Assessment of a mechano-regulation theory of skeletal tissue differentiation in an in vivo model of mechanically induced cartilage formation

  • Lauren Nicole Miller Hayward
  • Elise F. Morgan
Original Paper


Mechanical cues are known to regulate tissue differentiation during skeletal healing. Quantitative characterization of this mechano-regulatory effect has great therapeutic potential. This study tested an existing theory that shear strain and interstitial fluid flow govern skeletal tissue differentiation by applying this theory to a scenario in which a bending motion applied to a healing transverse osteotomy results in cartilage, rather than bone, formation. A 3-D finite element mesh was created from micro-computed tomography images of a bending-stimulated callus and was used to estimate the mechanical conditions present in the callus during the mechanical stimulation. Predictions regarding the patterns of tissues—cartilage, fibrous tissue, and bone—that formed were made based on the distributions of fluid velocity and octahedral shear strain. These predictions were compared to histological sections obtained from a previous study. The mechano-regulation theory correctly predicted formation of large volumes of cartilage within the osteotomy gap and many, though not all patterns of tissue formation observed throughout the callus. The results support the concept that interstitial fluid velocity and tissue shear strain are key mec- hanical stimuli for the differentiation of skeletal tissues.


Mechanobiology Finite element analysis Mechanical stimulation Mesenchymal stem cell Bending motion Pseudarthrosis 


  1. Angele P, Schumann D, Angele M, Kinner B, Englert C, Hente R, Fuchtmeier B, Nerlich M, Neumann C, Kujat R (2004) Cyclic, mechanical compression enhances chondrogenesis of mesenchymal progenitor cells in tissue engineering scaffolds. Biorheology 41(3–4): 335–346Google Scholar
  2. Bailon-Plaza A, Vander Meulen MC (2003) Beneficial effects of moderate, early loading and adverse effects of delayed or excessive loading on bone healing. J Biomech 36: 1069–1077. doi:10.1016/S0021-9290(03)00117-9 CrossRefGoogle Scholar
  3. Blenman PR, Carter DR, Beaupre GS (1989) Role of mechanical loading in the progressive ossification of a fracture callus. J Orthop Res 7(3): 398–407. doi:10.1002/jor.1100070312 CrossRefGoogle Scholar
  4. Byrne DP, Lacroix D, Planell JA, Kelly DJ, Prendergast PJ (2007) 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. doi:10.1016/j.biomaterials.2007.09.003 CrossRefGoogle Scholar
  5. Carter DR, Beaupre GS, Giori NJ, Helms JA (1998) Mechanobiology of skeletal regeneration. Clin Orthop Relat Res 355(Suppl): S41–S55. doi:10.1097/00003086-199810001-00006 CrossRefGoogle Scholar
  6. Carter DR, Blenman PR, Beaupre GS (1988) Correlations between mechanical stress history and tissue differentiation in initial fracture healing. J Orthop Res 6(5): 736–748. doi:10.1002/jor.1100060517 CrossRefGoogle Scholar
  7. Claes LE, Heigele CA (1999) Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. J Biomech 32(3): 255–266. doi:10.1016/S0021-9290(98)00153-5 CrossRefGoogle Scholar
  8. Cullinane DM, Fredrick A, Eisenberg SR, Pacicca D, Elman MV, Lee C, Salisbury K, Gerstenfeld LC, Einhorn TA (2002) Induction of a neoarthrosis by precisely controlled motion in an experimental mid-femoral defect. J Orthop Res 20(3): 579–586. doi:10.1016/S0736-0266(01)00131-0 CrossRefGoogle Scholar
  9. Cullinane DM, Salisbury KT, Alkhiary Y, Eisenberg S, Gerstenfeld L, Einhorn TA (2003) Effects of the local mechanical environment on vertebrate tissue differentiation during repair: does repair recapitulate development?. J Exp Biol 206(Pt 14): 2459–2471. doi:10.1242/jeb.00453 CrossRefGoogle Scholar
  10. Davisson T, Kunig S, Chen A, Sah R, Ratcliffe A (2002a) Static dynamic compression modulate matrix metabolism in tissue engineered cartilage. J Orthop Res 20: 842–848. doi:10.1016/S0736-0266(01)00160-7 CrossRefGoogle Scholar
  11. Davisson T, Sah RL, Ratcliffe A (2002b) Perfusion increases cell content and matrix synthesis in chondrocyte three-dimensional cultures. Tissue Eng 8(5): 807–816. doi:10.1089/10763270260424169 CrossRefGoogle Scholar
  12. Epari DR, Taylor WR, Heller M, Duda GN (2006) Mechanical conditions in the initial phase of bone healing. Clin Biomech (Bristol, Avon) 21: 646–655. doi:10.1016/j.clinbiomech.2006.01.003 CrossRefGoogle Scholar
  13. Gerstenfeld LC, Alkhiary YM, Krall EA, Nicholls FH, Stapleton SN, Fitch JL, Bauer M, Kayal R, Graves DT, Jepsen KJ et al (2006) Three-dimensional reconstruction of fracture callus morphogenesis. J Histochem Cytochem 54(11): 1215–1228. doi:10.1369/jhc.6A6959.2006 CrossRefGoogle Scholar
  14. Goodship AE, Kenwright J (1985) The influence of induced micromovement upon the healing of experimental tibial fractures. J Bone Joint Surg Br 67(4): 650–655Google Scholar
  15. Hente R, Fuchtmeier B, Schlegel U, Ernstberger A, Perren SM (2004) The influence of cyclic compression and distraction on the healing of experimental tibial fractures. J Orthop Res 22: 709–715. doi:10.1016/j.orthres.2003.11.007 CrossRefGoogle Scholar
  16. Hung CT, Mauck RL, Wang CC, Lima EG, Ateshian GA (2004) A paradigm for functional tissue engineering of articular cartilage via applied physiologic deformational loading. Ann Biomed Eng 32(1): 35–49. doi:10.1023/B:ABME.0000007789.99565.42 CrossRefGoogle Scholar
  17. Isaksson H, Comas O, van Donkelaar CC, Mediavilla J, Wilson W, Huiskes R, Ito K (2007) Bone regeneration during distraction osteogenesis: mechano-regulation by shear strain and fluid velocity. J Biomech 40(9): 2002–2011. doi:10.1016/j.jbiomech.2006.09.028 CrossRefGoogle Scholar
  18. Isaksson H, van Donkelaar CC, Huiskes R, Ito K (2006a) Corroboration of mechanoregulatory algorithms for tissue differentiation during fracture healing: Comparison with in vivo results. J Orthop Res 24(5): 898–907. doi:10.1002/jor.20118 CrossRefGoogle Scholar
  19. Isaksson H, Wilson W, van Donkelaar CC, Huiskes R, Ito K (2006b) Comparison of biophysical stimuli for mechano-regulation of tissue differentiation during fracture healing. J Biomech 39(8): 1507–1516. doi:10.1016/j.jbiomech.2005.01.037 CrossRefGoogle Scholar
  20. Kelly DJ, Prendergast PJ (2005) Mechano-regulation of stem cell differentiation and tissue regeneration in osteochondral defects. J Biomech 38(7): 1413–1422. doi:10.1016/j.jbiomech.2004.06.026 CrossRefGoogle Scholar
  21. Kelly DJ, Prendergast PJ (2006) Prediction of the optimal mechanical properties for a scaffold used in osteochondral defect repair. Tissue Eng 12(9): 2509–2519. doi:10.1089/ten.2006.12.2509 CrossRefGoogle Scholar
  22. Knippenberg M, Helder MN, Doulabi BZ, Semeins CM, Wuisman PIJM, Klein-Nulend J (2005) Adipose tissue-derived mesenchymal stem cells acquire bone cell-like responsiveness to fluid shear stress on osteogenic stimulation. Tissue Eng 11(11/12): 1780–1788. doi:10.1089/ten.2005.11.1780 CrossRefGoogle Scholar
  23. Lacroix D, Chateau A, Ginebra MP, Planell JA (2006) Micro-finite element models of bone tissue-engineering scaffolds. Biomaterials 27(30): 5326–5334. doi:10.1016/j.biomaterials.2006.06.009 CrossRefGoogle Scholar
  24. Lacroix D, Prendergast PJ (2000) A homogenization procedure to prevent numerical instabilities in poroelastic tissue differentiation models. In: Eighth annual symposium: computational methods in orthopaedic biomechanicsGoogle Scholar
  25. Lacroix D, Prendergast PJ (2002) A mechano-regulation model for tissue differentiation during fracture healing: analysis of gap size and loading. J Biomech 35(9): 1163–1171. doi:10.1016/S0021-9290(02)00086-6 CrossRefGoogle Scholar
  26. Mauck RL, Byers BA, Yuan X, Tuan RS (2007) Regulation of cartilaginous ECM gene transcription by chondrocytes and MSCs in 3D culture in response to dynamic loading. Biomech Model Mechanobiol 6: 113–125. doi:10.1007/s10237-006-0042-1 CrossRefGoogle Scholar
  27. McKibbin B (1978) The biology of fracture healing in long bones. J Bone Joint Surg Br 60-B(2): 150–162Google Scholar
  28. Perren M, Cordey J (1980) The concept of interfragmentary strain. In: Uhthoff HK(eds) Current concepts of internal fixation of fractures. Springer, Berlin, pp 63–77Google Scholar
  29. Prendergast PJ, Huiskes R, Soballe K (1997) ESB Research Award 1996. Biophysical stimuli on cells during tissue differentiation at implant interfaces. J Biomech 30(6): 539–548. doi:10.1016/S0021-9290(96)00140-6 Google Scholar
  30. Riddle RC, Taylor AF, Genetos DC, Donahue HJ (2006) MAP kinase and calcium signaling mediate fluid flow-induced human mesenchymal stem cell proliferation. Am J Physiol Cell Physiol 290: C776–C784. doi:10.1152/ajpcell.00082.2005 CrossRefGoogle Scholar
  31. Sah RL, Kim YJ, Doong JY, Grodzinsky AJ, Plaas AH, Sandy JD (1989) Biosynthetic response of cartilage explants to dynamic compression. J Orthop Res 7(5): 619–636. doi:10.1002/jor.1100070502 CrossRefGoogle Scholar
  32. Salisbury KT, Einhorn TA, Gerstenfeld LC, Morgan EF (2005) Mechanobiological regulation of molecular expression and tissue differentiation during bone healing. Vail, Colorado. Compendex, pp 1530–1531Google Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Lauren Nicole Miller Hayward
    • 1
    • 2
  • Elise F. Morgan
    • 1
    • 2
  1. 1.Department of Mechanical EngineeringBoston UniversityBostonUSA
  2. 2.Department of Biomedical EngineeringBoston UniversityBostonUSA

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