Intrinsic fibroblast-mediated remodeling of damaged collagenous matrices in vivo

Numerous studies have examined wound healing and tissue repair after a complete tissue rupture and reported provisional matrix and scar tissue formation in the injury gap. The initial phases of the repair are largely mediated by the coagulation response and a principally extrinsic inflammatory response followed by type III collagen deposition to form scar tissue that may be later remodeled. In this study, we examine subfailure (Grade II sprain) damage to collagenous matrices in which no gross tissue gap is present and a localized concentration of provisional matrix or scar tissue does not form. This results in extracellular matrix remodeling that relies heavily upon type I collagen, and associated proteoglycans, and less heavily on type III scar tissue collagen. For instance, following subfailure tissue damage, collagen I and III expression was suppressed after 1 day, but by day 7 expression of both genes was significantly increased over controls, with collagen I expression significantly larger than type III expression. Concurrent with increased collagen expression were significantly increased expression of the collagen fibrillogenesis supporting proteoglycans fibromodulin, lumican, decorin, the large aggregating proteoglycan versican, and proteases cathepsin K and L. Interestingly, this remodeling process appears intrinsic with little or no inflammation response as damaged tissues show no changes in macrophage or neutrophils levels following injury and expression of the inflammatory markers, tumor necrosis factor-alpha and tartrate-resistant acid phosphatase were unchanged. Hence, since inflammation plays a large role in wound healing by inducing cell migration and proliferation, and controlling extracellular matrix scar formation, its absence leaves fibroblasts to principally direct tissue remodeling. Therefore, following a Grade II subfailure injury to the collagen matrix, we conclude that tissue remodeling is fibroblast-mediated and occurs without scar tissue formation, but instead with type I collagen fibrillogenesis to repair the tissue. As such, this system provides unique insight into acute tissue damage and offers a potentially powerful model to examine fibroblast behavior.     

Preparatory co-activation of the ankle muscles may prevent ankle inversion injuries

Ankle inversion sprains are the most frequent acute musculoskeletal injuries occurring in physical activity. Interventions that retrain muscle coordination have helped rehabilitate injured ankles, but it is unclear which muscle coordination strategies, if any, can prevent ankle sprains. The purpose of this study was to determine whether coordinated activity of the ankle muscles could prevent excessive ankle inversion during a simulated landing on a 30° incline. We used a set of musculoskeletal simulations to evaluate the efficacy of two strategies for coordinating the ankle evertor and invertor muscles during simulated landing scenarios: planned co-activation and stretch reflex activation with physiologic latency (60-ms delay). A full-body musculoskeletal model of landing was used to generate simulations of a subject dropping onto an inclined surface with each coordination condition. Within each condition, the intensity of evertor and invertor co-activity or stretch reflexes were varied systematically. The simulations revealed that strong preparatory co-activation of the ankle evertors and invertors prior to ground contact prevented ankle inversion from exceeding injury thresholds by rapidly generating eversion moments after initial contact. Conversely, stretch reflexes were too slow to generate eversion moments before the simulations reached the threshold for inversion injury. These results suggest that training interventions to protect the ankle should focus on stiffening the ankle with muscle co-activation prior to landing. The musculoskeletal models, controllers, software, and simulation results are freely available online at http://simtk.org/home/ankle-sprains, enabling others to reproduce the results and explore new injury scenarios and interventions.