Effect of hyaluronic acid on microscale deformations of collagen gels.

As fibrous collagen is the most abundant protein in mammalian tissues, gels of collagen fibers have been extensively used as an extracellular matrix scaffold to study how cells sense and respond to cues from their microenvironment. Other components of native tissues, such as glycosaminoglycans like hyaluronic acid, can affect cell behavior in part by changing the mechanical properties of the collagen gel. Prior studies have quantified the effects of hyaluronic acid on the mechanical properties of collagen gels in experiments of uniform shear or compression at the macroscale.

Effect of matrix heterogeneity on cell mechanosensing.

Cells sense mechanical signals within the extracellular matrix, the most familiar being stiffness, but matrix stiffness cannot be simply described by a single value. Randomness in matrix structure causes stiffness at the scale of a cell to vary by more than an order of magnitude. Additionally, the extracellular matrix contains ducts, blood vessels, and, in cancer or fibrosis, regions with abnormally high stiffness.

Directional cues in the tumor microenvironment due to cell contraction against aligned collagen fibers.

It is well established that collagen alignment in the breast tumor microenvironment provides biophysical cues to drive disease progression. Numerous mechanistic studies have demonstrated that tumor cell behavior is driven by the architecture and stiffness of the collagen matrix. However, the mechanical properties within a 3D collagen microenvironment, particularly at the scale of the cell, remain poorly defined.

Cells exploit a phase transition to mechanically remodel the fibrous extracellular matrix.

Through mechanical forces, biological cells remodel the surrounding collagen network, generating striking deformation patterns. Tethers-tracts of high densification and fibre alignment-form between cells, thinner bands emanate from cell clusters. While tethers facilitate cell migration and communication, how they form is unclear.

Modulus of Fibrous Collagen at the Length Scale of a Cell.

The extracellular matrix provides macroscale structural support to tissues as well as microscale mechanical cues, like stiffness, to the resident cells. As those cues modulate gene expression, proliferation, differentiation, and motility, quantifying the stiffness that cells sense is crucial to understanding cell behavior. Whereas the macroscopic modulus of a collagen network can be measured in uniform extension or shear, quantifying the local stiffness sensed by a cell remains a challenge due to the inhomogeneous and nonlinear nature of the fiber network at the scale of the cell.

Heterogeneity and nonaffinity of cell-induced matrix displacements.

Cell contractile forces deform and reorganize the surrounding matrix, but the relationship between the forces and the resulting displacements is complicated by the fact that the fibrous structure brings about a complex set of mechanical properties. Many studies have quantified nonlinear and time-dependent properties at macroscopic scales, but it is unclear whether macroscopic properties apply to the scale of a cell, where the matrix is composed of a heterogeneous network of fibers. To address this question, we mimicked the contraction of a cell embedded within a fibrous collagen matrix and quantified the resulting displacements.