Bruce Gardiner

Fibrosis and loss of functional capillary surface area may contribute to renal tissue hypoxia in a range of kidney diseases. However, there is limited quantitative information on the impact of kidney disease on the barriers to oxygen diffusion from cortical peritubular capillaries (PTCs) to kidney epithelial tubules. Here, we used stereological methods to quantify changes in total cortical PTC length and surface area, PTC length and surface densities, and diffusion distances between PTCs and kidney tubules in adenine-induced kidney injury. After 7 days of oral gavage of adenine (100 mg), plasma creatinine was 3.5-fold greater than in vehicle-treated rats, while total kidney weight was 83% greater. The total length of PTCs was similar in adenine-treated (1.47 ± 0.23 km (mean ± standard deviation)) to vehicle-treated (1.24 ± 0.24 km) rats, as was the surface density of PTCs (0.025 ± 0.002 vs. 0.024 ± 0.004 μm2/μm3). The total surface area of PTCs was 69% greater in adenine-treated than vehicle-treated rats. However, the length density of PTCs was 28% less in adenine-treated than vehicle-treated rats. Diffusion distances, from PTCs to the basal membrane of the nearest renal tubule (108%), and to the mid-point of the cytoplasmic height of the nearest tubular epithelial cell (57%), were markedly increased. These findings indicate that, in adenine-induced kidney injury, expansion of the renal cortical interstitium increases the distance required for diffusion of oxygen from PTCs to tubules, rendering the kidney cortex susceptible to hypoxia.

This study focuses on the relationship between meniscectomy and osteochondral junction health, and their integrity on cartilage lubrication. Using a previously published multi-component joint computational model, we explored the impact of increasing degree of meniscectomy and osteochondral flow conductivity on joint lubrication. Results suggest a greater effect of meniscectomy on joint lubrication when the osteochondral junction is healthy. However, the impact is less pronounced when the osteochondral junction is already diseased due to compromised lubrication capability. This research provides a first-time quantitative analysis of this interaction, which highlights the importance of adequately evaluating the osteochondral junction’s condition before meniscectomy surgery. It also suggests that reducing post-surgery activity level may be beneficial for patients with diseased junctions undergoing meniscectomy.

Background and Objectives: Previous studies have shown that there is potentially interstitial fluid ex-change between cartilage tissue and the subarticular spongiosa region in the case of injury or disease (e.g., osteoarthritis and osteoporosis). Interstitial flow is also required for cartilage lubrication under joint load. A key question then is how cartilage lubrication is modified by increased interstitial fluid leakage across the osteochondral junction. Thus, the purpose of this study is to develop a numerical model to investigate changes in cartilage lubrication with changes in osteochondral junction leakage.
Methods: The multi-phase coupled model includes domains corresponding to the contact gap, cartilage tissue and subchondral bone plate region (ScBP). Each of these domains are treated as poroelastic sys-tems, with their coupling implemented through mass and pressure continuity. The effects of osteochon-dral junction leakage on lubrication were investigated with a parametric study on the relative permeabil-ity between the ScBP and cartilage tissue.
Results: Significant effects of ScBP permeability were predicted, especially during the early stage of the junction leakage development (early stage of the disease). There is a significant reduction in mixed-mode lubrication duration under the effect of increased junction leakage (the cartilage tissue mixed-mode lubri-cation duration is about 33% decrease for a relative permeability ratio of 0.1 between ScBP and cartilage tissue, and about 52% decrease under the osteoarthritis condition). In addition, the time for cartilage to reach steady-state consolidation is significantly reduced when ScBP permeability increases (the consoli-dation time reduces from roughly 2 h to 1.2 h when the relative permeability ratio increases from 0.001 to 0.1, and it reduces to 0.8 h for an advanced osteoarthritis condition). It is predicted that the initial fric-tion coefficient could increase by over 60% when the ScBP permeability is consistent with an advanced osteoarthritis (OA) condition.
Conclusion: Increased osteochondral junction leakage induced by joint injury and disease could result in increased cartilage surface wear rates due to more rapid interstitial fluid depressurization within articular cartilage. (c) 2023 Elsevier B.V. All rights reserved.

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.

The glomerular basement membrane (GBM) is an important tissue structure in kidney function. It is the membrane through which filtrate and solutes must pass to reach the nephron tubules. This review focuses on the spatial location of the main extracellular matrix components of the GBM. It also attempts to explain this organization in terms of their synthesis, transport, and loss. The picture that emerges is that the collagen IV and laminin content of GBM are in a very slow dynamic disequilibrium, leading to GBM thickening with age, and in contrast, some heparan sulfate proteoglycans are in a dynamic equilibrium with a very rapid turnover (i.e. half-life measured in ~hours) and flow direction against the flow of filtrate. The highly rapid heparan sulfate turnover may serve several roles, including an unclogging mechanism for the GBM, compressive stiffness of the GBM fiber network, and/or enabling podocycte-endothelial crosstalk against the flow of filtrate.

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.

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.

Background and Objective The geometrical and mechanical properties that characterise the cartilage contact gap are uncertain and spatially varied. To date the effects of such uncertainties on cartilage lubrication have not been explored. Using a probabilistic approach, the purpose of this study is to numerically investigate the influence of surficial cartilage glycoaminoglycan (GAG) content on joint lubrication behaviour. Gap asperity stiffness and polymer brush border (PBB) thickness are affected by the uncertainty of surficial GAG concentration, and so their correlated effects in maintaining hydrodynamic joint lubrication are investigated. Methods Correlated sampling data are first generated by Monte Carlo simulation. These data are used as inputs for the cartilage contact model, which includes three distinctive features of cartilage tissue (tension-compression nonlinearity, aggrecan dependent permeability and compressive modulus) and fluid flow resistance effects of PBB on cartilage surface. The degree of hydrodynamic lubrication after thirty minutes of constant loading is used as an indicator for assessing the lubrication performance at the contact interface. Results The increase of PBB thickness with GAG concentration enhances the hydrodynamic lubrication component in the cartilage contact gap, whereas increasing the asperity stiffness with GAG concentration impairs hydrodynamic lubrication. GAG loss rate increases with the rise of GAG concentration. More aggrecan shedding through the surface could result in a thicker and denser PBB, and therefore enhance the lubrication performance in mixed-mode regime. On the other hand, higher GAG content makes the asperities stiffer, which may impede contact gap closure, and thus encourage gap fluid loss and impair the lubrication performance of cartilage. Conclusion The lubrication performance of cartilage varies with the physiological conditions of the joint. Since a range of variables are internally related, the outcomes on joint lubrication are difficult to predict. A probabilistic approach accounting for the uncertainties can potentially result in more accurate evaluations of joint lubrication performance.

We have previously developed a new theory for pressure dependent outflow from the human eye, and tested the model using experimental data at intraocular pressures above normal eye pressures. In this paper, we use our model to analyze a hypotensive pressure-time dataset obtained following application of a Honan balloon. Here we show that the hypotensive pressure-time data can be successfully analyzed using our proposed pressure dependent outflow model. When the most uncertain initial data point is removed from the dataset, then parameter estimates are close to our previous parameter estimates, but clearly parameter estimates are very sensitive to assumptions. We further show that (i) for a measured intraocular pressure-time curve, the estimated model parameter for whole eye surface hydraulic conductivity is primarily a function of the ocular rigidity, and (ii) the estimated model parameter that controls the rate of decrease of outflow with increasing pressure is primarily a function of the convexity of the monotonic pressure-time curve. Reducing parameter uncertainty could be accomplished using new technologies to obtain higher quality datasets, and by gathering additional data to better define model parameter ranges for the normal eye. With additional research, we expect the pressure dependent outflow analysis described herein may find applications in the differential diagnosis, prognosis and monitoring of the glaucomatous eye.