Skeletal muscle possesses a remarkable capacity for repair and regeneration following a variety of injuries. When successful, this highly orchestrated regenerative process requires the contribution of several muscle resident cell populations including satellite stem cells (SSCs), fibroblasts, macrophages and vascular cells. However, volumetric muscle loss injuries (VML) involve simultaneous destruction of multiple tissue components (e.g., as a result of battlefield injuries or vehicular accidents) and are so extensive that they exceed the intrinsic capability for scarless wound healing and result in permanent cosmetic and functional deficits. In this scenario, the regenerative process fails and is dominated by an unproductive inflammatory response and accompanying fibrosis. The failure of current regenerative therapeutics to completely restore functional muscle tissue is not surprising considering the incomplete understanding of the cellular mechanisms that drive the regeneration response in the setting of VML injury. To begin to address this profound knowledge gap, we developed an agent-based model to predict the tissue remodeling response following surgical creation of a VML injury. Once the model was able to recapitulate key aspects of the tissue remodeling response in the absence of repair, we validated the model by simulating the tissue remodeling response to VML injury following implantation of either a decellularized extracellular matrix scaffold or a minced muscle graft. The model suggested that the SSC microenvironment and absence of pro-differentiation SSC signals were the most important aspects of failed muscle regeneration in VML injuries. The major implication of this work is that agent-based models may provide a much-needed predictive tool to optimize the design of new therapies, and thereby, accelerate the clinical translation of regenerative therapeutics for VML injuries.

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.

In this paper, we propose an automated segmentation algorithm for human leg muscles from 3D MRI data using a deep convolutional neural network (CNN). Using a generalized cylinder model, a 3D human leg muscle is represented by two smooth 2D images. The CNN predicts these two images from raw 3D voxels. For our base CNN, we use a pre-trained AlexNet that is coupled with a principle components analysis (PCA)-head. The AlexNet predicts a compressed vector, which is then back-projected by the PCA-head into two 2D images representing a 3D leg muscle boundary. This structured-output CNN architecture is fine-tuned in an end-to-end fashion. Our proposed CNN outperforms the conventional model-based approach, the active appearance model (AAM) image segmentation algorithm. The average Dice score between the ground truth segmentation and the obtained segmentation image is 0.85 using our CNN model, whereas the AAM yields a Dice score of 0.60.

Simulation of the musculoskeletal system has important applications in biomechanics, biomedical engineering, surgery simulation, and computer graphics. The accuracy of the muscle, bone, and tendon geometry as well as the accuracy of muscle and tendon dynamic deformation are of paramount importance in all these applications. We present a framework for extracting and simulating high resolution musculoskeletal geometry from the segmented visible human data set. We simulate 30 contact/collision coupled muscles in the upper limb and describe a computationally tractable implementation using an embedded mesh framework. Muscle geometry is embedded in a nonmanifold, connectivity preserving simulation mesh molded out of a lower resolution BCC lattice containing identical, well-shaped elements, leading to a relaxed time step restriction for stability and, thus, reduced computational cost. The muscles are endowed with a transversely isotropic, quasi-incompressible constitutive model that incorporates muscle fiber fields as well as passive and active components. The simulation takes advantage of a new robust finite element technique that handles both degenerate and inverted tetrahedra.