Influence of the stiffness of three-dimensional alginate/collagen-I interpenetrating networks on fibroblast biology

Cunha, Cristiana Branco da; Klumpers, Darinka D.; Li, Aileen W.; Koshy, Sandeep T.; Weaver, James C.; Chaudhuri, Ovijit; Granja, Pedro L.; Mooney, David J.

doi:10.1016/j.biomaterials.2014.06.047

Cited by 237 publications

(146 citation statements)

References 60 publications

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“…As the gels were stiffened, the cells' ability to remodel the matrix was impaired and the cells were predominately rounded, either because the matrix was too stiff to deform or because degradation sites were blocked by the introduction of additional cross-links (19). Using alginate-collagen I interpenetrating networks, a similar inverse relationship between cell elongation and matrix stiffness has been observed with both static and dynamically cross-linked systems (29,30). However, it is still unclear if the inhibition of cell elongation is due to matrix stiffness per se, or because the high cross-link density blocks degradation sites.…”

Section: Resultsmentioning

confidence: 50%

“…Later, cell-mediated degradation was demonstrated to be necessary for cell elongation within 3D covalently cross-linked gels, independent of matrix stiffness (19). However, recently matrix stiffness was shown to dictate cell morphology in 3D alginate-collagen I interpenetrating networks (29). Thus, the extent to which matrix stiffness or degradability regulates cell morphology in 3D environments is unclear.…”

Section: Resultsmentioning

confidence: 99%

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Dynamic phototuning of 3D hydrogel stiffness

Stowers

Allen

Suggs

2015

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

269

219

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Hydrogels are widely used as in vitro culture models to mimic 3D cellular microenvironments. The stiffness of the extracellular matrix is known to influence cell phenotype, inspiring work toward unraveling the role of stiffness on cell behavior using hydrogels. However, in many biological processes such as embryonic development, wound healing, and tumorigenesis, the microenvironment is highly dynamic, leading to changes in matrix stiffness over a broad range of timescales. To recapitulate dynamic microenvironments, a hydrogel with temporally tunable stiffness is needed. Here, we present a system in which alginate gel stiffness can be temporally modulated by light-triggered release of calcium or a chelator from liposomes. Others have shown softening via photodegradation or stiffening via secondary cross-linking; however, our system is capable of both dynamic stiffening and softening. Dynamic modulation of stiffness can be induced at least 14 d after gelation and can be spatially controlled to produce gradients and patterns. We use this system to investigate the regulation of fibroblast morphology by stiffness in both nondegradable gels and gels with degradable elements. Interestingly, stiffening inhibits fibroblast spreading through either mesenchymal or amoeboid migration modes. We demonstrate this technology can be translated in vivo by using deeply penetrating near-infrared light for transdermal stiffness modulation, enabling external control of gel stiffness. Temporal modulation of hydrogel stiffness is a powerful tool that will enable investigation of the role that dynamic microenvironments play in biological processes both in vitro and in well-controlled in vivo experiments.hydrogel | dynamic microenvironment | cell spreading | transdermal

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Section: Resultsmentioning

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Dynamic phototuning of 3D hydrogel stiffness

Stowers

Allen

Suggs

2015

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

269

219

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“…In relation to this finding, it is interesting to note that fibroblasts cultured in a 3D matrix of enhanced stiffness in a wound healing context express greater levels of IL10. 62 Taken together, our data on IL6 and IL10 suggest that chondrocytes in a 3D environment have an overall anti-inflammatory phenotype.…”

supporting

confidence: 54%

Chondrocyte responses to neurovascular peptides, cytokines, and a 3D environment: focus on ADAMs

Bevan¹,

Baker²,

Goldring

et al. 2016

MNM

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Chondrocyte exposure to inflammatory stimuli in several arthritic conditions, including osteoarthritis, results in the well-characterized induction of extracellular matrix degrading proteinases, notably members of a disintegrin and metalloproteinase (ADAM) with thrombospondin domains and matrix metalloproteinase families. Here we briefly review the less-studied ADAM family of proteinases in chondrocyte and cartilage biology. Following damage, cartilage is exposed to neurovascular peptides, and in this study we hypothesized that substance P and bradykinin, alongside inflammatory cytokines, may modulate chondrocyte steady-state messenger RNA levels for the proteolytic ADAM family members as well as for key cytokines and neuropeptides. We compared chondrocytes cultured in both two-dimensional and three-dimensional (3D) environments and found that 3D culture generally resulted in repression of expression of the genes under investigation, with the exception of anti-inflammatory interleukin 10 which was markedly upregulated in a 3D environment. Substance P and bradykinin had little effect on ADAM family expression, but further investigation revealed that a combination of bradykinin and cytokines led to enhanced expression of ADAM28 and a synergistic upregulation of interleukin 6, also observed under hypoxic conditions. Overall these data reveal wider chondrocyte responses to neurovascular peptides which may have an impact in an osteoarthritis context.

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“…29-34 For instance, dermal fibroblasts exhibited upregulated mediators of inflammation when encapsulated in stiff hydrogels (1200 Pa) compared to soft hydrogels (50 Pa). 29 In another example, MMP activity of encapsulated hMSCs increased with stiffness when comparing soft (200 Pa), medium (500 Pa), and stiff (1200 Pa) hydrogels. 34 This range of moduli for 3D cell behaviors is similar to that shown by the photoresponsive gels developed here, and current efforts are focused on tuning the parameters of this system to study activation of fibroblasts in 3D.…”

Section: Resultsmentioning

confidence: 99%

Photoresponsive Elastic Properties of Azobenzene-Containing Poly(ethylene-glycol)-Based Hydrogels

et al. 2015

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The elastic modulus of the extracellular matrix is a dynamic property that changes during various biological processes, such as disease progression or wound healing. Most cell culture platforms, however, have traditionally exhibited static properties, making it necessary to replate cells to study the effects of different elastic moduli on cell phenotype. Recently, much progress has been made in the development of substrates with mechanisms for either increasing or decreasing stiffness in situ, but there are fewer examples of substrates that can both stiffen and soften, which may be important for simulating the effects of repeated ECM injury and resolution. In the work presented here, poly(ethylene glycol)-based hydrogels reversibly stiffen and soften with multiple light stimuli via photoisomerization of an azobenzene-containing crosslinker. Upon irradiation with cytocompatible doses of 365 nm light (10 mW/cm2, 5 min), isomerization to the azobenzene cis configuration leads to a softening of the hydrogel up to 100-200 Pa (shear storage modulus, G’). This change in gel properties is maintained over a timescale of several hours due to the long half-life of the cis isomer. The initial modulus of the gel can be recovered upon irradiation with similar doses of visible light. With applications in mechanobiology in mind, cytocompatibility with a mechanoresponsive primary cell type is demonstrated. Porcine aortic valvular interstitial cells were encapsulated in the developed hydrogels and shown to exhibit high levels of survival, as well as a spread morphology. The developed hydrogels enable a route to the noninvasive control of substrate modulus independent of changes in the chemical composition or network connectivity, allowing for investigations of the effect of dynamic matrix stiffness on adhered cell behavior.

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Influence of the stiffness of three-dimensional alginate/collagen-I interpenetrating networks on fibroblast biology

Cited by 237 publications

References 60 publications

Dynamic phototuning of 3D hydrogel stiffness

Dynamic phototuning of 3D hydrogel stiffness

Chondrocyte responses to neurovascular peptides, cytokines, and a 3D environment: focus on ADAMs

Photoresponsive Elastic Properties of Azobenzene-Containing Poly(ethylene-glycol)-Based Hydrogels

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