Dually degradable click hydrogels for controlled degradation and protein release

Kharkar, Prathamesh M.; Kloxin, April M.; Kiick, Kristi L.

doi:10.1039/c4tb00496e

Cited by 63 publications

(95 citation statements)

References 65 publications

(91 reference statements)

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“…The nucleophilicity of the thiolate species can be reduced by employing acidic buffer conditions, which significantly affects the Michael-type addition reaction kinetics. [36–38] Hence, the hydrogels were prepared under slightly acidic pH to limit the rate of gelation sufficiently to permit the production of uniform and homogeneous hydrogels. The storage moduli of swollen hydrogel discs (diameter = 4.6 mm, thickness = 1.8 mm) were also measured via oscillatory rheometry in the linear viscoelastic regime after preparing the hydrogels.…”

Section: Resultsmentioning

confidence: 99%

Decreasing matrix modulus of PEG hydrogels induces a vascular phenotype in human cord blood stem cells

et al. 2015

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Adult and congenital cardiovascular diseases are significant health problems that are often managed using surgery. Bypass grafting is a principal therapy, but grafts fail at high rates due to hyperplasia, fibrosis, and atherosclerosis. Biocompatible, cellularized materials that attenuate these complications and encourage healthy microvascularization could reduce graft failure, but an improved understanding of biomaterial effects on human stem cells is needed to reach clinical utility. Our group investigates stem-cell-loaded biomaterials for placement along the adventitia of at-risk vessels and grafts. Here, the effects of substrate modulus on human CD34+ stem cells from umbilical cord blood were evaluated. Cells were isolated by immunomagnetic separation and encapsulated in 3, 4, and 6 weight% PEG hydrogels containing 0.032% gelatin and 0.0044% fibronectin. Gels reached moduli of 0.34, 4.5, and 9.1 kPa. Cell viability approached 100%. Cell morphologies appeared similar across gels, but proliferation was significantly lower in 6 wt% gels. Expression profiling using stem cell signaling arrays indicated enhanced self-renewal and differentiation into vascular endothelium among cells in the lower weight percent gels. Thus, modulus was associated with cell proliferation and function. Gels with moduli in the low kilopascal range may be useful in stimulating cell engraftment and microvascularization of graft adventitia.

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Section: Resultsmentioning

confidence: 99%

Decreasing matrix modulus of PEG hydrogels induces a vascular phenotype in human cord blood stem cells

et al. 2015

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“…The degradation kinetics of mercatophenyl-based thiols in response to reducing microenvironments have been investigated previously by Kiick and coworkers. 30, 31, 37 Since the concentration of glutathione is elevated in carcinoma tissues compared to surrounding healthy tissues, 49, 50 the incorporation of aryl-thiol-based linkages that cleave in response to glutathione may provide increased release of therapeutics in carcinoma tissues and thus provide higher therapeutic efficacy. In addition, both macromers (PEG-4-PD-MI and PEG-4-arylSH) contain an ester linkage allowing for hydrolysis of the resulting polymeric network under aqueous conditions ultimately leading to complete degradation of the hydrogel in aqueous environments.…”

Section: Design and Synthesis Of Building Blocks With Different Degramentioning

confidence: 99%

“…In recent years, a few groups including ours have developed dually degradable hydrogels for modulating drug release profiles based on degradation kinetics. 36, 37 While these materials allow microenvironment-responsive release, hydrogel-based drug carriers that degrade in response to multiple triggers, both exogenous (e.g., light) and endogenous (e.g., reducing and aqueous microenvironments), would allow for sustained and complex therapeutic release profiles with spatial and temporal control post fabrication. Several pioneering studies have demonstrated the synthesis of different water-soluble photodegradable macromers with various reactive functionalities, including acrylates, azides, alcohols, amines, halides, and carboxylic acids.…”

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Design of thiol- and light-sensitive degradable hydrogels using Michael-type addition reactions

2015

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Injectable depots that respond to exogenous and endogenous stimuli present an attractive strategy for tunable, patient-specific drug delivery. Here, the design of injectable and multimodal degradable hydrogels that respond to externally applied light and physiological stimuli, specifically aqueous and reducing microenvironments, is reported. Rapid hydrogel formation was achieved using a thiol-maleimide click reaction between multifunctional poly(ethylene glycol) macromers. Hydrogel degradation kinetics in response to externally applied cytocompatible light, reducing conditions, and hydrolysis were characterized, and degradation of the gel was controlled over multiple time scales from seconds to days. Further, tailored release of an encapsulated model cargo, fluorescent nanobeads, was demonstrated.

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“…Moreover, these injectable materials can be engineered to display tunable biodegradation under different environmental conditions depending on the chemistry used to form the cross-links. 9,11,12 However, injectable hydrogels are often limited by a relatively low elastic modulus, [13][14][15][16] limiting their utility in applications demanding at least a degree of mechanical strength (e.g. engineering of stiffer tissues such as cartilage, 17 implantation in high-shear environments, 18 or spinal applications 19 ).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Mechanical Properties in Cellulose Nanocrystal–Poly(oligoethylene glycol methacrylate) Injectable Nanocomposite Hydrogels through Control of Physical and Chemical Cross-Linking

2016

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While injectable hydrogels have several advantages in the context of biomedical use, their generally weak mechanical properties often limit their applications. Herein we describe in situgelling nanocomposite hydrogels based on poly(oligoethylene glycol methacrylate) (POEGMA) and rigid rod-like cellulose nanocrystals (CNCs) that can overcome this challenge. By physically incorporating CNCs into hydrazone cross-linked POEGMA hydrogels, macroscopic properties including gelation rate, swelling kinetics, mechanical properties, and hydrogel stability can be readily tailored. Strong adsorption of aldehyde and hydrazide modified POEGMA precursor polymers onto the surface of CNCs promotes uniform dispersion of CNCs within the hydrogel, imparts physical cross-links throughout the network, and significantly improves mechanical strength overall, as demonstrated by quartz crystal microbalance gravimetry and rheometry.When POEGMA hydrogels containing mixtures of long and short ethylene oxide side chain precursor polymers were prepared, transmission electron microscopy reveals that phase segregation occurs with CNCs hypothesized to preferentially locate within the stronger adsorbing short side chain polymer domains. Incorporating as little as 5 wt % CNCs results in dramatic enhancements in mechanical properties (up to 35-fold increases in storage modulus) coupled with faster gelation rates, decreased swelling ratios, and increased stability versus hydrolysis. Furthermore, cell viability can be maintained within 3D culture using these hydrogels independent of the CNC content. These properties collectively make POEGMA-CNC

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Dually degradable click hydrogels for controlled degradation and protein release

Abstract: Crosslinks that can undergo click bond cleavage and ester hydrolysis were incorporated to design glutathione-sensitive, dually degradable hydrogels for degradation-mediated, controlled release of cargo molecules.

Cited by 63 publications

References 65 publications

Decreasing matrix modulus of PEG hydrogels induces a vascular phenotype in human cord blood stem cells

Decreasing matrix modulus of PEG hydrogels induces a vascular phenotype in human cord blood stem cells

Design of thiol- and light-sensitive degradable hydrogels using Michael-type addition reactions

Enhanced Mechanical Properties in Cellulose Nanocrystal–Poly(oligoethylene glycol methacrylate) Injectable Nanocomposite Hydrogels through Control of Physical and Chemical Cross-Linking

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