An Agent-Based Discrete Collagen Fiber Network Model of Dynamic Traction Force-Induced Remodeling

Authored by James W Reinhardt, Keith J Gooch

Date Published: 2018

DOI: 10.1115/1.4037947

Sponsors: No sponsors listed

Platforms: NetLogo

Model Documentation: Other Narrative

Model Code URLs: https://drive.google.com/file/d/0B0E2WdML7GEmNC1Fejh1emNONlk/view

Abstract

Microstructural properties of extracellular matrix (ECM) promote cell and tissue homeostasis as well as contribute to the formation and progression of disease. In order to understand how microstructural properties influence the mechanical properties and traction force-induced remodeling of ECM, we developed an agent-based model that incorporates repetitively applied traction force within a discrete fiber network. An important difference between our model and similar finite element models is that by implementing more biologically realistic dynamic traction, we can explore a greater range of matrix remodeling. Here, we validated our model by reproducing qualitative trends observed in three sets of experimental data reported by others: tensile and shear testing of cell-free collagen gels, collagen remodeling around a single isolated cell, and collagen remodeling between pairs of cells. In response to tensile and shear strain, simulated acellular networks with straight fibrils exhibited biphasic stress-strain curves indicative of strain-stiffening. When fibril curvature was introduced, stress-strain curves shifted to the right, delaying the onset of strain-stiffening. Our data support the notion that strain-stiffening might occur as individual fibrils successively align along the axis of strain and become engaged in tension. In simulations with a single, contractile cell, peak collagen displacement occurred closest to the cell and decreased with increasing distance. In simulations with two cells, compaction of collagen between cells appeared inversely related to the initial distance between cells. These results for cell-populated collagen networks match in vitro findings. A demonstrable benefit of modeling is that it allows for further analysis not feasible with experimentation. Within two-cell simulations, strain energy within the collagen network measured from the final state was relatively uniform around the outer surface of cells separated by 250 mu m, but became increasingly nonuniform as the distance between cells decreased. For cells separated by 75 and 100 mu m, strain energy peaked in the direction toward the other cell in the region in which fibrils become highly aligned and reached a minimum adjacent to this region, not on the opposite side of the cell as might be expected. This pattern of strain energy was partly attributable to the pattern of collagen compaction, but was still present when mapping strain energy divided by collagen density. Findings like these are of interest because fibril alignment, density, and strain energy may each contribute to contact guidance during tissue morphogenesis.

Tags

Agent-based modeling remodeling mechanics transmission elasticity Organization Tissue Discrete fiber network simulation Collagen network Mechanical properties Fibril alignment Matrix stiffness Human-fibroblasts Cell behavior Gels Tension