Synthesis and characterization of a novel pH-responsive nanocomposite hydrogel based on chitosan for targeted drug release

Over the last decade, nanocomposite hydrogels have been provided a new approach for the biomedical field. In this work, a novel pH-responsive nanocomposite hydrogel was fabricated using simultaneous in situ formation of magnetite iron oxide nanoparticles and hydrogel networks of poly(acrylic acid) grafted onto chitosan. The effects of various types of precursor molecules, pH, salt, and loading pressure were examined on the swelling properties of resulting nanocomposite hydrogels. The synthesized nanocomposite hydrogel was well characterized using different instruments. In vitro drug releasing behavior of doxorubicin was studied at pH 5.4 and 7.4. The drug release mechanism was investigated through different kinetic models. These experimental results open a new opportunity to make pH-responsive nanocomposite hydrogel devices for controlled delivery of drug.     

Temperature/pH/magnetic triple‐sensitive nanogel–hydrogel nanocomposite for release of anticancer drug

Hydrogels, nanogels and nanocomposites show increasing potential for application in drug delivery systems due to their good chemical and physical properties. Therefore, we were encouraged to combine them to produce a new compound with unique properties for a long‐term drug release system. In this regard, the design and application of a nanocomposite hydrogel containing entrapped nanogel for drug delivery are demonstrated. To this aim, we first prepared an iron oxide nanocomposite nanogel based on poly(N‐isopropylacrylamide)‐co‐((2‐dimethylaminoethyl) methacrylate) (PNIPAM‐co‐PDMA) grafted onto sodium alginate (NaAlg) as a biocompatible polymer and iron oxide nanoparticles (ION) as nanometric base (PND/ION‐NG). This was then added into a solution of PDMA grafted onto NaAlg. Through dropwise addition of mixed aqueous solution of iron salts into the prepared polymeric solution, a novel hydrogel nanocomposite with excellent pH, thermal and magnetic responsivity was fabricated. The synthesized samples were fully characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy with energy‐dispersive X‐ray analysis, vibrating sample magnetometry and atomic force microscopy. A mechanism for the formation of PNIPAM‐co‐PDMA/NaAlg‐ION nanogel–PDMA/NaAlg‐ION hydrogel and PND/ION nanogel is suggested. Swelling capacity was measured at various temperatures (25 to 45 °C), pH values (from 2 to 11) and magnetic field and under load (0.3 psi) and the dependence of swelling properties of the nanogel–hydrogel nanocomposite on these factors was well demonstrated. The release rate of doxorubicin hydrochloride (DOX) as an anticancer drug was studied at different pH values and temperatures in the presence and absence of a magnetic field. The results showed that these factors have a high impact on drug release from this nanocomposite. The result showed that DOX release could be sustained for up to 12.5 days from these nanocomposite hydrogels, significantly longer than that achievable using the constituent hydrogel or nanogel alone (<1 day). The results indicated that the nanogel–hydrogel nanocomposite can serve as a novel nanocarrier for anticancer drug delivery. © 2019 Society of Chemical Industry     

Covalently cross‐linked and hydrophobically modified alginic acid hydrogels and their application as drug carriers

Covalently crosslinked and hydrophobically modified alginate hydrogels were prepared through esterification of alginic acid (ALG‐H) with 1,10‐decanediol that functioned as a crosslinking agent and hydrophobic component. The preparation was accomplished with one step and was carried out in N,N‐dimethylformamide solution at a reduced pressure for removing the water produced. The characterization results confirmed the esterification of the products. The modified alginate hydrogels could be used as drug delivery vehicles for controlled release. The drug release study revealed that compared with a calcium alginate hydrogel the modified hydrogels possessed improved loading rate and encapsulation efficiency for the hydrophobic drug(ibuprofen), and a remarkable sustained release behavior was observed. The release kinetics was close to zero order, a desirable drug release pattern. The modified alginate hydrogels were nontoxic and were potentially applicable as a promising biomaterial. POLYM. ENG. SCI., 2013. © 2012 Society of Plastics Engineers     

Mechanical properties and drug release rate of poly(vinyl alcohol)/poly(ethylene glycol)/clay nanocomposite hydrogels: Correlation with structure and physical properties

Poly(vinyl alcohol)/poly(ethylene glycol) hydrogels containing curcumin as a drug and the various amounts of a montmorillonite nanoclay are prepared using the freezing–thawing method. Nanoclay quantity influence on the physicomechanical properties and the drug release rate of the hydrogel as well as relationship between them is investigated. X-Ray diffraction and Atomic force microscopy analysis reveal the nanoclays have an intercalation structure in the hydrogel, and the hydrogel crystallization decreases with increasing the nanoclay inclusion. From the SEM micrographs observation, it was revealed that due to the presence of the nanoclay in the hydrogel, its porosity decreased. The naonoclay has an amount-depended dual effect on the hydrogel swelling. The swelling mechanism is a normal Fickian diffusion for all the hydrogel samples. Strong physical interactions between the nanoclays and the polymer chains in the nanocomposite hydrogels are evidenced by the rheological studies. These interactions lead to significant reinforcement of the hydrogel tensile strength, intensified by the nanoclay amount. Interestingly, the nanoclays show the capability of accelerating and, also, decelerating the drug release of the hydrogel. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47843.     

Structure and properties of polysaccharide nanocrystal-doped supramolecular hydrogels based on Cyclodextrin inclusion

Polysaccharide nanocrystals, such as the rod-like whiskers of cellulose and chitin, and platelet-like starch nanocrystals, were for the first time incorporated into supramolecular hydrogels based on cyclodextrin/polymer inclusion in order to enhance mechanical strength and regulate drug release behavior. The structures and properties of the resultant nanocomposite hydrogels were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and rheological testing. As expected, the elastic modulus of the nanocomposite hydrogels climbed, owing to the reinforcing function of the polysaccharide nanocrystals. The modulus of the cellulose whisker-doped hydrogel was 50 times higher than that of the native hydrogel. Furthermore, the presence of polysaccharide nanocrystals increased the stability of the hydrogel framework and inhibited the diffusion of bovine serum albumin, which served as a model protein drug in the nanocomposite hydrogels and showed prominent sustained release profiles. Importantly, the incorporation of polysaccharide nanocrystals did not show additional cytotoxicity as comparison with the native hydrogel. In addition, the inherited shear-thinning property of the nanocomposite hydrogels contributed to their potential as injectable biomaterials.     

Synthesis of dual physical self-healing starch-based hydrogels for repairing tissue defects

Hydrogels have the potential to simulate and permeate body tissues. They can be used in many biomedical applications, such as drug delivery, wound dressings, contact lenses, synthetic implants, biosensors, and tissue engineering. Despite recent significant advances in hydrogel fabrication, with the introduction of double network hydrogels, with ionic or hydrogen bonds, there is still the challenge of achieving optimal mechanical properties with appropriate self-healing ability. To solve the above problem, in this study, a new type of starch/chitosan/PVA/borax hydrogel was synthesized by adopting the one-pot method. The effect of concentration and ratio of raw materials on the final properties of hydrogels, such as the degree of hydrophilicity, morphology, degradation, mechanical strength, and drug release rate, was investigated. The properties of hydrogels were examined by scanning electron microscopy, thermogravimetric analysis, Fourier-transform infrared spectroscopy, X-ray diffractometry, and contact angle, which confirmed the composite synthesis and uniform distribution of HNT and curcumin. In addition, the composite hydrogel showed excellent mechanical properties. Drug release studies confirmed that the drug is slowly released from the nanocomposite hydrogels. The results showed that starch-based nanocomposite hydrogels could provide appropriate repairing potential for defects exposed to changeable parameters.     

Self‐Healing,Injectable Gelatin Hydrogels Cross‐Linked by Dynamic Schiff Base Linkages Support Cell Adhesion and Sustained Release of Antibacterial Drugs

A new class of dynamic hydrogels made through Schiff base bonds based on gelatin (type A and B) and polyethylene glycol dibenzaldehyde (diBA‐PEG, 2000 and 4000 g mol^?1) is developed. Hydrogels form in situ by mixing aqueous solutions of gelatin and diBA‐PEG at a carefully adjusted pH. Compression test shows that the samples based on gelatin A are able to withstand at least ten cyclic loading/unloading without crack formation and significant permanent deformation. Self‐healing behavior of the hydrogel is proved by rheological measurements and also visual method. This hydrogel is proven to be injectable and nontoxic. Performance of the hydrogel in loading and delivery of clindamycin hydrochloride, as an antibacterial model drug, is evaluated against Staphylococcus aureus via antibacterial activity test. In vitro release of clindamycin hydrochloride is studied through an innovative method and it becomes clear that the release of clindamycin hydrochloride from this hydrogel follows a zero‐order kinetics.     

In situ incorporation of monodisperse drug nanoparticles into hydrogel scaffolds for hydrophobic drug release

The effective and locally sustained delivery of hydrophobic drug with hydrogels as carriers is still a challenge owing to the inherent incompatibility of hydrophilic hydrogel network and hydrophobic drug. One promising approach is to use porous hydrogels to encapsulate and deliver hydrophobic drug in the form of nanoparticles to the disease sites. However, this approach is currently limited by the inability to load concentrated hydrophobic drug nanoparticles into the hydrogels because of the severe nanoparticle aggregation during the loading process. In this article, we firstly designed and fabricated efficient drug nanoparticles embedded hydrogels for hydrophobic drug delivery by incorporating monodisperse silybin (hydrophobic drug for liver protection) nanoparticles into acrylated hyaluronic acid (HA‐AC) based hydrogels through in situ cross‐linking. The silybin nanoparticles embedded hydrogel scaffolds proved to be a good sustained release system with a long period of 36 h. The drug release from this hybrid hydrogels could be modulated by tuning HA‐AC concentration, cross‐linking ratio, chain length of cross‐linker and drug loading amount. The different kinetic models were applied, and it was observed that the release profile of silybin best followed the Hixson‐Crowell model for the release of drug from the hydrogels embedding silybin nanoparticles. It could be envisioned that this process would significantly advance the potential applications of hydrogel scaffolds mediated hydrophobic drug delivery in clinical therapies. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43111.     

Construction of chitosan-carboxymethyl β-cyclodextrin silver nanocomposite hydrogel to improve antibacterial activity

Silver nanoparticles (AgNPs) are widely used in various fields but their physical and chemical instability have limited their applications. The present work demonstrates a novel approach for the synthesis and stabilising of AgNPs. Chitosan and carboxymethyl β-cyclodextrin were used to prepare a polymeric hydrogel with glutaraldehyde as cross-linker. As a result, AgNPs were formed with very high dispersion and stability in the hydrogel structure. It is possible to create nanoreactors to produce AgNPs by adding CM-βCD to the structure of the hydrogel. Fourier transform infrared (FTIR) analysis was employed to characterise the Cs-CM-βCD hydrogel. The morphologies of pure Cs-CM-βCD hydrogel and silver nanocomposite were observed by scanning electron microscopy. Moreover, UV–VIS spectroscopy and X-ray diffraction were used to characterise the prepared silver nanocomposite. In addition, the antibacterial properties of these silver nanocomposite hydrogels were investigated against Staphylococcus aureus (Gram positive) and Escherichia coli (Gram negative).     

β‐cyclodextrin‐conjugated hyaluronan hydrogel as a potential drug sustained delivery carrier for wound healing

In order to develop a potential drug sustained delivery carrier suitable for wound healing, a series of β‐cyclodextrin conjugated hyaluronan hydrogels (β‐CD‐HA) with adjustable crosslink densities were synthesized and characterized, meanwhile the delivery kinetics and mechanism of diclofenac as a model anti‐inflammatory drug from these hydrogels were investigated. By controlling the feeding molar ratio of β‐CD/HA, a β‐CD substitution degree of 4.65% was obtained by ¹H‐NMR analysis. The incorporation of β‐CD modification had little effect on the internal porous structure, water swelling ratio, and rheological property of HA hydrogel, which however were influenced by the crosslink density. Although the crosslink density had an influence on the drug loading and release profile by altering the water swelling property, the interaction between β‐CD and drug was the primary factor for the high loading capacity and long‐term sustained delivery of diclofenac. The semiempirical equation fit showed that the release of diclofenac from HA‐based hydrogels followed a pseudo‐Fickian diffusion mechanism. By the aid of β‐CD and controlled crosslink density, a β‐CD‐HA hydrogel with a diclofenac sustained delivery period of over 28 days and desirable physicochemical properties was achieved, which will be a promising drug sustained delivery carrier for wound healing. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43072.     

Sustained delivery of hydrocortisone acetate by CS/N‐vinyl‐2‐pyrrolidone/CaCO3 microparticle hybrid hydrogels

The goal of this research is to develop a composite hydrogel system for sustained release of therapeutic agents. The hybrid hydrogels were prepared by radiation crosslinking on aqueous solution of Chitosan (CS)/N‐vinyl‐2‐pyrrolidone (NVP) with different loads of CaCO₃ in the presence of hydrocortisone acetate (HCA), an anti‐inflammatory drugs. Physical characteristics of CS/NVP/CaCO₃ were studied using X‐ray diffraction (XRD) and infrared spectrophotometery (IR). The porous structure of resulted hydrogel was confirmed by SEM micrographs. The effect of doses and calcium carbonate amount on the swelling of the hydrogels was investigated. The ability of the prepared CS/NVP/CaCO₃‐based hybrid hydrogels to be used as drug carriers for anti‐inflammatory‐specific drug delivery system was estimated using HCA as a model drug. POLYM. COMPOS., 35:1176–1183, 2014. © 2013 Society of Plastics Engineers     

Synthesis and evaluation of sucrose‐containing polymeric hydrogels for oral drug delivery

Biodegradable and biocompatible copolymeric hydrogels based on sucrose acrylate, N‐vinyl‐2‐pyrrolidinone, and acrylic acid were designed and synthesized. Because of the growing importance of sugar‐based hydrogels as drug delivery systems, these new pH‐responsive sucrose‐containing copolymeric hydrogels were investigated for oral drug delivery. The sucrose acrylate monomer was synthesized and characterized. The copolymeric hydrogel was synthesized by free‐radical polymerization. Azobisisobutyronitrile (AIBN) was the free‐radical initiator employed and bismethyleneacrylamide (BIS) was the crosslinking agent used for hydrogel preparations. Homopolymeric vinyl pyrrolidone hydrogels were also prepared by the same technique. The hydrogels were characterized by differential scanning calorimetry, thermogravimetric analysis, and scanning electron microscopy. Equilibrium swelling studies were carried out in enzyme‐free simulated gastric and intestinal fluids (SGF and SIF, respectively). These results indicate the pH‐responsive nature of the hydrogels. The gels swelled more in SIF than in SGF. A model drug, propranolol hydrochloride (PPH), was entrapped in these gels and the in vitro release profiles were established separately in both enzyme‐free SGF and enzyme‐free SIF. The drug release was found to be faster in SIF. About 93 and 99% of the entrapped drug was released over a period of 24 h in SGF and SIF, respectively. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 84: 2597–2604, 2002     

Dual stimuli responsive glycidyl methacrylate chitosan‐quaternary ammonium hybrid hydrogel and its bovine serum albumin release

A new family of cationic hybrid hydrogels from two new positively charged aqueous soluble precursors, glycidyl methacrylate‐chitosan (GMA‐chitosan), and 2‐(acryloyloxy) ethyl trimethylammonium (AETA), was developed via a simple photocrosslinking fabrication method. These hybrid hydrogels have pendant quaternary ammonium functional groups on the AETA segments. The chemical composition of GMA‐chitosan/AETA hybrid hydrogels were characterized by Fourier transform infrared spectroscopy and their mechanical, swelling, and morphological properties were examined as a function of the composition of the hybrids as well as the effect of pH and ionic strength of the surrounding medium. GMA‐chitosan/AETA hybrid hydrogels show a porous network structure with average pore diameter 20–50 μm. The compression moduli of these hybrid hydrogels ranged from 27.24 to 28.94 kPa, which are significantly higher than a pure GMA‐chitosan (17.64 kPa). GMA‐chitosan/AETA hybrid hydrogel shows pH/ionic strength responsive swelling behavior because of the presence of the positive charge pendant groups. These hybrid hydrogels showed a sustained BSA protein release and a significantly lower initial burst release than a pure GMA‐chitosan hydrogel. The two aqueous soluble precursors and the cationic charge characteristics of the resulting GMA‐chitosan/AETA hybrid hydrogels may suggest that this new family of biomaterials may have promising applications as the pH responsive protein drug delivery vehicles. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 3736–3745, 2013     

Composites of polymeric gels and magnetic nanoparticles: Preparation and drug release behavior

The article is concerned with the preparation of polymer–iron oxide nanocomposites and the study as drug‐delivery matrices under the influence of applied magnetic field. Biocompatible materials were prepared by incorporating an aqueous ferrofluid in poly(vinyl alcohol) and scleroglucan (SCL) hydrogels, loaded with theophylline as model drug for release studies. The in vitro release profile was obtained using a flat Franz cell and the kinetic parameters were derived applying a semiempirical power law. A magnetic characterization of nanoparticles contained in the ferrofluid was performed by obtaining the magnetization curve. For both systems, the observed drug release profiles decreased when a uniform external magnetic field is applied suggesting they can be used as environmental responsive matrices for biomedical applications. Dynamic rheological measurements show that a higher storage modulus and a more compact structure are obtained by incorporating the ferrofluid into the hydrogels. These rheological results and environmental electron scanning microscopy micrographs point to an understanding of release behavior once the magnetic field is applied. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Dual pH‐ and thermal‐responsive nanocomposite hydrogels for controllable delivery of hydrophobic drug baicalein

Hydrogels have been widely used as mild biomaterials due to their bio‐affinity, high drug loading capability and controllable release profiles. However, hydrogel‐based carriers are greatly limited for the delivery of hydrophobic payloads due to the lack of hydrophobic binding sites. Herein, nano‐liposome micelles were embedded in semi‐interpenetrating poly[(N‐isopropylacrylamide)‐co‐chitosan] (PNIPAAm‐co‐CS) and poly[(N‐isopropylacrylamide)‐co‐(sodium alginate)] (PNIPAAm‐co‐SA) hydrogels which were responsive to both temperature and pH, thereby establishing tunable nanocomposite hydrogel delivery systems. Nano‐micelles formed via the self‐assembly of phospholipid could serve as the link between hydrophobic drug and hydrophilic hydrogel due to their special amphiphilic structure. The results of transmission and scanning electron microscopies and infrared spectroscopy showed that the porous hydrogels were successfully fabricated and the liposomes encapsulated with baicalein could be well contained in the network. In addition, the experimental results of response release in vitro revealed that the smart hydrogels showed different degree of sensitiveness under different pH and temperature stimuli. The results of the study demonstrate that combining PNIPAAm‐co‐SA and PNIPAAm‐co‐CS hydrogels with liposomes encapsulated with hydrophobic drugs is a feasible method for hydrophobic drug delivery and have potential application prospects in the medical field. © 2018 Society of Chemical Industry     

Swelling behaviour and paracetamol release from poly(<Emphasis Type="Italic">N</Emphasis>-isopropylacrylamide-itaconic acid) hydrogels

Copolymer hydrogels of N-isopropylacrylamide and itaconic acid (IA), crosslinked with N,N′-methylenebisacrylamide, were prepared by radical copolymerization. These hydrogels were investigated with regard to their composition to find materials with satisfactory swelling and drug release properties. A paracetamol is used as a model drug to investigate drug release profile of the hydrogels. It was found that the investigated hydrogels exhibited pH- and temperature-dependent swelling behaviour with restricted swelling and lower equilibrium degree of swelling at lower pH values and temperatures above the LCST value of PNIPAM (around 34 °C). The diffusion exponent for paracetamol release indicate that the mechanism of paracetamol release are governed by Fickian diffusion, while in all release media initial diffusion coefficient was lower than late time diffusion coefficient. Furthermore, the paracetamol release rate depends on the hydrogel degree of swelling and it increased in the first stage of diffusion process, whereas was no significant difference thereafter. The presence of the IA moieties incorporated into the network weakened the shear resistance of the hydrogels. In order to calculate the pore size the characteristic ratio for PNIPAM, C _n  = 11.7, was calculated. Based on the pore size, the investigated hydrogels can be regarded as microporous. According to the obtained results swelling behaviour, mechanical properties, drug-loading capacity and the drug release rate could be controlled by hydrogel composition and crosslinking density, which is important for application of the investigated hydrogels as drug delivery systems.     

A novel temperature and pH dual‐responsive hybrid hydrogel with polyhedral oligomeric silsesquioxane as crosslinker: synthesis,characterization and drug release properties

Octavinyl polyhedral oligomeric silsesquioxane (OVPS) is used as the crosslinker instead of N,N′‐methylenebisacrylamide (BIS) to copolymerize with 2‐(dimethylamino)ethyl methacrylate (DMAEMA) or DMAEMA and N‐isopropylacrylamide (NIPAM) to prepare hybrid hydrogels: P(OVPS‐co‐DMAEMA) and P(OVPS‐co‐DMAEMA‐co‐NIPAM). The prepared hydrogels are transparent and show dual response to temperature and pH. The hydrogels were characterized using Fourier transform infrared spectroscopy, scanning electron microscopy, X‐ray diffraction, differential scanning calorimetry, thermogravimetric analysis, dynamic mechanical analysis and tensile tests. Their mechanical properties, swelling ratio, deswelling and reswelling behaviors as well as drug release properties were investigated. The results indicate that OVPS can be incorporated into polymer networks in proportion to feed ratios. The P(OVPS‐co‐DMAEMA) hydrogel exhibits more homogeneous interior structure, higher swelling ratio and faster response than the conventional hydrogel prepared with BIS. Moreover, the incorporation of OVPS enhances the compression and tensile properties of the hydrogels. The feed ratios of OVPS and NIPAM have a great effect on volume phase transition temperature, thermal sensitivity, swelling behavior, mechanical properties and drug release properties of the hybrid hydrogels. The prepared dual‐responsive OVPS‐containing hydrogels are expected to be used as biomedical materials in drug release and tissue engineering. © 2014 Society of Chemical Industry     

Radiation synthesis and characterization of poly(ethylene oxide)/chitosan hydrogels

Recent advances in hydrogel technology have focused on finding more biocompatible, nontoxic materials intended for pharmaceutical and biomedical applications. In this study, a series of pH‐sensitive hydrogels were prepared from poly(ethylene oxide) (PEO) and chitosan in aqueous solutions by electron beam irradiation. This method is a suitable tool for the formation of biocompatible hydrogels because in radiation processing no initiators or crosslinkers, potentially toxic and difficult to remove, are needed. In this frame, also the PEO and chitosan choice was based on their characteristic of low toxicity. The properties of the prepared hydrogels were investigated in terms of the gel fraction and of the swelling behavior in solutions at different pHs. Some swelling kinetic and diffusional parameters were also determined. The observed properties show that increasing the chitosan content, or lowering the pH, the crosslinking density of these networks increases inducing the formation of more stable, but less swellable, hydrogels. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Effect of graphene oxide on the pH-responsive drug release from supramolecular hydrogels

Polypseudorotaxane (PPR) hydrogels formed by inclusion complexes between poly(ethylene glycol) (PEG) and α-cyclodextrin (α-CD) are highlighted as promising biomaterial for drug delivery. Here, we report a novel injectable PPR hydrogel containing graphene oxide (GO) for pH-responsive controlled release of doxorubicin hydrochloride (DOX). Our results showed that the gelation rates of the PEG/α-CD supramolecular structures could be tailored depending on the reagent concentrations. The formation of PEG/α-CD inclusion complexes was confirmed by TEM and XRD, the latter further confirming that GO restricts their formation. The supramolecular hydrogels were easily loaded with DOX by simple addition into the PEG solution before the complex formation with the α-CD solution. Noteworthy, disruption of ionic interactions between DOX and GO in the nanocomposite at pH = 5.5 resulted in higher DOX release than under physiological conditions (pH = 7.4). This pH dependence was barely observed in pure PPR hydrogel. These findings introduce DOX-loaded supramolecular hydrogels nanocomposites as promising carriers for pH-responsive and therefore localized, drug delivery systems.