Whole cell mechanics of contractile fibroblasts: relations between effective cellular and extracellular matrix moduli

Marquez, J. Pablo; Elson, Elliot L.; Genin, Guy M.

doi:10.1098/rsta.2009.0240

Cited by 47 publications

(45 citation statements)

References 70 publications

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“…Fibroblasts remodel their extracellular neighborhood considerably when activated, stiffening and compressing their extracellular matrix (ECM) environment [1, 2, 3, 4, 5, 6, 7, 8, 9]. During remodeling, fibroblasts secrete ECM proteins, including collagens, proteoglycans, glycoproteins, and proteases, and cross-linking proteins and enzymes [1, 2, 3, 4, 10].…”

Section: Introductionmentioning

confidence: 99%

Remodeling by fibroblasts alters the rate-dependent mechanical properties of collagen

et al. 2016

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The ways that fibroblasts remodel their environment is central to wound healing, development of musculoskeletal tissues, and progression of pathologies such as fibrosis. However, the changes that fibroblasts make to the material around them and the mechanical consequences of these changes have proven difficult to quantify, especially in a realistic, viscoelastic three dimensional culture environments, leaving a critical need for quantitative data. Here, we observed the mechanisms and quantified the mechanical effects of fibroblast remodeling in engineered tissue constructs (ETCs) comprised of reconstituted rat tail (type I) collagen and human fibroblast cells. To study the effects of remodeling on tissue mechanics, stress-relaxation tests were performed on ETCs cultured for 24, 48, and 72 hours. ETCs were treated with deoxycholate and tested again to assess the ECM response. Viscoelastic relaxation spectra were obtained using the generalized Maxwell model. Cells exhibited viscoelastic damping at two finite time constants over which the ECM showed little damping, approximately 0.2 s and 10-30 s. Different finite time constants in the range of 1-7000 s were attributed to ECM relaxation. Cells remodeled the ECM to produce a relaxation time constant on the order of 7000 s, and to merge relaxation finite time constants in the 0.5-2 s range into a single time content in the 1 s range. Results shed light on hierarchical deformation mechanisms in tissues, and on pathologies related to collagen relaxation such as diastolic dysfunction.

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Section: Introductionmentioning

confidence: 99%

Remodeling by fibroblasts alters the rate-dependent mechanical properties of collagen

et al. 2016

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“…The cell density in the gels, even after compaction, was relatively low, so we would not expect a percolation of the sample by cells (as discussed in Ref. [51]) but rather a situation in which cells were largely isolated and surrounded by a dense region of compacted collagen [52][53][54]. How these cells affect the failure behavior of the sample is not clear.…”

Section: Discussionmentioning

confidence: 87%

Crack Propagation Versus Fiber Alignment in Collagen Gels: Experiments and Multiscale Simulation

Vanderheiden

Hadi

Barocas

2015

Journal of Biomechanical Engineering

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It is well known that the organization of the fibers constituting a collagenous tissue can affect its failure behavior. Less clear is how that effect can be described computationally so as to predict the failure of a native or engineered tissue under the complex loading conditions that can occur in vivo. Toward the goal of a general predictive strategy, we applied our multiscale model of collagen gel mechanics to the failure of a double-notched gel under tension, comparing the results for aligned and isotropic samples. In both computational and laboratory experiments, we found that the aligned gels were more likely to fail by connecting the two notches than the isotropic gels. For example, when the initial notches were 30% of the sample width (normalized tip-to-edge distance ¼ 0.7), the normalized tip-to-tip distance at which the transition occurred from between-notch failure to across-sample failure shifted from 0.6 to 1.0. When the model predictions for the type of failure event (between the two notches versus across the sample width) were compared to the experimental results, the two were found to be strongly covariant by Fisher's exact test (p < 0.05) for both the aligned and isotropic gels with no fitting parameters. Although the double-notch system is idealized, and the collagen gel system is simpler than a true tissue, it presents a simple model system for studying failure of anisotropic tissues in a controlled setting. The success of the computational model suggests that the multiscale approach, in which the structural complexity is incorporated via changes in the model networks rather than via changes to a constitutive equation, has the potential to predict tissue failure under a wide range of conditions.

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“…Hence, it may be necessary to take this effect into account to obtain an accurate estimate of the modulus of the ECM from measurements of the stiffness of a construct after detergent treatment. FPMs at 3 days of culture and myofibroblast concentrations less than 10 7 cells ml 21 showed an ECM modulus that was nearly indistinguishable from that measured on the CD-treated construct, whereas for FPMs containing approximately 14 Â 10 7 cells ml 21 the difference between the two was about an order of magnitude [140]. Short-term (immediately after rapid loading) and long-term (after 3600 s of relaxation) elastic moduli increased by roughly four orders of magnitude as the cell concentration was increased from about 0.6 Â 10 6 to about 150 Â 10 6 cells ml 21 ( figure 7).…”

Section: Polymer-based Structural Models Can Explain Certain Aspects mentioning

confidence: 92%

Tissue constructs: platforms for basic research and drug discovery

Elson

Genin

2016

Interface Focus.

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The functions, form and mechanical properties of cells are inextricably linked to their extracellular environment. Cells from solid tissues change fundamentally when, isolated from this environment, they are cultured on rigid two-dimensional substrata. These changes limit the significance of mechanical measurements on cells in two-dimensional culture and motivate the development of constructs with cells embedded in three-dimensional matrices that mimic the natural tissue. While measurements of cell mechanics are difficult in natural tissues, they have proven effective in engineered tissue constructs, especially constructs that emphasize specific cell types and their functions, e.g. engineered heart tissues. Tissue constructs developed as models of disease also have been useful as platforms for drug discovery. Underlying the use of tissue constructs as platforms for basic research and drug discovery is integration of multiscale biomaterials measurement and computational modelling to dissect the distinguishable mechanical responses separately of cells and extracellular matrix from measurements on tissue constructs and to quantify the effects of drug treatment on these responses. These methods and their application are the main subjects of this review.

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Whole cell mechanics of contractile fibroblasts: relations between effective cellular and extracellular matrix moduli

Cited by 47 publications

References 70 publications

Remodeling by fibroblasts alters the rate-dependent mechanical properties of collagen

Remodeling by fibroblasts alters the rate-dependent mechanical properties of collagen

Crack Propagation Versus Fiber Alignment in Collagen Gels: Experiments and Multiscale Simulation

Tissue constructs: platforms for basic research and drug discovery

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