title: Unravelling the Role of Mechanical Stimuli in Regulating Cell Fate During Osteochondral Defect Repair.
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.
authors.affiliation: Trinity Centre for Bioengineering, Trinity Biomedical Sciences, Trinity College Dublin, Dublin, Ireland.|Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland.
authors.forename: Adam
authors.initials: A
authors.lastname: O'Reilly
authors.affiliation: Trinity Centre for Bioengineering, Trinity Biomedical Sciences, Trinity College Dublin, Dublin, Ireland. kellyd9@tcd.ie.|Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland. kellyd9@tcd.ie.|Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, Ireland. kellyd9@tcd.ie.
authors.forename: Daniel J
authors.identifier: 0000-0001-8149-6551
authors.initials: DJ
authors.lastname: Kelly
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051445:Fibrocartilage / Q000293:injuries / Q000378:metabolism; D007718:Knee Injuries / Q000378:metabolism / Q000628:therapy; D040542:Mechanotransduction, Cellular; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D013552:Swine
keywords: Computational modelling; Mechanical stimuli; Osteochondral defect; Spontaneous repair; Tissue differentiation