Stress relaxing hyaluronic acid-collagen hydrogels promote cell spreading, fiber remodeling, and focal adhesion formation in 3D cell culture

Lou, Junzhe; Stowers, R. Steven; Nam, Sungmin; Xia, Yan; Chaudhuri, Ovijit

doi:10.1016/j.biomaterials.2017.11.004

Cited by 423 publications

(364 citation statements)

References 48 publications

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“…However, the fiber assembly was largely rescued by decreasing the w/v % of NbTz, which delays the covalent crosslinking gelation time. In agreement with our results, static covalent crosslinking has previously been reported to be incompatible with collagen self-assembly into fibrillar structures [17]. The sequential ionic and covalent crosslinking of aECM here is analogous to how collagen is covalently modified in tissues.…”

Section: Discussionsupporting

confidence: 91%

“…In addition, the effects of time-dependent mechanical properties, such as stress relaxation, on cell behavior have also been investigated on two dimensional substrates by using materials formed via non-covalent crosslinking [9, 10]. A variety of naturally-derived and synthetic polymers are used as three-dimensional cell culture substrates, typically following covalent crosslinking by photoinitiated- [11, 12], free-radical- [13], click- [14–16], or dynamic [17, 18] mechanisms to form substrates with tunable stiffness and viscoelasticity. However, changes in the weight percent (% w/v) of the polymers or degree of crosslinking may also affect the resulting polymer mesh size and transport properties of macromolecules.…”

Section: Introductionmentioning

confidence: 99%

“…Fibrillar collagen can be challenging to incorporate and maintain in three-dimensional matrices, because its fibers can be inhibited or altered by changes in collagen content and matrix crosslinking mode and density. Collagen type I can form interpenetrating networks with hydrogels formed with non-covalently [20] or dynamic covalently [17] crosslinked polymers, as well as methacrylated-gelatin [21]. However, none of these studies have reported that collagen fiber architecture can be maintained independent of matrix viscoelasticity.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sequential modes of crosslinking tune viscoelasticity of cell-instructive hydrogels

2019

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Materials that can mimic the fibrillar architecture of native extracellular matrix (ECM) while allowing for independent regulation of viscoelastic properties may serve as ideal, artificial ECM (aECM) to regulate cell functions. Here we describe an interpenetrating network of click-functionalized alginate, crosslinked with a combination of ionic and covalent crosslinking, and fibrillar collagen type I. Varying the mode and magnitude of crosslinking enables tunable stiffness and viscoelasticity, while altering neither the hydrogel’s microscale architecture nor diffusional transport of molecules with molecular weight relevant to typical nutrients. Further, appropriately timing sequential ionic and covalent crosslinking permits self-assembly of collagen into fibrillar structures within the network. Culture of human mesenchymal stem cells (MSCs) in this mechanically-tunable ECM system revealed that MSC expression of immunomodulatory markers is differentially impacted by the viscoelasticity and stiffness of the matrix. Together, these results describe and validate a novel material system for investigating how viscoelastic mechanical properties of ECM regulate cellular behavior.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sequential modes of crosslinking tune viscoelasticity of cell-instructive hydrogels

2019

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“…Therefore, synthetic materials with a broader range of fast matrix relaxation kinetics may allow one to probe more connections between time‐dependent material mechanics and cell behavior. Furthermore, based on findings from previous studies,6, 7, 8, 9, 14 it is reasoned that increasing the rate of matrix relaxation better promotes cell–matrix interactions and potentially amplifies cellular responses to the viscoelastic properties of synthetic ECMs.…”

mentioning

confidence: 99%

Adaptable Fast Relaxing Boronate‐Based Hydrogels for Probing Cell–Matrix Interactions

et al. 2018

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Hydrogels with tunable viscoelasticity hold promise as materials that can recapitulate many dynamic mechanical properties found in native tissues. Here, covalent adaptable boronate bonds are exploited to prepare hydrogels that exhibit fast relaxation, with relaxation time constants on the order of seconds or less, but are stable for long‐term cell culture and are cytocompatible for 3D cell encapsulation. Using human mesenchymal stem cells (hMSC) as a model, the fast relaxation matrix mechanics are found to promote cell–matrix interactions, leading to spreading and an increase in nuclear volume, and induce yes‐associated protein/PDZ binding domain nuclear localization at longer times. All of these effects are exclusively based on the hMSCs' ability to physically remodel their surrounding microenvironment. Given the increasingly recognized importance of viscoelasticity in controlling cell function and fate, it is expected that the synthetic strategies and material platform presented should provide a useful system to study mechanotransduction on and within viscoelastic environments and explore many questions related to matrix biology.

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“…Chaudhuri et al (Chaudhuri et al, , ) demonstrated the importance of stress relaxation time in modulating not only spreading but also differentiation of mesenchymal stem cells (MSCs), and McKinnon et al explored the impact of stress relaxation time on encapsulated myoblasts in a PEG‐based gel, where the relaxation time was controlled via adaptable covalent cross‐linking chemistry (McKinnon, Domaille, Cha, & Anseth, ). Somewhat similar to our multicomponent gels, recent work by Lou, Stowers, Nam, Xia, and Chaudhuri () has focused on spreading and functionality of MSCs encapsulated in interpenetrating networks (IPNs) comprising collagen and hyaluronic acid, where the stress relaxation profile of the gels is controlled via dynamic crosslinks; these are compared to MSCs encapsulated in hyaluronic acid gels with static crosslinks. Although our focus is on materials for wound healing applications, the presence of temperature‐dependent plasticity in our alginate‐F127 materials may suggest strategies for creating similar biomaterials for cell delivery and regenerative medicine applications with a temperature‐dependent stress relaxation response.…”

Section: Resultsmentioning

confidence: 96%

Temperature‐dependent structure and compressive mechanical behavior of alginate/polyethylene oxide–poly(propylene oxide)–poly(ethylene oxide) hydrogels

2019

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We report the structural and mechanical behavior of multicomponent hydrogels comprising the commercial poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) block copolymer F127 and alginate. Previous studies on this system have shown thermoreversible behavior in shear rheology. Here we explore the properties of these materials under compression and large deformations, relevant to applications such as wound dressings that require mechanical robustness. For gels with lower F127 concentration, we find that the stiffness of the gels can be ascribed to the alginate network, and that the Young's modulus and fracture stress do not strongly depend on temperatures. However, for gels with an F127 concentration of 30 wt %, the Young's modulus is enhanced at higher temperatures. Under large deformations, the fracture stress and fracture strain of the materials can be independently varied using the alginate and F127 concentrations, respectively; without the trade‐off in these properties that is often observed in rigid polymer networks. Small‐angle X‐ray scattering shows a power‐law dependence scattering intensity on q arising from the alginate network and scattering peaks consistent with rearranging micelles. For gels with lower F127 concentrations, we find a disordered–body‐centered cubic (BCC)‐face‐centered cubic (FCC) progression of states with temperature, and a BCC/FCC mixture for gels with higher F127 concentrations.

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Stress relaxing hyaluronic acid-collagen hydrogels promote cell spreading, fiber remodeling, and focal adhesion formation in 3D cell culture

Cited by 423 publications

References 48 publications

Sequential modes of crosslinking tune viscoelasticity of cell-instructive hydrogels

Sequential modes of crosslinking tune viscoelasticity of cell-instructive hydrogels

Adaptable Fast Relaxing Boronate‐Based Hydrogels for Probing Cell–Matrix Interactions

Temperature‐dependent structure and compressive mechanical behavior of alginate/polyethylene oxide–poly(propylene oxide)–poly(ethylene oxide) hydrogels

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