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Research Article

Matching material and cellular timescales maximizes cell spreading on viscoelastic substrates

Ze Gong, Spencer E. Szczesny, Steven R. Caliari, Elisabeth E. Charrier, Ovijit Chaudhuri, Xuan Cao, Yuan Lin, Robert L. Mauck, Paul A. Janmey, Jason A. Burdick, and Vivek B. Shenoy
PNAS March 20, 2018 115 (12) E2686-E2695; first published March 5, 2018; https://doi.org/10.1073/pnas.1716620115
Ze Gong
aDepartment of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA 19104;
bDepartment of Mechanical Engineering, University of Hong Kong, Hong Kong, China;
cCenter for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104;
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Spencer E. Szczesny
dMcKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Steven R. Caliari
eDepartment of Chemical Engineering, University of Virginia, Charlottesville, VA 22904;
fDepartment of Biomedical Engineering, University of Virginia, Charlottesville, VA 22904;
gDepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104;
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Elisabeth E. Charrier
hInstitute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104;
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Ovijit Chaudhuri
iDepartment of Mechanical Engineering, Stanford University, Stanford, CA 94305
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Xuan Cao
aDepartment of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA 19104;
cCenter for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104;
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Yuan Lin
bDepartment of Mechanical Engineering, University of Hong Kong, Hong Kong, China;
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  • For correspondence: vshenoy@seas.upenn.edu ylin@hku.hk
Robert L. Mauck
cCenter for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104;
dMcKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Paul A. Janmey
cCenter for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104;
hInstitute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104;
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Jason A. Burdick
cCenter for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104;
gDepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104;
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Vivek B. Shenoy
aDepartment of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA 19104;
cCenter for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104;
gDepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104;
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  • For correspondence: vshenoy@seas.upenn.edu ylin@hku.hk
  1. Edited by David A. Weitz, Harvard University, Cambridge, MA, and approved February 5, 2018 (received for review September 21, 2017)

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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.

  • mechanotransduction
  • viscoelasticity
  • cell spreading
  • focal adhesion
  • timescales

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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Matching material and cellular timescales maximizes cell spreading on viscoelastic substrates
Ze Gong, Spencer E. Szczesny, Steven R. Caliari, Elisabeth E. Charrier, Ovijit Chaudhuri, Xuan Cao, Yuan Lin, Robert L. Mauck, Paul A. Janmey, Jason A. Burdick, Vivek B. Shenoy
Proceedings of the National Academy of Sciences Mar 2018, 115 (12) E2686-E2695; DOI: 10.1073/pnas.1716620115

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Matching material and cellular timescales maximizes cell spreading on viscoelastic substrates
Ze Gong, Spencer E. Szczesny, Steven R. Caliari, Elisabeth E. Charrier, Ovijit Chaudhuri, Xuan Cao, Yuan Lin, Robert L. Mauck, Paul A. Janmey, Jason A. Burdick, Vivek B. Shenoy
Proceedings of the National Academy of Sciences Mar 2018, 115 (12) E2686-E2695; DOI: 10.1073/pnas.1716620115
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