Skip to main content
SpringerLink
Log in

Unravelling the Role of Mechanical Stimuli in Regulating Cell Fate During Osteochondral Defect Repair

  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

Abstract

We have previously developed a computational mechanobiological model to explore the role of substrate stiffness and oxygen availability in regulating stem cell fate during spontaneous osteochondral defect repair. This model successfully simulated many aspects of the regenerative process, however it was unable to predict the spatial patterns of endochondral bone and fibrocartilaginous tissue formation observed during the latter stages of the repair process. It is hypothesised that this was because the mechanobiological model did not consider the role of tissue strain in regulating specific aspects of chondrocyte differentiation. To test this, our mechanobiological model was updated to include rules whereby intermediate levels of octahedral shear strain inhibited chondrocyte hypertrophy, while excessively high octahedral shear strains resulted in the formation of fibrocartilage. This model was used to simulate spontaneous osteochondral defect repair, where it correctly predicted the experimentally observed patterns of bone formation. Overall the results suggest that oxygen availability regulates chondrogenesis and endochondral ossification during the early phases of osteochondral defect repair, while direct mechanical cues play a greater role in regulating chondrocyte differentiation during the latter stages of this process. In particular, these results suggest that an appropriate loading regime can assist in promoting the development of stable hyaline cartilage during osteochondral defect repair.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Appeddu, P. A., and B. D. Shur. Molecular analysis of cell surface fi-1, 4-galactosyltransferase function during cell migration. Proc. Natl. Acad. Sci. USA 91:2095–2099, 1994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Baker, B. M., R. P. Shah, A. H. Huang, and R. L. Mauck. Dynamic tensile loading improves the functional properties of mesenchymal stem cell-laden nanofiber-based fibrocartilage. Tissue Eng. Part A 17:1445–1455, 2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bian, L., D. Y. Zhai, E. C. Zhang, R. L. Mauck, and J. A. Burdick. Dynamic compressive loading enhances cartilage matrix synthesis and distribution and suppresses hypertrophy in hMSC-laden hyaluronic acid hydrogels. Tissue Eng. Part A 18:715–724, 2012.

    Article  CAS  PubMed  Google Scholar 

  4. Burke, D. P., and D. J. Kelly. Substrate stiffness and oxygen as regulators of stem cell differentiation during skeletal tissue regeneration: a mechanobiological model. PLoS One 7:e40737, 2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Carlier, A., L. Geris, N. Van Gastel, G. Carmeliet, and H. Van Oosterwyck. Oxygen as a critical determinant of bone fracture healing—a multiscale model. J. Theor. Biol. 365:247–264, 2015.

    Article  CAS  PubMed  Google Scholar 

  6. Chae, H.-J., S.-C. Kim, K.-S. Han, S.-W. Chae, N.-H. An, H.-M. Kim, H.-H. Kim, Z.-H. Lee, and H.-R. Kim. Hypoxia induces apoptosis by caspase activation accompanying cytochrome C release from mitochondria in MC3T3E1 osteoblasts. p38 MAPK is related in hypoxia-induced apoptosis. Immunopharmacol. Immunotoxicol. 23:133–152, 2001.

    Article  CAS  PubMed  Google Scholar 

  7. Checa, S., and P. J. Prendergast. A mechanobiological model for tissue differentiation that includes angiogenesis: a lattice-based modeling approach. Ann. Biomed. Eng. 37:129–145, 2009.

    Article  PubMed  Google Scholar 

  8. Claes, L. E., C. A. Heigele, C. Neidlinger-Wilke, D. Kaspar, W. Seidl, K. J. Margevicius, and P. Augat. Effects of mechanical factors on the fracture healing process. Clin. Orthop. Relat. Res. 355:S132–S147, 1998.

    Article  Google Scholar 

  9. Connelly, J. T., E. J. Vanderploeg, J. K. Mouw, C. G. Wilson, and M. E. Levenston. Tensile loading modulates bone marrow stromal cell differentiation and the development of engineered fibrocartilage constructs. Tissue Eng. Part A 16:1913–1923, 2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. de Vries, S. A. H., M. C. van Turnhout, C. W. J. Oomens, A. Erdemir, K. Ito, and C. C. van Donkelaar. Deformation thresholds for chondrocyte death and the protective effect of the pericellular matrix. Tissue Eng. Part A 20:1–7, 2014.

    Article  CAS  Google Scholar 

  11. Epari, D. R., J. Lienau, H. Schell, F. Witt, and G. N. Duda. Pressure, oxygen tension and temperature in the periosteal callus during bone healing—an in vivo study in sheep. Bone 43:734–739, 2008.

    Article  PubMed  Google Scholar 

  12. Hershey, D., and T. Karhan. Diffusion coefficients for oxygen transport in whole blood. AIChE 14:969–972, 1968.

    Article  CAS  Google Scholar 

  13. Holzwarth, C., M. Vaegler, F. Gieseke, S. M. Pfister, R. Handgretinger, G. Kerst, and I. Müller. Low physiologic oxygen tensions reduce proliferation and differentiation of human multipotent mesenchymal stromal cells. BMC Cell Biol. 11:1, 2010.

    Article  CAS  Google Scholar 

  14. Hori, R. Y., and J. L. Lewis. Mechanical properties of the fibrous tissue found at the bone-cement interface following total joint replacement. J. Biomed. Mater. Res. 16:911–927, 1982.

    Article  CAS  PubMed  Google Scholar 

  15. Isaksson, H., C. C. van Donkelaar, R. Huiskes, and K. Ito. A mechano-regulatory bone-healing model incorporating cell-phenotype specific activity. J. Theor. Biol. 252:230–246, 2008.

    Article  PubMed  Google Scholar 

  16. Khoshgoftar, M., W. Wilson, K. Ito, and C. C. van Donkelaar. Influence of tissue- and cell-scale extracellular matrix distribution on the mechanical properties of tissue-engineered cartilage. Biomech. Model. Mechanobiol. 2012. doi:10.1007/s10237-012-0452-1.

    Google Scholar 

  17. Kim, H. K., M. E. Moran, and R. B. Salter. The potential for regeneration of articular cartilage in defects created by chondral shaving and subchondral abrasion. An experimental investigation in rabbits. J. Bone Jt. Surg. 73:1301–1315, 1991.

    Article  CAS  Google Scholar 

  18. Lacroix, D., and P. J. Prendergast. A mechano-regulation model for tissue differentiation during fracture healing: analysis of gap size and loading. J. Biomech. 35:1163–1171, 2002.

    Article  CAS  PubMed  Google Scholar 

  19. Lacroix, D., P. J. Prendergast, G. Li, and D. Marsh. Biomechanical model to simulate tissue differentiation and bone regeneration: application to fracture healing. Med. Biol. Eng. Comput. 40:14–21, 2002.

    Article  CAS  PubMed  Google Scholar 

  20. Luo, L., S. D. Thorpe, C. T. Buckley, and D. J. Kelly. The effects of dynamic compression on the development of cartilage grafts engineered using bone marrow and infrapatellar fat pad derived stem cells. Biomed. Mater. 10:055011, 2015.

    Article  CAS  PubMed  Google Scholar 

  21. Mackie, E. J., Y. A. Ahmed, L. Tatarczuch, K.-S. Chen, and M. Mirams. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int. J. Biochem. Cell Biol. 40:46–62, 2008.

    Article  CAS  PubMed  Google Scholar 

  22. Malda, J., J. Rouwkema, D. E. Martens, E. P. Le Comte, F. K. Kooy, J. Tramper, C. A. van Blitterswijk, and J. Riesle. Oxygen gradients in tissue-engineered PEGT/PBT cartilaginous constructs: measurement and modeling. Biotechnol. Bioeng. 86:9–18, 2004.

    Article  CAS  PubMed  Google Scholar 

  23. O’Reilly, A., K. D. Hankenson, and D. J. Kelly. A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing. Biomech. Model. Mechanobiol. 2016. doi:10.1007/s10237-016-0759-4.

    Google Scholar 

  24. O’Reilly, A., and D. J. Kelly. The role of oxygen as a regulator of stem cell fate during the spontaneous repair of an osteochondral defect. J. Orthop. Res. 2015. doi:10.1002/jor.22396.

    PubMed  Google Scholar 

  25. Orth, P., M. Cucchiarini, G. Kaul, M. F. Ong, S. Gräber, D. M. Kohn, and H. Madry. Temporal and spatial migration pattern of the subchondral bone plate in a rabbit osteochondral defect model. Osteoarthr. Cartil. 20:1161–1169, 2012.

    Article  CAS  PubMed  Google Scholar 

  26. Pérez, M. A., and P. J. Prendergast. Random-walk models of cell dispersal included in mechanobiological simulations of tissue differentiation. J. Biomech. 40:2244–2253, 2007.

    Article  PubMed  Google Scholar 

  27. Qui, Y. S., B. F. Shahgaldi, W. J. Revell, and F. W. Heatley. Observations of subchondral plate advancement during osteochondral repair: a histomorphometric and mechanical study in the rabbit femoral condyle. Osteoarthr. Cartil. 11:810–820, 2003.

    Article  Google Scholar 

  28. Salter, R. B., D. F. Simmonds, B. Malcolm, E. J. Rumble, D. MacMicheal, and N. D. Clements. The biological effect of continuous passive motion on the healing of full-thickness defects in articular cartilage. An experimental investigation. J. Bone Jt. Surg. 62:1232–1251, 1980.

    Article  CAS  Google Scholar 

  29. Shapiro, F., S. Koide, and M. J. Glimcher. Cell origin and differentiation in the repair of full-thickness defects of articular cartilage. J. Bone Jt. Surg. 75-A:532–553, 1993.

    Article  Google Scholar 

  30. Shirazi, R., and A. Shirazi-Adl. Computational biomechanics of articular cartilage of human knee joint: effect of osteochondral defects. J. Biomech. 42:2458–2465, 2009.

    Article  CAS  PubMed  Google Scholar 

  31. Song, J. Q., F. Dong, X. Li, C. P. Xu, Z. Cui, N. Jiang, J. J. Jia, and B. Yu. Effect of treadmill exercise timing on repair of full-thickness defects of articular cartilage by bone-derived mesenchymal stem cells: an experimental investigation in rats. PLoS One 9:1–10, 2014.

    Google Scholar 

  32. Thorpe, S. D., T. Nagel, S. F. Carroll, and D. J. Kelly. Modulating gradients in regulatory signals within mesenchymal stem cell seeded hydrogels: a novel strategy to engineer zonal articular cartilage. PLoS One 8:e60764, 2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Van Donkelaar, C. C., and W. Wilson. Mechanics of chondrocyte hypertrophy. Biomech. Model. Mechanobiol. 11:655–664, 2012.

    Article  PubMed  Google Scholar 

  34. Yao, J., A. D. Salo, M. Barbau-McInnis, and A. L. Lerner. Finite element modeling of knee joint contact pressures and comparison to magnetic resonance imaging of the loaded knee. 2003

  35. Zhou, S., Z. Cui, and J. P. G. Urban. Factors influencing the oxygen concentration gradient from the synovial surface of articular cartilage to the cartilage-bone interface: a modeling study. Arthritis Rheum. 50:3915–3924, 2004.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Funding was provided by a European Research Council Starter Grant (StemRepair – No. 258463).

Conflict of Interest

Grants from the European Research Council are reported. There are no other conflicts of interest pertaining to this study.

Author information

Authors and Affiliations

  1. Trinity Centre for Bioengineering, Trinity Biomedical Sciences, Trinity College Dublin, Dublin, Ireland

    Adam O’Reilly & Daniel J. Kelly

  2. Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland

    Adam O’Reilly & Daniel J. Kelly

  3. Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, Ireland

    Daniel J. Kelly

Authors
  1. Adam O’Reilly
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel J. Kelly
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel J. Kelly.

Additional information

Associate Editor Michael S. Detamore oversaw the review of this article.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

O’Reilly, A., Kelly, D.J. Unravelling the Role of Mechanical Stimuli in Regulating Cell Fate During Osteochondral Defect Repair. Ann Biomed Eng 44, 3446–3459 (2016). https://doi.org/10.1007/s10439-016-1664-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-016-1664-9

Keywords

Search

Navigation