough? Ann. Biomed. Eng. 43, 489–500 (2015).

    Article  Google Scholar 

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

    Article  Google Scholar 

  37. Reyes, C. D. & Garcia, A. J. Engineering integrin-specific surfaces with a triple-helical collagen-mimetic peptide. J. Biomed. Mater. Res. A 65, 511–523 (2003).

    Article  Google Scholar 

  38. Nagase, H. & Fields, G. B. Human matrix metalloproteinase specificity studies using collagen sequence-based synthetic peptides. Biopolymers 40, 399–416 (1996).

    Article  Google Scholar 

  39. Patterson, J. & Hubbell, J. A. SPARC-derived protease substrates to enhance the plasmin sensitivity of molecularly engineered PEG hydrogels. Biomaterials 32, 1301–1310 (2011).

    Article  Google Scholar 

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

    Article  ADS  Google Scholar 

  41. Hennink, W. E. & van Nostrum, C. F. Novel crosslinking methods to design hydrogels. Adv. Drug Deliv. Rev. 54, 13–36 (2002).

    Article  Google Scholar 

  42. Rizwan, M., Baker, A. E. G. & Shoichet, M. S. Designing hydrogels for 3D cell culture using dynamic covalent crosslinking. Adv. Healthc. Mater. 10, e2100234 (2021).

    Article  Google Scholar 

  43. Wilems, T. S. et al. Effects of free radical initiators on polyethylene glycol dimethacrylate hydrogel properties and biocompatibility. J. Biomed. Mater. Res. A 105, 3059–3068 (2017).

    Article  Google Scholar 

  44. Azagarsamy, M. A. & Anseth, K. S. Bioorthogonal click chemistry: an indispensable tool to create multifaceted cell culture scaffolds. ACS Macro Lett. 2, 5–9 (2013).

    Article  Google Scholar 

  45. Hoyle, C. E. & Bowman, C. N. Thiol–ene click chemistry. Angew. Chem. Int. Ed. 49, 1540–1573 (2010).

    Article  Google Scholar 

  46. Ehrbar, M. et al. Enzymatic formation of modular cell-instructive fibrin analogs for tissue engineering. Biomaterials 28, 3856–3866 (2007).

    Article  Google Scholar 

  47. Hu, B. H. & Messersmith, P. B. Rational design of transglutaminase substrate peptides for rapid enzymatic formation of hydrogels. J. Am. Chem. Soc. 125, 14298–14299 (2003).

    Article  Google Scholar 

  48. Tang, S. C., Richardson, B. M. & Anseth, K. S. Dynamic covalent hydrogels as biomaterials to mimic the viscoelasticity of soft tissues. Prog. Mater. Sci. 120, 100738 (2021).

    Article  Google Scholar 

  49. Parhi, R. Cross-linked hydrogel for pharmaceutical applications: a review. Adv. Pharm. Bull. 7, 515–530 (2017).

    Article  Google Scholar 

  50. Douglas, S. M. et al. Self-assembly of DNA into nanoscale three-dimensional shapes. Nature 459, 414–418 (2009).

    Article  ADS  Google Scholar 

  51. Hartgerink, J. D., Beniash, E. & Stupp, S. I. Self-assembly and mineralization of peptide-amphiphile nanofibers. Science 294, 1684–1688 (2001).

    Article  ADS  Google Scholar 

  52. Chrisnandy, A., Blondel, D., Rezakhani, S., Broguiere, N. & Lutolf, M. P. Synthetic dynamic hydrogels promote degradation-independent in vitro organogenesis. Nat. Mater. 21, 479–487 (2021). This original research article explores recent advances in using hybrid hydrogels (covalent and supramolecular) to create materials that exhibit stress relaxation and support the culture of crypt-bearing intestinal organoids.

    Article  ADS  Google Scholar 

  53. Dankers, P. Y. et al. Hierarchical formation of supramolecular transient networks in water: a modular injectable delivery system. Adv. Mater. 24, 2703–2709 (2012).

    Article  Google Scholar 

  54. Diba, M. et al. Engineering the dynamics of cell adhesion cues in supramolecular hydrogels for facile control over cell encapsulation and behavior. Adv. Mater. 33, e2008111 (2021). This article describes supramocular hydrogels based on the ureido-pyrimidinone motif with tunable mechanical, dynamic and bioactive properties for cell and spheroid encapsulation.

    Article  Google Scholar 

  55. Vereroudakis, E. et al. Competitive supramolecular associations mediate the viscoelasticity of binary hydrogels. ACS Cent. Sci. 6, 1401–1411 (2020).

    Article  Google Scholar 

  56. Hafeez, S. et al. Modular mixing of benzene-1,3,5-tricarboxamide supramolecular hydrogelators allows tunable biomimetic hydrogels for control of cell aggregation in 3D. Biomater. Sci. 10, 4740–4755 (2022).

    Article  Google Scholar 

  57. Loebel, C. et al. Tailoring supramolecular guest–host hydrogel viscoelasticity with covalent fibrinogen double networks. J. Mater. Chem. B 7, 1753–1760 (2019).

    Article  Google Scholar 

  58. Dhand, A. P. et al. Simultaneous one-pot interpenetrating network formation to expand 3D processing capabilities. Adv. Mater. 34, e2202261 (2022).

    Article  Google Scholar 

  59. Evans, N. D. & Gentleman, E. The role of material structure and mechanical properties in cell–matrix interactions. J. Mater. Chem. B 2, 2345–2356 (2014).

    Article  Google Scholar 

  60. Guimaraes, C. F., Gasperini, L., Marques, A. P. & Reis, R. L. The stiffness of living tissues and its implications for tissue engineering. Nat. Rev. Mater. 5, 351–370 (2020).

    Article  ADS  Google Scholar 

  61. Mason, B. N. & Reinhart-King, C. A. Controlling the mechanical properties of three-dimensional matrices via non-enzymatic collagen glycation. Organogenesis 9, 70–75 (2013).

    Article  Google Scholar 

  62. Lust, S. T. et al. Selectively cross-linked tetra-PEG hydrogels provide control over mechanical strength with minimal impact on diffusivity. ACS Biomater. Sci. Eng. 7, 4293–4304 (2021).

    Article  Google Scholar 

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

    Article  ADS  Google Scholar 

  64. Tang, S. et al. Adaptable fast relaxing boronate-based hydrogels for probing cell–matrix interactions. Adv. Sci. 5, 1800638 (2018).

    Article  Google Scholar 

  65. Nam, S., Hu, K. H., Butte, M. J. & Chaudhuri, O. Strain-enhanced stress relaxation impacts nonlinear elasticity in collagen gels. Proc. Natl Acad. Sci. USA 113, 5492–5497 (2016).

    Article  ADS  Google Scholar 

  66. Clark, A. G. et al. Self-generated gradients steer collective migration on viscoelastic collagen networks. Nat. Mater. 21, 1200–1210 (2022).

    Article  ADS  Google Scholar 

  67. McKinnon, D. D., Domaille, D. W., Cha, J. N. & Anseth, K. S. Biophysically defined and cytocompatible covalently adaptable networks as viscoelastic 3D cell culture systems. Adv. Mater. 26, 865–872 (2014).

    Article  Google Scholar 

  68. Alvarez, Z. et al. Bioactive scaffolds with enhanced supramolecular motion promote recovery from spinal cord injury. Science 374, 848–856 (2021).

    Article  ADS  Google Scholar 

  69. Zheng, Y., Kim Liong Han, M., Jiang, Q., Feng, J. & del Campo, A. 4D hydrogel for dynamic cell culture with orthogonal, wavelength-dependent mechanical and biochemical cues. Mater. Horiz. 7, 111–116 (2020).

    Article  Google Scholar 

  70. Kloxin, A. M., Tibbitt, M. W. & Anseth, K. S. Synthesis of photodegradable hydrogels as dynamically tunable cell culture platforms. Nat. Protoc. 5, 1867–1887 (2010).

    Article  Google Scholar 

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

    Article  Google Scholar 

  72. Rosales, A. M., Vega, S. L., DelRio, F. W., Burdick, J. A. & Anseth, K. S. Hydrogels with reversible mechanics to probe dynamic cell microenvironments. Angew. Chem. Int. Ed. 56, 12132–12136 (2017). This articles describes hyaluronic acid-based hydrogels with reversible mechanical properties that rely on photodegradation and photopolymerization strategies.

    Article  Google Scholar 

  73. Doyle, A. D., Carvajal, N., Jin, A., Matsumoto, K. & Yamada, K. M. Local 3D matrix microenvironment regulates cell migration through spatiotemporal dynamics of contractility-dependent adhesions. Nat. Commun. 6, 8720 (2015).

    Article  ADS  Google Scholar 

  74. Aston, R., Sewell, K., Klein, T., Lawrie, G. & Grondahl, L. Evaluation of the impact of freezing preparation techniques on the characterisation of alginate hydrogels by cryo-SEM. E Polym. J. 82, 1–15 (2016).

    Article  Google Scholar 

  75. Moyle, L. A. et al. Three-dimensional niche stiffness synergizes with Wnt7a to modulate the extent of satellite cell symmetric self-renewal divisions. Mol. Biol. Cell 31, 1703–1713 (2020).

    Article  Google Scholar 

  76. Pluen, A., Netti, P. A., Jain, R. K. & Berk, D. A. Diffusion of macromolecules in agarose gels: comparison of linear and globular configurations. Biophys. J. 77, 542–552 (1999).

    Article  Google Scholar 

  77. Cai, L., Dewi, R. E. & Heilshorn, S. C. Injectable hydrogels with in situ double network formation enhance retention of transplanted stem cells. Adv. Funct. Mater. 25, 1344–1351 (2015).

    Article  Google Scholar 

  78. Kang, M., Day, C. A., Kenworthy, A. K. & DiBenedetto, E. Simplified equation to extract diffusion coefficients from confocal FRAP data. Traffic 13, 1589–1600 (2012).

    Article  Google Scholar 

  79. Rehmann, M. S. et al. Tuning and predicting mesh size and protein release from step growth hydrogels. Biomacromolecules 18, 3131–3142 (2017).

    Article  Google Scholar 

  80. Wisdom, K. M. et al. Matrix mechanical plasticity regulates cancer cell migration through confining microenvironments. Nat. Commun. 9, 4144 (2018).

    Article  ADS  Google Scholar 

  81. Nam, S., Lee, J., Brownfield, D. G. & Chaudhuri, O. Viscoplasticity enables mechanical remodeling of matrix by cells. Biophys. J. 111, 2296–2308 (2016).

    Article  ADS  Google Scholar 

  82. Oyen, M. L. Mechanical characterisation of hydrogel materials. Int. Mater. Rev. 59, 44–59 (2014).

    Article  Google Scholar 

  83. Chaudhuri, O., Cooper-White, J., Janmey, P. A., Mooney, D. J. & Shenoy, V. B. Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature 584, 535–546 (2020). This article provides a detailed review of tissue and extracellular matrix viscoelasticity and its impact on cells.

    Article  ADS  Google Scholar 

  84. 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).

    Article  ADS  Google Scholar 

  85. Norman, M. D. A., Ferreira, S. A., Jowett, G. M., Bozec, L. & Gentleman, E. Measuring the elastic modulus of soft culture surfaces and three-dimensional hydrogels using atomic force microscopy. Nat. Protoc. 16, 2418–2449 (2021). This protocol describes how to use atomic force microscopy to measure the elastic modulus of soft hydrogels.

    Article  Google Scholar 

  86. Buxboim, A., Rajagopal, K., Brown, A. E. X. & Discher, D. E. How deeply cells feel: methods for thin gels. J. Phys. Condens. Matter 22, 194116 (2010).

    Article  ADS  Google Scholar 

  87. Tusan, C. G. et al. Collective cell behavior in mechanosensing of substrate thickness. Biophys. J. 114, 2743–2755 (2018).

    Article  ADS  Google Scholar 

  88. Chen, F., Tillberg, P. W. & Boyden, E. S. Optical imaging. Expansion microscopy. Science 347, 543–548 (2015).

    Article  ADS  Google Scholar 

  89. Blatchley, M. R. et al. In situ super-resolution imaging of organoids and extracellular matrix interactions via phototransfer by allyl sulfide exchange-expansion microscopy (PhASE-ExM). Adv. Mater. 34, e2109252 (2022).

    Article  Google Scholar 

  90. Chen, B. C. et al. Lattice light-sheet microscopy: imaging molecules to embryos at high spatiotemporal resolution. Science 346, 1257998 (2014).

    Article  Google Scholar 

  91. Gut, G., Herrmann, M. D. & Pelkmans, L. Multiplexed protein maps link subcellular organization to cellular states. Science 361, eaar7042 (2018).

    Article  Google Scholar 

  92. Hickey, J. W. et al. Spatial mapping of protein composition and tissue organization: a primer for multiplexed antibody-based imaging. Nat. Methods 19, 284–295 (2022).

    Article  Google Scholar 

  93. Ruan, J. L. et al. An improved cryosection method for polyethylene glycol hydrogels used in tissue engineering. Tissue Eng. Part C Methods 19, 794–801 (2013).

    Article  Google Scholar 

  94. Valdez, J. et al. On-demand dissolution of modular, synthetic extracellular matrix reveals local epithelial–stromal communication networks. Biomaterials 130, 90–103 (2017).

    Article  Google Scholar 

  95. 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).

    Article  Google Scholar 

  96. Stowers, R. S. et al. Matrix stiffness induces a tumorigenic phenotype in mammary epithelium through changes in chromatin accessibility. Nat. Biomed. Eng. 3, 1009–1019 (2019).

    Article  Google Scholar 

  97. Madl, C. M., LeSavage, B. L., Khariton, M. & Heilshorn, S. C. Neural progenitor cells alter chromatin organization and neurotrophin expression in response to 3D matrix degradability. Adv. Healthc. Mater. 9, e2000754 (2020).

    Article  Google Scholar 

  98. Qazi, T. H., Mooney, D. J., Duda, G. N. & Geissler, S. Biomaterials that promote cell–cell interactions enhance the paracrine function of MSCs. Biomaterials 140, 103–114 (2017).

    Article  Google Scholar 

  99. Drzeniek, N. M. et al. Bio-instructive hydrogel expands the paracrine potency of mesenchymal stem cells. Biofabrication 13, 045002 (2021).

    Article  Google Scholar 

  100. Ferreira, S. A. et al. Neighboring cells override 3D hydrogel matrix cues to drive human MSC quiescence. Biomaterials 176, 13–23 (2018).

    Article  Google Scholar 

  101. Sawicki, L. A., Choe, L. H., Wiley, K. L., Lee, K. H. & Kloxin, A. M. Isolation and identification of proteins secreted by cells cultured within synthetic hydrogel-based matrices. ACS Biomater. Sci. Eng. 4, 836–845 (2018).

    Article  Google Scholar 

  102. Legant, W. R. et al. Measurement of mechanical tractions exerted by cells in three-dimensional matrices. Nat. Methods 7, 969–971 (2010). This study demonstrated the technique of 3D traction force microscopy to study mechanical interactions between cells and hydrogels in 3D.

    Article  Google Scholar 

  103. Toyjanova, J. et al. 3D viscoelastic traction force microscopy. Soft Matter 10, 8095–8106 (2014).

    Article  ADS  Google Scholar 

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

    Article  ADS  Google Scholar 

  105. Stabley, D. R., Jurchenko, C., Marshall, S. S. & Salaita, K. S. Visualizing mechanical tension across membrane receptors with a fluorescent sensor. Nat. Methods 9, 64–67 (2011).

    Article  Google Scholar 

  106. Shin, D. S. et al. Synthesis of microgel sensors for spatial and temporal monitoring of protease activity. ACS Biomater. Sci. Eng. 4, 378–387 (2018).

    Article  Google Scholar 

  107. Blache, U. et al. Notch-inducing hydrogels reveal a perivascular switch of mesenchymal stem cell fate. EMBO Rep. 19, e45964 (2018).

    Article  Google Scholar 

  108. Ferreira, S. A. et al. Bi-directional cell–pericellular matrix interactions direct stem cell fate. Nat. Commun. 9, 4049 (2018).

    Article  ADS  Google Scholar 

  109. Loebel, C., Mauck, R. L. & Burdick, J. A. Local nascent protein deposition and remodelling guide mesenchymal stromal cell mechanosensing and fate in three-dimensional hydrogels. Nat. Mater. 18, 883–891 (2019).

    Article  ADS  Google Scholar 

  110. Horton, E. R. et al. Extracellular matrix production by mesenchymal stromal cells in hydrogels facilitates cell spreading and is inhibited by FGF-2. Adv. Healthc. Mater. 9, e1901669 (2020).

    Article  Google Scholar 

  111. Schultz, K. M., Kyburz, K. A. & Anseth, K. S. Measuring dynamic cell–material interactions and remodeling during 3D human mesenchymal stem cell migration in hydrogels. Proc. Natl Acad. Sci. USA 112, E3757–E3764 (2015).

    Article  ADS  Google Scholar 

  112. Guo, M. et al. Probing the stochastic, motor-driven properties of the cytoplasm using force spectrum microscopy. Cell 158, 822–832 (2014).

    Article  Google Scholar 

  113. Han, Y. L. et al. Cell swelling, softening and invasion in a three-dimensional breast cancer model. Nat. Phys. 16, 101–108 (2020).

    Article  Google Scholar 

  114. Mizuno, D., Tardin, C., Schmidt, C. F. & Mackintosh, F. C. Nonequilibrium mechanics of active cytoskeletal networks. Science 315, 370–373 (2007).

    Article  ADS  Google Scholar 

  115. Pokki, J., Zisi, I., Schulman, E., Indana, D. & Chaudhuri, O. Magnetic probe-based microrheology reveals local softening and stiffening of 3D collagen matrices by fibroblasts. Biomed. Microdevices 23, 27 (2021).

    Article  Google Scholar 

  116. Swift, J. et al. Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 341, 1240104 (2013).

    Article  Google Scholar 

  117. Iskratsch, T., Wolfenson, H. & Sheetz, M. P. Appreciating force and shape-the rise of mechanotransduction in cell biology. Nat. Rev. Mol. Cell Biol. 15, 825–833 (2014). This perspectives article explores the emergence of the study of mechanobiology and the basics of mechanotransduction, from the timescales associated with mechanotransduction to the formation of focal adhesions and mature stress fibers.

    Article  Google Scholar 

  118. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011). This original research article explores how YAP/TAZ act as sensors during mechanotransduction and mediate cell response to various stimuli including matrix stiffness, cell geometry, and cytoskeletal tension.

    Article  Google Scholar 

  119. Zhao, B., Tumaneng, K. & Guan, K. L. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat. Cell Biol. 13, 877–883 (2011).

    Article  Google Scholar 

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

    Article  ADS  Google Scholar 

  121. Huebsch, N. et al. Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat. Mater. 9, 518–526 (2010). This article was one of the first that identified a role for 3D matrix stiffness in hMSC differentiation, which was driven by integrin binding and reorganoisation of adhesive ligands.

    Article  ADS  Google Scholar 

  122. Blache, U., Stevens, M. M. & Gentleman, E. Harnessing the secreted extracellular matrix to engineer tissues. Nat. Biomed. Eng. 4, 357–363 (2020).

    Article  Google Scholar 

  123. Sharma, B. et al. Human cartilage repair with a photoreactive adhesive–hydrogel composite. Sci. Transl. Med. 5, 167ra166 (2013).

    Article  Google Scholar 

  124. Aisenbrey, E. A. et al. A stereolithography-based 3D printed hybrid scaffold for in situ cartilage defect repair. Macromol. Biosci. 18, 201700267 (2018).

    Article  Google Scholar 

  125. Coluccino, L. et al. Porous poly(vinyl alcohol)-based hydrogel for knee meniscus functional repair. ACS Biomater. Sci. Eng. 4, 1518–1527 (2018).

    Google Scholar 

  126. Fujii, M. & Sato, T. Somatic cell-derived organoids as prototypes of human epithelial tissues and diseases. Nat. Mater. 20, 156–169 (2021).

    Article  ADS  Google Scholar 

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

    Article  ADS  Google Scholar 

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

    Article  ADS  Google Scholar 

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

    Article  Google Scholar 

  130. Pagliuca, F. W. et al. Generation of functional human pancreatic β cells in vitro. Cell 159, 428–439 (2014).

    Article  Google Scholar 

  131. Takasato, M. et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 536, 238 (2016).

    Article  ADS  Google Scholar 

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

    Article  Google Scholar 

  133. Kratochvil, M. J. et al. Engineered materials for organoid systems. Nat. Rev. Mater. 4, 606–622 (2019).

    Article  ADS  Google Scholar 

  134. Gjorevski, N. et al. Designer matrices for intestinal stem cell and organoid culture. Nature 539, 560–564 (2016). This article was the first to report using synthetic hydrogels to support murine intestinal organoids and identified roles for 3D matrix stiffness and degradability in maintaining their culture.

    Article  Google Scholar 

  135. Gjorevski, N. et al. Tissue geometry drives deterministic organoid patterning. Science 375, eaaw9021 (2022).

    Article  Google Scholar 

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

    Article  Google Scholar 

  137. Indana, D., Agarwal, P., Bhutani, N. & Chaudhuri, O. Viscoelasticity and adhesion signaling in biomaterials control human pluripotent stem cell morphogenesis in 3D culture. Adv. Mater. 33, e2101966 (2021).

    Article  Google Scholar 

  138. Decembrini, S., Hoehnel, S., Brandenberg, N., Arsenijevic, Y. & Lutolf, M. P. Hydrogel-based milliwell arrays for standardized and scalable retinal organoid cultures. Sci. Rep. 10, 10275 (2020).

    Article  ADS  Google Scholar 

  139. Brandenberg, N. et al. High-throughput automated organoid culture via stem-cell aggregation in microcavity arrays. Nat. Biomed. Eng. 4, 863–874 (2020).

    Article  Google Scholar 

  140. Luciano, M. et al. Cell monolayers sense curvature by exploiting active mechanics and nuclear mechanoadaptation. Nat. Phys. 17, 1382 (2021).

    Article  Google Scholar 

  141. Pahapale, G. J. et al. Directing multicellular organization by varying the aspect ratio of soft hydrogel microwells. Adv. Sci. 9, e2104649 (2022).

    Article  Google Scholar 

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

    Article  Google Scholar 

  143. Sorrentino, G. et al. Mechano-modulatory synthetic niches for liver organoid derivation. Nat. Commun. 11, 3416 (2020).

    Article  ADS  Google Scholar 

  144. Yoder, B. K. Role of primary cilia in the pathogenesis of polycystic kidney disease. J. Am. Soc. Nephrol. 18, 1381–1388 (2007).

    Article  Google Scholar 

  145. Bernink, J. H. et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol. 14, 221–229 (2013).

    Article  Google Scholar 

  146. Davidson, M. D., Burdick, J. A. & Wells, R. G. Engineered biomaterial platforms to study fibrosis. Adv. Healthc. Mater. 9, e1901682 (2020).

    Article  Google Scholar 

  147. Batan, D. et al. Hydrogel cultures reveal transient receptor potential vanilloid 4 regulation of myofibroblast activation and proliferation in valvular interstitial cells. FASEB J. 36, e22306 (2022).

    Article  Google Scholar 

  148. Sadeghi, A. H. et al. Engineered 3D cardiac fibrotic tissue to study fibrotic remodeling. Adv. Healthc. Mater. 6, 201601434 (2017).

    Google Scholar 

  149. Spill, F., Reynolds, D. S., Kamm, R. D. & Zaman, M. H. Impact of the physical microenvironment on tumor progression and metastasis. Curr. Opin. Biotechnol. 40, 41–48 (2016).

    Article  Google Scholar 

  150. Zaman, M. H. The role of engineering approaches in analysing cancer invasion and metastasis. Nat. Rev. Cancer 13, 596–603 (2013).

    Article  Google Scholar 

  151. Zhang, X. et al. Unraveling the mechanobiology of immune cells. Curr. Opin. Biotechnol. 66, 236–245 (2020).

    Article  Google Scholar 

  152. Judokusumo, E., Tabdanov, E., Kumari, S., Dustin, M. L. & Kam, L. C. Mechanosensing in T lymphocyte activation. Biophys. J. 102, L5–L7 (2012).

    Article  Google Scholar 

  153. Harrison, D. L., Fang, Y. & Huang, J. T-cell mechanobiology: force sensation, potentiation, and translation. Front. Phys. 7, 45 (2019).

    Article  Google Scholar 

  154. Chin, M. H. W., Norman, M. D. A., Gentleman, E., Coppens, M. O. & Day, R. M. A Hydrogel-integrated culture device to interrogate T cell activation with physicochemical cues. ACS Appl. Mater. Interfaces 12, 47355–47367 (2020).

    Article  Google Scholar 

  155. O’Connor, R. S. et al. Substrate rigidity regulates human T cell activation and proliferation. J. Immunol. 189, 1330–1339 (2012).

    Article  Google Scholar 

  156. Alatoom, A. et al. Artificial biosystem for modulation of interactions between antigen-presenting cells and T cells. Adv. Biosyst. 4, e2000039 (2020).

    Article  Google Scholar 

  157. Zhang, J. et al. Micropatterned soft hydrogels to study the interplay of receptors and forces in T cell activation. Acta Biomater. 119, 234–246 (2021).

    Article  Google Scholar 

  158. Hickey, J. W. et al. Engineering an artificial T-cell stimulating matrix for immunotherapy. Adv. Mater. 31, e1807359 (2019). This article shows that the biophysical properties of engineered HA hydrogels potentiate T cell stimulation, which can be harnessed for adoptive immunotherapy.

    Article  Google Scholar 

  159. Majedi, F. S. et al. T-cell activation is modulated by the 3D mechanical microenvironment. Biomaterials 252, 120058 (2020).

    Article  Google Scholar 

  160. Chin, M. H. W., Gentleman, E., Coppens, M. O. & Day, R. M. Rethinking cancer immunotherapy by embracing and engineering complexity. Trends Biotechnol. 38, 1054–1065 (2020).

    Article  Google Scholar 

  161. Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

    Article  Google Scholar 

  162. Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).

    Article  Google Scholar 

  163. Schuster, S. J. et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380, 45–56 (2019).

    Article  Google Scholar 

  164. Blache, U., Popp, G., Dünkel, A., Koehl, U. & Fricke, S. Potential solutions for manufacture of CAR T cells in cancer immunotherapy. Nat. Commun. 13, 5225 (2022).

    Article  ADS  Google Scholar 

  165. Finck, A. V., Blanchard, T., Roselle, C. P., Golinelli, G. & June, C. H. Engineered cellular immunotherapies in cancer and beyond. Nat. Med. 28, 678–689 (2022).

    Article  Google Scholar 

  166. Hu, Q. et al. Inhibition of post-surgery tumour recurrence via a hydrogel releasing CAR-T cells and anti-PDL1-conjugated platelets. Nat. Biomed. Eng. 5, 1038–1047 (2021).

    Article  Google Scholar 

  167. Wang, K. et al. GD2-specific CAR T cells encapsulated in an injectable hydrogel control retinoblastoma and preserve vision. Nat. Cancer 1, 990–997 (2020).

    Article  Google Scholar 

  168. Barrett, T. et al. NCBI GEO: archive for functional genomics data sets — update. Nucleic Acids Res. 41, D991–D995 (2013).

    Article  Google Scholar 

  169. Blache, U. et al. Mesenchymal stromal cell activation by breast cancer secretomes in bioengineered 3D microenvironments. Life Sci. Alliance 2, e201900304 (2019).

    Article  Google Scholar 

  170. Vizcaino, J. A. et al. ProteomeXchange provides globally coordinated proteomics data submission and dissemination. Nat. Biotechnol. 32, 223–226 (2014).

    Article  Google Scholar 

  171. Trappmann, B. et al. Extracellular-matrix tethering regulates stem-cell fate. Nat. Mater. 11, 642–649 (2012). This manuscript shows that varying nanoscale anchoring distance of cell adhesive ligands on soft hydrogels potentiates stiffness sensing to guide cell fate.

    Article  ADS  Google Scholar 

  172. Wen, J. H. et al. Interplay of matrix stiffness and protein tethering in stem cell differentiation. Nat. Mater. 13, 979–987 (2014).

    Article  ADS  Google Scholar 

  173. Cossu, G. et al. Lancet commission: stem cells and regenerative medicine. Lancet 391, 883–910 (2018).

    Article  Google Scholar 

  174. Sun, J. Y. et al. Highly stretchable and tough hydrogels. Nature 489, 133–136 (2012).

    Article  ADS  Google Scholar 

  175. Xu, L. et al. Conjoined-network rendered stiff and tough hydrogels from biogenic molecules. Sci. Adv. 5, eaau3442 (2019).

    Article  ADS  Google Scholar 

  176. Rodrigo-Navarro, A., Sankaran, S., Dalby, M. J., del Campo, A. & Salmeron-Sanchez, M. Engineered living biomaterials. Nat. Rev. Mater. 6, 1175–1190 (2021).

    Article  ADS  Google Scholar 

  177. Neves, S. C., Moroni, L., Barrias, C. C. & Granja, P. L. Leveling up hydrogels: hybrid systems in tissue engineering. Trends Biotechnol. 38, 292–315 (2020).

    Article  Google Scholar 

  178. Champeau, M. et al. 4D printing of hydrogels: a review. Adv. Funct. Mater. 30, 1910606 (2020).

    Article  Google Scholar 

  179. Weiss, F., Lauffenburger, D. & Friedl, P. Towards targeting of shared mechanisms of cancer metastasis and therapy resistance. Nat. Rev. Cancer 22, 157–173 (2022).

    Article  Google Scholar 

  180. Shellard, A. & Mayor, R. Collective durotaxis along a self-generated stiffness gradient in vivo. Nature 600, 690–694 (2021). This article demonstrates that embryonic cell populations self-generate a stiffness gradient to collectively direct their migration by durotaxis.

    Article  ADS  Google Scholar 

  181. Davidson, M. D. et al. Programmable and contractile materials through cell encapsulation in fibrous hydrogel assemblies. Sci. Adv. 7, eabi8157 (2021).

    Article  ADS  Google Scholar 

  182. Mok, S. et al. Mapping cellular-scale internal mechanics in 3D tissues with thermally responsive hydrogel probes. Nat. Commun. 11, 4757 (2020).

    Article  ADS  Google Scholar 

  183. Daly, A. C., Riley, L., Segura, T. & Burdick, J. A. Hydrogel microparticles for biomedical applications. Nat. Rev. Mater. 5, 20–43 (2020).

    Article  ADS  Google Scholar 

  184. Shadish, J. A., Benuska, G. M. & DeForest, C. A. Bioactive site-specifically modified proteins for 4D patterning of gel biomaterials. Nat. Mater. 18, 1005–1014 (2019).

    Article  ADS  Google Scholar 

  185. Baneyx, G., Baugh, L. & Vogel, V. Coexisting conformations of fibronectin in cell culture imaged using fluorescence resonance energy transfer. Proc. Natl Acad. Sci. USA 98, 14464–14468 (2001).

    Article  ADS  Google Scholar 

  186. Legant, W. R. et al. High-density three-dimensional localization microscopy across large volumes. Nat. Methods 13, 359–365 (2016).

    Article  Google Scholar 

  187. Razafiarison, T. et al. Biomaterial surface energy-driven ligand assembly strongly regulates stem cell mechanosensitivity and fate on very soft substrates. Proc. Natl Acad. Sci. USA 115, 4631–4636 (2018). This study shows that cell mechanotransduction and fate depend heavily on hydrogel hydrophilicity and the conformation of secreted matrix proteins.

    Article  ADS  Google Scholar 

  188. Davidson, M. D. et al. Mechanochemical adhesion and plasticity in multifiber hydrogel networks. Adv. Mater. 32, e1905719 (2020).

    Article  Google Scholar 

  189. Friedl, P. & Alexander, S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147, 992–1009 (2011).

    Article  Google Scholar 

  190. Weigelin, B., Bakker, G. J. & Friedl, P. Intravital third harmonic generation microscopy of collective melanoma cell invasion: principles of interface guidance and microvesicle dynamics. Intravital 1, 32–43 (2012).

    Article  Google Scholar 

  191. Charelli, L. E., Ferreira, J. P. D., Naveira-Cotta, C. P. & Balbino, T. A. Engineering mechanobiology through organoids-on-chip: a strategy to boost therapeutics. J. Tissue Eng. Regen. Med. 15, 883–899 (2021).

    Article  Google Scholar 

  192. Zhang, Y. S. et al. 3D extrusion bioprinting. Nat. Rev. Methods Primers 1, 75 (2021).

    Article  Google Scholar 

  193. Liu, L. et al. Cyclic stiffness modulation of cell-laden protein–polymer hydrogels in response to user-specified stimuli including light. Adv. Biosyst. 2, 201800240 (2018).

    Google Scholar 

  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).

    Article  Google Scholar 

  195. Arkenberg, M. R., Moore, D. M. & Lin, C. C. Dynamic control of hydrogel crosslinking via sortase-mediated reversible transpeptidation. Acta Biomater. 83, 83–95 (2019).

    Article  Google Scholar 

  196. Broguiere, N., Formica, F. A., Barreto, G. & Zenobi-Wong, M. Sortase A as a cross-linking enzyme in tissue engineering. Acta Biomater. 77, 182–190 (2018).

    Article  Google Scholar 

  197. Corral-Acero, J. et al. The ‘Digital Twin’ to enable the vision of precision cardiology. Eur. Heart J. 41, 4556–4564 (2020).

    Article  Google Scholar 

  198. Garcia, R. Nanomechanical mapping of soft materials with the atomic force microscope: methods, theory and applications. Chem. Soc. Rev. 49, 5850–5884 (2020).

    Article  Google Scholar 

  199. Seliktar, D. Designing cell-compatible hydrogels for biomedical applications. Science 336, 1124–1128 (2012).

    Article  ADS  Google Scholar 

Download references

Acknowledgements

U.B. acknowledges funding from the Fraunhofer Cluster of Immune Mediated Diseases (CIMD). L.R. and P.Y.W.D. gratefully acknowledge the Gravitation Program ‘Materials Driven Regeneration’, funded by the Netherlands Organization for Scientific Research (024.003.013). O.C. acknowledges support from a National Institutes of Health (NIH) National Cancer Institute grant (R37 CA214136). B.H. acknowledges support from a US National Science Foundation (NSF) Postdoctoral Fellowship in Biology grant (2209411). E.G. acknowledges support from the UK Regenerative Medicine Platform ‘Acellular/Smart Materials — 3D Architecture’ (MR/R015651/1) and the Rosetrees Trust. E.M.F. and A.M.K. acknowledge support from the NIH Director’s New Innovator Award (DP2 HL152424-01) and from the NSF through the University of Delaware Materials Research Science and Engineering Center (DMR-2011824). The authors thank B. Simona for providing helpful suggestions during manuscript revision.

Author information

Authors and Affiliations

  1. Fraunhofer Institute for Cell Therapy and Immunology and Fraunhofer Cluster of Excellence for Immune-Mediated Disease, Leipzig, Germany

    Ulrich Blache

  2. Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, USA

    Eden M. Ford & April M. Kloxin

  3. Department of Mechanical Engineering, Stanford University, Stanford, CA, USA

    Byunghang Ha & Ovijit Chaudhuri

  4. Institute for Complex Molecular Systems, Department of Biomedical Engineering, Laboratory of Chemical Biology, Eindhoven University of Technology, Eindhoven, Netherlands

    Laura Rijns & Patricia Y. W. Dankers

  5. Department of Material Science and Engineering, University of Delaware, Newark, DE, USA

    April M. Kloxin

  6. University Hospital Balgrist and ETH Zurich, Zurich, Switzerland

    Jess G. Snedeker

  7. Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK

    Eileen Gentleman

Authors
  1. Ulrich Blache
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eden M. Ford
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Byunghang Ha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura Rijns
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ovijit Chaudhuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Patricia Y. W. Dankers
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. April M. Kloxin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jess G. Snedeker
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eileen Gentleman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Introduction (E.G. and U.B.); Experimentation (E.G., U.B., L.R., O.C., P.Y.W.D. and J.G.S.); Results (E.G., U.B., O.C. and B.H.); Applications (E.G., U.B., E.M.F. and A.M.K.); Reproducibility and data deposition (E.G., U.B., E.M.F. and A.M.K.); Limitations and optimizations (E.G., U.B. and J.G.S.); Outlook (E.G. and U.B.); Overview of the Primer (E.G.).

Corresponding author

Correspondence to Eileen Gentleman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Methods Primers thanks Sara Baratchi, Sylvain Gabriele and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

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

Glossary

Anoikis

Cell death in anchorage-dependent cells driven by a lack of cell–extracellular matrix interactions.

Creep

The process by which a viscoelastic material undergoes gradually increasing and irreversible deformation in response to a constant applied force.

Disease modelling

The modelling of a diseased tissue using animal models or cells/organoids cultured in vitro to study disease progression and possible treatment.

Elastic modulus

The tangent of a material’s stress–strain curve, which is an intrinsic property of the material. The modulus is a measure of stiffness that is independent of the material’s size and geometry.

Matrix metalloproteinase

(MMP). A class of cellular proteases that biochemically degrade extracellular matrix proteins.

Mechanosensing

The ability of a cell to probe or sense mechanical cues in its extracellular environment, including force, stress, strain, confinement and substrate topology.

Mechanotransduction

The cellular conversion of mechanical stimuli into biochemical signalling, such as via activation of receptors, signalling pathways, transcriptional activity or protein activation.

Mesh size

The distance between polymers or cross-link points in a polymer network. Mesh size can impact solute diffusivity.

Micro-rheology

Microscale measurements of the mechanical properties of a material.

Organoids

3D stem cell-derived tissue cultures that exhibit aspects or properties of the parent organ.

Stiffness

A material’s ability to resist deformation in response to an applied force.

Stress relaxation

The process by which a viscoelastic material, which initially resists an applied strain, reduces its resistance to the deformation over time. In hydrogels this is often related to fluid movements within the solid material backbone, or in weakly cross-linked hydrogels to the unbinding of weak cross links followed by polymer flow.

Stress stiffening

The process by which materials stiffen due to an applied strain, sometimes as a result of fibre alignment.

Tissue engineering

The combination of biologically active materials platforms with cells to develop systems that may be used to restore or treat damaged tissues.

Viscoelasticity

A mechanical response on a material that combines characteristics of viscous liquids and elastic solids.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blache, U., Ford, E.M., Ha, B. et al. Engineered hydrogels for mechanobiology. Nat Rev Methods Primers 2, 98 (2022). https://doi.org/10.1038/s43586-022-00179-7

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s43586-022-00179-7

This article is cited by

Search

Advanced 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