壳聚糖-聚丙烯酸复合水凝胶的药物控制释放行为

以壳聚糖(Cs)和丙烯酸(AA)为原料,利用自由基聚合法制备了具有孔洞结构的复合水凝胶Cs-PAA,并研究了AA的量、交联剂的量、聚合温度和AA的中和度对水凝胶溶胀度的影响以及复合水凝胶对烟酸的控制释放。 结果表明,Cs-PAA复合水凝胶具有良好的pH值、离子强度敏感性,且溶胀度最高达1228 g/g,其在pH=686的缓冲溶液中的烟酸累积释放率明显大于其在pH=1.80的缓冲溶液,因此Cs-PAA水凝胶可作为肠口服药物的载体。     

Formation and transformations of polyelectrolyte gel-ampholyte dendrimer-surfactant ternary complexes

The reactions of complex gels formed via the sorption of a poly(propylenimine) ampholyte dendrimer of the fourth generation by oppositely charged lightly cross-linked polyelectrolyte hydrogels with ionogenic micelle-forming surfactants have been studied. The sorption of surfactant ions likely charged relative to the complexed ampholyte dendrimer by complex gels is associated with two parallel chemical reactions controlled by the concentration of the surfactant and pH which give rise to the formation of network-dendrimer-surfactant tertiary complexes. The reactions of complex gels with surfactant ions likely charged relative to the network polyelectrolyte make it possible at different solution pHs to prepare both negatively and positively charged hydrogels reinforced by disperse particles of the dendrimer-surfactant complex.     

响应性凝胶及其在药物控释上的应用

综述近年来在响应性凝胶材料研究方面的进展，介绍了能感应ｐＨ、温度、光、电场以及生化物质等外界因素变化的响应性凝胶的结构特点与响应机理，同时介绍了此类凝胶应用于药物控制释放方面的研究近况。     

双重响应性生物基自修复凝胶的制备及其性能

为拓宽多重响应性凝胶在生物医学领域中的应用,本文基于生物大分子构筑具有pH响应、糖响应性的可自修复性水凝胶。 本文选用3-氨基苯硼酸(APBA)和2,3-环氧丙基三甲基氯化铵(CHGTA)分别对聚谷氨酸(γ-PGA)和瓜尔胶(GG)进行改性制备了聚谷氨酸-g-氨基苯硼酸(γ-PGA-g-APBA)和阳离子瓜尔胶,在此基础上,对γ-PGA-g-APBA和阳离子瓜尔胶进行物理共混制备生物基凝胶。 通过傅里叶变换红外光谱仪(FTIR)、核磁共振波谱仪(¹H NMR)和流变仪对聚合物化学结构、接枝率、流变性能和力学性能进行表征,并考察了凝胶在不同pH值及糖浓度下刺激响应性。 结果表明,凝胶具有自修复性,修复效率可达100%;具有pH响应性,在环境pH值较高时更易形成凝胶,且凝胶强度随pH值升高而增大;同时所制凝胶具有糖响应性,在4 g/L的葡萄糖溶液中浸泡后即可导致凝胶解体。 这些结果说明功能基团APBA的引入可赋予凝胶多重响应性。 所制的双重响应性生物基凝胶具有良好的生物相容性,有望应用于生物医学、功能器件、传感等领域。     

A novel amphiphilic pH-sensitive hydrogel based on pullulan

Novel polyelectrolyte and amphiphilic hydrogels based on pullulan have been prepared using 1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride and N-hydroxysuccinimide. The cross-linking reaction is fast and lead to zero length ester cross-links by the reaction of a carboxylate group with an alcohol function of the polysaccharide. The charge density and the hydrophobic rate of the precursor carboxymethylpullulan (CMP) are controlled during the carboxymethylation of pullulan and the grafting reaction of octyl chains on CMP, respectively. The grafting degree influences the conformation of the hydrophobically modified CMP (HMCMP) in solution and leads to the formation of hydrophobic clusters firstly in the HMCMP solutions and further in the HMCMP hydrogels. The swelling measurements of HMCMP hydrogels at different salt concentrations (0–0.2 M NaCl) and different pH (3–11) shows the ionic strength and pH sensitivity of the gels. The loading of a hydrophobic probe molecule can be controlled by the grafting degree of HMCMP hydrogels.     

（2-羟基-3-丁氧基）丙基-羟丙基壳聚糖/聚乙二醇互穿网络凝胶的制备及其释药作用

将壳聚糖改性为（2-羟基-3-丁氧基）丙基 羟丙基壳聚糖（2-H-3-B-P-HPCS）,并以（2-羟基-3-丁氧基）丙基-羟丙基壳聚糖和聚乙二醇（PEG）为原料制备（2-羟基-3-丁氧基）丙基-羟丙基壳聚糖/聚乙二醇互穿网络凝胶,研究了（2-羟基-3-丁氧基）丙基-羟丙基壳聚糖浓度、聚乙二醇的用量、交联剂戊二醛用量、反应温度对该凝胶溶胀性能的影响。 通过红外光谱分析和扫描电子显微镜的方法比较了壳聚糖、（2-羟基-3-丁氧基）丙基-羟丙基壳聚糖和（2-羟基-3-丁氧基）丙基-羟丙基壳聚糖/聚乙二醇互穿网络凝胶结构和形态上的不同。 以阿昔洛韦为模型药物研究了其释药性能。 结果表明,该凝胶均具有良好的溶胀性、pH敏感性和药物缓释作用,有望用作新型的药物载体。     

Dual thermal- and pH-responsive polypeptide-based hydrogels

Smart hydrogels have received increasing attention for their great potential for the applications in many fields. Herein, we report a facile approach to prepare a class of dual-responsive hydrogels assembled from synthetic statistical/block thermal-responsive copoly(L-glutamate)s copolymerized with poly(ethylene glycol), which were prepared by ring-opening polymerization(ROP) and post-modification strategy. The incorporation of oligo(ethylene glycol)(OEG) and glutamic acid residues offers the gels with thermal-and p H-responsive properties simultaneously. We have systematically studied the influence of both temperature and p H on the gelation behaviors of these copolymers. It is found that the increase of glutamic acid content and solution p H values can significantly suppress the gelation ability of the samples. Circular dichroism(CD) results show that the α-helix conformation appears to be the dominant secondary conformation. More interestingly, the gelation property of the block copolymer with statistical thermal-responsive copoly(L-glutamate)s shows greater dependence on p H as compared to that with block segments due to the distinct morphology of the self-assemblies. The obtained hydrogels exhibit p H-dependent and thermal-responsive gelation behaviors, which enable them as an ideal smart hydrogel system for biomedical applications.     

Stimuli-responsive nanocomposite gels

A new class of polymer hydrogels, nanocomposite hydrogels (NC gels), consisting of a unique organic (polymer)/inorganic (clay) network structure, was synthesized by in situ free-radical polymerization in the presence of exfoliated clay nanoparticles in an aqueous system. The resulting NC gels overcame most of the disadvantages associated with chemically cross-linked hydrogels, such as mechanical fragility, structural heterogeneity, and slow de-swelling rate. By using thermo-sensitive poly(N-isopropylacrylamide) (PNIPA) as a constituent polymer, NC gels with remarkable mechanical, optical, and swelling properties as well as thermo-sensitivity were obtained. The various properties of NC gels, such as transparency, gel volume, cell culturing, and surface friction changed significantly in response to the temperature and surrounding conditions. All the excellent properties and new stimuli-responsive characteristics of NC gels are attributed to the unique PNIPA/clay network structure. The thermo-sensitivities and the transition temperature can largely be controlled by varying the clay content and by the addition of solutes.     

Konjac glucomannan‐graft‐acrylic acid hydrogels containing azo crosslinker for colon‐specific delivery

In this article, the synthesis and characterization of novel hydrogel systems designed for colon‐targeting drug delivery are reported. The gels were composed of konjac glucomannan, copolymerized with acrylic acid, and crosslinked by the aromatic azo agent bis(methacryloylamino)‐azobenzene. The influence of various parameters on the dynamic and equilibrium swelling ratios (SRs) of the hydrogels was investigated. It is shown that the SR was inversely proportional to the grafting degree of acrylic acid and the content of bis(methacryloylamino)‐azobenzene. The dependence of SR on the pH indicates that obtained hydrogels are potential for drug delivery to colon. It was possible to modulate the degree of swelling and the pH sensitivity of the gels by changing crosslinking density of the polymer. The main chain of hydrogels can be degraded by β‐glycosidase which is abundant in colon. They can be in vitro degraded for 73% in a month by Cereflo® and 86% in 20 days by Mannaway25L. We have also prepared the hydrogels that loaded with bovine serum albumin about 1.5%, 3%, 9%, and 20% by weight. In vitro release of model drug bovine serum albumin was studied in the presence of Mannaway25L or Fungamyl®800L in pH 7.4 phosphate buffer at 37 °C. The drug release can be controlled by the biodegradation of the hydrogels. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4370–4378, 2004     

Study on the release of invertase from enzymatically degradable dextran hydrogels

Chemically crosslinked dextran hydrogels were prepared for application in the controlled delivery of bioactive proteins. Dextran was functionalized by reacting with glycidyl acrylate to introduce reactive double bonds. Upon exposure to γ-irradiation the functionalized dextran formed a crosslinked gel which could be degraded by dextranase. The effect of dextranase-induced degradation on the swelling kinetics of the prepared hydrogels was examined. Enzymatic degradation of the gels became slower as the γ-irradiation dose increased for the formation of the gels. The dextran hydrogels were examined as a potential delivery system for proteins by using invertase as a model protein. Invertase was incorporated into the hydrogel by mixing it with the purified, functionalized dextran before exposure to γ-irradiation. The effect of γ-irradiation on the bioactivity of the incorporated invertase was determined. The γ-irradiation did not change the bioactivity of the incorporated invertase as long as the total γ-irradiation dose was limited below 0.4 Mrad. The release study showed that the release of invertase from the dextran gel was controlled by dextranase-induced degradation rather than diffusion through the dextran network. The release study also showed that the invertase release was pulsatile. Parameters such as the degree of functionalization, dextran molecular weight, and γ-irradiation dose can be adjusted to prepare delivery systems which meet the desired degradation kinetics and protein release profiles.     

Stimuli Responsive Scaffolds Based on Carboxymethyl Starch and Poly(2‐Dimethylaminoethyl Methacrylate) for Anti‐Inflammatory Drug Delivery

The purpose of the study is to obtain multicomponent polyelectrolyte hydrogels with optimal synergistic properties by combining a modified starch with a synthetic one. Thus, new low‐cost and biocompatible semi‐interpenetrating polymer network (semi‐IPN) hydrogels of carboxymethyl starch and poly(2‐dimethylaminoethyl methacrylate) are prepared and investigated. The synthesized hydrogels are studied with respect to the specific characteristics of the gels: swelling kinetics, thermal analysis, viscoelastic characteristics, and their ability to be used as a matrix in drug delivery systems. Therefore, the semi‐IPN gels are loaded with ibuprofen, followed by additional tests to assess the in vitro drug release. The cytocompatibility of the hydrogels with respect to their composition is evaluated in vitro on fibroblast cell culture. The investigations confirm the obtainment of new semi‐IPN hydrogels with pH and temperature responsiveness, good mechanical strength, and potential for use as drug delivery systems or transdermal patches.     

智能水凝胶在生物医学领域中的研究进展

水凝胶是最常用的生物材料之一。它们在化学和结构上的多样性使其能够在广泛的场景中使用,目前 水凝胶材料在生物医药领域主要用于药物输送、癌症治疗和伤口愈合等。聚合物网络是水凝胶的核心组成部分,赋予水凝胶最独特的功能和性质。在分子层面上可以控制水凝胶的连接方式和聚合物的网络结构。因此,在材料研发的初期,了解聚合物网络的连接方式、结构、功能和特性,选择合适的聚合物对于制备特定功能的水凝胶至关重要。本文首先概述了水凝胶的凝胶机理和影响凝胶的因素,在分子层面上可以控制聚合物网络的形成,从而制备临床上需要的水凝胶。最后介绍了水凝胶在临床医学上的应用,展望了水凝胶材料的未来发展趋势。     

Synthesis and characterization of polyhedral oligomeric silsesquioxane hybrid co‐crosslinked poly(N‐isopropylacrylamide‐co‐dimethylaminoethyl methacrylate) hydrogels

Polyhedral oligomeric silsesquioxane hybrid temperature and pH double‐responsive hydrogels with organic–inorganic co‐crosslinked networks are synthesized by in situ, free‐radical polymerization of N‐isopropylacrylamide and dimethylaminoethyl methacrylate in the presence of both organic crosslinker N,N′‐methylenebis(acrylamide) (BIS) and inorganic crosslinker octavinyl polyhedral oligomeric silsesquioxane (OvPOSS) in tetrahydrofuran media. The resulting hydrogels (OR‐OvP gels) display obvious temperature and pH double responsiveness, OvPOSS particles dispersed in polymer make a dominant effect on the properties of gels. With the increase of OvPOSS, the aggregation of particles on nano‐ or microscale happens and causes a considerable change on the properties of gels, such as the lower critical solution temperature and better compression strength. Specially, the interconnected microporous structure of gels ascribed to the microphase separation results in faster deswelling rate, which makes the gel become attractive. Besides, the crosslink by BIS intensifies the heterogeneity of gels significantly, which could also be used to adjust the properties of gels. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2013 , 51, 1494–1504     

Reversible gelatin-based hydrogels: Finetuning of material properties

The present work reports on the synthesis and evaluation of a crosslinkable thiolated gelatin derivative. The effect of varying two parameters including the pH of the reaction buffer and the thiolating agent applied (i.e. N-acetylhomocysteine thiolactone versus Traut’s reagent) on the obtained modification degree was studied in a first part. The gelatin derivatives synthesized starting from N-acetylhomocysteine thiolactone and Traut’s reagent were characterized in depth using size exclusion chromatography and UV–VIS spectrophotometry. In a subsequent part of the present work, hydrogel films were prepared starting from the thiolated gelatin derivative developed using N-acetylhomocysteine thiolactone. The contributions of both the chemical and the physical crosslinking of the hydrogels developed were studied in depth using rheology, swelling experiments and texturometry. The results indicate that the physical structuring, inherent to gelatin, contributes to a large extent to the mechanical properties. However, the chemical crosslinking mostly determines the final hydrogel properties and can be controlled to a large extent. The gelatin-based gels are flexible, strong and transparent. A major advantage of disulfide-crosslinked hydrogels is the fact that the crosslinking is reversible. The latter could be interesting in view of future applications as cell carriers for tissue engineering.     

A method to prepare gels with controllable morphology through a three‐phase system

Traditional methods for preparing hydrogels with specific morphology need molds with different shapes, which should bring about a complicated process. In order to control the size and morphology of hydrogels conveniently, a new simple synthesis method was advanced to prepare the gels. In this method, the prepolymer solution achieves diffusion in the interface between the upper oil phase and lower hydrogel matrix, which constitutes a three‐phase system, and the morphology of prepared gels was determined by the balanced diffusion status of the prepolymer solution. Hence, through controlling the composition and character of the three different phases in this system, the balanced diffusion status could be adjusted because of the changed interaction acting on the prepolymer solution diffused in the phase interface. The common rule with regards to the resulting morphology of prepared gels was investigated by surface tension analysis. The results prove that this synthetic method is feasible in preparing many kinds of hydrogels with controllable morphology as a common approach.     

Preparation and characterization of hyaluronate-hydroxyethyl acrylate blend hydrogel for controlled release device

Hyaluronate-hydroxyethyl acrylate blend hydrogels were investigated as matrices for controlled release devices. Glycidyl methacrylate (GMA) derivatized HA (GMA-HA) was synthesized by coupling of GMA to HA in the presence of a suitable catalyst. These hydrogels were prepared by a free radical copolymerization of GMA-HA and hydroxyethyl acrylate. The water content of these hydrogels at equilibrium swelling in water (Ww) was 0.978+/-0.0073 (n=18); however, these hydrogel was mechanically tough and could be used as disk shape. The hydrogels swelling were found to depend on ionic strength and pH. The dried hydrogels quickly regained their original condition in water, and they swelled to more than 90% of its initial water contents after 30 min. This swelling-deswelling behavior was reproducible. The release of chlorpromazine HCl as a model cationic drug from the gels was suppressed significantly in water. The release increased with increasing the ionic strength and decreasing pH of bulk solutions.     

Radiation-induced synthesis and swelling properties of p(2-hydroxyethyl methacrylate/itaconic acid/oligo (ethylene glycol) acrylate) terpolymeric hydrogels

Since it is presumed that by incorporation of pH-responsive (IA) and temperature-responsive (OEGA) co-monomers, it is possible to prepare P(HEMA/IA/OEGA) hydrogels with dual (pH and thermo) responsiveness, the main purpose of our study is to investigate the influence of different mole fractions of IA and especially OEGA on the diversity of the swelling properties of the obtained hydrogels. For that reason, a series of terpolymeric hydrogels with different mole ratios of 2-hydroxyethyl methacrylate (HEMA), itaconic acid (IA) and oligo(ethylene glycol) acrylates (OEGA) was synthesised by gamma radiation. The obtained hydrogels were characterised by swelling studies in the wide pH (2.2–9.0) and temperature range (20–70 °C), confirming dual (pH and thermo) responsiveness and a large variation in the swelling capability. It was observed that the equilibrium swelling of P(HEMA/IA/OEGA) hydrogels, for a constant amount of IA, increased progressively with an increase in OEGA share. On the other hand, the dissociation of carboxyl groups from IA occurs at pH>4; therefore, small mole fractions of IA render good pH sensitivity and a large increase in the swelling capacity of these hydrogels at higher pH values. Additional characterisation of structure and properties was conducted by Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM) and mechanical measurements, confirming that the inherent properties of P(HEMA/IA/OEGA) hydrogels can be significantly tuned by variation in their composition. According to all presented, it seems that the obtained hydrogels can be a beneficial synergetic combination for controlled delivery of bioactive molecules such as drugs, peptides, proteins, etc.     

Sequential Assembly of Mutually Interactive Supramolecular Hydrogels and Fabrication of Multi-Domain Materials

A two-component self-sorting hydrogel based on acylhydrazide and carboxylic acid derivatives of 1,3:2,4-dibenzylidene-d -sorbitol (DBS-CONHNH₂ and DBS-COOH) is reported. A heating–cooling cycle induces the self-assembly of DBS-CONHNH₂, followed by the self-assembly of DBS-COOH induced by decreasing pH. Although the networks are formed sequentially, there is spectroscopic evidence of interactions between them, which impact on the mechanical properties and significantly enhance the ability of these low-molecular-weight gelators (LMWGs) to form gels when mixed. The DBS-COOH network can be switched “off” and “on” within the two-component gel through a pH change. By using a photo-acid generator, the two-component gel can be prepared combining the thermal trigger with photo-irradiation. Photo-patterned self-assembly of DBS-COOH within a pre-formed DBS-CONHNH₂ gel under a mask yields spatially controlled multi-domain gels. Different gel domains can have different functions, for example, controlling the rate of release of heparin incorporated into the gel, or directing gold nanoparticle assembly. Such photo-patterned multi-component hydrogels have potential applications in regenerative medicine or bio-nano-electronics.     

Photoswitchable PEG‐CA hydrogels and factors that affect their photosensitivity

The photoswitching behavior of polyethylene glycol‐based hydrogels was determined by monitoring the changes in their swellability and absorption spectra upon exposure to alternating wavelengths of irradiation. Highly hydrophilic PEG‐based hydrogels were prepared by the irradiation of a cinnamylidene acetate‐terminated PEG solution (PEG‐CA). The degree of swelling of the PEG‐CA hydrogels was predictably modulated by alternating the wavelength of exposing irradiation. Exposing the PEG‐CA gels to >300 nm irradiation resulted in the decrease of their swellability, while short exposure to 254 nm led to more hydrophilic gels. That is, the physical properties of the PEG‐CA gels can be controlled by the selection of wavelength of irradiation. Interestingly, it was found that 254 nm irradiation could not only lead to the photoscission of the PEG‐CA gels, but also initiate a crosslinking reaction between PEG‐CA monomers. On the contrary, only photocrosslinking via a cyclobutane ring formation was observed under >300‐nm irradiation. Finally, the factors that could affect an efficient photoswitching behavior of the PEG‐CA gels were investigated. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1466–1476, 2000     

Double network hydrogels with controlled shape deformation: A mini review

Double network hydrogels (DN gels), consisting of two networks with strongly asymmetric network structures and properties, are one of most investigated high strength hydrogels. In most cases, the first network of DN gels is rigid, brittle and tightly crosslinked, while the second network is soft, ductile and loosely crosslinked. Because of the tunable and diverse network structures, DN gels with controlled shape deformation have attracted great attention in recent years. The shape deformation of DN gels can be controlled by first network, second network, or both networks. In this mini review, the shape deformation of DN gels via different networks will be summarized, and the application and future perspectives also are discussed. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2018 , 56, 1351–1362