Bruce Gardiner

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.

In this paper we describe a discrete element method (DEM) framework we have developed for modelling the mechanical behavior of cells and tissues. By using a particle method we are able to simulate mechanical phenomena involved in tissue cell biomechanics (such as extracellular matrix degradation, secretion, growth) which would be very difficult to simulate using a continuum approach. We use the DEM framework to study chondrocyte behavior in the growth plate. Chondrocytes have an important role in the growth of long bones. They produce cartilage on one side of the growth plate, which is gradually replaced by bone. We will model some mechanical aspects of the chondrocyte behavior during two stages of this process. The DEM framework can be extended by including other mechanical and chemical processes (such as cell division or chemical regulation). This will help us gain more insight into the complex phenomena governing bone growth.

All established (e.g., serum creatinine, albuminuria) and emerging (e.g., neutrophil gelatinase-associated lipocalin, cystatin C) biomarkers of kidney disease suffer from the disadvantage that they are markers of damage to the kidney or loss of renal function. Tissue hypoxia is believed to be an initiating factor, in both chronic kidney disease (CKD) and acute kidney injury (AKI), so may provide a physiological biomarker for early diagnosis of both conditions. Currently blood oxygen dependent magnetic resonance imaging (BOLD MRI) appears to have little diagnostic value in human CKD. On the other hand, the measurement of urinary oxygen tension (PO2) has potential as a biomarker of risk of AKI in a hospital setting because: (i) Hypoxia in the renal medulla plays a central role in AKI of multiple causes; (ii) The vasa recta are closely associated with collecting ducts in the medulla so that pelvic urinary PO2 would be expected to equilibrate with medullary tissue PO2; (iii) The PO2 of urine in both the renal pelvis and the bladder varies in response to stimuli that would be expected to alter medullary tissue PO2; and (iv) New fibre-optic methods make it feasible to measure bladder urine PO2 in patients with a bladder catheter. But translation of this approach to hospital practice requires: (i) A quantitative understanding of the impact of oxygen transport across the epithelium of the ureter and bladder on urinary PO2 measured from the bladder, (ii) confirmation that changes in urinary PO2 parallel those in medullary PO2 in physiology and pathology, and (iii) Studies of the prognostic utility of urinary PO2 in hospital settings associated with risk of AKI, such as in patients undergoing cardiac surgery with cardiopulmonary bypass, those at risk of sepsis, and those undergoing imaging procedures requiring administration of radiocontrast agents.

Micromechanical constitutive equations are developed which allow for the broad range of interparticle interactions observed in a real deforming granular assembly: microslip contact, gross slip contact, loss of contact and an evolution in these modes of contact as the deformation proceeds. This was accomplished through a synergetic use of contact laws, which account for interparticle resistance to both sliding and rolling, together with strain-dependent anisotropies in contacts and the normal contact force. By applying the constitutive model to the bi-axial test it is demonstrated that the model can correctly predict the evolution of various anisotropies as well as the formation of a distinct shear band. Moreover, the predicted shear-band properties (e.g. thickness, prolonged localisation, void ratio) are an even better fit with experimental observations than were previously found by use of previously developed micromechanical models.