Regular and irregular deswelling of polyacrylate and hyaluronate gels induced by oppositely charged surfactants

New multiresponsive core-shell microgels have been synthesized, with a thermoresponsive core and a glucose-responsive shell, made respectively of poly(N-isopropylacrylamide) (pNIPAM) and pNIPAM-co-acrylamidophenylboronic acid (pNIPAM-co-APBA). The structure of the particles was elucidated by means of dynamic light scattering. Their thermal properties were investigated and compared to those of the core alone. Without glucose, the hydrophobic shell prevented the core from swelling in a certain temperature range where the shell was shown to be collapsed. This core compression vanished upon glucose addition, when the shell became hydrophilic and swelled. Therefore, the extent of core swelling was regulated by two processes: its own internal stimulus, i.e. temperature, and shell compression, which is proportional to glucose concentration, even at physiological salinity. The concept was applied to a selected chemical composition. Core-shell microgels with a response to glucose at physiological pH were obtained and used to encapsulate insulin. Insulin release was shown to be regulated by the presence of glucose.     

Glucosamine-carrying temperature- and pH-sensitive microgels: preparation, characterization, and in vitro drug release studies

Glucosamine-carrying temperature- and pH-sensitive microgels with an average diameter of about 100 nm were successfully prepared by free radical precipitation polymerization. The thermo- and pH-responsive properties of the microgels were designed by the incorporation of N-isopropylacrylamide (NIPAM) and acrylic acid (AAc) to copolymerize with acrylamido-2-deoxyglucose (AADG). The stimuli sensitivity of the microgels was studied by the measurement of their sizes and volume phase transition temperature (VPTT) under different surrounding conditions. The results showed that the microgels were responsive to temperature, pH, and ionic strength, and could have a desired VPTT by modifying AADG and AAc contents. The effect of temperature and pH on insulin release from the microgels was also investigated. The release of drug at the tumor-surrounding environment is faster than that under normal physiological conditions. A preliminary in vitro cell study showed that the glucosamine-carrying microgels are more biocompatible to mouse fibroblast cells, compared to the microgels without glucosamine. These glucosamine-carrying dual-sensitive microgels may be promising carriers for targeted drug delivery to tumors.     

High stability amperometric biosensor based on enzyme entrapment in microgels

The preparation and characterization of an amperometric glucose biosensor based on the entrapment of glucose oxidase (GOx) in a polyacrylamide microgel is described. This study proves that polyacrylamide microgels provide an excellent matrix for GOx immobilization that can be used as a biological material in amperometric biosensors. The interference produced by ascorbic and uric acid has been eliminated by including acrylic acid in the polymeric matrix. With this modification, we obtain an adequate device for glucose determination in complex samples such as blood and serum. The study of the temperature effect in the response of biosensors indicates that swelling of the microgels directly influences the enzymatic activity. Thus, the behaviour of the enzyme in the swollen microgels is similar to the enzyme in solution, but the enzyme's activation energy increases when the water content in the microgels decreases. One important property of these biosensors is their remarkable stability. After 4 months of its manufacture, there is no loss in the initial response. Furthermore, the enzymatic activity of freeze-dried microgels containing enzyme remains unaltered for at least 18 months.     

Thermosensitive and control release behavior of poly (N‐isopropylacrylamide‐co‐acrylic acid) latex particles

In this work, poly(N‐isopropylacrylamide‐co‐acrylic acid) (poly(NIPAAm‐AA)) copolymer latex particles (microgels) were synthesized by the method of soapless emulsion polymerization. Poly(NIPAAm‐AA) copolymer microgels have the property of being thermosensitive. The concentration of acrylic acid (AA) and crosslinking agent N,N′‐methylenebisacrylamide were important factors to influence the lower critical solution temperature (LCST) of poly(NIPAAm‐AA) microgels. The effects of AA and crosslinking agent on the swelling behavior of poly(NIPAAm‐AA) microgels were also studied. The poly(NIPAAm‐AA) copolymer microgels were then used as a thermosensitive drug carrier to load caffeine. The effects of concentration of AA and crosslinking agent on the control release of caffeine were investigated. How the AA content and crosslinking agent influenced the morphology and LCST of the microgels was discussed in detail. The relationship of morphology, swelling, and control release behavior of these thermosensitive microgels was established. A new scheme was proposed to interpret the control release of the microgels with different morphological structures. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5734–5741, 2008     

Glucose‐Regulated Insulin Release from Acid‐Disintegrable Microgels Covalently Immobilized with Glucose Oxidase and Catalase

The fabrication of a novel type of positively charged acid‐disintegrable microgel loaded with insulin by electrostatic interactions and covalently immobilized with glucose oxidase (GOx) and catalase by inverse emulsion polymerization is reported, aiming for glucose‐regulated insulin release by utilizing GOx/catalase cascade enzymatic reactions to trigger local pH decrease and acid‐cleavage of crosslinking moieties. At the same time, a local pH decrease within the microgels also leads to the diminishment of net surface negative charges of encapsulated insulin. The above two factors both synergistically contribute to the prominently enhanced insulin release at high glucose levels (∼10–20 mM ) compared to that in the absence of glucose.     

Thermosensitive phase behavior and drug release of in situ gelable poly(N-isopropylacrylamide-co-acrylamide) microgels

In situ gelable poly(N-isopropylacrylamide-co-acrylamide) microgels were prepared by precipitation polymerization in the presence of various amounts of N,N′-methlenebisacrylamide as a crosslinker. The diameters of microgels were in the range of 200–300 nm with narrow distributions as determined by photo correlation spectroscopy. The equilibrium swelling ratio and thermosensitive properties of the microgels increased with decreasing crosslinker content. The volume phase transition of microgels dispersions at high concentrations were investigated by phase diagrams. The microgels dispersions experienced four phases when the temperature was increased: semitranslucent swollen gel, clear flowable suspension, cloud flowable suspension, and white shrunken gel. The related phase transition temperatures were influenced by crosslinker content and the concentration of the microgel dispersions. Herein, the gelation temperature was changed by more than 20 °C, shrinking temperatures were slightly changed by about 3 °C, and cloud point temperatures showed almost no change. The three phase transition temperatures of microgels dispersed in phosphate-buffered saline solutions were lower than that in water. As drug carriers, the release rates of bleomycin from bleomycin-loaded microgel dispersions exhibited diffusion control at human body temperature.     

The synthesis and responsive properties of novel glucose-responsive microgels

A novel routine for preparing of glucose-responsive microgels was developed. Following the routine of copolymerizing two functional monomers, a series of microgels with phenylboronic acid dispersed inside were prepared. The thermo-behavior of the microgel was tested, which revealed the retaining property of the thermo-responsive monomer after polymerization. In addition, the glucose-responsive behavior under different temperatures and pH values were also researched. It was demonstrated that the novel microgel was able to response to glucose. Furthermore, it was found that the swelling behavior of the microgel caused by glucose was enhanced, which benefited the drug release of the system.     

Fluorine-containing pH-responsive core/shell microgel particles: preparation,characterization, and their applications in controlled drug release

A kind of novel fluorine-containing pH-responsive core/shell microgels poly(DMAEMA-co-HFMA)-g-PEG were prepared via surfactant-free emulsion polymerization using water as the solvent. The well-defined chemical structure of the copolymers was characterized by FTIR, ¹H-NMR, ¹⁹F-NMR, and elemental analysis. The microgel particles were studied by florescence probe technique, dynamic light scattering, and zeta potential measurement; the microgels displayed a significant pH-responsive behavior. Furthermore, the cytotoxicity assay indicated that the copolymer microgels had low toxicity, and 5-FU-loaded microgels offered a certain killing potency against cancer cells. In addition, the drug loading and in vitro drug release demonstrated that 5-FU was successfully incorporated into polymeric microgels, and the drug-loaded microgels showed a marked pH-dependent drug release behavior. This study suggests that the poly(DMAEMA-co-HFMA)-g-PEG microgels play an important role in the release mechanism stimulated by the change in the pH and have potential applications as a controlled drug release carrier.     

Synthesis and characterization of degradable p(HEMA) microgels: use of acid-labile crosslinkers

New divinyl-functionalized acetal-based crosslinkers were synthesized as building elements to form acid-labile microgel particles for controlled-release applications. The synthesized crosslinkers underwent hydrolysis at slightly acidic pHs in less than 1 h while they were stable at neutral pHs for longer times. HEMA was copolymerized with the crosslinkers via an inverse emulsion polymerization technique using a redox initiator system at room temperature to form crosslinked, colloidal p(HEMA) microgels. Microgels in diameters ranging from 150 to 475 nm with narrow distribution could be produced. The crosslinking density and the diameter of the microgels were found to be controlled by monomer/crosslinker feed ratio. The microgels demonstrated a pH-dependent cleavage behavior that mimicked the pH-dependent hydrolysis profile of the acid-labile crosslinkers. Model biomacromolecules, i.e., Rhodamine B-labeled dextran and BSA were efficiently loaded into the microgels. The release of the biomolecules from p(HEMA) microgels was also found to be controllable by the pH of the environment similar to the particle degradation. The protein released from the microgels was observed to retain its structural stability.     

Multi‐responsive methylcellulose/Fe‐alginate‐g‐PVA/PVA/Fe3O4 microgels for immobilizing enzyme

To take advantage of the respective character of methylcellulose (MC), poly(vinyl alcohol) (PVA), and alginate, novel physically cross‐linked methylcellulose/Fe‐alginate‐g‐PVA/PVA (MC/Fe‐Alg‐g‐PVA/PVA) microgels were prepared by emulsification/thermal gelation/freezing–thawing/ionic cross‐linking technique. Subsequently, some ferrous ions bound in the microgels were transformed into magnetite via in situ self oxidation. A model enzyme α‐amylase was immobilized into microgels by direct adsorption. The release behavior of α‐amylase indicated that the obtained complex microgels were magnetic‐, temperature‐, and pH‐ triple sensitive. Copyright © 2010 John Wiley & Sons, Ltd.     

苯硼酸类糖敏感微凝胶制备及其糖敏感性研究

制备了以葡聚糖作为交联剂的氨基苯硼酸类糖敏感微凝胶,用1H-NMR和FT-IR表征了其结构。利用微凝胶的不同条件下的粒径变化,深入研究了该类凝胶对糖浓度的刺激响应行为。结果表明,葡聚糖的引入使微凝胶在生理条件下具有更加优秀的依糖刺激响应行为。     

Designed glucose-responsive microgels with selective shrinking behavior

We report on the synthesis of various glucose-responsive microgels based on N-alkylacrylamide derivatives and phenylboronic acid (PBA) as a glucose sensing moiety. Depending on their chemical composition, the microgels exhibit opposite behaviors in response to glucose concentration increase: they can either swell or shrink, using two different mechanisms for glucose recognition. Both behaviors may be suitable for glucose sensing and insulin delivery. When glucose binds a single boronate receptor, the microgel swells as glucose concentration increases. This mechanism can be used to deliver a drug by diffusion through the network. In other cases, glucose binds specifically to two boronates, which creates additional cross-links within the network and provokes shrinkage. Such systems are promising for the development of sensors with improved selectivity and also as potential "intelligent" valves in microfabricated delivery systems. By a rational choice of the constituting units of the network structure, we show how to favor one or the other type of response to glucose variation. Therefore, glucose-swelling microgels operating under physiological conditions have been obtained by copolymerization with an appropriate choice of alkylacrylamide monomer and boronate derivative. At a pH above the pK(a) of the boronic acid derivative, the same structures shrink in response to glucose concentration. The nature of the cross-linker is a key parameter to enable this dual behavior. In other microgels, an amine group is introduced in the vicinity of the boronic acid, which lowers its pK(a) and favors microgel contraction at physiological pH. This work has allowed us to give some general rules to control the swelling/shrinking behavior of glucose-responsive microgels.     

Physicochemical characterization and drug release properties of PDMAEMA/OSA Semi‐IPN hydrogels with microporous structure

A new poly(2‐(dimethylamino) ethyl methacrylate)/oxidized sodium alginate (PDMAEMA) semi‐interpenetrating network (Semi‐IPN) hydrogel with microporous structure was prepared by using PDMAEMA microgels as an additive during the polymerization/crosslinking process. The interior morphology characterized by scanning electron microscopy showed the Semi‐IPN hydrogels have different pore sizes by changing the amount of microgels. The hydrogels were also characterized by using Fourier transform infrared and DSC. The swelling behaviors of hydrogels indicated that the hydrogels have excellent pH and temperature sensitivity. Bovine serum albumin was entrapped in the hydrogels and the in vitro drug release profiles were established in different buffer solutions at various temperatures. The release behaviors of the model drug were dependent on the pore size of the hydrogels and environmental temperature/pH, which suggested that these materials have potential application as intelligent drug carriers. Copyright © 2011 John Wiley & Sons, Ltd.     

Copolymeric nano/microgels of N-isopropylacrylamide and carboxyalkyl methacrylamides: Effect of methylene chains and the ionization state of the weak acids on size and sensitivity to pH and temperature

ABSTRACT

We prepared nano/microgels by precipitation copolymerization of N-isopropylacrylamide (NIPAAm), and one of three different carboxyalkyl methacrylamides [methacryloylamido hexanoic acid (M₅), 8-methacryloylamido octanoic acid (M₇), and 11-methacryloylamido undecanoic acid (M₁₀)], either in the acid forms or as carboxylates (potassium salts). The hydrodynamic diameter (Dh) of the nano/microgels prepared with the carboxylates was smaller (≈100 nm for M₁₀ copolymers), compared to the size of homopolymeric NIPAAm microgels prepared by dispersion polymerization (around 600 nm), indicating that the carboxylates act as surfactants reducing the size of the seeds during the polymerization process. These materials presented a swollen-shrunken transition temperature (T _tr) similar to the T _tr of the homopolymeric NIPAAm microgels, without pH sensitivity. On the other hand, the copolymeric microgels prepared from the acid form of the comonomers have a similar or bigger size than NIPAAm microgels. For these copolymers, the T _tr can be tuned by the type and proportion of acid comonomer used and present pH sensitivity. This is important for biomedical applications such as positive temperature control release. Polyelectrolyte titration demonstrates that the nano/microgels prepared with the carboxylates behave as hard spheres, while the microgels prepared with the weak acid behave as porous materials.     

基于互穿网络结构的pH/温度双重刺激响应性微凝胶的研究

室温下采用氧化-还原引发体系,以低交联密度的聚(N-异丙基丙烯酰胺)(PNIPAM)微凝胶为种子,通过种子乳液聚合法合成由PNIPAM和聚丙烯酸(PAA)形成的具有互穿聚合物网络结构的微凝胶.傅立叶变换红外光谱分析结果表明微凝胶由PNIPAM和PAA两种聚合物组成,透射电镜表征结果证实微凝胶中PNIPAM和PAA两种聚合物形成了互穿网络结构.用动态激光光散射测试不同温度或pH值水介质中微凝胶的粒径,结果发现微凝胶具有良好的pH/温度双重刺激响应性.在水介质pH值大于5.5的情况下,PAA组分对微凝胶的体积相转变温度没有影响;而在水介质pH值为4.0的情况下,由于PAA与PNIPAM之间的氢键作用,微凝胶的体积相转变温度稍微降低.微凝胶中PAA组分含量越高,其pH刺激响应性越显著.     

Microgels for the encapsulation and stimulus-responsive release of molecules with distinct polarities

A microfluidic strategy for the encapsulation and stimulus-responsive release of molecules with distinct polarities from the interior of microgels is reported. The approach relies on (i) the generation of a primary O/W emulsion by the ultrasonication method, (ii) MF emulsification of the primary emulsion, and (iii) photopolymerization of the monomer present in the aqueous phase of the droplets, thereby transforming them into microgels. Non-polar molecules are dissolved in oil droplets embedded in the microgels. Polar molecules are physically associated with the hydrogel network. Upon heating, the microgels contract and release polar and non-polar cargo molecules. The approach paves the way for stimuli-responsive vehicles for multiple drug delivery.     

葡萄糖敏感微凝胶的溶胀动力学研究

通过沉淀聚合法合成了P(NIPAM-co-AA)微凝胶,然后在EDC催化下用3-氨基苯硼酸对微凝胶进行改性,制备了P(NIPAMI-co-AAPBA)微凝胶.红外光谱检测证明改性完全.改性后的微凝胶仍具有很好的温敏性,但由于引入疏水的苯硼酸基团,微凝胶的体积相转变温度大大降低.P(NIPAM-co-AAPBA)微凝胶具...     

Glucose sensitive poly (<Emphasis Type="Italic">N</Emphasis>-isopropylacrylamide) microgel based etalons

Thermoresponsive microgels have been shown to be an excellent platform for designing sensor materials. Recently, poly (N-isopropylacrylamide)-co-acrylic acid (pNIPAm-co-AAc) microgel based etalon materials have been described as direct sensing materials that can be designed to have a single, unique color. These color tunable materials show immense promise for sensing due to their spectral sensitivity and bright visual color. Here, we describe a proof-of-concept for etalon sensing of glucose. We found that aminophenylboronic acid (APBA)-functionalized pNIPAm-co-AAc microgels in an etalon respond to 3 mg/mL glucose concentrations by red shifting their reflectance peaks by 110 nm up to 150 nm. Additionally, APBA-functionalized pNIPAm-co-AAc microgels have a depressed volume phase transition temperature at 18–20 °C, which shifts to 24–26 °C after glucose binding. We also demonstrate that these materials show a marked visual color change, which is a first step towards developing direct read-out sensor devices.     

含功能性羟基的温敏性聚(N-异丙基丙烯酰胺)微凝胶的制备及性能研究

采用两步合成路线合成了二缩三乙二醇单甲基丙烯酸酯 (TREGMA) ,并对其结构进行了表征 ;利用无皂乳液聚合法使N 异丙基丙烯酰胺 (NIPAM)、TREGMA和N ,N 亚甲基双丙烯酰胺 (BA)交联共聚 ,制备了含有功能性羟基的温敏性微凝胶 .微凝胶的去溶胀性能研究表明 ,TREGMA的引入使得微凝胶的体积相转变温度得到提高 ,同时所制得微凝胶具有较好的温敏性 .该类微凝胶有望成为良好的生物医用材料 .     

Aloe vera–eluting collagen I microgels: physicochemical characterization and in vitro biological performance

Microgels absorb and retain high amounts of solvents, especially water. Because of their size, and association, the release kinetics of active molecules from microgels is easier to control than in hydrogels. Collagen I is one of the most extensively investigated biomaterials, although the key process parameters to produce microgels must be understood well before they can be used in veterinary and human medicine. Emulsification-gelation is widely used to obtain microgels because of its ease of handling and high yields. The concentration of the biomaterial and the homogenization method are among the critical parameters in this method. In this work, we produced cytocompatible collagen I microgels by emulsification-gelation and evaluated the effect of three different concentrations and homogenization methods on their physicochemical, mechanical, and biological properties. As proof of concept, microgels were loaded with an Aloe vera extract and the loading efficiency and the polyphenol release kinetics, as well as their properties assessed. When the same homogenization method (e.g. magnetic stirring) was used, the size of the microgels decreased with an increase of collagen I concentration, and the size distribution increased. In addition, the size and size distribution of microgels prepared with the same collagen I concentration were smaller when produced by high-energy homogenization methods (shear stress and ultrasound) than with a low-energy one (magnetic stirring). Collagen I concentration and the homogenization method also influenced the zeta-potential, the enzymatic degradation, and the encapsulation efficiency of the microgels. Overall, we show that the size of these microgels can be fine-tuned by the collagen I concentration and the homogenization method. Moreover, the integration of microgels of different sizes into the same carrier platform will pave the way for the combination of active compounds with different release kinetics.