Stiffening of a fibrous matrix after recovery of contracted inclusions

Abstract

Disordered fibrous matrices in living tissues are subjected to forces exerted by cells that contract to pull on matrix fibers. To maintain homeostasis or facilitate disease progression, contracted cells often push on matrix fibers as they recover their original sizes. Recent advances have shown that matrix geometry encodes loading history into mechanical memory independently of plasticity mechanisms such as inter-fiber cohesion or fiber yielding. Conceptualizing cells as inclusions undergoing sequential contraction and recovery, prior work documented matrix remodeling surrounding a solitary recovered inclusion. However, because the remodeling induced by the contraction of multiple inclusions differs from that caused by a single contracted inclusion, we investigate how matrix remodeling occurs when multiple contracted inclusions recover simultaneously, a scenario that more accurately reflects real tissues containing many closely spaced cells. Using mechanics-based computational models of fibrous matrices embedded with clusters of inclusions, we studied the mechanical remodeling of the matrix during the simultaneous recovery of inclusions after contraction. The results revealed permanent mechanical remodeling of the matrix within the cluster, with stiffening observed in areas of the matrix enclosed by closely spaced inclusions. This stiffening was driven by microstructural changes in matrix geometry and was corroborated in experiments, where collagen matrices permanently remodeled by the contraction and recovery of closely spaced embedded cells also exhibited stiffening. By enriching the understanding of memory formation in fibrous matrices, this study opens new possibilities for estimating cell forces on matrix substrates and refining metamaterial design strategies.