ORCID Profile
0000-0001-8770-5908
Current Organisation
Murdoch University
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Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.JTBI.2012.04.019
Abstract: To maintain bone mass during bone remodelling, coupling is required between bone resorption and bone formation. This coordination is achieved by a network of autocrine and paracrine signalling molecules between cells of the osteoclastic lineage and cells of the osteoblastic lineage. Mathematical modelling of signalling between cells of both lineages can assist in the interpretation of experimental data, clarify signalling interactions and help develop a deeper understanding of complex bone diseases. Several mathematical models of bone cell interactions have been developed, some including RANK-RANKL-OPG signalling between cells and systemic parathyroid hormone PTH. However, to our knowledge these models do not currently include key aspects of some more recent biological evidence for anabolic responses. In this paper, we further develop a mathematical model of bone cell interactions by Pivonka et al. (2008) to include the proliferation of precursor osteoblasts into the model. This inclusion is important to be able to account for Wnt signalling, believed to play an important role in the anabolic responses of bone. We show that an increased rate of differentiation to precursor cells or an increased rate of proliferation of precursor osteoblasts themselves both result in increased bone mass. However, modelling these different processes separately enables the new model to represent recent experimental discoveries such as the role of Wnt signalling in bone biology and the recruitment of osteoblast progenitor cells by transforming growth factor β. Finally, we illustrate the power of the new model's capabilities by applying the model to prostate cancer metastasis to bone. In the bone microenvironment, prostate cancer cells are believed to release some of the same signalling molecules used to coordinate bone remodelling (i.e.,Wnt and PTHrP), enabling the cancer cells to disrupt normal signalling and coordination between bone cells. This disruption can lead to either bone gain or bone loss. We demonstrate that the new computational model developed here is capable of capturing some key observations made on the evolution of the bone mass due to metastasis of prostate cancer to the bone microenvironment.
Publisher: American Physiological Society
Date: 05-2018
DOI: 10.1152/AJPRENAL.00339.2017
Abstract: Vascular topology and morphology are critical in the regulation of blood flow and the transport of small solutes, including oxygen, carbon dioxide, nitric oxide, and hydrogen sulfide. Renal vascular morphology is particularly challenging, since many arterial walls are partially wrapped by the walls of veins. In the absence of a precise characterization of three-dimensional branching vascular geometry, accurate computational modeling of the intrarenal transport of small diffusible molecules is impossible. An enormous manual effort was required to achieve a relatively precise characterization of rat renal vascular geometry, highlighting the need for an automated method for analysis of branched vasculature morphology to allow characterization of the renal vascular geometry of other species, including humans. We present a semisupervised method for three-dimensional morphometric analysis of renal vasculature images generated by computed tomography. We derive quantitative vascular attributes important to mass transport between arteries, veins, and the renal tissue and present methods for their computation for a three-dimensional vascular geometry. To validate the algorithm, we compare automated vascular estimates with subjective manual measurements for a portion of rabbit kidney. Although increased image resolution can improve outcomes, our results demonstrate that the method can quantify the morphological characteristics of artery-vein pairs, comparing favorably with manual measurements. Similar to the rat, we show that rabbit artery-vein pairs become less intimate along the course of the renal vasculature, but the total wrapped mass transfer coefficient increases and then decreases. This new method will facilitate new quantitative physiological models describing the transport of small molecules within the kidney.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.JBIOMECH.2014.10.001
Abstract: Achilles tendon injuries including rupture are one of the most frequent musculoskeletal injuries, but the mechanisms for these injuries are still not fully understood. Previous in vivo and experimental studies suggest that tendon rupture mainly occurs in the tendon mid-section and predominantly more in men than women due to reasons yet to be identified. Therefore we aimed to investigate possible mechanisms for tendon rupture using finite element (FE) analysis. Specifically, we have developed a framework for generating subject-specific FE models of human Achilles tendon. A total of ten 3D FE models of human Achilles tendon were generated. Subject-specific geometries were obtained using ultrasound images and a mesh morphing technique called Free Form Deformation. Tendon material properties were obtained by performing material optimization that compared and minimized difference in uniaxial tension experimental results with model predictions. Our results showed that both tendon geometry and material properties are highly subject-specific. This subject-specificity was also evident in our rupture predictions as the locations and loads of tendon ruptures were different in all specimens tested. A parametric study was performed to characterize the influence of geometries and material properties on tendon rupture. Our results showed that tendon rupture locations were dependent largely on geometry while rupture loads were more influenced by tendon material properties. Future work will investigate the role of microstructural properties of the tissue on tendon rupture and degeneration by using advanced material descriptions.
Publisher: IEEE
Date: 11-2018
Publisher: Public Library of Science (PLoS)
Date: 12-09-2013
Publisher: Elsevier BV
Date: 05-2021
Publisher: Public Library of Science (PLoS)
Date: 21-02-2012
Publisher: Springer Science and Business Media LLC
Date: 2014
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 05-10-2012
Abstract: Prior models of glaucoma filtration surgery assess bleb morphology, which does not always reflect function. Our aim is to establish a model that directly measures tissue hydraulic conductivity of postsurgical outflow in rabbit bleb capsules following experimental glaucoma filtration surgery. Nine rabbits underwent insertion of a single-plate pediatric Molteno implant into the anterior chamber of their left eye. Right eyes were used as controls. The rabbits were then allocated to one of two groups. Group one had outflow measurements performed at 1 week after surgery (n = 5), and group two had measurements performed at 4 weeks (n = 4). Measurements were performed by cannulating the drainage tube ostium in situ with a needle attached to a pressure transducer and a fluid column at 15 mm Hg. The drop in the fluid column was measured every minute for 5 minutes. For the control eyes (n = 6), the anterior chamber of the unoperated fellow eye was cannulated. Animals were euthanized with the implant and its surrounding capsule dissected and fixed in 4% paraformaldehyde, and embedded in paraffin before 6-μm sections were cut for histologic staining. By 7 days after surgery, tube outflow was 0.117 ± 0.036 μL/min/mm Hg at 15 mm Hg (mean ± SEM), whereas at 28 days, it was 0.009 ± 0.003 μL/min/mm Hg. Control eyes had an outflow of 0.136 ± 0.007 μL/min/mm Hg (P = 0.004, one-way ANOVA). Hematoxylin and eosin staining demonstrated a thinner and looser arrangement of collagenous tissue in the capsules at 1 week compared with that at 4 weeks, which had thicker and more densely arranged collagen. We describe a new model to directly measure hydraulic conductivity in a rabbit glaucoma surgery implant model. The principal physiologic endpoint of glaucoma surgery can be reliably quantified and consistently measured with this model. At 28 days post glaucoma filtration surgery, a rabbit bleb capsule has significantly reduced tissue hydraulic conductivity, in line with loss of implant outflow facility, and increased thickness and density of fibrous encapsulation.
Publisher: American Physiological Society
Date: 09-2012
DOI: 10.1152/AJPRENAL.00186.2012
Abstract: To understand how geometric factors affect arterial-to-venous (AV) oxygen shunting, a mathematical model of diffusive oxygen transport in the renal cortex was developed. Preglomerular vascular geometry was investigated using light microscopy (providing vein shape, AV separation, and capillary density near arteries) and published micro-computed tomography (CT) data (providing vessel size and AV separation Nordsletten DA, Blackett S, Bentley MD, Ritman EL, Smith NP. IUPS Physiome Project. www.physiome.org.nz ublications/nordsletten_blackett_ritman_bentley_smith_2005/folder_contents ). A “U-shaped” relationship was observed between the arterial radius and the distance between the arterial and venous lumens. Veins were found to partially wrap around the artery more consistently for larger rather than smaller arteries. Intrarenal arteries were surrounded by an area of fibrous tissue, lacking capillaries, the thickness of which increased from ∼5 μm for the smallest arteries ( -μm diameter) to ∼20 μm for the largest arteries ( -μm diameter). Capillary density was greater near smaller arteries than larger arteries. No capillaries were observed between wrapped AV vessel pairs. The computational model comprised a single AV pair in cross section. Geometric parameters critical in renal oxygen transport were altered according to variations observed by CT and light microscopy. Lumen separation and wrapping of the vein around the artery were found to be the critical geometric factors determining the amount of oxygen shunted between AV pairs. AV oxygen shunting increases both as lumen separation decreases and as the degree of wrapping increases. The model also predicts that capillaries not only deliver oxygen, but can also remove oxygen from the cortical parenchyma close to an AV pair. Thus the presence of oxygen sinks (capillaries or tubules) near arteries would reduce the effectiveness of AV oxygen shunting. Collectively, these data suggest that AV oxygen shunting would be favored in larger vessels common to the cortical and medullary circulations (i.e., arcuate and proximal interlobular arteries) rather than the smaller vessels specific to the cortical circulation (distal interlobular arteries and afferent arterioles).
Publisher: American Physiological Society
Date: 15-07-2015
Publisher: Wiley
Date: 05-09-2017
Abstract: We assessed the utility of synchrotron-radiation micro-computed tomography (micro-CT) for quantification of the radial geometry of the renal cortical vasculature. The kidneys of nine rats and six rabbits were perfusion fixed and the renal circulation filled with Microfil. In order to assess shrinkage of Microfil, rat kidneys were imaged at the Australian Synchrotron immediately upon tissue preparation and then post fixed in paraformaldehyde and reimaged 24 hours later. The Microfil shrank only 2-5% over the 24 hour period. All subsequent micro-CT imaging was completed within 24 hours of s le preparation. After micro-CT imaging, the kidneys were processed for histological analysis. In both rat and rabbit kidneys, vascular structures identified in histological sections could be identified in two-dimensional (2D) micro-CT images from the original kidney. Vascular morphology was similar in the two sets of images. Radial geometry quantified by manual analysis of 2D images from micro-CT was consistent with corresponding data generated by light microscopy. However, due to limited spatial resolution when imaging a whole organ using contrast-enhanced micro-CT, only arteries ≥100 and ≥60 μm in diameter, for the rat and rabbit respectively, could be assessed. We conclude that it is feasible and valid to use micro-CT to quantify vascular geometry of the renal cortical circulation in both the rat and rabbit. However, a combination of light microscopic and micro-CT approaches are required to evaluate the spatial relationships between intrarenal arteries and veins over an extensive range of vessel size.
Publisher: Geological Society of America
Date: 2005
DOI: 10.1130/G21259.1
Publisher: Wiley
Date: 2015
DOI: 10.14814/PHY2.12260
Publisher: Elsevier BV
Date: 10-2003
Publisher: Informa UK Limited
Date: 05-2000
Publisher: Wiley
Date: 30-09-2020
DOI: 10.1002/AR.24260
Abstract: Per gram of tissue, the kidneys are among our most highly perfused organs. Yet the renal cortex and, in particular, the renal medulla are susceptible to hypoxia. In turn, hypoxia is a major pathophysiological feature of both acute kidney injury and chronic kidney disease. We identify seven factors that render the kidney susceptible to hypoxia: (1) the large metabolic demand imposed by active reabsorption of sodium (2) limitations on oxygen delivery to cortical tissue imposed by the density of peritubular capillaries (3) the poor capacity for angiogenesis in the adult kidney (4) the limited ability of the renal vasculature to dilate in response to hypoxia (5) diffusive oxygen shunting between arteries and veins in the cortex and descending and ascending vasa recta in the medulla (6) the physiological requirement for low medullary blood flow to facilitate urinary concentration and (7) the topography of vascular-tubular arrangements in the outer medulla that limit oxygen delivery to the thick ascending limb of Henle's loop. Recent collaborative efforts between anatomists, physiologists, and mathematicians have improved our understanding of the roles of these factors in both physiological regulation of intrarenal oxygenation and development of renal hypoxia under pathophysiological conditions. We are also better able to understand these apparent maladaptations in the context of evolution. That is, they can be explained by the combined effects of historical contingency (our ancestral life in the sea) and selection pressures imposed by the multiple functions of the kidney to regulate extracellular fluid volume, retain water, and control erythrocyte production.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JBIOMECH.2018.08.022
Abstract: The tibiofemoral joint (TFJ) experiences large compressive articular contact loads during activities of daily living, caused by inertial, ligamentous, capsular, and most significantly musculotendon loads. Comparisons of relative contributions of in idual muscles to TFJ contact loading between walking and sporting movements have not been previously examined. The purpose of this study was to determine relative contributions of in idual lower-limb muscles to compressive articular loading of the medial and lateral TFJ during walking, running, and sidestepping. The medial and lateral compartments of the TFJ were loaded by a combination of medial and lateral muscles. During all gait tasks, the primary muscles loading the medial and lateral TFJ were the vastus medialis (VM) and vastus lateralis (VL) respectively during weight acceptance, while typically the medial gastrocnemii (MG) and lateral gastrocnemii (LG) dominated medial and lateral TFJ loading respectively during midstance and push off. Generally, the contribution of the quadriceps muscles were higher in running compared to walking, whereas gastrocnemii contributions were higher in walking compared to running. When comparing running and sidestepping, contributions to medial TFJ contact loading were generally higher during sidestepping while contributions to lateral TFJ contact loading were generally lower. These results suggests that after orthopaedic procedures, the VM, VL, MG and LG should be of particular rehabilitation focus to restore TFJ stability during dynamic gait tasks.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.JMBBM.2019.04.008
Abstract: Synovial fluid flow in articular joint capsule plays an important role during mixed mode lubrication. However, the actual fluid flow behaviour during cartilage contact has not been fully understood so far. This is due to the difficulties in measuring the gap permeability using conventional experimental techniques. The problem becomes further complicated with consideration of the cartilage surface roughness. Here a validated numerical study was developed to quantify the gap permeability of lateral synovial fluid flow. Both macro- and micro-scale gap flow models were created based on Darcy's law at the macro-scale and the Navier-stokes equation at the micro-scale. To generate model inputs, the cartilage topography was numerically synthesised based on the experimental measurements of bovine medial tibia cartilage surface roughness using Dektak Stylus Profilers. The experimental results show that the average roughness height R
Publisher: Public Library of Science (PLoS)
Date: 09-04-2019
Publisher: Informa UK Limited
Date: 02-12-2016
DOI: 10.1080/10255842.2015.1115022
Abstract: It is now commonplace to represent materials in a simulation using assemblies of discrete particles. Sometimes, one wishes to maintain the integrity of boundaries between particle types, for ex le, when modelling multiple tissue layers. However, as the particle assembly evolves during a simulation, particles may pass across interfaces. This behaviour is referred to as 'seepage'. The aims of this study were (i) to examine the conditions for seepage through a confining particle membrane and (ii) to define some simple rules that can be employed to control seepage. Based on the force-deformation response of spheres with various sizes and stiffness, we develop analytic expressions for the force required to move a 'probe particle' between confining 'membrane particles'. We analyse the influence that particle's size and stiffness have on the maximum force that can act on the probe particle before the onset of seepage. The theoretical results are applied in the simulation of a biological cell under unconfined compression.
Publisher: Elsevier BV
Date: 2010
DOI: 10.1016/J.JTBI.2009.09.021
Abstract: The RANK-RANKL-OPG system is an essential signaling pathway involved in bone cell-cell communication, with le evidence that modification of the RANK-RANKL-OPG signaling pathway has major effects on bone remodeling. The first focus of this paper is to demonstrate that a theoretical model of bone cell-cell interactions is capable of qualitatively reproducing changes in bone associated with RANK-RANKL-OPG signaling. To do this we consider either biological experiments or bone diseases related to receptor and/or ligand deficiencies, including RANKL over-expression, ablation of OPG production and/or RANK receptor modifications. The second focus is to investigate a wide range of possible therapeutic strategies for re-establishing bone homeostasis for various pathologies of the RANK-RANKL-OPG pathway. These simulations indicate that bone diseases associated with the RANK-RANKL-OPG pathway are very effective in triggering bone resorption compared to bone formation. These results align with Hofbauer's "convergence hypothesis", which states that catabolic bone diseases most effectively act through the RANK-RANKL-OPG system. Additionally, we demonstrate that severity of catabolic bone diseases strongly depends on how many components of this pathway are affected. Using optimization algorithms and the theoretical model, we identify a variety of successful "virtual therapies" for different disease states using both single and dual therapies.
Publisher: Public Library of Science (PLoS)
Date: 26-06-2013
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.JMBBM.2017.05.018
Abstract: Recently we presented a computational model of articular cartilage calibrated for normal human tissue explants. This model was able to capture the transient deformation of cartilage experiencing a cyclic load. The model takes into account the tension-compression nonlinearity of the cartilage and incorporates the dependency of the compressive stiffness and fluid permeability of cartilage on the deformation-dependent aggrecan concentration in cartilage tissue. As such it represents a leading constitutive model of articular cartilage. Here we build on the previous study to develop an experimentally validated computational model to simulate mechanical consolidation response of intact and previously injured cartilage under sustained static loading, to develop our understanding of the implications for rates of tissue damage. We see that the type of prior injuries compromise the cartilage function in different ways. Relatively rapid consolidation is predicted for cartilage with a complete meniscectomy and that with a full thickness defect, indicating the inability of cartilage with such injuries to sustain interstitial fluid pressurisation for long periods of time, as does uninjured cartilage. By comparing the consolidation response of articular cartilage predicted by computational model against experimental measurements of the apparent friction coefficient following static loading, we find a strong linear positive correlation exists between cartilage degree of consolidation (DoC) and friction coefficient at the joint. As the DoC of articular cartilages can be estimated in vivo via medical imaging, the DoC can be used as an index to non-invasively evaluate the apparent friction coefficient between opposing cartilage surfaces, and so estimate the likelihood of frictional surface wear and/or cartilage damage.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2017
DOI: 10.1007/S10237-017-0890-X
Abstract: In this study, we propose a method for quantitative prediction of changes in concentrations of a number of key signaling, structural and effector molecules within the extracellular matrix of tendon. To achieve this, we introduce the notion of elementary cell responses (ECRs). An ECR defines a normal reference secretion profile of a molecule by a tenocyte in response to the tenocyte's local strain. ECRs are then coupled with a model for mechanical damage of tendon collagen fibers at different straining conditions of tendon and then scaled up to the tendon tissue level for comparison with experimental observations. Specifically, our model predicts relative changes in ECM concentrations of transforming growth factor beta, interleukin 1 beta, collagen type I, glycosaminoglycan, matrix metalloproteinase 1 and a disintegrin and metalloproteinase with thrombospondin motifs 5, with respect to tendon straining conditions that are consistent with the observations in the literature. In good agreement with a number of in vivo and in vitro observations, the model provides a logical and parsimonious explanation for how excessive mechanical loading of tendon can lead to under-stimulation of tenocytes and a degenerative tissue profile, which may well have bearing on a better understanding of tendon homeostasis and the origin of some tendinopathies.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.JTBI.2009.11.023
Abstract: Here a reactive-diffusion transport model is used to demonstrate two previously undescribed functional roles for diffusible binding partners in the transport of molecules into tissues. The uptake of the insulin-like growth (IGF) and its binding partner the IGF binding protein (IGFBP3) into cartilage is used a specific tissue ex le to demonstrate a general principal. First, we show that reversible binding between free protein (IGF) and its diffusible binding partner (free IGFBPs) increases the rate of protein uptake into the tissue. Second, selective degradation of the binding partner can increase the transient and steady state free protein in tissues, well above the concentration at the source boundary, with the maximum free concentration occurring distant from the source boundary, deep within the tissue. This finding is very much at odds with expectations based on a traditional diffusion analysis. In cartilage, using realistic parameters, these new mechanisms raise the free IGF concentration by an order of magnitude deep within the tissue. As the increase in free protein is 'tunable' by cells, our analyses are postulated to demonstrate a general regulatory principle that may operate in any tissues throughout the body.
Publisher: Mary Ann Liebert Inc
Date: 04-2013
Publisher: Elsevier BV
Date: 09-2012
Publisher: Wiley
Date: 29-10-2008
DOI: 10.1111/J.1440-1681.2008.05063.X
Abstract: 1. An improved understanding of the regulation of kidney oxygenation has the potential to advance preventative, diagnostic and therapeutic strategies for kidney disease. Here, we review the strengths and limitations of available and emerging methods for studying kidney oxygen status. 2. To fully characterize kidney oxygen handling, we must quantify multiple parameters, including renal oxygen delivery (DO2) and consumption (VO2), as well as oxygen tension (Po2). Ideally, these parameters should be quantified both at the whole-organ level and within specific vascular, tubular and interstitial compartments. 3. Much of our current knowledge of kidney oxygen physiology comes from established techniques that allow measurement of global kidney DO2 and VO2, or local tissue Po2. When used in tandem, these techniques can help us understand oxygen mass balance in the kidney. Po2 can be resolved to specific tissue compartments in the superficial cortex, but not deep below the kidney surface. We have limited ability to measure local kidney tissue DO2 and VO2. 4. Mathematical modelling has the potential to provide new insights into the physiology of kidney oxygenation, but is limited by the quality of the information such models are based on. 5. Various imaging techniques and other emerging technologies have the potential to allow Po2 mapping throughout the kidney and/or spatial resolution of Po2 in specific renal tissues, even in humans. All currently available methods have serious limitations, but with further refinement should provide a pathway through which data obtained from experimental animal models can be related to humans in the clinical setting.
Publisher: Hindawi Limited
Date: 20-06-2016
DOI: 10.1002/TERM.1751
Publisher: Wiley
Date: 29-01-2013
Abstract: Renal blood flow, local tissue perfusion and blood oxygen content are the major determinants of oxygen delivery to kidney tissue. Arterial pressure and segmental vascular resistance influence kidney oxygen consumption through effects on glomerular filtration rate and sodium reabsorption. Diffusive shunting of oxygen from arteries to veins in the cortex and from descending to ascending vasa recta in the medulla limits oxygen delivery to renal tissue. Oxygen shunting depends on the vascular network, renal haemodynamics and kidney oxygen consumption. Consequently, the impact of changes in renal haemodynamics on tissue oxygenation cannot necessarily be predicted intuitively and, instead, requires the integrative approach offered by computational modelling and multiple measuring modalities. Tissue hypoxia is a hallmark of acute kidney injury (AKI) arising from multiple initiating insults, including ischaemia-reperfusion injury, radiocontrast administration, cardiopulmonary bypass surgery, shock and sepsis. Its pathophysiology is defined by inflammation and/or ischaemia resulting in alterations in renal tissue oxygenation, nitric oxide bioavailability and oxygen radical homeostasis. This sequence of events appears to cause renal microcirculatory dysfunction, which may then be exacerbated by the inappropriate use of therapies common in peri-operative medicine, such as fluid resuscitation. The development of new ways to prevent and treat AKI requires an integrative approach that considers not just the molecular mechanisms underlying failure of filtration and tissue damage, but also the contribution of haemodynamic factors that determine kidney oxygenation. The development of bedside monitors allowing continuous surveillance of renal haemodynamics, oxygenation and function should facilitate better prevention, detection and treatment of AKI.
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.ABB.2006.10.007
Abstract: Diffusive transport must play an important role in transporting nutrients into cartilage due to its avascular nature. Recent theoretical studies generally support the idea that cyclic loading enhances large molecule transport through advection. However, to date, reactive transport, i.e. the effects of solute binding, has not yet been taken into consideration in cyclically deformed cartilage. In the present study, we develop a reactive transport model to describe the potential role of binding of solute within cyclically deformed cartilage. Our results show that binding does have a significant effect on transport, particularly for the low IGF-I concentrations typical of synovial fluid. A dynamic loading regime of high strain magnitudes (up to 10%) in combination with high frequencies (e.g. 1 Hz) was seen to produce the most dramatic results with enhanced total uptake ratio as high as 25% averaged over the first 5h of cyclic loading.
Publisher: Public Library of Science (PLoS)
Date: 04-10-2010
Publisher: Begell House
Date: 2009
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.ABB.2016.02.008
Abstract: In this study, we develop a computational model to simulate the in vitro biochemical degradation of articular cartilage explants sourced from the femoropatellar grooves of bovine calves. Cartilage explants were incubated in culture medium with and without the inflammatory cytokine IL-1α. The spatio-temporal evolution of the cartilage explant's extracellular matrix components is modelled. Key variables in the model include chondrocytes, aggrecan, collagen, aggrecanase, collagenase and IL-1α. The model is first calibrated for aggrecan homeostasis of cartilage in vivo, then for data on (explant) controls, and finally for data on the IL-1α driven proteolysis of aggrecan and collagen over a 4-week period. The model was found to fit the experimental data best when: (i) chondrocytes continue to synthesize aggrecan during the cytokine challenge, (ii) a one to two day delay is introduced between the addition of IL-1α to the culture medium and subsequent aggrecanolysis, (iii) collagen degradation does not commence until the total concentration of aggrecan (i.e. both intact and degraded aggrecan) at any specific location within the explant becomes ≤ 1.5 mg/ml and (iv) degraded aggrecan formed due to the IL-1α induced proteolysis of intact aggrecan protects the collagen network while collagen degrades in a two-step process which, together, significantly modulate the collagen network degradation. Under simulated in vivo conditions, the model predicts increased aggrecan turnover rates in the presence of synovial IL-1α, consistent with experimental observations. Such models may help to infer the course of events in vivo following traumatic joint injury, and may also prove useful in quantitatively evaluating the efficiency of various therapeutic molecules that could be employed to avoid or modify the course of cartilage disease states.
Publisher: IOP Publishing
Date: 1999
Publisher: Wiley
Date: 28-07-2004
DOI: 10.1002/NAG.343
Publisher: IOP Publishing
Date: 06-2010
Publisher: Springer Science and Business Media LLC
Date: 21-10-2015
DOI: 10.1007/S10439-014-1164-8
Abstract: Recent imaging has revealed that in vivo contact deformations of human knee cartilage under physiological loadings are surprisingly large-typically on the order of 10%, but up to 20 or 30% of tibiofemora cartilage thickness depending on loading conditions. In this paper we develop a biphasic, large deformation, non-linear poroelastic model of cartilage that can accurately represent the time dependence and magnitude of cyclic cartilage deformations in vivo. The model takes into account cartilage tension-compression nonlinearity and a new constitutive relation in which the compressive stiffness and hydraulic permeability of the cartilage adjusts in response to the strain-dependent aggrecan concentration. The model predictions are validated using experimental test results on osteochondral plugs obtained from human cadavers. We find that model parameters can be optimised to give an excellent fit to the experimental data. Using typical hydraulic conductivity and stiffness parameters for healthy cartilage, we find that the experimentally observed transient and steady state tissue deformations under cyclic loading and unloading can be reproduced by the model. Steady state tissue deformations are shown to cycle between 10% (exudation strain) and 20% (total strain) in response to the cyclic test loads. At steady-state cyclic loading, the pore fluid exuded from the tissue is exactly equal to the pore fluid imbibed by the tissue during each load cycle.
Publisher: Wiley
Date: 30-11-2018
DOI: 10.1111/APHA.12995
Abstract: Acute kidney injury (AKI) is a common complication following cardiac surgery performed on cardiopulmonary bypass (CPB) and has important implications for prognosis. The aetiology of cardiac surgery-associated AKI is complex, but renal hypoxia, particularly in the medulla, is thought to play at least some role. There is strong evidence from studies in experimental animals, clinical observations and computational models that medullary ischaemia and hypoxia occur during CPB. There are no validated methods to monitor or improve renal oxygenation during CPB, and thus possibly decrease the risk of AKI. Attempts to reduce the incidence of AKI by early transfusion to ameliorate intra-operative anaemia, refinement of protocols for cooling and rewarming on bypass, optimization of pump flow and arterial pressure, or the use of pulsatile flow, have not been successful to date. This may in part reflect the complexity of renal oxygenation, which may limit the effectiveness of in idual interventions. We propose a multi-disciplinary pathway for translation comprising three components. Firstly, large-animal models of CPB to continuously monitor both whole kidney and regional kidney perfusion and oxygenation. Secondly, computational models to obtain information that can be used to interpret the data and develop rational interventions. Thirdly, clinically feasible non-invasive methods to continuously monitor renal oxygenation in the operating theatre and to identify patients at risk of AKI. In this review, we outline the recent progress on each of these fronts.
Publisher: Informa UK Limited
Date: 08-2007
DOI: 10.1080/10255840701309163
Abstract: There are no blood vessels in cartilage to transport nutrients and growth factors to chondrocytes dispersed throughout the cartilage matrix. Insulin-like growth factor-I (IGF-I) is a large molecule with an important role in cartilage growth and metabolism, however, it first must reach the chondrocytes to exert its effect. While diffusion of IGF-I through cartilage is possible, it has been speculated that cyclic loading can enhance the rate of solute transport within cartilage. To better understand this process, here a one-dimensional axisymmetric mathematical model is developed to examine the transport of solutes through a cylindrical plug of cartilage undergoing cyclic axial deformation in the range of 10(-3) -1 Hz. This study has revealed the role of timescales in interpreting transport results in cartilage. It is shown that dynamic strains can either enhance or inhibit IGF-I transport at small timescales (< 20 min after onset of loading), depending on loading frequency. However, on longer timescales it is found that dynamic loading has negligible effect on IGF-I transport. Most importantly, in all cases examined the steady state IGF-I concentration did not exceed the fixed boundary value, in contrast to the predictions of Mauk et al. (2003).
Publisher: Springer Singapore
Date: 2018
Publisher: American Physiological Society
Date: 09-2016
DOI: 10.1152/AJPREGU.00195.2016
Abstract: Oxygen tension (Po 2 ) of urine in the bladder could be used to monitor risk of acute kidney injury if it varies with medullary Po 2 . Therefore, we examined this relationship and characterized oxygen diffusion across walls of the ureter and bladder in anesthetized rabbits. A computational model was then developed to predict medullary Po 2 from bladder urine Po 2 . Both intravenous infusion of [Phe 2 ,Ile 3 ,Orn 8 ]-vasopressin and infusion of N G -nitro-l-arginine reduced urinary Po 2 and medullary Po 2 (8–17%), yet had opposite effects on renal blood flow and urine flow. Changes in bladder urine Po 2 during these stimuli correlated strongly with changes in medullary Po 2 (within-rabbit r 2 = 0.87–0.90). Differences in the Po 2 of saline infused into the ureter close to the kidney could be detected in the bladder, although this was diminished at lesser ureteric flow. Diffusion of oxygen across the wall of the bladder was very slow, so it was not considered in the computational model. The model predicts Po 2 in the pelvic ureter (presumed to reflect medullary Po 2 ) from known values of bladder urine Po 2 , urine flow, and arterial Po 2 . Simulations suggest that, across a physiological range of urine flow in anesthetized rabbits (0.1–0.5 ml/min for a single kidney), a change in bladder urine Po 2 explains 10–50% of the change in pelvic urine/medullary Po 2 . Thus, it is possible to infer changes in medullary Po 2 from changes in urinary Po 2 , so urinary Po 2 may have utility as a real-time biomarker of risk of acute kidney injury.
Publisher: Public Library of Science (PLoS)
Date: 09-10-2015
Publisher: American Physiological Society
Date: 11-2016
DOI: 10.1152/AJPREGU.00246.2016
Abstract: Countercurrent systems have evolved in a variety of biological systems that allow transfer of heat, gases, and solutes. For ex le, in the renal medulla, the countercurrent arrangement of vascular and tubular elements facilitates the trapping of urea and other solutes in the inner medulla, which in turn enables the formation of concentrated urine. Arteries and veins in the cortex are also arranged in a countercurrent fashion, as are descending and ascending vasa recta in the medulla. For countercurrent diffusion to occur, barriers to diffusion must be small. This appears to be characteristic of larger vessels in the renal cortex. There must also be gradients in the concentration of molecules between afferent and efferent vessels, with the transport of molecules possible in either direction. Such gradients exist for oxygen in both the cortex and medulla, but there is little evidence that large gradients exist for other molecules such as carbon dioxide, nitric oxide, superoxide, hydrogen sulfide, and ammonia. There is some experimental evidence for arterial-to-venous (AV) oxygen shunting. Mathematical models also provide evidence for oxygen shunting in both the cortex and medulla. However, the quantitative significance of AV oxygen shunting remains a matter of controversy. Thus, whereas the countercurrent arrangement of vasa recta in the medulla appears to have evolved as a consequence of the evolution of Henle’s loop, the evolutionary significance of the intimate countercurrent arrangement of blood vessels in the renal cortex remains an enigma.
Publisher: Public Library of Science (PLoS)
Date: 20-12-2017
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 05-2020
Publisher: American Physiological Society
Date: 06-2011
DOI: 10.1152/AJPRENAL.00544.2010
Abstract: To understand how arterial-to-venous (AV) oxygen shunting influences kidney oxygenation, a mathematical model of oxygen transport in the renal cortex was created. The model consists of a multiscale hierarchy of 11 countercurrent systems representing the various branch levels of the cortical vasculature. At each level, equations describing the reactive-advection-diffusion of oxygen are solved. Factors critical in renal oxygen transport incorporated into the model include the parallel geometry of arteries and veins and their respective sizes, variation in blood velocity in each vessel, oxygen transport (along the vessels, between the vessels and between vessel and parenchyma), nonlinear binding of oxygen to hemoglobin, and the consumption of oxygen by renal tissue. The model is calibrated using published measurements of cortical vascular geometry and microvascular Po 2 . The model predicts that AV oxygen shunting is quantitatively significant and estimates how much kidney V̇o 2 must change, in the face of altered renal blood flow, to maintain cortical tissue Po 2 at a stable level. It is demonstrated that oxygen shunting increases as renal V̇o 2 or arterial Po 2 increases. Oxygen shunting also increases as renal blood flow is reduced within the physiological range or during mild hemodilution. In severe ischemia or anemia, or when kidney V̇o 2 increases, AV oxygen shunting in proximal vascular elements may reduce the oxygen content of blood destined for the medullary circulation, thereby exacerbating the development of tissue hypoxia. That is, cortical ischemia could cause medullary hypoxia even when medullary perfusion is maintained. Cortical AV oxygen shunting limits the change in oxygen delivery to cortical tissue and stabilizes tissue Po 2 when arterial Po 2 changes, but renders the cortex and perhaps also the medulla susceptible to hypoxia when oxygen delivery falls or consumption increases.
Publisher: Public Library of Science (PLoS)
Date: 21-10-2013
Publisher: Elsevier BV
Date: 08-2000
Publisher: American Physiological Society
Date: 2014
DOI: 10.1152/AJPREGU.00437.2013
Abstract: We describe the determinants of urinary oxygen tension (Po 2 ) and the potential for use of urinary Po 2 as a “physiological biomarker” of the risk of acute kidney injury (AKI) in hospital settings. We also identify knowledge gaps required for clinical translation of bedside monitoring of urinary Po 2 . Hypoxia in the renal medulla is a hallmark of AKI of erse etiology. Urine in the collecting ducts would be expected to equilibrate with the tissue Po 2 of the inner medulla. Accordingly, the Po 2 of urine in the renal pelvis changes in response to stimuli that would be expected to alter oxygenation of the renal medulla. Oxygen exchange across the walls of the ureter and bladder will confound measurement of the Po 2 of bladder urine. Nevertheless, the Po 2 of bladder urine also changes in response to stimuli that would be expected to alter renal medullary oxygenation. If confounding influences can be understood, urinary bladder Po 2 may provide prognostically useful information, including for prediction of AKI after cardiopulmonary bypass surgery. To translate bedside monitoring of urinary Po 2 into the clinical setting, we require 1) a more detailed knowledge of the relationship between renal medullary oxygenation and the Po 2 of pelvic urine under physiological and pathophysiological conditions 2) a quantitative understanding of the impact of oxygen transport across the ureteric epithelium on urinary Po 2 measured from the bladder and 3) a simple, robust medical device that can be introduced into the bladder via a standard catheter to provide reliable and continuous measurement of urinary Po 2 .
Publisher: Springer Netherlands
Date: 2005
Publisher: Informa UK Limited
Date: 20-03-2018
DOI: 10.1080/03008207.2018.1432605
Abstract: The composition of extracellular matrix (ECM) in tendon depends on the secretion profile of resident cells known as tenocytes. For tissues with a mechanical role like tendon, mechanical strain is known to play an important role in determining the secretion profile of resident cells. Previously we explored the idea of estimating average concentrations of ECM molecules as a function of tendon strain magnitude and number of loading cycles. Specifically, we developed a model of the mechanical fatigue damage of tendon collagen fibers and introduced elementary cell responses (ECRs) by which local cellular-level responses to the strain environment, combined with the fatigue damage model, were scaled up to predict tissue-level responses. Using this approach, we demonstrated that the proposed model is capable of estimating average concentrations of ECM molecules that qualitatively accord with experimental observations. In this study, we increase model realism by extending this approach to consider the implications of a non-uniform collagen fiber distribution, and the influence of time delay on repair of damaged collagen fibers. Using this approach, we focus the study on the average tenocyte secretion profile for active transforming growth factor beta (TGF-β), and discover that increasing fiber length dispersion and/or increasing repair delay leads to increasing active TGF-β concentrations, and reduced sensitivity of average concentration profile of TGF-β to tendon strain.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Public Library of Science (PLoS)
Date: 15-12-2016
Publisher: Elsevier BV
Date: 10-2004
Publisher: American Physiological Society
Date: 08-2017
DOI: 10.1152/AJPRENAL.00659.2016
Abstract: To assess the physiological significance of arterial-to-venous (AV) oxygen shunting, we generated a new pseudo-three-dimensional computational model of oxygen diffusion from intrarenal arteries to cortical tissue and veins. The model combines the 11 branching levels (known as “Strahler” orders) of the preglomerular renal vasculature in the rat, with an analysis of an extensive data set obtained using light microscopy to estimate oxygen mass transfer coefficients for each Strahler order. Furthermore, the AV shunting model is now set within a global oxygen transport model that includes transport from arteries, glomeruli, peritubular capillaries, and veins to tissue. While a number of lines of evidence suggest AV shunting is significant, most importantly, our AV oxygen shunting model predicts AV shunting is small under normal physiological conditions (~0.9% of total renal oxygen delivery range 0.4–1.4%), but increases during renal ischemia, glomerular hyperfiltration (~2.1% of total renal oxygen delivery range 0.84–3.36%), and some cardiovascular disease states (~3.0% of total renal oxygen delivery range 1.2–4.8%). Under normal physiological conditions, blood Po 2 is predicted to fall by ~16 mmHg from the root of the renal artery to glomerular entry, with AV oxygen shunting contributing ~40% and oxygen diffusion from arteries to tissue contributing ~60% of this decline. Arterial Po 2 is predicted to fall most rapidly from Strahler order 4, under normal physiological conditions. We conclude that AV oxygen shunting normally has only a small impact on renal oxygenation, but may exacerbate renal hypoxia during renal ischemia, hyperfiltration, and some cardiovascular disease states.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.KINT.2018.09.025
Abstract: Erythropoietin is released from the kidney in response to tissue hypoxia. Montero and Lundby found that increases in plasma erythropoietin induced by reducing arterial oxygen content in healthy humans were independent of arterial oxygen tension. Their observations accord with the established physiology of kidney oxygenation and can be predicted by a computational model of renal oxygen transport. However, model simulations indicate that the interpretation implicit in the title of their paper may be an oversimplification.
Publisher: Springer Science and Business Media LLC
Date: 07-2005
Publisher: Springer International Publishing
Date: 15-05-2018
Publisher: Elsevier BV
Date: 07-2002
Publisher: Springer Science and Business Media LLC
Date: 2011
Publisher: Public Library of Science (PLoS)
Date: 23-07-2012
Publisher: Elsevier BV
Date: 2006
Publisher: American Physiological Society
Date: 11-2008
DOI: 10.1152/AJPRENAL.90230.2008
Abstract: The kidney is faced with unique challenges for oxygen regulation, both because its function requires that perfusion greatly exceeds that required to meet metabolic demand and because vascular control in the kidney is dominated by mechanisms that regulate glomerular filtration and tubular reabsorption. Because tubular sodium reabsorption accounts for most oxygen consumption (V̇o 2 ) in the kidney, renal V̇o 2 varies with glomerular filtration rate. This provides an intrinsic mechanism to match changes in oxygen delivery due to changes in renal blood flow (RBF) with changes in oxygen demand. Renal V̇o 2 is low relative to supply of oxygen, but diffusional arterial-to-venous (AV) oxygen shunting provides a mechanism by which oxygen superfluous to metabolic demand can bypass the renal microcirculation. This mechanism prevents development of tissue hyperoxia and subsequent tissue oxidation that would otherwise result from the mismatch between renal V̇o 2 and RBF. Recent evidence suggests that RBF-dependent changes in AV oxygen shunting may also help maintain stable tissue oxygen tension when RBF changes within the physiological range. However, AV oxygen shunting also renders the kidney susceptible to hypoxia. Given that tissue hypoxia is a hallmark of both acute renal injury and chronic renal disease, understanding the causes of tissue hypoxia is of great clinical importance. The simplistic paradigm of oxygenation depending only on the balance between local perfusion and V̇o 2 is inadequate to achieve this goal. To fully understand the control of renal oxygenation, we must consider a triad of factors that regulate intrarenal oxygenation: local perfusion, local V̇o 2 , and AV oxygen shunting.
Publisher: World Scientific Pub Co Pte Ltd
Date: 06-2008
DOI: 10.1142/S0218339008002575
Abstract: Experiments on the transport of radiolabeled Insulin-like Growth Factors (IGF-I and -II) into bovine articular cartilage show differential uptake depending on the relative proportion of IGF-I and -II. In this study, we present a mathematical model describing both the transport and competition of IGF-I and -II for binding sites represented by two functional groupings of IGF binding proteins (IGFBPs). The first grouping has approximately similar binding affinity to both IGF-I and -II (i.e. IGFBPs 1–5), whereas the second group has significantly higher binding preference for IGF-II compared to IGF-I (i.e. IGFBP-6). Using nonlinear least squares, it is shown that the experimental equilibrium competitive binding results can be described using a reversible Langmuir sorption isotherm involving two dominant IGFBP functional groups. After coupling the sorption model with a poromechanical continuum model, parametric studies are carried out to investigate the effect of model changes including IGF boundary conditions and the ratios of the two IGFBP functional groups. The results show that ignoring competitive binding leads to a significant overestimation of total IGF-I uptake, but an underestimation the rate of "free" (physiologically active) IGF-I within the cartilage. An increase of first group of IGFBPs (i.e. IGFBPs 1–5) as has been reported for osteoarthritis, is observed to hinder the bioavailability of free IGF-I in cartilage, even though the total IGF-I uptake is enhanced. Furthermore, the combination of dynamic compression and competitive binding is seen to enhance the IGF-I uptake within cartilage, but this enhancement is overestimated if competitive binding is neglected.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Elsevier BV
Date: 04-2003
Publisher: Springer Science and Business Media LLC
Date: 14-12-2007
Publisher: Wiley
Date: 14-02-2020
DOI: 10.1111/APHA.13450
Publisher: Public Library of Science (PLoS)
Date: 29-09-2016
Publisher: Elsevier BV
Date: 03-2023
Publisher: Public Library of Science (PLoS)
Date: 25-08-2020
Publisher: American Physiological Society
Date: 08-2017
DOI: 10.1152/AJPRENAL.00657.2016
Abstract: We develop a pseudo-three-dimensional model of oxygen transport for the renal cortex of the rat, incorporating both the axial and radial geometry of the preglomerular circulation and quantitative information regarding the surface areas and transport from the vasculature and renal corpuscles. The computational model was validated by simulating four sets of published experimental studies of renal oxygenation in rats. Under the control conditions, the predicted cortical tissue oxygen tension ([Formula: see text]) or microvascular oxygen tension (µPo 2 ) were within ±1 SE of the mean value observed experimentally. The predicted [Formula: see text] or µPo 2 in response to ischemia-reperfusion injury, acute hemodilution, blockade of nitric oxide synthase, or uncoupling mitochondrial respiration, were within ±2 SE observed experimentally. We performed a sensitivity analysis of the key model parameters to assess their in idual or combined impact on the predicted [Formula: see text] and µPo 2 . The model parameters analyzed were as follows: 1) the major determinants of renal oxygen delivery ([Formula: see text]) (arterial blood Po 2 , hemoglobin concentration, and renal blood flow) 2) the major determinants of renal oxygen consumption (V̇o 2 ) [glomerular filtration rate (GFR) and the efficiency of oxygen utilization for sodium reabsorption (β)] and 3) peritubular capillary surface area (PCSA). Reductions in PCSA by 50% were found to profoundly increase the sensitivity of [Formula: see text] and µPo 2 to the major the determinants of [Formula: see text] and V̇o 2 . The increasing likelihood of hypoxia with decreasing PCSA provides a potential explanation for the increased risk of acute kidney injury in some experimental animals and for patients with chronic kidney disease.
Publisher: Springer Science and Business Media LLC
Date: 08-2004
Publisher: Wiley
Date: 17-07-2015
DOI: 10.1002/JOR.22960
Abstract: Physiotherapy is one of the effective treatments for tendinopathy, whereby symptoms are relieved by changing the biomechanical environment of the pathological tendon. However, the underlying mechanism remains unclear. In this study, we first established a model of progressive tendinopathy-like degeneration in the rabbit Achilles. Following ex vivo loading deprivation culture in a bioreactor system for 6 and 12 days, tendons exhibited progressive degenerative changes, abnormal collagen type III production, increased cell apoptosis, and weakened mechanical properties. When intervention was applied at day 7 for another 6 days by using cyclic tensile mechanical stimulation (6% strain, 0.25 Hz, 8 h/day) in a bioreactor, the pathological changes and mechanical properties were almost restored to levels seen in healthy tendon. Our results indicated that a proper biomechanical environment was able to rescue early-stage pathological changes by increased collagen type I production, decreased collagen degradation and cell apoptosis. The ex vivo model developed in this study allows systematic study on the effect of mechanical stimulation on tendon biology.
Publisher: Wiley
Date: 02-05-2017
DOI: 10.1002/JOR.23240
Abstract: Similar to most biological tissues, the biomechanical, and functional characteristics of the Achilles tendon are closely related to its composition and microstructure. It is commonly reported that type I collagen is the predominant component of tendons and is mainly responsible for the tissue's function. Although elastin has been found in varying proportions in other connective tissues, previous studies report that tendons contain very small quantities of elastin. However, the morphology and the microstructural relationship among the elastic fibres, collagen, and cells in tendon tissue have not been well examined. We hypothesize the elastic fibres, as another fibrillar component in the extracellular matrix, have a unique role in mechanical function and microstructural arrangement in Achilles tendons. It has been shown that elastic fibres present a close connection with the tenocytes. The close relationship of the three components has been revealed as a distinct, integrated and complex microstructural network. Notably, a "spiral" structure within fibril bundles in Achilles tendons was observed in some s les in specialized regions. This study substantiates the hierarchical system of the spatial microstructure of tendon, including the mapping of collagen, elastin and tenocytes, with 3-dimensional confocal images. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1203-1214, 2017.
Publisher: American Physiological Society
Date: 12-2019
DOI: 10.1152/AJPRENAL.00315.2019
Abstract: We have previously developed a three-dimensional computational model of oxygen transport in the renal medulla. In the present study, we used this model to quantify the sensitivity of renal medullary oxygenation to four of its major known determinants: medullary blood flow (MBF), medullary oxygen consumption rate (V̇o 2,M ), hemoglobin (Hb) concentration in the blood, and renal perfusion pressure. We also examined medullary oxygenation under special conditions of hydropenia, extracellular fluid volume expansion by infusion of isotonic saline, and hemodilution during cardiopulmonary bypass. Under baseline (normal) conditions, the average medullary tissue Po 2 predicted for the whole renal medulla was ~30 mmHg. The periphery of the interbundle region in the outer medulla was identified as the most hypoxic region in the renal medulla, which demonstrates that the model prediction is qualitatively accurate. Medullary oxygenation was most sensitive to changes in renal perfusion pressure followed by Hb, MBF, and V̇o 2,M , in that order. The medullary oxygenation also became sensitized by prohypoxic changes in other parameters, leading to a greater fall in medullary tissue Po 2 when multiple parameters changed simultaneously. Hydropenia did not induce a significant change in medullary oxygenation compared with the baseline state, while volume expansion resulted in a large increase in inner medulla tissue Po 2 (by ~15 mmHg). Under conditions of cardiopulmonary bypass, the renal medulla became severely hypoxic, due to hemodilution, with one-third of the outer stripe of outer medulla tissue having a Po 2 of mmHg.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2021
DOI: 10.1007/S40544-020-0468-Y
Abstract: Although experimental evidence has suggested that the polymer brush border (PBB) on the cartilage surface is important in regulating fluid permeability in the contact gap, the current theoretical understanding of joint lubrication is still limited. To address this research gap, a multiscale cartilage contact model that includes PBB, in particular its effect on the fluid permeability of the contact gap, is developed in this study. Microscale modeling is employed to estimate the permeability of the contact gap. This permeability is classified into two categories: For a gap size 1 µm, the flow resistance is assumed to be dominated by the cartilage roughness for gap size 1 µm, flow resistance is assumed to be dominated by the surface polymers extending beyond the collagen network of the articular cartilage. For gap sizes of less than 1 µm, the gap permeability decreases exponentially with increasing aggrecan concentration, whereas the aggrecan concentration varies inversely with the gap size. Subsequently, the gap permeability is employed in a macroscale cartilage contact model, in which both the contact gap space and articular cartilage are modeled as two interacting poroelastic systems. The fluid exchange between these two media is achieved by imposing pressure and normal flux continuity boundary conditions. The model results suggest that PBB can substantially enhance cartilage lubrication by increasing the gap fluid load support (e.g., by 26 times after a 20-min indentation compared with the test model without a PBB). Additionally, the fluid flow resistance of PBB sustains the cartilage interstitial fluid pressure for a relatively long period, and hence reduces the vertical deformation of the tissue. Furthermore, it can be inferred that a reduction in the PBB thickness impairs cartilage lubrication ability.
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.BONE.2008.03.025
Abstract: It is generally accepted that RANKL is highly expressed in osteoblast precursor cells while OPG is highly expressed in mature osteoblasts, but to date no functional utility to the BMU has been proposed for this particular ligand-decoy-receptor expression profile. As discovered in the mid 90s, the RANK-RANKL-OPG signaling cascade is a major signaling pathway regulating bone remodeling. In this paper we study theoretically the functional implications of particular RANKL/OPG expression profiles on bone volume. For this purpose we formulate an extended bone-cell dynamics model describing functional behaviour of basic multicellular units (BMUs) responsible for bone resorption and formation. This model incorporates the RANK-RANKL-OPG signaling together with the regulating action of TGF-beta on bone cells. The bone-cell population model employed here builds on the work of Lemaire et al. (2004) [1], but incorporates the following significant modifications: (i) addition of a rate equation describing changes in bone volume with time as the key 'output function' tracking functional behaviour of BMUs, (ii) a rate equation describing release of TGF-beta from the bone matrix, (iii) expression of OPG and RANKL on both osteoblastic cell lines, and (iv) modified activator/repressor functions. Using bone volume as a functional selection criterion, we find that there is a preferred arrangement for ligand expression on particular cell types, and further, that this arrangement coincides with biological observations. We then investigate the model parameter space combinatorially, searching for preferred 'groupings' of changes in differentiation rates of various cell types. Again, a criterion of bone volume change is employed to identify possible ways of optimally controlling BMU responses. While some combinations of changes in differentiation rates are clearly unrealistic, other combinations of changes in differentiation rates are potentially functionally significant. Most importantly, the combination of parameter changes representing the signaling pathway for TGF-beta gives a unique result that appears to have a clear biological rationale. The methodological approach for the investigation of model structure described here offers a theoretical explanation as to why TGF-beta has its particular suite of biological effects on bone-cell differentiation rates.
Publisher: CRC Press
Date: 24-08-2010
Publisher: American Physiological Society
Date: 12-2018
DOI: 10.1152/AJPRENAL.00363.2018
Abstract: The renal medulla is prone to hypoxia. Medullary hypoxia is postulated to be a leading cause of acute kidney injury, so there is considerable interest in predicting the oxygen tension in the medulla. Therefore we have developed a computational model for blood and oxygen transport within a physiologically normal rat renal medulla, using a multilevel modeling approach. For the top-level model we use the theory of porous media and advection-dispersion transport through a realistic three-dimensional representation of the medulla’s gross anatomy to describe blood flow and oxygen transport throughout the renal medulla. For the lower-level models, we employ two-dimensional reaction-diffusion models describing the distribution of oxygen through tissue surrounding the vasculature. Steady-state model predictions at the two levels are satisfied simultaneously, through iteration between the levels. The computational model was validated by simulating eight sets of experimental data regarding renal oxygenation in rats (using 4 sets of control groups and 4 sets of treatment groups, described in 4 independent publications). Predicted medullary tissue oxygen tension or microvascular oxygen tension for control groups and for treatment groups that underwent moderate perturbation in hemodynamic and renal functions is within ±2 SE values observed experimentally. Diffusive shunting between descending and ascending vasa recta is predicted to be only 3% of the oxygen delivered. The validation tests confirm that the computational model is robust and capable of capturing the behavior of renal medullary oxygenation in both normal and early-stage pathological states in the rat.
Publisher: Springer Science and Business Media LLC
Date: 18-02-2019
DOI: 10.1038/S41467-019-08360-5
Abstract: Partitioning space into cells with certain extreme geometrical properties is a central problem in many fields of science and technology. Here we investigate the Quantizer problem, defined as the optimisation of the moment of inertia of Voronoi cells, i.e., similarly-sized ‘sphere-like’ polyhedra that tile space are preferred. We employ Lloyd’s centroidal Voronoi diagram algorithm to solve this problem and find that it converges to disordered states associated with deep local minima. These states are universal in the sense that their structure factors are characterised by a complete independence of a wide class of initial conditions they evolved from. They moreover exhibit an anomalous suppression of long-wavelength density fluctuations and quickly become effectively hyperuniform. Our findings warrant the search for novel amorphous hyperuniform phases and cellular materials with unique physical properties.
Publisher: Society of Rheology
Date: 07-2005
DOI: 10.1122/1.1917841
Publisher: Wiley
Date: 11-06-2013
DOI: 10.1002/WSBM.1229
Abstract: Computational modeling of tendon lags the development of computational models for other tissues. A major bottleneck in the development of realistic computational models for Achilles tendon is the absence of detailed conceptual and theoretical models as to how the tissue actually functions. Without the conceptual models to provide a theoretical framework to guide the development and integration of multiscale computational models, modeling of the Achilles tendon to date has tended to be piecemeal and focused on specific mechanical or biochemical issues. In this paper, we present a new conceptual model of Achilles tendon tissue homeostasis, and discuss this model in terms of existing computational models of tendon. This approach has the benefits of structuring the research on relevant computational modeling to date, while allowing us to identify new computational models requiring development. The critically important functional issue for tendon is that it is continually damaged during use and so has to be repaired. From this follows the centrally important issue of homeostasis of the load carrying collagen fibrils within the collagen fibers of the Achilles tendon. Collagen fibrils may be damaged mechanically-by loading, or damaged biochemically-by proteases. Upon reviewing existing computational models within this conceptual framework of the Achilles tendon structure and function, we demonstrate that a great deal of theoretical and experimental research remains to be done before there are reliably predictive multiscale computational model of Achilles tendon in health and disease.
Publisher: American Physiological Society
Date: 15-11-2014
DOI: 10.1152/AJPRENAL.00382.2014
Abstract: Renal arterial-to-venous (AV) oxygen shunting limits oxygen delivery to renal tissue. To better understand how oxygen in arterial blood can bypass renal tissue, we quantified the radial geometry of AV pairs and how it differs according to arterial diameter and anatomic location. We then estimated diffusion of oxygen in the vicinity of arteries of typical geometry using a computational model. The kidneys of six rats were perfusion fixed, and the vasculature was filled with silicone rubber (Microfil). A single section was chosen from each kidney, and all arteries ( n = 1,628) were identified. Intrarenal arteries were largely isible into two “types,” characterized by the presence or absence of a close physical relationship with a paired vein. Arteries with a close physical relationship with a paired vein were more likely to have a larger rather than smaller diameter, and more likely to be in the inner-cortex than the mid- or outer cortex. Computational simulations indicated that direct diffusion of oxygen from an artery to a paired vein can only occur when the two vessels have a close physical relationship. However, even in the absence of this close relationship oxygen can diffuse from an artery to periarteriolar capillaries and venules. Thus AV oxygen shunting in the proximal preglomerular circulation is dominated by direct diffusion of oxygen to a paired vein. In the distal preglomerular circulation, it may be sustained by diffusion of oxygen from arteries to capillaries and venules close to the artery wall, which is subsequently transported to renal veins by convection.
Publisher: American Society of Civil Engineers (ASCE)
Date: 05-2009
Publisher: Wiley
Date: 04-02-2013
DOI: 10.1002/BIT.24809
Abstract: Identification of functional programmable mechanical stimulation (PMS) on tendon not only provides the insight of the tendon homeostasis under physical athological condition, but also guides a better engineering strategy for tendon regeneration. The aims of the study are to design a bioreactor system with PMS to mimic the in vivo loading conditions, and to define the impact of different cyclic tensile strain on tendon. Rabbit Achilles tendons were loaded in the bioreactor with/without cyclic tensile loading (0.25 Hz for 8 h/day, 0-9% for 6 days). Tendons without loading lost its structure integrity as evidenced by disorientated collagen fiber, increased type III collagen expression, and increased cell apoptosis. Tendons with 3% of cyclic tensile loading had moderate matrix deterioration and elevated expression levels of MMP-1, 3, and 12, whilst exceeded loading regime of 9% caused massive rupture of collagen bundle. However, 6% of cyclic tensile strain was able to maintain the structural integrity and cellular function. Our data indicated that an optimal PMS is required to maintain the tendon homeostasis and there is only a narrow range of tensile strain that can induce the anabolic action. The clinical impact of this study is that optimized eccentric training program is needed to achieve maximum beneficial effects on chronic tendinopathy management.
Start Date: 2017
End Date: 2019
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 2019
Funder: National Health and Medical Research Council
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End Date: 2016
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2011
End Date: 2014
Funder: Australian Research Council
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: Australian Research Council
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: Australian Research Council
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