(347d) A Multiscale Mechanical Model Predicts Tissue-Level and Fiber-Level Reorganization in Stretched Cell-Compacted Collagen Gels

Mechanical interactions between the cells and their environment mediate many cellular activities, including proliferation, migration, gene expression, and chemical responsiveness. Unraveling connections between externally applied loads and the cellular response is, however, confounded by the structural heterogeneity and mechanical anisotropy of the extracellular matrix (ECM). Therefore, we need to know how mechanical forces are transmitted among the fibers of the ECM and between the ECM and the cells.

To examine these fine details of tissue behavior we developed a multiscale mechanical model that accounted directly for the heterogeneity and anisotropy of a cell-compacted collagen gel subjected to an off-axis hold mechanical test and subsequently to biaxial extension [1]. Based on polarized light images of the gel, we generated in silico spatially varying fiber networks to represent the ECM of the tissue. Subsequently, we used volume-averaging theory and a finite element model to predict the macroscopic response of the tissue from the sum of the networks micro-responses [2, 3, 4]. Finally, the model predictions for the macroscopic behavior of the gel and the reorganization of the collagen fibers were compared to experimental data.

Tissue-level deformation and fiber-level reorganization predicted by the model were consistent with our experimental measurements obtained with a high speed video camera and polarized light imaging. In both the model and experiments, the ECM reorganization proceeded in a non-affine and heterogeneous fashion that was dependent on multiscale interactions between the fiber networks. Simulations also showed that even though the tissue was subjected to tensile loading conditions, a significant fraction of the fibers (12.1% during off-axis test) was under compression, which revealed the complex mechanical interactions among the components of the ECM. The collagen network reorganization, as predicted by the model and observed experimentally, provided insights on how ECM structure determines tissue-level behavior, and gave us a framework to understand how fiber reorganization can lead to mechanotransductive cell signaling.

1. E. A. Sander, T. Stylianopoulos, R. T. Tranquillo, and V. H. Barocas, ?Image-based multi-scale modeling predicts tissue-level and network-level fiber reorganization in stretched cell-compacted collagen gels?, PNAS, 2009, under review.

2. T. Stylianopoulos, and V. H. Barocas, ?Volume Averaging Theory for the Study of the Mechanics of Collagen Networks?, Comput. Meth. Appl. Mech. Engrg., 196, pp. 2981-2990, 2007.

3. T. Stylianopoulos, C. A. Bashur, A. S. Goldstein, S. A. Guelcher, and V. H. Barocas, "Computational Predictions of the Tensile Properties of Electrospun Fiber Meshes: Effect of Fiber Diameter and Fiber Orientation", Journal of the Mechanical Behavior of Biomedical Materials, 1(4), pp. 326-335, 2008.

4. E. A. Sander, T. Stylianopoulos, R. T. Tranquillo, and V. H. Barocas, ?The Mechanics of Collagen Fiber Networks in Bioartificial Tissues: Multiscale Models Compared to Quantitative Polarized Light Microscopy?, IEEE Engineering in Medicine and Biology, 28(3), pp. 10-18, 2009.