An in silico Framework of Cartilage Degeneration That Integrates Fibril Reorientation and Degradation Along With Altered Hydration and Fixed Charge Density Loss

Abstract

Injurious mechanical loading of articular cartilage and associated lesions compromise the mechanical and structural integrity of joints and contribute to the onset and progression of cartilage degeneration leading to osteoarthritis (OA). Despite extensive in vitro and in vivo research, it remains unclear how the changes in cartilage composition and structure that occur during cartilage degeneration after injury, interact. Recently, in silico techniques provide a unique integrated platform to investigate the causal mechanisms by which the local mechanical environment of injured cartilage drives cartilage degeneration. Here, we introduce a novel integrated Cartilage Adaptive REorientation Degeneration (CARED) algorithm to predict the interaction between degenerative variations in main cartilage constituents, namely collagen fibril disorganization and degradation, proteoglycan (PG) loss, and change in water content. The algorithm iteratively interacts with a finite element (FE) model of a cartilage explant, with and without variable depth to full-thickness defects. In these FE models, intact and injured explants were subjected to normal (2 MPa unconfined compression in 0.1 s) and injurious mechanical loading (4 MPa unconfined compression in 0.1 s). Depending on the mechanical response of the FE model, the collagen fibril orientation and density, PG and water content were iteratively updated. In the CARED model, fixed charge density (FCD) loss and increased water content were related to decrease in PG content. Our model predictions were consistent with earlier experimental studies. In the intact explant model, minimal degenerative changes were observed under normal loading, while the injurious loading caused a reorientation of collagen fibrils toward the direction perpendicular to the surface, intense collagen degradation at the surface, and intense PG loss in the superficial and middle zones. In the injured explant models, normal loading induced intense collagen degradation, collagen reorientation, and PG depletion both on the surface and around the lesion. Our results confirm that the cartilage lesion depth is a crucial parameter affecting tissue degeneration, even under physiological loading conditions. The results suggest that potential fibril reorientation might prevent or slow down fibril degradation under conditions in which the tissue mechanical homeostasis is perturbed like the presence of defects or injurious loading.

Rapid X-Ray-Based 3-D Finite Element Modeling of Medial Knee Joint Cartilage Biomechanics During Walking

“… 3 , 11 In recent years, these simulated biomechanical responses have been utilized in predictive FE models to predict biomechanically-driven progression of knee OA based on clinical imaging data. 10 , 33 In those studies, subject-specific 3-D joint geometries of the models have been based on computed tomography (CT) or magnetic resonance imaging (MRI). The potential of X-ray imaging under a similar workflow has not been evaluated so far.…”

A musculoskeletal finite element model of rat knee joint for evaluating cartilage biomechanics during gait

“…To the best of our knowledge, this approach represents the first 3-D rat knee MSFE model that can be used to investigate cartilage and meniscus stresses and strains during gait. As the main methodological novelty, this approach can be applied to characterize collagen damage and proteoglycan loss mechanisms during OA progression [ 57 – 61 ] as well as to evaluate the effect of knee joint disorders and gait impairments on articular cartilage in preclinical models of joint injury and disease [ 62 ]. The rat knee joint geometries were extracted from a 3-D MRI dataset and the boundary conditions regarding loading of the joint were extracted from a musculoskeletal model of the rat hindlimb.…”

Signatures of disease progression in knee osteoarthritis: insights from an integrated multi-scale modeling approach, a proof of concept

“…2 ). Thresholds of MSS = 30% and SFD = 10% were chosen as being indicative of PG depletion and collagen degeneration respectively, as implemented in the most recently developed CARED model ( Elahi et al, 2021 ) and based on literature findings ( Eskelinen et al, 2019 ). where ɛ p,1 , ɛ p,2 , ɛ p,3 are the principal strains of the Green-Lagrangian strain tensor.…”

“…The interactions between these constituents dictate the mechanical behavior of cartilage and enable it to distribute mechanical load across the joint surface ( Sophia Fox et al, 2009 ; Heinegård and Saxne, 2011 ; Mukherjee et al, 2020 ). However, changes in mechanical loading during locomotion will alter stresses and strains within the tissue, which—upon exceeding a critical threshold—is associated with irreversible changes to the collagen network and depletion of the PG content ( Speirs et al, 2014 ; Tanska et al, 2018 ; Elahi et al, 2021 ; Elahi et al, 2023 ). Indeed, the mechanical joint environment is considered to be a significant contributor to the disease process, with pathomechanical loading potentially leading to maladaptive responses of chondrocytes and ECM, as well as increased inflammation, further aggravating cartilage tissue degeneration ( Hurwitz et al, 2000 ; Baliunas et al, 2002 ; Sun, 2010 ).…”

“…Cartilage degeneration algorithms, also referred to as adaptive algorithms have emerged that mimic time-dependent, OA-associated cartilage degeneration processes ( Mononen et al, 2018 ; Orozco et al, 2018 ; 2021 ; Eskelinen et al, 2019 ; Elahi et al, 2021 ). The Cartilage Adaptive Reorientation Degeneration (CARED) model, namely, the most recently developed integrated adaptive model, uses a fibril-reinforced poroviscoelastic material model to calculate the strain in collagen fibrils and maximum shear strain as mechanoregulatory parameters that drive collagen degradation and PG depletion, respectively ( Elahi et al, 2021 ; Elahi et al, 2023 ). Although the CARED model is able to predict degenerative changes in an explant model (osteochondral plug with 3 mm diameter) under different loading conditions, this is not representative for cartilage degeneration in the whole knee joint.…”