Biomechanics and Modeling in Mechanobiology

, Volume 15, Issue 5, pp 1279–1294 | Cite as

A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing

  • Adam OReilly
  • Kurt D. Hankenson
  • Daniel J. Kelly
Original Paper


While it is well established that an adequate blood supply is critical to successful bone regeneration, it remains poorly understood how progenitor cell fate is affected by the altered conditions present in fractures with disrupted vasculature. In this study, computational models were used to explore how angiogenic impairment impacts oxygen availability within a fracture callus and hence regulates mesenchymal stem cell (MSC) differentiation and bone regeneration. Tissue differentiation was predicted using a previously developed algorithm which assumed that MSC fate is governed by oxygen tension and substrate stiffness. This model was updated based on the hypothesis that cell death, chondrocyte hypertrophy and endochondral ossification are regulated by oxygen availability. To test this, the updated model was used to simulate the time course of normal fracture healing, where it successfully predicted the observed quantity and spatial distribution of bone and cartilage at 10 and 20 days post-fracture (dpf). It also predicted the ratio of cartilage which had become hypertrophic at 10 dpf. Following this, three models of fracture healing with increasing levels of angiogenic impairment were developed. Under mild impairment, the model predicted experimentally observed reductions in hypertrophic cartilage at 10 dpf as well as the persistence of cartilage at 20 dpf. Models of more severe impairment predicted apoptosis and the development of fibrous tissue. These results provide insight into how factors specific to an ischemic callus regulate tissue regeneration and provide support for the hypothesis that chondrocyte hypertrophy and endochondral ossification during tissue regeneration are inhibited by low oxygen.


Stem cell differentiation Finite element analysis  Fracture healing Endochondral ossification Oxygen  Angiogenic impairment 



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

Supplementary material

10237_2016_759_MOESM1_ESM.pdf (2.4 mb)
Supplementary material 1 (pdf 2495 KB)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Adam OReilly
    • 1
    • 2
  • Kurt D. Hankenson
    • 3
    • 4
  • Daniel J. Kelly
    • 1
    • 2
    • 5
  1. 1.Trinity Centre for Bioengineering, Trinity Biomedical SciencesTrinity College DublinDublinIreland
  2. 2.Department of Mechanical and Manufacturing Engineering, School of EngineeringTrinity College DublinDublinIreland
  3. 3.Department of Small Animal Clinical Sciences, College of Veterinary MedicineMichigan State UniversityEast LansingUSA
  4. 4.Department of Orthopaedic Surgery, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  5. 5.Advanced Materials and Bioengineering Research Centre (AMBER)Royal College of Surgeons in Ireland and Trinity College DublinDublinIreland

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