Chemically Crosslinked pH- and Temperature-Sensitive (N-isopropylacrylamide-co-1-vinyl-2-pyrrolidone) Based on New Crosslinker: I. Swelling Behavior

Novel pH- and temperature-sensitive polymer matrices based on N-isopropylacrylamide have been developed. The hydrogels were prepared by bulk radical polymerization of N-isopropylacrylamide and 1-vinyl-2-pyrrolidinone in appropriate amounts of distilled water using different mol% of traditional N,N-methylene bisacrylamide (MBA) and the new synthesized N,N,N-tris acryloyl melamine (MAAm) crosslinkers. Lower critical solution transition temperatures (LCST) were measured by differential scanning calorimetry. The synthesized hydrogels have LCST lower than 40°C. The influence of environmental conditions such as temperature and pH on the swelling behavior of these polymeric gels was investigated. The swelling behaviors of the resulting gels show pH sensitivity. The crosslinked NIPAAm/VP with MAAm hydrogels exhibited more rapid deswelling rate than NIPAAm/VP hydrogels crosslinked with MBA in pure water in response to abrupt temperature changes from 20°C to 50°C.     

Swelling behaviors of thermoresponsive hydrogels cross-linked with acryloyloxyethylaminopolysuccinimide

Based on a biodegradable cross-linker, acryloyloxyethylaminopolysuccinimide (AEA-PSI), a series of looser cross-linked poly(N-isopropylacrylamide-co-acrylic acid) [P(NIPAAm-co-AAc)] hydrogels were prepared, and their water content, swelling/deswelling kinetics, and the morphology of the gels were investigated. The swelling behaviors of AEA-PSI-cross-linked P(NIPAAm/AAc) hydrogels were investigated in Dulbecco’s phosphate-buffered saline (pH = 7.4), in the distilled water, and in the simulated gastric fluids (pH = 1.2), respectively. The water contents of the hydrogels were controlled by the monomer molar ratio of NIPAAm/AAc, swelling media, and the temperature. In the swelling kinetics, all the dried hydrogels exhibited fast swelling behavior, and the swelling ratios were influenced significantly by the amounts of AEA-PSI and AAc content. The deswelling kinetics of the hydrogel were independent of the content of AAc and cross-linker. Lastly, the morphology of the hydrogels was estimated by the field scan electron microscopy.     

磁性半互穿网络智能水凝胶的合成及性质评价

以甲基丙烯酸(MAA)、N-异丙基丙烯酰胺(NIPAAm)、丙烯酰胺(AM)为原料,N,N′-亚甲基双丙烯酰胺(MBA)为交联剂,利用IPN技术并结合磁性的γ-Fe2O3增强剂,在水溶液中制备了半互穿网络水凝胶(PMAA/PAM-NIPAAm/γ-Fe2O3),研究了水凝胶的溶胀性﹑热稳定性和电磁性。实验表明,水凝胶形成稳定的IPN互穿网络结构且该水凝胶具温度、pH双重敏感性和顺电磁性。所合成的水凝胶在低临界溶解温度31℃以下,具有明显正向温敏性,高于此温度,水凝胶的温度敏感性会逐渐减弱。产品成功克服了NIPAAm类水凝胶的温缩性。     

Anticancer drug release from poly(N-isopropylacrylamide/itaconic acid) copolymeric hydrogels

The drug uptake and release of anticancer drug from N-isopropylacrylamide/itaconic acid copolymeric hydrogels containing 0–3 mol% of itaconic acid irradiated at 48 kGy have been investigated. 5-Fluorouracil (5-FU) is used as a model anticancer drug. The effect of 5-FU solution on swelling characteristics of PNIPAAm and P(NIPAAm/IA) copolymeric hydrogels have also been studied. The percent swelling, equilibrium swelling, equilibrium water/5-FU content and diffusion constant values are evaluated for poly(N-isopropylacrylamide) (PNIPAAm) and poly(N-isopropylacrylamide/itaconic) (P(NIPAAm/IA)) hydrogels at 130 ppm of 5-FU solution at room temperature. Diffusion of 5-FU solution into the hydrogels has been found to be the non-Fickian type. Finally, the kinetics of drug release from the hydrogels are examined.     

Synthesis and Characterization of Hydrogels Based on Gamma Radiation Copolymerization of N‐isopropylacrylamide and Ethylene Glycol Dimethacrylate Monomers

Hydrogels based essentially on N‐isopropylacrylamide (NIPAAm) and different ratios of ethylene glycol dimethacrylate (EGDMA) monomer were synthesized by gamma radiation copolymerization. The thermal decomposition behavior of NIPAAm/EGDMA hydrogels was determined by thermogravimetric analysis (TGA). The effect of temperature and pH on the swelling behavior was also studied. The results showed that the ratio of EGDMA in the comonomer feeding solution has a great effect on the yield product, gel fraction and water content in the final hydrogel. In this regard, it was observed that the increase of EGDMA ratio decreased these properties. The TGA study showed that all the compositions of NIPAAm/EGDMA hydrogels displayed higher thermal stability than the hydrogel based on pure PNIPAAm hydrogel. The swelling kinetics in water showed that pure PNIPAAm and NIPAAm/EGDMA hydrogels reached equilibrium after 6 h. However, NIPAAm/EGDMA hydrogels show swelling in water lower than pure PNIPAAm. The results showed that the swelling character of pure PNIPAAm and NIPAAm/EGDMA hydrogels was affected by the change in temperature within the temperature range 25–40°C, and showed a reversible change in swelling in the pH range 4–7 depending on composition.     

Synthesis and characterization of thermoresponsive hydrogels cross-linked with acryloyloxyethylaminopolysuccinimide

Biodegradable cross-linkers acryloyloxyethylaminopolysuccinimide (AEA-PSI) were obtained by microwave irradiation using maleic anhydride as materials. With AEA-PSI cross-linker, cross-linked poly(N-isopropylacrylamide-co-acrylic acid) [P(NIPAAm-co-AAc)] hydrogels were prepared, and their phase transition behavior, lower critical solution temperature (LCST), water content, thermodynamics stability, and enzymatic degradation properties were investigated. By alternating the NIPAAm/AAc molar ratio, hydrogels were synthesized to have LCST in the vicinity of 37 °C. The LCST of AEA-PSI-cross-linked P(NIPAAm-co-AAc) hydrogels was significantly influenced by monomer ratio of the NIPAAm/AAc but not by the cross-linking density within the polymer network. The water content of AEA-PSI-cross-linked P(NIPAAm-co-AAc) hydrogels was more than 90% even at 37 °C, which was controlled by the monomer molar ratio of NIPAAm/AAc, swelling media, and the cross-linking density. The thermodynamics stability was also characterized by thermogravimetry. In enzymatic degradation studies, breakdown of the AEA-PSI-cross-linked P(NIPAAm-co-AAc) hydrogels was dependent on the cross-linking density. Submitted to Colloid and Polymer Science, 2007-1-28.     

Studies on preparation and properties of NIPAAm/hydrophobic monomer copolymeric hydrogels

A series of thermoreversible copolymeric hydrogels with various molar ratios of N-isopropylacrylamide (NIPAAm) and hydrophobic monomers such as 2,2,3,3,4,4,5,5-octafluoropentyl methacrylate (OFPMA) and n-butyl methacrylate (BMA) were prepared by emulsion polymerization. The effect of hydrophobic monomer on the swelling behavior and mechanical properties of the present copolymeric hydrogels was investigated. Results showed that the equilibrium swelling ratio and critical gel transition temperature (CGTT) decreased with an increase of the content of hydrophobic monomer, but the gel strength of the gel increased with an increase of the content of hydrophobic monomer. Due to stronger hydrophobicity of OFPMA, the NIPAAm/OFPMA copolymeric hydrogels had lower swelling ratios and higher gel strengths than NIPAAm/BMA copolymeric gels.     

“Smart” carboxymethylchitosan hydrogels crosslinked with poly(N-isopropylacrylamide) and poly(acrylic acid) for controlled drug release

Carboxymethylchitosan (CMC) hydrogels containing thermo-responsive poly(N-isopropylacrylamide) (poly(NIPAAm)) and pH-responsive poly(acrylic acid) (poly(AA)) were prepared via a free radical polymerization in the presence of hexamethylene-1,6-di-(aminocarboxysulfonate) crosslinking agents. A proper ratio of CMC to NIPAAm and AA used in the reaction was investigated such that the thermo- and pH-responsive properties of the hydrogels were obtained. Water swelling of the hydrogels was improved when the solution pH was in basic conditions (pH 10) or the temperature was below its lower critical solution temperature (LCST). Effects of the change in solution temperature and pH on water swelling properties of the hydrogel as well as the releasing rate of an entrapped drug were also investigated. The hydrogels were not toxic and showed antibacterial activity against Straphylococcus aureus (S. aureus). The pH- and thermo-responsive properties of this novel “smart” hydrogel might be efficiently used as dual triggering mechanisms in controlled drug release applications.     

Preparation and characterization of temperature- and pH-sensitive hemicellulose-containing hydrogels

In this work, a hemicellulose-containing hydrogel was synthesized. As the first step, a temperature- and pH-sensitive copolymer was synthesized from itaconic acid and N-isopropylacrylamide (NIPAAm). Then the hydrogel was prepared by reacting the copolymer with acylated hemicellulose and polyvinyl alcohol. The morphology, compressive strength, thermal stability, swelling/deswelling behavior, drug-release behavior performances of the hydrogels were investigated. The lower critical solution temperature of the hydrogels varied in 34–44°C when the NIPAAm and itaconic acid mass ratios ranged in 100/0–90/10. Both temperature and pH had a significant influence on equilibrium swelling ratio of hydrogels. The equilibrium swelling ratio increased with pH, but decreased with temperature. Cytocompatibility assay demonstrated that this hemicellulose-containing hydrogel was biocompatible. The release process of salicylic acid suggested that this hydrogel had a potential use in controlled drug release.     

Synthesis of thermosensitive hydrogels from acryloyloxyethyl trialkyl phosphonium chloride–N‐isopropylacrylamide–N,N′‐methylenebisacrylamide terpolymers and their temperature dependence of water absorption

Thermosensitive polymer hydrogels were prepared by the copolymerization of three kinds of acryloyloxyethyl trialkyl phosphonium chlorides (AETRs) with alkyl chains of different lengths, with N‐isopropyl acrylamide (NIPAAm) and N,N′‐methylenebisacrylamide (MBAAm). The water content of the AETR–NIPAAm–MBAAm terpolymers obtained at molar ratios of the crosslinking agent greater than 2 decreased with increasing temperature and decreased sharply around 35 °C. However, the water contents of the AETR–NIPAAm–MBAAm (X/100/1) terpolymers obtained at a molar ratio of 1 of the crosslinking agent increased once with increasing temperature and then decreased from 3 to around 40 °C. The water contents of the AETR–NIPAAm–MBAAm (3/100/1 or 2) terpolymers decreased with the increasing length of alkyl chains in phosphonium groups in the terpolymers. The water contents of the AETR–NIPAAm–MBAAm terpolymers increased by the addition of a small amount of urea and then decreased with increasing urea concentration. However, the water contents decreased abruptly with the addition of NaCl. The AETR–NIPAAm–MBAAm terpolymers exhibited high adsorption for sodium dodecylbenzene sulfonate but no adsorption for sodium benzene sulfonate. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 1505–1514, 2001     

Synthesis and characterization of thermoresponsive hydrogels cross-linked with chitosan

Hydrogels composed of N-isopropylacrylamide (NIPAAm) and acrylic acid (AAc) were prepared by redox polymerization with degradable chitosan cross-linkers. Chitosan degradable cross-linkers were synthesized by the acrylation of the amine groups of glucosamine units within chitosan and characterized with ¹H NMR. With the chitosan cross-linkers, loosely cross-linked poly(N-isopropylacryamideco-acrylic acid) [P(NIPAAm-co-AAc)] hydrogels were prepared, and their phase transition behavior, lower critical solution temperature (LCST), water content and degradation properties were investigated. The chitosan cross-linked P(NIPAAm-co-AAc) hydrogels were pliable and transparent at room temperature. The LCST could be adjusted at 32∼39°C by alternating the feed ratio. Swelling was influenced by NIPAAm/AAc monomer ratio, cross-linking density, swelling media, and temperature. All hydrogels with different feeding ratios contained more than 95% water at 25°C in the ultra pure water and phosphate-buffered saline (PBS, pH = 7.4 ± 0.1), and had a prospective swelling in the simulated gastric fluids (SGF, pH = 1.2) > 72.54%. In degradation studies, breakdown of the chitosan cross-linked P(NIPAAm-co-AAc) hydrogels was dependent on the cross-linking density. The chitosan cross-linked P(NIPAAm-co-AAc) hydrogels which can be tailored to create environmentally-responsive artificial extracellular materials have great potential for future use.      

Insulin release behavior of poly(N-isopropylacrylamide-co-N-vinyl-2-pyrrolidone) hydrogel based on modified melamine crosslinkers

Novel hydrogels based on poly(N-isopropylacrylamide-co-N-vinyl-2-pyrrolidone) (PNIPAAm/PNVP), were synthesized by solution radical polymerization using water as solvent and different weight percentage of crosslinkers ranging from 0.5 to 4%. The monomer mol ratios of NIPAAm/VP (0.9/0.1, 0.5/0.5, and 0.1/0.9) were used in all cases. N,N′-methylenebisacrylamide (MBA) and the new synthesized N,N,N-triacrylamido melamine (MAAm) were used as crosslinkers. The swelling parameters such as the swelling ratio Q, equilibrium water content (EWC), volume fraction of polymer φ_p and volume fraction at crosslinking φ_r were calculated from swelling measurements at different temperatures. The lower critical solution temperatures (LCST) of the prepared hydrogels were measured using DSC technique. The data of LCST indicated that the NIPAAm/VP crosslinked with MAAm or MBA showed reversible swelling and shrinking with temperature changes. The temperature dependence of swelling ratio and response kinetics upon heating or cooling was also investigated to understand the smart properties, i.e., temperature sensitive properties of these smart hydrogels. The in vitro release experiments were carried out at 22 and 37°C, respectively, to investigate the effect of temperature-sensitive property of these PNIPAAm/PNVP hydrogels crosslinked with MAAm and MBA crosslinkers on insulin release profiles.     

Synthesis of hydrophilic microspheres with LCST close to body temperature for controlled dual‐sensitive drug release

Novel stimuli‐responsive hydrophilic microspheres were prepared by free radical polymerization of hydroxyethyl methacrylate (HEMA) and methacrylic acid (MA), as hydrophilic monomers, and N‐isopropylacrylamide (NIPAAm) and N,N′‐ethylenebisacrylamide (EBA), as thermo‐sensitive monomer and crosslinker, respectively. Hydrophilic comonomers were introduced in the macromolecular network to synthesize materials with tunable thermal behavior. In addition, by introducing in the polymerization feed both a hydrophilic and a pH‐sensitive monomer, such as MA, dual stimuli‐responsive (pH and temperature) hydrogels were synthesized. The incorporation of monomers in the network was confirmed by infrared spectroscopy, while the network density and the shape of hydrogels was found to strictly depend on the concentration of monomers in the polymerization feed. Thermal analyses showed negative thermo‐responsive behavior with pronounced water affinity of microspheres at a temperature lower than lower critical solution temperature (LCST). In our experiment, the LCST values of the hydrogels were in the range 34.6–37.5°C, close to the body temperature, and the amount of hydrophilic moieties in the polymeric network allows to collect shrinking/swelling transition temperatures higher than the LCST of NIPAAm homopolymers. In order to test the preformed materials as drug carriers, diclofenac diethylammonium salt (DDA) was chosen and drug entrapment percent was determined. Drug release profiles, in media at different temperature and pH, depend on hydrogels crosslinking degree and drug–bead interactions. By using semi‐empirical equations, the release mechanism was extensively studied and the diffusional contribute was evaluated. Copyright © 2010 John Wiley & Sons, Ltd.     

Thermoresponsive drug controlled release from chitosan‐based hydrogel embedded with poly(N‐isopropylacrylamide) nanogels

A facile synthetic strategy was developed for the preparation of thermoresponsive nanocomposite hydrogels comprising crosslinked chitosan (CS) networks and poly(N‐isopropylacrylamide) [p(NIPAAm)] nanogels. First, thermoresponsive p(NIPAAm) nanogels were synthesized via emulsion polymerization. The p(NIPAAm) nanogels were introduced into methacrylamide CS (MC) solution and the free‐radical initiated crosslinking reaction of MC produced nanogel‐embedded hydrogels. The last step involves the loading of the antibacterial model drug levofloxacin (LFX) into the prepared nanocomposite hydrogels by allowing the preformed hydrogels to swell to equilibrium in the drug's aqueous solution. The integration of p(NIPAAm) nanogel into CS networks facilitates thermoresponsive release of LFX with an enhancement of the drug‐loading capacity within the hydrogel. Notably, thermoresponsive drug‐release was achieved without unwarranted modification of the hydrogel's dimension and shape, although an increase in temperature caused the collapse of the p(NIPAAm) nanogels. The thermoresponsive property of the investigated nanocomposite hydrogel is beneficial and may offer broad opportunities for drug temperature‐triggered release for clinical applications. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 1907–1914     

Effect of kappa-carrageenan on the properties of poly(N-vinyl pyrrolidone)/kappa-carrageenan blend hydrogel synthesized by γ-radiation technology

A series of hydrogels in the form of rods were prepared from kappa-carrageenan (KC) and poly (N-vinyl pyrrolidone) (PVP) by gamma radiation with ⁶⁰Co γ source at room temperature. The properties of the prepared hydrogels, such as the gel strength, gel fraction and swelling behavior were investigated. Incorporation of KC into the PVP/water system increased obviously the gel strength and equilibrium degree of swelling (EDS) of PVP hydrogel. The experimental analyses showed that the crosslinking reaction of PVP was quicker than the degradation of KC at a low dose (less than 30 kGy), and the degradation of KC was inhibited in the PVP/KC mixture system. So an interpenetrating polymer network (IPN) hydrogel composed of PVP (a chemical crosslinking network) and KC (a physical crosslinking network) was proposed here. The existence of different classes of water in this IPN system was shown by water melting curves using DCS.     

Synthesis and properties of pH and temperature sensitive P(NIPAAm-co-DMAEMA) hydrogels

In order to investigate the influence of the continuous alkylamide sequence having pH sensitive unit on the temperature sensitivity of poly(N-isopropylacrylamide) (PNIPAAm)-based hydrogel, a monomer, N-(2-(dimethylamino) ethyl)-methacrylamide (DMAEMA), having an ethylamide group as well as an aliphatic tertiary amino group, was designed and synthesized. Hydrogels based on NIPAAm and DMAEMA were prepared via free radical polymerization. The resulted P(NIPAAm-co-DMAEMA) hydrogels were characterized in terms of maximum swelling ratio, swelling kinetics, temperature response kinetics, and effect of pH. The data obtained show that the novel hydrogels have the strong desire to respond to external temperature and pH stimuli. Importantly, because the P(NIPAAm-co-DMAEMA) hydrogels have the continuous alkylamide sequence containing isopropylamide pendant groups from PNIPAAm and ethylamide pendant groups from PDMAEMA, the incorporation of DMAEMA moiety not only provides the pH sensitivity, but also maintains the thermal properties of P(NIPAAm-co-DMAEMA) hydrogels, even as the molar percentage of DMAEMA moiety reaches 14 mol%.     

The effect of external stimuli on the Bovine Serum Albumin adsorption capacity of poly(acrylamide/maleic acid) hydrogels prepared by gamma rays

The effects of external stimuli such as pH of the buffer solution, ionic strength, temperature and the amount of poly-electrolyte monomer in the hydrogel system on the Bovine Serum Albumin (BSA) adsorption capacity of poly(acrylamide/maleic acid) [P(AAm/MA)] hydrogels were investigated. Poly-electrolyte P(AAm/MA) hydrogels with varying compositions were prepared by irradiating acrylamide/maleic acid/water mixtures with γ rays at ambient temperature. Langmuir type adsorption isotherms were observed for all prepared hydrogels. Increase of ionic strength of the buffer solution from 0.01 to 0.1 mol dm⁻³ decreased the adsorption capacity of hydrogels and zero adsorption was observed in the presence of 0.1 mol dm⁻³ Na⁺ and Ca²⁺ ion in the adsorption medium. The adsorption capacity of hydrogels was found to increase from 0 to 120 mg BSA/g dry gel, by changing external stimuli and hydrogel composition.     

Radiation preparation of PVA-g-NIPAAm in a homogeneous system and its application in controlled release

Thermosensitive PVA-g-NIPAAm copolymers were prepared by graft copolymerization of N-isopropylacrylamide (NIPAAm) onto poly (vinyl alcohol) (PVA) in homogeneous system of dimethyl sulfoxide (DMSO) by ⁶⁰Co-γ irradiation at room temperature. The factors of affecting the grafting yield, such as radiation dose, dose rate, acid concentration, were investigated. It was found that the grafting yield was increased with dose up to 30 kGy, but decreased slightly with dose rate from 61.2 to 50.1 Gy/min. The acid concentration also had influence on the grafting yield. Then the hydrogel of PVA-g-NIPAAm copolymer was made through a freezing–thawing process. The PVA-g-NIPAAm hydrogel exhibited obvious thermal sensitivity, which was observed from the differences of swelling behavior in water at different temperatures (below or above LCST). In addition, the release of Methylene Blue (MB) from this kind of hydrogel was studied. The release rate of MB from PVA-g-NIPAAm copolymer hydrogel at 48°C was faster than that at 15°C due to the shrinkage of the hydrogel at 48°C.     

Cu(II) immobilization in AAc/NIPAAm-based polymer systems synthesized using ionizing radiation

Polymer systems based on the pH-responsive monomer acrylic acid (AAc) and the thermosensitive monomer N-isopropylacrylamide (NIPAAm) were synthesized using gamma radiation. Three systems were synthesized: a comb-type hydrogel structure (grafting of NIPAAm onto crosslinked PAAc), a binary graft of both monomers onto a polypropylene (PP) film synthesized by a one-step method and a binary graft prepared by a two-step method. The binary graft systems were characterized by swelling behavior and the reversibility of water uptake. The three systems were compared with respect to their Cu(II) adsorption quantity, reversibility and time response. The binary graft system synthesized in one step exhibited the best adsorption response. The comb-type hydrogel required 150 h to reach its maximum swelling percentage, and the binary graft systems on polypropylene (PP) prepared by the one- and two-step irradiation-based methods required 10 and 30 min, respectively. The optimum pH range for Cu(II) immobilization was 5-6 in the binary graft system synthesized in one step. The maximum adsorption capacity for Cu(II) in the (PP-g-(AAc/NIPAAm)) (45% graft) was found to be 337 mg g⁻¹, and the adsorption followed the Freundlich model.     

Synthesis and characterization of temperature-sensitive and biodegradable hydrogel based on N-isopropylacrylamide

Based on a biodegradable cross-linker, N-maleyl chitosan (N-MACH), a series of Poly(N-isopropylacrylamide) (PNIPAAm) and Poly(N-isopropylacrylamide-co-acrylamide) [P(NIPAAm-co-Am)] hydrogels were prepared, and their lower critical solution temperature (LCST), swelling kinetics, equilibrium swelling ratio in NaCl solution, and enzymatic degradation behavior in simulated gastric fluids (SGF) were discussed. The LCST did not change with different cross-linker contents. By altering the NIPAAm/Am molar ratio of P(NIPAAm-co-Am) hydrogels, the LCST could be increased to 39°C. The LCST of the hydrogel was significantly influenced by the monomer ratio of the NIPAAm/Am but not by the cross-linker content. In the swelling kinetics, all the dry hydrogels exhibited fast swelling behavior, and the swelling ratios were influenced by the cross-linker content and NIPAAm/Am molar ratios. Equilibrium swelling ratio of all the hydrogels decreased with increasing NaCl solution concentration. In enzymatic degradation tests, the weight loss of hydrogels was dependent on the cross-linker contents and the enzyme concentration.