Synthesis of pH-sensitive inulin hydrogels and characterization of their swelling properties

In this study, pH-responsive inulin hydrogels were prepared by radical copolymerization of methacrylated inulin (MA-inulin) with acrylic acid (AAc) in aqueous solution using ammonium peroxydisulfate (APS) and N,N,N',N'-tetramethylethylenediamine (TMEDA) as an initiation system. The AAc content in hydrogels was evaluated by FTIR spectroscopy. The covalent bridging of AAc among MA moieties of MA-inulins was observed by a significant increase in the effective network density of hydrogels and further confirmed by TGA studies. While, at a low content of AAc, the hydration of hydrogels at pH 7.4 decreased owing to the increased crosslinking density, the swelling subsequently increased with further increasing AAc as a consequence of the increased ionic osmotic pressure within hydrogels. The change in swelling of hydrogels in response to pH change between 7.4 and 2.2 was therefore enlarged when the AAc content increased.     

Radiation synthesis of poly(ethylene glycol)/acrylic acid hydrogel as carrier for site specific drug delivery

pH-sensitive hydrogels were prepared from poly(ethylene glycol) (PEG) and acrylic acid (AAc) in aqueous solution employing gamma-radiation-induced copolymerization and crosslinking. The swelling behavior of the prepared hydrogels was determined by investigating the time and pH-dependent swelling of the (PEG/AAc) hydrogels of different PEG content. The effect of environmental parameters such as pH and ionic strength on the swelling kinetics was studied. The results not only show the dependence of the swelling indices on the pH value of the swelling medium but also show a clear dependence of the diffusion coefficient on the ionic strength of the medium. To estimate the ability of the prepared copolymer to be used as a colon-specific drug carrier, the release of ketoprofen was studied as a function of time at pH 1 and pH 7.     

Synthesis and characterization of dextran-maleic acid based hydrogel.

A new class of hydrogel precursor, dextran-maleic acid (Dex-MA), was synthesized by the reaction of dextran with maleic anhydride in the presence of the catalyst triethylamine. The effects of temperature, time, catalyst amount, and reactant concentration on the degree of substitution (DS) by MA was studied to establish an optimum reaction condition. The new hydrogel precursor had excellent solubility in various common organic solvents. The hydrogels based on Dex-MA precursor were made by the irradiation of Dex-MA with a long wave UV lamp. The Dex-MA hydrogels showed a very high swelling ratio in water, and the magnitude of swelling depended on the pH of the medium and the DS by MA. The Dex-MA hydrogels exhibited the highest swelling ratio in neutral pH, followed by acidic (pH 3) and alkaline pH (10). The most distinctive characteristic of Dex-MA hydrogels was that a carboxylic acid group was generated by the reaction of dextran with maleic anhydride. As a result, the swelling ratio increased with an increase of the DS of the MA segment (ionizable moiety that affects swelling ratio) in the Dex-MA hydrogel.     

The effect of pH on the LCST of poly(N-isopropylacrylamide) and poly(N-isopropylacrylamide-co-acrylic acid)

Poly(N-isopropylacrylamide) (PNIPAAm) and poly(N-isopropylacrylamide-co-acrylic acid) (P(NIPAAm-co-AAc)) hydrogels are synthesized by irradiating the aqueous solutions of NIPAAm and NIPAAm/AAc with ⁶⁰Co γ-ray. The effects of pH on the swelling ratio and on the lower critical solution temperature (LCST) are studied by determining the dependence of swelling ratio on temperature in different pH butter solutions. Differential scanning calorimetry (DSC) is applied in determination of the LCST of the hydrogels. Fourier transform infrared (FT-IR) spectrometry is used in the comparison of hydrogels swelled in various pH conditions. As a result, PNIPAAm was found to be a pH-sensitive hydrogel and the LCST of the PNIPAAm and P(NIPAAm-co-AAc) hydrogels are influenced by pH.     

The effect of pH on the LCST of poly(N-isopropylacrylamide) and poly(N-isopropylacrylamide-co-acrylic acid)

Poly(N-isopropylacrylamide) (PNIPAAm) and poly(N-isopropylacrylamide-co-acrylic acid) (P(NIPAAm-co-AAc)) hydrogels are synthesized by irradiating the aqueous solutions of NIPAAm and NIPAAm/AAc with 60Co gamma-ray. The effects of pH on the swelling ratio and on the lower critical solution temperature (LCST) are studied by determining the dependence of swelling ratio on temperature in different pH butter solutions. Differential scanning calorimetry (DSC) is applied in determination of the LCST of the hydrogels. Fourier transform infrared (FT-IR) spectrometry is used in the comparison of hydrogels swelled in various pH conditions. As a result, PNIPAAm was found to be a pH-sensitive hydrogel and the LCST of the PNIPAAm and P(NIPAAm-co-AAc) hydrogels are influenced by pH.     

A facile method to fabricate thermo- and pH-sensitive hydrogels with good mechanical performance based on poly(ethylene glycol) methyl ether methacrylate and acrylic acid as a potential drug carriers

Abstract

A thermo- and pH-sensitive hydrogel was prepared by a facile free aqueous radical copolymerization of PEGMA and AAc without any crosslinkers for controlled drug delivery. The successful fabrication of hydrogels was confirmed by Fourier transform infrared spectroscopy (FT-IR) and thermo gravimetric analysis (TGA) measurements. The morphological, mechanical and swelling properties of the obtained hydrogels were studied systematically. The results showed that the morphological and mechanical behaviors of the resultant hydrogels were strongly affected by the content of AAc. Moreover, the obtained hydrogels showed an excellent thermo-, pH- and salinity sensitivities. Release profiles of 5-Fu were studied at different pH (gastric pH 1.2 and intestinal pH 7.4) and temperatures (25?°C and 37?°C). The results showed that the release is very low at pH 1.2/37?°C and high at pH 7.4/25?°C. The cytotoxicity of hydrogels to cells was determined by an MTT assay. The result demonstrated that the blank hydrogels had negligible toxicity to cells, whereas the 5-Fu-loaded hydrogels remained high in cytotoxicity for LO2 and HepG-2 cells. Results of the present investigation exemplify the potential of this novel thermo- and pH-sensitive hydrogel for the controlled and targeted delivery of the anti cancer drug 5-Fu.     

Oscillating Swelling–Shrinking Dynamics and Diffusive Properties of Weakly Cationic Poly(Aminoalkyl Methacrylate)‐Based Cryogels: Quantifying the Influence of Polymer Network Parameters

Thermodynamic properties of swelling equilibria and variability of dynamic response of pH‐sensitive polybases are examined. Poly(aminoalkyl methacrylate)‐based cryogels and hydrogels are prepared in a facile way by crosslinking polymerization of amine functional monomer N,N‐dimethylaminoethyl methacrylate (DMAEMA) in the presence of diethyleneglycol dimethacrylate as crosslinker at temperatures below and above freezing point of polymerization solvent, water, via cryogelation and conventional crosslinking polymerization. The effect of polymerization temperature on swelling characteristics of the prepared polybasic gels is investigated as a function of the gel‐preparation concentration. The overshooting effect is observed during pH‐dependent swelling of poly(N,N‐dimethylaminoethyl methacrylate) (PDMAEMA) hydrogels in acidic medium. Protonation/deprotonation of tertiary amine groups in network‐forming polymer demonstrates critical swelling behavior as pH of the swelling medium increases. Oscillating swelling–shrinking studies are performed and effective diffusion coefficient of water within PDMAEMA cryogel and hydrogel matrices is estimated using the dynamic swelling profiles. The mechanism of cyclic swelling–shrinking process of PDMAEMA cryogels and hydrogels are analyzed to control their pulsatile output patterns in metabolic oscillations. Considering the swelling process occurs through Fickian diffusion mechanism in acidic solutions, polybasic cryogels and hydrogels prepared in this study are thus proposed as good candidates for delivery applications.     

Synthesis and pH sensitivity of carboxymethyl chitosan-based polyampholyte hydrogels for protein carrier matrices

Novel polyampholyte hydrogels based on carboxymethyl chitosans (CMC) of various degree of deacetylation (DD) and substitution (DS) were prepared by crosslinking with glutaraldehyde. The hydrogel showed typical amphoteric character responding to pH of the external medium. At the isoelectric point (IEP), the hydrogel shrunk most, when the pH deviated from IEP, the swelling degree (Ds) increased. With increasing DD or DS value, the hydrogel changed from polyampholyte into polycations or polyanions, respectively. Osmotic forces and intermolecular interactions among CMC chains regulate the swelling behavior of CMC gel. The carboxymethyl chitin hydrogels were loaded with bovine blood proteins (BSA), and their release studies were performed in both the simulated gastric and intestinal pH conditions. The release was much quicker in pH 7.4 buffer than pH 1.2 solution; the release followed Fickian diffusion in the first 4h and then steadily increased with the dissolution of the hydrogels.     

pH-sensitive behavior of two-component hydrogels composed of N,O-carboxymethyl chitosan and alginate

A two-component pH-sensitive hydrogel system composed of a water-soluble chitosan derivative (N,O-carboxymethyl chitosan, NOCC) and alginate cross-linked by genipin, glutaraldehyde or Ca2+ was investigated. Preparation and structures of these hydrogels and their swelling characteristics and release profiles of a model protein drug (bovine serum albumin, BSA) in simulated gastrointestinal media are reported. At pH 1.2, the swelling ratios of the hydrogels cross-linked by distinct methods were limited. Of note is that the lowest swelling ratios of test hydrogels were found at pH 4.0. At pH 7.4, the carboxylic acid groups on test hydrogels became progressively ionized and led to a significant swelling. There was barely any BSA released from the glutaraldehyde-cross-linked hydrogel throughout the entire course of the study. The amounts of BSA released at pH 1.2 from the genipin- and Ca(2+)-cross-linked hydrogels were relatively low (approx. 20%). At pH 4.0, there was still significant BSA release from the Ca(2+)-cross-linked hydrogel, while the cumulative BSA released from the genipin-cross-linked hydrogel was limited due to its shrinking behavior. At pH 7.4, the amount of BSA released from the genipin- and Ca(2+)-cross-linked hydrogels increased significantly (approx. 80%) because the swelling of both test hydrogels increased considerably. The aforementioned results indicated that the swelling behaviors and drug-release profiles of these test hydrogels are significantly different due to their distinct cross-linking structures.     

Study of polyampholyte hydrogels and interpenetrating polyelectrolyte networks based on 4-(but-3-en-1-ynyl)-1-methylpiperidin-4-ol

Polyampholyte hydrogels and interpenetrating polyelectrolyte networks (IPPN) based on 4-(but-3-en-1-ynyl)-1-methylpiperidin-4-ol ( 1 ) have been synthesized by γ-irradiation polymerization. The influence of the pH and ionic strength of the solution on the degree of swelling ? for both polyampholyte hydrogels and IPPN has been studied. The shrinking and swelling behaviour of crosslinked samples was explained by the formation or destruction of intra- and interpoly-electrolyte complexes.     

Preparation and characterization of pH-sensitive hydrogel of chitosan/poly(acrylic acid) co-polymer

A pH-sensitive co-polymer hydrogel of chitosan/poly(acrylic acid) (CS/PAAc) was prepared by irradiating the aqueous solution mixture of chitosan and acrylic acid with 60Co gamma-ray irradiation. The effect of the composition of chitosan and AAc on the properties of the hydrogel, such as swelling ratio and pH-sensitivity, were determined. Fourier Transform Infrared (FT-IR) spectrometry was applied in the attenuated total reflectance (ATR) mode for analyzing the structure change of the hydrogels after the treatment in different pH buffer solutions.     

Structural analysis of dextran-based hydrogels obtained chemoenzymatically

This work reports the results of structural analysis in novel dextran-acrylate (dexT70-VA) hydrogels generated chemoenzymatically. Porous structure as well as hydrogel surface and interior morphologies were evaluated by mercury intrusion porosimetry (MIP), nitrogen adsorption (NA), and scanning electron microscopy (SEM) analyses, as a function of the degree of substitution (DS), and initial water content used in the preparation of the hydrogel. MIP analysis showed that the overall networks were clearly macroporous with pore sizes ranging from 0.065 to 10 microm. As expected, the average pore size decreased as DS increased and as initial water content decreased. Moreover, the porosity values ranged from 75 up 90%, which shows that these hydrogels present an interconnected pore structure. Nitrogen adsorption analyses showed that the specific surface area of dexT70-VA hydrogels increased either by increasing the DS or by decreasing the initial water content of the hydrogel. SEM results revealed that the surface of hydrogels with lower DS presented either a porous structure or a polymeric "skin" covering the pores, whereas hydrogels with higher DS were totally porous. Furthermore, the interior morphology varied according to the DS and the initial water content of the hydrogels. Finally, the average pore size was also determined from the swelling of hydrogel using a theoretical model developed by Flory-Rehner. The comparison of the SEM and MIP results with the ones obtained by the equilibrium swelling theory of Flory-Rehner shows that this approach highly underestimates the average pore size.     

Enzyme-mediated fast in situ formation of hydrogels from dextran-tyramine conjugates

Dextran hydrogels were formed in situ by enzymatic crosslinking of dextran-tyramine conjugates and their mechanical, swelling and degradation properties were evaluated. Two types of dextran-tyramine conjugates (M(n,dextran)=14k, M(w)/M(n)=1.45), i.e. dextran-tyramine linked by a urethane bond (denoted as Dex-TA) or by an ester-containing diglycolic group (denoted as Dex-DG-TA), with different degrees of substitution (DS) were prepared. Hydrogels were rapidly formed under physiological conditions from Dex-TA DS 10 or 15 and Dex-DG-TA DS 10 at or above a concentration of 2.5 wt% in the presence of H(2)O(2) and horseradish peroxidase (HRP). The gelation time ranged from 5s to 9 min depending on the polymer concentration and HRP/TA and H(2)O(2)/TA ratios. Rheological analysis showed that these hydrogels are highly elastic. The storage modulus (G'), which varied from 3 to 41 kPa, increased with increasing polymer concentration, increasing HRP/TA ratio and decreasing H(2)O(2)/TA ratio. The swelling/degradation studies showed that under physiological conditions, Dex-TA hydrogels are rather stable with less than 25% loss of gel weight in 5 months, whereas Dex-DG-TA hydrogels are completely degraded within 4-10d. These results demonstrate that enzymatic crosslinking is an efficient way to obtain fast in situ formation of hydrogels. These dextran-based hydrogels are promising for use as injectable systems for biomedical applications including tissue engineering and protein delivery.     

Preparation and characterization of pH-sensitive hydrogel of chitosan/poly(acrylic acid) co-polymer

A pH-sensitive co-polymer hydrogel of chitosan/poly(acrylic acid) (CS/PAAc) was prepared by irradiating the aqueous solution mixture of chitosan and acrylic acid with ⁶⁰Co γ-ray irradiation. The effect of the composition of chitosan and AAc on the properties of the hydrogel, such as swelling ratio and pH-sensitivity, were determined. Fourier Transform Infrared (FT-IR) spectrometry was applied in the attenuated total reflectance (ATR) mode for analyzing the structure change of the hydrogels after the treatment in different pH buffer solutions.     

Preliminary studies on pH-sensitive hydrogels and in vitro release profiles of two model drugs

The main aim of the present study was to develop a series of pH-sensitive hydrogels for targeted releasing drugs under simulated intestinal environment instead of stomach condition. These hydrogels were prepared via free radical polymerization with polyethylene glycol methacrylate 475 (PEGMA475), PEGMA950 and methacrylic acid as monomers, triethylene glycol dimethacrylate (TRGDMA), and ethylene glycol dimethacrylate as cross-link agents. The surface morphology and internal structures of hydrogels were detected by scanning electron microscope. The swelling experiments were also performed and the results revealed that the smart hydrogels were pH sensitive and their sensitiveness was reversible. Diclofenac sodium and bull serum albumin used as model drugs were loaded in the hydrogels to target releasing them in simulative intestinal tract. In vitro releasing studies showed that medicated hydrogels released model drugs slowly in acid conditions (pH 1.2), while the cumulated release amounts of drugs increased greatly when ambient pH value increased to 7.4. These phenomena indicated that these hydrogels tended to target release stimulating and destructible drugs in intestinal canal instead of gastric environment.     

Poly(glutamic acid) poly(ethylene glycol) hydrogels prepared by photoinduced polymerization: Synthesis,characterization, and preliminary release studies of protein drugs

A class of new biodegradable hydrogels based on poly(ethylene glycol) methacrylate-graft-poly(glutamic acid) and poly(ethylene glycol) dimethacrylate was synthesized by photoinduced polymerization. Because all the polymeric constituents were highly hydrophilic, crosslinking could be performed in aqueous solutions. This type of crosslinked hydrogel was prepared by modifying a select number of acidic side-groups on poly(glutamic acid) with poly(ethylene glycol) methacrylate. These modified chains were then crosslinked in the presence of poly(ethylene glycol) dimethacrylate under a photoinduced polymerization at a wavelength of 365 nm. Swelling experiments were conducted to study the crosslinking density, pH-responsive behavior, and degradation of the hydrogel. Results showed that the degree of swelling of this type of hydrogels increased as the crosslinker concentration (or density) was reduced. Because of the presence of acidic side chains on poly(glutamic acid), swelling behavior was found to be pH-responsive, increasing at high pH in response to the increase in the amount of ionized acidic side chains. The degradation rate of these hydrogels also varied with pH. More rapid degradation was observed under stronger alkaline conditions because of the hydrolysis of the ester bonds between the crosslinker and the polymer backbone. Practically useful degradation rates could be achieved for such hydrogels under physiological conditions. Drug release rates from these hydrogels were found to be proportional to the protein molecular weight and the crosslinker density; increasing at lower protein molecular weight or crosslinker density. The preliminary findings presented in this article suggest that this class of biodegradable hydrogels could be an attractive avenue for drug delivery applications. The specific photoinduced crosslinking chemistry used would permit hydrogels to be synthesized in existence of the entrapped macromolecular drugs including peptides, proteins, and cells. In addition, the rapid feature of this polymerization procedure along with the ability to perform hydrogel synthesis and drug loading in an aqueous environment would offer great advantages in retaining drug activity during hydrogel synthesis.     

Synthesis of superporous hydrogels: hydrogels with fast swelling and superabsorbent properties.

We have been interested in the synthesis of hydrogels with fast swelling kinetics and superabsorbent properties. To increase the water absorption rate, interconnected pores were introduced to the hydrogels. Since the pore size in the dried hydrogels is in the order of hundreds of micrometers, these hydrogels are called "superporous" hydrogels. Superporous hydrogels were synthesized by crosslinking polymerization of various vinyl monomers in the presence of gas bubbles formed by the chemical reaction of acid and NaHCO3. The polymerization process was optimized to capture the gas bubbles inside the synthesized hydrogels. The use of the NaHCO3/acid system allowed easy control of timing for gelation and foam formation. We found that PF127 was the best foam stabilizer for most of the monomer systems used in our study. Scanning electron microscope (SEM) pictures showed interconnected pores forming capillary channels. The capillary channels, which were critical for fast swelling, were preserved during drying by dehydrating water-swollen hydrogels with ethanol before drying. The ethanol-dehydrated superporous hydrogels reached equilibrium swelling within minutes. The equilibrium swelling time could be reduced to less than a minute with the use of a wetting agent. In our study, water moisture was used as a wetting agent since the amount of moisture content in the dried hydrogels easily could be controlled. Preparation of superporous hydrogels using the right blowing system, foam stabilizer, drying method, and wetting agent makes it possible to reduce the swelling time to less than a minute regardless of the size of the dried gels. The superporous hydrogels can be used where fast swelling and superabsorbent properties are critical.     

Synthesis and characterization of pH-sensitive dextran hydrogels as a potential colon-specific drug delivery system.

pH-Sensitive dextran hydrogels were prepared by activation of dextran (T-70) with 4-nitrophenyl chloroformate, followed by conjugation of the activated dextran with 4-aminobutyric acid and cross-linking with 1,10-diaminodecane. The cross-linking efficiencies determined by mechanical measurements were in the range of 52-63%. Incorporation of carboxylpropyl groups in dextran hydrogels led to a higher equilibrium and faster swelling under high pH conditions. The swelling reversibility of hydrogels was also observed after repeated changes in buffers between pH 2.0 and 7.4. The slow rates of swelling and deswelling in response to changes in pH were attributed to the hydrophilic nature of dextran and formation of hydrogen bonds between the hydroxyl groups of dextran with water molecules. The pronounced effect of carboxylic acid content on degradation of hydrogels was observed after 4 h of incubation with dextranase and the influence significantly decreased after exposure to the enzyme for 8 h. The mechanism of bulk degradation of hydrogels under high swelling extent was substantiated using Coomassie blue protein assay. The release rate of bovine serum albumin from hydrogels was primarily determined by the swelling extent. The release rate was further enhanced by addition of dextranase in buffer solutions.     

Synthesis, characterization, and hydrolytic degradation behavior of a novel biodegradable pH-sensitive hydrogel based on polycaprolactone, methacrylic acid, and poly(ethylene glycol)

In this work, a new kind of biodegradable pH-sensitive hydrogel was successfully synthesized by UV-initiated free radical polymerization. The obtained hydrogel was characterized by (1)H NMR and FTIR. Swelling behavior in different aqueous media and pH responsivity of the hydrogels were studied in detail as well. With increase in pH from 1.2 to 7.2, swelling ratio of the hydrogel increased. The morphology was observed by scanning electron microscopy, and the hydrolytic degradation behavior was also investigated in this work.     

Preparation and Theophylline Delivery Applications of Novel PMAA/MWCNT-COOH Nanohybrid Hydrogels

A series of nanohybrid hydrogels was designed and developed based on a hydrogen bond self-assembly of poly(methacrylic acid) (PMAA) networks and carboxyl-functionalized multi-walled carbon nanotubes (MWCNT-COOH). The nanohybrid hydrogels show low micropore densities and large mesh sizes with an increase in MWCNT-COOH content. Particularly, the hydrogels containing 10 wt% MWCNT-COOH was observed to collapse at pore walls because of large holes, which is believed to be responsible for high swelling. The ability of the MWCNT-COOH to self-associate with PMAA or water molecules via hydrogen-bonding interactions and an additional electrostatic repulsion govern both pH response of the network and drug release. Increasing pH values causes equilibrium swelling ratios and accumulative release to be elevated. On the other hand, modified mechanical behavior can be obtained under a low content of the MWCNT-COOH in that the high MWCNT-COOH filling effects the formation of PMAA gel networks. Swelling and controlled release profiles of theophylline could be modulated by changing pH values, introducing the MWCNT-COOH and adjusting the proportions of the MWCNT-COOH component.