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Effects of extracellular matrix viscoelasticity on cellular behaviour

Abstract

Substantial research over the past two decades has established that extracellular matrix (ECM) elasticity, or stiffness, affects fundamental cellular processes, including spreading, growth, proliferation, migration, differentiation and organoid formation. Linearly elastic polyacrylamide hydrogels and polydimethylsiloxane (PDMS) elastomers coated with ECM proteins are widely used to assess the role of stiffness, and results from such experiments are often assumed to reproduce the effect of the mechanical environment experienced by cells in vivo. However, tissues and ECMs are not linearly elastic materials—they exhibit far more complex mechanical behaviours, including viscoelasticity (a time-dependent response to loading or deformation), as well as mechanical plasticity and nonlinear elasticity. Here we review the complex mechanical behaviours of tissues and ECMs, discuss the effect of ECM viscoelasticity on cells, and describe the potential use of viscoelastic biomaterials in regenerative medicine. Recent work has revealed that matrix viscoelasticity regulates these same fundamental cell processes, and can promote behaviours that are not observed with elastic hydrogels in both two- and three-dimensional culture microenvironments. These findings have provided insights into cell–matrix interactions and how these interactions differentially modulate mechano-sensitive molecular pathways in cells. Moreover, these results suggest design guidelines for the next generation of biomaterials, with the goal of matching tissue and ECM mechanics for in vitro tissue models and applications in regenerative medicine.

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Fig. 1: Mechanical interactions between cells and extracellular matrices.
Fig. 2: Biological tissues and extracellular matrices are viscoelastic and exhibit stress relaxation in response to a deformation.
Fig. 3: The molecular clutch model of mechanotransduction explains the effect of matrix viscoelasticity on cell spreading in two dimensions.
Fig. 4: Matrix viscoplasticity mediates mechanical confinement in three-dimensional culture.
Fig. 5: Designing viscoelastic biomaterials for regenerative medicine.

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Acknowledgements

O.C. acknowledges support from a National Institutes of Health National Cancer Institute grant (R37 CA214136), a National Science Foundation CAREER award (CMMI 1846367), and an American Cancer Society Research Scholar Grant (RSG-16-028-01). J.C.-W. acknowledges support from the Australian Research Council Discovery Grants Scheme (DP190101969). P.A.J. acknowledges NIH awards EB017753, GM136259 and CA193417 and the Penn Materials Research Science and Engineering Center (DMR-1720530). D.J.M. acknowledges support from the NIH (R01 DE013033, U01CA214369) and the Harvard University Materials Research Science and Engineering Center (grant DMR-1420570). V.B.S. acknowledges NIH awards R01EB017753, U01CA202177, U54CA193417 and R01CA232256 and the NSF Center for Engineering Mechanobiology (CMMI-154857).

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Chaudhuri, O., Cooper-White, J., Janmey, P.A. et al. Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature 584, 535–546 (2020). https://doi.org/10.1038/s41586-020-2612-2

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