Annals of Biomedical Engineering

, Volume 42, Issue 5, pp 1037–1048 | Cite as

Influence of Spreading and Contractility on Cell Detachment

  • Enda P. Dowling
  • J. Patrick McGarry


Cell adhesion is a key phenomenon that affects fundamental cellular processes such as morphology, migration, and differentiation. In the current study, an active modelling framework incorporating actin cytoskeleton remodelling and contractility, combined with a cohesive zone model to simulate debonding at the cell–substrate interface, is implemented to investigate the increased resistance to detachment of highly spread chondrocytes from a substrate, as observed experimentally by Huang et al. (J. Orthop. Res. 21: 88–95, 2003). 3D finite element meshes of the round and spread cell geometries with the same material properties are created. It is demonstrated that spread cells with a flattened morphology and a larger adhesion area have a more highly developed actin cytoskeleton than rounded cells. Rounded cells provide less support for tension generated by the actin cytoskeleton; hence, a high level of dissociation is predicted. It is revealed that the more highly developed active contractile actin cytoskeleton of the spread cell increases the resistance to shear deformation, and subsequently increases the shear detachment force. These findings provide new insight into the link between cell geometry, cell contractility, and cell–substrate detachment.


Actin cytoskeleton Chondrocyte Cartilage Finite element modelling Cell mechanics In vitro shear Cell adhesion 



Funding support was provided by the Irish Research Council for Science, Engineering and Technology (IRCSET) postgraduate scholarship under the EMBARK initiative, and by the Science Foundation Ireland Research Frontiers Programme (SFI-RFP/ENM1726). The authors wish to acknowledge the SFI/HEA Irish Centre for High-End Computing (ICHEC) for the provision of computational facilities and support. The authors would like to thank Prof. K.A. Athanasiou, Prof. V.S. Deshpande, Prof. R.M. McMeeking, and Dr. W. Ronan for helpful discussions and insights relating to this study.

Supplementary material

10439_2013_965_MOESM1_ESM.pdf (481 kb)
Supplementary material 1 (PDF 481 kb)


  1. 1.
    Brown, P. D., and P. D. Benya. Alterations in chondrocyte cytoskeletal architecture during phenotypic modulation by retinoic acid and dihydrocytochalasin B-induced reexpression. J. Cell Biol. 106:171–179, 1988.PubMedCrossRefGoogle Scholar
  2. 2.
    Buckwalter, J., and H. Mankin. Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation. Instr. Course Lect. 47:487, 1998.PubMedGoogle Scholar
  3. 3.
    Caille, N., O. Thoumine, Y. Tardy, and J.-. J. Meister. Contribution of the nucleus to the mechanical properties of endothelial cells. J. Biomech. 35:177–187, 2002.PubMedCrossRefGoogle Scholar
  4. 4.
    Chen, C. S., J. L. Alonso, E. Ostuni, G. M. Whitesides, and D. E. Ingber. Cell shape provides global control of focal adhesion assembly. Biochem. Biophys. Res. Commun. 307:355–361, 2003.PubMedCrossRefGoogle Scholar
  5. 5.
    Chen, J., J. Irianto, S. Inamdar, P. Pravincumar, D. A. Lee, D. L. Bader, and M. M. Knight. Cell mechanics, structure, and function are regulated by the stiffness of the three-dimensional microenvironment. Biophys. J. 103:1188–1197, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Cheng, Q., P. Liu, H. Gao, and Y. Zhang. A computational modeling for micropipette-manipulated cell detachment from a substrate mediated by receptor–ligand binding. J. Mech. Phys. Solids 57:205–220, 2009.CrossRefGoogle Scholar
  7. 7.
    Chrzanowska-Wodnicka, M., and K. Burridge. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J. Cell Biol. 133:1403–1415, 1996.PubMedCrossRefGoogle Scholar
  8. 8.
    Darling, E. M., and K. A. Athanasiou. Rapid phenotypic changes in passaged articular chondrocyte subpopulations. J. Orthop. Res. 23:425–432, 2005.PubMedCrossRefGoogle Scholar
  9. 9.
    Deshpande, V. S., R. M. McMeeking, and A. G. Evans. A bio–chemo–mechanical model for cell contractility. Proc. Natl. Acad. Sci. 103:14015–14020, 2006.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Deshpande, V. S., M. Mrksich, R. M. McMeeking, and A. G. Evans. A bio–mechanical model for coupling cell contractility with focal adhesion formation. J. Mech. Phys. Solids 56:1484–1510, 2008.CrossRefGoogle Scholar
  11. 11.
    Dowling, E. P., W. Ronan, and J. P. McGarry. Computational investigation of in situ chondrocyte deformation and actin cytoskeleton remodelling under physiological loading. Acta Biomater. 9:5943–5955, 2012.PubMedCrossRefGoogle Scholar
  12. 12.
    Dowling, E. P., W. Ronan, G. Ofek, V. Deshpande, R. M. McMeeking, K. A. Athanasiou, and J. P. McGarry. The effect of remodelling and contractility of the actin cytoskeleton on the shear resistance of single cells: a computational and experimental investigation. J. R. Soc. Interface 9:3469–3479, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Engler, A., L. Bacakova, C. Newman, A. Hategan, M. Griffin, and D. Discher. Substrate compliance versus ligand density in cell on gel responses. Biophys. J. 86:617–628, 2004.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Frenkel, S. R., R. M. Clancy, J. L. Ricci, P. E. Di Cesare, J. J. Rediske, and S. B. Abramson. Effects of nitric oxide on chondrocyte migration, adhesion, and cytoskeletal assembly. Arthritis Rheum. 39:1905–1912, 1996.PubMedCrossRefGoogle Scholar
  15. 15.
    Genes, N. G., J. A. Rowley, D. J. Mooney, and L. J. Bonassar. Effect of substrate mechanics on chondrocyte adhesion to modified alginate surfaces. Arch. Biochem. Biophys. 422:161–167, 2004.PubMedCrossRefGoogle Scholar
  16. 16.
    Haudenschild, D. R., J. Chen, N. Steklov, M. K. Lotz, and D. D. D’Lima. Characterization of the chondrocyte actin cytoskeleton in living three-dimensional culture: response to anabolic and catabolic stimuli. Mol. Cell. Biomech. 6:135–144, 2009.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Huang, W., A. J. H. Bahman, R. Torres, G. Lebaron, and K. A. Athanasiou. Temporal effects of cell adhesion on mechanical characteristics of the single chondrocyte. J. Orthop. Res. 21:88–95, 2003.PubMedCrossRefGoogle Scholar
  18. 18.
    Idowu, B. D., M. M. Knight, D. L. Bader, and D. A. Lee. Confocal analysis of cytoskeletal organisation within isolated chondrocyte sub-populations cultured in agarose. Histochem. J. 32:165–174, 2000.PubMedCrossRefGoogle Scholar
  19. 19.
    Ishaug-Riley, S. L., L. E. Okun, G. Prado, M. A. Applegate, and A. Ratcliffe. Human articular chondrocyte adhesion and proliferation on synthetic biodegradable polymer films. Biomaterials 20:2245–2256, 1999.PubMedCrossRefGoogle Scholar
  20. 20.
    Jean, R. P., C. S. Chen, and A. A. Spector. Finite-element analysis of the adhesion–cytoskeleton–nucleus mechanotransduction pathway during endothelial cell rounding: axisymmetric model. J. Biomech. Eng. 127:594–600, 2005.PubMedCrossRefGoogle Scholar
  21. 21.
    Knight, M. M., B. D. Idowu, D. A. Lee, and D. L. Bader. Temporal changes in cytoskeletal organisation within isolated chondrocytes quantified using a novel image analysis technique. Med. Biol. Eng. Comput. 39:397–404, 2001.PubMedCrossRefGoogle Scholar
  22. 22.
    Knight, M. M., T. Toyoda, D. A. Lee, and D. L. Bader. Mechanical compression and hydrostatic pressure induce reversible changes in actin cytoskeletal organisation in chondrocytes in agarose. J. Biomech. 39:1547–1551, 2006.PubMedCrossRefGoogle Scholar
  23. 23.
    Kurtis, M. S., B. P. Tu, O. A. Gaya, J. Mollenhauer, W. Knudson, R. F. Loeser, C. B. Knudson, and R. L. Sah. Mechanisms of chondrocyte adhesion to cartilage: role of β1-integrins, CD44, and annexin V. J. Orthop. Res. 19:1122–1130, 2006.CrossRefGoogle Scholar
  24. 24.
    Leckband, D., and J. Israelachvili. Intermolecular forces in biology. Q. Rev. Biophys. 34:105–267, 2001.PubMedCrossRefGoogle Scholar
  25. 25.
    Li, W. J., Y. J. Jiang, and R. S. Tuan. Chondrocyte phenotype in engineered fibrous matrix is regulated by fiber size. Tissue Eng. Part A 12:1775–1785, 2006.CrossRefGoogle Scholar
  26. 26.
    Lyman, J. R., J. D. Chappell, T. I. Morales, S. S. Kelley, and G. M. Lee. Response of chondrocytes to local mechanical injury in an ex vivo model. Cartilage 3:58–69, 2012.CrossRefGoogle Scholar
  27. 27.
    Máirtín, É. Ó., G. Parry, G. E. Beltz, and J. P. McGarry. Potential-based and non-potential-based cohesive zone formulations under mixed-mode separation and over-closure—part II: finite element applications. J. Mech. Phys. Solids, 2013.Google Scholar
  28. 28.
    Mallein-Gerin, F., R. Garrone, and M. Van der Rest. Proteoglycan and collagen synthesis are correlated with actin organization in dedifferentiating chondrocytes. Eur. J. Cell Biol. 56:364–373, 1991.PubMedGoogle Scholar
  29. 29.
    McGarry, J. P. Characterization of cell mechanical properties by computational modeling of parallel plate compression. Ann. Biomed. Eng. 37:2317–2325, 2009.PubMedCrossRefGoogle Scholar
  30. 30.
    McGarry, J. P., É. Ó Máirtín, G. Parry, and G. E. Beltz. Potential-based and non-potential-based cohesive zone formulations under mixed-mode separation and over-closure. Part I: Theoretical analysis. J. Mech. Phys. Solids, 2013.Google Scholar
  31. 31.
    McGarry, J. P., J. Fu, M. T. Yang, C. S. Chen, R. M. McMeeking, A. G. Evans, and V. S. Deshpande. Simulation of the contractile response of cells on an array of micro-posts. Philos. Trans. R. Soc. A Math. Phys. Eng. Sci. 367:3477–3497, 2009.CrossRefGoogle Scholar
  32. 32.
    McGarry, J. P., and P. E. McHugh. Modelling of in vitro chondrocyte detachment. J. Mech. Phys. Solids 56:1554–1565, 2008.CrossRefGoogle Scholar
  33. 33.
    McGarry, J. P., B. P. Murphy, and P. E. McHugh. Computational mechanics modelling of cell–substrate contact during cyclic substrate deformation. J. Mech. Phys. Solids 53:2597–2637, 2005.CrossRefGoogle Scholar
  34. 34.
    McGarry, J., and P. Prendergast. A three-dimensional finite element model of an adherent eukaryotic cell. Eur. Cell. Mater. 7:27–33, 2004.PubMedGoogle Scholar
  35. 35.
    Ofek, G., E. P. Dowling, R. M. Raphael, J. P. McGarry, and K. A. Athanasiou. Biomechanics of single chondrocytes under direct shear. Biomech. Model. Mechanobiol. 9:153–162, 2009.PubMedCrossRefGoogle Scholar
  36. 36.
    Parker, K. K., A. L. Brock, C. Brangwynne, R. J. Mannix, N. Wang, E. Ostuni, N. A. Geisse, J. C. Adams, G. M. Whitesides, and D. E. Ingber. Directional control of lamellipodia extension by constraining cell shape and orienting cell tractional forces. FASEB J. 16:1195–1204, 2002.PubMedCrossRefGoogle Scholar
  37. 37.
    Pathak, A., V. S. Deshpande, R. M. McMeeking, and A. G. Evans. The simulation of stress fibre and focal adhesion development in cells on patterned substrates. J. R. Soc. Interface 5:507–524, 2008.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Riveline, D., E. Zamir, N. Q. Balaban, U. S. Schwarz, T. Ishizaki, S. Narumiya, Z. Kam, B. Geiger, and A. D. Bershadsky. Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism. J. Cell Biol. 153:1175–1186, 2001.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Rodriguez, M. L., J. P. McGarry, and N. J. Sniadecki. Review on cell mechanics: experimental and modeling approaches. Appl. Mech. Rev. 65, 2013.Google Scholar
  40. 40.
    Ronan, W., V. Deshpande, R. M. McMeeking, and J. P. McGarry. Numerical investigation of the active role of the cytoskeleton in the compression resistance of cells. J. Mech. Behav. Biomed. Mater. 14:143–157, 2012.PubMedCrossRefGoogle Scholar
  41. 41.
    Ronan, W., V. Deshpande, R. M. McMeeking, and J. P. McGarry. Cellular contractility and substrate elasticity: a numerical investigation of the actin cytoskeleton and cell adhesion. Biomech. Model. Mechanobiol. 2013. doi: 10.1007/s10237-013-0506-z.PubMedGoogle Scholar
  42. 42.
    Ronan, W., P. McGarry, A. Pathak, V. Deshpande, and R. McMeeking. Simulation of the mechanical response of cells on micro-post substrates. J. Biomech. Eng. 135, 2013.Google Scholar
  43. 43.
    Schinagl, R. M., M. S. Kurtis, K. D. Ellis, S. Chien, and R. L. Sah. Effect of seeding duration on the strength of chondrocyte adhesion to articular cartilage. J. Orthop. Res. 17:121–129, 1999.PubMedCrossRefGoogle Scholar
  44. 44.
    Tan, J. L., J. Tien, D. M. Pirone, D. S. Gray, K. Bhadriraju, and C. S. Chen. Cells lying on a bed of microneedles: an approach to isolate mechanical force. Proc. Natl. Acad. Sci. 100:1484–1489, 2003.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Thoumine, O., O. Cardoso, and J. J. Meister. Changes in the mechanical properties of fibroblasts during spreading: a micromanipulation study. Eur. Biophys. J. 28:222–234, 1999.PubMedCrossRefGoogle Scholar
  46. 46.
    Weafer, P., W. Ronan, S. Jarvis, and J. McGarry. Experimental and computational investigation of the role of stress fiber contractility in the resistance of osteoblasts to compression. Bull. Math. Biol. 75:1284–1303, 2013.PubMedCrossRefGoogle Scholar
  47. 47.
    Woods, A., G. Wang, and F. Beier. RhoA/ROCK signaling regulates Sox9 expression and actin organization during chondrogenesis. J. Biol. Chem. 280:11626–11634, 2005.PubMedCrossRefGoogle Scholar
  48. 48.
    Yamamoto, A., S. Mishima, N. Maruyama, and M. Sumita. Quantitative evaluation of cell attachment to glass, polystyrene, and fibronectin-or collagen-coated polystyrene by measurement of cell adhesive shear force and cell detachment energy. J. Biomed. Mater. Res. Part A 50:114–124, 2000.CrossRefGoogle Scholar
  49. 49.
    Yeung, T., P. C. Georges, L. A. Flanagan, B. Marg, M. Ortiz, M. Funaki, N. Zahir, W. Ming, V. Weaver, and P. A. Janmey. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil. Cytoskelet. 60:24–34, 2005.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2013

Authors and Affiliations

  1. 1.Department of Mechanical and Biomedical Engineering, College of Engineering and InformaticsNational University of Ireland, GalwayGalwayIreland

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