Stiffness-Modulated Water Retention and Neovascularization of Dermal Fibroblast-Encapsulating Collagen Gel

Abstract

There is increasing evidence that matrix stiffness modulates various phenotypic activities of cells surrounded by a three-dimensional (3D) matrix. These findings suggest that matrix stiffness can also regulate dermal fibroblasts activities to remodel, repair, and recreate skin dermis, but this has not yet been systematically demonstrated to date. This study examines the effects of matrix rigidity on the morphology, growth rates, and glycosaminoglycan (GAG) production of dermal fibroblasts cultured in collagen-based hydrogels with controlled elastic moduli. The elastic moduli (E) of collagen hydrogels were increased from 0.7 to 1.6 and 2.2 kPa by chemically cross-linking collagen fibrils with poly(ethylene glycol) disuccinimidylester. Increasing E of the hydrogel led to decreases in cellular spreading, nuclear aspect ratio, and growth rate. In contrast, the cellular GAG production level was elevated by increasing E from 0.7 to 1.6 kPa. The larger accumulation of GAG in the stiffer hydrogel led to increased water retention during exposure to air, as confirmed with magnetic resonance imaging. Additionally, in a chicken chorioallantoic membrane, a cell-encapsulating hydrogel with E of 1.6 kPa created dermis-like tissue with larger amount of GAG and density of blood vessels, while a cell-hydrogel construct with E of 0.7 kPa generated scar-like tissue. Overall, the results of this study will be highly useful for designing advanced tissue engineering scaffolds that can enhance the quality of a wide array of regenerated tissues including skin.

Palladin Mediates Stiffness-Induced Fibroblast Activation in the Tumor Microenvironment

“…PEG-diNHS can cross-link collagen-I fibrils by forming amide bonds to tether collagen molecules together, mimicking the physiological cross-links formed in vivo (23). These collagen-I PEG-diNHS hydrogels have been previously used in studies of tumor spheroid formation and in tissue engineering, and show good biocompatibility (24,25).…”

pH responsive gels that deliver anti-inflammatory drugs

“…216 However, the hypodermal adipose layer of skin, which is often exposed upon injury, was reported to have a moduli under 10 kPa. 217,218 In addition, dermal implants with lower moduli (0.7 kPa) have been found to favor dermal fibroblasts ingrowth, 219 which is essential for wound healing. The moduli of the chitosan gels fabricated here were found to be adjustable through the different gelation methods, as expected since the mechanical strength of hydrogels with the same backbone mainly depends on the crosslinking density.…”

“…This may result from the decreased mechanical properties 219 of the hydrogel compared to TCP. Human dermal fibroblasts are known to preferentially attach to stiffer substrates and have a higher proliferation rate on those substrates, 233 which is in line with our observations.…”

Augmenting endogenous repair of soft tissues with nanofibre scaffolds

“…Despite the well-accepted role that substrate stiffness plays in fibroblast biology, to date, this has seen only limited translation into the tissue engineering arena [192][193][194]. Unfortunately, with many of the methodologies used it is often difficult to separate the influence of matrix stiffness from the concurrent changes in porosity and surface chemistry.…”