Dynamic filopodial forces induce accumulation, damage, and plastic remodeling of 3D extracellular matrices

Abstract

The mechanical properties of the extracellular matrix (ECM)–a complex, 3D, fibrillar scaffold of cells in physiological environments–modulate cell behavior and can drive tissue morphogenesis, regeneration, and disease progression. For simplicity, it is often convenient to assume these properties to be time-invariant. In living systems, however, cells dynamically remodel the ECM and create time-dependent local microenvironments. Here, we show how cell-generated contractile forces produce substantial irreversible changes to the density and architecture of physiologically relevant ECMs–collagen I and fibrin–in a matter of minutes. We measure the 3D deformation profiles of the ECM surrounding cancer and endothelial cells during stages when force generation is active or inactive. We further correlate these ECM measurements to both discrete fiber simulations that incorporate fiber crosslink unbinding kinetics and continuum-scale simulations that account for viscoplastic and damage features. Our findings further confirm that plasticity, as a mechanical law to capture remodeling in these networks, is fundamentally tied to material damage via force-driven unbinding of fiber crosslinks. These results characterize in a multiscale manner the dynamic nature of the mechanical environment of physiologically mimicking cell-in-gel systems.

Robust and Precise Wounding and Analysis of Engineered Contractile Tissues

“…Briefly, linear elastic and viscoelastic models are described by an elastic modulus E e , without/with viscous modulus E v and viscosity l. The viscoelastic model is extended to incorporate viscoplastic behavior by adding a viscosity term with a yield stress threshold, and a softening function to reduce yield stress under constant material loading. 41 Viscoplasticity is described with a linear Norton/Hoff model:…”

“…where the exponent n is set to 1 as per the perfect viscoplastic assumption and the viscoplastic rate coefficient A is selected to be the inverse of viscosity l. Initial material parameters for these models were obtained from literature sources for mechanical characterization of cell-laden collagen hydrogels. 38,[41][42][43] For all models, tissue prestress is introduced by applying a positive radial displacement boundary condition to match the collagen pull-away distance observed at the micropillars. Tissue wounds are initiated by setting the material properties of a central ''hole'' 678 DUBOIS ET AL.…”

“…4C) using values obtained from literature. 38,[41][42][43]45 Linear elastic material models did not exhibit time-dependent retraction, as the wound instantly expanded to release tissue stress. While viscoelastic models did improve on this and capture time-dependent wound expansion (Fig.…”

Tissue mimetic hyaluronan bioink containing collagen fibers with controlled orientation modulating cell morphology and alignment

“…Col structure, orientation and spatial arrangement are fundamental towards mechanical stability and anisotropic properties of tissues [11]. The network architecture is also crucial to transmit forces to cells via cell-matrix interaction [12,13] and contributes to the matrix biochemical environment. To bring the 3D printing technology one step closer to native tissue architectures, it is necessary to capture micro-and nanostructures within macroscopically complex scaffold geometries [14].…”

“…Microarchitectural properties can be introduced with polymer selfassembling, a process where macromolecules arrange into stable non-covalent structures. Col [15], fibrin [12], cellulose [16] and silk fibroin [17] are the most prominent materials selfassembling into fibrous structures. Most studies printing Col bio(material) inks employ soluble (acidic) and/or non-fibrillar Col inks or blended neutralized Col (Col fractions).…”