Measuring cellular forces using bis-aliphatic hydrazone crosslinked stress-relaxing hydrogels

McKinnon, Daniel D.; Domaille, Dylan W.; Brown, Tobin E.; Kyburz, Kyle A.; Kiyotake, Emi A.; N., J.; Anseth, Kristi S.

doi:10.1039/c4sm01365d

Cited by 71 publications

(114 citation statements)

References 34 publications

(47 reference statements)

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“…The fast gelation is attributed to the rapid formation of dynamic covalent hydrazone linkages between the hydrazine and aldehyde groups at physiological conditions. [25, 35] Generally speaking, a fast gelation rate is desirable to prevent cell sedimentation and to enable homogeneous cell encapsulation within the matrix. [36] To evaluate if the gelation rate is fast enough for 3D cell encapsulation, neonatal bovine chondrocytes were encapsulated within the ELP-HA hydrogel, followed by Live/Dead staining and confocal microscopy imaging.…”

Section: Resultsmentioning

confidence: 99%

“…[25] Tri-Boc hydrazinoacetic acid (0.149 g, 0.37 mmol, 2 equiv. per amine) was dissolved in anhydrous DMF and activated with HATU (0.145 g, 0.37 mmol, 2.0 equiv.)…”

Section: Methodsmentioning

confidence: 99%

“…[24] Previous literature has shown that compared with hydrogels fabricated from stable covalent chemistry, cells encapsulated in hydrogels crosslinked with DCC can locally modify and overcome physical restrictions in 3D to to spread, extend processes, and migrate while maintaining the long-term integrity of the matrix. [25-27] Here DCC crosslinking was used to form ELP-HA hydrogels through dynamic hydrazone bond via the reaction between hydrazine-modified ELP (ELP-HYD) and aldehyde-modified HA (HA-ALD). Hydrogel stiffness can be tuned by controlling the ratio of ALD/HYD and the concentration of ELP-HYD or HA-ALD.…”

Section: Introductionmentioning

confidence: 99%

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Elastin-like protein-hyaluronic acid (ELP-HA) hydrogels with decoupled mechanical and biochemical cues for cartilage regeneration

et al. 2017

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Hyaluronic acid (HA) is a major component of cartilage extracellular matrix and is an attractive material for use as 3D injectable matrices for cartilage regeneration. While previous studies have shown the promise of HA-based hydrogels to support cell-based cartilage formation, varying HA concentration generally led to simultaneous changes in both biochemical cues and stiffness. How cells respond to the change of biochemical content of HA remains largely unknown. Here we report an adaptable elastin-like protein-hyaluronic acid (ELP-HA) hydrogel platform using dynamic covalent chemistry, which allows varyiation of HA concentration without affecting matrix stiffness. ELP-HA hydrogels were created through dynamic hydrazone bonds via the reaction between hydrazine-modified ELP (ELP-HYD) and aldehyde-modified HA (HA-ALD). By tuning the stoichiometric ratio of aldehyde groups to hydrazine groups while maintaining ELP-HYD concentration constant, hydrogels with variable HA concentration (1.5%, 3%, or 5%) (w/v) were fabricated with comparable stiffness. To evaluate the effects of HA concentration on cell-based cartilage regeneration, chondrocytes were encapsulated within ELP-HA hydrogels with varying HA concentration. Increasing HA concentration led to a dose-dependent increase in cartilage-marker gene expression and enhanced sGAG deposition while minimizing undesirable fibrocartilage phenotype. The use of adaptable protein hydrogels formed via dynamic covalent chemistry may be broadly applicable as 3D scaffolds with decoupled niche properties to guide other desirable cell fates and tissue repair.

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Section: Resultsmentioning

confidence: 99%

“…[25] Tri-Boc hydrazinoacetic acid (0.149 g, 0.37 mmol, 2 equiv. per amine) was dissolved in anhydrous DMF and activated with HATU (0.145 g, 0.37 mmol, 2.0 equiv.)…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Elastin-like protein-hyaluronic acid (ELP-HA) hydrogels with decoupled mechanical and biochemical cues for cartilage regeneration

et al. 2017

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“…Mismatch between these factors can lead to a non-supportive gel or a gel that essentially behaves as elastic. Second, the amount of cellular spreading observed in these types of gel can be very different depending on the cell type: for example, neurons show extensive axon extension 91,114 , but the spreading of mesenchymal stem cells is limited 68 . Potential reasons for this include the nature of cellular extensions (whether the cells are pushing or pulling on the matrix), and the architecture and connectivity of the hydrogel itself.…”

Section: Reversible Crosslinks For 3d Hydrogelsmentioning

confidence: 99%

The design of reversible hydrogels to capture extracellular matrix dynamics

2016

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The extracellular matrix (ECM) is a dynamic environment that constantly provides physical and chemical cues to embedded cells. Much progress has been made in engineering hydrogels that can mimic the ECM, but hydrogel properties are, in general, static. To recapitulate the dynamic nature of the ECM, many reversible chemistries have been incorporated into hydrogels to regulate cell spreading, biochemical ligand presentation and matrix mechanics. For example, emerging trends include the use of molecular photoswitches or biomolecule hybridization to control polymer chain conformation, thereby enabling the modulation of the hydrogel between two states on demand. In addition, many non-covalent, dynamic chemical bonds have found increasing use as hydrogel crosslinkers or tethers for cell signalling molecules. These reversible chemistries will provide greater temporal control of adhered cell behaviour, and they allow for more advanced in vitro models and tissue-engineering scaffolds to direct cell fate.

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“…A gentle hydrazone bond crosslinking method was recently reported to synthesize HA hydrogels by reacting HA aldehyde with HA adipic dihydrazide (Oommen et al, 2013). However, macromolecular aldehydes used for the preparation of hydrogels based on hydrazone bond crosslinking still show cytotoxicity and might hinder the migration of cells, although they display better biocompatibility than small molecular aldehydes (Mckinnon et al, 2014). Significantly, a recent study indicates that the hydrogels formed via ketone-hydrazide crosslinking have better biocompatibility than those formed through aldehyde-hydrazide crosslinking (Patenaude, & Hoare, 2014).…”

Section: Introductionmentioning

confidence: 97%

Hyaluronic acid hydrogel scaffolds with a triple degradation behavior for bone tissue engineering

Cui

Qian

Liu

et al. 2015

Carbohydrate Polymers

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Measuring cellular forces using bis-aliphatic hydrazone crosslinked stress-relaxing hydrogels

Abstract: A covalently adaptable hydrazone-crosslinked PEG hydrogel is used to measure the force of extension exerted by motor neurites.

Cited by 71 publications

References 34 publications

Elastin-like protein-hyaluronic acid (ELP-HA) hydrogels with decoupled mechanical and biochemical cues for cartilage regeneration

Elastin-like protein-hyaluronic acid (ELP-HA) hydrogels with decoupled mechanical and biochemical cues for cartilage regeneration

The design of reversible hydrogels to capture extracellular matrix dynamics

Hyaluronic acid hydrogel scaffolds with a triple degradation behavior for bone tissue engineering

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