Mechanobiochemical finite element model to analyze impact-loading-induced cell damage, subsequent proteoglycan loss, and anti-oxidative treatment effects in articular cartilage

Joint trauma often leads to articular cartilage degeneration and post-traumatic osteoarthritis (PTOA). Pivotal determinants include trauma-induced excessive tissue strains that damage cartilage cells. As a downstream effect, these damaged cells can trigger cartilage degeneration via oxidative stress, cell death, and proteolytic tissue degeneration. N-acetylcysteine (NAC) has emerged as antioxidant capable of inhibiting oxidative stress, cell death, and cartilage degeneration post-impact. However, temporal effects of NAC are not fully understood and remain difficult to assess solely by physical experiments. Thus, we developed a computational framework to simulate a drop tower impact of cartilage with finite element analysis in ABAQUS, and model subsequent oxidative stress-related cell damage, and NAC treatment upon cartilage proteoglycan content in COMSOL Multiphysics, based on prior ex vivo experiments. Model results provide evidence that by inhibiting further cell damage by mechanically induced oxidative stress, immediate NAC treatment can reduce proteoglycan loss by mitigating cell death (loss of proteoglycan biosynthesis) and enzymatic proteoglycan depletion. Our simulations also indicated that delayed NAC treatment may not inhibit cartilage proteoglycan loss despite reduced cell death after impact. These results enhance understanding of temporal effects of impact-related cell damage and treatment that are critical for the development of effective treatments for PTOA. In the future, our modeling framework could increase understanding of time-dependent mechanisms of oxidative stress and downstream effects in injured cartilage and aid in developing better treatments to mitigate PTOA progression. Author summaryPost-traumatic osteoarthritis is a debilitating disease which is often initiated by trauma and characterized by cartilage degeneration. The degeneration is partly driven by trauma-induced damage, including oxidative stress, to cartilage cells. Multiple drugs have been studied to counteract the cell damage, but it remains difficult to inhibit the disease progression since temporal effects of such treatments are not fully understood. Here, we developed a computational framework to study effects of antioxidant treatment in mechanically impacted cartilage and compared our computational simulations with previously published experiments. Our results showed that the high strain induced cell damage occurring in the mechanically impacted region could be mitigated by N-acetylcysteine treatment. This mechanism could partly explain reduced cartilage proteoglycan loss compared to untreated samples. Our modeling framework could help enhance development of treatments to better inhibit osteoarthritis progression.