Synthesis,characterization, and evaluation of enzymatically degradable poly(N‐isopropylacrylamide‐co‐acrylic acid) hydrogels for colon‐specific drug delivery

The enzymatically degradable poly(N‐isopropylacrylamide‐co‐acrylic acid) hydrogels were prepared using 4,4^′‐bis(methacryloylamino)azobenzene (BMAAB) as the crosslinker. It was found that the incorporated N‐isopropylacrylamide (NIPAAm) monomer did not change the enzymatic degradation of hydrogel, but remarkably enhanced the loading of protein drug. The hydrogels exhibited a phase transition temperature between 4°C (refrigerator temperature) and 37°C (human body temperature). Bovine serum albumin (BSA) as a model drug was loaded into the hydrogels by soaking the gels in a pH 7.4 buffer solution at 4°C, where the hydrogel was in a swollen status. The high swelling of hydrogels at 4°C enhanced the loading of BSA (loading capability, ca. 144.5 mg BSA/g gel). The drug was released gradually in the pH 7.4 buffer solution at 37°C, where the hydrogel was in a shrunken state. In contrast, the enzymatic degradation of hydrogels resulted in complete release of BSA in pH 7.4 buffer solution containing the cecal suspension at 37°C (cumulative release: ca. 100 mg BSA/g gel after 4 days). Copyright © 2008 John Wiley & Sons, Ltd.     

Chitosan‐Based Thermo/pH Double Sensitive Hydrogel for Controlled Drug Delivery

A series of thermo/pH sensitive N‐succinyl hydroxybutyl chitosan (NSHBC) hydrogels with different substitution degrees of succinyl are prepared for drug delivery. Rheology analysis shows that the gelation temperature of NSHBC hydrogels is 3.8 °C higher than that of hydroxybutyl chitosan (HBC) hydrogels. A model drug bovine serum albumin (BSA) is successfully loaded and released. NSHBC hydrogels show excellent pH sensitivity drug release behaviors. After incubation for 24 h, 93.7% of BSA is released from NSHBC hydrogels in phosphate buffer saline (PBS) (pH 7.4), which is significantly greater than that of 24.6% at pH 3.0. In contrast, the release rate of BSA from HBC is about 70.0% at pH 3.0 and 7.4. Thus, these novel hydrogels have the prominent merits of high adaptability to soluble drugs and pH sensitivity triggered release, indicating that NSHBC hydrogels have promising applications in oral drug delivery.     

Preparation, characterization, swelling and in vitro drug release behaviour of poly[N-acryloylglycine-chitosan] interpolymeric pH and thermally-responsive hydrogels

Novel biodegradable pH- and thermal-responsive interpenetrating polymer network (IPN) hydrogels were prepared for controlled drug delivery studies. The IPN hydrogels were obtained in mild aqueous acid media by irradiation of solutions of N-acryloylglycine (NAGly) mixed with chitosan, in the presence of glutaraldehyde as a crosslinking agent and using 2,2-dimethoxy-2-phenyl acetophenone as photoinitiator. These hydrogels were subjected to equilibrium swelling studies at different temperatures (25 °C, 37 °C and 45 °C) in buffer solutions of pH 2.1 and 7.4 (similar to that of gastric and intestinal fluids respectively). 5-Fluorouracil (5-FU) was entrapped in the hydrogels, and drug release studies carried out at 37 °C in buffer solutions at pH 2.1 and 7.4.     

γ-irradiated chitosan-polyvinyl pyrrolidone hydrogels as pH-sensitive protein delivery system

The effects of pH of the buffer solution and the composition of the hydrogel system on the bovine serum albumin (BSA) adsorption capacity of chitosan (CS)–polyvinyl pyrrolidone (PVP) (CSPVP) hydrogels and release of BSA were investigated. Poly-electrolyte CSPVP hydrogels with different compositions were prepared by irradiating CS/PVP/water mixtures with γ-rays at ambient temperature. The adsorption capacity of hydrogels was found to increase from 0 to 350 mg BSA/g dry gel, by changing external stimuli and hydrogel composition. The adsorption of BSA within CSPVP hydrogels increased with increase in CS content in the hydrogels. When the irradiation doses of hydrogel increased, the adsorption of BSA decreased. The maximum adsorption of BSA was observed at pH 5. A significant amount of the adsorbed BSA (up to 95%) was eluted in the phosphate medium containing 0.1 M NaCl at pH 7.4.     

A spheres-in-sphere structure for improving protein-loading poly (lactide-co-glycolide) microspheres

In present study, protein loaded poly (lactide-co-glycolide)/chitosan microspheres (PLGA/CS MSs) with spheres-in-sphere structure were prepared in order to weaken the burst release of protein from PLGA microspheres (PLGA MSs) and to buffer acidic micro-milieu. The PLGA MSs and PLGA/CS MSs were characterized in terms of their size distribution, morphology, drug-loading rate, zeta potential and physical-chemical properties. The incubation experiments of PLGA MSs and PLGA/CS MSs were manipulated in PBS solution at pH 7.4, 37 °C to monitor the release of BSA and the vehicles degradation. The release kinetic of BSA was illuminated mainly based on the degradation processes of the matrices. External CS crusts were proved to strikingly improve the release kinetic of the model protein by reducing initial burst release and extending continuous release while acting as a diffusion barrier. Moreover, using PLGA/CS MSs could avoid the decrease of pH value resulted from the acidic products of PLGA MSs because of the effective buffer action of the basic groups in CS. The results demonstrated that the spheres-in-sphere structure is an effective way to control the initial burst release of protein and to overcome the acidic problem of protein-loading PLGA MSs.     

Degradation of electrospun SF/P(LLA-CL) blended nanofibrous scaffolds in vitro

Nanofibrous scaffolds of silk fibroin (SF) and poly(l-lactic acid-co-?-caprolactone) (P(LLA-CL)) blends fabricated via electrospinning possessed good mechanical property and biocompatibility, as demonstrated by a previous study in vitro. However, the degradation behavior of the scaffolds, which may significantly influence tissue repair and regeneration, needs further exploration. In this study, in vitro degradation of pure SF, P(LLA-CL) and SF/P(LLA-CL) blended nanofibrous scaffolds were performed in phosphate-buffered saline (PBS, pH 7.4 ± 0.1) at 37 °C for 6 months. A series of analyses and characterizations (including morphologic changes, loss weight, pH changes of PBS solutions, DSC, XRD and FTIR-ATR) were conducted to the nanofibrous scaffolds after degradation and the results showed that the pure SF nanofibrous scaffolds were not completely degradable in PBS while pure P(LLA-CL) nanofibrous scaffolds had the fastest degradation rate. Moreover, the addition of SF reduced the degradation rate of P(LLA-CL) in SF/P(LLA-CL) blended nanofibrous scaffolds. This was probably caused by the intermolecular interactions between SF and P(LLA-CL), which hindered the movement of P(LLA-CL) molecular chains.     

Hydrolytic degradation of POSS-PEG-lactide hybrid hydrogels

A polyhedral oligomeric silsesquioxane (POSS), functionalized with eight arms of poly(ethylene glycol) (PEG; MW 400) and then acrylated, was incorporated into a hydrogel network based on triblock copolymers of poly(lactide-b-ethylene glycol-b-lactide) diacrylates using a redox-initiated polymerization. The organic-inorganic hybrid hydrogels so prepared contained the inorganic crosslinker POSS from 1 to 28 wt.%. The degradation properties of the hydrogels in a pH 7.4 phosphate-buffered saline solution at 37 °C were studied using measurements of mass loss, cryogenic SEM, and ATR-FTIR spectroscopy. It was found that copolymerization of acrylated 1kPEG-lactide with increasing amounts of POSS created a more porous network which was more resistant to hydrolysis. The ATR-FTIR technique was used to monitor the progress of degradation with exposure time through the changes in the carbonyl and C-H deformation bands of the lactide and the Si-C stretching band of the POSS. Increasing POSS incorporation resulted in decreased rate of degradation due to its hydrophobic nature and inertness to hydrolysis. Conversely, an increase in lactide content increased the degradation rate due to the increased number of hydrolytically-sensitive ester groups in the network.     

Nano engineered biodegradable capsules for the encapsulation and kinetic release studies of ciprofloxacin hydrochloride

Polyelectrolyte based nano and micro capsules have been extensively studied as promising drug carrier in recent years. Natural degradable capsules have received great deal of attention due to their fascinating structural and morphological characteristics, biocompatibility, sustained and targeted-release capabilities. In this work, chitosan - dextran sulphate nano capsules were prepared via Layer-by-Layer (L-b-L) technique using sacrificial template for drug delivery applications. The loading and in vitro release studies were performed using ciprofloxacin hydrochloride as a model drug. The release media used in the study are plain water and Phosphate Buffered Saline (PBS). The optimum drug load was 389 ​μg, at a loading pH of 2.1 and a temperature of 25 ​°C for 50 ​min encapsulation time. The drug loaded capsules exhibited a slow and sustained release up to 24 ​h and the maximum release rate was obtained at pH 1.2 in water and pH 7.4 in PBS. Least amount of drug release occurred at pH 5.0 in both the release media. The amounts of drug release in water at pH 1.2, pH 5.0 and pH 7.4 are 309 ​μg, 163 ​μg and 251 ​μg respectively where as the corresponding values in the case of PBS (at pH 1.2, pH 5.0 and pH 7.4) are 236 ​μg, 198 ​μg and 251 ​μg respectively. Two different models namely, Ritger - Peppas and Higuchi models were chosen to study the release kinetics behaviour of ciprofloxacin hydrochloride. The prepared bio-degradable capsules had potential as drug carrier for targeting antibacterial drugs with diverse functionality.     

Synthesis, characterisation and evaluation of poly[lactose acrylate-N-vinyl-2-pyrrolidinone] hydrogels for drug delivery

New biodegradable polymeric hydrogels based on biocompatible materials, lactose acrylate (LA) and N-vinyl-2-pyrrolidinone were designed and synthesized. LA was synthesized and characterized by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. Hydrogel synthesis was carried out by free-radical polymerization of the co-monomers using azobisisobutyronitrile as initiator and N,N^′-methylenebisacrylamide as crosslinker. These hydrogels were also characterized. Equilibrium swelling of the hydrogels was studied in phosphate buffer of physiological pH, 7.4 and at 37 °C. Propranolol hydrochloride was entrapped into these hydrogels and the in vitro release profile of this drug was established in phosphate buffer. The drug release followed a near zero-order fashion in the first 6 h and thereafter slowed down releasing more than 90% of the entrapped drug at the end of 48 h.     

A comparison of the increased temperature accelerated degradation of Poly(d,l-lactide-co-glycolide) and Poly(l-lactide-co-glycolide)

Bioresorbable polymers composed of Poly(lactide), Poly(glycolide) and their related copolymers have become increasingly popular for the preparation of bone substitute constructs. In vitro tests assessing the degradative changes in physicochemical, mechanical, and biological properties of bioresorbable polymers are generally carried out at 37 °C, in pH 7.4 phosphate-buffered saline (PBS). However, long degradation times, varying from months to years make it difficult to assess these polymers at their late stages of degradation. An increased temperature accelerated degradation methodology, that simulates the long-term degradation of Poly(d,l-lactide-co-glycolide) and Poly(l-lactide-co-glycolide), has been validated in this study. Samples were degraded in PBS, under sterile conditions. Degradation temperatures of 47 °C, 57 °C and 70 °C were selected and compared to physiological temperature, 37 °C. At predetermined time intervals, samples were retrieved and evaluated for changes in mass, swelling, molecular weight, crystallinity, and thermal properties. The results from this study suggest that the degradation mechanism at elevated temperatures is similar to that observed at 37 °C. It is recommended that 47 °C is adopted by the research community to accelerate the degradation of these polymers. It is hoped the application of this methodology could be used as a valuable tool, prior to the assessment of the long-term biocompatibility of these polymers.     

Synthesis and characterization of poly(methacrylic acid) hydrogels for metoclopramide delivery

Polymeric hydrogels based on biocompatible materials, methacrylic acid (MAA), were designed and synthesized. Synthesis was carried out by free-radical copolymerization using potassium persulfate as initiator and N,N^′-methylenebisacrylamide as crosslinker. Hydrogels were also characterized by Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance spectroscopy (¹H NMR) and differential scanning calorimetry (DSC). DSC was used for the quantitive determination of the amounts of freezing and non-freezing water of the hydrogels with 0.5% of N,N^′-methylenebisacrylamide. Equilibrium swelling of hydrogels was studied in phosphate buffer of physiological pH (1.0, 4.0, 7.4 and 8.5) at 37 °C. The swelling kinetic of the hydrogels were studied and the kinetic characteristic constant of copolymeric systems, k, and the exponent which characterizes the mechanism of water transport at short times, n, were obtained. Metoclopramide hydrochloride was entrapped into the hydrogels by sorption and the “in vitro” release profile of this drug was established in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). It was observed that the drug release mechanism was non-Fickian.     

Synthesis of three-dimensional hydrogels based on poly(glycidyl methacrylate-alt-maleic anhydride): Characterization and study of furosemide drug release

In the present work, three-dimensional drug carriers were synthesized via chemical modification of poly (glycidyl methacrylate-alt-maleic anhydride) P(GMA-alt-MA) by isopropylamine (IPA) and ethylenediamine (EDA) with different molar ratios. Then furosemide drug (FR) was loaded on the hydrogels and studied for its slow release in phosphate-buffered saline (PBS) solution (pH = 7.41) at 37 °C. According to the obtained results, the sample with the lowest amount of crosslinking agent (Sample A) showed the highest swelling ratio in comparison to the others. By increasing the rigidity of carrier in the result of increasing the crosslinker density, the amount of the released drug was decreased. However, the release rate for all of samples (slope of the profiles) were rather similar. All the synthesized carriers have shown pH dependent properties and the maximum release rate was shown in basic pH. Also, the drug release experiments in different temperatures showed almost thermal sensitivity properties for synthesized carriers and release rate become faster by increasing the medium temperature. The FT-IR, TGA, and FE-SEM analyses were carried out for characterization of prepared samples and the swelling behavior of prepared hydrogels were measured too. Investigation of the release data with different mathematical models showed the highest adaption with the Higuchi model for all samples.     

Development of Antibacterial,Degradable and pH-Responsive Chitosan/Guar Gum/Polyvinyl Alcohol Blended Hydrogels for Wound Dressing

The present research is based on the fabrication preparation of CS/PVA/GG blended hydrogel with nontoxic tetra orthosilicate (TEOS) for sustained paracetamol release. Different TEOS percentages were used because of their nontoxic behavior to study newly designed hydrogels’ crosslinking and physicochemical properties. These hydrogels were characterized using Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and wetting to determine the functional, surface morphology, hydrophilic, or hydrophobic properties. The swelling analysis in different media, degradation in PBS, and drug release kinetics were conducted to observe their response against corresponding media. The FTIR analysis confirmed the components added and crosslinking between them, and surface morphology confirmed different surface and wetting behavior due to different crosslinking. In various solvents, including water, buffer, and electrolyte solutions, the swelling behaviour of hydrogel was investigated and observed that TEOS amount caused less hydrogel swelling. In acidic pH, hydrogels swell the most, while they swell the least at pH 7 or higher. These hydrogels are pH-sensitive and appropriate for controlled drug release. These hydrogels demonstrated that, as the ionic concentration was increased, swelling decreased due to decreased osmotic pressure in various electrolyte solutions. The antimicrobial analysis revealed that these hydrogels are highly antibacterial against Gram-positive (Staphylococcus aureus and Bacillus cereus) and Gram negative (Pseudomonas aeruginosa and Escherichia coli) bacterial strains. The drug release mechanism was 98% in phosphate buffer saline (PBS) media at pH 7.4 in 140 min. To analyze drug release behaviour, the drug release kinetics was assessed against different mathematical models (such as zero and first order, Higuchi, Baker–Lonsdale, Hixson, and Peppas). It was found that hydrogel (CPG2) follows the Peppas model with the highest value of regression (R² = 0.98509). Hence, from the results, these hydrogels could be a potential biomaterial for wound dressing in biomedical applications.     

In vitro degradation of porous poly(l-lactide-co-glycolide)/β-tricalcium phosphate (PLGA/β-TCP) scaffolds under dynamic and static conditions

In vitro degradation of porous poly(l-lactide-co-glycolide)/β-tricalcium phosphate (PLGA/β-TCP) scaffolds was studied by incubating the samples in phosphate buffered saline (PBS) at 37 °C and pH 7.4 under dynamic loading with respect to static conditions for 12 weeks. Under dynamic conditions, acidity of PBS was alleviated by the better solution circulation, and water absorption of the scaffolds increased more than that under static conditions in the first 8 weeks. Changes in mass, height, diameter, relative molecular mass and its distribution also happened more remarkably under dynamic conditions. Moreover, obvious cracks and a larger amount of β-TCP particles were observed on the wall of the scaffolds after degradation for 12 weeks under dynamic loading. Compressive modulus and strength showed an increase from the beginning to the 10th week but were lower after then. Results showed that degradation of PLGA/β-TCP scaffolds under dynamic conditions exhibited a significantly faster rate than that under static conditions.     

Effects of mechanical load on the degradation of poly(d,l-lactic acid) foam

Degradable behaviors of polymer for implantation in body should be evaluated before clinical application. The effect of continuous mechanical load on the degradation progress of poly(d,l-lactic acid) (PDLLA) foam gasket was investigated in detail by specially designed load-providing devices. While PDLLA degraded in the PBS solution (pH, 7.4) at 37 °C for 3 months, the changes of surface morphology, molecular weight, elastic modulus, tensile strength and mass loss were recorded. The results revealed that the degradation rates of PDLLA under continuous loads were obviously quicker than those without load. Moreover, the influence of tensile plus compressive load was larger than that of tensile load. It was indicated that in vivo degradation of PDLLA would not only be influenced by the local solution, but also by the surrounding load. When regulating the degradation rate of bioabsorbable polymer, one should consider the indispensable effect of load where implanted.     

Swelling and thermodynamic studies of temperature responsive 2-hydroxyethyl methacrylate/itaconic acid copolymeric hydrogels prepared via gamma radiation

The copolymeric hydrogels based on 2-hydroxyethyl methacrylate (HEMA) and itaconic acid (IA) were synthesized by gamma radiation induced radical polymerization. Swelling and thermodynamic properties of PHEMA and copolymeric P(HEMA/IA) hydrogels with different IA contents (2, 3.5 and 5 mol%) were studied in a wide pH and temperature range. Initial studies of so-prepared hydrogels show interesting pH and temperature sensitivity in swelling and drug release behavior. Special attention was devoted to temperature investigations around physiological temperature (37 °C), where small changes in temperature significantly influence swelling and drug release of these hydrogels. Due to maximum swelling of hydrogels around 40 °C, the P(HEMA/IA) hydrogel containing 5 mol% of IA without and with drug-antibiotic (gentamicin) were investigated at pH 7.40 and in the temperature range 25–42 °C, in order to evaluate their potential for medical applications.     

Preparation and in vitro degradation of porous three-dimensional silk fibroin/chitosan scaffold

Degradation behaviors of porous scaffolds play an important role in the engineering process of a new tissue. In this study, three-dimensional porous silk fibroin/chitosan (SFCS) scaffolds were successfully prepared by freeze-drying method. In vitro degradation behaviors of SFCS scaffolds have been systematically investigated up to 8 weeks in phosphate buffer saline (PBS) solution at 37 °C. The following properties of the scaffolds were measured as a function of degradation time: pore morphology, structure, weight loss, and wet/dry weight value. The pH value of the PBS solution during degradation was also detected. SFCS scaffolds maintained its porous structure till 6 weeks of degradation. During the first 2 weeks, the pH value fluctuated in a narrow range from 6.53 to 6.93. SFCS scaffolds degraded much more quickly during the first 2 weeks, and the weight loss reached 19.28 wt% after 8 weeks of degradation. The degradation process affects little SFCS scaffolds' swelling properties.     

Biodegradable in situ gel-forming controlled vancomycin delivery system based on a thermosensitive mPEG-PLCPPA hydrogel

In this study, a biodegradable in situ gel-forming controlled drug delivery system based on a thermosensitive methoxy polyethylene glycol-co-poly (lactic acid-co-aromatic anhydride) (mPEG-PLCPPA) hydrogel was studied. The hydrogels were formed by micelle aggregation with rising temperature. The hydrogels underwent a temperature-dependent sol–gel–sol transition, which was a flowing sol at ambient temperature and a non-flowing gel at the physiological body temperature. The residual weight and pH value changes after degradation and the viscosity properties of the hydrogel were investigated. The in vitro release behavior of vancomycin from the mPEG-PLCPPA hydrogels at different concentrations was also investigated. The results showed that the mPEG-PLCPPA amphiphilic copolymer could self-assemble to form micelles at low concentrations, and that the particle sizes gradually increased with increasing temperature. The hydrogel maintained a stable degradation rate and provided a moderate pH microenvironment after degradation for 30 days. Vancomycin sustained a stable release profile from the hydrogel over a 10-day period. Furthermore, good biocompatibility was proven by MTT assay and live and dead test. Therefore, the mPEG-PLCPPA hydrogel shows promise as an injectable local antibiotic delivery system.     

Synthesis,characterization and evaluation of semi‐IPN hydrogels consisted of poly(methacrylic acid) and guar gum for colon‐specific drug delivery

The semi‐IPN hydrogels consisting of poly(methacrylic acid) and guar gum (GG) are prepared at room temperature using water as solvent. 5‐aminosalicylic acid (5‐ASA) is entrapped in the hydrogel in the synthesis of hydrogel and all entrapment efficiencies are found above 85%. The hydrogel shows excellent pH‐sensitivity. It exhibited minimum swelling in an acidic pH medium through the formation of a complex hydrogen‐bonded structure and maximal swelling due to the electrostatic repulsion due to the ionization of the carboxylic groups in pH 7.4 medium. The degradation in vitro shows that the degree of degradation (R%) depended on the concentration of cross‐linking agent and content of GG. The hydrogel shows a minimum release of 5‐ASA due to the complex hydrogen bonded structure of the hydrogels in the medium of pH 2.2. The enzymatic degradation of hydrogels by cecal bacteria can accelerate the release of 5‐ASA entrapped in the hydrogel in pH 7.4 medium. Copyright © 2007 John Wiley & Sons, Ltd.     

In vitro and in vivo degradation behaviors of thermosensitive poly(organophosphazene) hydrogels

Biodegradable and thermosensitive poly(organophosphazenes) with various substituents were synthesized and their hydrolytic degradation properties were investigated in vitro and in vivo. The aqueous solutions of all polymers showed a sol-gel phase transition behavior depending on temperature changes. The side groups of polymers significantly affected the polymer degradation and accelerated hydrolysis of polymers in the order of carboxylic acid > depsipeptide > without carboxylic acid and depsipeptide. The increased gel strength led to the decreased hydrolysis rate. The polymer hydrogels with 750 Da of α-amino-ω-methoxy poly(ethylene glycol) were rapidly decreased by dissolution. The polymer degradation was also influenced by pH and temperature. The in vivo behaviors of mass decrease of the polymer hydrogels were similar with the in vitro results. These results suggest that the biodegradable and thermosensitive poly(organophosphazenes) hold great potentials as an injectable and biodegradable hydrogel for biomedical applications with controllable degradation rate.