Modification of polysaccharides via thiol‐ene chemistry: A versatile route to functional biomaterials

We present herein a mild and rapid method for the modular functionalization of polysaccharides. Several ene‐functional charged and neutral polysaccharides, that is, hyaluronic acid and dextran, were prepared by esterification of the hydroxyl groups with pentenoic anhydride. The modified polysaccharides were then reacted with six model mercaptans under UV light, leading to linear polymers modified with hydrophobic groups, peptides, or oligosaccharides as well as chemical hydrogels. The thiol‐ene coupling reactions were found to proceed with high efficiency in short reaction times and with nearly no degradation of the polysaccharide backbone. Moreover, they were carried out in aqueous media, without the use of any metal catalysts, enhancing the attractive nature of this process. Notably, we investigated whether it is feasible to prepare cell‐responsive hydrogels by sequential bioconjugation and cross‐linking of the polysaccharide backbone with a bioactive peptide and poly(ethylene glycol)‐dithiol, respectively. All together, these results highlight the potential of this coupling strategy for the modular functionalization of polysaccharides under click chemistry‐like conditions. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Baked hydrogel from corn starch and chitosan blends cross‐linked by citric acid: Preparation and properties

Citric acid (CA)–modified hydrogels from corn starch and chitosan were synthesized using a semidry condition. This strategy has great benefits of friendly environment because of the absence of organic solvents and compatible with the industrial process. The hydrogel blends were prepared with starch/chitosan ratios of 75/25, 50/50, and 25/75. The thermal stability, morphology, water absorption, weight loss in water, and methylene blue absorption were determined. Multi‐carboxyl structure of CA could result in a chemical cross‐linking reaction between starch, chitosan, and CA. The cross‐linking reaction between free hydroxyl groups of starch, amino groups of chitosan, and carboxyl groups of CA has been confirmed by attenuated total reflectance infrared (ATR‐IR) spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) analysis. The water absorption properties of CA‐modified hydrogel blends were increased significantly compared with the native starch and chitosan. Moreover, the hydrogel blends modified with CA showed good water resistance and gel content. The morphology study confirmed the complete chemical cross‐linking and porous structure of hydrogel blends. The hydrogel blend with the starch/chitosan ratio of 50/50 presented powerful absorption of methylene blue as well as chemical cross‐linking reaction and dense structure. In sum, the hydrogel blend comprising 50% starch and 50% chitosan has the potential to be applied for water maintaining at large areas, for example, in agriculture.     

Unravelling a Direct Role for Polysaccharide β‐Strands in the Higher Order Structure of Physical Hydrogels

The mechanical properties of agarose‐derived hydrogels depend on the scaffolding of the polysaccharide network. To identify and quantify such higher order structure, we applied Raman optical activity (ROA)—a spectroscopic technique that is highly sensitive toward carbohydrates—on native agarose and chemically modified agarose in the gel phase for the first time. By spectral global fitting, we isolated features that change as a function of backbone carboxylation (28, 40, 50, 60, 80, and 93 %) from other features that remain unchanged. We assigned these spectral features by comparison to ROA spectra calculated for different oligomer models. We found a 60:40 ratio of double‐ and single‐stranded α‐helix in the highly rigid hydrogel of native agarose, while the considerably softer hydrogels made from carboxylated agarose use a scaffold of unpaired β‐strands.     

Stimuli‐Responsive Polypeptide‐Based Supramolecular Hydrogels Mediated by Ca2+ Ion Cross‐Linking

Hydrogels cross‐linked with metal ions (e.g., Ca²⁺) represent a promising class of bioinspired materials for a wide range of biomedical applications. Herein, we report a facile approach to obtain cross‐linked stimuli‐responsive supramolecular polypeptide hydrogels. The hydrogel is prepared by statistical/block copoly(L‐glutamate)s based copolymers cross‐linked with calcium ions. The incorporation of both oligo(ethylene glycol) (OEG) and glutamic acid residues in the polymer offers thermal‐responsive property and cooperative binding sites with Ca²⁺ ions simultaneously. We present a systematic study of the influence of calcium ions on the gelation behaviors of these copolymers. It is observed that the addition of calcium ions induces the formation of hydrogels. Increasing the concentration of Ca²⁺ ions can significantly enhance the gelation ability of the samples as indicated by increased storage modulus and decreased sol‐to‐gel transition temperature (T_sol‐gel). We further demonstrate that the influence of monomer distribution on the gelation behavior is trivial, which is possibly due to similar morphology of the self‐assemblies. The obtained hydrogels exhibit thermal‐responsive gelation behavior mediated by ion cross‐linking, which enables them to be ideal smart hydrogel system for many applications.     

Self‐Healing Supramolecular Hydrogels for Tissue Engineering Applications

Self‐healing supramolecular hydrogels have emerged as a novel class of biomaterials that combine hydrogels with supramolecular chemistry to develop highly functional biomaterials with advantages including native tissue mimicry, biocompatibility, and injectability. These properties are endowed by the reversibly cross‐linked polymer network of the hydrogel. These hydrogels have great potential for realizing yet to be clinically translated tissue engineering therapies. This review presents methods of self‐healing supramolecular hydrogel formation and their uses in tissue engineering as well as future perspectives.     

Synthesis,characterization and evaluation of semi‐IPN hydrogels consisted of poly(methacrylic acid) and guar gum for colon‐specific drug delivery

The semi‐IPN hydrogels consisting of poly(methacrylic acid) and guar gum (GG) are prepared at room temperature using water as solvent. 5‐aminosalicylic acid (5‐ASA) is entrapped in the hydrogel in the synthesis of hydrogel and all entrapment efficiencies are found above 85%. The hydrogel shows excellent pH‐sensitivity. It exhibited minimum swelling in an acidic pH medium through the formation of a complex hydrogen‐bonded structure and maximal swelling due to the electrostatic repulsion due to the ionization of the carboxylic groups in pH 7.4 medium. The degradation in vitro shows that the degree of degradation (R%) depended on the concentration of cross‐linking agent and content of GG. The hydrogel shows a minimum release of 5‐ASA due to the complex hydrogen bonded structure of the hydrogels in the medium of pH 2.2. The enzymatic degradation of hydrogels by cecal bacteria can accelerate the release of 5‐ASA entrapped in the hydrogel in pH 7.4 medium. Copyright © 2007 John Wiley & Sons, Ltd.     

Property and Application of BACy‐Based Functional Hydrogels

Conventional polyacrylamide hydrogels prepared from the free radical polymerization between acrylamide and N,N′‐methylenebisacrylamide (NMBA) have been frequently used in the biochemical technique like the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS‐PAGE) to resolve protein mixtures. In this study, we have prepared an alternative polyacrylamide hydrogel from the cross‐linking of acrylamide and N,N′‐bisacrylylcystamine (BACy). In addition, we have compared the BACy‐based hydrogel with the NMBA‐based polyacrylamide hydrogel for their physical properties such as swelling ratio, shear modulus, crosslink density and morphology. Moreover, we further determined whether BACy‐based polyacrylamide hydrogel could be applied to SDS‐PAGE and proteomics research. The results showed that this type of hydrogel is capable of separating proteins and facilitates further in‐gel protein digestion and the following protein identifications by mass spectrometry. In summary, our study provides a basis for the putative application of BACy‐based hydrogels.     

Multistimuli‐Responsive,Moldable Supramolecular Hydrogels Cross‐Linked by Ultrafast Complexation of Metal Ions and Biopolymers

A new type of multistimuli‐responsive hydrogels cross‐linked by metal ions and biopolymers is reported. By mixing the biopolymer chitosan (CS) with a variety of metal ions at the appropriate pH values, we obtained a series of transparent and stable hydrogels within a few seconds through supramolecular complexation. In particular, the CS–Ag hydrogel was chosen as the model and the gelation mechanism was revealed by various measurements. It was found that the facile association of Ag⁺ ions with amino and hydroxy groups in CS chains promoted rapid gel‐network formation. Interestingly, the CS–Ag hydrogel exhibits sharp phase transitions in response to multiple external stimuli, including pH value, chemical redox reactions, cations, anions, and neutral species. Furthermore, this soft matter showed a remarkable moldability to form shape‐persistent, free‐standing objects by a fast in situ gelation procedure.     

Cross‐linking induced thermoresponsive hydrogel with light emitting and self‐healing property

Development of self‐healing hydrogels with thermoresponse is very important for artificial smart materials. In this article, the self‐healing hydrogels with reversible thermoresponses were designed through across‐linking‐induced thermoresponse (CIT) mechanism. The hydrogels were prepared from ketone group containing copolymer bearing tetraphenyl ethylene (TPE) and cross‐linked by naphthalene containing acylhydrazide cross‐linker. The mechanical property, light emission, self‐healing, and thermo‐response of the hydrogels were investigated intensively. With regulation of the copolymer composition, the hydrogels showed thermoresponse with the LCST varied from above to below body temperature. At the same time, the hydrogels showed self‐healing property based on the reversible characteristic of the acylhydrazone bond. The hydrogel also showed temperature‐regulated light emission behavior based on AIE property of the TPE unit. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 869–877     

Time‐Controllable Lipophilic‐Drug Release System Designed by Loading Lipid Nanoparticles into Polysaccharide Hydrogels

A hybrid hydrogel composed of solid lipid nanoparticles (LNPs) entrapped within chemically cross‐linked carboxymethylcellulose (CMC) is developed to achieve localized and sustained release of lipophilic drugs. The analysis of LNP stability as well as the hydrogel swelling and mechanical properties confirm the successful incorporation of particles up to a concentration of 50% w/w_CMC. The initial LNP release rate can be prolonged by increasing the particle diameter from 50 to 120 nm, while the amount of long‐term release can be adjusted by tailoring the particle surface charge or the cross‐linking density of the polymer. After 30 d, 58% of 50 nm diameter negatively charged LNPs escape from the matrix while only 17% of positively charged nanoparticles are released from materials with intermediate cross‐linking density. A mathematical diffusion model based on Fick's second law is efficient to predict the diffusion of the particles from the hydrogels.     

Multistimuli‐Responsive,Moldable Supramolecular Hydrogels Cross‐Linked by Ultrafast Complexation of Metal Ions and Biopolymers

A new type of multistimuli‐responsive hydrogels cross‐linked by metal ions and biopolymers is reported. By mixing the biopolymer chitosan (CS) with a variety of metal ions at the appropriate pH values, we obtained a series of transparent and stable hydrogels within a few seconds through supramolecular complexation. In particular, the CS–Ag hydrogel was chosen as the model and the gelation mechanism was revealed by various measurements. It was found that the facile association of Ag⁺ ions with amino and hydroxy groups in CS chains promoted rapid gel‐network formation. Interestingly, the CS–Ag hydrogel exhibits sharp phase transitions in response to multiple external stimuli, including pH value, chemical redox reactions, cations, anions, and neutral species. Furthermore, this soft matter showed a remarkable moldability to form shape‐persistent, free‐standing objects by a fast in situ gelation procedure.     

Stimuli‐Responsive Biomolecule‐Based Hydrogels and Their Applications

This Review presents polysaccharides, oligosaccharides, nucleic acids, peptides, and proteins as functional stimuli‐responsive polymer scaffolds that yield hydrogels with controlled stiffness. Different physical or chemical triggers can be used to structurally reconfigure the crosslinking units and control the stiffness of the hydrogels. The integration of stimuli‐responsive supramolecular complexes and stimuli‐responsive biomolecular units as crosslinkers leads to hybrid hydrogels undergoing reversible triggered transitions across different stiffness states. Different applications of stimuli‐responsive biomolecule‐based hydrogels are discussed. The assembly of stimuli‐responsive biomolecule‐based hydrogel films on surfaces and their applications are discussed. The coating of drug‐loaded nanoparticles with stimuli‐responsive hydrogels for controlled drug release is also presented.     

Doubly Dynamic Self‐Healing Materials Based on Oxime Click Chemistry and Boronic Acids

The dynamic covalent characteristics of oxime and boronate ester bonds have been explored. A small excess of a competing aldehyde under acidic conditions resulted in oxime polymer degradation from high molecular weights (30 kDa) to low molecular weight oligomers (2.2 kDa). The dynamic nature of oxime bonds imparts oxime cross‐linked hydrogels with self‐healing properties and the incorporation of phenyl boronic acid groups into the hydrogel network provides a platform for hydrogel functionalization. The addition of a polyphenol (tannic acid) proves a facile means to incorporate a second, dynamic covalent cross‐linking network through boronate ester formation which, owing to the increase in the degree of cross‐linking, is found to be nearly double the hydrogel strength (storage modulus increased from 4.6 to 8.5 kPa). Finally, the tannic acid cross‐linking network is selectively degraded returning the hydrogel storage modulus to its initial value and providing a means for the synthesis of materials with tunable mechanical properties.

     

A Moldable Nanocomposite Hydrogel Composed of a Mussel‐Inspired Polymer and a Nanosilicate as a Fit‐to‐Shape Tissue Sealant

The engineering of bioadhesives to bind and conform to the complex contour of tissue surfaces remains a challenge. We have developed a novel moldable nanocomposite hydrogel by combining dopamine‐modified poly(ethylene glycol) and the nanosilicate Laponite, without the use of cytotoxic oxidants. The hydrogel transitioned from a reversibly cross‐linked network formed by dopamine–Laponite interfacial interactions to a covalently cross‐linked network through the slow autoxidation and cross‐linking of catechol moieties. Initially, the hydrogel could be remolded to different shapes, could recover from large strain deformation, and could be injected through a syringe to adhere to the convex contour of a tissue surface. With time, the hydrogel solidified to adopt the new shape and sealed defects on the tissue. This fit‐to‐shape sealant has potential in sealing tissues with non‐flat geometries, such as a sutured anastomosis.     

Graphene Oxide/Polyacrylamide/Aluminum Ion Cross‐Linked Carboxymethyl Hemicellulose Nanocomposite Hydrogels with Very Tough and Elastic Properties

Development of high‐strength hydrogels has recently attracted ever‐increasing attention. In this work, a new design strategy has been proposed to prepare graphene oxide (GO)/polyacrylamide (PAM)/aluminum ion (Al³⁺)‐cross‐linked carboxymethyl hemicellulose (Al‐CMH) nanocomposite hydrogels with very tough and elastic properties. GO/PAM/Al‐CMH hydrogels were synthesized by introducing graphene oxide (GO) into PAM/CMH hydrogel, followed by ionic cross‐linking of Al³⁺. The nanocomposite hydrogels were characterized by means of FTIR, X‐ray diffraction (XRD), and scanning electron microscopy/energy‐dispersive X‐ray analysis (SEM‐EDX) along with their swelling and mechanical properties. The maximum compressive strength and the Young's modulus of GO_3.5/PAM/Al‐CMH_0.45 hydrogel achieved values of up to 1.12 and 13.27 MPa, increased by approximately 6488 and 18330 % relative to the PAM hydrogel (0.017 and 0.072 MPa). The as‐prepared GO/PAM/Al‐CMH nanocomposite hydrogels possess high strength and great elasticity giving them potential in bioengineering and drug‐delivery system applications.     

Synthesis and Spatiotemporal Modification of Biocompatible and Stimuli‐Responsive Carboxymethyl Cellulose Hydrogels Using Thiol‐Norbornene Chemistry

Carboxymethyl cellulose (CMC) is functionalized with norbornene groups to undergo thiol‐norbornene cross‐linking reactions. Hydrogels synthesized from a single norbornene‐modified carboxymethyl cellulose (NorCMC) via a light‐initiated thiol‐ene cross‐linking reaction with a variety of dithiol cross‐linkers yield hydrogels with a tunable compression modulus ranging from 1.7 to 103 kPa. Additionally, thermoresponsiveness is spatiotemporally imparted to NorCMC hydrogels by photopatterning a dithiol‐terminated poly(N‐isopropyl acrylamide) cross‐linker, enabling swelling and topological control of the hydrogels as a function of incubation temperature. NorCMC hydrogels are cytocompatible as the viability of encapsulated human mesenchymal stem cells (hMSCs) is greater than 85% after 21 d while using a variety of cross‐linkers. Moreover, hMSCs can remodel, adhere, and spread in the NorCMC matrix cross‐linked with a matrix metalloproteinase‐degradable peptide, further demonstrating the utility of these materials as a tunable biomaterial.     

Readily Prepared Dynamic Hydrogels by Combining Phenyl Boronic Acid‐ and Maltose‐Modified Anionic Polysaccharides at Neutral pH

Dynamic covalent hydrogels are facilely prepared from biocompatible polysaccharides in physiological conditions by the formation of phenylboronate ester cross‐links. This is based on the simple mixing of carboxylate‐containing polysaccharides (i.e., hyaluronic acid or carboxymethylcellulose) modified with phenylboronic acid and maltose moieties according to mild coupling reactions performed in aqueous solution. The formation of dynamic networks based on reversible boronic‐ester cross‐links is demonstrated by analyzing their rheological behavior. This study shows that these gels can adapt their structure in response to chemical stimuli such as variations in pH or addition of glucose and self‐heal.

     

A Sustainable Freeze‐Drying Route to Porous Polysaccharides with Tailored Hierarchical Meso‐ and Macroporosity

Bio‐derived polysaccharide aerogels are of interest for a broad range of applications. To date, these aerogels have been obtained through the time‐ and solvent‐intensive procedure of hydrogel fomation, solvent exchange, and scCO2 drying, which offers little control over meso/macropore distribution. A simpler and more versatile route is developed, using freeze drying to produce highly mesoporous polysaccharide aerogels with various degrees of macroporosity. The hierarchical pore distribution is controlled by addition of different quantities of t‐butanol (TBA) to hydrogels before drying. Through a systematic study an interesting relationship between the mesoporosity and t‐butanol/water phase diagram is found, linking mesoporosity maxima with eutectic points for all polysaccharides studied (pectin, starch, and alginic acid). Moreover, direct gelation of polysaccharides in aqueous TBA offers additional time savings and the potential for solvent reuse. This finding is a doorway to more accessible polysaccharide aerogels for research and industrial scale production, due to the widespread accessibility of the freeze drying technology and the simplicity of the method.

     

Promotion of Cell Migration into a Hydrophobically modified Alaska Pollock Gelatin‐Based Hydrogel

In situ chemically cross‐linkable hydrogels composed of hexyl group–modified Alaska pollock–derived gelatin (C6‐ApGltn) and poly(ethylene glycol)‐based four‐armed cross‐linker is developed. Water droplets are quickly absorbed into the C6‐ApGltn hydrogel in the first 10 s compared with original ApGltn (Org‐ApGltn), and the final contact angle on C6‐ApGltn is significantly lower than that on Org‐ApGltn. Using a fluorescent probe, an increase in fluorescence intensity on C6‐ApGltn compared to that on Org‐ApGltn is found, indicating the formation of a hydrophobic pocket. Moreover, the promotion of cell migration into the C6‐ApGltn hydrogel is observed in vitro and in vivo compared with Org‐ApGltn hydrogel, despite no significant difference in elastic modulus. Therefore, the C6‐ApGltn hydrogel could potentially be used as a supporting material for cell transplantation and tissue/organ engineering.     

Swelling properties of pH‐responsive hydrophobically modified hydrogels of poly(methacrylic acid‐co‐diallylammonium salt) in aqueous solution

Using diallylmethyl alkyl ammonium salts (CCX) (X is alkyl's chain length, represents 12, 14, 16, and 18, respectively) as a comonomer of methacrylic (MAA), hydrophobically modified hydrogels of poly diallylmethyl alkyl ammonium salts‐methacrylic acid (PCCX‐MAA) were prepared by free radical copolymerization in aqueous solution. The synthetic conditions, such as dosage of cross‐linking agent, reaction concentration and length of alkyl chain were studied in detail. Results indicated that the swelling degree of hydrogels was decreased with dosage of cross‐linking agent, or monomer concentration increased at different pH. Incorporation of the different length of alkyl chain hydrophobic CCX units on PMAA chains by random distribution can change reswelling kinetics. The required time for reaching equilibrium swelling state was longest for PCC16‐MAA. Copyright © 2011 John Wiley & Sons, Ltd.