Synthesis and characterization of hydrogels based on grafted chitosan for the controlled drug release

Temperature and pH-responsive hydrogels based on chitosan grafted with poly acrylic acid (PAAc), poly hydroxy propyl methacrylate (PHPMA), poly (vinyl alcohol) (PVA) and gelatin were prepared for controlled drug delivery. These stimuli-responsive hydrogels were synthesized by gamma irradiation technique. The degree of gelation was over 90% and increased as chitosan, AAc and PVA content increased, while the degree of gelation decrease with the increase of gelatin content. The equilibrium swelling studies of hydrogels prepared in various conditions were carried out in an aqueous solution, and the pH sensitivity in the range of 2–9 was investigated. An increase of swelling degree with an increase in the pH was noticed and showed the highest value at pH 9. Also antibiotic drug Oxttetracycline was loaded into the hydrogels and the release studies were carried out at different pH and temperature. The in vitro release profiles of the drug showed that, the release of the drug increased as the time, temperature and pH increased and reached to maximum after 48 h at pH 9. The prepared hydrogels were characterized by using SEM, FTIR, and DSC.     

Design,Optimization, and Evaluation of a Novel Metronidazole-Loaded Gastro-Retentive pH-Sensitive Hydrogel

Floating pH-sensitive chitosan hydrogels containing metronidazole were developed for the eradication of Helicobacter pylori from the stomach. Hydrogels were prepared by crosslinking medium or high molecular weight chitosan in lyophilized solutions containing metronidazole using either citrate or tripolyphosphate (TPP) salts at 1% or 2% concentration. A 2³ factorial design was developed to study the influence of formulation parameters on the physical characteristics of the prepared hydrogels. The interaction between hydrogel components was investigated. The morphology of the prepared hydrogels was inspected and their percentage swelling, release pattern, and moisture content were evaluated. The results revealed the absence of interaction between hydrogel components and their highly porous structure. Percentage swelling of the hydrogels was much higher, and drug release was faster in gastric pH compared with intestinal pH. The formula prepared using 2% high molecular weight chitosan and 2% TPP significantly swelled (700%) within the first 4 h and released the loaded drug over a period of 24 h. Its moisture content was not affected by storage at high relative humidity. Therefore, this formula was selected to be tested in dogs for its gastric retention (using X-ray radiography) and efficacy in the eradication of H. pylori (using histopathological and microbiological examination). The results revealed that the prepared hydrogel formula was retained in dog stomach for at least 48 h, and it was more effective against H. pylori than the commercially available oral metronidazole tablets (Flagyl®).     

Studies on effect of pH on cross-linking of chitosan with sodium tripolyphosphate: A technical note

The ionotropic gelation method for formation of crosslinked chitosan particles can be easily modified from ionic cross-linking to deprotonation by adjusting the pH of TPP. Chitosan was cross-linked ionically with TPP at lower pH and by deprotonation mechanism at higher pH. The swelling behavior of cross-linked chitosan appeared to depend on the pH of TPP. The ionically cross-linked chitosan showed higher swelling ability. Thus the nature of crosslinked chitosan can be tailor made to obtain the desired properties in terms of cross-linking density, crystallinity, and hydrophilicity.     

Preparation of <Emphasis Type="Italic">in situ</Emphasis> Injectable Chitosan/Gelatin Hydrogel Using an Acid-tolerant Tyrosinase

An in situ injectable chitosan/gelatin hydrogel was formed under slightly acidic conditions (pH 4.0 ~ 4.5) using an acid-tolerant tyrosinase, tyrosinase-CNK. A homogeneous chitosan/tyrosinase-CNK solution was prepared in one part of a dual-barrel syringe, and highly soluble gelatin in distilled water was prepared in the other part of the syringe without any additional crosslinking materials. Chitosan/gelatin hydrogel was formed in situ by simple injection of the solutions at room temperature followed by curing at 37°C. However, conventional mushroom tyrosinase did not catalyze this permanent gel formation. Tyrosinase- CNK-catalyzed glycol chitosan/gelatin hydrogel was similarly formed by this in situ injection approach. The hydrogels exhibited a high swelling ratio of 20-fold their own weight, interconnected micropores with an average diameter of approximately 260 μm and in vitro biodegradability suitable for tissue engineering and drug delivery applications. These results showed that tyrosinase-CNK-mediated chitosan/gelatin hydrogel formation has remarkable potential for the development of novel formulations for in situ injectable gel-forming systems.     

Chemically cross-linked chitosan hydrogel loaded with gelatin for chondrocyte encapsulation

Composite hydrogels can be used as a scaffolding material for chondrogenesis, which requires a biomimetic environment to maintain chondrocyte morphology and phenotype. In this study, gelatin molecules were loaded into a hydrogel polymerized from a chitosan derivative (CML) to form a semi-interpenetrating polymer network. While the porous structure of the hydrogels in the dry state was not dependent on the gelatin content, the collapse extent and pore size decreased as the gelatin content increased. The gelatin loading also reduced the swelling ratio of the CML hydrogel and enhanced the hydrogel strength at 20°C due to gelation of the gelatin. The release behavior of the gelatin from the CML hydrogel could be controlled by many factors, such as the amount of gelatin, temperature, and solution pH. The weight loss of the composite hydrogel was expedited after gelatin loading and showed a positive relationship with the gelatin content. The results of in vitro cell culture in the hydrogels revealed that gelatin loading improved cell viability and promoted proliferation and glycosaminoglycans secretion of chondrocytes. This new scaffold production technology for chondrocyte encapsulation provides a further step towards CML applications in tissue engineering and other biomedical areas.     

Synthesis of antibacterial PVA/CM-chitosan blend hydrogels with electron beam irradiation

A series of excellent hydrogels were prepared from poly(vinyl alcohol) (PVA) and carboxymethylated chitosan (CM-chitosan) with electron beam irradiation (EB) at room temperature. Electron spectroscopy analysis of the blend hydrogels revealed that good miscibility was sustained between CM-chitosan and PVA. The properties of the prepared hydrogels, such as the mechanical properties, gel fraction and swelling behavior were investigated. The mechanical properties and equilibrium degree of swelling improved obviously after adding CM-chitosan into PVA hydrogels. The gel fraction determined gravimetrically showed that a part of CM-chitosan was immobilized onto PVA hydrogel. The further analyses of FTIR and DSC spectra of the prepared gels after extracting sol manifested that there was a grafting interaction between PVA and CM-chitosan molecules under irradiation. The antibacterial activity of the hydrogels against Escherichia coli was also measured via optical density method. The blend hydrogels exhibited satisfying antibacterial activity against E. coli, even when the CM-chitosan concentration was only 3 wt%.     

Synthesis and properties of thermo- and pH-sensitive poly(N-isopropylacrylamide)/polyaspartic acid IPN hydrogels

Various interpenetrating polymer network (IPN) hydrogels with sensitivity to temperature and pH were prepared by introducing the pH-sensitive polymer polyaspartic acid (PASP) hydrogel, into the poly(N-isopropylacrylamide) (PNIPAAm) hydrogel system for the purpose of improving its response rate to temperature. The morphologies and thermal behavior of the prepared IPN hydrogels were studied by both scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The IPN hydrogels showed a large and uneven porous network structure, without showing the common PNIPAAm hydrogel structure. The paper moreover studied their swelling properties, such as temperature dependence of equilibrium swelling ratio, shrinking kinetics, re-swelling kinetics and oscillatory swelling behavior in water. The swelling experiment results revealed that IPN hydrogels exhibited much faster shrinking and re-swelling in function of the composition ratio of the two network components. These fast responsive hydrogels foster potential applications in biomedical and biotechnology fields.     

Swelling and de-swelling kinetics of gelatin hydrogels in ethanol-water marginal solvent

Controlled osmotic swelling and de-swelling measurements have been performed on gelatin, a polyampholyte, hydrogels suspended in water-ethanol marginal solvent at room temperature (20 degrees C) where the alcohol concentration was changed from 0 to 100% (v/v). The change in gel mass was monitored as function of time until osmotic equilibrium was established with the surrounding solvent. It was observed that osmotic pressure of polymer-solvent mixing, pi(m)相似文献   

Development of a Model for Analyzing the Swelling Rate of Ionic Gels on the Basis of the Diffusion of Mobile Ions: Application to the pH-Sensitive Swelling of a Polyelectrolyte Complex Gel Prepared from Xanthan and Chitosan

A model for analyzing the swelling rate of ionic gels was developed on the basis of the diffusion of a species of mobile ion. This model was applied to the analysis of pH-sensitive swelling of a xanthan/chitosan complex gel in NaOH solutions of pH 9–12, using the sodium ion as the reference mobile ion. The time–course for swelling of gel beads with a pH change from 11 to 10 was successfully described by the developed model. The values for the diffusion coefficient obtained by fitting the model to the data were of the same order as those for the diffusion coefficient of the sodium ion measured for a membrane of the complex gel. Thus, it was confirmed that the swelling rate of the gel due to pH change was mainly controlled by the diffusion of mobile ions. However, the time-course for swelling of the gel at pH values below 10 was not satisfactorily explained by the model developed, suggesting that the change in the degree of ionization during swelling also affected the swelling rate of the xanthan/chitosan complex gel.     

Photopolymerization of methacrylated chitosan/PNIPAAm hybrid dual-sensitive hydrogels as carrier for drug delivery

A series of hybrid hydrogels based on glycidyl methacrylated chitosan (CS-GMA) and N-isopropylacrylamide (NIPAAm) were designed and prepared via photopolymerization technology. The hydrogels were characterized by Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC) and optical transmittance. The interior morphology of hydrogels was investigated by scanning electron microscopy (SEM). The swelling experiment results revealed that hybrid hydrogel exhibited combined pH and temperature sensitivities. Acid orange 8 (AO8) and 5-flurouracil (5-Fu) were selected as model drugs for examining their release from hydrogels. The results suggested that hydrogel composition and pH value of buffer solution had great influences on release profiles.     

Preparation and characterization of N-(2-carboxybenzyl)chitosan as a potential pH-sensitive hydrogel for drug delivery

A novel water-soluble chitosan derivative [N-(2-carboxybenzyl)chitosan, CBCS] was synthesized. The chemical structure of CBCS was characterized by FTIR, (1)H NMR and UV spectroscopies. The degree of substitution (DS) of N-2-carboxybenzyl was determined by colloid titration. In different pH buffer solutions, the swelling characteristics of hydrogels based on CBCS (CBCSG) prepared by crosslinking with glutaraldehyde have been studied. Results showed that the swelling ratio (SR) of CBCSG decreased with an increase of the amount of glutaraldehyde, and that CBCSG swelled more significantly in alkaline solution than in acidic medium, showing the lowest SR at pH5.0. The SR of CBCSG increased with the raising of the DS of the N-2-carboxybenzyl group in alkaline solution, but no significant change was observed in an acidic environment. CBCSG showed swelling reversibility when alternately soaked in pH1.0 and 7.4 buffer solutions. Release profiles of fluorouracil (5-FU), a poorly water-soluble drug, from CBCSG were studied under both simulated gastric and intestinal pHconditions. The release was much quicker in pH7.4 buffer than in pH1.0 solution. Results indicated that CBCS could be a potential pH-sensitive carrier for colon-specific drug delivery system.     

One-step synthesis of interpenetrating network hydrogels: Environment sensitivities and drug delivery properties

A novel interpenetrating network hydrogel for drug controlled release, composed of modified poly(aspartic acid) (KPAsp) and carboxymethyl chitosan (CMCTS), was prepared in aqueous system. The surface morphology and composition of hydrogels were characterized by SEM and FTIR. The swelling properties of KPAsp, KPAsp/CMCTS semi-IPN and KPAsp/CMCTS IPN hydrogels were investigated and the swelling dynamics of the hydrogels was analyzed based on the Fickian equation. The pH, temperature and salt sensitivities of hydrogels were further studied, and the prepared hydrogels showed extremely sensitive properties to pH, temperature, the ionic salts kinds and concentration. The results of controlled drug release behaviors of the hydrogels revealed that the introduction of IPN observably improved the drug release properties of hydrogels, the release rate of drug from hydrogels can be controlled by the structure of the hydrogels and pH value of the external environment, a relative large amount of drug released was preferred under simulated intestinal fluid. These results illustrated high potential of the KPAsp/CMCTS IPN hydrogels for application as drug carriers.     

Electrical behavior of polymer hydrogel composed of poly(vinyl alcohol)-hyaluronic acid in solution

Interpenetrating polymer networks (IPN), as polymer hydrogels composed of poly(vinyl alcohol) (PVA) and hyaluronic acid (HA), which exhibited electrical sensitive behavior were prepared. The swelling behavior of the IPN/HA IPN was studied by immersing the gel in various concentrations of aqueous NaCl solutions and various pH buffer solutions. The response of the PVA/HA IPN to electric fields stimuli was also investigated. When swollen IPN was placed between a pair of electrodes, and an electric field applied, it exhibited bending behavior. The PVA/HA IPN also displayed stepwise bending behavior, depending on the magnitude of the electric stimulus. Also, for use in biosensors application, their bending behavior was studied in Hank's solution at pH 7.4.     

Hydrogels of dihydroxypropyl chitosan crosslinked with irradiation at paste-like condition

In present study, a series of environmentally friendly hydrogel films were prepared from dihydroxypropyl chitosan (DHP-chitosan) using irradiation technique without any bifunctional crosslinking compounds. DHP-chitosan irradiated at high concentrated solution state (more than 10%, paste-like state) was found to introduce crosslinking structure. Crosslinking behavior, mechanical property, morphology, and swelling behavior of the hydrogel films were studied. It has been found that a concentration of 40% solution is the most effective for crosslinking. The hydrogel films of DHP-chitosan exhibited controllable mechanical property and typically pH-sensitive character in their swelling behavior. A preliminary biodegradation study confirmed that DHP-chitosan hydrogels also undergo biodegradation by enzymatic degradation test.     

Swelling and mechanical properties of biopolymer hydrogels containing chitosan and bovine serum albumin

Experimental and theoretical investigations of the swelling and mechanical properties of hydrogels formed from chitosan, bovine serum albumin (BSA), and chitosan/BSA mixtures cross-linked with genipin were performed. The properties of cross-linked chitosan hydrogels were explained in terms of its polyelectrolyte behavior, which led to a gradual increase in swelling ratio below the pK value, but whereby its swelling ability was eliminated by the presence of salt that screened the charges. Comparison of theoretical and experimental calculations of the swelling ratio, however, indicated that complications arising from wastage of cross-links, and formation of polymerized genipin cross-links must be considered before quantitative prediction can be achieved. Cross-linked BSA hydrogels swelled even in the presence of salt, and a marked increase in swelling was observed below pH = 3 that was explained as the result of an acid induced denaturation of the protein that led to unfolding of the molecule. Swollen BSA hydrogels were mechanically weak, however. Composite gels made from a cross-linked mixture of chitosan and BSA exhibited the swelling behavior of BSA combined with the mechanical properties of chitosan and were therefore considered most suitable for use in a gastric environment.     

Development of chitosan-tripolyphosphate fibers through pH dependent ionotropic gelation

Incorporation of phosphate groups into a material may be of particular interest as they act as templates for hydroxyapatite growth through complexation with Ca²⁺ and thus improve the osteoconduction property. The phosphate groups can be incorporated into chitosan through ionotropic gelation with tripolyphosphate (TPP). Interestingly, the ion pairs formed through negatively charged phosphate groups with protonated amine functionality of chitosan in ionotropic gelation are expected to provide chitosan with an amphoteric character, which may facilitate protein adhesion following enhanced attachment of anchorage dependant cells than chitosan, which shows poor cell adhesion properties. In this study, chitosan–tripolyphosphate (TPP) fibers with varying phosphate contents were prepared through wet spinning in STPP baths of different pH. Gelation kinetics and gel strength of chitosan with STPP solutions of three different pH were evaluated and compared with that of NaOH solution for evaluation of their influence on nature of gelation. The solution pH of STPP baths was found to have significant control on the extent of ionic cross-linking and physico-chemical properties of the fibers. Moreover, this kinetically driven ionotropic gelation of chitosan by TPP results in low degree of crystallinity of chitosan–TPP fibers and consequently their lower thermal stability than chitosan fibers.     

Method for Analyzing pH-Sensitive Swelling of Amphoteric Hydrogels—Application to a Polyelectrolyte Complex Gel Prepared from Xanthan and Chitosan—

The pH-sensitive swelling of a natural-polyelectrolyte complex gel, prepared from xanthan and chitosan, was investigated using a model based on the Donnan equilibrium theory with special attention to the dissociation behavior of the polyelectrolytes. First, the pH dependence of the degree of ionization for the xanthan-chitosan complex was evaluated by the potentiometric titration method, and the value of the dissociation constant for analyzing the swelling behavior was obtained. Second, the validity of the Donnan equilibrium was confirmed by measuring the concentration of sodium ion in the gels. By analyzing the swelling behavior of the gel using the model, it was suggested that the network properties of the gel altered with changes in the ambient pH. These results indicate that analysis using the parameters evaluated by potentiometric titration is useful for investigating the swelling behavior of ionic gels.     

Facile synthesis of degradable and electrically conductive polysaccharide hydrogels

Degradable and electrically conductive polysaccharide hydrogels (DECPHs) have been synthesized by functionalizing polysaccharide with conductive aniline oligomers. DECPHs based on chitosan (CS), aniline tetramer (AT), and glutaraldehyde were obtained by a facile one-pot reaction by using the amine group of CS and AT under mild conditions, which avoids the multistep reactions and tedious purification involved in the synthesis of degradable conductive hydrogels in our previous work. Interestingly, these one-pot hydrogels possess good film-forming properties, electrical conductivity, and a pH-sensitive swelling behavior. The chemical structure and morphology before and after swelling of the hydrogels were verified by FT-IR, NMR, and SEM. The conductivity of the hydrogels was tuned by adjusting the content of AT. The swelling ratio of the hydrogels was altered by the content of tetraaniline and cross-linker. The hydrogels underwent slow degradation in a buffer solution. The hydrogels obtained by this facile approach provide new possibilities in biomedical applications, for example, biodegradable conductive hydrogels, films, and scaffolds for cardiovascular tissue engineering and controlled drug delivery.     

Synthesis and characterization of pH-sensitive hydrogel composed of carboxymethyl chitosan for colon targeted delivery of ornidazole

In the present study, carboxymethyl chitosan was prepared from chitosan, crosslinked with glutaraldehyde and evaluated in vitro as a potential carrier for colon targeted drug delivery of ornidazole. Ornidazole was incorporated at the time of crosslinking of carboxymethyl chitosan. The chitosan was evaluated for its degree of deacetylation (DD) and average molecular weight; which were found to be 84.6% and 3.5×10(4) Da, respectively. The degree of substitution on prepared carboxymethyl chitosan was found to be 0.68. All hydrogel formulations showed more than 85% and 74% yield and drug loading, respectively. The swelling behaviour of prepared hydrogels checked in different pH values, 1.2, 6.8 and 7.4, indicated pH responsive swelling characteristic with very less swelling at pH 1.2 and quick swelling at pH 6.8 followed by linear swelling at pH 7.4 with slight increase. In vitro release profile was carried out at the same conditions as in swelling and drug release was found to be dependant on swelling of hydrogels and showed biphasic release pattern with non-fickian diffusion kinetics at higher pH. The carboxymethylation of chitosan, entrapment of drug and its interaction in prepared hydrogels were checked by FTIR, (1)H NMR, DSC and p-XRD studies, which confirmed formation of carboxymethyl chitosan from chitosan and absence of any significant chemical change in ornidazole after being entrapped in crosslinked hydrogel formulations. The surface morphology of formulation S6 checked before and after dissolution, revealed open channel like pores formation after dissolution.     

Methacrylated glycol chitosan as a photopolymerizable biomaterial

Glycol chitosan is a derivative of chitosan that is soluble at neutral pH and possesses potentially useful biological properties. With the goal of obtaining biocompatible hydrogels for use as tissue engineering scaffolds or drug delivery depots, glycol chitosan was converted to a photopolymerizable prepolymer through graft methacrylation using glycidyl methacrylate in aqueous media at pH 9. N-Methacrylation was verified by both (1)H NMR and (13)C NMR. The degree of N-methacrylation, measured via (1)H NMR, was easily varied from 1.5% to approximately 25% by varying the molar ratio of glycidyl methacrylate to glycol chitosan and the reaction time. Using a chondrocyte cell line, the N-methacrylated glycol chitosan was found to be noncytotoxic up to a concentration of 1 mg/mL. The prepolymer was cross-linked in solution using UV light and Irgacure 2959 photoinitiator under various conditions to yield gels of low sol content ( approximately 5%), high equilibrium water content (85-95%), and thicknesses of up to 6 mm. Cross-polarization magic-angle spinning (13)C solid state NMR verified the complete conversion of the double bonds in the gel. Chondrocytes seeded directly onto the gel surface, populated the entirety of the gel and remained viable for up to one week. The hydrogels degraded slowly in vitro in the presence of lysozyme at a rate that increased as the cross-link density of the gels decreased.