Computational Modeling of Mouse Colorectum Capturing Longitudinal and Through-thickness Biomechanical Heterogeneity.

Mechanotransduction, the encoding of local mechanical stresses and strains at sensory endings into neural action potentials at the viscera, plays a critical role in evoking visceral pain, e.g., in the distal colon and rectum (colorectum). The wall of the colorectum is structurally heterogeneous, including two major composites: the inner consists of muscular and submucosal layers, and the outer consists of circular muscular, intermuscular, longitudinal muscular, and serosal layers. In fact the colorectum presents biomechanical heterogenity across both the longitudinal and through-thickness directions thus highlighting the differential roles of sensory nerve endings within different regions of the colorectum in visceral mechanotransduction. We determined constitutive models and model parameters for individual layers of the colorectum from three longitudinal locations (colonic, intermediate, and distal) using nonlinear optimization to fit our experimental results from biaxial extension tests on layer-separated colorectal tissues (mouse model, 7×7 mm2, Siri et al., Am. J. Physiol. Gastrointest. Liver Physiol. 316, G473-G481 and 317, G349-G358), and quantified the thicknesses of the layers. In this study we also quantified the residual stretches stemming from separating colorectal specimens into inner and outer composites and we completed new pressure-diameter mechanical testing to provide an additional validation case. We implemented the constitutive equations and created two-layered, 3-D finite element models using FEBio (University of Utah), and incorporated the residual stretches. We validated the modeling framework by comparing FE-predicted results for both biaxial extension testing of bulk specimens of colorectum and pressure-diameter testing of bulk segments against corresponding experimental results independent of those used in our model fitting. We present the first theoretical framework to simulate the biomechanics of distal colorectum, including both longitudinal and through-thickness heterogeneity, based on constitutive modeling of biaxial extension tests of colon tissues from mice. Our constitutive models and modeling framework facilitate analyses of both fundamental questions (e.g., the impact of organ/tissue biomechanics on mechanotransduction of the sensory nerve endings, structure-function relationships, and growth and remodeling in health and disease) and specific applications (e.g., device design, minimally invasive surgery, and biomedical research).