Skip to main content

The Mechanical Environment of Cells in Collagen Gel Models

Global and Local Effects in Three-dimensional Biological Hydrogels

  • Chapter
  • First Online:
Cellular and Biomolecular Mechanics and Mechanobiology

Part of the book series: Studies in Mechanobiology, Tissue Engineering and Biomaterials ((SMTEB,volume 4))

Abstract

It is becoming increasingly clear that cells behave differently in two-dimensional (2D) culture than in three-dimensional (3D) tissues, and that 3D culture models and new tools for probing them are needed for advancing our knowledge of mechanobiology. Cells physically interact with their surrounding extracellular matrix; they are able to sense the local stiffness, tension, and deformation within the matrix and, in turn, are able to remodel the matrix and generate forces with long-range effects. In tissues with sufficiently high cell density, the cells interact and generate coordinated forces which can be regulated by controlling the macroscopic mechanical boundary conditions. Understanding this dynamic reciprocity between the cells, matrix, and external environment is critical for determining how the cells sense, transduce, and respond to their mechanical surroundings. However, even in simplified models of 3D tissues, quantification of local (non-linear viscoelastic) mechanical properties is problematic, and the transfer of strain and stress to the cells is complicated by non-affine, non-uniform deformation of the cell/matrix composite. This review focuses on methods for characterizing and modulating the mechanical environment of cells cultured within reconstituted collagen gels, the most extensively utilized in vitro models of native 3D tissue.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ahlfors, J.E., Billiar, K.L.: Biomechanical and biochemical characteristics of a human fibroblast-produced and remodeled matrix. Biomaterials 28(13), 2183–2191 (2007)

    Article  Google Scholar 

  2. Akhouayri, O., Lafage-Proust, M.H., Rattner, A., Laroche, N., Caillot-Augusseau, A., Alexandre, C., Vico, L.: Effects of static or dynamic mechanical stresses on osteoblast phenotype expression in three-dimensional contractile collagen gels. J. Cell Biochem. 76(2), 217–230 (1999)

    Article  Google Scholar 

  3. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., Walter, P.: Molecular Biology of the Cell. Garland Science, New York (2002)

    Google Scholar 

  4. Allen, T.D., Schor, S.L.: The contraction of collagen matrices by dermal fibroblasts. J. Ultrastruct. Res. 83(2), 205–219 (1983)

    Article  Google Scholar 

  5. Altman, G.H., Horan, R.L., Martin, I., Farhadi, J., Stark, P.R., Volloch, V., Richmond, J.C., Vunjak-Novakovic, G., Kaplan, D.L.: Cell differentiation by mechanical stress. FASEB J. 16(2), 270–272 (2002)

    Google Scholar 

  6. Arora, P.D., Narani, N., Mcculloch, C.A.: The compliance of collagen gels regulates transforming growth factor-beta induction of alpha-smooth muscle actin in fibroblasts. Am. J. Pathol. 154(3), 871–882 (1999)

    Article  Google Scholar 

  7. Baker, E.L., Zaman, M.H.: The biomechanical integrin. J. Biomech. 43, 38–44 (2010)

    Article  Google Scholar 

  8. Balestrini, J.L., Billiar, K.L.: Magnitude and duration of stretch modulate fibroblast remodeling. J. Biomech. Eng. 131, 051005 (2009)

    Article  Google Scholar 

  9. Balestrini, J.L., Skorinko, J.K., Hera, A., Gaudette, G.R., Billiar, K.L.: Applying controlled non-uniform deformation for in vitro studies of cell mechanobiology. Biomech. Model Mechanobiol. 9(3), 329–344 (2010)

    Article  Google Scholar 

  10. Bell, E., Ivarsson, B., Merril, C.: Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro. Proc. Natl. Acad. Sci. U.S.A. 76(3), 1274–1278 (1979)

    Article  Google Scholar 

  11. Berg, R., Birk, D., Silver, F.: Physical characterization of type I procollagen in solution: evidence that the propeptides limit self-assembly. Int. J. Biol. Macromol. 8(3), 177–182 (1986)

    Article  Google Scholar 

  12. Billiar, K.L., Sacks, M.S.: A method to quantify the fiber kinematics of planar tissues under biaxial stretch. J. Biomech. 30(7), 753–756 (1997)

    Article  Google Scholar 

  13. Billiar, K.L., Throm, A.M., Frey, M.T.: Biaxial failure properties of planar living tissue equivalents. J. Biomed. Mater. Res. A 73A(2), 182–191 (2005)

    Article  Google Scholar 

  14. Brinkman, W.T., Nagapudi, K., Thomas, B.S., Chaikof, E.L.: Photo-cross-linking of type I collagen gels in the presence of smooth muscle cells: mechanical properties, cell viability, and function. Biomacromolecules 4(4), 890–895 (2003)

    Article  Google Scholar 

  15. Brown, R.A., Prajapati, R., Mcgrouther, D.A., Yannas, I.V., Eastwood, M.: Tensional homeostasis in dermal fibroblasts: mechanical responses to mechanical loading in three-dimensional substrates. J. Cell. Physiol. 175(3), 323–332 (1998)

    Article  Google Scholar 

  16. Brown, R.A., Wiseman, M., Chuo, C.-B., Cheema, U., Nazhat, S.N.: Ultrarapid engineering of biomimetic materials and tissues: fabrication of nano- and micro-structures by plastic compression. Adv. Funct. Mater. 15, 1762–1770 (2005)

    Article  Google Scholar 

  17. Butcher, J.T., Barrett, B.C., Nerem, R.M.: Equibiaxial strain stimulates fibroblastic phenotype shift in smooth muscle cells in an engineered tissue model of the aortic wall. Biomaterials 27(30), 5252–5258 (2006)

    Article  Google Scholar 

  18. Butcher, J.T., Nerem, R.M.: Valvular endothelial cells regulate the phenotype of interstitial cells in co-culture: effects of steady shear stress. Tissue Eng. 12, 905–915 (2006)

    Article  Google Scholar 

  19. Carver, W., Nagpal, M.L., Nachtigal, M., Borg, T.K., Terracio, L.: Collagen expression in mechanically stimulated cardiac fibroblasts. Circ. Res. 69(1), 116–122 (1991)

    Google Scholar 

  20. Chandran, P.L., Barocas, V.H.: Affine versus non-affine fibril kinematics in collagen networks: theoretical studies of network behavior. J. Biomech. Eng. 128(2), 259–270 (2006)

    Article  Google Scholar 

  21. Chapuis, J.F., Agache, P.: A new technique to study the mechanical properties of collagen lattices. J. Biomech. 25, 115–120 (1992)

    Article  Google Scholar 

  22. Chiquet, M., Renedo, A.S., Huber, F., Fluck, M.: How do fibroblasts translate mechanical signals into changes in extracellular matrix production? Matrix Biol. 22(1), 73–80 (2003)

    Article  Google Scholar 

  23. Christiansen, D.L., Huang, E.K., Silver, F.H.: Assembly of type I collagen: fusion of fibril subunits and the influence of fibril diameter on mechanical properties. Matrix Biol. 19(5), 409–420 (2000)

    Article  Google Scholar 

  24. Chung, H.J., Steplewski, A., Chung, K.Y., Uitto, J., Fertala, A.: Collagen fibril formation. A new target to limit fibrosis. J. Biol. Chem. 283(38), 25879–25886 (2008)

    Article  Google Scholar 

  25. Clark, R.A., Nielsen, L.D., Welch, M.P., Mcpherson, J.M.: Collagen matrices attenuate the collagen-synthetic response of cultured fibroblasts to tgf-beta. J. Cell. Sci. 108(Pt 3), 1251–1261 (1995)

    Google Scholar 

  26. Costa, K.D., Lee, E.J., Holmes, J.W.: Creating alignment and anisotropy in engineered heart tissue: role of boundary conditions in a model three-dimensional culture system. Tissue Eng. 9(4), 567–577 (2003)

    Article  Google Scholar 

  27. Cox, M.A.J., Gawlitta, D., Driessen, N.J.B., Oomens, C.W.J., Baaijens, F.P.T.: The non-linear mechanical properties of soft engineered biological tissues determined by finite spherical indentation. Comput. Methods Biomech. Biomed. Eng. 11(5), 585–592 (2008)

    Article  Google Scholar 

  28. Cukierman, E., Pankov, R., Stevens, D.R., Yamada, K.M.: Taking cell–matrix adhesions to the third dimension. Science 294(5547), 1708–1712 (2001)

    Article  Google Scholar 

  29. Daley, W.P., Peters, S.B., Larsen, M.: Extracellular matrix dynamics in development and regenerative medicine. J. Cell. Sci. 121(Pt 3), 255–264 (2008)

    Article  Google Scholar 

  30. Danielsen, C.C.: Reconstituted collagen fibrils. Fibrillar and molecular stability of the collagen upon maturation in vitro. Biochem. J. 222, 663–668 (1984)

    Google Scholar 

  31. Delvoye, P., Wiliquet, P., Leveque, J.L., Nusgens, B.V., Lapiere, C.M.: Measurement of mechanical forces generated by skin fibroblasts embedded in a three-dimensional collagen gel. J. Invest. Dermatol. 97(5), 898–902 (1991)

    Article  Google Scholar 

  32. Discher, D.E., Janmey, P., Wang, Y.L.: Tissue cells feel and respond to the stiffness of their substrate. Science 310(5751), 1139–1143 (2005)

    Article  Google Scholar 

  33. Eastwood, M., Mcgrouther, D.A., Brown, R.A.: A culture force monitor for measurement of contraction forces generated in human dermal fibroblast cultures: evidence for cell-matrix mechanical signalling.” Biochim. Biophys. Acta (BBA) Gen. Subj. 1201(2), 186–192 (1994)

    Article  Google Scholar 

  34. Eastwood, M., Mudera, V.C., Mcgrouther, D.A., Brown, R.A.: Effect of precise mechanical loading on fibroblast populated collagen lattices: morphological changes. Cell Motil. Cytoskeleton 40(1), 13–21 (1998)

    Article  Google Scholar 

  35. Eastwood, M., Porter, R., Khan, U., Mcgrouther, G., Brown, R.: Quantitative analysis of collagen gel contractile forces generated by dermal fibroblasts and the relationship to cell morphology. J. Cell. Physiol. 166, 33–42 (1996)

    Article  Google Scholar 

  36. Engler, A., Bacakova, L., Newman, C., Hategan, A., Griffin, M., Discher, D.: Substrate compliance versus ligand density in cell on gel responses. Biophys. J. 86(1 Pt 1), 617–628 (2004)

    Article  Google Scholar 

  37. Evans, M.C., Barocas, V.H.: The modulus of fibroblast-populated collagen gels is not determined by final collagen and cell concentration: experiments and an inclusion-based model. J. Biomech. Eng. 131, 101014 (2009)

    Article  Google Scholar 

  38. Feng, Z., Yamato, M., Akutsu, T., Nakamura, T., Okano, T., Umezu, M.: Investigation on the mechanical properties of contracted collagen gels as a scaffold for tissue engineering. Artif. Organs 27(1), 84–91 (2003)

    Article  Google Scholar 

  39. Forgacs, G., Newman, S., Hinner, B., Maier, C., Sackmann, E.: Assembly of collagen matrices as a phase transition revealed by structural and rheologic studies. Biophys. J. 84, 1272–1280 (2003)

    Article  Google Scholar 

  40. Freyman, T.M., Yannas, I.V., Yokoo, R., Gibson, L.J.: Fibroblast contraction of a collagen-gag matrix. Biomaterials 22(21), 2883–2891 (2001)

    Article  Google Scholar 

  41. Freyman, T.M., Yannas, I.V., Yokoo, R., Gibson, L.J.: Fibroblast contractile force is independent of the stiffness which resists the contraction. Exp. Cell Res. 272(2), 153–162 (2002)

    Article  Google Scholar 

  42. Friess, W.: Collagen—biomaterial for drug delivery. Eur. J. Pharm. Biopharm. 45, 113–136 (1998)

    Article  Google Scholar 

  43. Ghibaudo, M., Trichet, L., Le Digabel, J., Richert, A., Hersen, P., Ladoux, B.: Substrate topography induces a crossover from 2d to 3d behavior in fibroblast migration. Biophys. J. 97, 357–368 (2009)

    Article  Google Scholar 

  44. Gieni, R.S., Hendzel, M.J.: Mechanotransduction from the ECM to the genome: are the pieces now in place? J. Cell. Biochem. 104, 1964–1987 (2008)

    Article  Google Scholar 

  45. Gildner, C.D., Lerner, A.L., Hocking, D.C.: Fibronectin matrix polymerization increases tensile strength of model tissue. Am. J. Physiol. Heart Circ. Physiol. 287(1), H46–H53 (2004)

    Article  Google Scholar 

  46. Girton, T.S., Oegema, T.R., Grassl, E.D., Isenberg, B.C., Tranquillo, R.T.: Mechanisms of stiffening and strengthening in media-equivalents fabricated using glycation. J. Biomech. Eng. 122(3), 216–223 (2000)

    Article  Google Scholar 

  47. Gordon, M.K., Hahn, R.A.: Collagens. Cell Tissue Res. 339, 247–257 (2010)

    Article  Google Scholar 

  48. Grinnell, F.: Fibroblasts, myofibroblasts, and wound contraction. J. Cell. Biol. 124(4), 401–404 (1994)

    Article  Google Scholar 

  49. Grinnell, F.: Fibroblast–collagen–matrix contraction: growth-factor signalling and mechanical loading. Trends Cell Biol. 10(9), 362–365 (2000)

    Article  Google Scholar 

  50. Grinnell, F.: Fibroblast biology in three-dimensional collagen matrices. Trends Cell Biol. 13(5), 264–269 (2003)

    Article  Google Scholar 

  51. Grinnell, F., Ho, C.H., Tamariz, E., Lee, D.J., Skuta, G.: Dendritic fibroblasts in three-dimensional collagen matrices. Mol. Biol. Cell 14(2), 384–395 (2003)

    Article  Google Scholar 

  52. Grinnell, F., Zhu, M., Carlson, M.A., Abrams, J.M.: Release of mechanical tension triggers apoptosis of human fibroblasts in a model of regressing granulation tissue. Exp. Cell Res. 248(2), 608–619 (1999)

    Article  Google Scholar 

  53. Gross, J., Highberger, J.H., Schmitt, F.O.: Some factors involved in the fibrogenesis of collagen in vitro. Proc. Soc. Exp. Biol. Med. 80(3), 462–465 (1952)

    Google Scholar 

  54. Guido, S., Tranquillo, R.T.: A methodology for the systematic and quantitative study of cell contact guidance in oriented collagen gels. Correlation of fibroblast orientation and gel birefringence. J. Cell. Sci. 105(Pt 2), 317–331 (1993)

    Google Scholar 

  55. Gupta, V., Tseng, H., Lawrence, B.D., Grande-Allen, K.J.: Effect of cyclic mechanical strain on glycosaminoglycan and proteoglycan synthesis by heart valve cells. Acta Biomater. 5, 531–540 (2009)

    Article  Google Scholar 

  56. Hadjipanayi, E., Mudera, V., Brown, R.A.: Close dependence of fibroblast proliferation on collagen scaffold matrix stiffness. J. Tissue Eng. Regen. Med. 3, 77–84 (2009)

    Article  Google Scholar 

  57. Harley, B.A., Freyman, T.M., Wong, M.Q., Gibson, L.J.: A new technique for calculating individual dermal fibroblast contractile forces generated within collagen-gag scaffolds. Biophys. J. 93(8), 2911–2922 (2007)

    Article  Google Scholar 

  58. Helary, C., Bataille, I., Abed, A., Illoul, C., Anglo, A., Louedec, L., Letourneur, D., Meddahi-Pellé, A., Giraud-Guille, M.M.: Concentrated collagen hydrogels as dermal substitutes. Biomaterials 31, 481–490 (2010)

    Article  Google Scholar 

  59. Hinz, B., Gabbiani, G.: Mechanisms of force generation and transmission by myofibroblasts. Curr. Opin. Biotechnol. 14(5), 538–546 (2003)

    Article  Google Scholar 

  60. Hu, J.-J., Humphrey, J.D., Yeh, A.T.: Characterization of engineered tissue development under biaxial stretch using nonlinear optical microscopy. Tissue Eng. Part A 15, 1553–1564 (2009)

    Article  Google Scholar 

  61. Huang, D., Chang, T.R., Aggarwal, A., Lee, R.C., Ehrlich, H.P.: Mechanisms and dynamics of mechanical strengthening in ligament-equivalent fibroblast-populated collagen matrices. Ann. Biomed. Eng. 21(3), 289–305 (1993)

    Article  Google Scholar 

  62. Hubbell, J.A.: Biomaterials in tissue engineering. Biotechnology 13, 565–576 (1995)

    Article  Google Scholar 

  63. Isenberg, B.C., Tranquillo, R.T.: Long-term cyclic distention enhances the mechanical properties of collagen-based media-equivalents. Ann. Biomed. Eng. 31(8), 937–949 (2003)

    Article  Google Scholar 

  64. Jackson, D.S., Fessler, J.H.: Isolation and properties of a collagen soluble in salt solution at neutral pH. Nature 176(4471), 69–70 (1955)

    Article  Google Scholar 

  65. Jhun, C.S., Evans, M.C., Barocas, V.H., Tranquillo, R.T.: Planar biaxial mechanical behavior of bioartificial tissues possessing prescribed fiber alignment. J. Biomech. Eng. 131(8), 081006 (2009)

    Article  Google Scholar 

  66. Jiang, H., Rhee, S., Ho, C.H., Grinnell, F.: Distinguishing fibroblast promigratory and procontractile growth factor environments in 3-d collagen matrices. FASEB J. 22, 2151–2160 (2008)

    Article  Google Scholar 

  67. John, J., Quinlan, A.T., Silvestri, C., Billiar, K.: Boundary stiffness regulates fibroblast behavior in collagen gels. Ann. Biomed. Eng. 38, 658–673 (2010)

    Article  Google Scholar 

  68. Jungbauer, S., Gao, H., Spatz, J.P., Kemkemer, R.: Two characteristic regimes in frequency-dependent dynamic reorientation of fibroblasts on cyclically stretched substrates. Biophys. J. 95, 3470–3478 (2008)

    Article  Google Scholar 

  69. Kadler, K.E., Hojima, Y., Prockop, D.J.: Assembly of collagen fibrils de novo by cleavage of the type I pc-collagen with procollagen c-proteinase. Assay of critical concentration demonstrates that collagen self-assembly is a classical example of an entropy-driven process. J. Biol. Chem. 262, 15696–15701 (1987)

    Google Scholar 

  70. Kanda, K., Matsuda, T., Oka, T.: Mechanical stress induced cellular orientation and phenotypic modulation of 3-d cultured smooth muscle cells. ASAIO J. 39(3), M686–M690 (1993)

    Article  Google Scholar 

  71. Karamichos, D., Brown, R.A., Mudera, V.: Complex dependence of substrate stiffness and serum concentration on cell-force generation. J. Biomed. Mater. Res. A 78(2), 407–415 (2006)

    Google Scholar 

  72. Karamichos, D., Brown, R.A., Mudera, V.: Collagen stiffness regulates cellular contraction and matrix remodeling gene expression. J. Biomed. Mater. Res. A 83(3), 887–894 (2007)

    Google Scholar 

  73. Karamichos, D., Skinner, J., Brown, R., Mudera, V.: Matrix stiffness and serum concentration effects matrix remodelling and ECM regulatory genes of human bone marrow stem cells. J. Tissue Eng. Regen. Med. 2(2–3), 97–105 (2008)

    Article  Google Scholar 

  74. Katsumi, A., Orr, A.W., Tzima, E., Schwartz, M.A.: Integrins in mechanotransduction. J. Biol. Chem. 279(13), 12001–12004 (2004)

    Article  Google Scholar 

  75. Kemp, P., Falco, L., Regan, K., Bell, E.: Collagen Compositions and Methods for Preparation Thereof. Organogenesis Inc., USA (1992)

    Google Scholar 

  76. Knapp, D.M., Barocas, V.H., Moon, A.G., Yoo, K., Petzold, L.R., Tranquillo, R.T.: Rheology of reconstituted type I collagen gel in confined compression. J. Rheol. 4(15), 971–993 (1997)

    Article  Google Scholar 

  77. Knapp, D.M., Tower, T.T., Tranquillo, R.T., Barocas, V.H.: Estimation of cell traction and migration in an isometric cell traction assay. AIChE J. 45, 2628–2640 (1999)

    Article  Google Scholar 

  78. Knezevic, V., Sim, A.J., Borg, T.K., Holmes, J.W.: Isotonic biaxial loading of fibroblast-populated collagen gels: a versatile, low-cost system for the study of mechanobiology. Biomech. Model. Mechanobiol. 1, 59–67 (2002)

    Article  Google Scholar 

  79. Kolodney, M.S., Wysolmerski, R.B.: Isometric contraction by fibroblasts and endothelial cells in tissue culture: A quantitative study. J. Cell. Biol. 117(1), 73–82 (1992)

    Article  Google Scholar 

  80. Krishnan, L., Weiss, J.A., Wessman, M.D., Hoying, J.B.: Design and application of a test system for viscoelastic characterization of collagen gels. Tissue Eng. 10(1–2), 241–252 (2004)

    Article  Google Scholar 

  81. Kuntz, R., Saltzman, W.: Neutrophil motility in extracellular matrix gels: mesh size and adhesion affect speed of migration. Biophys. J. 72, 1472–1480 (1997)

    Article  Google Scholar 

  82. L’heureux, N., Paquet, S., Labbe, R., Germain, L., Auger, F.A.: A completely biological tissue-engineered human blood vessel. FASEB J. 12(1), 47–56 (1998)

    Google Scholar 

  83. Latinovic, O., Hough, L.A., Daniel Ou-Yang, H.: Structural and micromechanical characterization of type I collagen gels. J. Biomech. 43, 500–505 (2010)

    Article  Google Scholar 

  84. Lee, E.J., Holmes, J.W., Costa, K.D.: Remodeling of engineered tissue anisotropy in response to altered loading conditions. Ann. Biomed. Eng. 36(8), 1322–1334 (2008)

    Article  Google Scholar 

  85. Legant, W.R., Pathak, A., Yang, M.T., Deshpande, V.S., Mcmeeking, R.M., Chen, C.S.: Microfabricated tissue gauges to measure and manipulate forces from 3d microtissues. Proc. Natl. Acad. Sci. U.S.A. 106(25), 10097–10102 (2009)

    Article  Google Scholar 

  86. Leung, L.Y., Tian, D., Brangwynne, C.P., Weitz, D.A., Tschumperlin, D.J.: A new microrheometric approach reveals individual and cooperative roles for tgf-beta1 and IL-1beta in fibroblast-mediated stiffening of collagen gels. FASEB J. 21(9), 2064–2073 (2007)

    Article  Google Scholar 

  87. Marenzana, M., Wilson-Jones, N., Mudera, V., Brown, R.A.: The origins and regulation of tissue tension: identification of collagen tension-fixation process in vitro. Exp. Cell Res. 312(4), 423–433 (2006)

    Article  Google Scholar 

  88. Mauck, R.L., Baker, B.M., Nerurkar, N.L., Burdick, J.A., Li, W.-J., Tuan, R.S., Elliott, D.M.: Engineering on the straight and narrow: the mechanics of nanofibrous assemblies for fiber-reinforced tissue regeneration. Tissue Eng. Part B 15(2), 171–193 (2009)

    Article  Google Scholar 

  89. Mierke, C.T., Rösel, D., Fabry, B., Brábek, J.: Contractile forces in tumor cell migration. Eur. J. Cell. Biol. 87, 669–676 (2008)

    Article  Google Scholar 

  90. Miron-Mendoza, M., Seemann, J., Grinnell, F.: Collagen fibril flow and tissue translocation coupled to fibroblast migration in 3d collagen matrices. Mol. Biol. Cell 19(5), 2051–2058 (2008)

    Article  Google Scholar 

  91. Mochitate, K., Pawelek, P., Grinnell, F.: Stress relaxation of contracted collagen gels: disruption of actin filament bundles, release of cell surface fibronectin, and down-regulation of DNA and protein synthesis. Exp. Cell Res. 193(1), 198–207 (1991)

    Article  Google Scholar 

  92. Nemir, S., West, J.L.: Synthetic materials in the study of cell response to substrate rigidity. Ann. Biomed. Eng. 38, 2–20 (2009)

    Article  Google Scholar 

  93. Ng, C.P., Hinz, B., Swartz, M.A.: Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J. Cell. Sci. 118(Pt 20), 4731–4739 (2005)

    Article  Google Scholar 

  94. Nishiyama, T., Tominaga, N., Nakajima, K., Hayashi, T.: Quantitative evaluation of the factors affecting the process of fibroblast-mediated collagen gel contraction by separating the process into three phases. Coll. Relat. Res. 8(3), 259–273 (1988)

    Google Scholar 

  95. Olsen, D., Yang, C., Bodo, M., Chang, R., Leigh, S., Baez, J., Carmichael, D., Perälä, M., Hämäläinen, E.-R., Jarvinen, M., Polarek, J.: Recombinant collagen and gelatin for drug delivery. Adv. Drug Deliv. Rev. 55, 1547–1567 (2003)

    Article  Google Scholar 

  96. Ozerdem, B., Tozeren, A.: Physical response of collagen to gels to tensile strain. J. Biomech. Eng. 117, 397–401 (1995)

    Article  Google Scholar 

  97. Paik, D.C., Saito, L.Y., Sugirtharaj, D.D., Holmes, J.W.: Nitrite-induced cross-linking alters remodeling and mechanical properties of collagenous engineered tissues. Connect. Tissue Res. 47(3), 163–176 (2006)

    Article  Google Scholar 

  98. Parekh, A., Velegol, D.: Collagen gel anisotropy measured by 2-d laser trap microrheometry. Ann. Biomed. Eng. 35(7), 1231–1246 (2007)

    Article  Google Scholar 

  99. Parsons, J.W., Coger, R.N.: A new device for measuring the viscoelastic properties of hydrated matrix gels. J. Biomech. Eng. 124(2), 145–154 (2002)

    Article  Google Scholar 

  100. Pedersen, J.A., Swartz, M.A.: Mechanobiology in the third dimension. Ann. Biomed. Eng. 33(11), 1469–1490 (2005)

    Article  Google Scholar 

  101. Petersen, O.W., Rønnov-Jessen, L., Howlett, A.R., Bissell, M.J.: Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc. Natl. Acad. Sci. U.S.A. 89, 9064–9068 (1992)

    Article  Google Scholar 

  102. Peyton, S.R., Ghajar, C.M., Khatiwala, C.B., Putnam, A.J.: The emergence of ECM mechanics and cytoskeletal tension as important regulators of cell function. Cell. Biochem. Biophys. 47(2), 300–320 (2007)

    Article  Google Scholar 

  103. Prajapati, R.T., Chavally-Mis, B., Herbage, D., Eastwood, M., Brown, R.A.: Mechanical loading regulates protease production by fibroblasts in three-dimensional collagen substrates. Wound Repair Regen. 8(3), 226–237 (2000)

    Article  Google Scholar 

  104. Pryse, K.M., Nekouzadeh, A., Genin, G.M., Elson, E.L., Zahalak, G.I.: Incremental mechanics of collagen gels: new experiments and a new viscoelastic model. Ann. Biomed. Eng. 31(10), 1287–1296 (2003)

    Article  Google Scholar 

  105. Raub, C.B., Suresh, V., Krasieva, T., Lyubovitsky, J., Mih, J.D., Putnam, A.J., Tromberg, B.J., George, S.C.: Noninvasive assessment of collagen gel microstructure and mechanics using multiphoton microscopy. Biophys. J. 92, 2212–2222 (2007)

    Article  Google Scholar 

  106. Redden, R.A., Doolin, E.J.: Collagen crosslinking and cell density have distinct effects on fibroblast-mediated contraction of collagen gels. Skin Res. Technol. 9(3), 290–293 (2003)

    Article  Google Scholar 

  107. Reilly, G.C., Engler, A.J.: Intrinsic extracellular matrix properties regulate stem cell differentiation. J. Biomech. 43, 55–62 (2010)

    Article  Google Scholar 

  108. Rhee, S., Grinnell, F.: Fibroblast mechanics in 3d collagen matrices. Adv. Drug Deliv. Rev. 59, 1299–1305 (2007)

    Article  Google Scholar 

  109. Roeder, B.A., Kokini, K., Robinson, J.P., Voytik-Harbin, S.L.: Local, three-dimensional strain measurements within largely deformed extracellular matrix constructs. J. Biomech. Eng. 126, 699–708 (2004)

    Article  Google Scholar 

  110. Roeder, B.A., Kokini, K., Sturgis, J.E., Robinson, J.P., Voytik-Harbin, S.L.: Tensile mechanical properties of three-dimensional type I collagen extracellular matrices with varied microstructure. J. Biomech. Eng. 124(2), 214–222 (2002)

    Article  Google Scholar 

  111. Roeder, B.A., Kokini, K., Voytik-Harbin, S.L.: Fibril microstructure affects strain transmission within collagen extracellular matrices. J. Biomech. Eng. 131, 031004 (2009)

    Article  Google Scholar 

  112. Sander, E.A., Stylianopoulos, T., Tranquillo, R.T., Barocas, V.H.: Image-based multiscale modeling predicts tissue-level and network-level fiber reorganization in stretched cell-compacted collagen gels. Proc. Natl. Acad. Sci. U.S.A. 106, 17675–17680 (2009)

    Article  Google Scholar 

  113. Seliktar, D., Black, R.A., Vito, R.P., Nerem, R.M.: Dynamic mechanical conditioning of collagen-gel blood vessel constructs induces remodeling in vitro. Ann. Biomed. Eng. 28(4), 351–362 (2000)

    Article  Google Scholar 

  114. Seliktar, D., Nerem, R.M., Galis, Z.S.: The role of matrix metalloproteinase-2 in the remodeling of cell-seeded vascular constructs subjected to cyclic strain. Ann. Biomed. Eng. 29(11), 923–934 (2001)

    Article  Google Scholar 

  115. Sell, S.A., Mcclure, M.J., Garg, K., Wolfe, P.S., Bowlin, G.L.: Electrospinning of collagen/biopolymers for regenerative medicine and cardiovascular tissue engineering. Adv. Drug Deliv. Rev. 61, 1007–1019 (2009)

    Article  Google Scholar 

  116. Shi, Y., Vesely, I.: Characterization of statically loaded tissue-engineered mitral valve chordae tendineae. J. Biomed. Mater. Res. A 69(1), 26–39 (2004)

    Article  Google Scholar 

  117. Shi, Y., Vesely, I.: A dynamic straining bioreactor for collagen-based tissue engineering. In: Chaudhuri, J.B., Al-Rubeai, M. (eds.) Bioreactors for Tissue Engineering, pp. 209–219. Springer, Dordrecht (2005)

    Chapter  Google Scholar 

  118. Shreiber, D.I., Barocas, V.H., Tranquillo, R.T.: Temporal variations in cell migration and traction during fibroblast-mediated gel compaction. Biophys. J. 84(6), 4102–4114 (2003)

    Article  Google Scholar 

  119. Silver, F.H., Freeman, J.W., Seehra, G.P.: Collagen self-assembly and the development of tendon mechanical properties. J. Biomech. 36(10), 1529–1553 (2003)

    Article  Google Scholar 

  120. Stegemann, J.P., Nerem, R.M.: Phenotype modulation in vascular tissue engineering using biochemical and mechanical stimulation. Ann. Biomed. Eng. 31(4), 391–402 (2003)

    Article  Google Scholar 

  121. Stopak, D., Harris, A.K.: Connective tissue morphogenesis by fibroblast traction. I. Tissue culture observations. Dev. Biol. 90(2), 383–398 (1982)

    Article  Google Scholar 

  122. Storm, C., Pastore, J.J., Mackintosh, F.C., Lubensky, T.C., Janmey, P.A.: Nonlinear elasticity in biological gels. Nature 435, 191–194 (2005)

    Article  Google Scholar 

  123. Sundararaghavan, H.G., Monteiro, G.A., Lapin, N.A., Chabal, Y.J., Miksan, J.R., Shreiber, D.I.: Genipin-induced changes in collagen gels: correlation of mechanical properties to fluorescence. J. Biomed. Mater. Res. A 87(2), 308–320 (2008)

    Google Scholar 

  124. Thomopoulos, S., Fomovsky, G.M., Holmes, J.W.: The development of structural and mechanical anisotropy in fibroblast populated collagen gels. J. Biomed. Eng. 127(5), 742–750 (2005)

    Google Scholar 

  125. Tibbitt, M.W., Anseth, K.S.: Hydrogels as extracellular matrix mimics for 3d cell culture. Biotechnol. Bioeng. 103, 655–663 (2009)

    Article  Google Scholar 

  126. Tomasek, J.J., Gabbiani, G., Hinz, B., Chaponnier, C., Brown, R.A.: Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3(5), 349–363 (2002)

    Article  Google Scholar 

  127. Tomasek, J.J., Haaksma, C.J., Eddy, R.J., Vaughan, M.B.: Fibroblast contraction occurs on release of tension in attached collagen lattices: dependency on an organized actin cytoskeleton and serum. Anat. Rec. 232(3), 359–368 (1992)

    Article  Google Scholar 

  128. Tomei, A.A., Boschetti, F., Gervaso, F., Swartz, M.A.: 3d Collagen cultures under well-defined dynamic strain: a novel strain device with a porous elastomeric support. Biotechnol. Bioeng. 103, 217–225 (2009)

    Article  Google Scholar 

  129. Trzewik, J., Artmann-Temiz, A., Linder, P.T., Demirci, T., Digel, I., Artmann, G.M.: Evaluation of lateral mechanical tension in thin-film tissue constructs. Ann. Biomed. Eng. 32(9), 1243–1251 (2004)

    Article  Google Scholar 

  130. Vanni, S., Lagerholm, B.C., Otey, C., Taylor, D.L., Lanni, F.: Internet-based image analysis quantifies contractile behavior of individual fibroblasts inside model tissue. Biophys. J. 84, 2715–2127 (2003)

    Article  Google Scholar 

  131. Velegol, D., Lanni, F.: Cell traction forces on soft biomaterials. I. Microrheology of type I collagen gels. Biophys. J. 81(3), 1786–1792 (2001)

    Article  Google Scholar 

  132. Vorp, D.A., Severyn, D.A., Steed, D.L., Webster, M.W.: A device for the application of cyclic twist and extension on perfused vascular segments. Am. J. Physiol. 270, H787–H795 (1996)

    Google Scholar 

  133. Voytik-Harbin, S.L., Roeder, B.A., Sturgis, J.E., Kokini, K., Robinson, J.P.: Simultaneous mechanical loading and confocal reflection microscopy for three-dimensional microbiomechanical analysis of biomaterials and tissue constructs. Microsc. Microanal. 9, 74–85 (2003)

    Article  Google Scholar 

  134. Wakatsuki, T., Kolodney, M.S., Zahalak, G.I., Elson, E.L.: Cell mechanics studied by a reconstituted model tissue. Biophys. J. 79(5), 2353–2368 (2000)

    Article  Google Scholar 

  135. Wille, J.J., Elson, E.L., Okamoto, R.J.: Cellular and matrix mechanics of bioartificial tissues during continuous cyclic stretch. Ann. Biomed. Eng. 34(11), 1678–1690 (2006)

    Article  Google Scholar 

  136. Yamamura, N., Sudo, R., Ikeda, M., Tanishita, K.: Effects of the mechanical properties of collagen gel on the in vitro formation of microvessel networks by endothelial cells. Tissue Eng. 13(7), 1443–1453 (2007)

    Article  Google Scholar 

  137. Yang, Y.-L., Kaufman, L.J.: Rheology and confocal reflectance microscopy as probes of mechanical properties and structure during collagen and collagen/hyaluronan self-assembly. Biophys. J. 96, 1566–1585 (2009)

    Article  Google Scholar 

  138. Yip, C.Y., Chen, J.H., Zhao, R., Simmons, C.A.: Calcification by valve interstitial cells is regulated by the stiffness of the extracellular matrix. Arterioscler. Thromb. Vasc. Biol. 29(6), 936–942 (2009)

    Article  Google Scholar 

  139. Zaman, M.H., Trapani, L.M., Sieminski, A.L., Siemeski, A., Mackellar, D., Gong, H., Kamm, R.D., Wells, A., Lauffenburger, D.A., Matsudaira, P.: Migration of tumor cells in 3d matrices is governed by matrix stiffness along with cell–matrix adhesion and proteolysis. Proc. Natl. Acad. Sci. U.S.A. 103, 10889–10894 (2006)

    Article  Google Scholar 

  140. Zeugolis, D.I., Li, B., Lareu, R.R., Chan, C.K., Raghunath, M.: Collagen solubility testing, a quality assurance step for reproducible electro-spun nano-fibre fabrication. A technical note. J. Biomater. Sci. Polym. Ed. 19, 1307–1317 (2008)

    Article  Google Scholar 

  141. Zeugolis, D.I., Paul, R.G., Attenburrow, G.: Factors influencing the properties of reconstituted collagen fibers prior to self-assembly: animal species and collagen extraction method. J. Biomed. Mater. Res. A 86, 892–904 (2008)

    Google Scholar 

  142. Zhu, Y.K., Umino, T., Liu, X.D., Wang, H.J., Romberger, D.J., Spurzem, J.R., Rennard, S.I.: Contraction of fibroblast-containing collagen gels: Initial collagen concentration regulates the degree of contraction and cell survival. In Vitro Cell. Dev. Biol. Anim. 37(1), 10–16 (2001)

    Article  Google Scholar 

Download references

Acknowledgments

I would like to thank Drs. Sherry Voytik-Harbin, Frederick Grinnell and Christophe Helary for the generous confocal, fluorescent, and electron micrographs. I also extend my thanks to Heather Cirka for her help with drawing schematics and configuring the table. Finally, I would like to acknowledge the Fulbright Commission in Ireland and the NIH (1 R15 HL087257) for their financial support of this work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kristen L. Billiar .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Billiar, K.L. (2010). The Mechanical Environment of Cells in Collagen Gel Models. In: Gefen, A. (eds) Cellular and Biomolecular Mechanics and Mechanobiology. Studies in Mechanobiology, Tissue Engineering and Biomaterials, vol 4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8415_2010_30

Download citation

  • DOI: https://doi.org/10.1007/8415_2010_30

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-14217-8

  • Online ISBN: 978-3-642-14218-5

  • eBook Packages: EngineeringEngineering (R0)

Publish with us

Policies and ethics