Reversible Sol-gel Phase Transitions Research Articles

Recent research progress on tumour-specific responsive hydrogels.

Most existing hydrogels, even recently developed injectable hydrogels that undergo a reversible sol-gel phase transition in response to external stimuli, are designed to gel immediately before or after implantation/injection to prevent the free diffusion of materials and drugs; however, the property of immediate gelation leads to a very weak tumour-targeting ability, limiting their application in anticancer therapy. Therefore, the development of tumour-specific responsive hydrogels for anticancer therapy is imperative because tumour-specific responses improve their tumour-targeting efficacy, increase therapeutic effects, and decrease toxicity and side effects. In this review, we introduce the following three types of tumour-responsive hydrogels: (1) hydrogels that gel specifically at the tumour site; (2) hydrogels that decompose specifically at the tumour site; and (3) hydrogels that react specifically with tumours. For each type, their compositions, the mechanisms of tumour-specific responsiveness and their applications in anticancer treatment are comprehensively discussed.

Quinoline-cored Poly(Aryl Ether) Dendritic Organogels with Multiple Stimuli-Responsive and Adsorptive Properties.

Functional supramolecular gel materials have potential applications in sensors, optical switches, artificial antennae, drug delivery and so on. In this paper, quinoline-cored poly(aryl ether) dendritic organogelators were designed, synthesized and fully characterized. The gelation behaviour of the dendritic organogelator was tested in organic solvents, mixed solvents and ionic liquids. The dendron Q-G1 was found to be an efficient and versatile organogelator toward various apolar and polar organic solvents with the critical gelation concentrations (CGCs) approaching 1.2×10-2 mol/L, indicating one dendritic organogelator could immobilize 1.2×103 solvent molecules in the organogel network. Interestingly, these dendrons exhibited excellent gel formation in ionic liquids. Notably, these dendritic organogels were found to display multiple stimuli-responsive properties toward external stimuli including heat, ultrasound and shear stress, with a reversible sol-gel phase transition. In addition, the dendritic organogel could effectively adsorb heavy metals and organic dyes. The removal rate of Pb2+ was up to 20% and the adsorption rate for Rhodamine B was as high as 89%.

The Thermogel Chronicle─From Rational Design of Thermogelling Copolymers to Advanced Thermogel Applications

ConspectusTemperature responsive supramolecular hydrogels, also known as thermogels, are produced by the self-assembly of amphiphilic copolymers in solution following temperature stimulus. They are a class of high caliber novel materials possessing highly attractive properties such as injectability, ability to undergo temperature controlled reversible sol–gel phase transitions, high biocompatibility, and tunable biodegradability. Much research vigor has been dedicated to designing advanced amphiphilic copolymers and investigating their molecular interactions in order to enhance the properties of the thermogelling systems and expand the scope of their applications. As such, thermogelling systems have since become well established in the field of sustained localized drug or protein delivery and have also been demonstrated as high potential materials for niche applications such as three-dimensional cell culture, wound healing patches, and vitreous endotamponades. Recent developments saw the advent of thermogelling systems with advanced biomedical applications ranging from enhanced cancer therapy to radiology imaging to tissue engineering, and these are usually achieved by the conjugating of biologically relevant molecules such as drugs and peptides to the thermogel copolymer or by incorporating nanoparticles into the thermogel systems. New developments in this field see a shift away from employing traditional synthetic polymers such as polypropylene glycol (PPG) and poly(lactic-co-glycolic acid) (PLGA) to utilizing more advanced nature-derived bioactive molecules and also introducing chiral moieties in the thermogelling copolymer backbone.There are currently a few main types of thermogel copolymers such as diblock, triblock, end-capped, graft, and random multiblock polyurethane thermogels. Among these, our lab is specialized in the synthesis and application of polyurethane multiblock thermogels. These thermogels have the advantage of high molecular weights and enhanced intermolecular hydrogen bonding arising from the urethane groups. These generally allow for the formation of thermogelling systems with higher gel stiffness, resilience, and encapsulation efficiency, allowing these polyurethane thermogels to be well suited for niche applications such as sustained drug delivery and vitreous endotamponades. In this Account, we summarize the fundamental polymeric factors influencing the micellar and bulk polyurethane thermogel properties, provide our group’s insights into the rational design of these thermogels for various advanced applications and finally discuss the future possibilities of thermogelling systems. We speculate that there is still much untapped potential of thermogels in the biomedical field and these can possibly be achieved by designing thermogel copolymers with bioactive moieties and exploring more advanced branched architectures. In addition, we also propose the expansion of thermogels beyond biomedical fields, for which our lab has demonstrated thermogels as electrode contacts for noninvasive plant health monitoring.

Chaperone Copolymer-Assisted Aptamer-Patterned DNA Hydrogels for Triggering Spatiotemporal Release of Protein.

In this paper, a DNA hydrogel with low DNA concentration, short sticky end, and good mechanical strength was simply prepared via one-pot self-assembly from two kinds of DNA building block (X- and L-shaped DNA units) chaperoned by a cationic comb-type copolymer (CCC). The gelling process was completed under physiological conditions within 1 min, and the reversible sol-gel phase transition was achieved at room temperature through the continuous addition of CCC and an anionic polymer poly(sodium vinylsulfonate). Moreover, aptamer was successfully patterned into the hydrogel system via click chemistry. Upon the addition of complementary sequences (CSs) of aptamer, the aptamer was hybridized with CSs, leading to the fast dissociation of protein from aptamer with an adjustable release rate in specific regions at prospective times. The hydrogel with excellent cytocompatibility was successfully applied to human serum, a complex matrix. The aptamer-patterned DNA hydrogel is a potential candidate for controlled protein delivery.

Responsive Self-Assembly of Supramolecular Hydrogel Based on Zwitterionic Liquid Asymmetric Gemini Guest.

A low-molecular-weight supramolecular hydrogel has been fabricated based on host-guest interactions between β-cyclodextrin (β-CD) and an asymmetric gemini zwitterionic liquid (ZIL) containing an azobenzene and bis(trifluoromethanesulfonyl)imide. Reversible sol-gel phase transitions were triggered by light and temperature. The binding stoichiometry, mainly noncovalent interactions in the hydrogel, photo- and thermoresponsive mechanisms, and mode of inclusion in the complex were studied in detail by NMR spectroscopy, UV/Vis spectroscopy, isothermal titration calorimetry, and control experiments. Interestingly, the β-CD in the complex can be photo-manipulated to shuttle along the guest molecule, accompanied by a change in the circular dichroism signals. Reversible switching of the conductivity accompanies the sol-gel phase transition, which demonstrates the stability of the supramolecular hydrogel and its potential application in multi-stimuli-responsive electric sensor materials.

Supramolecular Organic Radical Gels Formed with 2,2,6,6-Tetramethylpiperidin-1-oxyl-Substituted Cyclohexanediamines: A Very Efficient Charge-Transporting and -Storable Soft Material

A supramolecular gelator, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO)-substituted cyclohexanediamine derivative, was synthesized, and its excellent charge-transporting capability was explored. The gels with organic solvents and electrolytes, or with ionic liquids, were formed via reversible sol–gel phase transition at ca. 50 °C. The organogels displayed electrochemical redox responses at E1/2 = 0.72 V (vs Ag/AgCl) ascribed to the TEMPO moiety. Charge diffusion coefficient of the gel reached 3.3 × 10–7 cm2/s even in the quasi-solid state, which was comparable to those of the homogeneous solution (ca. 10–6). The high charge-transporting capability led to the tremendously large current density (a diffusion limited one) of ca. 1.0 mA/cm2 on a current collector and long distance for the charge-transporting beyond the organogel thickness of 50 μm. A half-cell of the organogel performed a plateau output voltage at the E1/2, very high rate, and almost quantitative charging–discharging, and it had cyclability with...

Quasi-Solid-State Dye-Sensitized Solar Cell with Ionic Gel Electrolytes by Semifluorinated Alkoxyl Benzene Derivatives

Low molecular-mass organic compounds 1 and 2 having 2-(perfluoroalkyl)ethyl groups at both terminal positions were prepared and their gelation abilities were explored. Compounds 1 and 2 without hydrogen bonding group can gelatinize various organic solvents and/or ionic liquids at low concentration. Compound 1 can gelatinize toluene, while compound 2 dissolve in toluene. Compounds 1 and 2 gelatinize electrolyte showing effective gelation properties. The firmed supramolecular gels are physical gels with thermally reversible sol-gel phase transition. The difference of ionic conductivity between liquid state and gel state were analyzed.

CO2 Responsive Imidazolium-Type Poly(Ionic Liquid) Gels.

Poly(ionic liquid) (PIL) gels with CO2 stimulus responsiveness have been synthesized through the copolymerization of an imidazolium-type ionic liquid monomer with 2-(dimethyl amino) ethyl methacrylate. Upon bubbling with CO2 gas, the prepared PIL solution is converted to a transparent and stable gel, which can be turned back to the initial solution state after N2 bubbling. The reversible sol-gel phase transition behavior is proved by the reversible values of viscosity and ionic conductivity. The possible mechanism for such a reversible sol-gel phase transition is demonstrated by NMR, conductivity, and rheological measurements.

MPTTF-containing tripeptide-based organogels: receptor for 2,4,6-trinitrophenol and multiple stimuli-responsive properties

A series of monopyrrolotetrathiafulvalene-tripeptide conjugates have been synthesized and investigated as new low-molecular mass organogelators. It was found that most of these compounds could immobilize low-polarity solvents readily and the gelation behaviors of these gelators showed a dependence on the amino acid residues. These organogels were thoroughly studied using various techniques including atomic force microscopy (AFM), field-emission scanning electron microscopy (FE-SEM), circular dichroism (CD) spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy, (1)H NMR spectroscopy, UV-Vis absorption spectroscopy and X-ray diffraction (XRD). The results showed that the cooperative interplay of hydrogen bonding, π-π stacking and SS interactions were the main driving force for the formation of the gels. Of all the organogels, the aromatic solvent gels, such as toluene gel, exhibited multiple-stimulus responsiveness towards heating, shaking, chemical redox activity and the presence of anions, thus leading to reversible sol-gel phase transitions. Most interestingly, gelation in the presence of 2,4,6-trinitrophenol (TNP) in organic solvents could be observed visually with a concomitant color change through donor-acceptor interactions. The strength of the charge-transfer interaction between gelators and TNP was proportional to the incubation time and increasing critical gelation concentration (CGC). The gels could function as efficient absorbents for potential application in removal of crystal violet and rhodamine B dyes from water.

Fluorescent Dendritic Organogels Based on 2‐(2′‐Hydroxyphenyl)benzoxazole: Emission Enhancement and Multiple Stimuli‐Responsive Properties

A new highly efficient and versatile poly(benzyl ether) dendritic organogelator HPB-G1 with 2-(2'-hydroxyphenyl)benzoxazole (HPB) at the focal point has been designed and synthesized. HPB-G1 can form stable organogels toward various apolar and polar organic solvents. Further studies revealed that intermolecular multiple π-π stacking interactions are the main driving forces for the formation of the organogels. Notably, dendron HPB-G1 exhibited a significantly enhanced emission in the gel state in contrast to weak emission in solution. Most interestingly, these dendritic organogels exhibited multiple stimuli-responsive behaviors upon exposure to environmental stimuli, including temperature, sonication, shear stress, and the presence of anions, metal cations, acids/bases, thus leading to reversible sol-gel phase transitions.

Gelation by Novel Aprotic Low-molecular-mass Organic Gelators Based on a Gemini 4-[2-(Perfluorobutyl)ethylthio]phenoxy Unit

Abstract We found novel aprotic low-molecular-mass organic gelators (LMOGs) with simple molecular structure based on a gemini 4-[2-(perfluorobutyl)ethylthio]phenoxy unit. These aprotic LMOGs formed a physical gel with a thermally reversible sol–gel phase transition in a wide variety of alcoholic and polar solvents such as 1-octanol and propylene carbonate at concentrations below 1 wt %.

Novel Tri-Cholesteryl Derivatives-Based Low Molecular Mass Organic Gelators with Multi-Stimuli Responsive Properties

Two novel tri-cholesteryl derivatives 1 and 2 have been designed and prepared. Gelation tests in 30 liquids revealed that 1 is a more efficient gelator than 2. Interestingly, the gel of 1/cyclohexane shows a reversible sol–gel phase transition in response to a variety of disparate stimuli such as temperature, stress, and HCl gas. In particular, a fully reversible thixotropic property was observed, which has been rarely reported before. Fourier transform infrared spectroscopy and 1H NMR measurements revealed that hydrogen bonding is an important driving force for the formation of the gel networks. The network structures of 1 and 2 in their cyclohexane gels were studied by scanning electron microscopy and X-ray diffraction analyses, and possible packing models were proposed accordingly. The findings demonstrated in the present work suggest that there is a big potential for developing tri-cholesteryl derivatives into extraordinary low molecular mass gelators.

A glucose-based diblock copolymer: synthesis, characterization and its injectable/temperature-sensitive behaviors

To be more biocompatible, poly(N-isopropyl acrylamide) (PNIPAM) hydrogel, as a typical temperature-sensitive hydrogel, is expected to be linked with other materials of excellent biocompatibility. For this propose, poly(N-isopropyl acrylamide)-block-poly(3-O-allyl-α-D-glucose) (PNIPAM-b-POAG), a new diblock copolymer, was successfully synthesized from N-isopropyl acrylamide (NIPAM) and 3-O-allyl-1,2:5,6-di-O-isopropynylene-α-D-glucose (OAIG) via reversible addition-fragmentation chain transfer (RAFT) polymerization in the presence of cumyl dithiobenzoate (CDB). PNIPAM-b-POAG was characterized byFourier transform infrared (FT-IR) spectroscopy, proton nuclear magnetic resonance (1H NMR) spectroscopy, and gel permeation chromatography (GPC). The critical micelle concentration (CMC) of the copolymer was 0.045 mg/ml measured by fluorescence spectroscopy. The copolymer solution exhibited a reversible sol-gel phase transitions with the increase or decrease of temperature. An in situ gel formed rapidly after subcutaneously injecting the copolymer solution into a Sprague Dawley (SD) rat, which indicated the copolymer has a good injectable property. The in vitro release result showed that methylene blue (MB) as a model was sustainably released by the temperature-sensitive PNIPAM-b-POAG diblock copolymer at 37 °C within 120 h. The copolymer showed no apparent cytotoxicity on L929 cells by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The novel temperature-sensitive hydrogel is a promising candidate for drug delivery.

Multistimuli Responsive and Electroactive Supramolecular Gels Based on Ionic Liquid Gemini Guest.

Electroactive supramolecular gels with multistimuli responsiveness were fabricated through host-guest interactions between a host polymer containing β-cyclodextrin (CD) and an ionic liquid (IL) type asymmetric gemini guest, which contains both ferrocene (Fc) and bis(trifluoromethyl-sulfonyl)imide (TFSI-) as the respective α- and ω-guest groups. Owing to the multiple stimuli-responsiveness of the host-guest interactions, reversible sol-gel phase transition could be triggered by various stimuli, including temperature, electrochemical/chemical redox and anion-exchange reactions. Due to the intrinsically conductive properties of the IL gemini guest, the sol-gel transition behavior could be electrochemically controlled by the applied voltage, without using additional supporting electrolyte.

Fabrication of Reversible Phase Transition Polymer Gels toward Metal Ion Sensing

We report the synthesis of a new type of triple stimuli-responsive, i.e., thermo-, pH-, and metal ion-responsive copolymers based on poly(N-vinylimidazole-co-methacrylic acid) (poly(VI-co-MAA)) and their application as metal ion sensors. The copolymers exhibit reversible sol–gel phase transition behavior in aqueous media. The sol-to-gel transition temperature (Tsol–gel) can be shifted in the range of 20–80 °C, by varying monomer ratio and feeding glycerol content, by adjusting the copolymer concentration in aqueous solution, by tuning the pH of the solution, or by adding various divalent metal ions. Metal ion sensors were designed upon an inverse opal photonic film loaded with aqueous solution of poly(VI-co-MAA), which allows the easy reorganization of various divalent metal ions by combining the diversity of Tsol–gel of the copolymers on different metal ions and flexible reflection spectra of the film. In addition, a fluorescent reversible sol–gel transition system was established by in situ generation of nanocrystals in the copolymer matrix. These extensions may provide the multiresponsive copolymers great flexibility for applications in biomedical, optical, and sensory fields.

Synthesis and Physical Properties of Ionic Liquid Gels Based on Novel Low Molecular Weight Gelators

Low molecular weight organic compounds 1-n and 2-n having 2-(perfluoroalkyl)ethyl groups at both terminal positions were prepared and their gelation ability was examined. Compounds 1-n and 2-n gelate various ionic liquids and/or organic solvents at low concentration, while they have no hydrogen bonding group required for conventional organic gelators. Compounds 1-n gelate alcoholic and polar solvents, however, these are difficult to gelate ionic liquids and only 1-12 formed a gel in [BMIM][TFSA]. On the other hand, compounds 2-n gelate ionic liquids as well as organic solvents and the gelation ability in ionic liquids is higher than that of organic solvents. The formed gels are a physical gel with a thermally reversible sol-gel phase transition. Furthermore, ionic liquid gel electrolyte using compounds 1-n or 2-n as a gelator was prepared and the ionic conductivity of these gel electrolytes and that of the corresponding ionic liquid electrolyte were examined.

Supramolecular approaches to metal–organic gels using ‘Chevrel-type’ coordination clusters as building units

A novel hexanuclear {Mn(6)} coordination complex with octahedral topology has been prepared and was subsequently used as a building unit for the construction of coordination polymers and metal-organic gels; the latter exhibit thixotropic behavior and reversible sol-gel phase transitions.

Physical gels made of liquid crystalline B4 phase

The achiral liquid crystalline materials showing two B4 (HN) phases have been found to exhibit strong gelation ability for various organic solvents with reversible sol-gel phase transition. The gel is formed by helical tubules, which build entangled 3D network, encapsulating the solvent. The equilibrium of left- and right-handed tubules is preserved in the gel, even if the chiral solvent is used.

Phenylboronate-diol crosslinked polymer gels with reversible sol-gel transition

Covalent dynamic gels based on reversible phenylboronic acid-diol ester bonds were prepared by crosslinking of N,N-dimethylacrylamide-4-((4-vinylbenzyloxy)carbonyl)phenylboronic acid copolymer, poly(VPB-co-DMA), and poly(2,2-bis(hydroxymethyl)butyl acrylate) (PHBA) in several organic solvents at ambient temperature. These gels formed rapidly and revealed typical properties of chemical gels. Analysis of the composition–property relationships of these polymer gels, specifically considering the effects of pH, molar ratio of HBA to VPB units, and gelator concentrations on dynamic rheological properties, were performed. Additionally, the polymer gels can be switched into their starting polymer solutions by adjusting pH of the system. The reversible sol-gel phase transition can be performed for several cycles in a similar way of supramolecular gel. Moreover, the gel revealed interesting self-healing property which occurred autonomously without any outside intervention. Employing this dynamic character, it is possible to regenerate the used gel, and thus has the potential to perform in a range of dynamic or bioresponsive applications.

Preparation and study of alkyl carbamylated polyrotaxanes with large hysteresis during sol–gel phase transition

Ethyl carbamylated polyrotaxane (ECPR) and propyl carbamylated polyrotaxane (PCPR) were prepared based on the reactions between ethyl/propyl isocyanate and polyrotaxane (PR) in anhydrous DMSO under an argon atmosphere. By changing the alkyl type and substitution ratio, the PR derivative with good water-solubility was obtained and its solutions showed reversible sol–gel phase transition. During the heating process, transition temperature from sol to gel decreased from 32 °C to 18 °C with increasing the solution concentration from 2.44% to 13.5%, while in the cooling process, all the gels with various concentration did not turn into sols until the temperature decreased to 1 °C, exhibiting large hysteresis between heating and cooling.