Abstract
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.
Highlights
Many mechanically loaded tissues including skin, tendon, ligament, and heart respond to injury by forming a collagen-rich scar
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
We used multiscale modeling to integrate information from the literature on fibroblast responses to stretch, scar formation following injury, and musculoskeletal mechanics to interpret apparently conflicting data from a range of experimental studies
Summary
Many mechanically loaded tissues including skin, tendon, ligament, and heart respond to injury by forming a collagen-rich scar. To better understand the impact of loading, rat animal models of Achilles tendon rupture have been utilized so that scar tissue can be excised to determine quantitative biomechanical scar properties. These studies have led to a wide variety of results, with mechanical loading sometimes appearing to increase, but at other times appearing to decrease, tendon properties such as stiffness or rupture strength. We developed a multiscale computational model of the healing rat Achilles tendon that integrates information about how local mechanics influences cellular alignment and collagen remodeling to predict the effects of various repair and loading protocols on tendon structure. The model simulations identified a potential mechanism underlying the apparently paradoxical finding that mechanical loading enhances collagen alignment in unrepaired Achilles tendons yet decreases it in repaired tendons
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