Computational Modelling for Managing Pathways to Cartilage Failure.

Over several decades the perception and therefore description of articular cartilage changed substantially. It has transitioned from being described as a relatively inert tissue with limited repair capacity, to a tissue undergoing continuous maintenance and even adaption, through a range of complex regulatory processes. Even from the narrower lens of biomechanics, the engagement with articular cartilage has changed from it being an interesting, slippery material found in the hostile mechanical environment between opposing long bones, to an intriguing example of mechanobiology in action. The progress revealing this complexity, where physics, chemistry, material science and biology are merging, has been described with increasingly sophisticated computational models. Here we describe how these computational models of cartilage as an integrated system can be combined with the approach of structural reliability analysis. That is, causal, deterministic models placed in the framework of the probabilistic approach of structural reliability analysis could be used to understand, predict, and mitigate the risk of cartilage failure or pathology. At the heart of this approach is seeing cartilage overuse and disease processes as a 'material failure', resulting in failure to perform its function, which is largely mechanical. One can then describe pathways to failure, for example, how homeostatic repair processes can be overwhelmed leading to a compromised tissue. To illustrate this 'pathways to failure' approach, we use the interplay between cartilage consolidation and lubrication to analyse the increase in expected wear rates associated with cartilage defects or meniscectomy.

Predicting oxygen tension along the ureter.

Continuous measurement of bladder urine oxygen tension (Po2) is a method to potentially detect renal medullary hypoxia in patients at risk of acute kidney injury (AKI). To assess its practicality, we developed a computational model of the peristaltic movement of a urine bolus along the ureter and the oxygen exchange between the bolus and ureter wall. This model quantifies the changes in urine Po2 as urine transits from the renal pelvis to the bladder. The model parameters were calibrated using experimental data in rabbits, such that most of the model predictions are within ±1 SE of the reported mean in the experiment, with the average percent difference being 7.0%. Based on parametric experiments performed using a model scaled to the geometric dimensions of a human ureter, we found that bladder urine Po2 is strongly dependent on the bolus volume (i.e., bolus volume-to-surface area ratio), especially at a volume less than its physiological (baseline) volume (<0.2 mL). For the model assumptions, changes in peristaltic frequency resulted in a minimal change in bladder urine Po2 (<1 mmHg). The model also predicted that there exists a family of linear relationships between the bladder-urine Po2 and pelvic urine Po2 for different input conditions. We conclude that it may technically be possible to predict renal medullary Po2 based on the measurement of bladder urine Po2, provided that there are accurate real-time measurements of model input parameters.NEW & NOTEWORTHY Measurement of bladder urine oxygen tension has been proposed as a new method to potentially detect the risk of acute kidney injury in patients. A computational model of oxygen exchange between urine bolus and ureteral tissue shows that it may be technically possible to determine the risk of acute kidney injury based on the measurement of bladder urine oxygen tension, provided that the measurement data are properly interpreted via a computational model.

Analysis of the critical determinants of renal medullary oxygenation.

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 (V̇o2,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 Po2 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 V̇o2,M, in that order. The medullary oxygenation also became sensitized by prohypoxic changes in other parameters, leading to a greater fall in medullary tissue Po2 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 Po2 (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 Po2 of <5 mmHg.

Stimulation of erythropoietin release by hypoxia and hypoxemia: similar but different.

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.

A model of oxygen transport in the rat renal medulla.

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.

Three-dimensional morphometric analysis of the renal vasculature.

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.

Effect of collagen length distribution and timing for repair on the active TGF-ß concentration in tendon.

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-ß), and discover that increasing fiber length dispersion and/or increasing repair delay leads to increasing active TGF-ß concentrations, and reduced sensitivity of average concentration profile of TGF-ß to tendon strain.

A pseudo-three-dimensional model for quantification of oxygen diffusion from preglomerular arteries to renal tissue and renal venous blood.

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 Po2 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 Po2 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.

Accounting for oxygen in the renal cortex: a computational study of factors that predispose the cortex to hypoxia.

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 (µPo2) were within ±1 SE of the mean value observed experimentally. The predicted [Formula: see text] or µPo2 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 individual or combined impact on the predicted [Formula: see text] and µPo2 The model parameters analyzed were as follows: 1) the major determinants of renal oxygen delivery ([Formula: see text]) (arterial blood Po2, hemoglobin concentration, and renal blood flow); 2) the major determinants of renal oxygen consumption (V̇o2) [glomerular filtration rate (GFR) and the efficiency of oxygen utilization for sodium reabsorption (ß)]; and 3) peritubular capillary surface area (PCSA). Reductions in PCSA by 50% were found to profoundly increase the sensitivity of [Formula: see text] and µPo2 to the major the determinants of [Formula: see text] and V̇o2 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.

Adaptive Remodeling of Achilles Tendon: A Multi-scale Computational Model.

While it is known that musculotendon units adapt to their load environments, there is only a limited understanding of tendon adaptation in vivo. Here we develop a computational model of tendon remodeling based on the premise that mechanical damage and tenocyte-mediated tendon damage and repair processes modify the distribution of its collagen fiber lengths. We explain how these processes enable the tendon to geometrically adapt to its load conditions. Based on known biological processes, mechanical and strain-dependent proteolytic fiber damage are incorporated into our tendon model. Using a stochastic model of fiber repair, it is assumed that mechanically damaged fibers are repaired longer, whereas proteolytically damaged fibers are repaired shorter, relative to their pre-damage length. To study adaptation of tendon properties to applied load, our model musculotendon unit is a simplified three-component Hill-type model of the human Achilles-soleus unit. Our model results demonstrate that the geometric equilibrium state of the Achilles tendon can coincide with minimization of the total metabolic cost of muscle activation. The proposed tendon model independently predicts rates of collagen fiber turnover that are in general agreement with in vivo experimental measurements. While the computational model here only represents a first step in a new approach to understanding the complex process of tendon remodeling in vivo, given these findings, it appears likely that the proposed framework may itself provide a useful theoretical foundation for developing valuable qualitative and quantitative insights into tendon physiology and pathology.

Micro-computed tomographic analysis of the radial geometry of intrarenal artery-vein pairs in rats and rabbits: Comparison with light microscopy.

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 sample 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.

Bladder urine oxygen tension for assessing renal medullary oxygenation in rabbits: experimental and modeling studies.

Oxygen tension (Po2) of urine in the bladder could be used to monitor risk of acute kidney injury if it varies with medullary Po2 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 Po2 from bladder urine Po2 Both intravenous infusion of [Phe(2),Ile(3),Orn(8)]-vasopressin and infusion of N(G)-nitro-l-arginine reduced urinary Po2 and medullary Po2 (8-17%), yet had opposite effects on renal blood flow and urine flow. Changes in bladder urine Po2 during these stimuli correlated strongly with changes in medullary Po2 (within-rabbit r(2) = 0.87-0.90). Differences in the Po2 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 Po2 in the pelvic ureter (presumed to reflect medullary Po2) from known values of bladder urine Po2, urine flow, and arterial Po2 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 Po2 explains 10-50% of the change in pelvic urine/medullary Po2 Thus, it is possible to infer changes in medullary Po2 from changes in urinary Po2, so urinary Po2 may have utility as a real-time biomarker of risk of acute kidney injury.

Diffusive shunting of gases and other molecules in the renal vasculature: physiological and evolutionary significance.

Countercurrent systems have evolved in a variety of biological systems that allow transfer of heat, gases, and solutes. For example, 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.

Modeling IL-1 induced degradation of articular cartilage.

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.

Discrete Element Framework for Modelling Extracellular Matrix, Deformable Cells and Subcellular Components.

This paper presents a framework for modelling biological tissues based on discrete particles. Cell components (e.g. cell membranes, cell cytoskeleton, cell nucleus) and extracellular matrix (e.g. collagen) are represented using collections of particles. Simple particle to particle interaction laws are used to simulate and control complex physical interaction types (e.g. cell-cell adhesion via cadherins, integrin basement membrane attachment, cytoskeletal mechanical properties). Particles may be given the capacity to change their properties and behaviours in response to changes in the cellular microenvironment (e.g., in response to cell-cell signalling or mechanical loadings). Each particle is in effect an 'agent', meaning that the agent can sense local environmental information and respond according to pre-determined or stochastic events. The behaviour of the proposed framework is exemplified through several biological problems of ongoing interest. These examples illustrate how the modelling framework allows enormous flexibility for representing the mechanical behaviour of different tissues, and we argue this is a more intuitive approach than perhaps offered by traditional continuum methods. Because of this flexibility, we believe the discrete modelling framework provides an avenue for biologists and bioengineers to explore the behaviour of tissue systems in a computational laboratory.

Short-term consolidation of articular cartilage in the long-term context of osteoarthritis.

Over ten percent of the population are afflicted by osteoarthritis, a chronic disease of diarthrodial joints such as the knees and hips, costing hundreds of billions of dollars every year. In this condition, the thin layers of articular cartilage on the bones degrade and weaken over years, causing pain, stiffness and eventual immobility. The biggest controllable risk factor is long-term mechanical overloading of the cartilage, but the disparity in time scales makes this process a challenge to model: loading events can take place every second, whereas degradation occurs over many months. Therefore, a suitable model must be sufficiently simple to permit evaluation over long periods of variable loading, yet must deliver results sufficiently accurate to be of clinical use, conditions unmet by existing models. To address this gap, we construct a two-component poroelastic model endowed with a new flow restricting boundary condition, which better represents the joint space environment compared to the typical free-flow condition. Under both static and cyclic loading, we explore the rate of gradual consolidation of the medium. In the static case, we analytically characterise the duration of consolidation, which governs the duration of effective fluid-assisted lubrication. In the oscillatory case, we identify a region of persistent strain oscillations in otherwise consolidated tissue, and derive estimates of its depth and magnitude. Finally, we link the two cases through the concept of an equivalent static stress, and discuss how our results help explain the inexorable cartilage degeneration of osteoarthritis.

Vascular geometry and oxygen diffusion in the vicinity of artery-vein pairs in the kidney.

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 divisible 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.

Urinary oxygen tension: a clinical window on the health of the renal medulla?

We describe the determinants of urinary oxygen tension (Po2) and the potential for use of urinary PO2 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 PO2. Hypoxia in the renal medulla is a hallmark of AKI of diverse etiology. Urine in the collecting ducts would be expected to equilibrate with the tissue PO2 of the inner medulla. Accordingly, the PO2 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 PO2 of bladder urine. Nevertheless, the PO2 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 PO2 may provide prognostically useful information, including for prediction of AKI after cardiopulmonary bypass surgery. To translate bedside monitoring of urinary PO2 into the clinical setting, we require 1) a more detailed knowledge of the relationship between renal medullary oxygenation and the PO2 of pelvic urine under physiological and pathophysiological conditions; 2) a quantitative understanding of the impact of oxygen transport across the ureteric epithelium on urinary PO2 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 PO2.

Programmable mechanical stimulation influences tendon homeostasis in a bioreactor system.

Identification of functional programmable mechanical stimulation (PMS) on tendon not only provides the insight of the tendon homeostasis under physical/pathological 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.

Haemodynamic influences on kidney oxygenation: clinical implications of integrative physiology.

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.