Synthesis and characterisation of stimuli-responsive poly(N,N′-diethylacrylamide) hydrogels

Stimuli-responsive poly(N,N′-diethylacrylamide) gels were prepared by free radical polymerisation in aqueous solution, using N,N-methylenebisacrylamide as crosslinking agent. The gels were compared with the corresponding poly(N-isopropylacrylamide)-based gels. In particular, the swelling ratio of both gel types including the effect of the crosslinker content, their swelling and deswelling kinetics, their permeability and finally their drug (insulin) storage and controlled release ability were compared. In spite of the similarity in the monomer/crosslinker ratio, the deswelling kinetics and the critical temperatures (ca. 30-32 °C in pure water), some differences could be observed. Compared to poly(N-isopropylacrylamide)-based gels, poly(N,N′-diethylacrylamide)-based gels show a broader phase transition temperature interval, a more pronounced dependency of the swelling ratio on the crosslinker content, slower reswelling kinetics, a higher ingress percentage for dextran standards ranging from 5 to 70 kD, but lower ingress percentages for proteins (BSA, insulin) and much faster drug (insulin) release kinetics. While a non-linear release kinetic was observed in the case of the poly(N-isopropylacraylamide)-based gels both in water and in PBS (phosphate buffered saline), this was not the case for the poly(N,N′-diethylacrylamide)-based gels.     

Thermosensitive hydrogels from copolymers of N-isopropylacrylamide and anionic monomers

Thermosensitive hydrogels containing anionic monomer have been prepared from copolymerization of N-isopropylacrylamide and 3-sulphopropylacrylate potassium salt, 3-sulphopropylmethacrylate potassium salt and 2-acrylamido-2-methyl-1-propanesulphonic acid in the presence of N,N′-methylene-bisacrylamide as crosslinking agent with potassium persulphate/N,N,N′,N′,-tetramethylethylenediamine as initiator in water at room temperature. The swelling behaviour and volume transition temperature of the gels containing different anionic monomers were studied. It was found that with increasing content of anionic monomer, the swelling ratio as well as the volume transition temperature of the gel increased. The swelling behaviour of the gels in salt-containing water was investigated.     

Equilibrium swelling of thermo-responsive core-shell microgels

Design of new routes for preparation of hydrogels with fast response and enhanced mechanical and physical properties requires adequate modeling of their swelling. A model is developed for the equilibrium swelling of thermo-responsive gels. A characteristic feature of the model is that it accounts for a strong increase in the elastic moduli above the volume phase transition temperature T_c driven by aggregation of hydrophobic segments into clusters that serve as extra physical bonds between chains. The model is applied to the analysis of swelling diagrams on poly(N-isopropylacrylamide) macroscopic gels, microgel latices, and core-shell microgels with rigid cores. Good agreement is shown between the experimental data and results of simulation. It is demonstrated that the elastic moduli of microgels are higher, while their degrees of swelling in the stress-free state are lower compared with those of macroscopic gels.     

Influence of the synthesis conditions and ionic additives on the swelling behaviour of thermo-responsive polyalkylacrylamide hydrogels

Temperature-responsive poly(N,N-diethylacrylamide) and poly(N-isopropylacrylamide) hydrogels were synthesised by free radical polymerisation at room temperature with different crosslinker and constant initiator/accelerator concentration. At low crosslinker concentration transparent or translucent gels were obtained, while the gels produced at high crosslinker concentration were opaque. Whereas little difference could be observed between these gels in regard to the temperature of collapse, the swelling/deswelling behaviour showed discrepancies, in that the opaque gels (higher degree of crosslinking) showed a lower swelling ratio, but more efficient water release and more pronounced relative water uptake (reswelling). Low molecular weight additives (potassium salts) had an effect on the on the critical temperature and the swelling ratio; the strength of the observed effect corresponded to the position of the anion in the Hoffmeister series. For most salts the critical temperature was found to decrease (‘salting out’ effect) almost linearly with increasing salt concentration. A linear relationship could be established between the change in critical temperature of the gels and the ‘Viscosity B Coefficient’ of the added anion. Low concentrations of KI showed a ‘salting in’ effect for all investigated gels, while low amounts of KCl showed such an effect only in the case of the poly(N,N-diethylacrylamide) gels. The ‘salting in’ effect was accompanied by an increase in the maximum swelling ratio below the critical temperature. In a cytotoxicity test with Jurkat cells the poly(N-isopropylacrylamide) gels, but less the poly(N,N-diethylacrylamide) gels negatively influenced the morphology, if not the number and viability of the cells, after a contact time of 6 h.     

pH–thermoreversible hydrogels. II. Synthesis and swelling behaviors of N-isopropylacrylamide-co-acrylic acid-co-sodium acrylate hydrogels

A series of pH–thermoreversible hydrogels are prepared from the three molar ratios of N-isopropylacrylamide (NIPAAm) and acrylic acid neutralized 50 mol % by sodium hydroxide (SA50) and N,N′-methylene bisacrylamide (NMBA). The influence of the environmental conditions, such as temperature and pH values, on the swelling behavior of these copolymeric gels is also investigated in this article. Results show that the hydrogels bearing negative charges exhibit different equilibrium swelling ratios under various pH media. The pH sensitivities of these gels also strongly depend on the molar ratio of SA50 in the copolymeric gels; thus, the more the SA50 content, the higher the gel pH sensitivity. These hydrogels exhibited thermosensitivity demonstrating a larger change of the equilibrium swelling ratio in aqueous media under temperature changes. An overshooting phenomenon is observed from the gel swelling kinetics under high-temperature conditions. The said hydrogels are also used to investigate the release of model drugs in this study. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 73: 1955–1967, 1999     

Swelling and mechanical behavior of charged poly(<Emphasis Type="Italic">N</Emphasis>-isopropylmethacrylamide) and poly(<Emphasis Type="Italic">N</Emphasis>-isopropylacrylamide) networks in water/ethanol mixtures. Cononsolvency effect

Summary Swelling and mechanical behavior of negatively (ionic comonomer-sodium methacrylate) and positively (ionic comonomer-(2-acrylamidoethyl)trimethyl ammonium chloride) charged networks of poly(N-isopropylmethacrylamide) (PIPMAm) and poly(N-isopropylacrylamide) (PIPAAm) was investigated in water/ethanol mixtures at room temperature. Strong cononsolvency effect was observed for uncharged and negatively charged gels of both systems; while for neat solvents high degree of swelling Q was observed, for solvent mixtures pronounced minima in swelling were found. Swelling minima are connected with the coil-to-globule transition of network chains and their characteristic parameters-concentration of ethanol at the minimum, c_eth,m, and corresponding swelling degree, Q_m, were determined. With increasing amount of negatively charged ionic comonomer the minimum in swelling shifts to higher c_eth,m values and Q_m increase. On the other hand, positively charged networks of both systems exhibit roughly constant Q values practically independent of solvent mixtures compositions. For all four systems it was found that mechanical behavior is predominantly determined by the degree of swelling regardless of charge concentration.     

Novel synthesis of thermosensitive porous hydrogels

The simplified method for the synthesis of thermosensitive porous hydrogels by a radical polymerization was presented and their swelling properties were examined experimentally. N,N-Diethylacrylamide (DEAAm) or N-isopropylacrylamide (NIPAm) as primary monomers and N,N′-methylenebisacrylamide (BIS) as a crosslinker were used. They were polymerized in water at various temperatures above the lower critical solution temperature (LCST) of poly-DEAAm (ca. 32°C) or poly-NIPAm (ca. 31°C) by using N,N,N′,N′-,tetramethylethylenediamine (TEMED) and ammonium peroxsodisulfate (APS) as the polymerization accelerator and initiator, respectively. From the observation by a scanning electron microscope, it was found that these gels consisted of aggregated microgel particles, namely, a porous structure. The gels swelled below their LCSTs, and the swelling degree increased with lowering temperature. Furthermore, the gels swelled or shrank very fast in response to the change in temperature, and the shrinking rate was larger than the swelling rate. Such swelling properties and mechanical properties depended on the porous structure of the gels such as the size of the microgels and the pore volume, which largely changed with the synthesis temperature and the component of the primary monomer. © 1998 John Wiley & Sons, Inc. J Appl Polym Sci 69: 895–906, 1998     

Synthesis and characterization of biresponsive graft copolymer gels

Graft copolymer gels with different compositions were prepared by the radical polymerization of N-isopropylacrylamide (NIPAAm) and poly(2-vinylpyridine) (P2VP) macromonomers in dioxane with 1 mol% N,N′-methylenebisacrylamide (BIS) as the crosslinking agent. The graft copolymer gels were analyzed at different temperatures and pH values. They demonstrated the typical swelling behavior for poly(N-isopropylacrylamide) (PNIPAAm) gels with changing temperature. In addition to the temperature dependent measurements, the graft copolymer with a high P2VP content showed a pronounced swelling transition with changing pH value. By separating the temperature and the pH sensitive component, it was possible to obtain a gel which could be swelled independently in response to temperature and pH.     

Phase transition in swollen gels 30. Temperature-induced phase transition in positively charged poly(N-isopropylacrylamide) hydrogels in water and aqueous NaCl solutions

Summary The swelling and mechanical behaviour of ionized networks of N-isopropylacrylamide with an ionic comonomer, (2-acrylamidoethyl)trimethylammonium chloride (mole fractions x _S= 0−0.1), in the presence of a crosslinker, N,N'-methylenebisacrylamide, was investigated in water as a function of temperature and in aqueous NaCl solutions (c _NaCl= 10⁻⁵− 1 M) at 23 °C. On heating, a continuous decrease in the swelling degree in water, Q _w, was observed; increasing x _S shifts the volume transition temperature, T _tr, (from the swollen to collapsed state) to higher temperatures. The expected decrease in the swelling degree, Q, with increasing NaCl concentration in aqueous NaCl solutions was observed and two shrinking regions in ionic gels were found. The decrease in Q _w with increasing temperature and the decrease in Q with increasing c _NaCl are accompanied by an increase in equilibrium shear modulus of gels, so that the mechanical behaviour of gels is predominantly determined by the swelling degree. The experimental swelling behaviour could be, in the first approximation, described by the theory of polyelectrolyte networks in which repulsion of charges on the chain and finite chain extensibility were considered. Received: 7 June 2001 / Accepted: 21 September 2001     

Thermoreversible hydrogels VI: Swelling behavior of the (N-isopropylacrylamide-co-diethyl methyl methacryloyloxyethyl ammonium iodide) copolymeric hydrogels in aqueous salt solutions

A series of N-isopropylacrylamide/diethyl methyl methacryloyloxyethyl ammonium iodide (NIPAAm/DEMMAI) copolymeric gels were prepared from blending NIPAAm, cationic monomer DEMMAI, and N,N′-methylene bisacrylamide (NMBA) in various molar ratios in this article. The effects of the amount of the cationic monomer in the copolymeric gels on the swelling behaviors in water and various saline solutions at various temperatures were investigated. Results showed that the swelling ratios of copolymeric gels were significantly larger than those of pure NIPAAm gel, and that the more the DEMMAI content, the higher the gel transition temperature. In the saline solution, results showed that the swelling ratio for pure NIPAAm gel had not changed significantly with an increase of the salt concentration until the salt concentration was larger than 0.1 M. The swelling ratios for the copolymeric gels NIPAAm/DEMMAI were decreased with increasing salt concentration. In various saline solutions, results showed that the anionic effects were greater than cationic effects in the presence of common anion with different cations and common cation with different anions for these hydrogels. Finally, we also tested the reversibility of the NIPAAm/DEMMAI copolymeric gels. The deswelling and reswelling kinetics were dependent on the temperature which was below or above the gel transition temperature. The gel with a small DEMMAI content has a good reversibility.     

Removal of cationic dyes from aqueous solutions with poly (<Emphasis Type="Italic">N</Emphasis>-isopropylacrylamide-<Emphasis Type="Italic">co</Emphasis>-itaconic acid) hydrogels

In this study, N-isopropylacrylamide-based temperature and pH-sensitive hydrogels were synthesized by free radical polymerization for removal of cationic dyes from aqueous solutions. For this purpose, N-isopropylacrylamide was copolymerized with various amounts of sodium salt of itaconic acid in the presence of crosslinking agent (N,N-methylene bisacrylamide). The chemical structures of hydrogels were characterized by FT-IR analysis. In order to investigate swelling properties of the hydrogels, water absorption (swelling) and shrinking (deswelling) kinetics, the equilibrium swelling ratios in water and different pH buffer solutions, and the temperature dependent swelling ratios were determined. Then, their adsorption properties such as adsorption capacities, kinetics, isotherms were investigated in case of their usage in removal of Safranine T (ST), Brilliant Green (BG), and Brilliant Cresyl Blue (BCB) aqueous solutions. According to adsorbed dye amount, the adsorption capacities are followed the order BG > ST ≅ BCB. In addition, the results indicated that the pseudo-second-order kinetic model fitted better than the data obtained from pseudo-first-order model for the adsorption of all dyes onto hydrogels. Furthermore, according to effect of the initial dye concentration findings, it is concluded that, Freundlich isotherm explains the adsorption better than Langmuir isotherm.     

Swelling of and solute exclusion by poly(N-alkylacrylamide) gels

Temperature-sensitive hydrogels of poly(N-isopropylacrylamide) poly(N,N-diethylacrylamide), poly(N-N-propylacrylamide), copolymer of N-isopropylacrylamide and methylacrylamide, and copolymer of N,N-diethylacrylamide and N-tert-butylacrylamide were prepared. The swelling characteristics of the gels were studied and gel extraction of macromolecules, based on the solute exclusion by the gel network, were investigated. © 1995 John Wiley & Sons, Inc.     

Thermoreversible hydrogels. XV. Swelling behaviors and drug release for thermoreversible hydrogels containing silane monomers

Three series of thermosensitive copolymeric hydrogels were prepared from [3‐(methacryloyloxy)propyl]trimethoxysilane (MPTMOS), [2‐(methacryloyloxy)ethoxy]trimethylsilane (METMS), and (methacryloyloxy)trimethylsilane (MTMS), referred to as the silane monomer, and N‐isopropylacrylamide (NIPAAm) by solution polymerization. The influence of the structures and amounts of silane monomers on the swelling and drug‐released behaviors were studied. The results showed that, because of the hydrophobicity of the silyl group, the more silane monomers in the copolymeric hydrogels the lower was the swelling ratio of the gels. The hydrophobicity of the silyl group affected the swelling mechanism, which resulted from the non‐Fickian diffusion for the gels. The copolymeric gels clearly exhibited gel transition temperatures. The copolymeric hydrogels could be applied to a drug‐release and drug‐delivery system. The delivery amount would approach a steady state after three cycle operations of delivery. The gels also showed an on–off switch behavior on drug release depending on the temperature, and the gels released more CV with the gels in a swollen state. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 84: 2523–2532, 2002     

Thermoreversible hydrogel. V. Synthesis and swelling behavior of the N-isopropylacrylamide-co-trimethyl methacryloyloxyethyl ammonium iodide copolymeric hydrogels

A series of N-isopropylacrylamide/trimethyl methacryloyloxyethyl ammonium iodide (NIPAAm/TMMAI) copolymeric gels are prepared from the various molar ratios of NIPAAm, cationic monomer TMMAI, and N,N′-methylene bisacrylamide (NMBA) in this article. The influences of the amount of the cationic monomer in the copolymeric gels on the swelling behavior in water, various saline solutions, and various temperatures are investigated. Results show that the swelling ratios of copolymeric gels are significantly larger than those of pure homopolymer NIPAAm gel, and the more the TMMAI content, the higher the gel transition temperature. In the saline solution, results show that the swelling ratio of pure NIPAAm gel has not significantly changed with an increase of the salt concentration until the salt concentration is larger than 0.1M. The swelling ratios for the copolymeric gels NIPAAm/TMMAI decrease with increasing salt concentration. In various saline solutions, results show that the anionic effects are greater than cationic effects in the presence of common anion, different cations and common cation, and different anions for these hydrogels. Finally, we also tested the reversibility of the NIPAAm/TMMAI copolymeric gels. The deswelling and reswelling kinetics are dependent on the temperature, which is below or above the gel transition temperature. The gel with little TMMAI content has a good reversibility. © 1998 John Wiley & Sons, Inc. J Appl Polym Sci 69: 1793–1803, 1998     

Porous poly(<Emphasis Type="Italic">N</Emphasis>-isopropylacrylamide) gels polymerized in mixed solvents of water and <Emphasis Type="Italic">N,N</Emphasis>-dimethylformamide

The structures of gels polymerized using a mixed solvent that induces cononsolvency during the free radical polymerization were investigated.N,N -isopropylacrylamide (NIPA) gels were polymerized in water and N,N-dimethylformamide (DMF) mixtures. The NIPA gels can have homogeneous/heterogeneous structures depending on the mole fraction of DMF, x_D. The NIPA gel synthesized at x_D = ca. 0.25 was opaque in appearance, and its porous structure was observed by the SEM micrograph; the porous structure is formed as the aggregates of microgels phase-separated due to the cononsolvency. The porous NIPA gels achieve a very rapid shrinking rate in response to the temperature jump, which are desirable for their applications.     

Synthesis and characterization of pH- and/or temperature-sensitive hydrogels

A series of pH-sensitive hydrogels that exhibit volume phase transition phenomena have been synthesized in aqueous solution and characterized with respect to their dynamic swelling behaviors. Positively charged hydrogels were prepared by copolymerizing varying ratios of N-isopropylacrylamide and NN′-dimethylaminopropylmethacrylamide. The hydrogels based on a temperature-sensitive hydrogel demonstrate a large change of equilibrium swelling in response to small variations of pH and/or temperature. These hydrogels exhibit different lower critical solution temperature (LCST) ranges depending on the environmental pH values. Below their LCST, they exhibit small and broad pH sensitivities normally observed in most hydrophilic polyelectrolyte gels, but above their LCST, they exhibit sharp pH dependent phase transition behaviors. The pH-dependent phase transition is strongly affected by temperature, while the temperature-dependent transition is, in turn, largely influenced by the pH. As the temperature is raised, the transitional degree of gel swelling change becomes sharper and larger, and the phase transition pH value shifts to a lower pH. It was also found that swelling is faster than deswelling for these cationic hydrogels, which suggests the existence of a water diffusion barrier during the deswelling. The swelling kinetics of initially dry and glassy gels were strongly dependent on both the pH value and temperature.     

Contributions to the thermodynamics of polymer hydrogel systems

In this work, an extended version of a quasichemical thermodynamic model is presented. The swelling behavior of crosslinked acrylamide polymer gels and N-substituted derivatives, such as N-isopropylacrylamide and N-tert-butylacrylamide has been compared to predictions from such model which takes into account the specific hydrogen bonding interactions encountered in these systems. The calculated volume transition temperature of the poly(N-isopropylacrylamide) gel is 0.8 °C lower than the experimental value and the predicted solvent volume fraction in the collapsed and swollen gel states are about 2% larger than the corresponding experimental data measured at the transition point. Applying the same energy parameters obtained from regressing poly(N-isopropylacrylamide) gel swelling pressure data, the model has also been capable to correctly represent the major features found in the swelling behavior of linear poly(N-tert-butylacrylamide) and poly(N-tert-butylacrylamide) gels, after the model parameters that characterize the molecular structure were changed in accord to each polymer repetitive unit.     

The effects of interaction energy on the volume phase transition of N-isopropylacrylamide-co-N-isopropylmethacrylamide nano-sized gel particles: Applicability of molecular simulation technique

We investigated the volume phase transition temperatures of N-isopropylmethacrylamide (NIPMA)-co-N-isopropylacrylamide (NIPA) gels with various mole ratios. Nanometer-sized NIPA-co-NIPMA gel particles were prepared by precipitation polymerization and their swelling behaviors were measured using photon correlation spectroscopy (PCS). After applying the interaction energies found using the molecular simulation technique, we predicted the swelling equilibria for the hydrogels in a water system. For studying cross-linked hydrogel particles in water, we have combined the modified double-lattice theory with Flory and Erman's theory of elasticity. To correct for the deviation of the volume transition temperature, we considered the additional energy parameter (?_h) between the cross-linker and solvent molecules. We used the corrected model to describe the swelling behavior of the hydrogel and the volume transition temperature. The corrected model was agreed well with their experimental data with no fitting parameters.     

pH- and thermo-sensitive semi-IPN hydrogels composed of chitosan, <Emphasis Type="Italic">N</Emphasis>-isopropylacrylamide,and poly(ethylene glycol)-<Emphasis Type="Italic">co</Emphasis>-poly(ε-caprolactone) macromer for drug delivery

In this study, semi-IPN chitosan/poly(N-isopropylacrylamide) (PNIPAAm) hydrogels have been prepared via in situ UV-photo-crosslinking of N-isopropylacrylamide monomer using poly(ethylene glycol)-co-poly(ε-caprolactone) (PEG-co-PCL) macromer as a crosslinker in the presence of chitosan. Swelling properties of the resultant hydrogels were studied by investigating pH- and temperature dependence of equilibrium swelling ratio and oscillatory swelling–deswelling kinetics. It was found that semi-IPN hydrogels responded to both temperature and pH changes, and such stimuli-responsiveness was rapidly reversible. The rheological measurements demonstrated that the incorporation of chitosan greatly improved the mechanical strength of the hydrogels prepared. The release profiles of bovine serum albumin (BSA) from the hydrogels were also evaluated. The results showed that the release rate of BSA was higher in pH 2.0 buffer solution than in pH 7.4 buffer solution at 37 °C. Such double-sensitive hydrogels have the potential to use as smart carriers for drug delivery systems.     

Photo cross-linkable poly(N-isopropylacrylamide) copolymers III: micro-fabricated temperature responsive hydrogels

Micro-fabricated temperature responsive poly(N-isopropylacrylamide) (PNIPAAm) hydrogels were produced by photolithographic patterning of photo cross-linkable polymers. These polymers were synthesized by copolymerization of N-isopropylacrylamide (NIPAAm) and 2-(dimethyl maleimido)-N-ethyl-acrylamide (DMIAAm). The patterning process of polymers with 9.2 mol% DMIAAm and film thickness below 5 μm in the dry state was able to depict a lateral resolution of 4 μm with insignificant shape change. In order to increase the adhesion of the swollen hydrogels, and thus, the resolution of a particular pattern, a special adhesion promoter based on a monochlorosilane anchor group and a chromophore head group was synthesized. If a silicon wafer surface was pretreated with the adhesion promoter, the structures were stable and well adhered even at lower cross-linking densities. The hydrogels are suitable as working substances for micro-actuators because of their thermally induced volume changes. The swelling ratio of the pattern at low temperatures increased with a decreased cross-linking density. As expected from the chemical composition of the gels, the phase transition temperature (T_c) decreased with increasing DMIAAm content. The swelling of microstructures in water in comparison to macroscopic objects occured significantly faster. This behavior was attributed to the small gel dimension but it was even more pronounced because of the sponge-like nanostructure of the hydrogels characterized by high-resolution field emission scanning electron microscopy. Suitable applications of these hydrogels are adjusting limbs in fluid micro-systems such as micro-pumps and micro-valves.