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Matching material and cellular timescales maximizes cell spreading on viscoelastic substrates
Edited by David A. Weitz, Harvard University, Cambridge, MA, and approved February 5, 2018 (received for review September 21, 2017)

Significance
It is well known that cell proliferation, differentiation, and migration depend strongly on the mechanical stiffness of the extracellular matrix (ECM). Natural ECMs also exhibit dissipative (i.e., plastic, viscoelastic) properties, which can modulate cellular behavior. However, to fully utilize this information in bioengineering applications, a systematic understanding of the role of substrate viscosity on cell function is needed. Using combined theoretical and experimental approaches, we demonstrated that viscous dissipation can be as important as elasticity in determining cell response. Specifically, we found that intermediate viscosity maximizes cell spreading on soft substrates, while cell spreading is independent of viscosity on stiff substrates. This information can now be used to design dissipative biomaterials for optimal control of cell behavior.
Abstract
Recent evidence has shown that, in addition to rigidity, the viscous response of the extracellular matrix (ECM) significantly affects the behavior and function of cells. However, the mechanism behind such mechanosensitivity toward viscoelasticity remains unclear. In this study, we systematically examined the dynamics of motor clutches (i.e., focal adhesions) formed between the cell and a viscoelastic substrate using analytical methods and direct Monte Carlo simulation. Interestingly, we observe that, for low ECM rigidity, maximum cell spreading is achieved at an optimal level of viscosity in which the substrate relaxation time falls between the timescale for clutch binding and its characteristic binding lifetime. That is, viscosity serves to stiffen soft substrates on a timescale faster than the clutch off-rate, which enhances cell−ECM adhesion and cell spreading. On the other hand, for substrates that are stiff, our model predicts that viscosity will not influence cell spreading, since the bound clutches are saturated by the elevated stiffness. The model was tested and validated using experimental measurements on three different material systems and explained the different observed effects of viscosity on each substrate. By capturing the mechanism by which substrate viscoelasticity affects cell spreading across a wide range of material parameters, our analytical model provides a useful tool for designing biomaterials that optimize cellular adhesion and mechanosensing.
Footnotes
- ↵1To whom correspondence may be addressed. Email: vshenoy{at}seas.upenn.edu or ylin{at}hku.hk.
Author contributions: V.B.S. designed research; Z.G., S.R.C., E.E.C., and O.C. performed research; Z.G., S.E.S., X.C., R.L.M., P.A.J., and J.A.B. analyzed data; Z.G., S.E.S., Y.L., and V.B.S. wrote the paper; and S.R.C., E.E.C., and O.C. conducted the experiments.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1716620115/-/DCSupplemental.
Published under the PNAS license.
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- Biophysics and Computational Biology