Chitosan‐based interpolymeric pH‐responsive hydrogels for in vitro drug release

Two series of pH‐responsive biodegradable interpolymeric (IPN) hydrogels based on chitosan (Ch) and poly(vinyl alcohol) (PVA) were prepared for controlled drug release investigations. The first series was chemically crosslinked with different concentrations of glutaraldehyde and the second was crosslinked upon γ‐irradiation by different doses. The equilibrium swelling characteristics were investigated for the gels at 37°C in buffer solutions of pH 2.1 and 7.4 as simulated gastric and intestinal fluids, respectively. 5‐Fluorouracil (FU) was entrapped in the hydrogels, as a model therapeutic agent, and the in vitro release profiles of the drug were established at 37°C in pH 2.1 and 7.4. FTIR, SEM, and X‐ray diffraction analyses were used to characterize and investigate the structural changes of the gels with the variation of the blend composition and crosslinker content before and after the drug loading. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 2864–2874, 2007     

Synthesis and properties of silver nanoparticles in chitosan‐based thermosensitive semi‐interpenetrating hydrogels

In this article, thermosensitive poly(N‐isopropyl acrylamide‐co‐vinyl pyrrolidone)/chitosan [P(NIPAM‐co‐NVP)/CS] semi‐interpenetrating (semi‐IPN) hydrogels were prepared by redox‐polymerization using N,N‐methylenebisacrylamide as crosslinker and ammonium persulfate/N,N,N′,N′‐tetramethylethylenediamine as initiator. Highly stable and uniformly distributed Ag nanoparticles were prepared by using the semihydrogel networks as templates via in situ reduction of silver nitrate in the presence of sodium borohydride as a reducing agent. Introduction of CS improves the hydrogels swelling ratio (SR) and stabilizes the formed Ag nanoparticles in networks. Scanning electron microscopy and transmission electron microscopy revealed that Ag nanoparticles were well dispersed with diameters of 10 nm. The semi‐IPN hydrogel/Ag composites had higher SR and thermal stability than its corresponding semi‐IPN hydrogels. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Preparation and properties of crosslinked chitosan thermosensitive hydrogel for injectable drug delivery systems

The aim of this study was to prepare and investigate the physical properties of a thermosensitive crosslinked chitosan pregel solution, and evaluate the in vitro release profiles of macromolecules from this sol–gel transition system. Chitosan and poly (vinyl alcohol) were used to form an interpenetrating polymeric network with glutaraldehyde as the crosslinker, and glycerophosphate (GP) was added to transform the pH‐dependent solutions into thermosensitive pH‐dependent solutions. Rheological study showed that the gelation was dependent on the crosslink degree and GP concentration of the solution. The crosslinked gel had excellent mechanic properties and no apparent “pores” and formed an integrated hydrogel texture according to scanning electronic micrograph. Gas chromatography test guaranteed the medication safety with no detection of glutaraldehyde remnants in the hydrogels. In vitro release study showed that the gelation does not significantly affect the macromolecules diffusion but the crosslinking degree does. These results indicated that the hydrogel formed an intensified three‐dimensional hybrid network with interpenetrating molecules, which effectively buffered or delayed the macromolecules diffusion. The hydrogels sustained the drug release over 30 days and could be potentially used as in situ gelling implants. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 1892–1898, 2006     

Mechanical properties of poly(N‐isopropyl‐acrylamide‐co‐itaconic acid) hydrogels

Hydrogels of N‐isopropylacrylamide and itaconic acid were synthesized with different monomer ratios and with two crosslinking agent concentrations. The different xerogels were immersed in water and the swelling process was conducted up to equilibrium conditions at two temperatures (22 and 37°C). These temperatures are lower and higher than the transition temperature shown by PNIPA hydrogels. The mechanical properties of the different solvated hydrogels were examined by oscillatory shear measurements at 22 and 37°C. The copolymer volume fraction and the elastic storage modulus of the hydrogels decreased as the itaconic acid percentage in the copolymer increased. This behavior was attributed to the higher hydrophilic character of the itaconic acid comonomer. Effective crosslinking density, molar mass between crosslinks, and the polymer–solvent interaction parameter were determined from the experimental values of the elastic storage moduli and the copolymer volume fractions. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 85: 2540–2545, 2002     

Fluconazole release through semi‐interpenetrating polymer network hydrogels based on chitosan,acrylic acid,and citraconic acid

Semi‐interpenetrating polymer network hydrogels with different compositions of chitosan (Cs), acrylic acid, and citraconic acid were synthesized via free‐radical polymerization with ethylene glycol dimethacrylate as a crosslinker. The variations of the swelling percentages of the hydrogels with time, temperature, and pH were determined, and Cs–poly(acrylic acid) (PAA) hydrogels were found to be most swollen at pH 7.4 and 37°C. Scanning electron micrographs of Cs–PAA and Cs–P(AA‐co‐CA)‐1 (Cs‐poly(acrylicacid‐co‐citraconir acid)^?1) were taken to observe the morphological differences in the hydrogels. Although the less swollen hydrogel, Cs–P(AA‐co‐CA)‐1, had a sponge‐type structure, the most swollen hydrogel, Cs–PAA, displayed a uniform porous appearance. Fluconazole was entrapped in Cs–P(AA‐co‐CA)‐1 and Cs–PAA hydrogels, and the release was investigated at pH 4.0 and 37°C. The kinetic release parameters of the hydrogels (the gel characteristic constant and the swelling exponent) were calculated, and non‐Fickian diffusion was established for Cs–PAA, which released fluconazole much more slowly than the Cs–P(AA‐co‐CA)‐1 hydrogel. A therapeutic range was reached at close to 1 h for both hydrogels. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Novel polyurethane‐based thermosensitive hydrogels as drug release and tissue engineering platforms: design and in vitro characterization

Poloxamer P407 (P407) is a Food and Drug Administration approved triblock copolymer; its hydrogels show fast dissolution in aqueous environment and weak mechanical strength, limiting their in vivo application. In this work, an amphiphilic poly(ether urethane) (NHP407) was synthesized from P407, an aliphatic diisocyanate (1,6‐hexanediisocyanate) and an amino acid derived diol (N‐Boc serinol). NHP407 solutions in water‐based media were able to form biocompatible injectable thermosensitive hydrogels with a lower critical gelation temperature behavior, having lower critical gelation concentration (6% w/v versus 18% w/v), superior gel strength (G′ at 37 °C about 40 000 Pa versus 10 000 Pa), faster gelation kinetics (<5 min versus 15–30 min) and higher stability in physiological conditions (28 days versus 5 days) compared to P407 hydrogels. Gel strength and PBS absorption at 37 °C increased whereas dissolution rate (in phosphate‐buffered saline (PBS) at 37 °C) and permeability to nutrients (studied using fluorescein isothiocyanate–dextran model molecule) decreased as a function of NHP407 hydrogel concentration from 10% to 20% w/v. By varying the concentration, NHP407 hydrogels were thus prepared with different properties which could suit specific applications, such as in situ drug/cell delivery or bioprinting of scaffolds. Moreover, deprotected amino groups in NHP407 could be exploited for the grafting of bioactive molecules obtaining biomimetic hydrogels. © 2016 Society of Chemical Industry     

Design of a drug delivery system based on poly(acrylamide‐co‐acrylic acid)/chitosan nanostructured hydrogels

To obtain biodegradable materials for biomedical applications, new biopolymeric hydrogels based on blends of polyacrylamide nanoparticles and chitosan have been prepared. In this work, we have studied the behavior of the diffusion of ascorbic acid (V‐C) from poly(acrylamide‐co‐acrylic acid)/chitosan nanostructured hydrogels. The process involves the synthesis of nanoparticles of polyacrylamide by inverse microemulsion polymerization and their complexation with chitosan dissolved in an acrylic acid aqueous solution. We have studied the effect of the concentration of the polyacrylamide nanoparticles, which are crosslinked with N,N′‐methylenebisacrylamide, in the delivery of V‐C. The results indicate that the drug delivery operates by a non‐Fickian mechanism. Also, we have obtained the diffusion coefficient for V‐C in gels for different nanoparticle concentrations, using a modified form of Fick's second law that takes into account dimensional changes in the hydrogels during drug release. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Interpenetrating networks hydrogels based on hyaluronic acid for drug delivery and tissue engineering

There are several techniques for preparing hydrogel biomaterials. Among these techniques, preparation of interpenetrating polymer networks hydrogel (IPNs) has been more interested during last years. IPNs are fabricated by the incorporation of monomers or polymeric chains in hydrogel network. Natural polymers such as hyaluronic acids have some advantages such as biocompatibility, biodegradability and non-toxicity. In this review, we would have a brief view to the interpenetrating polymer networks hydrogel based on hyaluronic acids and its applications as a drug delivery system and tissue engineering applications.     

Rheological properties and drug release characteristics of pH‐responsive hydrogels

Rheological properties, blend compatibility, and gel‐forming capacity of carbopol 940 (CP‐940), sodium alginate (NaAlg), and guar gum (GG) have been studied. These matrices have been used in delivery of timolol maleate for ophthalmic applications. Aqueous solutions of CP‐940, NaAlg, and GG in concentrations between 0.1 and 1% (wt/vol) and their blends have been prepared. In situ gel forming polymeric solutions have shown an increase in viscosity upon exposure to specific pH, ions, and temperature of the eyeball. Blend miscibility was studied by calculating polymer–polymer interaction parameters using viscosity data. Rheological properties viz., torque, viscosity, shear stress, and shear rate were obtained using a Brookfield rheometer. Viscosities of polymer solutions were obtained by a Schott Gerate viscometer. Rheological data were analyzed using Bingham, Casson Standard, and Casson Chocolate equations. The hydrogels were subjected to ex vivo release studies on timolol maleate through the excised bovine cornea using a modified Franz diffusion cell. Results were compared with the conventional drug solution. The release could be extended when the drug is incorporated into hydrogel‐forming solution. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 2057–2064, 2004     

Temperature and pH‐response swelling behavior of poly(2‐ethyl‐2‐oxazoline)/chitosan interpenetrating polymer network hydrogels

Interpenetrating polymer network (IPN) hydrogels composed of poly(2‐ethyl‐2‐oxazoline) (PEtOz) and chitosan (CS) were prepared with radical polymerization and were characterized for their swelling properties. Sample OC11 (hydrogel weight ratio PEtOz/CS = 1/1) swelled more than samples OC21 (PEtOz/CS = 2/1) and OC31 (PEtOz/CS =3/1), exhibiting a swelling ratio of about 2000 wt % in deionized water; the swelling ratios of the other samples were about 1000 and 700 wt %. The swelling behavior of the IPN hydrogels was observed under various pH and temperature conditions. The swelling ratios of the samples ranged from about 2000 to 6500 wt % at lower pHs, with a maximum swelling ratio of about 6500 wt % in a pH 2 aqueous solution. They exhibited low critical solution temperature behavior, with sample OC31 more sensitive to temperature and sample OC11 more sensitive to pH. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 99: 1100–1103, 2006     

Investigation of loading and release in PVA‐based hydrogels

We used Methylene Blue (MB) and Methyl Orange (MO) as model drugs to investigate the controlled release behavior of hydrogels from poly(vinyl alcohol) crosslinked with ethylenediaminetetraacetic dianhydride. The cationic or anionic character of these compounds and the molecular weight between crosslinks of the hydrogel and the concentration of ionizable groups in the hydrogel greatly affected the loading and release of the drugs. MB loading was favored, therefore, by a higher content of negative charges in the hydrogel, although this implied a greater degree of crosslinking and, therefore, a lower mesh size. On the other hand, the overall loading of negative MO, favored by a higher mesh size, was very low because of unfavorable interactions with the electrolyte charges. Release studies showed that one of the parameters that most affected the drug release behavior of these hydrogels was the pH of the solution. MB and MO were not completely released, even at pH 1. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 85: 1644– 1651, 2002.     

Recent advances in shear-thinning and self-healing hydrogels for biomedical applications

Shear-thinning and self-healing hydrogels are being investigated in various biomedical applications including drug delivery, tissue engineering, and 3D bioprinting. Such hydrogels are formed through dynamic and reversible interactions between polymers or polypeptides that allow these shear-thinning and self-healing properties, including physical associations (e.g., hydrogen bonds, guest–host interactions, biorecognition motifs, hydrophobicity, electrostatics, and metal–ligand coordination) and dynamic covalent chemistry (e.g., Schiff base, oxime chemistry, disulfide bonds, and reversible Diels–Alder). Their shear-thinning properties allow for injectability, as the hydrogel exhibits viscous flow under shear, and their self-healing nature allows for stabilization when shear is removed. Hydrogels can be formulated as uniform polymer and polypeptide assemblies, as hydrogel nanocomposites, or in granular hydrogel form. This review focuses on recent advances in shear-thinning and self-healing hydrogels that are promising for biomedical applications. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48668.     

Biomimetic protein‐based elastomeric hydrogels for biomedical applications

In recent years, protein‐based elastomeric hydrogels have gained increased research interest in biomedical applications for their remarkable self‐assembly behaviour, tunable 3D porous structure, high resilience (elasticity), fatigue lifetime (durability), water uptake, excellent biocompatibility and biological activity. The proteins and polypeptides can be derived naturally (animal or insect sources) or by recombinant (bacterial expression) routes and can be crosslinked via physical or chemical approaches to obtain elastomeric hydrogels. Here we review and present the recent accomplishments in the synthesis, fabrication and biomedical applications of protein‐based elastomeric hydrogels such as elastin, resilin, flagelliform spider silk and their derivatives. © 2013 Society of Chemical Industry     

Preparation and characterization of polyacrylic acid‐poly(vinyl alcohol)‐based interpenetrating hydrogels

Some structural features of hydrogels from poly(acrylic acid) (PAAc) of various crosslinking degrees have been investigated through mechanical and swelling measurements. Interpenetrating polymer hydrogels (IPHs) of poly(vinyl alcohol) (PVA) and PAAc have been prepared by a sequential method: crosslinked PAAc chains were formed in aqueous solution by crosslinking copolymerization of acrylic acid and N,N‐methylenebisacrylamide in the presence of PVA. The application of freeze–thaw (F–T) cycles leads to the formation of a PVA hydrogel within the synthesized PAAc hydrogel. The swelling and viscoelastic properties of the IPHs were evaluated as a function of the content of crosslinker and the application of one F–T cycle. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 5789–5794, 2006     

Radiation crosslinking and sorption properties of hydrogels based on 1‐vinyl‐2‐pyrrolidone,hydroxyethyl methacrylate,and their copolymers

This work has been concerned with the synthesis of the hydrogels of poly (vinyl pyrrolidone) (NVP), poly (hydroxy ethylmethacrylate) (HEMA), and their copolymer under the effect of gamma radiation in the presence of N,N‐methylenebisacryl‐amide (MBAm) as a crosslinking agent. The effect of the different factors that may affect the gelation and yield product, such as solvent composition and irradiation dose, was investigated. The formed hydrogels were characterized in terms of swelling in water and different organic solvents, X‐ray diffraction (XRD), and IR spectroscopic analysis. The sorption capability of these hydrogels towards some commercial basic and acid dyesstuffs was also studied. The results showed that a solvent mixture composed of equal contents of water and methanol is the most suitable to afford the minimum sol fraction and the highest yield product at a minimal irradiation dose of 10 kGy. It was observed that NVP hydrogel displayed the highest swelling in water, alcohols, and dimethyformamide of ～1300% and a lower tendency to swell in nonpolar solvents. The results showed that HEMA hydrogel has a high affinity to absorb basic dyes while NVP has a tendency for acid dyes. Also, the sorption of either the basic or acid dyes by the different hydrogels was found to greatly depend on the concentration of dye in solution and the mass of the used hydrogel. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 91: 3274–3280, 2004     

Immobilization of 2,5‐dimethyl‐4‐benzoyl‐oxypiperidine succinate over polyacrylic acid (PAA) gels. I. Study of interaction between linear and network PAA with succinate of 2,5‐dimethyl‐4‐benzoyl‐oxypiperidine

The interaction of water‐soluble and crosslinked polyacrylic acid (PAA) with a medicinal compound (MC) of 2,5‐dimethyl‐4‐benzoyl‐oxypiperidine succinate was investigated. By methods of potentiometry, viscosimetry, and equilibrium swelling it was confirmed that the interaction of linear and network PAA with MC proceeds with complex formation. The degree of complex formation depends on the effect of pH, MC concentration, and degree of polyacid crosslinking. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 96: 1183–1186, 2005     

Effect of sodium hexametaphosphate concentration on the swelling and controlled drug release properties of chitosan hydrogels

An ionically crosslinked polymer network composed of chitosan and sodium hexametaphosphate (SHMP) was synthesized to determine their swelling and ascorbic acid release kinetics at various SHMP concentrations. The chitosan/SHMP hydrogels were synthesized using an acetic acid aqueous solution (1% v/v). Ionization constants (pK_b) of the SHMP were obtained by potentiometric titration. The results show that the SHMP was hydrolyzed in acidic medium forming orthophosphate and trimetaphosphate. The swelling percentages were measured at different swelling media pH's; the higher swelling capacities were for the systems that were swollen in neutral solution. Also, it was studied the ionic crosslinking degree by turbidimetric titration, comparing the electrostatic interactions between the chitosan and the SHMP; the results shows that electrostatic interactions between the amine groups of the chitosan and the anionic groups of the SHMP are dependent of the swelling medium pH. The ascorbic acid diffusion inside the hydrogel follows the second law of Fick, and the diffusion coefficients were obtained for different SHMP concentrations. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Fabrication of interpenetrating polymer network to enhance the biological activity of synthetic hydrogels

A three dimensional porous hydrogel with suitable biological and mechanical properties are required for bone tissue engineering. Hydrogels of poly(lactic-ethylene oxide fumarate) (PLEOF), crosslinked with poly(ethylene glycol)-diacrylate (PEG-da) have desirable mechanical properties, however, their application for bone regeneration is limited due to the lack of cell motif sites within their structure. The aim of this study was to incorporate a naturally derived polymer such as gelatin into PLEOF hydrogels to promote their biological properties. Interpenetrating polymer network (IPN) was used as an efficient technique to acquire uniform mixture of these two polymers. Additionally gas foaming agents were used to create pores with average diameter of 250 μm in these IPN hydrogels. The concentrations of PEG-da and gelatin were optimized to tune the mechanical strength and degradation properties of these hydrogels. A compression modulus of 500 kPa was achieved for hydrogel fabricated with 400 mg/ml PLEOF, 200 mg/ml PEG-da and 150 mg/ml gelatin. The addition of gelatin to PLEOF elevated the compression modulus by two-fold and decreased the energy loss by 40%. The result of protein analysis demonstrated that IPN substantially enhanced the retention of physically crosslinked gelatin in the 3D structure of hydrogel. More than 50% of gelatin was retained in IPN hydrogel after two weeks of incubation in simulated physiological environment. Preserving gelatin in the hydrogel structure provides cell motif sites for a longer period of time, which is desirable for uniform cell proliferation. In vitro studies showed that primary human osteoblast cells adhered and proliferated in PLEOF-gelatin hydrogel. These results demonstrated the potential of using this IPN hydrogel for bone tissue engineering.     

Enzyme‐based hydrogels containing dextran as drug delivery carriers: Preparation,characterization, and protein release

Novel enzyme‐based hydrogels for drug delivery were prepared by combining dextran with 5,5′‐azodisalicylic acid using isophorone diisocyanate as the crosslinking agent. The structure of the resultant dextran/5,5′‐azodisalicylic acid hydrogels was determined by infrared spectra, and the properties of the hydrogels were characterized by swelling measurements and scanning electron microscopy analysis. It was found that changing the concentration of 5,5′‐azodisalicylic acid affected the crosslinking density of the hydrogels and resulted in significant differences in the water swelling property and degradability of the hydrogels. Compared with their degradability, the degradation of the hydrogels seemed to be more pronounced by azoreductase in cecum content medium than that by hydrolysis in phosphate buffer solution (PBS). Also, the release rate of the protein in cecum content medium was faster than that in PBS. Attributing to the results of the resultant hydrogels described earlier, it could be concluded that dextran/5,5′‐azodisalicylic acid hydrogels could be used as a potential enzyme‐based carrier for colon‐specific drug delivery. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Semi‐interpenetrating polymer network hydrogels based on aspen hemicellulose and chitosan: Effect of crosslinking sequence on hydrogel properties

Semi‐interpenetrating network hydrogel films were prepared using hemicellulose and chemically crosslinked chitosan. Hemicellulose was extracted from aspen by using a novel alkaline treatment and characterized by HPSEC, and consisted of a mixture of high and low molecular weight polymeric fractions. HPLC analysis of the acid hydrolysate of the hemicellulose showed that its major constituent sugar was xylose. X‐ray analysis showed that the relative crystallinity of hydrogels increased with increasing hemicellulose content up to 31.3%. Strong intermolecular interactions between chitosan and hemicellulose were evidenced by FT‐IR analysis. Quantitative analysis of free amino groups showed that hemicellulose could interrupt the chemical crosslinking of chitosan macromolecules. Mechanical testing and swelling experiments were used to define the effective network crosslink density and average molecular weight between crosslinks. Swelling ratios increased with increasing hemicellulose content and mainly consisted of H‐bonded bound water. Results revealed that by altering the hydrogel preparation steps and hemicellulose content, crosslink density and swelling behavior of semi‐IPN hydrogels could be controlled without deteriorating their mechanical properties. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012