Strain-enhanced stress relaxation impacts nonlinear elasticity in collagen gels

Nam, Sungmin; Hu, Kenneth H.; Butte, Manish J.; Chaudhuri, Ovijit

doi:10.1073/pnas.1523906113

Cited by 258 publications

(236 citation statements)

References 51 publications

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“…Furthermore, as fibroblasts move, they contract and align ECM fibers depending on their direction of motion (18,19). Recent experimental results also show that a fiber network under strain over a threshold time can change its structural and A B properties in a nonreversible fashion (21). As a result, the fiber network at some point in space can "remember" the average orientation of the particles that have previously traversed close to that location (22).…”

Section: Resultsmentioning

confidence: 99%

On the mechanism of long-range orientational order of fibroblasts

Balagam

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Long-range alignment ordering of fibroblasts have been observed in the vicinity of cancerous tumors and can be recapitulated with in vitro experiments. However, the mechanisms driving their ordering are not understood. Here, we show that local collisiondriven nematic alignment interactions among fibroblasts are insufficient to explain observed long-range alignment. One possibility is that there exists another orientation field coevolving with the cells and reinforcing their alignment. We propose that this field reflects the mechanical cross-talk between the fibroblasts and the underlying fibrous material on which they move. We show that this long-range interaction can give rise to high nematic order and to the observed patterning of the cancer microenvironment.alignment | fibroblasts | long-range order | extracellular matrix | collagen fibers F ibroblasts are spindle-shaped cells that are highly motile and are involved in many critical biological processes, such as wound healing (1, 2). Recently, their major role in shaping the local microenvironment around a growing tumor was shown in numerous studies (3-5). As a result, fibroblasts can affect the ability of cancer cells to metastasize (6-8) and conversely, the ability of the immune system to find and attack those cells (9).An isolated fibroblast moves back and forth on coverslips for over 60 h without significant change of the direction of its major axis (10). Typically, those fibroblasts are in a spindle shape with an aspect ratio from two to five. Apart from steric constraints, fibroblasts barely interact with each other (10). Curiously, imaging of tumor microenvironments often indicates longrange ordering of fibroblasts. This order often takes the form of circumferential alignment of the cells in a region surrounding the cancer cells (11,12). The mechanisms that lead to this ordering are not well-understood.Notably, a similar ordering can be observed for underlying collagen fibers (6, 13). Collagen fibers are the main structural component in the extracellular space of various normal connective tissues and play a significant role in local cancer cell invasion and in metastasis (14). Aligned fibers perpendicular to the boundary cancer cell clusters facilitate local invasions of cancer cells, and conversely, aligned fibers parallel to the tumor boundary may restrict the migration of cancer cells. Furthermore, the circumferential collagen fiber structure has been hypothesized to be responsible for the observed separation between immune and cancer cells (13). Specifically, ex vivo assays indicate that the migration of tumor-killing CD8 + T cells is reduced where dense collagen fibers form conduit-like structures (15). Therefore, understanding the mechanism of the pattern formation of fibroblasts and collagen fibers in the cancer microenvironment is important to strike a balance between constraining cancer cell from invasion and enabling the infiltration of cancer-killing immune cells.In vivo experimental observation of this pattern formation dynamically is techn...

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Section: Resultsmentioning

confidence: 99%

On the mechanism of long-range orientational order of fibroblasts

Balagam

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…We must point out that local fiber recruitment is closely related to the inelastic (history-dependent) bulk response of biopolymer networks (27)(28)(29). In particular, mechanical straining accelerates the dissociation of weak cross-links (30), leading to macroscale plastic deformation of the matrix.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, mechanical straining accelerates the dissociation of weak cross-links (30), leading to macroscale plastic deformation of the matrix. It had been shown that such an effect is more prominent at long timescales (27) and large strains (28,29), whereas it diminishes with the addition of permanent covalent cross-links (28,29). In contrast, networks that only have weak crosslinks are more dissipative and undergo larger stress relaxations (29).…”

Section: Discussionmentioning

confidence: 99%

“…It had been shown that such an effect is more prominent at long timescales (27) and large strains (28,29), whereas it diminishes with the addition of permanent covalent cross-links (28,29). In contrast, networks that only have weak crosslinks are more dissipative and undergo larger stress relaxations (29). In this regard, it is expected that the fiber recruitment index, n, introduced here is a quantitative measure of the plastic response of the ECM, a parameter that has not been considered and appreciated in previous theoretical investigations.…”

Section: Discussionmentioning

confidence: 99%

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Multiscale model predicts increasing focal adhesion size with decreasing stiffness in fibrous matrices

Cao

Ban

Baker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

100

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We describe a multiscale model that incorporates force-dependent mechanical plasticity induced by interfiber cross-link breakage and stiffness-dependent cellular contractility to predict focal adhesion (FA) growth and mechanosensing in fibrous extracellular matrices (ECMs). The model predicts that FA size depends on both the stiffness of ECM and the density of ligands available to form adhesions. Although these two quantities are independent in commonly used hydrogels, contractile cells break cross-links in soft fibrous matrices leading to recruitment of fibers, which increases the ligand density in the vicinity of cells. Consequently, although the size of focal adhesions increases with ECM stiffness in nonfibrous and elastic hydrogels, plasticity of fibrous networks leads to a departure from the well-described positive correlation between stiffness and FA size. We predict a phase diagram that describes nonmonotonic behavior of FA in the space spanned by ECM stiffness and recruitment index, which describes the ability of cells to break cross-links and recruit fibers. The predicted decrease in FA size with increasing ECM stiffness is in excellent agreement with recent observations of cell spreading on electrospun fiber networks with tunable cross-link strengths and mechanics. Our model provides a framework to analyze cell mechanosensing in nonlinear and inelastic ECMs.focal adhesion | mechanosensing | cell contractility | matrix physical remodeling | Rho pathway F ocal adhesions (FAs) are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix (ECM) and cells. FAs play important roles in many cellular behaviors, including proliferation, differentiation, and locomotion, and pathological processes like tumorigenesis and wound healing (1-4). For this reason, intense efforts have been devoted to understanding how key signaling molecules and ECM characteristics influence the formation and growth of FAs. In particular, in vitro studies using elastic hydrogels have shown that forces generated by actomyosin contraction are essential for the stabilization of FAs (5, 6). Numerous observations have convincingly demonstrated that cells form larger FAs as well as develop higher intracellular traction forces on stiffer ECMs (7,8), evidencing the mechanosensitive nature of FAs which has been quantitatively modeled using different (continuum, coarse-grain, and molecular) approaches (9, 10).It must be pointed out that in all of the aforementioned investigations, the substrates considered were flat (2D) and linear elastic. However, in vivo, many cells reside within 3D fibrous scaffolds where the density and diameter of fibers can vary depending on the nature of the tissue (11-13). The local architecture of these fibrous networks may change significantly when cells exert forces on them, leading to phenomena such as nonlinear stiffening, reorientation, and physical remodeling of the ECM (14, 15). Our recent study on cells in synthetic fibrous matrices wit...

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“…Shear stress relaxation tests and creep tests were conducted using an AR-G2 stress-controlled rheometer (TA Instruments, DE). Samples were prepared for rheological analysis following a previously published method 51 . Alginate solution was directly deposited between two plates of the rheometer immediately after crosslinking, but before gelation.…”

Section: Methodsmentioning

confidence: 99%

Mechanical confinement regulates cartilage matrix formation by chondrocytes

et al. 2017

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Cartilage tissue equivalents formed from hydrogels containing chondrocytes could provide a solution for replacing damaged cartilage. Previous approaches have often utilized elastic hydrogels. However, elastic stresses may restrict cartilage matrix formation and alter the chondrocyte phenotype. Here we investigated the use of viscoelastic hydrogels, in which stresses are relaxed over time and which exhibit creep, for 3D culture of chondrocytes. We found that faster relaxation promoted a striking increase in the volume of interconnected cartilage matrix formed by chondrocytes. In slower relaxing gels, restriction of cell volume expansion by elastic stresses led to increased secretion of IL-1β, which in turn drove strong up-regulation of genes associated with cartilage degradation and cell death. As no cell adhesion ligands are presented by the hydrogels, these results reveal cell sensing of cell volume confinement as an adhesion-independent mechanism of mechanotransduction in 3D culture, and highlight stress relaxation as a key design parameter for cartilage tissue engineering.

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Strain-enhanced stress relaxation impacts nonlinear elasticity in collagen gels

Cited by 258 publications

References 51 publications

On the mechanism of long-range orientational order of fibroblasts

On the mechanism of long-range orientational order of fibroblasts

Multiscale model predicts increasing focal adhesion size with decreasing stiffness in fibrous matrices

Mechanical confinement regulates cartilage matrix formation by chondrocytes

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