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ItemThe influence of mechano-regulation on bone fracture healing( 2020)Bone fracture healing is a unique biological process characterised by differentiation of mesenchymal stem cells (MSCs) in fracture callus into bone forming cells while the process is regulated by biochemical and mechanical factors. The mechanical microenvironment can be influenced by several factors, including mechanical loading, fixation stiffness and flexibility; and fracture geometry (i.e. gap and angle of fracture). However, the fundamental relationship between the various loading regimes and different healing outcomes has not been fully understood. In this research, a computational model is developed to investigate advective transport of cells and growth factors under various strain and frequency of dynamic loading during early stage of diaphyseal bone healing. The model takes into account cell and growth factor transport under dynamic loading, and mechanical stimuli mediated MSC differentiation and tissue production. While literatures have suggested that dynamic loading induced deformation and fluid flow contributes to the biomechanical environment, the combined effects of biochemical and biomechanical stimuli on bone healing have not been fully investigated so far. To our knowledge, this is the first study to incorporate direct contribution of dynamic loading induced mechanical stimuli as well as the indirect contribution through advective transport of cells and growth factors into a computational model within the fracture callus which is the novelty of this work. The results demonstrate that, there is an optimal dynamic loading that enhances MSCs and growth factors transport in a spatially dependent manner (Ghimire et al., 2018). This research further investigates the effects of fixation on the MSCs migration and differentiation as well as growth factor transport using finite element method (FEM) simulation. There is limited research on the effects of dynamic loading on growth factor and cell transport during early stage of fracture healing under different Locking Compression Plate (LCP) configurations and optimal LCP configurations for directed cell migration are yet to be established for various fracture geometries. Therefore, this represents the first step towards fundamental understanding of the mechanical loading mediated MSCs transport and differentiation under LCP fixation with various flexibilities, and results demonstrate that MSCs and growth factor transport are highly dependent on flexibility of the fixation (Ghimire et al., 2019). The model was further developed to simulate oblique bone fracture healing stabilized by different fixation configurations to study the influence of fracture geometry on the angiogenesis during bone fracture healing. Using the simulation results, the allowable level of partial weight bearing loading at early stages of healing for promoting angiogenesis and bone healing are suggested. The results of this study would assist in the design of patient specific weight-bearing exercises during bone fracture healing following a surgical intervention with internal fixations. Osteoporotic fractures are generally different to normal bone fractures, due to the changes in the diffusion and perfusion of non-mineralised bone marrow with the loss of mineralised bone component. A better understanding of the impact of osteoporosis in fracture healing can lead to a better fracture treatment and optimum healing outcome in osteoporotic fractures. To achieve this aim, this research compares interfragmentary movement (IFM) between normal and osteoporotic bone fracture using ex-vivo mechanical experiments on ovine model of bone fractures under different bone plate distance (BPD) configurations of LCP. The experimental results suggest that osteoporotic bones experience more asymmetric healing across near and far cortex compared to healthy bones. The bone formation rate between the two mechanisms of bone fracture healing (intramembranous and endochondral ossification) was compared in this research by developing a novel time dependent simulation of bone fracture healing using experimentally determined bone density data in sheep tibia stabilized by the Locking Compression Plate (LCP) fixation system. The model results show that, there are two different thresholds for intramembranous and endochondral ossification that activates significant bone formation. Upon reaching the threshold, the rate of bone formation in endochondral ossification is generally higher than that in intramembranous ossification. In summary, through developing a computational model with consideration of biochemical as well as mechanical aspects of the fracture healing, this research is a significant step towards the crucial understanding of the mechanical loading mediated MSCs transport and differentiation under LCP with various flexibilities. The outcomes of this research could potentially be implemented to assist orthopaedic surgeons in identifying optimal configuration of LCP and loading regimes for patient specific conditions (e.g. fracture geometry, body weight).