Biomedical Engineering - Research Publications

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    Biomechanical testing of the calcified metacarpal articular surface and its association with subchondral bone microstructure in Thoroughbred racehorses
    Williamson, AJ ; Sims, NA ; Thomas, CDL ; Lee, PVS ; Stevenson, MA ; Whitton, RC (WILEY, 2018-03)
    BACKGROUND: Palmar/plantar osteochondral disease (POD) and third metacarpal/-tarsal condylar fractures are considered fatigue injuries of subchondral bone (SCB) and calcified cartilage due to repetitive high loads in racehorses. In combination with adaptive changes in SCB in response to race training, the accumulation of SCB fatigue is likely to result in changes of joint surface mechanical properties. OBJECTIVES: To determine the spatial relationship and correlation of calcified articular surface biomechanical properties with SCB microstructure and training history in the distal palmar metacarpal condyle of Thoroughbred racehorses. STUDY DESIGN: Cross-sectional study. METHODS: Third metacarpal condyles were examined from 31 Thoroughbred horses with micro-computed tomography (microCT). Hyaline cartilage was removed and reference point indentation (RPI) mechanical testing of the calcified articular surface was performed. Training histories were obtained from trainers. The association among indentation distance increase (IDI, an inverse RPI measure of toughness), and microCT and training variables was assessed using a mixed-effects generalised linear model. RESULTS: Untrained horses had higher IDI than horses that had commenced training (P<0.001). Death as a result of musculoskeletal bone fatigue injury (P = 0.044) and presence of POD (P = 0.05) were associated with higher IDI. The microCT variables connectivity density and trabecular pattern factor were positively (P = 0.002) and negatively (P<0.001) correlated with IDI respectively. MAIN LIMITATIONS: The application of RPI to the calcified articular surface is novel and there is a potential for measurement variability with surface unevenness. CONCLUSION: Commencement of race training is associated with altered material properties of the calcified articular surface in horses. Reduced articular surface material properties can also be detected in horses that have fatigue injuries of the distal metacarpus and at other sites in the skeleton. Measures of SCB connectivity and trabecular surface shape may be more important determinants of resistance to failure of the calcified articular surface than traditional measures such as SCB volume and density.
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    Microstructure Variations in the Soft-Hard Tissue Junction of the Human Anterior Cruciate Ligament
    Zhao, L ; Lee, PVS ; Ackland, DC ; Broom, ND ; Thambyah, A (WILEY, 2017-09)
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    The influence of rotator cuff tears on muscle and joint-contact loading after reverse total shoulder arthroplasty
    Ackland, DC ; Robinson, DL ; Wilkosz, A ; Wu, W ; Richardson, M ; Lee, P ; Tse, KM (WILEY, 2019-01)
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    Modelling apical columnar epithelium mechanics from circumferential contractile fibres
    Boyd, ARB ; Moore, S ; Sader, JE ; Lee, PVS (SPRINGER HEIDELBERG, 2017-10)
    Simple columnar epithelia are formed by individual epithelial cells connecting together to form single cell high sheets. They are a main component of many important body tissues and are heavily involved in both normal and cancerous cell activities. Prior experimental observations have identified a series of contractile fibres around the circumference of a cross section located in the upper (apical) region of each cell. While other potential mechanisms have been identified in both the experimental and theoretical literature, these circumferential fibres are considered to be the most likely mechanism controlling movement of this cross section. Here, we investigated the impact of circumferential contractile fibres on movement of the cross section by creating an alternate model where movement is driven from circumferential contractile fibres, without any other potential mechanisms. In this model, we utilised a circumferential contractile fibre representation based on investigations into the movement of contractile fibres as an individual system, treated circumferential fibres as a series of units, and matched our model simulation to experimental geometries. By testing against laser ablation datasets sourced from existing literature, we found that circumferential fibres can reproduce the majority of cross-sectional movements. We also investigated model predictions related to various aspects of cross-sectional movement, providing insights into epithelium mechanics and demonstrating the usefulness of our modelling approach.
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    Computational modeling of single-cell mechanics and cytoskeletal mechanobiology
    Rajagopal, V ; Holmes, WR ; Lee, PVS (WILEY, 2018-03)
    Cellular cytoskeletal mechanics plays a major role in many aspects of human health from organ development to wound healing, tissue homeostasis and cancer metastasis. We summarize the state-of-the-art techniques for mathematically modeling cellular stiffness and mechanics and the cytoskeletal components and factors that regulate them. We highlight key experiments that have assisted model parameterization and compare the advantages of different models that have been used to recapitulate these experiments. An overview of feed-forward mechanisms from signaling to cytoskeleton remodeling is provided, followed by a discussion of the rapidly growing niche of encapsulating feedback mechanisms from cytoskeletal and cell mechanics to signaling. We discuss broad areas of advancement that could accelerate research and understanding of cellular mechanobiology. A precise understanding of the molecular mechanisms that affect cell and tissue mechanics and function will underpin innovations in medical device technologies of the future. WIREs Syst Biol Med 2018, 10:e1407. doi: 10.1002/wsbm.1407 This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Physiology > Mammalian Physiology in Health and Disease Models of Systems Properties and Processes > Cellular Models.
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    The application of finite element modelling based on clinical pQCT for classification of fracture status
    Robinson, DL ; Jiang, H ; Song, Q ; Yates, C ; Lee, PVS ; Wark, JD (SPRINGER HEIDELBERG, 2019-02)
    Fracture risk assessment using dual-energy X-ray absorptiometry (DXA) frequently fails to diagnose osteoporosis amongst individuals who later experience fragility fractures. Hence, more reliable techniques that improve the prediction of fracture risk are needed. In this study, we evaluated a finite element (FE) modelling framework based on clinical peripheral quantitative computed tomography (pQCT) imaging of the tibial epiphysis and diaphysis to predict the stiffness at these locations in compression, shear, torsion and bending. The ability of these properties to identify a group of women who had recently sustained a low-trauma fracture from an age- and weight-matched control group was determined and compared to clinical pQCT and DXA properties and structural properties based on composite beam theory. The predicted stiffnesses derived from the FE models and composite beam theory were significantly different (p < 0.05) between the control and fracture groups, whereas no meaningful differences were observed using DXA and for the stress-strain indices (SSIs) derived using pQCT. The diagnostic performance of each property was assessed by the odds ratio (OR) and the area under the receiver operating curve (AUC), and both were greatest for the FE-predicted shear stiffness (OR 16.09, 95% CI 2.52-102.56, p = 0.003) (AUC: 0.80, 95% CI 0.67-0.93). The clinical pQCT variable total density (ρtot) and a number of structural and FE-predicted variables had a similar probability of correct classification between the control and fracture groups (i.e. ORs and AUCs with mean values greater than 5.00 and 0.80, respectively). In general, the diagnostic characteristics were lower for variables derived using DXA and for the SSIs (i.e. ORs and AUCs with mean values of 1.65-2.98 and 0.64-0.71, respectively). For all properties considered, the trabecular-dominant tibial epiphysis exhibited enhanced classification characteristics, as compared to the cortical-dominant tibial diaphysis. The results of this study demonstrate that bone properties may be derived using FE modelling that have the potential to enhance fracture risk assessment using conventional pQCT or DXA instruments in clinical settings.
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    Load response of the natural tooth and dental implant: A comparative biomechanics study
    Robinson, D ; Aguilar, L ; Gatti, A ; Abduo, J ; Lee, PVS ; Ackland, D (The Korean Academy of Prosthodontics, 2019-06-26)
    While dental implants have displayed high success rates, poor mechanical fixation is a common complication, and their biomechanical response to occlusal loading remains poorly understood. This study aimed to develop and validate a computational model of a natural first premolar and a dental implant with matching crown morphology, and quantify their mechanical response to loading at the occlusal surface. A finite-element model of the stomatognathic system comprising the mandible, first premolar and periodontal ligament (PDL) was developed based on a natural human tooth, and a model of a dental implant of identical occlusal geometry was also created. Occlusal loading was simulated using point forces applied at seven landmarks on each crown. Model predictions were validated using strain gauge measurements acquired during loading of matched physical models of the tooth and implant assemblies. For the natural tooth, the maximum vonMises stress (6.4 MPa) and maximal principal strains at the mandible (1.8 mε, −1.7 mε) were lower than those observed at the prosthetic tooth (12.5 MPa, 3.2 mε, and −4.4 mε, respectively). As occlusal load was applied more bucally relative to the tooth central axis, stress and strain magnitudes increased. Occlusal loading of the natural tooth results in lower stress-strain magnitudes in the underlying alveolar bone than those associated with a dental implant of matched occlusal anatomy. The PDL may function to mitigate axial and bending stress intensities resulting from off-centered occlusal loads. The findings may be useful in dental implant design, restoration material selection, and surgical planning.
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    Cortical and Trabecular Bone Fracture Characterisation in the Vertebral Body Using Acoustic Emission
    Robinson, DL ; Tse, KM ; Franklyn, M ; Zhang, JY ; Ackland, D ; Lee, PVS (SPRINGER, 2019-12)
    The ability to rapidly detect localised fractures of cortical and/or trabecular bone sustained by the vertebral body would enhance the analysis of vertebral fracture initiation and propagation during dynamic loading. In this study, high rate axial compression tests were performed on twenty sets of three-vertebra lumbar spine specimens. Acoustic Emission (AE) sensor measurements of sound wave pressure were used to classify isolated trabecular fractures and severe compressive fractures of vertebral body cortical and trabecular bone. Fracture detection using standard AE parameters was compared to that of traditional mechanical parameters obtained from load cell and displacement readings. Results indicated that the AE parameters achieved slightly enhanced classification of isolated trabecular fractures, whereas the mechanical parameters better identified combined fractures of cortical and trabecular bone. These findings demonstrate that AE may be used to promptly and accurately identify localised fractures of trabecular bone, whereas more extensive fractures of the vertebral body are best identified by load cell readings due to the considerable loss in compressive resistance. The discrimination thresholds corresponding to the AE parameters were based on calibrated measurements of AE wave pressure and may ultimately be used to examine the onset and progression of vertebral fracture in other loading scenarios.
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    Bone Health in Rats With Temporal Lobe Epilepsy in the Absence of Anti-Epileptic Drugs
    Brady, RD ; Wong, KR ; Robinson, DL ; Mychasiuk, R ; McDonald, SJ ; D'Cunha, RA ; Yamakawa, GR ; Sun, M ; Wark, JD ; Lee, PVS ; O'Brien, TJ ; Casillas-Espinosa, PM ; Shultz, SR (Frontiers Media, 2019-10-29)
    Rationale: Epilepsy patients often exhibit reduced bone mineral density and are at an increased risk of bone fracture. Whether these bone abnormalities are due to the use of anti-epileptic drugs (AED’s) or the disease itself is unknown. For example, although decreased bone health in epilepsy patients is generally attributed to the use of AED’s, seizures can also trigger a number of physiological processes that have the potential to affect bone. Therefore, to assess whether bone abnormalities occur in epilepsy in the absence of AED’s, the current study investigated mechanical characteristics and trabecular bone morphology in rats with chronic temporal lobe epilepsy. Methods: Ten-week old male Wistar rats underwent kainic acid-induced status epilepticus (SE; n = 7) or a sham procedure (n = 9). Rats were implanted with EEG recording electrodes at nine weeks post-SE, and video-EEG was continuously recorded for one week at 10- and 22-weeks post-SE to confirm that SE rats had spontaneous seizures. Open-field testing to assess locomotion was conducted at 23-weeks post-SE. At 24-weeks post-SE, rats were euthanized and tibia were extracted to determine trabecular morphology by micro-computed tomography (µCT), while femurs were used to investigate mechanical properties via 3-point bending. Results: All post-SE rats had spontaneous seizures at 10- and 22-weeks post-SE, while none of the sham rats had seizures. µCT trabecular analysis of tibia revealed no differences in total volume, bone volume, bone volume fraction, trabecular number, or trabecular separation between post-SE or sham rats, although post-SE rats did have increased trabecular thickness. There were also no group differences in total distance travelled in the open field suggesting that activity levels did not account for the increased trabecular thickness. In addition, no differences in mechanical properties of femurs were observed between the two groups. Conclusion: There was a lack of overt bone abnormalities in rats with chronic temporal lobe epilepsy in the absence of AED treatment. Although further studies are still needed, these findings may have important implications towards understanding the source (e.g., AED treatments) of bone abnormalities in epilepsy patients.
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    Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis
    Keenan, CR ; Langenbach, SY ; Jativa, F ; Harris, T ; Li, M ; Chen, Q ; Xia, Y ; Gao, B ; Schuliga, MJ ; Jaffar, J ; Prodanovic, D ; Tu, Y ; Berhan, A ; Lee, PVS ; Westall, GP ; Stewart, AG (FRONTIERS MEDIA SA, 2018-07-10)
    Transforming growth factor-beta (TGF-β) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition of TGF-β is limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover a little-known connection between TGF-β signaling and casein kinase (CK) activity. We have examined the abundance of CK1 delta and epsilon (CK1δ/ε) in lung tissue from IPF patients and non-diseased controls, and investigated whether inhibition of CK1δ/ε with PF670462 inhibits pulmonary fibrosis. CK1δ/ε levels in lung tissue from IPF patients and non-diseased controls were assessed by immunohistochemistry. Anti-fibrotic effects of the CK1δ/ε inhibitor PF670462 were assessed in pre-clinical models, including acute and chronic bleomycin mouse models and in vitro experiments on spheroids made from primary human lung fibroblast cells from IPF and control donors, and human A549 alveolar-like adenocarcinoma-derived epithelial cells. Increased expression of CK1δ and ε in IPF lungs compared to non-diseased controls was accompanied by increased levels of the product, phospho-period 2. In vitro, PF670462 prevented TGF-β-induced epithelial-mesenchymal transition. The stiffness of IPF-derived spheroids was reduced by PF670462 and TGF-β-induced fibrogenic gene expression was inhibited. The CK1δ/ε inhibitor PF670462 administered systemically or locally by inhalation prevented both acute and chronic bleomycin-induced pulmonary fibrosis in mice. PF670462 administered in a 'therapeutic' regimen (day 7 onward) prevented bleomycin-induced lung collagen accumulation. Elevated expression and activity of CK1 δ and ε in IPF and anti-fibrogenic effects of the dual CK1δ/ε inhibitor, PF670462, support CK1δ/ε as novel therapeutic targets for IPF.