Mechanobiological model for simulation of injured cartilage degradation via pro-inflammatory cytokines and mechanical stimulus

Abstract

Post-traumatic osteoarthritis (PTOA) is associated with cartilage degradation, ultimately leading to disability and decrease of quality of life. Two key mechanisms have been suggested to occur in PTOA: tissue inflammation and abnormal biomechanical loading. Both mechanisms have been suggested to result in loss of cartilage proteoglycans, the source of tissue fixed charge density (FCD). In order to predict the simultaneous effect of these degrading mechanisms on FCD content, a computational model has been developed. We simulated spatial and temporal changes of FCD content in injured cartilage using a novel finite element model that incorporates (1) diffusion of the pro-inflammatory cytokine interleukin-1 into tissue, and (2) the effect of excessive levels of shear strain near chondral defects during physiologically relevant loading. Cytokine-induced biochemical cartilage explant degradation occurs near the sides, top, and lesion, consistent with the literature. In turn, biomechanically-driven FCD loss is predicted near the lesion, in accordance with experimental findings: regions near lesions showed significantly more FCD depletion compared to regions away from lesions (p<0.01). Combined biochemical and biomechanical degradation is found near the free surfaces and especially near the lesion, and the corresponding bulk FCD loss agrees with experiments. We suggest that the presence of lesions plays a role in cytokine diffusion-driven degradation, and also predisposes cartilage for further biomechanical degradation. Models considering both these cartilage degradation pathways concomitantly are promising in silico tools for predicting disease progression, recognizing lesions at high risk, simulating treatments, and ultimately optimizing treatments to postpone the development of PTOA.

An EMG-assisted Muscle-Force Driven Finite Element Analysis Pipeline to Investigate Joint- and Tissue-Level Mechanical Responses in Functional Activities: Towards a Rapid Assessment Toolbox

“…For instance, collagen fibril strain (related to, e.g., collagen damage) and fluid flow or maximum shear strain (related to, e.g., cell death and fixed charged density loss of the proteoglycans within the cartilage) are reported as measures for the prediction of cartilage adaptation and degradation response, consistent with experiments [6,9,46,47,91]. Nonetheless, none of these studies [6,9,46,47,91] have been incorporated into a multiscale MS-FE model considering subject-specific joint loading. Integrating the EMG-assisted MS-FE pipeline of our study with cartilage remodeling algorithms [6,9,46,47,91], as a part of our further research, may bring more accuracy when subject-specific mechanically-induced soft tissue adaptation and degeneration is of interest.…”

“…The stress and strain within the fibrillar (collagen) and nonfibrillar (proteoglycans) matrices of the cartilage and menisci are reported as indicators governing the cartilage adaptation and degradation response [43, 46, 47]. Hence, our workflow employing the FRPVE material model may promisingly be used in the subject-specific modification of different activities and the design of rehabilitation protocols, to slow the onset or progression of the KOA according to the estimated subject-specific joint mechanics.…”

“…Summarizing, FE models utilizing subjectspecific joint geometries and complex FRPVE material models have shown great potential for estimating highly-detailed tissue mechanics and predicting cartilage damage and degeneration [6,39,43,[46][47][48]. However, creating the above-mentioned FRPVE FE models is a cumbersome manual task requiring several weeks of high-level expertise [48].…”

“…Moreover, poroviscoelasticity is needed to replicate fluid-flow-dependent and -independent mechanisms of biphasic tissues [44], with within-tissue fluid pressurization carrying up to 90% of a dynamic load [40, 45]. These characteristics of the knee soft tissue emphasize the use of a fibrilreinforced poroviscoelastic (FRPVE) material model, which can potentially provide the FE analysis with a more detailed estimation of tissue-level mechanical responses, especially if adaptation and degradation of cartilage and its fibrillar and nonfibrillar matrices are of interest [6, 43, 46, 47].…”

An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

“…Others have shown that extracellular vesicles released from OA senescent chondrocytes are capable of transmitting the senescent phenotype to nearby cells and thereby inhibiting ECM deposition by healthy chondrocytes [ 270 ] and the number of SnCs positively correlated with OA severity [ 271 ]. It has also been shown that physiological loading increases the diffusion of inflammatory cytokines into injured articular cartilage [ 272 ]. These mechanisms could induce senescence in nearby cells and, along with the circulating Th17 cells [ 189 ], could reinforce the long-term production of the inflammatory, such as the prominent “inflammaging” IL-6 [ 244 , 245 ], and tissue-degenerating molecules that are increased in those with knee trauma, as shown in our comprised Figure 1 .…”