Title:
Multiscale cartilage biomechanics: technical challenges in realizing a high-throughput modelling and simulation workflow.

Abstract:
Understanding the mechanical environment of articular cartilage and chondrocytes is of the utmost importance in evaluating tissue damage which is often related to failure of the fibre architecture and mechanical injury to the cells. This knowledge also has significant implications for understanding the mechanobiological response in healthy and diseased cartilage and can drive the development of intervention strategies, ranging from the design of tissue-engineered constructs to the establishment of rehabilitation protocols. Spanning multiple spatial scales, a wide range of biomechanical factors dictate this mechanical environment. Computational modelling and simulation provide descriptive and predictive tools to identify multiscale interactions, and can lead towards a greater comprehension of healthy and diseased cartilage function, possibly in an individualized manner. Cartilage and chondrocyte mechanics can be examined in silico, through post-processing or feed-forward approaches. First, joint-tissue level simulations, typically using the finite-element method, solve boundary value problems representing the joint articulation and underlying tissue, which can differentiate the role of compartmental joint loading in cartilage contact mechanics and macroscale cartilage field mechanics. Subsequently, tissue-cell scale simulations, driven by the macroscale cartilage mechanical field information, can predict chondrocyte deformation metrics along with the mechanics of the surrounding pericellular and extracellular matrices. A high-throughput modelling and simulation framework is necessary to develop models representative of regional and population-wide variations in cartilage and chondrocyte anatomy and mechanical properties, and to conduct large-scale analysis accommodating a multitude of loading scenarios. However, realization of such a framework is a daunting task, with technical difficulties hindering the processes of model development, scale coupling, simulation and interpretation of the results. This study aims to summarize various strategies to address the technical challenges of post-processing-based simulations of cartilage and chondrocyte mechanics with the ultimate goal of establishing the foundations of a high-throughput multiscale analysis framework. At the joint-tissue scale, rapid development of regional models of articular contact is possible by automating the process of generating parametric representations of cartilage boundaries and depth-dependent zonal delineation with associated constitutive relationships. At the tissue-cell scale, models descriptive of multicellular and fibrillar architecture of cartilage zones can also be generated in an automated fashion. Through post-processing, scripts can extract biphasic mechanical metrics at a desired point in the cartilage to assign loading and boundary conditions to models at the lower spatial scale of cells. Cell deformation metrics can be extracted from simulation results to provide a simplified description of individual chondrocyte responses. Simulations at the tissue-cell scale can be parallelized owing to the loosely coupled nature of the feed-forward approach. Verification studies illustrated the necessity of a second-order data passing scheme between scales and evaluated the role that the microscale representative volume size plays in appropriately predicting the mechanical response of the chondrocytes. The tools summarized in this study collectively provide a framework for high-throughput exploration of cartilage biomechanics, which includes minimally supervised model generation, and prediction of multiscale biomechanical metrics across a range of spatial scales, from joint regions and cartilage zones, down to that of the chondrocytes.