Skip to main content

Advertisement

SpringerLink
Log in

Mechano-regulation of mesenchymal stem cell differentiation and collagen organisation during skeletal tissue repair

  • Original Paper
  • Published:
Biomechanics and Modeling in Mechanobiology Aims and scope Submit manuscript

Abstract

A number of mechano-regulation theories have been proposed that relate the differentiation pathway of mesenchymal stem cells (MSCs) to their local biomechanical environment. During spontaneous repair processes in skeletal tissues, the organisation of the extracellular matrix is a key determinant of its mechanical fitness. In this paper, we extend the mechano-regulation theory proposed by Prendergast et al. (J Biomech 30(6):539–548, 1997) to include the role of the mechanical environment on the collagen architecture in regenerating soft tissues. A large strain anisotropic poroelastic material model is used in a simulation of tissue differentiation in a fracture subject to cyclic bending (Cullinane et al. in J Orthop Res 20(3):579–586, 2002). The model predicts non-union with cartilage and fibrous tissue formation in the defect. Predicted collagen fibre angles, as determined by the principal decomposition of strain- and stress-type tensors, are similar to the architecture seen in native articular cartilage and neoarthroses induced by bending of mid-femoral defects in rats. Both stress and strain-based remodelling stimuli successfully predicted the general patterns of collagen fibre organisation observed in vivo. This provides further evidence that collagen organisation during tissue differentiation is determined by the mechanical environment. It is envisioned that such predictive models can play a key role in optimising MSC-based skeletal repair therapies where recapitulation of the normal tissue architecture is critical to successful 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

Similar content being viewed by others

References

  • Akizuki S, Mow VC, Muller F, Pita JC, Howell DS (1987) Tensile properties of human knee joint cartilage. ii. correlations between weight bearing and tissue pathology and the kinetics of swelling. J Orthop Res 5(2): 173–186. doi:10.1002/jor.1100050204

    Article  Google Scholar 

  • Andreykiv A, van Keulen F, Prendergast PJ (2008) Simulation of fracture healing incorporating mechanoregulation of tissue differentiation and dispersal/proliferation of cells. Biomech Model Mechanobiol 7(6): 443–461. doi:10.1007/s10237-007-0108-8

    Article  Google Scholar 

  • Bailón-Plaza A, van der Meulen M (2001) A mathematical framework to study the effects of growth factor influences on fracture healing. J Theor Biol 212(2):191–209. doi:10.1006/jtbi.2001.2372. http://www.sciencedirect.com/science/article/B6WMD-457VD8R-4G/2/9713489c72b7712ab8fea9380b22cde7

  • Boccaccio A, Pappalettere C, Kelly DJ (2007) The influence of expansion rates on mandibular distraction osteogenesis: a computational analysis. Ann Biomed Eng 35(11): 1940–1960. doi:10.1007/s10439-007-9367-x

    Article  Google Scholar 

  • Boccaccio A, Lamberti L, Pappalettere C, Cozzani M, Siciliani G (2008) Comparison of different orthodontic devices for mandibular symphyseal distraction osteogenesis: a finite element study. Am J Orthod Dentofacial Orthop 134(2): 260–269. doi:10.1016/j.ajodo.2006.09.066

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Carter DR, Blenman PR, Beauprcé 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

    Article  Google Scholar 

  • Carter DR, Beauprcé GS, Giori NJ, Helms JA (1998) Mechanobiology of skeletal regeneration. Clin Orthop Relat Res 355 (Suppl):S41–S55

    Google Scholar 

  • Checa S, Prendergast PJ (2009) A mechanobiological model for tissue differentiation that includes angiogenesis: a lattice-based modeling approach. Ann Biomed Eng 37(1): 129–145. doi:10.1007/s10439-008-9594-9

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Claes LE, Heigele CA, Neidlinger-Wilke C, Kaspar D, Seidl W, Margevicius KJ, Augat P (1998) Effects of mechanical factors on the fracture healing process. Clin Orthop Relat Res 355(Suppl): S132–S147

    Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Driessen NJB, Boerboom RA, Huyghe JM, Bouten CVC, Baaijens FPT (2003a) Computational analyses of mechanically induced collagen fiber remodeling in the aortic heart valve. J Biomech Eng 125(4):549–557. doi:10.1115/1.1590361. http://link.aip.org/link/?JBY/125/549/1

    Google Scholar 

  • Driessen NJB, Peters GWM, Huyghe JM, Bouten CVC, Baaijens FPT (2003b) Remodelling of continuously distributed collagen fibres in soft connective tissues. J Biomech 36(8): 1151–1158

    Article  Google Scholar 

  • Driessen NJB, Bouten CVC, Baaijens FPT (2005) Improved prediction of the collagen fiber architecture in the aortic heart valve. J Biomech Eng 127(2): 329–336

    Article  Google Scholar 

  • Driessen NJB, Cox MAJ, Bouten CVC, Baaijens FPT (2008) Remodelling of the angular collagen fiber distribution in cardiovascular tissues. Biomech Model Mechanobiol 7(2): 93–103. doi:10.1007/s10237-007-0078-x

    Article  Google Scholar 

  • Fisher NI (1993) Statistical analysis of circular data. Cambridge University Press, Cambridge

    MATH  Google Scholar 

  • García-Aznar JM, Kuiper JH, Gómez-Benito MJ, Doblaré M, Richardson JB (2007) Computational simulation of fracture healing: influence of interfragmentary movement on the callus growth. J Biomech 40(7): 1467–1476. doi:10.1016/j.jbiomech.2006.06.013

    Article  Google Scholar 

  • Garikipati K, Arruda EM, Grosh K, Narayanan H, Calve S (2004) A continuum treatment of growth in biological tissue: the coupling of mass transport and mechanics. J Mech Phys Solids 52(7):1595–1625. doi:10.1016/j.jmps.2004.01.004. http://www.sciencedirect.com/science/article/B6TXB-4BV4PW5-1/2/b94b1174d8b02f1709a495f8bae22bc2

    Google Scholar 

  • Garikipati K, Olberding J, Narayanan H, Arruda E, Grosh K, Calve S (2006) Biological remodelling: stationary energy, configurational change, internal variables and dissipation. J Mech Phys Solids 54(7):1493–1515. doi:10.1016/j.jmps.2005.11.011. http://www.sciencedirect.com/science/article/B6TXB-4J9MV5T-1/2/b3086bfcb28b11b9b94379805b44cc0e

    Google Scholar 

  • Geris L, Sloten JV, Oosterwyck HV (2006) Mathematical modeling of bone regeneration including the angiogenic process. J Biomech 39(Suppl 1):S411–S412. doi:10.1016/S0021-9290(06)84671-3. http://www.sciencedirect.com/science/article/B6T82-4KR88PB-28G/2/bfa4556efcc77303ea8f535ccbe8049b. Abstracts of the 5th World Congress of Biomechanics

    Google Scholar 

  • Giori NJ, Beaupré GS, Carter DR (1993) Cellular shape and pressure may mediate mechanical control of tissue composition in tendons. J Orthop Res 11(4): 581–591. doi:10.1002/jor.1100110413

    Article  Google Scholar 

  • Gleason RL, Humphrey JD (2004) A mixture model of arterial growth and remodeling in hypertension: altered muscle tone and tissue turnover. J Vasc Res 41(4): 352–363. doi:10.1159/000080699

    Article  Google Scholar 

  • Gómez-Benito MJ, García-Aznar JM, Kuiper JH, Doblaré M (2005) Influence of fracture gap size on the pattern of long bone healing: a computational study. J Theor Biol 235(1): 105–119. doi:10.1016/j.jtbi.2004.12.023

    Article  Google Scholar 

  • Gómez-Benito MJ, García-Aznar JM, Kuiper JH, Doblaré M (2006) A 3d computational simulation of fracture callus formation: influence of the stiffness of the external fixator. J Biomech Eng 128(3): 290–299. doi:10.1115/1.2187045

    Article  Google Scholar 

  • Hariton I, de Botton G, Gasser TC, Holzapfel GA (2007a) Stress-driven collagen fiber remodeling in arterial walls. Biomech Model Mechanobiol 6(3): 163–175. doi:10.1007/s10237-006-0049-7

    Article  Google Scholar 

  • Hariton I, deBotton G, Gasser TC, Holzapfel GA (2007b) Stress-modulated collagen fiber remodeling in a human carotid bifurcation. J Theor Biol 248(3): 460–470. doi:10.1016/j.jtbi.2007.05.037

    Article  Google Scholar 

  • Hayward L, Morgan E (2009) Assessment of a mechano-regulation theory of skeletal tissue differentiation in an in vivo model of mechanically induced cartilage formation. Biomech Model Mechanobiol doi:10.1007/s10237-009-0148-3

  • Holzapfel G, Gasser T, Ogden R (2002) A new constitutive framework for arterial wall mechanics and a comparative study of material models. Cardiovasc Soft Tissue Mech 1–48.

  • Huang CY, Stankiewicz A, Ateshian GA, Mow VC (2005) Anisotropy, inhomogeneity, and tension–compression nonlinearity of human glenohumeral cartilage in finite deformation. J Biomech 38(4): 799–809. doi:10.1016/j.jbiomech.2004.05.006

    Article  Google Scholar 

  • Huiskes R, Driel WDV, Prendergast PJ, Søballe K (1997) A biomechanical regulatory model for periprosthetic fibrous-tissue differentiation. J Mater Sci Mater Med 8(12): 785–788

    Article  Google Scholar 

  • Humphrey JD, Rajagopal KR (2003) A constrained mixture model for arterial adaptations to a sustained step change in blood flow. Biomech Model Mechanobiol 2(2): 109–126. doi:10.1007/s10237-003-0033-4

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Isaksson H, van Donkelaar CC, Huiskes R, Ito K (2008a) Corrigendum to a mechano-regulatory bone-healing model incorporating cell-phenotype specific activity. J Theor Biol 252(2008):230–246]. J Theor Biol 254(3):717 – 717. doi:10.1016/j.jtbi.2008.07.003. http://www.sciencedirect.com/science/article/B6WMD-4SYCR1P-1/2/cf015f26dd844846ac59e30a31552fbf

    Google Scholar 

  • Isaksson H, van Donkelaar CC, Huiskes R, Ito K (2008) A mechano-regulatory bone-healing model incorporating cell-phenotype specific activity. J Theor Biol 252(2): 230–246. doi:10.1016/j.jtbi.2008.01.030

    Article  Google Scholar 

  • Jurvelin JS, Buschmann MD, Hunziker EB (1997) Optical and mechanical determination of Poisson’s ratio of adult bovine humeral articular cartilage. J Biomech 30(3): 235–241

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Kuhl E, Holzapfel G (2007) A continuum model for remodeling in living structures. J Mater Sci 42(21): 8811–8823

    Article  Google Scholar 

  • Lacroix D, Prendergast P (2000) A homogenization procedure to prevent numerical instabilities in poroelastic tissue differentiation models. In: Eighth annual symposium: computational methods in orthopaedic biomechanics, Orlando, FL

  • Lacroix D, Prendergast PJ (2002a) A mechano-regulation model for tissue differentiation during fracture healing: analysis of gap size and loading. J Biomech 35(9): 1163–1171

    Article  Google Scholar 

  • Lacroix D, Prendergast PJ (2002b) Three-dimensional simulation of fracture repair in the human tibia. Comput Methods Biomech Biomed Engin 5(5): 369–376. doi:10.1080/1025584021000025014

    Article  Google Scholar 

  • Lacroix D, Prendergast PJ, Li G, Marsh D (2002) Biomechanical model to simulate tissue differentiation and bone regeneration: application to fracture healing. Med Biol Eng Comput 40(1): 14–21

    Article  Google Scholar 

  • Loboa EG, Beaupré GS, Carter DR (2001) Mechanobiology of initial pseudarthrosis formation with oblique fractures. J Orthop Res 19(6): 1067–1072. doi:10.1016/S0736-0266(01)00028-6

    Article  Google Scholar 

  • Loboa EG, Wren TAL, Beauprcé GS, Carter DR (2003) Mechanobiology of soft skeletal tissue differentiation—a computational approach of a fiber-reinforced poroelastic model based on homogeneous and isotropic simplifications. Biomech Model Mechanobiol 2(2): 83–96. doi:10.1007/s10237-003-0030-7

    Article  Google Scholar 

  • Mow VC, Guo XE (2002) Mechano-electrochemical properties of articular cartilage: their inhomogeneities and anisotropies. Annu Rev Biomed Eng 4: 175–209. doi:10.1146/annurev.bioeng.4.110701.120309

    Article  Google Scholar 

  • Mow VC, Kuei SC, Lai WM, Armstrong CG (1980) Biphasic creep and stress relaxation of articular cartilage in compression? Theory and experiments. J Biomech Eng 102(1): 73–84

    Article  Google Scholar 

  • MSC (2008a) Marc 2008r1—volume A: theory and user information. MSC.Software Corporation, 2 MacArthur Place, Santa Ana, CA 92707, USA. http://www.mscsoftware.com

  • MSC (2008b) Marc 2008r1—volume B: element library. MSC.Software Corporation, 2 MacArthur Place, Santa Ana, CA 92707, USA. http://www.mscsoftware.com

  • Pauwels F (1941) Grundri einer biomechanik der frakturheilung. In: Kongre der Deutschen Orthopädischen Gesellschaft, vol 34. Ferdinand Enke Verlag, Stuttgart Pauwels F (1980) Biomechanics of the locomotor apparatus [trans: Manquet P, Furlong R (eds)]. Springer, Berlin, pp 375–407.

  • Pauwels F (1960) Eine neue Theorie über den Einflu mechanischer Reize auf die Differenzierung der Stützgewebe. Anatomy and Embryology 121(6): 478–515

    Article  Google Scholar 

  • Perez M, Prendergast P (2007) Random-walk models of cell dispersal included in mechanobiological simulations of tissue differentiation. http://linkinghub.elsevier.com/retrieve/pii/S0021929006003988

  • Prendergast P, Huiskes R, Sballe K (1997) Esb research award 1996. Biophysical stimuli on cells during tissue differentiation at implant interfaces. J Biomech 30(6): 539–548

    Article  Google Scholar 

  • Roth V, Mow VC (1980) The intrinsic tensile behavior of the matrix of bovine articular cartilage and its variation with age. J Bone Joint Surg Am 62(7): 1102–1117

    Google Scholar 

  • Taber LA, Humphrey JD (2001) Stress-modulated growth, residual stress, and vascular heterogeneity. J Biomech Eng 123(6): 528–535

    Article  Google Scholar 

  • Wilson W, Driessen NJB, van Donkelaar CC, Ito K (2006a) Prediction of collagen orientation in articular cartilage by a collagen remodeling algorithm. Osteoarthritis Cartilage 14(11): 1196–1202. doi:10.1016/j.joca.2006.05.006

    Article  Google Scholar 

  • Wilson W, Huyghe JM, van Donkelaar CC (2006b) A composition-based cartilage model for the assessment of compositional changes during cartilage damage and adaptation. Osteoarthritis Cartilage 14(6): 554–560. doi:10.1016/j.joca.2005.12.006

    Article  Google Scholar 

  • Wilson W, Huyghe JM, van Donkelaar CC (2007) Depth-dependent compressive equilibrium properties of articular cartilage explained by its composition. Biomech Model Mechanobiol 6(1–2): 43–53. doi:10.1007/s10237-006-0044-z

    Article  Google Scholar 

  • Wren TA, Beaupré GS, Carter DR (2000) Mechanobiology of tendon adaptation to compressive loading through fibrocartilaginous metaplasia. J Rehabil Res Dev 37(2): 135–143

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Trinity Centre for Bioengineering, Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin 2, Ireland

    Thomas Nagel & Daniel J. Kelly

Authors
  1. Thomas Nagel
    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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nagel, T., Kelly, D.J. Mechano-regulation of mesenchymal stem cell differentiation and collagen organisation during skeletal tissue repair. Biomech Model Mechanobiol 9, 359–372 (2010). https://doi.org/10.1007/s10237-009-0182-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10237-009-0182-1

Keywords

Search

Navigation