Infrastructure Engineering - Theses
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ItemInvestigate the Inflammatory Response in Early Stage of Fracture Healing Under Various Disease Conditions( 2023-10)Secondary fracture healing is the predominant method of bone repair. The inflammatory phase, which is the initial stage, is vital to this process. Following a fracture, immune cells quickly migrate to the site, serving two purposes: clearing cellular and tissue debris resulting from the injury and releasing a cascade of cytokines to initiate the healing process. While an inflammatory response is essential for effective bone repair, uncontrolled inflammation can impair the healing outcome. Chronic inflammatory conditions, like diabetes, may intensify and prolong the inflammatory reaction at the fracture location. An overabundance of immune cells and cytokines has been found to disrupt the growth and differentiation of mesenchymal stem cells, resulting in a healing failure. The mechanical stability of a fracture site can be influenced by various factors, including changes in bone material properties due to osteoporosis, the choice of internal fixation methods, and the physiological stress exerted on the fracture. An unstable fracture site can lead to recurring microtraumas. The constant breaking of newly formed blood vessels at the site attracts more immune cells and releases additional inflammatory cytokines, amplifying inflammation. At present, the correlation between factors contributing to fracture instability and inflammatory responses remains unclear. The impact of different inflammatory conditions,whether induced by mechanical instability or chronic inflammatory diseases,on fracture healing outcomes is yet to be comprehensively understood. At first, this study developed a computational model designed to simulate the TNF-alpha mediated inflammatory response during early fracture healing. We validated this model using data from previously published experimental studies. Once validated, we employed the model to examine the effects of exacerbated inflammation, as seen in diabetes, and the absence of TNF on the proliferation of MSCs and subsequent fracture healing stages. Subsequently, we investigated the interplay between mechanical instability and the inflammatory response during the fracture healing process. To link interfragmentary strain with the inflammatory response, we developed a computational model that illustrates the impact of platelet-derived growth factor (PDGF) released from ruptured blood vessels on macrophage migration and subsequent fracture healing. This model was validated with experimental data from earlier research. The validated model was later used to investigate the bone healing process under mechanically stable or unstable condition with different inflammatory conditions. In further exploration, the study investigated the consequences of risk factors potentially impacting the stability of the fracture callus on both the inflammatory response and the proliferation and differentiation of bone cells. We introduced a numerical model that integrates a 2D fracture callus model with a 3D fracture fixation model. This was constructed to study how osteoporosis-induced alterations in bone material properties affect the interfragmentary strain in tibia fractures stabilized with a locking compression plate (LCP). This LCP fracture fixation model was then adapted to analyze the consequences of varying fixation strategies and loading rates on the fracture site's stability. We validated the model using experimental data sourced from mechanical tests conducted within this study. Lastly, the validated model was employed to forecast the uptake of inflammatory cells and cytokines into the fracture callus, as well as predict fracture healing outcomes. This research has shed light on the intricacies of the inflammation-mediated fracture healing process. It has unveiled the impact of several factors on the inflammatory response during bone repair. Key discoveries include: 1. There appears to be a specific optimal concentration of TNF-alpha in the fracture callus that promotes early-stage healing. Any significant deviation from this concentration, whether due to an overproduction or a deficiency of TNF-alpha, can potentially hinder the healing outcomes. 2. When diabetes and mechanical instability coexist, they can substantially disturb the standard processes of early-stage inflammation. This disturbance can transition acute inflammation into a chronic state, characterized by a persistently heightened TNF-alpha pathway. 3. Osteoporotic fracture calluses can impede the healing process by obstructing the growth and differentiation of mesenchymal stem cells. Moreover, when osteoporosis and diabetes co-occur, they can profoundly jeopardize fracture healing outcomes. 4. During the initial week of fracture healing, a lower frequency, such as 1 Hz, amplifies TNF-alpha production. Regarding osteoporotic fractures, the TNF-alpha concentration in the fracture callus markedly decreases under high loading rates. Especially, fractures with a more flexible configuration demonstrated increased TNF-alpha output. In contrast, the growth and differentiation of MSCs were promoted in fractures subjected to higher loading rates. Importantly, an increased bone-plate distance (BPD) and an extended working length (WL) were found to markedly amplify the inflammatory response, potentially acting as adverse factors in the bone healing process, particularly for patients with diabetes and osteoporosis.
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ItemMechanobiological investigation of bone fracture healing under Ilizarov circular fixators( 2020)Ilizarov circular fixator (ICF) is an external bone fixation device used by orthopaedic surgeons in treating variety of bone defects. Despite the fact that ICFs are being used for over seven decades, the interplay between ICF mechanics and biology of fracture healing remains poorly understood. The roles of ICF configurations on processes within the fracture site during fracture healing such as cell differentiations, solute (e.g. cell, growth factors etc.) transport and angiogenesis have not been explained well yet. Furthermore, how the interplay between ICF and other mechanical factors such as fracture geometry and loading affect these processes remains unclear. This knowledge gap in the mechanobiology of fracture healing under ICF is a barrier to address clinical problems associated with ICFs. Consequently, treatment failures and complications are significant with ICF treatments (around 10 – 30 %). This thesis intends to address this knowledge gap by conducting systematic mechanobiological investigations of fracture healing under ICFs. In this research, various computational models to simulate various aspects of fracture healing under ICFs were developed. In developing the models, various novel methodologies and modelling techniques were adopted. Firstly, unlike in most previous studies, a fully coupled fracture healing prediction model of fractured bone stabilized with ICFs, including soft tissues and mechano-regulation was developed to simulate early stage mesenchymal stem cell (MSC) differentiations. Secondly, a model combining both mechano-regulation and bio-regulation was implemented to simulate healing of fractures stabilized with ICF under dynamic loading. Thirdly, a new regulatory model considering level of vascularity and local tissue strain was proposed and implemented to simulate angiogenesis and fracture healing under ICF. Finally, a methodology using computational modelling in conjunction with engineering reliability analysis was implemented to investigate the role of uncertainties in mechanical parameters on fracture healing under ICFs. All computational models were developed based on the theory of porous media and continuum mechanics. The models were first validated using experimental data and subsequently used for fracture healing predictions. Mechanical experiments involving measurement of bone interfragmentary movements (IFM) using an advanced 3D optical measuring system (ARAMIS) were conducted in this research for model validation purposes. Wherever possible, the predictions of the models were corroborated by experimental and clinical data. Through systematic analyses, this thesis contributes to the existing body of knowledge by providing new insights into the mechanobiology of fracture healing under ICFs. This thesis elucidates the following mechanobiological aspects of fracture healing under ICF that have not been systematically studied so far: 1. The effects of ICF configuration, loading and fracture geometry on the early stage mesenchymal stem cell (MSC) differentiations during fracture healing; 2. The roles of physiologically relevant dynamic loading on cell differentiations and cell / growth factors transport within the early stage fracture site; 3. The effects of subject specific factors (i.e. body weight, fracture geometry and ICF configuration) on angiogenesis and optimal time dependent weight bearing levels for bone fractures treated with ICFs; and 4. The effects of uncertainties in mechanical factors (i.e. fracture geometry, weight bearing and ICF configuration) on fracture healing under ICF. In addition, the models presented in this thesis could potentially be used for further systematic investigations and in clinical settings for designing and comparing ICF treatment strategies.
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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).