The connection between cellular mechanoregulation and tissue patterns during bone healing
- 320 Downloads
The formation of different tissues in the callus during secondary bone healing is at least partly influenced by mechanical stimuli. We use computer simulations to test the consequences of different hypotheses of the mechanoregulation at the cellular level on the patterns of tissues formed during healing. The computational study is based on an experiment on sheep, where after a tibial osteotomy, histological sections were harvested at different time points. In the simulations, we used a recently proposed basic phenomenological model, which allows ossification to occur either via endochondral or intramembranous ossification, but tries otherwise to employ a minimal number of simulation parameters. The model was extended to consider also the possibility of bone resorption and consequently allowing a description of the full healing progression till the restoration of the cortex. Specifically, we investigated how three changes in the mechanoregulation influence the resulting tissue patterns: (1) a time delay between stimulation of the cell and the formation of the tissue, (2) a variable mechanosensitivity of the cells, and (3) an independence of long time intervals of the soft tissue maturation from the mechanical stimulus. For all three scenarios, our simulations do not show qualitative differences in the time development of the tissue patterns. Largest differences were observed in the intermediate phases of healing in the amount and location of the cartilage. Interestingly, the course of healing was virtually unaltered in case of scenario (3) where tissue maturation proceeded independent of mechanical stimulation.
KeywordsBone healing Simulation Cell sensitivity Tissue differentiation Mechanical stimulus
This study was supported by a grant of the German Research Foundation (Collaborative Research Centre “Biomechanics and Biology of Musculoskeletal Regeneration—From Functional Assessment to Guided Tissue Formation”, SFB 760). The authors like to thank Maria Gómez-Benito and Philip Kollmannsberger for fruitful discussions and Oliver Sander for his support with the finite element solver.
Supplementary material 1 (mpg 2081 KB)
- 8.Currey J (1995) The validation of algorithms used to explain adaptive bone remodeling in bone. In: Odgaard A, Weinans H (eds) Bone structure and remodeling. World Scientific, Singapore, pp 9–13Google Scholar
- 14.Garcia P, Histing T, Holstein J, Klein M, Laschke M, Matthys R, Ignatius A, Wildemann B, Lienau J, Peters A et al (2013) Rodent animal models of delayed bone healing and non-union formation: a comprehensive review. Eur Cells Mater 26:1–14Google Scholar
- 19.Gerstenfeld LC, Alkhiary YM, Krall EA, Nicholls FH, Stapleton SN, Fitch JL, Bauer M, Kayal R, Graves DT, Jepsen KJ, Einhorn TA (2006) Three-dimensional reconstruction of fracture callus morphogenesis. J Histochem Cytochem 54(11):1215–1228. doi:10.1369/jhc.6A6959.2006 PMID: 16864894CrossRefPubMedGoogle Scholar
- 20.Gibson LJ, Ashby MF (1999) Cellular solids: structure and properties. Cambridge University Press, CambridgeGoogle Scholar
- 22.Gómez-Benito MJ, González-Torres LA, Reina-Romo E, Grasa J, Seral B, García-Aznar JM, Gómez-Benito MJ, González-Torres LA, Reina-Romo E, Grasa J, Seral B, García-Aznar JM (2011) Influence of high-frequency cyclical stimulation on the bone fracture-healing process: mathematical and experimental models. Philos Trans R Soc A 369(1954):4278–4294. doi:10.1098/rsta.2011.0153 CrossRefGoogle Scholar
- 34.Khayyeri H, Isaksson H, Prendergast PJ (2013) Corroboration of computational models for mechanoregulated stem cell differentiation. Comput Methods Biomech Biomed Eng 1–9. doi:10.1080/10255842.2013.774381
- 44.Perren S, Cordey J (1980) The concept of interfragmentary strain. In: Uhthoff H (ed) Current concepts of internal fixation of fractures. Springer, Berlin, pp 67–77OGoogle Scholar
- 45.Reichert JC, Saifzadeh S, Wullschleger ME, Epari DR, Schütz MA, Duda GN, Schell H, van Griensven M, Redl H, Hutmacher DW (2009) The challenge of establishing preclinical models for segmental bone defect research. Biomaterials 30(12):2149–2163. doi:10.1016/j.biomaterials.2008.12.050 CrossRefPubMedGoogle Scholar
- 49.Steiner M, Claes L, Ignatius A, Niemeyer F, Simon U, Wehner T (2013) Prediction of fracture healing under axial loading, shear loading and bending is possible using distortional and dilatational strains as determining mechanical stimuli. J R Soc Interface 10(86). doi:10.1098/rsif.2013.0389
- 52.Vetter A, Liu Y, Witt F, Manjubala I, Sander O, Epari D, Fratzl P, Duda G, Weinkamer R (2011) The mechanical heterogeneity of the hard callus influences local tissue strains during bone healing: a finite element study based on sheep experiments. J Biomech 44(3):517–523. doi:10.1016/j.jbiomech.2010.09.009 CrossRefPubMedGoogle Scholar