One injection for one-week controlled release: In vitro and in vivo assessment of ultrasound-triggered drug release from injectable thermoresponsive biocompatible hydrogels

Episodic release of bioactive compounds is often necessary for appropriate biological effects under specific physiological conditions. Here, we aimed to develop an injectable, biocompatible, and thermosensitive hydrogel system for ultrasound (US)-triggered drug release. An mPEG-PLGA-BOX block copolymer hydrogel was synthesized. The viscosity of 15 wt% hydrogel is 0.03 Pa*s at 25 °C (liquid form) and 34.37 Pa*s at 37 °C (gel form). Baseline and US-responsive in vitro release profile of a small molecule (doxorubicin) and that of a large molecule (FITC-dextran), from the hydrogel, was tested. A constant baseline release was observed in vitro for 7 d. When triggered by US (1 MHz, continuous, 0.4 W/cm²), the release rate increased by approximately 70 times. Without US, the release rate returned to baseline. Baseline and US-responsive in vivo release profile of doxorubicin was tested by subcutaneous injection in the back of mice and rats. Following injection into the subcutaneous layer, in vivo results also suggested that the hydrogels remained in situ and provided a steady release for at least 7 d; in the presence of the US-trigger, in vivo release from the hydrogel increased by approximately 10 times. Therefore, the mPEG-PLGA-BOX block copolymer hydrogel may serve as an injectable, biocompatible, and thermosensitive hydrogel system that is applicable for US-triggered drug release.     

Synthesis and Characterization of pH- and Temperature-sensitive Hydrogels of Poly (Styrene-alt-Maleic Anhydride)-co-Pluronic for Drug Release

A pH- and temperature-sensitive hydrogel of poly(styrene-alt-maleic anhydride) -co-Pluronic P123 (PSMA-P123) was prepared by the reaction of anhydride groups (MA) on PSMA with the hydroxyl groups on Pluronic (triblock polyethylene oxide-co-polypropylene oxide-co-polyethylene oxide, HO(CH₂CH₂O)₂₀(CH₂CH(CH₃)O)₇₀ (CH₂CH₂O)₂₀OH). The effect of proportions between PMSA and P123 on the gel fraction was determined. The effects of pH value and temperature on swelling ratio of the hydrogels were evaluated. Scanning electron microscopy was used to observe the morphology of the hydrogels. Differential scanning calorimetry was employed to characterize the thermo-sensitivity of the hydrogel. The drug-release behavior of the hydrogels was investigated by using chloromycetin as a model drug. The effect of temperature and pH on the release of chloromycetin from the hydrogels was studied. These results showed that PSMA-P123 hydrogels, being pH- and temperature-sensitive and reversible, appeared to be of potential for biomedical materials, especially for drug release applications.     

Preparation and Properties of Polyurethane Hydrogels Based on Methylene Diphenyl Diisocyanate/Polycaprolactone-Polyethylene Glycol

Polyurethane (PU) hydrogel is an important biomedical material for drug controlled release systems, wound dressings and medical bandages. Three series of polyurethane prepolymers based on methylene diphenyl diisocyanate (MDI), polycaprolactone (PCL) and polyethylene glycol (PEG), using diethylene glycol (DEG), N-methyldiethanolamine (MDEA) or dimethylolpropionic acid (DMPA), as the chain-extender, were prepared. Then the polyurethane hydrogels were obtained from the prepolymers, using benzoyl peroxide (BPO) as a cross-linking agent, by free radical polymerization. The influences of the types of chain-extenders and polyols on the contact angle, swelling ratio and morphology of the polyurethane hydrogels were investigated. The effect of the variety of the chain-extenders in the PU hydrogel on the drug release behavior was also studied. The FT-IR results showed that the PU hydrogels were successfully synthesized. The introduction of PEG improved the hydrophilicity of the PU hydrogels. The MDI/PCL-PEG/DEG hydrogel was hydrophobic, and there were small micropores on its surface; while the MDI/PCL-PEG/DMPA and MDI/PCL-PEG/MDEA hydrogels had high hydrophilicity and a micropouous structure on their surface due to the existence of carboxyl and tertiary amino functional groups. The change of chain-extenders had no significant effect on the cumulative drug release of chloramphenicol from the PU hydrogels. However, the introduction of PEG increased the drug release rate. The chloramphenicol release kinetics from the MDI/PCL-PEG hydrogels indicated non-Fickian diffusion.     

Rapid Deswelling of Porous Poly[2-(N-morpholino)ethyl methacrylate] Hydrogel and Controlled Release of Ibuprofen

A novel, rapidly responsive, cross-linkedpoly[(2-N morpholino)ethyl methacrylate] (PMEMA) hydrogel was synthesized through free radical polymerization at room temperature. The highly swellable PMEMA gel displayed rapid deswelling kinetics in response to salt and temperature changes in its environment. During the deswelling test the hydrogel lost 75% of its water within 4 min in response to the salt effect, while it lost only 30% of its water in response to a temperature change within the same interval. Scanning electron microscopy revealed that the PMEMA gel has numerous open pore channels allowing rapid diffusion of water or water-soluble molecules from the gel matrix. Such a rapid response to environmental stimuli is promising for biomedical applications. Therefore, the designed gel was used as a potential drug carrier using water insoluble Ibuprofen (IBU) as a test drug. The results suggest that the PMEMA hydrogel would be beneficial for achieving a slow/controlled release of water-insoluble drugs.     

Influence of Mass Ratio of Polyols on Properties of Polycaprolactone-Polyethylene Glycol/Methylene Diphenyl Diisocyanate/Diethylene Glycol Hydrogels

Polyurethane (PU) hydrogels with good hydrophilicity and biocompatibility have been applied as biomedical materials. A series of polyurethane prepolymers based on methylene diphenyl diisocyanate (MDI), polycaprolactone (PCL) and polyethylene glycol (PEG), using diethylene glycol (DEG) as the chain-extender, were synthesized; then the polyurethane hydrogels were obtained from the prepolymers using benzoyl peroxide (BPO) as a cross-linker by free radical polymerization. The influences of the ratio of polyols (PCL and PEG) on the contact angle, swelling ratio and morphology of the polyurethane hydrogel were investigated. The loading capacity and release behavior of chloramphenicol from the PCL-PEG/MDI/DEG hydrogels with different compositions were also studied. The contact angle and swelling degree results showed that the PCL-PEG/MDI/DEG hydrogel with PCL/PEG mass ratio of 3:1 had higher hydrophilicity than that with PCL/PEG mass ratios of 1:1 and 1:3. All PCL-PEG/MDI/DEG hydrogels showed three dimensional porous structures; however, the pore size increased with increasing PEG content. The chloramphenicol release kinetics from PCL-PEG/MDI/DEG hydrogels indicated Fickian diffusion, and the drug release rate increased with increasing PEG content in the PU hydrogels.     

Ultrasound-triggered nicotine release from nicotine-loaded cellulose hydrogel

Ultrasound (US)-triggered nicotine release system in a cellulose hydrogel drug carrier was developed with three different cellulose concentrations of 0.45 wt%, 0.9 wt%, and 1.8 wt%. The nicotine-loaded cellulose hydrogels were fabricated by the phase inversion method when the nicotine and cellulose mixture in the 6 wt% LiCl/N, N-dimethylacetamide solvent was exposed to water vapor at room temperature. Nicotine was used as the medicine due to its revealed therapeutic potential for neurodegenerative diseases like Alzheimer's and Parkinson's diseases. The behavior of US-triggered nicotine release from nicotine-cellulose hydrogel was studied at 43 kHz US frequency at the changing US output powers of 0 W, 5 W, 10 W, 20 W, 30 W, and 40 W. The significant US-triggered nicotine release enhancement was noted for the hydrogels made with 0.9 wt% and 1.8 wt% cellulose loading. The matrix made with 0.9 wt% cellulose was exhibited the highest nicotine release at the 40 W US power, and differences in nicotine release at different US powers were noticeable than at 0.45 wt% and 1.8 wt% cellulose loadings. For the three cellulose hydrogel systems, the storage modulus (G′) values at the 0.01 wt% strain rate were dropped from their initial values due to the US irradiation. This reduction was proportionately decreased when the US power was increased. The deconvolution of FTIR spectra of nicotine-loaded cellulose films before and after US exposure was suggested breakage of cellulose-nicotine and cellulose-water in the matrix; thus, the stimulated nicotine release from the cellulose matrix was promoted by the US irradiation.     

Stabilizer specific interaction of gold nanoparticles with a thermosensitive polymer hydrogel

We report the experimental results on temperature-dependent studies of interactions between a novel biocompatible thermosensitive polymer hydrogel and different stabilizing agent capped gold nanoparticles (Au NPs) with particle size ranging from 5 to 20 nm. Stabilizing agents such as thioglycolic acid, tryptophan, and phenylalanine have been used as capping agents for Au NPs. The poly-N-isopropyl acrylamide-co-acrylic acid (pNIPAm-AAc) with 3.0 ± 0.7 μm in size was synthesized by radical polymerization of a selected mixture of N-isopropyl acrylamide (NIPAm), methylene-bis-acrylamide and acrylic acid (AAc). The capped Au NPs were mixed with a solution of pNIPAm-AAc hydrogel. The temperature-dependent properties of the mixture were studied by UV–vis spectroscopy, dynamic light scattering based particle size analysis, and transmission electron microscopy (TEM). The observations indicated change in the lower critical solution temperature (LCST) depending on the nature of the stabilizer, with hydrophobic ones lowering the value while hydrophilic stabilizers increasing the same. Also, the optical absorption due to Au NPs, when stabilized with hydrophobic groups, reduced significantly at above LCST along with significant blue shift of wavelength maximum.     

Control of the temperature responsiveness of poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate) copolymer using ultrasonic irradiation

Poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate) (poly(NIPAM-co-HEMA)) is a temperature-responsive copolymer that is expected to be applicable as an advanced functional polymeric material in various fields. In this study, a novel method was developed to control the responsive temperature of poly(NIPAM-co-HEMA) using an ultrasonic polymerization technique. Initially, the behavior of the reaction was investigated using NIPAM and HEMA monomers under ultrasonic irradiation. A high ultrasonic power was found to produce a high reaction rate and low number average molecular weight of the copolymer. The polydispersity of the synthesized copolymer was approximately 1.5 for all ultrasonic powers examined. In the early stage of the reaction, the molar fraction of NIPAM in the copolymer was lower than the initial molar fraction of the monomers. It was concluded that ultrasonic irradiation affected the initiation reaction and polymer degradation, but did not affect the propagation reaction. Furthermore, the effect of the ultrasonic irradiation conditions on the temperature responsiveness of the copolymer was investigated. The lower critical solution temperature (LCST) of the copolymer was found to increase with increasing ultrasonic irradiation time. In addition, in the early stages of the reaction, the measured values of the LCST were higher than the estimated values using copolymer composition. This can be attributed to some parts of the copolymer chain possessing a higher NIPAM fraction than the overall fraction due to different reactivities of the monomers and terminated radicals. This hypothesis was indirectly verified by the synthesis of a block copolymer from the PNIPAM homopolymer and HEMA monomer.     

Ultrasound stimulated release of mimosa medicine from cellulose hydrogel matrix

Ultrasound (US) drug release system using cellulose based hydrogel films was developed as triggered to mimosa. Here, the mimosa, a fascinating drug to cure injured skin, was employed as the loading drug in cellulose hydrogel films prepared with phase inversion method. The mimosa hydrogels were fabricated from dimethylacetamide (DMAc)/LiCl solution in the presence of mimosa, when the solution was exposed to ethanol vapor. The US triggered release of the mimosa from the hydrogel matrix was carried out under following conditions of US powers (0–30 W) and frequencies (23, 43 and 96 kHz) for different mimosa hydrogel matrix from 0.5 wt% to 2 wt% cellulose solution. To release the drug by US trigger from the matrix, the better medicine release was observed in the matrix prepared from the 0.5 wt% cellulose solution when the 43 kHz US was exposed to the aqueous solution with the hydrogel matrix. The release efficiency increased with the increase of the US power from 5 to 30 W at 43 kHz. Viscoelasticity of the hydrogel matrix showed that the hydrogel became somewhat rigid after the US exposure. FT-IR analysis of the mimosa hydrogel matrixes showed that during the US exposure, hydrogen bonds in the structure of mimosa–water and mimosa–cellulose were broken. This suggested that the enhancement of the mimosa release was caused by the US exposure.     

Regulating the thermal response of PNIPAM hydrogels by controlling the adsorption of magnetite nanoparticles

Thermoswitchable magnetic hydrogels are being extensively investigated because of their great potential for medical applications. Indeed, they can behave as smart carriers able to transport drugs to a chosen part of the body and release them via magneto-thermal activation by an external alternating magnetic field. We report on the magnetization of the thermosensitive poly(N-isopropylacrylamide) hydrogel through the adsorption of controlled amounts of magnetite nanoparticles. We show that the temperature at which the hydrogel contraction occurs (i.e. the lower critical solution temperature) can be controlled from 32 ^°C to 52 ^°C by varying the concentration of adsorbed nanoparticles. This is clearly shown by photon correlation spectroscopy. The results are an advance in the use of the magnetized poly(N-isopropylacrylamide) hydrogel as a flexible and adjustable nanomaterial and are of great interest in numerous applications which require drug release on demand.     

Synthesis and Properties of Tannic Acid-Based Hydrogels

Hydrogels were synthesized by using tannic acid (TA) as a chemical cross-linker for the copolymer of allylglycidyl ether and acrylamide. The swelling ratio of the hydrogels increased with increasing amount of TA and decreased with increasing amounts of allylglycidyl ether. The hydrogels exhibited pH sensitivity; the swelling ratio increased with pH. Adsorption experiments of the hydrogel for Cu (II) ions suggested that the hydrogels can be used as an adsorbent for removal of Cu (II) heavy metal ions from dilute aqueous solutions.     

The Microstructure and Swelling Properties of Poly Acrylic Acid-Acrylamide Grafted Starch Hydrogels

Starch grafted acrylic acid-acrylamide hydrogel was synthesized using an aqueous solution polymerization method. The microstructures of the vacuum-dried hydrogel (VDH) and vacuum-freeze-dried hydrogel (VFDH) were studied by means of scanning electron microscopy and biomicroscopy. The water-absorption rate of the hydrogel was tested. The results showed that the microstructure of the two kinds of dried hydrogels exhibited significant differences. Before absorbing water, VDH had a relatively dense surface whereas the surface of VFDH had a clear macroporous structure. After absorbing water, a three-dimensional network structure was clearly visible in VDH. Many interlaced and free filaments occupied the space between the main skeleton and channels. The holes formed by vacuum-freeze-drying had the effect of squeezing the surrounding network structure, which had an impact on the water-absorption rate and water absorbency of the hydrogel.     

具有双网络结构高强度和形状记忆水凝胶

本文将形状记忆功能引入到双网络水凝胶设计之中.首先合成了聚乙二醇-聚丙烯酰氧乙基三甲基氯化铵/聚（丙烯酰胺-co-丙烯酸）（PEG-PDAC/P（AAm-co-AAc））双网络水凝胶,其中第一套网络由交联的聚乙二醇（PEG）链组成,包埋着聚电解质聚丙烯酰氧乙基三甲基氯化铵（PDAC）;第二套网络由丙烯酰胺（AAm）和丙烯酸（AAc）的共聚物交联组成,交联剂为N,N''-亚甲基双丙烯酰胺（MBAA）.结果表明,双网络水凝胶显示出高强度的特点,其断裂应力和韧性分别达到了0.9 MPa和3.8 MJ/m³.和传统地利用中性高分子作为柔软和韧性的第二套网络相比较,本文选择将具有弱电解质特性的丙烯酸单体引入到第二套网络中,利用丙烯酸与三价铁离子的络合作用,成功地赋予水凝胶在氧化环氧反应条件下的形状记忆功能.结果表明,只要巧妙地引入响应性单体,高强度和形状记忆这两种最重要的特性可以同时被引入到双网络水凝胶的设计之中.     

Novel pH-Sensitive Lactic Acid Oligomer Grafted Chitosan Hydrogel for Controlled Drug Release

A pH-sensitive hydrogel, using chitosan as hydrophilic segment and lactic acid oligomer (LAO) as hydrophobic segment, was successfully synthesized through a dehydration reaction between amino and carboxyl groups. Scanning electron microscope (SEM) images revealed that the channel-like network structure of the as-prepared hydrogels, which plays an important role in controllable drug release behavior, was gradually collapsed with increasing content of lactic acid. Fourier-transform infrared (FTIR) spectra were obtained to demonstrate the occurrence of the dehydration reaction. Furthermore, the swelling ratio measurement and release study were performed, and the results showed that the chitosan/LAO hydrogel had an outstanding pH-sensitive property, and thus has high potential for usage in controlled-drug release.     

Preparation and properties of morphology controlled poly(2-hydroxyethyl methacrylate)/poly(N-vinyl pyrrolidone) double networks for biomedical use

Poly(2-hydroxyethyl methacrylate)/poly(N-vinyl pyrrolidone) (PHEMA/PVP) double networks (DN) were prepared using a sequential method by incorporating a second network of crosslinked PVP into PHEMA. We found that the distributions of the two networks can be regulated just by modulating the morphology of the first network, thus giving expected high water content of these gels. Fourier transform infrared (FTIR) spectroscopy and scanning electronic microscopy (SEM) were used to confirm the structure of the DN. The incorporation of more hydrophilic PVP enhanced swelling ability of these gels. Because of improved hydrophilicity, the PHEMA/PVP DN exhibited higher loading capability for water-soluble substance than that of pure PHEMA, while showed a slower release rate than corresponding HEMA/NVP copolymer hydrogel. It is suggested that the DN gels are potential biomaterials for wound dressing, medical implants and other drug delivery systems.     

PDMAEMA多重环境响应行为的NMR研究

利用原子转移自由基聚合（Atom Transfer Radical Polymerization, ATRP）合成了分子量分布较窄的聚甲基丙烯酸N, N-二甲氨基乙酯{Poly\[2 (diethylamino)ethylmethacry-late], PDMAEMA}并通过对液体核磁共振氢谱（¹H NMR）化学位移以及弛豫时间（T₁、T₂）的测量,研究了聚合物PDMAEMA的温度敏感、pH敏感以及离子敏感3种环境敏感行为. 发现聚合物链段的运动性,以及温度和离子强度诱导的相变行为,都与体系的pH值具有强依赖关系. 室温下,聚合物链段的运动性随pH值的增大而降低. 酸性条件下,聚合物表现出离子敏感性,而不表现出温度敏感性. 碱性条件下,聚合物表现出温度敏感性,不表现出离子敏感性.     

Preparation and Properties of 2, 4-2-Isocyanic Acid Methyl Ester/Poly(ϵ-caprolactone)/Diethylene Glycol Hydrogels

The hydrophilic polyurethane (PU) hydrogels have become attractive in the biomedical field for drug delivery. In this work 2, 4-2-isocyanic acid methyl ester (TDI), poly(?-caprolactone) (PCL), and poly(ethylene glycol) (PEG) were used to prepare a prepolymer and then diethylene glycol (DEG) was used as a chain extender to prepare a novel hydrophilic polyurethane, TDI/PCL-PEG/DEG. The obtained PU hydrogels were characterized by Fourier transform infrared (FT-IR) spectroscopy and scanning electronic microscopy (SEM). By varying the ratio of PCL to PEG in the copolymer, modulations of hydrophilicity and drug release behavior were observed. FT-IR analysis confirmed the successful synthesis of the TDI/PCL-PEG/DEG hydrogels. The introduction of PEG into the PU hydrogels led to a porous structure. The water contact angle and swelling ratio results confirmed that the hydrophilicity increased with increasing amounts of the PEG segments. The introduction of PEG also increased the release rate of chloramphenicol, used as model drug, from the PU hydrogels.     

Correlation of Diffusional Exponent with Structural Sequence of (N-Vinylpyrrolidone-alt-Acrylic Acid) Hydrogels: A Predictive Hydrogel Design Approach

Correlation of diffusional exponent of water into (N-Vinylpyrrolidone-alt-Acrylic acid) hydrogels with the structural sequence of hydrogel repeating units (i.e. hydrophilic and/or hydrophobic moieties) through a scaling law relationship has been investigated. The diffusional exponent (n) was found to depend linearly on Y/X² , where X equals to molar ratio of monomers in the feed (i.e. ([M₁ ]/[M₂ ])_feed) and Y equals to molar ratio of repeating units in the copolymer (i.e. ([M₁ ]/[M₂ ])_copolymer). Copolymers rich in hydrophilic acrylic acid (i.e. larger Y/X² ) were found to form more coiled polymeric chains as acrylic acid content increased due to H-bonding interactions, and hence results in lower diffusion coefficients and linear lowering of the n-value. On the other hand copolymers rich in partially hydrophobic N-vinylpyrrolidone (i.e. smaller Y/X²) formed more uncoiled polymeric chains as N-vinylpyrrolidone content increased due to larger amounts of positively charged protonated nitrogen atoms at pH 5.5 that tend to repel each other, which eventually lead to higher diffusion coefficients and a linear increase in n-value. These characteristic findings could be significant in sustained drug release studies, where the structural sequence of a hydrogel plays a dominant role in the release kinetics of a drug at certain positions and/or times.     

Liposomal Templating,Association with Mammalian Cells,and Cytotoxicity of Poly(vinyl alcohol) Physical Hydrogel Nanoparticles

The assembly, cellular internalization, and cytotoxicity of nanoparticles based on physical hydrogels of poly(vinyl alcohol) (PVA) are reported. PVA nanoparticles are assembled using a liposomal templating technique followed by removal of the lipids using isopropanol, a process that requires the presence of a custom‐made block copolymer, poly(vinyl alcohol‐b‐vinyl pyrrolidone), to avoid aggregation of the nanoparticles. Polymer hydrogelation is induced via incubation in aqueous isopropyl alcohol solution, which results in PVA hydrogel nanoparticles (PVA HNP) with excellent colloidal stability and stability towards disintegration over at least 24 h. Pristine PVA HNP are found to be remarkably stealth‐like and exhibit negligible cellular internalization. This feature is likely inherent with the low fouling nature of PVA and makes PVA HNP attractive for targeted drug delivery with a low level of association with non‐targeted cells and tissues. Blending PVA with varied amounts of collagen results in colloidal hydrogel particles with a well pronounced tendency towards association with mammalian cells, specifically hepatocytes and endothelial cells. The association of PVA HNP elicits minimal changes in cellular proliferation, making these novel hydrogel particles convenient tools for drug delivery applications and creation of implantable artificial organelles and sensors.     

The Effect of Hydrophilic Bentonite Nanoclay on the Thermogelation Properties of Poly(N-isopropylacrylamide)-poly(ethylene glycol)-poly(N-isopropylacrylamide) Triblock Copolymer Aqueous Solutions

The effect of hydrophilic bentonite addition on the thermogelation properties of aqueous solutions of poly(N-isopropylacrylamide)–poly(ethylene glycol)–poly(N-isopropylacrylamide) (PNIPAM-PEG-PNIPAM) triblock copolymers of various compositions and molecular weights was investigated. Dynamic rheometry and differential scanning calorimetry (DSC) measurements showed that increasing concentrations of clay added to 20 wt.% polymer aqueous solutions caused a decrease of the temperature at which the viscosity starts increasing, while the temperature corresponding to the maximum endothermic effect due to the PNIPAM chain dehydration remained practically unchanged. The storage modulus, G′, increased with clay concentration for shorter PNIPAM chain triblock copolymers, while an opposite situation occurred in the case of the block copolymer with the longest PNIPAM block. For bentonite concentrations above 1 wt.%, G′ was larger than the viscous modulus, G″, at temperatures higher than the phase separation temperature, indicating a predominantly elastic character of the resulting composite hydrogels. These findings were explained through the presence of polymer–clay interactions occurring mainly through the PEG blocks.