Influence of the swelling history on the swelling kinetics of stimuli-responsive poly[(N-isopropylacrylamide)-co-(methacrylic acid)] hydrogels

The influence of the swelling history on the swelling behavior of poly[(N-isopropylacrylamide)-co-(methacrylic acid)] P[(N-iPAAm)-co-(MAA)] random copolymers hydrogels synthesized by free radical polymerization in solution of N-iPAAm and MAA comonomers crosslinked with tetraethylene glycol dimethyl acrylate (TEGDMA) has been studied. The swelling behavior under pH 7 at 18, 29, 39 and 49 °C of this series of copolymers, previously soaked either at pH 2 or 7 has been investigated. The swelling kinetics of these two series of samples displays different behavior as function of the composition and temperature. However, the equilibrium swelling values only show slight dependences on the previous soaking pH and temperature. When samples are soaked at pH 7, then the swelling at pH 7 follows a first order kinetics, irrespective of the copolymer composition or the temperature at which the experiment has been carried out. In this case, the swelling process is very fast and depends only slightly on temperature. The first order rate constant increases with the MAA content in the hydrogel. Furthermore, the swelling rate of copolymer hydrogels soaked at pH 2, show strong dependence on composition and temperature. They follow an autocatalytic swelling kinetics due to the disruption of hydrogen bond arrangements. An initial slow water uptake is followed by an acceleration process, in which water molecules inside the gel help the next water molecules to come in. Two rate constants, a first-order rate constant and an autocatalytic one have been obtained from the kinetics analysis. They have revealed different temperature dependence which may be due to a balance between hydrophobic and hydrogen bond interactions. The temperature dependence of the swelling kinetics is stronger and more complex for copolymers treated under pH 2 than for copolymers soaked under pH 7.     

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.     

On the water swelling behaviour of poly(N-isopropylacrylamide) [P(N-iPAAm)], poly(methacrylic acid) [P(MAA)], their random copolymers and sequential interpenetrating polymer networks (IPNs)

Thermo- and pH-responsive stimuli hydrogels based on N-isopropylacrylamide (N-iPAAm) and methacrylic acid (MAA) have been synthesized and their swelling behaviour studied as a function of composition, pH and temperature. Copolymers varying in composition have been obtained by copolymerizing these two monomers and interpenetrating polymer networks (IPNs) of P(MAA) and P(N-iPAAm) by the sequential method. Temperature and pH have been changed in the ranges from 25 to 40 °C and from 2 to 9, respectively. The swelling behaviour of the hydrogels depends on the nature of the polymer and the environmental conditions, namely pH and temperature. Copolymer gels under basic conditions exhibit higher degree of swelling than the homopolymer ones. The disruption of the complexes dominates the kinetic swelling of MAA enriched gels under basic conditions. The hydrogen bond formation between carboxyl and amide groups has been made clear through the dynamic swelling behaviour of copolymers under acidic conditions. IPNs reduce their ability to swell in water with increasing P(N-iPAAm) content because of the formation of hydrophobic interpolymer complexes through hydrogen bonding. Lower critical solution temperature occurs only in the enriched N-iPAAm copolymers under acidic conditions when the MAA carboxyl groups are unionized.     

Synthesis and micellization of thermo- and pH-responsive block copolymer of poly(N-isopropylacrylamide)-block-poly(4-vinylpyridine)

A novel double-hydrophilic block copolymer poly(N-isopropylacrylamide)-block-poly(4-vinylpyridine) (PNIPAM-b-P4VP) with low polydispersity which could respond to both temperature and pH stimuli in aqueous solution was synthesized by atom transfer radical polymerization. Micellization of the copolymer in aqueous solution was characterized by dynamic and static laser scattering, ¹H NMR and transmission electron microscopy. In aqueous solution, the copolymer existed as unimer at pH 2.8 at 25 °C. When the temperature was raised to 50 °C at pH 2.8, the copolymer associated into spherical core-shell micelles with the PNIPAM block forming the core and the P4VP block forming the shell. On the other hand, when pH was increased from 2.8 to 6.5 at 25 °C, the copolymer associated into spherical core-shell micelles with the core formed by the P4VP block and the shell formed by the PNIPAM block. The process was reversible. The critical aggregation temperature of the block copolymer is 36 °C, and the critical aggregation pH value is 4.7.     

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.     

Schizophrenic copolymer from natural biopolymer by facile grafting

A novel schizophrenic copolymer responsive to pH and temperature change was developed through copolymerization of N-isopropylacrylamide (NIPAm) and acrylic acid (AA) on chitosan chains by a bio-friendly initiator. The behavior of purified graft copolymer in solution phase was studied in detail by NMR, Zetasizer, TEM, SEM and ATR-FTIR techniques. In dilute aqueous media, two types of reversible nanoparticles can be obtained by changing temperature and pH: positively charged micelles with chitosan-shell in acidic solutions above 33 °C and negatively charged micelles with P(NIPAm-co-AA)-shell in alkaline solutions. The transform between these two oppositely charged micelles can be easily controlled by changing pH at human body temperature. The effect of graft degree on the solution behavior was also studied. This novel schizophrenic copolymer has potential applications in drug delivery and other controlled releases.     

Poly(ethylene oxide)-grafted poly(N-isopropylacrylamide) networks: Preparation, characterization and rapid deswelling and reswelling behavior of hydrogels

Poly(ethylene oxide)-grafted poly(N-isopropylacrylamide) networks (PNIPAAm-g-PEO) were prepared via the reversible addition-fragmentation chain transfer polymerization (RAFT) of N-isopropylacrylamide with trithiocarbonate-terminated poly(ethylene oxide) and N,N′-methylenebisacrylamide as the chain transfer agent and the crosslinking agent, respectively. It was found that the PNIPAAm-g-PEO copolymer networks were microphase-separated and that PEO microdomains were dispersed in the PNIPAAm matrix. The hydrogel behavior of the PNIPAAm-g-PEO networks was investigated using swelling, deswelling and reswelling tests. The PNIPAAm-g-PEO hydrogels displayed faster responses to external temperature changes than did the control PNIPAAm hydrogel.     

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.     

Synthesis of rapid responsive gels comprising hydrophilic backbone and poly(N-isopropylacrylamide) graft chains by RAFT polymerization and end-linking processes

A thermosensitive poly(N-isopropylacrylamide) (PNIPAM) grafted gel, which comprises hydrophilic backbone and freely mobile PNIPAM graft chains, was synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization and end-linking processes. Functional PNIPAM bearing dithiobenzoate end group (-C(S)S-R) was prepared first, and then it was reacted with divinyl compounds to obtain gel. In order to adjust the composition of the gels, two divinyl compounds, N,N-methylenebisacrylamide (BIS) and poly(ethylene glycol) diacrylate (PEGDAC), were used. The cross-linking polymerization mechanism was proposed. The swelling and deswelling kinetics of the hydrogels were measured. The gels exhibit rapid deswelling kinetics. At the same time, they show rapid swelling kinetics within 30 min, whereas a conventional PNIPAM-co-PEG-co-BIS gel with the same feed composition requires more than 10 h to reach swelling equilibrium.     

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.     

Preparation of poly(N-isopropylacrylamide)–SiO2 hybrid gels and their thermosensitive properties

The swelling and adsorption behavior of poly(N-isopropylacrylamide)–SiO₂ hybrid gels, derived from copolymerization of N-isopropylacrylamide and 3-methacryloxypropyltrimethoxysilane (MPTMOS) and following hydrolysis and condensation, were investigated. The hybrid gels exhibited temperature dependence of both the swelling ratio and adsorption of solutes, and their temperature dependence of both the swelling ratio and adsorption of solutes, and their temperature dependence was related to the MPTMOS content in the hybrid gels. In addition, the modification of thermosensitive properties of the hybrid gels could be achieved by treatment with other silane compounds. © 1996 John Wiley & Sons, Inc.     

Synthesis and characterization of pH- and temperature-sensitive hydrogel of N-isopropylacrylamide/cyclodextrin based copolymer

A reactive β-Cyclodextrin (β-CD) based monomer carrying vinyl carboxylic acid functional groups was synthesized via reaction of β-CD with maleic anhydride (MAH) in N,N-dimethylformamide (DMF) at 80 °C. By copolymerization of the monomer with N-isopropylacrylamide (NIPA), a novel hydrogel, poly(NIPA-co-MAH-β-CD) with pH and temperature sensitivities plus molecular inclusion function, was obtained using free radical polymerization in aqueous solution. The hydrogel's composition was determined by element analysis and infrared spectroscopy. Equilibrium swelling ratio (ESR) of hydrogels was tested under different environment of pH, temperature and ionic strength. The results indicated that ESR of hydrogels presents marked variations following the change of experimental conditions used.     

Dynamic swelling of hydrogels based on random terpolymers of N-isopropylacrylamide, methacrylic acid and poly(ethylene glycol) macromonomer

A series of pH-responsive hydrogels based on N-isopropylacrylamide (N-iPAAm), methacrylic acid (MAA) and poly(ethylene glycol) monomethyl ether monomethacrylate macromonomer (PEGMEMA), P(N-iPAAm-co-MAA-co-PEGMEMA) random terpolymers, were synthesized and their swelling behaviour studied as a function of both monomer composition and previous swelling treatment. The swelling kinetic curves were followed using gravimetric, photographic and magnetic resonance imaging (MRI) techniques, which provide spatial and temporal resolution. The swelling behaviour was non-Fickian at pH 7, being this fact more relevant when the samples were pre-soaked in pH 2 solution. Low pH promotes hydrogen bond arrangements that disrupt at pH 7, where sigmoidal swelling curves were observed. The sigmoidal shape of the curves increases as well as the swelling time with increasing N-iPAAm/PEGMEMA ratio. This indicates that hydrogen bond arrangements between MAA and N-iPAAm are stronger that those formed by MAA and PEGMEMA. The influence of the polymer composition on the hydrogen bond arrangements was also studied from the swelling kinetics curves at different pH media, observing that the swelling rate, the swelling curve shape and the whole amount of water absorbed were clearly dependent on this parameter.     

Poly(N-isopropylacrylamide) hydrogels with improved shrinking kinetics by RAFT polymerization

Functional poly(N-isopropylacrylamide) (PNIPAM) hydrogels were prepared by reversible addition fragmentation chain transfer (RAFT) polymerization of N-isopropylacrylamide (NIPAM) in the presence of N,N-methylenebisacylamide (BIS) as a cross-linker and 4-cyanopentanoic acid dithiobenzoate as chain transfer reagent (CTA). The swelling behaviors were investigated and the hydrogels by RAFT polymerization (RAFT gels) showed accelerated shrinking kinetics and higher swelling ratio comparing with conventional hydrogel (CG). It could be attributed to the presence of dangling chains mainly caused by CTA, which could retard the crosslinking reaction rate greatly. Another CTA, 3-(trithiocarbonyl) propanoic acid, was adopted to further investigate the effect of CTA. It showed the similar effect except the different accelerated degree to the shrinking kinetics. Furthermore, the living character of the RAFT process was used to polymerize a new batch of monomer (NIPAM) from functional RAFT gels to introduce grafted structure. The PNIPAM-g-PNIPAM hydrogels indicted further accelerated shrinking kinetics than functional backbone hydrogels.     

Preparation and thermally induced adhesion properties of a poly(vinyl alcohol)-g-N-isopropylacrylamide copolymer membrane

In the work described here, poly(vinyl alcohol)-g-N-isopropylacrylamide was prepared via graft polymerisation of N-isopropylacrylamide (NIPAM) onto poly(vinyl alcohol) (PVA). The structure and components of the polymer were characterised by differential thermogravimetry (DTG), differential scanning calorimetry (DSC), ¹H nuclear magnetic resonance spectroscopy (¹H NMR) and fourier transform infrared spectroscopy (FT-IR) testing, respectively. The T-type peel adhesion strengths and water contact angles of the prepared graft copolymer membranes were determined at different temperatures. The results indicated that the membrane has an obvious change in adhesion and water contact angle around the lower critical solution temperature (LCST) of the thermosensitive PNIPAM, regardless of the composition of the copolymers. Based on the scanning electron microscope (SEM) and energy dispersive spectrometric (EDS) analysis of freeze-dried graft copolymer membranes swollen in water at various temperatures, a mechanism for the thermally induced adhesion properties of the graft copolymer was proposed.     

Thermoreversible swelling behaviour of hydrogels based on N-isopropylacrylamide with a hydrophobic comonomer

Hydrogels were prepared by free radical polymerisation in aqueous solution of N-isopropylacrylamide (NIPA) and of NIPA with di-n-propylacrylamide (DPAM), di-n-octylacrylamide (DOAM) or di-dodecylacrylamide (DDAM) as hydrophobic comonomer. N,N-methylene bisacrylamide (BIS) and glyoxal bis(diallyacetal) (GLY) were used as crosslinkers. A series of copolymers with three different comonomer contents was synthesised and for some polymers three different crosslinker concentrations were employed. The swelling equilibrium of these hydrogels was studied as a function of temperature, hydrophobic comonomer species and content in aqueous solutions of the anionic surfactant sodium dodecyl sulfate (SDS). In pure water the gels showed a discontinuous volume phase transition at 33 and 30 °C for PNIPA and hydrophobically modified PNIPA copolymeric hydrogels, respectively. The swelling ratio r and the transition temperature (LCST) increased at low temperatures with the addition of SDS, this is ascribed to the conversion of non-ionic PNIPA gels into polyelectrolyte gels through the binding of SDS. At SDS concentration below 0.5 wt%, gels exhibited a single discontinuous volume transition at 36-38 °C. However, for SDS concentration above 0.5 wt%, two discontinuous volume transitions at 36-40 and 70 °C were observed. Additionally, the replacement of BIS by the novel octafunctional crosslinker glyoxal bis(diallylacetal) (GLY) yielded an increase in the swelling ratio.     

Copolymer hydrogels based on N-isopropylacrylamide and itaconic acid

In this study, the swelling behaviour of copolymer hydrogels of N-isopropylacrylamide (NIPAM) and itaconic acid (IA) in response to temperature and pH value of the external media was studied. The equilibrium degree of swelling for PNIPAM and PNIPAM/IA copolymers was greater at 25 °C than at 37 °C. The degree of swelling was low at low pH values. As the degree of ionization increased above the nominal pK_a values of IA, the increased hydrophilicity resulted in larger degrees of swelling. At 37 °C, the PNIPAM hydrogel and some copolymers show anomalous swelling behaviour, i.e. the overshooting effect, in buffered solutions of certain pH values. A swelling-deswelling study showed that the deswelling process of the hydrogels was faster then the swelling process. According to dynamic swelling studies, the diffusion exponent and the diffusion coefficient both increase with increasing content of IA.     

Swelling and mechanical behavior of poly(N-isopropylacrylamide)/Na-montmorillonite layered silicates composite gels

Clay-polymer hydrogel composites have been synthesized based on poly(N-isopropylacrylamide) (PNIPAM) gels containing 0.25-4 wt% of the expandable smectic clay Na-montmorillonite layered silicates (Na-MLS). The morphology of the composite gels has been studied using a polarized optical microscope. The size of Na-MLS aggregates increases with Na-MLS concentration. The swelling ratio of the Na-MLS/PNIPAM composite in water is increased at the low Na-MLS concentration but decreases as the concentration increases. Correspondingly, the shear modulus of the gel is found to exhibit a distinct minimum against clay concentration. For Na-MLS concentrations ranging from 2.0 to 3.2 wt%, the composite gels have larger swelling ratio and stronger mechanical strength than those for a pure PNIPAM. The presence of Na-MLS does not affect the value of the lower critical solution temperature (LCST) of the PNIPAM. However, the gel volume change at the LCST is first increased and then decreased upon the increase of the Na-MLS. No pH induced phase transition is observed for the Na-MLS/PNIPAM composites. The experimental results can be explained by considering that Na-MLS is physically entrapped inside rather than chemically bonded into the gel.     

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.     

Cellular uptake of tailored copolymer synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization

The tailored copolymer poly(methoxy-PEG acrylate-co-N-hydroxysuccinimide-co-fluorescein diacetate 5-maleimide) (P1) and block copolymer poly(N-isopropylacrylamide)-b-poly(methoxy-PEG acrylate-co-N-hydroxysuccinimide-co-fluorescein diacetate 5-maleimide) (P2) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, which were both water-soluble, fluorescent and containing active group N-hydroxysuccinimide (NHS). Due to the temperature-sensitive poly(N-isopropylacrylamide) unit, the latter copolymer P2 formed nanoparticles at 37 °C in aqueous medium. Both P1 and P2 were taken up by cultured human umbilical vein endothelial cells (HUVECs) and localized mainly in the cytoplasm, which could subsequently be detected by confocal laser scanning microscopy (CLSM).