| 1. |
- Burke, Darren, et al.
(författare)
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Substrate stiffness and oxygen availability as regulators of mesenchymal stem cell differentiation within a mechanically loaded bone chamber
- 2015
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Ingår i: Biomechanics and Modeling in Mechanobiology. - : Springer Science and Business Media LLC. - 1617-7940 .- 1617-7959. ; 14:1, s. 93-105
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Tidskriftsartikel (refereegranskat)abstract
- Mechanical stimuli such as tissue deformation and fluid flow are often implicated as regulators of mesenchymal stem cell (MSC) differentiation during regenerative events in vivo. However, in vitro studies have identified several other physical and biochemical environmental cues, such as substrate stiffness and oxygen availability, as key regulators of stem cell fate. Hypotheses for how MSC differentiation is regulated in vivo can be either corroborated or rejected based on the ability of in silico models to accurately predict spatial and temporal patterns of tissue differentiation observed experimentally. The goal of this study was to employ a previously developed computational framework to test the hypothesis that substrate stiffness and oxygen availability regulate stem cell differentiation during tissue regeneration within an implanted bone chamber. To enable a prediction of the oxygen levels within the bone chamber, a lattice model of angiogenesis was implemented where blood vessel progression was dependent on the local mechanical environment. The model successfully predicted key aspects of MSC differentiation, including the correct spatial development of bone, marrow and fibrous tissue within the unloaded bone chamber. The model also successfully predicted chondrogenesis within the chamber upon the application of mechanical loading. This study provides further support for the hypothesis that substrate stiffness and oxygen availability regulate stem cell differentiation in vivo. These simulations also highlight the indirect role that mechanics may play in regulating MSC fate by inhibiting blood vessel progression and hence disrupting oxygen availability within regenerating tissues.
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| 2. |
- Gustafsson, Anna, et al.
(författare)
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An interface damage model that captures crack propagation at the microscale in cortical bone using XFEM
- 2019
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Ingår i: Journal of the Mechanical Behavior of Biomedical Materials. - : Elsevier BV. - 1751-6161. ; 90, s. 556-565
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Tidskriftsartikel (refereegranskat)abstract
- Reliable tools for fracture risk assessment are necessary to handle the challenge with an aging population and the increasing occurrence of bone fractures. As it is currently difficult to measure local damage parameters experimentally, computational models could be used to provide insight into how cortical bone microstructure and material properties contribute to the fracture resistance. In this study, a model for crack propagation in 2D at the microscale in cortical bone was developed using the extended finite element method (XFEM). By combining the maximum principal strain criterion with an additional interface damage formulation in the cement line, the model could capture crack deflections at the osteon boundaries as observed in experiments. The model was used to analyze how the Haversian canal and the interface strength of the cement line affected the crack trajectory in models depicting osteons with three different orientations in 2D. Weak cement line interfaces were found to reorient the propagating cracks while models with strong interfaces predicted crack trajectories that penetrated the cement line and propagated through the osteons. The presented model is a promising tool that could be used to analyze how local, age-related material changes influence the crack trajectory and fracture resistance in cortical bone.
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| 3. |
- Gustafsson, Anna, et al.
(författare)
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Crack propagation in cortical bone is affected by the characteristics of the cement line : a parameter study using an XFEM interface damage model
- 2019
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Ingår i: Biomechanics and Modeling in Mechanobiology. - : Springer Science and Business Media LLC. - 1617-7959 .- 1617-7940. ; 18:4, s. 1247-1261
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Tidskriftsartikel (refereegranskat)abstract
- Bulk properties of cortical bone have been well characterized experimentally, and potent toughening mechanisms, e.g., crack deflections, have been identified at the microscale. However, it is currently difficult to experimentally measure local damage properties and isolate their effect on the tissue fracture resistance. Instead, computer models can be used to analyze the impact of local characteristics and structures, but material parameters required in computer models are not well established. The aim of this study was therefore to identify the material parameters that are important for crack propagation in cortical bone and to elucidate what parameters need to be better defined experimentally. A comprehensive material parameter study was performed using an XFEM interface damage model in 2D to simulate crack propagation around an osteon at the microscale. The importance of 14 factors (material parameters) on four different outcome criteria (maximum force, fracture energy, crack length and crack trajectory) was evaluated using ANOVA for three different osteon orientations. The results identified factors related to the cement line to influence the crack propagation, where the interface strength was important for the ability to deflect cracks. Crack deflection was also favored by low interface stiffness. However, the cement line properties are not well determined experimentally and need to be better characterized. The matrix and osteon stiffness had no or low impact on the crack pattern. Furthermore, the results illustrated how reduced matrix toughness promoted crack penetration of the cement line. This effect is highly relevant for the understanding of the influence of aging on crack propagation and fracture resistance in cortical bone.
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| 4. |
- Gustafsson, Anna, et al.
(författare)
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Linking multiscale deformation to microstructure in cortical bone using in situ loading, digital image correlation and synchrotron X-ray scattering
- 2018
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Ingår i: Acta Biomaterialia. - : Elsevier BV. - 1742-7061. ; 69, s. 323-331
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of fragility fractures is expected to increase in the near future due to an aging population. Therefore, improved tools for fracture prediction are required to treat and prevent these injuries efficiently. For such tools to succeed, a better understanding of the deformation mechanisms in bone over different length scales is needed. In this study, an experimental setup including mechanical tensile testing in combination with digital image correlation (DIC) and small/wide angle X-ray scattering (SAXS/WAXS) was used to study deformation at multiple length scales in bovine cortical bone. Furthermore, micro-CT imaging provided detailed information about tissue microstructure. The combination of these techniques enabled measurements of local deformations at the tissue- and nanoscales. The orientation of the microstructure relative to the tensile loading was found to influence the strain magnitude on all length scales. Strains in the collagen fibers were 2-3 times as high as the strains found in the mineral crystals for samples with microstructure oriented parallel to the loading. The local tissue strain at fracture was found to be around 0.5%, independent of tissue orientation. However, the maximum force and the irregularity of the crack path were higher when the load was applied parallel to the tissue orientation. This study clearly shows the potential of combining these different experimental techniques concurrently with mechanical testing to gain a better understanding of bone damage and fracture over multiple length scales in cortical bone. Statement of Significance: To understand the pathophysiology of bone, it is important to improve our knowledge about the deformation and fracture mechanisms in bone. In this study, we combine several recently available experimental techniques with mechanical loading to investigate the deformation mechanisms in compact bone tissue on several length scales simultaneously. The experimental setup included mechanical tensile testing in combination with digital image correlation, microCT imaging, and small/wide angle X-ray scattering.The combination of techniques enabled measurements of local deformations at the tissue- and nanoscales. The study clearly shows the potential of combining different experimental techniques concurrently with mechanical testing to gain a better understanding of structure-property-function relationships in bone tissue.
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| 5. |
- Jovanovic, Milena, et al.
(författare)
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Perturbed bone composition and integrity with disorganized osteoblast function in zinc receptor/Gpr39-deficient mice
- 2018
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Ingår i: FASEB Journal. - 0892-6638. ; 32:5, s. 2507-2518
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Tidskriftsartikel (refereegranskat)abstract
- Changes in bone matrix composition are frequently found with bone diseases and may be associated with increased fracture risk. Bone is rich in the trace element zinc. Zinc was established to play a significant role in the growth, development, and maintenance of healthy bones; however, the mechanisms underlying zinc effects on the integrity of the skeleton are poorly understood. Here, we show that the zinc receptor (ZnR)/Gpr39 is required for normal bone matrix deposition by osteoblasts. Initial analysis showed that Gpr39-deficient (Gpr39-/-) mice had weaker bones as a result of altered bone composition. Fourier transform infrared spectroscopy analysis showed high mineral-to-matrix ratios in the bones of Gpr39-/- mice. Histologic analysis showed abnormally high numbers of active osteoblasts but normal osteoclast numbers on the surfaces of bones from Gpr39-/- mice. Furthermore, Gpr39-/- osteoblasts had disorganized matrix deposition in vitro with cultures exhibiting abnormally low collagen and high mineral contents, findings that demonstrateacell-intrinsic role for ZnR/Gpr39 in these cells. We show that both collagen synthesis and deposition by Gpr39-/- osteoblasts are perturbed. Finally, the expression of the zinc transporter Zip13 and a disintegrin and metalloproteinase with thrombospondin motifs family of zinc-dependent metalloproteases that regulate collagen processing was downregulated in Gpr39-/- osteoblasts. Altogether, our results suggest that zinc sensing by ZnR/Gpr39 affects the expression levels of zinc-dependent enzymes in osteo-blasts and regulates collagen processing and deposition.
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| 6. |
- Khayyeri, Hanifeh, et al.
(författare)
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A Fibre-Reinforced Poroviscoelastic Model Accurately Describes the Biomechanical Behaviour of the Rat Achilles Tendon
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Background Computational models of Achilles tendons can help understanding how healthy tendons are affected by repetitive loading and how the different tissue constituents contribute to the tendons biomechanical response. However, available models of Achilles tendon are limited in their description of the hierarchical multi-structural composition of the tissue. This study hypothesised that a poroviscoelastic fibre-reinforced model, previously successful in capturing cartilage biomechanical behaviour, can depict the biomechanical behaviour of the rat Achilles tendon found experimentally. Materials and Methods We developed a new material model of the Achilles tendon, which considers the tendons main constituents namely: water, proteoglycan matrix and collagen fibres. A hyperelastic formulation of the proteoglycan matrix enabled computations of large deformations of the tendon, and collagen fibres were modelled as viscoelastic. Specimen-specific finite element models were created of 9 rat Achilles tendons from an animal experiment and simulations were carried out following a repetitive tensile loading protocol. The material model parameters were calibrated against data from the rats by minimising the root mean squared error (RMS) between experimental force data and model output. Results and Conclusions All specimen models were successfully fitted to experimental data with high accuracy (RMS 0.42-1.02). Additional simulations predicted more compliant and soft tendon behaviour at reduced strain-rates compared to higher strain-rates that produce a stiff and brittle tendon response. Stress-relaxation simulations exhibited strain-dependent stress-relaxation behaviour where larger strains produced slower relaxation rates compared to smaller strain levels. Our simulations showed that the collagen fibres in the Achilles tendon are the main load-bearing component during tensile loading, where the orientation of the collagen fibres plays an important role for the tendons viscoelastic response. In conclusion, this model can capture the repetitive loading and unloading behaviour of intact and healthy Achilles tendons, which is a critical first step towards understanding tendon homeostasis and function as this biomechanical response changes in diseased tendons.
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| 7. |
- Khayyeri, Hanifeh, et al.
(författare)
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A novel semi-automatic hip morphology assessment tool is more accurate than manual radiographic evaluations
- 2020
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Ingår i: Computer Methods in Biomechanics and Biomedical Engineering: Imaging and Visualization. - : Informa UK Limited. - 2168-1163 .- 2168-1171. ; 8:1, s. 76-86
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Tidskriftsartikel (refereegranskat)abstract
- Radiological and pathological characteristics of hip osteoarthritis (OA) is joint-space loss due to degradation of articular cartilage. However, patients with early-stage OA do not yet show any radiological signs, which leaves them without diagnosis and treatment. This study evaluates the potential of a novel tool to identify pre-radiographic OA changes based on hip bone morphology. Two statistical appearance models for femur and pelvis were used to estimate the 3Dmorphology of the hip bones based on planar radiographs from patients. Well-known hip geometrical parameters (n = 22) were computed from patient CT scans (truth), 3D reconstructions (new method) and radiographs (calculated manually). The methods were compared by measuring relative error to truth. The new method was significantly more accurate in calculating hip geometrical parameters than the manual 2D calculations. The proposed approach could also capture rotational parameters like cross-over sign and anterior wall sign (100% correct predictions). The method can successfully reconstruct 3D hip shapes and densities for patients that have not yet developed severe osteoarthritis, and provided higher precision than manual estimations. Thus, it may be used to calculate morphological parameters that are predictors of OA and can become a powerful tool in human hip OA research and diagnostics.
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| 8. |
- Khayyeri, Hanifeh, et al.
(författare)
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Achilles tendon compositional and structural properties are altered after unloading by botox
- 2017
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Tendon function and homeostasis rely on external loading. This study investigates the biological mechanisms behind tendon biomechanical function and how the mechanical performance is affected by reduced daily loading. The Achilles tendons of 16 weeks old female Sprague Dawley rats (n = 40) were unloaded for 5 weeks by inducing muscle paralysis with botulinum toxin injections in the right gastrocnemius and soleus muscles. The contralateral side was used as control. After harvest, the tendons underwent biomechanical testing to assess viscoelasticity (n = 30 rats) and small angle X-ray scattering to determine the structural properties of the collagen fibrils (n = 10 rats). Fourier transform infrared spectroscopy and histological staining (n = 10 rats) were performed to investigate the collagen and proteoglycan content. The results show that the stiffness increased in unloaded tendons, together with an increased collagen content. Creep and axial alignment of the collagen fibers were reduced. Stress-relaxation increased whereas hysteresis was reduced in response to unloading with botox treatment. Our findings indicate that altered matrix deposition relies on mechanical loading to reorganize the newly formed tissue, without which the viscoelastic behavior is impaired. The results demonstrate that reduced daily loading deprives tendons of their viscoelastic properties, which could increase the risk of injury.
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| 9. |
- Khayyeri, Hanifeh, et al.
(författare)
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Comparison of structural anisotropic soft tissue models for simulating Achilles tendon tensile behaviour
- 2016
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Ingår i: Journal of the Mechanical Behavior of Biomedical Materials. - : Elsevier BV. - 1751-6161. ; 61, s. 431-443
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of tendon injury (tendinopathy) has increased over the past decades due to greater participation in sports and recreational activities. But little is known about the aetiology of tendon injuries because of our limited knowledge in the complex structure-function relationship in tendons. Computer models can capture the biomechanical behaviour of tendons and its structural components, which is essential for understanding the underlying mechanisms of tendon injuries. This study compares three structural constitutive material models for the Achilles tendon and discusses their application on different biomechanical simulations. The models have been previously used to describe cardiovascular tissue and articular cartilage, and one model is novel to this study. All three constitutive models captured the tensile behaviour of rat Achilles tendon (root mean square errors between models and experimental data are 0.50-0.64). They further showed that collagen fibres are the main load-bearing component and that the non-collagenous matrix plays a minor role in tension. By introducing anisotropic behaviour also in the non-fibrillar matrix, the new biphasic structural model was also able to capture fluid exudation during tension and high values of Poisson's ratio that is reported in tendon experiments.
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| 10. |
- Khayyeri, Hanifeh, et al.
(författare)
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Corroboration of computational models for mechanoregulated stem cell differentiation
- 2015
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Ingår i: Computer Methods in Biomechanics and Biomedical Engineering. - : Informa UK Limited. - 1025-5842 .- 1476-8259. ; 18:1, s. 15-23
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Tidskriftsartikel (refereegranskat)abstract
- Do computational models contribute to progress in mechanobiology? Jacobs and Kelly (in Advances on Modelling in Tissue Engineering, p. 1–14, 2011) suggest that they do, but at the same time propose a limitation in the form of the ‘paradox of validation’, whereby the information needed to validate mechanoregulation theories obviates the need for them in the first place. In this article, the corroboration of theories describing mechanoregulation of tissue differentiation is reviewed. Considering the falsifiability of computational models derived using the theories as a measure of their predictive power, it is shown that the predictive power of some theories is poor and that models based on these theories fall into the ‘paradox of validation’. Week theories for any phenomenon would succumb to such a paradox. We argue that mechanobiology needs theories that can have more potentially falsifying experiments and that perhaps the discipline does suffer from theories that are a priori designed to minimise falsifiability. However, several theories do have predictive power beyond the data used to validate them, so a paradox of validation should disappear as the subject develops.
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