| 1. |
- Korhonen, Rami K., et al.
(author)
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Multiscale In Silico Modeling of Cartilage Injuries
- 2023
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In: Advances in Experimental Medicine and Biology. - 2214-8019 .- 0065-2598. ; 1402, s. 45-56
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Book chapter (peer-reviewed)abstract
- Injurious loading of the joint can be accompanied by articular cartilage damage and trigger inflammation. However, it is not well-known which mechanism controls further cartilage degradation, ultimately leading to post-traumatic osteoarthritis. For personalized prognostics, there should also be a method that can predict tissue alterations following joint and cartilage injury. This chapter gives an overview of experimental and computational methods to characterize and predict cartilage degradation following joint injury. Two mechanisms for cartilage degradation are proposed. In (1) biomechanically driven cartilage degradation, it is assumed that excessive levels of strain or stress of the fibrillar or non-fibrillar matrix lead to proteoglycan loss or collagen damage and degradation. In (2) biochemically driven cartilage degradation, it is assumed that diffusion of inflammatory cytokines leads to degradation of the extracellular matrix. When implementing these two mechanisms in a computational in silico modeling workflow, supplemented by in vitro and in vivo experiments, it is shown that biomechanically driven cartilage degradation is concentrated on the damage environment, while inflammation via synovial fluid affects all free cartilage surfaces. It is also proposed how the presented in silico modeling methodology may be used in the future for personalized prognostics and treatment planning of patients with a joint injury.
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| 2. |
- Kosonen, Joonas P., et al.
(author)
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Injury-related cell death and proteoglycan loss in articular cartilage : Numerical model combining necrosis, reactive oxygen species, and inflammatory cytokines
- 2023
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In: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 19:1
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Journal article (peer-reviewed)abstract
- Osteoarthritis (OA) is a common musculoskeletal disease that leads to deterioration of articular cartilage, joint pain, and decreased quality of life. When OA develops after a joint injury, it is designated as post-traumatic OA (PTOA). The etiology of PTOA remains poorly understood, but it is known that proteoglycan (PG) loss, cell dysfunction, and cell death in cartilage are among the first signs of the disease. These processes, influenced by biomechanical and inflammatory stimuli, disturb the normal cell-regulated balance between tissue synthesis and degeneration. Previous computational mechanobiological models have not explicitly incorporated the cell-mediated degradation mechanisms triggered by an injury that eventually can lead to tissue-level compositional changes. Here, we developed a 2-D mechanobiological finite element model to predict necrosis, apoptosis following excessive production of reactive oxygen species (ROS), and inflammatory cytokine (interleukin-1)-driven apoptosis in cartilage explant. The resulting PG loss over 30 days was simulated. Biomechanically triggered PG degeneration, associated with cell necrosis, excessive ROS production, and cell apoptosis, was predicted to be localized near a lesion, while interleukin-1 diffusion-driven PG degeneration was manifested more globally. Interestingly, the model also showed proteolytic activity and PG biosynthesis closer to the levels of healthy tissue when pro-inflammatory cytokines were rapidly inhibited or cleared from the culture medium, leading to partial recovery of PG content. The numerical predictions of cell death and PG loss were supported by previous experimental findings. Furthermore, the simulated ROS and inflammation mechanisms had longer-lasting effects (over 3 days) on the PG content than localized necrosis. The mechanobiological model presented here may serve as a numerical tool for assessing early cartilage degeneration mechanisms and the efficacy of interventions to mitigate PTOA progression.
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| 3. |
- Orozco, Gustavo A., et al.
(author)
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Shear strain and inflammation-induced fixed charge density loss in the knee joint cartilage following ACL injury and reconstruction : A computational study
- 2022
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In: Journal of Orthopaedic Research. - : Wiley. - 0736-0266 .- 1554-527X. ; 40:7, s. 1505-1522
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Journal article (peer-reviewed)abstract
- Excessive tissue deformation near cartilage lesions and acute inflammation within the knee joint after anterior cruciate ligament (ACL) rupture and reconstruction surgery accelerate the loss of fixed charge density (FCD) and subsequent cartilage tissue degeneration. Here, we show how biomechanical and biochemical degradation pathways can predict FCD loss using a patient-specific finite element model of an ACL reconstructed knee joint exhibiting a chondral lesion. Biomechanical degradation was based on the excessive maximum shear strains that may result in cell apoptosis, while biochemical degradation was driven by the diffusion of pro-inflammatory cytokines. We found that the biomechanical model was able to predict substantial localized FCD loss near the lesion and on the medial areas of the lateral tibial cartilage. In turn, the biochemical model predicted FCD loss all around the lesion and at intact areas; the highest FCD loss was at the cartilage–synovial fluid-interface and decreased toward the deeper zones. Interestingly, simulating a downturn of an acute inflammatory response by reducing the cytokine concentration exponentially over time in synovial fluid led to a partial recovery of FCD content in the cartilage. Our novel numerical approach suggests that in vivo FCD loss can be estimated in injured cartilage following ACL injury and reconstruction. Our novel modeling platform can benefit the prediction of PTOA progression and the development of treatment interventions such as disease-modifying drug testing and rehabilitation strategies.
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