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.
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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.
The authors declare no competing interests.
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Cell death in anchorage-dependent cells driven by a lack of cell–extracellular matrix interactions.
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.
The ability of a cell to probe or sense mechanical cues in its extracellular environment, including force, stress, strain, confinement and substrate topology.
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.
Microscale measurements of the mechanical properties of a material.
3D stem cell-derived tissue cultures that exhibit aspects or properties of the parent organ.
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.
A mechanical response on a material that combines characteristics of viscous liquids and elastic solids.
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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