Multiscale computational model of Achilles tendon wound healing: Untangling the effects of repair and loading

Mechanical stimulation of the healing tendon is thought to regulate scar anisotropy and strength and is relatively easy to modulate through physical therapy. However, in vivo studies of various loading protocols in animal models have produced mixed results. To integrate and better understand the available data, we developed a multiscale model of rat Achilles tendon healing that incorporates the effect of changes in the mechanical environment on fibroblast behavior, collagen deposition, and scar formation. We modified an OpenSim model of the rat right hindlimb to estimate physiologic strains in the lateral/medial gastrocnemius and soleus musculo-tendon units during loading and unloading conditions. We used the tendon strains as inputs to a thermodynamic model of stress fiber dynamics that predicts fibroblast alignment, and to determine local collagen synthesis rates according to a response curve derived from in vitro studies. We then used an agent-based model (ABM) of scar formation to integrate these cell-level responses and predict tissue-level collagen alignment and content. We compared our model predictions to experimental data from ten different studies. We found that a single set of cellular response curves can explain features of observed tendon healing across a wide array of reported experiments in rats–including the paradoxical finding that repairing transected tendon reverses the effect of loading on alignment–without fitting model parameters to any data from those experiments. The key to these successful predictions was simulating the specific loading and surgical protocols to predict tissue-level strains, which then guided cellular behaviors according to response curves based on in vitro experiments. Our model results provide a potential explanation for the highly variable responses to mechanical loading reported in the tendon healing literature and may be useful in guiding the design of future experiments and interventions.Author summary: Tendons and ligaments transmit force between muscles and bones throughout the body and are comprised of highly aligned collagen fibers that help bear high loads. The Achilles tendon is exposed to exceptionally high loads and is prone to rupture. When damaged Achilles tendons heal, they typically have reduced strength and stiffness, and while most believe that appropriate physical therapy can help improve these mechanical properties, both clinical and animal studies of mechanical loading following injury have produced highly variable and somewhat disappointing results. To help better understand the effects of mechanical loading on tendon healing and potentially guide future therapies, we developed a computational model of rat Achilles tendon healing and showed that we could predict the main effects of different mechanical loading and surgical repair conditions reported across a wide range of published studies. Our model offers potential explanations for some surprising findings of prior studies and for the high variability observed in those studies and may prove useful in designing future therapies or experiments to test new therapies.