Dual-responsive Hydrogel Research Articles

Synthesis of an injectable, self-healable and dual responsive hydrogel for drug delivery and 3D cell cultivation

An injectable, self-healable and dual pH and temperature responsive hydrogel was facilely prepared and applied as a potential carrier for drug delivery and cell cultivation.

Temperature and ion dual responsive biphenyl-dipeptide supramolecular hydrogels as extracellular matrix mimic-scaffolds for cell culture applications.

Stimuli-responsive supramolecular hydrogels composed of aromatic short peptide gelators have attracted intensive attention in the field of biomedicine because of their stable chemical structure, simple and convenient synthetic route and intelligent response to external stimuli. In this paper, several dipeptides were coupled to biphenylacetic acid (BPAA) to generate aromatic short peptide compounds through the standard solid phase peptide synthesis. These BPAA-dipeptide compounds presented clearly different gelation behaviors from the generally employed Fmoc-dipeptide and Nap-dipeptide compounds, but only BPAA-diphenylalanine was able to form homogeneous and transparent hydrogels through temperature switching or ion induction. Utilizing the biphenyl group not only expanded the scope of aromatic molecules serving as building blocks of aromatic short peptide gelators but also demonstrated the critical role of aromatic molecules in the self-assembling process. Moreover, supramolecular hydrogels initiated by heating-cooling or salt addition could be exploited as extracellular matrix (ECM) mimic scaffolds to support the adhesive growth and proliferation of L929 cells in 2D/3D culture under physiological conditions, demonstrating their potential applications in regenerative medicine.

Dual responsive hydrogels based on functionalized mesoporous silica nanoparticles as an injectable platform for tumor therapy and tissue regeneration.

To achieve effective tumor therapy and regenerate new tissue from defects formed by tumor atrophy, a dual responsive hydrogel integrating the stepwise delivery of anti-tumor drugs/growth factors and pH/thermo induced structural transformation is developed, based on polymer (poly N-isopropylacrylamide (PNIPAM) and polyacrylic acid (PAA)) functionalized mesoporous silica nanoparticles (MSNs). Due to the thermally responsive tangle between PNIPAM chains and the pH triggered hydrogen bonds in PAA chains, these injectable MSNs would immediately switch from nanoparticles to compact hydrogels in a tumor environment (37.5 °C, pH 6.8), where the concentrated network structure in the hydrogel is in charge of the loading and local delivery of anti-tumor drugs. The MSNs serve as nanocarriers for growth factors, which are localized by crosslinked networks. The sustained release of growth factors only occurred with the cleavage of hydrogen bonds in PAA chains, which is triggered by the pH increase to 7.4 after the cure of the tumor. Moreover, the hydrogen bond cleavage would also cause the swelling of the hydrogel, which not only fills the defects but generates plenty of cell-level pores, resulting in an excellent scaffold for attachment and proliferation of healthy cells. Therefore, the dual responsive MSN-hydrogels offer a promising strategy for sequential tumor therapy and tissue regeneration.

Visible-light/temperature dual-responsive hydrogel constructed by α-cyclodextrin and an azobenzene linked surfactant.

A novel photo-responsive anionic surfactant with a dimethylamino-substituted azobenzene located at the end of the hydrophobic chain, 6-(4-dimethylaminoazobenzene-4'-oxy)hexanoate sodium (DAH), has been designed. Through the host-guest interaction in aqueous solution, the trans-DAH could be spontaneously included by using two native α-cyclodextrin (α-CD) molecules. The formed hydrophilic inclusion complex (DAH@2α-CD), however, could act as a gelator to induce the formation of a supramolecular hydrogel, which is driven mainly by hydrogen bonds between neighboring α-CDs and also between the carboxylate in DAH and water. Compared with common hydrogels that consist of networks with fibres or discrete polymer chains, the hydrogel formed by DAH@2α-CD was composed of periodic lamellar structures possessing good shear-thinning behavior and much swollen water layers. The more interesting point for such a hydrogel was its visible-light responsibility for gel-sol reversible phase transition. This originated from the introduction of an electron-donating group (dimethylamino) to azobenzene, which noticeably red-shifted the responsive wavelength for its trans-to-cis isomerization. It was also worth noting that the host-guest interaction between azobenzene in DAH and α-CD significantly improved the photo-transition efficiency from trans to cis forms of azobenzene, which played a critical role in the visible-light responsibility of the hydrogel. This unique visible-light-responsive behavior combined with the inherent thermo-responsive property from α-CD should make the prepared hydrogel find more potential applications in biomedical systems.

Novel nanostructured smart, photodynamic hydrogels based on poly(N-isopropylacrylamide) bearing porphyrin units in their crosslink chains: A potential sensitizer system in cancer therapy

Novel nanostructure, pH-thermo dual responsive photodynamic hydrogels based on poly(N-isopropylacrylamide) were successfully synthesized by in situ dispersion polymerization of NIPAAm with 5,10, 15, 20-tetrakis(4-N-carbonylacrylic aminophenyl)porphyrin (2% and 4% w/w) in the presence of methylene-bis-acrylamide (MBA) in water. 5, 10, 15, 20-tetrakis (4-N-carbonylacrylic aminophenyl)porphyrin (CAA-TPP) was designed and synthesized for the first time via reaction of tetrakis(4-aminophenyl)porphyrin (NH2-TPP) with maleic anhydrid and was applied as a crosslinker. The structure of the 5, 10, 15, 20-tetrakis(4-N-carbonylacrylic aminophenyl) porphyrin and hydrogels was thoroughly studied by a variety of techniques such as NMR, FT-IR and UV–visible spectrophotometer. The surface morphology of freeze-dried hydrogels using SEM showed one-dimensional nanostructured with uniform morphology of self-assembled interconnected nanofibers. Rheological measurement results were showed that the incorporation of porphyrin onto polymer structure can provide hydrogels without the loss of thermoresponsive viscoelastic properties. The lower critical solution temperatures (LCST) of P[NIPAAm-co-CAA-TPP] hydrogels in water were measured by the cloud point (CP) method. The LCST of P[NIPAAm-co-CAA-TPP (2%)] and P[NIPAAm-co-CAA-TPP (4%)] were at about 40 °C and 43 °C, respectively. The results showed that an increase in porphyrin content makes the LCSTs of the hydrogels increase. Swelling measurements of hydrogels indicated sensitivity to temperature and pH, suggesting that the P[NIPAAm-co-CAA-TPP]s were temperature/pH dual stimulus-responsive hydrogels. In this work, the efficiency of P[NIPAAm-co-CAA-TPP (2%)] and P[NIPAAm-co-CAA-TPP (4%)] as photodynamic therapy (PDT) systems were investigated. The production of reactive singlet oxygen, cytotoxity and phototoxicity of them were assessed. The study showed that the singlet oxygen production ability of P[NIPAAm-co-CAA-TPP (2%)] can be well controlled by irradiation time compared with free porphyrin. We tested these two hydrogels on A453 cells to compare their effectiveness. P[NIPAAm-co-CAA-TPP (2%)] and P[NIPAAm-co-CAA-TPP (4%)] exhibited cell viability over 97% and good photocytotoxity, indicating they are promising photodynamic systems for cancer therapy.

Highly Swellable, Dual-Responsive Hydrogels Based on PNIPAM and Redox Active Poly(ferrocenylsilane) Poly(ionic liquid)s: Synthesis, Structure, and Properties.

Highly swellable, dual-responsive hydrogels, consisting of thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) and redox-responsive poly(ferrocenylsilane) (PFS) based poly(ionic liquid)s (PILs) are formed by photo-polymerization. PFS chains bearing cross-linkable vinylimidazolium (VIm) side groups are copolymerized with NIPAM in aqueous solutions under ultraviolet light (λ = 365 nm) in the presence of a photoinitiator. The PFS-PILs serve as a macro-cross-linker and also provide redox responsiveness. The swelling ratio, morphology, and lower critical solution temperature (LCST) of the hydrogels are studied as a function of the PNIPAM/PFS ratio. The value of the LCST is dependent on the choice of the counterion of the PIL and the PNIPAM/PFS ratio. The hydrogel is employed as a reducing environment for the in situ fabrication of gold nanoparticles (AuNPs), forming AuNP-hydrogel composites. The localized surface plasmon resonance peak of the as-synthesized Au nanoparticles inside the hydrogel could be tuned by altering the temperature.

Dual responsive zein hydrogel membrane with selective protein adsorption and sustained release property

Drug-loaded hydrogels have been paid increasing attentions in biomedical fields. As a sort of natural plant protein, zein generally cannot form hydrogel with high water retention because of its predominant hydrophobicity, which will limit its application as biomaterial. In this paper, zein electrospun fibrous membranes (ZEFM) are fabricated through a chemical modification of zein using citric acid and acetic anhydride. The resulting ZEFM can be totally soluble in neutral phosphate buffer solution. After being crosslinked by sodium hexametaphosphate, the ZEFM can form a hydrogel membrane and displays stimuli-responsive behavior towards pH and ionic strength. The hydrogel membrane exhibits better protein adsorption, selectivity and sustained release profile for positively-charged proteins such as cytochrome C, compared with those unmodified ones, and also shows fast biodegradation behavior and qualified cytotoxicity, which all make it favourable for biomedical use.

An unprecedented dual responsive gelation of Carbopol induced by Pluronic P123 triblock copolymer

Abstract We present a dynamic dual responsive biocompatible composite hydrogel based on Carbopol (CBP) and P123 in presence of salt. The P123 could induce gelation of Carbopol in otherwise nongelled 1% CBP (in presence of salt) even below its pKa which it is believed to make its delivery system viable in strongly acidic environment like gut. The gelation properties of the gel can be tuned in a desired manner by altering polymeric concentrations, pH and temperature in order to tailor the system for delivery applications. The hydrogel when investigated for Naproxen release shows no burst release of the drug, significant for efficient drug delivery system. Different kinetic models fitted to the release data revealed diffusion predominant release at pH 7.4 and relaxation predominant release at pH 4.

In-line sensing of sodium ascorbate using a poly(ferrocenylsilane)-coated microfluidic device

Poly(ferrocenylsilane) (PFS) is a redox-active polymer that can be utilized in a variety of applications, such as sensing, nanoparticle foundries or dual-responsive hydrogels, due to the fact that it can be partially or completely oxidized, reversibly, by (electro)chemical means. In this research, PFS is tethered to a cysteamine-modified gold-coated microchannel electrode via amine alkylation, following a recent published procedure for conventional macro-sized electrodes. The PFS-coated microfluidic device is successfully employed as an electrochemical sensor for sodium l-ascorbate, or vitamin C, with a detection limit of 0.5mM in aqueous solution. The fabrication of the device, that comprises gold-coated electrodes of micrometers in width, is discussed, as well as the static and in-line detection of sodium l-ascorbate. The analyte concentration is sensed through an electrocatalytic process in both static and in-line cases, by cyclic voltammetry and amperometry, respectively. The findings presented in this work open novel opportunities for local surface modification of chip-integrated gold electrodes by redox-responsive polymers used, e.g., as electrochemical sensors.

Amino Acid Based Hydrogels with Dual Responsiveness for Oral Drug Delivery.

This study reports a series of novel amino acid based dual-responsive hydrogels. Prepared by a facile one-pot 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) coupling reaction, the solid content, structure, and mechanical behavior of hydrogels could be easily adjusted by changing the concentrations of the polymers and the crosslinkers. With pH-responsive anionic pseudo-peptides as backbones and disulfide-containing l-cystine dimethyl ester as crosslinkers, these hydrogels are able to collapse and form relatively compact structure at an acidic pH, while swelled and partly dissociated at a neutral pH. Further addition of dithiothreitol (DTT) facilitated complete degradation of hydrogels. The high loading efficiency, rapid but complete triggered-release, and good biocompatibility make these hydrogels promising candidates for oral delivery.

Synthesis and characterization of a novel pH-thermo dual responsive hydrogel based on salecan and poly(N,N-diethylacrylamide-co-methacrylic acid)

Salecan is a water-soluble microbial polysaccharide produced by Agrobacterium sp. ZX09, a salt-tolerant strain isolated from a soil sample in our laboratory. Previous work inspired us salecan is a good candidate to fabricate hydrogels. Poly(N,N-diethylacrylamide) is one type of thermo sensitive polymer which is not investigated extremely as poly(N-isopropylacrylamide). Here, we report a novel pH-thermo dual responsive hydrogel based on salecan and poly(N,N-diethylacrylamide-co-methacrylic acid) semi-interpenetrating polymer networks (semi-IPNs). The physicochemical property of this hydrogel was investigated by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analyses (TGA), rheological test and Scanning Electron Microscopy (SEM). It was interesting that the storage modulus (G′) and pore size of the hydrogel could be tuned by adjusting the content of salecan and crosslinker. The pH-thermo dual responsive property was demonstrated by swelling behavior test: the swelling ratio of the hydrogel decreased continuously as the temperature increased from 25°C to 37°C, while it was pH-dependent as well. Especially, when exposed to a higher temperature (37°C) and acidic environment (pH 4.0), drug-loaded hydrogel would have a quick release. Finally, the cytotoxicity of drug-free hydrogels was investigated on A549 and HepG2 cells, results showed that it was non-toxic while the DOX released from hydrogels had comparable cytotoxicity with respect to free DOX. In conclusion, the novel salecan/poly(N,N-diethylacrylamide-co-methacrylic acid) semi-interpenetrating polymer network hydrogels were pH-thermo dual responsive and may be a promising candidate for drug delivery system.

Synthesis of dual responsive cyclotriphosphazene-based IPN hydrogels for controlled release of chemotherapeutic agent

Dual responsive cyclotriphosphazene (CTP)-based hydrogels have been synthesized for a controlled release of FU, a hydrophilic drugs. These hydrogels composed of mono (methacryloyl-2-ethoxy)-pentakis(N1,N1-dimethylpropane-1,3-diamino)-cyclotriphosphazene (HEMA (DMPDA)5CP), acryl amide and pectin were synthesized by free radical polymerization method using methylenebisacrylamide cross linker. The CTP hydrogels were characterized to understand the structure, drug nature in the network and morphology by FTIR, DSC, XRD and SEM, respectively. In this paper, the swelling (dynamic and equilibrium) properties of cyclotriphosphazene hydrogels were investigated, showing dual (pH and thermo) responsiveness and large variation in the swelling capacity. Based on these results the structural parameters of the hydrogel networks such as the average molecular weight between cross-links (Mc) and polymer–solvent interaction parameter (χ) were determined. The CTP hydrogels has high FU loading efficiency 65 ± 0.5. In-vitro FU release of these hydrogels was controlled for about 24 hr also hydrogel showed a distinct initial burst. The CTP hydrogels are bearing both hydrophilic groups of pectin and hydrophobic groups of CTP exhibited dual responsive behaviors with pH and temperature. Copyright © 2015 John Wiley & Sons, Ltd.

Dual pH and temperature responsive hydrogels based on β-cyclodextrin derivatives for atorvastatin delivery

2-Methylacrylic acid modified β-cyclodextrin was copolymerized with 2-methylacrylic acid and N,N′-methylene diacrylamide to fabricate dual pH and temperature responsive hydrogels for the controlled release of atorvastatin. The swelling behaviors, pH and temperature responsive atorvastatin release profiles of the hydrogels were investigated. The results indicated that the hydrogel prepared in DMSO exhibited the best swelling rate, which was 51 for 10min and 252 for 16h when immersed in medium of buffer solution with pH=8.06. The media with low (pH≤3.84) and high (pH≥10.34) pH values would reduce the swelling rate of hydrogels. The swelling of the hydrogel was increased with increasing temperature from 30°C to 45°C. Atorvastatin was loaded in the hydrogel for drug release investigation. The cumulative release rate of atorvastatin was as high as 90.5% in pH=8.06 buffer solution. The solubility of atorvastatin was improved from 0.13 to 1.2mg/mL in the hydrogel.

Dual-Responsive Hydrogels for Direct-Write 3D Printing

Direct-write 3D printing enables the fabrication of three-dimensional objects via the extrusion from a nozzle. Stimuli responsive materials that shear-thin are well-suited as inks for these 3D printing systems. Poly(isopropyl glycidyl ether)-block-poly(ethylene oxide)-block-poly(isopropyl glycidyl ether) ABA triblock copolymers were synthesized using controlled ring-opening polymerization to afford dual stimuli-responsive polymers that respond to both shear forces and temperature. These polymers were demonstrated to form hydrogels in water. The gels were observed to be thermoreversible—driven by the lower critical solution temperature of the poly(isopropyl glycidyl ether) block which helps facilitate loading of the ink into the printer syringe. Rheological studies demonstrated that the gels had a rapid and reversible modulus response to shear stress. Thus, these materials were suitable as inks for direct-write 3D printing, as they were easily extruded during printing and maintained sufficient mechanical integrity which was necessary to support the next printed layer. Printed structures of high aspect ratio pillars and stacked layers were successfully demonstrated. These types of 3D hydrogel structures may ultimately have an impact in the biomedical field for applications such as tissue engineering.

Controlled release of cell sheet by saccharide and temperature dual-responsive hydrogel layer

Controlled release of cell sheet by saccharide and temperature dual-responsive hydrogel layer

Synthesis and swelling properties of a pH‐ and temperature‐dual responsive hydrogel by inverse microemulsion polymerization

ABSTRACTA novel pH‐ and temperature‐dual responsive hydrogel was synthesized by inverse microemulsion polymerization, using itonic acid (IA) as pH‐responsive monomer, N‐isopropylacrylamide (NPAM) as thermo‐responsive monomer and acrylamide (AM) as the nonionic hydrophilic monomer. Factors affecting water and salt absorption, as well as swellability of the dual responsive hydrogels, such as IA/NPAM mass ratio and crosslinker amount, were investigated. pH‐ and temperature‐sensitivity and dynamic viscoelasticity behaviors of the dual responsive hydrogels were also studied. The dual responsive responsive hydrogels showed suitable water and salt absorbency, remarkable pH‐, and temperature‐sensitivity, adjustable swellability and enhanced viscoelastic behaviors under high stress. Water absorbency and pH‐sensitivity increased while salt absorbency and temperature‐ sensitivity decreased with increasing IA/NIPAM mass ratio. Both water absorbency and salt absorbency increased first with crosslinker amount increased to 0.2 wt %, and then decreased with increasing crosslinker amount. Temperature‐induced shrinkage range of the dual responsive hydrogels was higher and broader than that of the conventional poly(N‐isopropylacrylamide) hydrogel. TEM indicated that the as‐synthesized hydrogel particles were regular and spherical‐like in shape and had the mean particle size of 49nm in the range of 30–78 nm. FTIR indicated the structure of the dual responsive hydrogels. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 42139.

Thermal properties and kinetic investigation of chitosan-PMAA based dual-responsive hydrogels

The influence of cross-linker (N,N-methylenebisacrylamide, MBA) and methacrylic acid (MAA) composition on the thermal stability, degradation kinetic, and lifetime, of Chitosan-based [Chitosan-poly(methacrylic acid, (Cs-PMAA)] dual responsive hydrogels was investigated in detail using the Flynn–Wall–Ozawa (F–W–O) method. The Cs-MAA–MBA derivatives showed only a glass transition temperature (Tg) that increased as the content of MAA increased. The stability of Cs-MAA–MBA has been achieved at a critical point where the MAA content was 300mg/ml and MBA was 15mg/ml. The lifetime of Cs-PMAA hydrogels (time at 5% mass loss) was estimated by increased temperature delivery in nitrogen atmosphere. On average, a higher Ea has been attributed to the greater cross-linking density of Cs hydrogel. Likewise, the lower swelling ability of Cs hydrogel can be due to the slower relaxation rate of the polymer chain, which then results in an increased lifetime of the potential drug-release rate.

Comparative study on temperature/pH sensitive xylan-based hydrogels: their properties and drug controlled release

Temperature/pH dual-responsive hydrogels as a new intestinal-targeted carriers were prepared by the grafting copolymerization of xylan possessing different functional groups with AM and NIPAm via ultraviolet irradiation.

Saccharides and temperature dual-responsive hydrogel layers for harvesting cell sheets.

Saccharides and temperature dual-responsive hydrogels have been prepared based on PNIPAAm copolymers containing phenylboronic acid (PBA) groups and used for harvesting cell sheets. The cell sheet could be released from the hydrogel layer at 37 °C simply by increasing sugar concentration, and could be more efficiently released at a lower temperature and elevated sugar concentration.

Synthesis and properties of a dual responsive hydrogel by inverse microemulsion polymerization

A novel dual responsive hydrogel was synthesized by inverse microemulsion polymerization, using itaconic acid as pH-responsive monomer and N- isopropylacrylamide as thermo-responsive monomer. pH- and temperature-sensitivity and dynamic viscoelasticity behaviour of the dual responsive hydrogels were investigated. Dual responsive hydrogels showed remarkable pH- and temperature-sensitivity and enhanced viscoelastic behaviour under high stress. Temperature-induced shrinkage range of the dual responsive hydrogels was higher and broader than that of the conventional poly(N-isopropylacrylamide) hydrogel. FTIR revealed the structure of dual responsive hydrogels. The as-synthesized regular and sphere-like hydrogel particles had the average particle size of 49 nm in the range of 30–78 nm. A novel dual responsive hydrogel, with average particle size of 49 nm, was synthesized by inverse microemulsion polymerization. Dual responsive hydrogels showed remarkable pH- and temperature-sensitivity and enhanced viscoelastic behaviour. Temperature-induced shrinkage range of the dual responsive hydrogels was higher and broader than that of conventional poly(N- isopropylacrylamide) hydrogel.