Computational Mechanobiology in Cartilage and Bone Tissue Engineering: From Cell Phenotype to Tissue Structure

  • Thomas Nagel
  • Daniel J. Kelly
Part of the Studies in Mechanobiology, Tissue Engineering and Biomaterials book series (SMTEB, volume 10)


This chapter gives a short overview of computational models in cartilage and bone tissue engineering with a focus on how mechanical cues can regulate tissue regeneration on multiple levels, from cell phenotype to tissue architecture. The chapter begins with a brief review of single cell models with a focus on cell-substrate interactions and cytoskeletal remodelling. After summarising a number of current theories for mechanoregulated tissue differentiation, we explain how such hypotheses can either be corroborated or rejected by attempting to simulate in vivo regenerative events. We then outline a recently introduced model for MSC differentiation based on substrate stiffness and oxygen tension as well as how tissue phenotype and organisation can be explored simultaneously within a computational model. The application of computational models to aid in the design of scaffolds for bone and cartilage repair is demonstrated. We also outline how such models can be used in the design and analysis of bioreactors, demonstrating how changes in tissue structure in response to mechanical loading during bioreactor culture can potentially impact the mechanical properties of the final engineered constructs. The chapter closes with a short overview of multiscale models with relevance to tissue engineering.


Tissue Engineering Focal Adhesion Tissue Differentiation Fracture Healing Representative Volume Element 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Dr. Patrick McGarry for image material. Funding was provided by IRCSET (G30345) and a SFI PIYRA award (08/YI5/B1336).


  1. 1.
    Ament, C., Hofer, E.P.: A fuzzy logic model of fracture healing. J. Biomechanics 33(8), 961–968 (2000). doi: 10.1016/S0021-9290(00)00049-X.
  2. 2.
    Balguid, A., Rubbens, M.P., Mol, A., Bank, R.A., Bogers, A.J.J.C, van Kats, J.P., de Mol, B.A.J.M., Baaijens, F.P.T., Bouten, C.V.C.: The role of collagen cross-links in biomechanical behavior of human aortic heart valve leaflets—relevance for tissue engineering. Tissue Eng. 13(7), 1501–1511 (2007). doi: 10.1089/ten.2006.0279.
  3. 3.
    Barocas, V.H., Tranquillo, R.T.: An anisotropic biphasic theory of tissue-equivalent mechanics: the interplay among cell traction, fibrillar network deformation, fibril alignment, and cell contact guidance. J. Biomech. Eng. 119(2), 137–145 (1997)CrossRefGoogle Scholar
  4. 4.
    Batra, N.N., Li, Y.J., Yellowley, C.E., You, L., Malone, A.M., Kim, C.H., Jacobs, C.R.: Effects of short-term recovery periods on fluid-induced signaling in osteoblastic cells. J. Biomech. 38(9), 1909–1917 (2005). doi: 10.1016/j.jbiomech.2004.08.009.
  5. 5.
    Bian, L., Fong, J.V., Lima, E.G., Stoker, A.M., Ateshian, G.A., Cook, J.L., Hung, C.T.: Dynamic mechanical loading enhances functional properties of tissue-engineered cartilage using mature canine chondrocytes. Tissue Eng. Part A 16(5), 1781–1790 (2010). doi: 10.1089/ten.TEA.2009.0482.
  6. 6.
    Bischofs, I.B., Schwarz, U.S.: Cell organization in soft media due to active mechanosensing. Proc. Natl Acad. Sci. U S A 100(16), 9274–9279 (2003).
  7. 7.
    Bjork, J., Safonov, A., Tranquillo, R.: Computational Modeling in Tissue Engineering. Oxygen Transport in Bioreactors for Engineered Vascular Tissues. Springer, Berlin-Heidelberg (2012)Google Scholar
  8. 8.
    Boccaccio, A., Pappalettere, C., Kelly, D.J.: The influence of expansion rates on mandibular distraction osteogenesis: a computational analysis. Ann. Biomed. Eng. 35(11), 1940–1960 (2007). doi: 10.1007/s10439-007-9367-x.
  9. 9.
    Boccaccio, A., Lamberti, L., Pappalettere, C., Cozzani, M., Siciliani, G.: Comparison of different orthodontic devices for mandibular symphyseal distraction osteogenesis: a finite element study. Am. J. Orthod. Dentofac. Orthop. 134(2), 260–269 (2008). doi: 10.1016/j.ajodo.2006.09.066.
  10. 10.
    Boccaccio, A., Ballini, A., Pappalettere, C., Tullo, D., Cantore, S., Desiate, A.: Finite element method (fem), mechanobiology and biomimetic scaffolds in bone tissue engineering. Int. J. Biol. Sci. 7(1), 112–132 (2011)CrossRefGoogle Scholar
  11. 11.
    Boccaccio, A., Kelly, D.J., Pappalettere, C.: A mechano-regulation model of fracture repair in vertebral bodies. J. Orthop. Res. 29(3), 433–443 (2011). doi: 10.1002/jor.21231.
  12. 12.
    Burke, D., Kelly, D.: Could substrate stiffness and oxygen tension regulate stem cell differentiation during fracture healing? In: Proceedings of the ASME 2011 Summer Bioengineering Conference, Farmington, Pennsylvania, USA, 22–25 June 2011Google Scholar
  13. 13.
    Butler, D.L., Goldstein, S.A., Guilak, F.: Functional tissue engineering: the role of biomechanics. J. Biomech. Eng. 122(6), 570–575 (2000)CrossRefGoogle Scholar
  14. 14.
    Byrne, D.P., Lacroix, D., Planell, J.A., Kelly, D.J., Prendergast, P.J.: Simulation of tissue differentiation in a scaffold as a function of porosity, young’s modulus and dissolution rate: application of mechanobiological models in tissue engineering. Biomaterials 28(36), 5544–5554 (2007). doi: 10.1016/j.biomaterials.2007.09.003.
  15. 15.
    Carter, D.R., Blenman, P.R., Beauprcé, G.S.: Correlations between mechanical stress history and tissue differentiation in initial fracture healing. J. Orthop. Res. 6(5), 736–748 (1988). doi: 10.1002/jor.1100060517.
  16. 16.
    Carter, D.R., Wong, M., Orr, T.E.: Musculoskeletal ontogeny, phylogeny, and functional adaptation. J. Biomech. 24(Suppl 1), 3–16 (1991). doi: 10.1016/0021-9290(91)90373-U. (proceedings of the NASA Symposium on the Influence of Gravity and Activity on Muscle and Bone)
  17. 17.
    Carter, D.R., Beauprcé, G.S., Giori, N.J., Helms, J.A.: Mechanobiology of skeletal regeneration. Clin. Orthop. Relat. Res. 355(355 Suppl), S41–S55 (1998)CrossRefGoogle Scholar
  18. 18.
    Chan, K.S., Liang, W., Francis, W.L., Nicolella, D.P.: A multiscale modeling approach to scaffold design and property prediction. J. Mech. Behav. Biomed. Mater. 3(8), 584–593 (2010). doi: 10.1016/j.jmbbm.2010.07.006.
  19. 19.
    Checa, S., Prendergast, P.J.: A mechanobiological model for tissue differentiation that includes angiogenesis: a lattice-based modeling approach. Ann. Biomed. Eng. 37(1), 129–145 (2009). doi: 10.1007/s10439-008-9594-9.
  20. 20.
    Checa, S., Prendergast, P.J.: Effect of cell seeding and mechanical loading on vascularization and tissue formation inside a scaffold: a mechano-biological model using a lattice approach to simulate cell activity. J. Biomech. 43(5), 961–968 (2010). doi: 10.1016/j.jbiomech.2009.10.044.
  21. 21.
    Christen, P., van Rietbergen, B., Lambers, F.M., Müller, R., Ito, K.: Bone morphology allows estimation of loading history in a murine model of bone adaptation. Biomech. Model Mechanobiol. 10(5), 663–670 (2011). doi: 10.1007/s10237-011-0327-x.
  22. 22.
    Claes, L.E., Heigele, C.A.: Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. J. Biomech. 32(3), 255–266 (1999)CrossRefGoogle Scholar
  23. 23.
    Claes, L.E., Heigele, C.A., Neidlinger-Wilke, C., Kaspar, D., Seidl, W., Margevicius, K.J., Augat, P.: Effects of mechanical factors on the fracture healing process. Clin. Orthop. Relat. Res. 355(355 Suppl), S132–S147 (1998)CrossRefGoogle Scholar
  24. 24.
    Cristofolini, L., Taddei, F., Baleani, M., Baruffaldi, F., Stea, S., Viceconti, M.: Multiscale investigation of the functional properties of the human femur. Philos. Trans. A Math. Phys. Eng. Sci. 366(1879), 3319–3341 (2008). doi: 10.1098/rsta.2008.0077.
  25. 25.
    Cullinane, D.M., Fredrick, A., Eisenberg, S.R., Pacicca, D., Elman, M.V., Lee, C., Salisbury, K., Gerstenfeld, L.C., Einhorn, T.A.: Induction of a neoarthrosis by precisely controlled motion in an experimental mid-femoral defect. J. Orthop. Res. 20(3), 579–586 (2002). doi: 10.1016/S0736-0266(01)00131-0.
  26. 26.
    Cullinane, D.M., Salisbury, K.T., Alkhiary, Y., Eisenberg, S., Gerstenfeld, L., Einhorn, T.A.: Effects of the local mechanical environment on vertebrate tissue differentiation during repair: does repair recapitulate development? J. Exp. Biol. 206(Pt 14), 2459–2471 (2003)CrossRefGoogle Scholar
  27. 27.
    Deshpande, V.S., McMeeking, R.M., Evans, A.G.: A model for the contractility of the cytoskeleton including the effects of stress-fibre formation and dissociation. Proc. Royal Soc. A Math. Phys. Eng. Sci. 463(2079), 787–815 (2007)
  28. 28.
    Deshpande, V.S., Mrksich, M., McMeeking, R.M., Evans, A.G.: A bio-mechanical model for coupling cell contractility with focal adhesion formation. J. Mech. Phys. Solids 56(4), 1484–1510 (2008). doi: 10.1016/j.jmps.2007.08.006.
  29. 29.
    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).
  30. 30.
    Engelmayr, G.C., Papworth, G.D., Watkins, S.C., Mayer, J.E., Sacks, M.S.: Guidance of engineered tissue collagen orientation by large-scale scaffold microstructures. J. Biomech. 39(10), 1819–1831 (2006). doi: 10.1016/j.jbiomech.2005.05.020.
  31. 31.
    Engler, A.J., Sen, S., Sweeney, H.L., Discher, D.E.: Matrix elasticity directs stem cell lineage specification. Cell 126(4), 677–689 (2006).
  32. 32.
    Fereol, S., Fodil, R., Pelle, G., Louis, B., Laurent, V., Planus, E., Isabey, D.: Understanding adhesion sites as mechanosensitive cellular elements. In: Chapman & Hall/CRC Mathematical and Computational Biology, pp. 221–241. Chapman & Hall/CRC, London (2010).
  33. 33.
    Foolen, J., van Donkelaar, C.C., Soekhradj-Soechit, S., Ito, K.: European society of biomechanics s.m. perren award 2010: an adaptation mechanism for fibrous tissue to sustained shortening. J. Biomech. 43(16), 3168–3176 (2010). doi: 10.1016/j.jbiomech.2010.07.040.
  34. 34.
    García-Aznar, J.M., Kuiper, J.H., Gómez-Benito, M.J., Doblaré, M., Richardson, J.B.: Computational simulation of fracture healing: influence of interfragmentary movement on the callus growth. J. Biomech. 40(7), 1467–1476 (2007). doi: 10.1016/j.jbiomech.2006.06.013.
  35. 35.
    Geris, L., Oosterwyck, H.V., Sloten, J.V., Duyck, J., Naert, I.: Assessment of mechanobiological models for the numerical simulation of tissue differentiation around immediately loaded implants. Comput. Methods Biomech. Biomed. Eng. 6(5–6), 277–288 (2003). doi: 10.1080/10255840310001634412.
  36. 36.
    Geris, L., Andreykiv, A., Oosterwyck, H.V., Sloten, J.V., van Keulen, F., Duyck, J., Naert, I.: Numerical simulation of tissue differentiation around loaded titanium implants in a bone chamber. J. Biomech. 37(5), 763–769 (2004). doi: 10.1016/j.jbiomech.2003.09.026.
  37. 37.
    Geris, L., Gerisch, A., Sloten, J.V., Weiner, R., Oosterwyck, H.V.: Angiogenesis in bone fracture healing: a bioregulatory model. J. Theor. Biol. 251(1), 137–158 (2008). doi: 10.1016/j.jtbi.2007.11.008.
  38. 38.
    Geris, L., Schugart, R., Van Oosterwyck, H.: In silico design of treatment strategies in wound healing and bone fracture healing. Philos. Trans. A Math. Phys. Eng. Sci. 368(1920), 2683–2706 (2010). doi: 10.1098/rsta.2010.0056.
  39. 39.
    Giori, N.J., Beaupr, G.S., Carter, D.R.: Cellular shape and pressure may mediate mechanical control of tissue composition in tendons. J. Orthop. Res. 11(4), 581–591 (1993). doi: 10.1002/jor.1100110413.
  40. 40.
    Guilak, F., Mow, V.C.: The mechanical environment of the chondrocyte: a biphasic finite element model of cell-matrix interactions in articular cartilage. J. Biomech. 33(12), 1663–1673 (2000)CrossRefGoogle Scholar
  41. 41.
    Hambli, R., Soulat, D., Gasser, A., Benhamou, C.L.: Strain-damage coupled algorithm for cancellous bone mechano-regulation with spatial function influence. Comput. Methods Appl. Mech. Eng. 198(33–36), 2673–2682 (2009). doi: 10.1016/j.cma.2009.03.014.
  42. 42.
    Hambli, R., Katerchi, H., Benhamou, C.L.: Multiscale methodology for bone remodelling simulation using coupled finite element and neural network computation. Biomech. Model Mechanobiol. 10(1), 133–145 (2011). doi: 10.1007/s10237-010-0222-x.
  43. 43.
    Hayward, L., Morgan, E.: Assessment of a mechano-regulation theory of skeletal tissue differentiation in an in vivo model of mechanically induced cartilage formation. Biomech. Model Mechanobiol. 2(2), 109–126 (2009). doi: 10.1007/s10237-009-0148-3.
  44. 44.
    Hoenig, E., Winkler, T., Mielke, G., Paetzold, H., Schuettler, D., Goepfert, C., Machens, H.G., Morlock, M.M., Schilling, A.F.: High amplitude direct compressive strain enhances mechanical properties of scaffold-free tissue-engineered cartilage. Tissue Eng. Part A 17(9–10), 1401–1411 (2011). doi: 10.1089/ten.tea.2010.0395.,
  45. 45.
    Huang, A., Farrell, M., Kim, M., Mauck, R.: Long-term dynamic loading improves the mechanical properties of chondrogenic mesenchymal stem cell-laden hydrogel. Eur. Cells Mater. 19, 72–85 (2010)Google Scholar
  46. 46.
    Huiskes, R., Driel, W.D.V., Prendergast, P.J., Søballe, K.: A biomechanical regulatory model for periprosthetic fibrous-tissue differentiation. J. Mater. Sci. Mater. Med. 8(12), 785–788 (1997)CrossRefGoogle Scholar
  47. 47.
    Hutmacher, D.W.: Scaffolds in tissue engineering bone and cartilage. Biomaterials 21(24), 2529–2543 (2000)CrossRefGoogle Scholar
  48. 48.
    Ingber, D.E.: Tensegrity: the architectural basis of cellular mechanotransduction. Annu. Rev. Physiol. 59(1), 575–599 (1997). doi: 10.1146/annurev.physiol.59.1.575.,
  49. 49.
    Isaksson, H., van Donkelaar, C.C., Huiskes, R., Ito, K.: Corroboration of mechanoregulatory algorithms for tissue differentiation during fracture healing: comparison with in vivo results. J. Orthop. Res. 24(5), 898–907 (2006). doi: 10.1002/jor.20118.
  50. 50.
    Isaksson, H., Wilson, W., van Donkelaar, C.C., Huiskes, R., Ito, K.: Comparison of biophysical stimuli for mechano-regulation of tissue differentiation during fracture healing. J. Biomech. 39(8), 1507–1516 (2006). doi: 10.1016/j.jbiomech.2005.01.037.
  51. 51.
    Isaksson, H., Comas, O., van Donkelaar, C.C., Mediavilla, J., Wilson, W., Huiskes, R., Ito, K.: Bone regeneration during distraction osteogenesis: mechano-regulation by shear strain and fluid velocity. J. Biomech. 40(9), 2002–2011 (2007). doi: 10.1016/j.jbiomech.2006.09.028.
  52. 52.
    Jaasma, M.J., O’Brien, F.J.: Mechanical stimulation of osteoblasts using steady and dynamic fluid flow. Tissue Eng. Part A 14(7), 1213–1223 (2008). doi: 10.1089/tea.2007.0321.
  53. 53.
    Janmey, P.A., McCulloch, C.A.: Cell mechanics: integrating cell responses to mechanical stimuli. Annu. Rev. Biomed. Eng. 9(1), 1–34 (2007). doi: 10.1146/annurev.bioeng.9.060906.151927.,
  54. 54.
    Jungreuthmayer, C., Jaasma, M.J., Al-Munajjed, A.A., Zanghellini, J., Kelly, D.J., O’Brien, F.J.: Deformation simulation of cells seeded on a collagen-gag scaffold in a flow perfusion bioreactor using a sequential 3d cfd-elastostatics model. Med. Eng. Phys. 31(4), 420–427 (2009). doi: 10.1016/j.medengphy.2008.11.003.
  55. 55.
    Kelly, D.J., Prendergast, P.J.: Mechano-regulation of stem cell differentiation and tissue regeneration in osteochondral defects. J. Biomech. 38(7), 1413–1422 (2005). doi: 10.1016/j.jbiomech.2004.06.026.
  56. 56.
    Kelly, D.J., Prendergast, P.J.: Prediction of the optimal mechanical properties for a scaffold used in osteochondral defect repair. Tissue Eng. 12(9), 2509–2519 (2006). doi: 10.1089/ten.2006.12.2509.
  57. 57.
    Kelly, K.: The third culture. Science 279(5353), 992–993 (1998). doi: 10.1126/science.279.5353.992.
  58. 58.
    Kelly, T.A.N., Ng, K.W., Wang, C.C.B., Ateshian, G.A., Hung, C.T.: Spatial and temporal development of chondrocyte-seeded agarose constructs in free-swelling and dynamically loaded cultures. J. Biomech. 39(8), 1489–1497 (2006). doi: 10.1016/j.jbiomech.2005.03.031.
  59. 59.
    Khayyeri, H., Checa, S., Tgil, M., Prendergast, P.J.: Corroboration of mechanobiological simulations of tissue differentiation in an in vivo bone chamber using a lattice-modeling approach. J. Orthop. Res. 27(12), 1659–1666 (2009). doi: 10.1002/jor.20926.
  60. 60.
    Khayyeri, H., Checa, S., Tägil, M., O’Brien, F., Prendergast, P.: Tissue differentiation in an in vivo bioreactor: in silico investigations of scaffold stiffness. J. Mater. Sci. Mater. Med. 21, 2331–2336 (2010). doi: 10.1007/s10856-009-3973-0.
  61. 61.
    Khayyeri, H., Checa, S., Tgil, M., Aspenberg, P., Prendergast, P.J.: Variability observed in mechano-regulated in vivo tissue differentiation can be explained by variation in cell mechano-sensitivity. J. Biomech. 44(6), 1051–1058 (2011). doi: 10.1016/j.jbiomech.2011.02.003.
  62. 62.
    Khoshgoftar, M., van Donkelaar, C.C., Ito, K.: Mechanical stimulation to stimulate formation of a physiological collagen architecture in tissue-engineered cartilage: a numerical study. Comput. Methods Biomech. Biomed. Eng. 14(2), 135–144 (2011). doi: 10.1080/10255842.2010.519335.,
  63. 63.
    Kjaer, M.: Role of extracellular matrix in adaptation of tendon and skeletal muscle to mechanical loading. Physiol. Rev. 84(2), 649–698 (2004). doi: 10.1152/physrev.00031.2003.
  64. 64.
    Klein, T.J., Rizzi, S.C., Reichert, J.C., Georgi, N., Malda, J., Schuurman, W., Crawford, R.W., Hutmacher, D.W.: Strategies for zonal cartilage repair using hydrogels. Macromol. Biosci. 9(11), 1049–1058 (2009). doi: 10.1002/mabi.200900176.
  65. 65.
    Klisch, S.M., Chen, S.S., Sah, R.L., Hoger, A.: A growth mixture theory for cartilage with application to growth-related experiments on cartilage explants. J. Biomech. Eng. 125(2), 169–179 (2003)CrossRefGoogle Scholar
  66. 66.
    Klisch, S.M., Asanbaeva, A., Oungoulian, S.R., Masuda, K., Thonar, E.J.M., Davol, A., Sah, R.L.: A cartilage growth mixture model with collagen remodeling: validation protocols. J. Biomech. Eng. 130(3), 031006 (2008). doi: 10.1115/1.2907754.
  67. 67.
    Lacroix, D., Prendergast, P.J.: A mechano-regulation model for tissue differentiation during fracture healing: analysis of gap size and loading. J. Biomech. 35(9), 1163–1171 (2002)CrossRefGoogle Scholar
  68. 68.
    Lacroix, D., Prendergast, P.J., Li, G., Marsh, D.: Biomechanical model to simulate tissue differentiation and bone regeneration: application to fracture healing. Med. Biol. Eng. Comput. 40(1), 14–21 (2002)CrossRefGoogle Scholar
  69. 69.
    Lau, A.W.C., Hoffman, B.D., Davies, A., Crocker, J.C., Lubensky, T.C.: Microrheology, stress fluctuations, and active behavior of living cells. Phys. Rev. Lett. 91(19), 198101 (2003). doi: 10.1103/PhysRevLett.91.198101
  70. 70.
    Lima, E.G., Bian, L., Ng, K.W., Mauck, R.L., Byers, B.A., Tuan, R.S., Ateshian, G.A., Hung, C.T.: The beneficial effect of delayed compressive loading on tissue-engineered cartilage constructs cultured with tgf-beta3. Osteoarthr. Cartil 15(9), 1025–1033 (2007). doi: 10.1016/j.joca.2007.03.008.
  71. 71.
    Loboa, E.G., Beaupr, G.S., Carter, D.R.: Mechanobiology of initial pseudarthrosis formation with oblique fractures. J. Orthop. Res. 19(6), 1067–1072 (2001).
  72. 72.
    Martin, I., Wendt, D., Heberer, M.: The role of bioreactors in tissue engineering. Trends Biotechnol. 22(2), 80–86 (2004). doi: 10.1016/j.tibtech.2003.12.001.
  73. 73.
    Mauck, R.L., Wang, C.C.B., Oswald, E.S., Ateshian, G.A., Hung, C.T.: The role of cell seeding density and nutrient supply for articular cartilage tissue engineering with deformational loading. Osteoarthr. Cartil. 11(12), 879–890 (2003). doi: 10.1016/j.joca.2003.08.006.
  74. 74.
    Mauck, R.L., Wang, C.C.B., Oswald, E.S., Ateshian, G.A., Hung, C.T.: The role of cell seeding density and nutrient supply for articular cartilage tissue engineering with deformational loading. Osteoarthr. Cartil. 11(12), 879–890 (2003)CrossRefGoogle Scholar
  75. 75.
    McGarry, J.P., Fu, J., Yang, M.T., Chen, C.S., McMeeking, R.M., Evans, A.G., Deshpande, V.S.: Simulation of the contractile response of cells on an array of micro-posts. Philos. Trans. A Math. Phys. Eng. Sci. 367(1902), 3477–3497 (2009). doi: 10.1098/rsta.2009.0097.
  76. 76.
    Meyer, E.G., Buckley, C.T., Thorpe, S.D., Kelly, D.J.: Low oxygen tension is a more potent promoter of chondrogenic differentiation than dynamic compression. J. Biomech. 43(13), 2516–2523 (2010). doi: 10.1016/j.jbiomech.2010.05.020.
  77. 77.
    Mohrdieck, C., Wanner, A., Roos, W., Roth, A., Sackmann, E., Spatz, J.P., Arzt, E.: A theoretical description of elastic pillar substrates in biophysical experiments. ChemPhysChem 6(8), 1492–1498 (2005).
  78. 78.
    Nagel, T., Kelly, D.: The influence of fibre orientation on the equilibrium properties of neutral and charged biphasic tissues. J. Biomech. Eng. 132(11), 114506 (2010) (7 pages)CrossRefGoogle Scholar
  79. 79.
    Nagel, T., Kelly, D.: Mechanically induced structural changes during dynamic compression of engineered cartilaginous constructs can potentially explain increases in bulk mechanical properties. J. Royal Soc. Interface (2011). doi: 10.1098/rsif.2011.0449.,
  80. 80.
    Nagel, T., Kelly, D.: Remodelling of collagen fibre transition stretch and angular distribution in soft biological tissues and cell-seeded hydrogels. Biomech. Model Mechanobiol. (2011). doi: 10.1007/s10237-011-0313-3.
  81. 81.
    Nagel, T., Kelly, D.J.: Mechano-regulation of mesenchymal stem cell differentiation and collagen organisation during skeletal tissue repair. Biomech. Model Mechanobiol. 9(3), 359–372 (2010). doi: 10.1007/s10237-009-0182-1.
  82. 82.
    Nagel, T., Loerakker, S., Oomens, C.W.J.: A theoretical model to study the effects of cellular stiffening on the damage evolution in deep tissue injury. Comput. Methods Biomech. Biomed. Eng. p. 1 (2009). doi: 10.1080/10255840902788603.
  83. 83.
    Nelson, C.M., Jean, R.P., Tan, J.L., Liu, W.F., Sniadecki, N.J., Spector, A.A., Chen, C.S.: Emergent patterns of growth controlled by multicellular form and mechanics. Proc. Natl Acad. Sci. U S A 102(33), 11594–11599 (2005). doi: 10.1073/pnas.0502575102.,
  84. 84.
    Nicolas, A., Safran, S.A.: Limitation of cell adhesion by the elasticity of the extracellular matrix. Biophys. J. 91(1), 61–73 (2006).
  85. 85.
    Nicolas, A., Geiger, B., Safran, S.A.: Cell mechanosensitivity controls the anisotropy of focal adhesions. Proc. Natl Acad. Sci. U S A 101(34), 12520–12525 (2004).
  86. 86.
    Oberkampf, W.L., Trucano, T.G., Hirsch, C.: Verification, validation, and predictive capability in computational engineering and physics. Appl. Mech. Rev. 57(5), 345–384 (2004). doi: 10.1115/1.1767847.
  87. 87.
    Pang, H., Shiwalkar, A.P., Madormo, C.M., Taylor, R.E., Andriacchi, T.P., Kuhl, E.: Computational modeling of bone density profiles in response to gait: a subject-specific approach. Biomech. Model Mechanobiol. (2011). doi: 10.1007/s10237-011-0318-y.
  88. 88.
    Pathak, A., Deshpande, V.S., McMeeking, R.M., Evans, A.G.: The simulation of stress fibre and focal adhesion development in cells on patterned substrates. J. Royal Soc. Interface 5(22), 507–524 (2008).
  89. 89.
    Pauwels, F.: Eine neue Theorie über den Einflu mechanischer Reize auf die Differenzierung der Stützgewebe. Anat. Embryol. 121(6), 478–515 (1960).
  90. 90.
    Perez, M., Prendergast, P.: Random-walk models of cell dispersal included in mechanobiological simulations of tissue differentiation. J. Biomech. 40, 2244–2253 (2007).
  91. 91.
    Prendergast, P., Huiskes, R., Sballe, K.: Esb research award 1996. Biophysical stimuli on cells during tissue differentiation at implant interfaces. J. Biomech. 30(6), 539–548 (1997)CrossRefGoogle Scholar
  92. 92.
    Prendergast, P.J., Galibarov, P.E., Lowery, C., Lennon, A.B.: Computer simulating a clinical trial of a load-bearing implant: an example of an intramedullary prosthesis. J. Mech. Behav. Biomed. Mater. 4(8), 1880–1887 (2011). doi: 10.1016/j.jmbbm.2011.06.005.
  93. 93.
    Raimondi, M., Causin, P., Lagana, M., Zunino, P., Sacco, R.: Computational Modeling in Tissue Engineering. Multiphysics Computational Modeling in Cartilage Tissue Engineering. Springer, Berlin-Heidelberg (2012)Google Scholar
  94. 94.
    Reina-Romo, E., Gómez-Benito, M., García-Aznar, J., Domínguez, J., Doblaré, M.: Modeling distraction osteogenesis: analysis of the distraction rate. Biomech. Model. Mechanobiol. 8, 323–335 (2009). doi: 10.1007/s10237-008-0138-x.
  95. 95.
    Roux, W.: Beiträge zur Morphologie der funktionellen Anpassung. 3. Beschreibung und Erluterung einer knöchernen Kniegelenksankylose. Arch. Anat. Entwicklungsgeschichte 10, 120–158 (1885)Google Scholar
  96. 96.
    Rubbens, M.P., Mol, A., van Marion, M.H., Hanemaaijer, R., Bank, R.A., Baaijens, F.P.T., Bouten, C.V.C.: Straining mode-dependent collagen remodeling in engineered cardiovascular tissue. Tissue Eng. Part A 15(4), 841–849 (2009). doi: 10.1089/ten.tea.2008.0185.
  97. 97.
    Sacks, M.S., Smith, D.B., Hiester, E.D.: The aortic valve microstructure: effects of transvalvular pressure. J. Biomed. Mater. Res. 41(1), 131–141 (1998).<131::AID-JBM16>3.0.CO;2-Q
  98. 98.
    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(42), 17675–17680 (2009). doi: 10.1073/pnas.0903716106.
  99. 99.
    Sandino, C., Planell, J., Lacroix, D.: A finite element study of mechanical stimuli in scaffolds for bone tissue engineering. J. Biomech. 41(5), 1005–1014 (2008). doi: 10.1016/j.jbiomech.2007.12.011.
  100. 100.
    Sandino, C., Checa, S., Prendergast, P.J., Lacroix, D.: Simulation of angiogenesis and cell differentiation in a cap scaffold subjected to compressive strains using a lattice modeling approach. Biomaterials 31(8), 2446–2452 (2010). doi: 10.1016/j.biomaterials.2009.11.063.
  101. 101.
    Sanz-Herrera, J., Garca-Aznar, J., Doblar, M.: Micro-macro numerical modelling of bone regeneration in tissue engineering. Comput. Methods Appl. Mech. Eng. 197(33–40), 3092–3107 (2008). doi: 10.1016/j.cma.2008.02.010.
  102. 102.
    Sanz-Herrera, J.A., García-Aznar, J.M., Doblaré, M.: On scaffold designing for bone regeneration: a computational multiscale approach. Acta. Biomater. 5(1), 219–229 (2009). doi: 10.1016/j.actbio.2008.06.021.
  103. 103.
    Sanz-Herrera, J.A., Doblaré, M., García-Aznar, J.M.: Scaffold microarchitecture determines internal bone directional growth structure: a numerical study. J. Biomech. 43(13), 2480–2486 (2010). doi: 10.1016/j.jbiomech.2010.05.027.
  104. 104.
    Semple, J.L., Woolridge, N., Lumsden, C.J.: In vitro, in vivo, in silico: computational systems in tissue engineering and regenerative medicine. Tissue Eng. 11(3–4), 341–356 (2005). doi: 10.1089/ten.2005.11.341.
  105. 105.
    Sheehy, E.J., Buckley, C.T., Kelly, D.J.: Oxygen tension regulates the osteogenic, chondrogenic and endochondral phenotype of bone marrow derived mesenchymal stem cells. Biochem. Biophys. Res. Commun. 63(11), 3284–3293 (2011). doi: 10.1016/j.bbrc.2011.11.105.
  106. 106.
    Shefelbine, S.J., Augat, P., Claes, L., Simon, U.: Trabecular bone fracture healing simulation with finite element analysis and fuzzy logic. J. Biomech. 38(12), 2440–2450 (2005). doi: 10.1016/j.jbiomech.2004.10.019.
  107. 107.
    Simon, U., Augat, P., Utz, M., Claes, L.: A numerical model of the fracture healing process that describes tissue development and revascularisation. Comput. Methods Biomech. Biomed. Eng. 14(1), 79–93 (2011). doi: 10.1080/10255842.2010.499865.
  108. 108.
    Stops, A.J.F., Heraty, K.B., Browne, M., O’Brien, F.J., McHugh, P.E.: A prediction of cell differentiation and proliferation within a collagen-glycosaminoglycan scaffold subjected to mechanical strain and perfusive fluid flow. J. Biomech. 43(4), 618–626 (2010). doi: 10.1016/j.jbiomech.2009.10.037.
  109. 109.
    Sun, W., Darling, A., Starly, B., Nam, J.: Computer-aided tissue engineering: overview, scope and challenges. Biotechnol. Appl. Biochem. 39(1), 29–47 (2004). doi: 10.1042/BA20030108.
  110. 110.
    Sun, W., Starly, B., Darling, A., Gomez, C.: Computer-aided tissue engineering: application to biomimetic modelling and design of tissue scaffolds. Biotechnol. Appl. Biochem. 39(1), 49–58 (2004). doi: 10.1042/BA20030109.
  111. 111.
    van der Meulen, M.C.H., Huiskes, R.: Why mechanobiology? a survey article. J. Biomech. 35(4), 401–414 (2002)CrossRefGoogle Scholar
  112. 112.
    van Turnhout, M., Kranenbarg, S., van Leeuwen, J.: Contribution of postnatal collagen reorientation to depth-dependent mechanical properties of articular cartilage. Biomech. Model. Mechanobiol. 10(2), 269–279 (2010).,10.1007/s10237-010-0233-7
  113. 113.
    Wang, J.: Substrate deformation determines actin cytoskeleton reorganization: a mathematical modeling and experimental study. J. Theor. Biol. 202(1), 33–41 (2000). doi: 10.1006/jtbi.1999.1035.
  114. 114.
    Wei, Z., Deshpande, V.S., McMeeking, R.M., Evans, A.G.: Analysis and interpretation of stress fiber organization in cells subject to cyclic stretch. J. Biomech. Eng. 130(3), 031009 (2008). doi: 10.1115/1.2907745.
  115. 115.
    Wilson, W., Driessen, N.J.B., van Donkelaar, C.C., Ito, K.: Prediction of collagen orientation in articular cartilage by a collagen remodeling algorithm. Osteoarthr. Cartil. 14(11), 1196–1202 (2006). doi: 10.1016/j.joca.2006.05.006.
  116. 116.
    Wren, T.A., Beaupr, G.S., Carter, D.R.: Mechanobiology of tendon adaptation to compressive loading through fibrocartilaginous metaplasia. J. Rehabil. Res. Dev. 37(2), 135–143 (2000)Google Scholar
  117. 117.
    Yan, D., Zhou, G., Zhou, X., Liu, W., Zhang, W.J., Luo, X., Zhang, L., Jiang, T., Cui, L., Cao, Y.: The impact of low levels of collagen ix and pyridinoline on the mechanical properties of in vitro engineered cartilage. Biomaterials 30(5), 814–821 (2009). doi: 10.1016/j.biomaterials.2008.10.042.

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Centre for Bioengineering, Trinity Biomedical Sciences InstituteTrinity College DublinDublin 2Ireland
  2. 2.Department of Mechanical and Manufacturing Engineering, School of EngineeringTrinity College DublinDublin 2Ireland

Personalised recommendations