基于动态共价键的自愈性水凝胶及其在医学领域的应用

自愈性水凝胶作为一种新型仿生智能材料受到了科研人员的广泛关注.近年来,人们利用动态共价键、超分子作用,发展了一系列自愈性水凝胶,并将其应用于药物控释、细胞三维培养、组织工程等生物医用领域.本文总结和评述了基于动态共价键的自愈性水凝胶及这些水凝胶作为药物载体的相关研究,并展望了基于动态化学的自愈性水凝胶的未来发展.     

Molecular Imprinting of Cyclodextrin Supramolecular Hydrogels Improves Drug Loading and Delivery

Cyclodextrin‐based controlled delivery materials have previously been developed for controlled release of different therapeutic drugs. In this study, a supramolecular hydrogel made from cyclodextrin‐based macromonomers is subjected to molecular imprinting to investigate the impact on release kinetics and drug loading, when compared with non‐imprinted, or alternately imprinted hydrogels. Mild synthesis conditions are used to molecularly imprint three antibiotics—novobiocin, rifampicin, and vancomycin—and to test two different hydrogel chemistries. The release profile and drug loading of the molecularly imprinted hydrogels are characterized using ultraviolet spectroscopy over a period of 35 days and compared to non‐imprinted, and alternately imprinted hydrogels. While only modest differences are observed in the release rate of the antibiotics tested, a substantial difference is observed in the total drug‐loading amount possible for hydrogels releasing drugs which has been templated by those drugs. Hydrogels releasing drugs which are templated by other drugs do not show improved release or loading. Analysis by FTIR does not show substantial incorporation of drug into the polymer. Lastly, bioactivity assays confirmed long‐term stability and release of incorporated antibiotics.     

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.     

Modification of Dietary Fiber Psyllium with Poly(vinyl pyrrolidone) through Network Formation for Use in Slow Drug Delivery Application

In view of the pharmacological importance of dietary fibre, psyllium, to cure the constipation and diverticulitis, in the present study, an attempt has been made to modify psyllium polysaccharide with PVP to develop the hydrogel meant for slow and controlled drug delivery systems. The polymer was characterized by SEMs, FTIR, XRD, TGA and swelling studies. Swelling of hydrogels and drug (ciprofloxacin) release profile from the drug loaded hydrogels were determined for the evaluation of the swelling/release mechanism. Biomedical properties; biocompatibility and mucoadhesion of the hydrogels, were also studied. Swelling of the hydrogels and release of drugs from drug loaded hydrogels occurred through non-Fickian diffusion mechanism. Here it is pertinent to mention that both psyllium husk polysaccharide and antibiotic drug ciprofloxacin are used for gastrointestinal tract (GIT) problem, especially in case of diverticulitis. Hence, degradation of the polymer matrix and release of drug may exert the synergic effect and the present drug delivery system may act with enhanced potential.     

Chitosan based hybrid hydrogels for drug delivery: Preparation,biodegradation, thermal,and mechanical properties

In the present paper, biodegradable hybrid hydrogels were prepared by using chitosan as a natural polymer and polyurethane containing azomethine as a synthetic polymer for the drug delivery application for 5-fluorouracil. The fabricated hydrogels were characterized via FT-IR and SEM analysis. Besides, the thermal, mechanical, and wettability properties, water uptake, biodegradation, protein absorption, drug loading, and release behaviors of the hybrid hydrogels were studied. The obtained results indicated that the fabricated hybrid hydrogels have exhibited good mechanical, hydrophilic, water uptake, and biodegradation behaviors. The hybrid hydrogels also showed 50% drug release amounts and they could be a good candidate for the controlled delivery of 5-FU due to these properties.     

Hydrophobically modified alginate for extended release of pharmaceuticals

Hydrophobically modified alginate hydrogels have great potential in drug delivery as they are biologically compatible and cost efficient. While previous works have shown successful protein, and hydrophobic and hydrophilic drug delivery, little information regarding the relationship between crosslinker density and drug release rate is known. This paper investigates the impact of crosslinker density and hydrophobic degree of substitution within modified alginate gels and solutions on the release kinetics using model hydrophobic drug, sulindac. Near zero‐order release was obtained for an extended period of 5 days. Drug release rates decreased as the crosslinker density within both modified alginate hydrogels and solutions increased. Release data fit well to a simplified Fickian relationship, suggesting that the release mechanism is diffusion‐limited. These release characteristics also correlate with bulk rheological measurements, indicating a strong interrelationship between the mechanical properties and the drug release characteristics of the hydrogels.     

Strong and Injectable Hydrogels Based on Multivalent Metal Ion-Peptide Cross-linking

Injectable hydrogels are ideal biomaterials for delivering cells, growth factors and drugs specifically to localized lesions and subsequent controlled release. Many factors can affect the efficacy of injectable hydrogels. To avoid potential damage to encapsulated cells or drugs, injectable hydrogels should be highly dynamic so that they can undergo shear-thinning at low strain rates and rapidly reform after injection. However, dynamic hydrogels are often mechanically weak, leading to the leakage of encapsulated cells or drugs. Here we demonstrated a convenient method to improve the mechanical strength without jeopardizing the dynamic properties of hydrogels by using metal ion-peptide crosslinkers containing multiple metal ion-ligand bonds. We showed that the dynamic properties of the hydrogels correlated with the intrinsic dynamics of the metal-ligand bonds and were not affected by the formation of multivalent binding. Yet, the mechanical stability of the hydrogels was significantly improved due to the increased thermodynamic stability of the crosslinkers. We further showed that the drug release rates were slowed down by the formation of multivalent crosslinkers. Our results highlight the importance of ligand valency to the mechanical response of hydrogels and provide a universal route to rationally tune the dynamic and mechanical properties of injectable hydrogels.     

Physicochemical aspects of drug delivery and release from polymer-based colloids

Recent advances in the preparation/loading, surface properties, and applications of polymer-based colloidal drug delivery and release systems, such as block copolymer micelles, polymer nano- and microparticles, polymer-modified liposomes, and chemical and physical hydrogels are presented. Drug release from polymer-based systems is affected by the drug–polymer interactions as well as the polymer microstructure and dissociation/erosion properties. Surface modification with poly(ethylene oxide) has become common in improving the biocompatibility and biodistribution of drug delivery carriers. Site-specific drug delivery can be achieved by polymer-based colloidal drug carriers when ligands of targeting information are attached on the carrier surface or when a phase transition is induced by an external stimulus. While significant progress in being made, many challenges remain in preserving the biological activity and attaining the desired drug release properties, especially for protein and DNA drugs.     

Hybrid cross‐linked hydrogels as a technology platform for in vitro release of cephradine

Hydrogel‐based drug delivery systems can leverage therapeutically favorable upshots of drug release and found clinical uses. Hydrogels offer temporal and spatial control over the release of different therapeutic agents. Because of their tailor made controllable degradability, physical properties, and ability to prevent the labile drugs from degradation, hydrogels provide platform on which diverse physicochemical interactions with entrapped drugs cause to control drug release. Herein, we report the fabrication of novel vinyltrimethoxy silane (VTMS) cross‐linked chitosan/polyvinyl pyrrolidone hydrogels. Swelling in distilled water in conjunction with different buffer and electrolyte solutions was performed to assess the swellability of hydrogels. Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and X‐ray diffraction (XRD) analysis were further conducted to investigate the possible interactions between components, thermal stability, and crystallinity of as‐prepared hybrid hydrogels, respectively. In vitro time‐dependent biodegradability, antimicrobial study, and cytotoxicity were also carried out to evaluate their extensive biocompatibility and cytotoxic behavior. More interestingly, in vitro drug release study allowed for the controlled release of cephradine. Therefore, this facile strategy developed the novel biocompatible and biodegradable hybrid hydrogels, which could significantly expand the scope of these hydrogels in other biomedical applications like scaffolds, skin regeneration, tissue engineering, etc.     

Biodegradable and antibacterial poly(azomethine‐urethane)‐chitosan hydrogels for potential drug delivery application

In this study, biodegradable and antibacterial poly(azomethine‐urethane) (PAMU)‐ and chitosan (CS)‐based hydrogels have been prepared for controlled drug delivery applications. Structural and morphological characterizations of the hydrogels were performed via Fourier transform‐infrared and scanning electron microscopy analyses. Thermal stability, hydrophilicity, swelling, mechanical, biodegradation, protein absorption properties, and drug delivery application of PAMU‐ and CS‐based hydrogels were also investigated. The swelling performance of the hydrogels was studied in acidic, neutral, and alkaline media. Swelling results showed that the hydrogels have higher swelling capacity in acidic and alkaline media than neutral medium. Biodegradation experiments of the hydrogels were also studied via hydrolytic and enzymatic experiments. The drug release property of the hydrogel was carried out using 5‐fluoro uracil (5‐FU), and 5‐FU release capacity of the hydrogels was found in the range from 40.10% to 58.40% after 3 days.     

Polysaccharide-based supramolecular drug delivery systems mediated via host-guest interactions of cucurbiturils

With excellent biocompatibility and biodegradability,natural polysaccharides and their derivative s have exhibited great potential in constructing drug delivery ve hicles for tissue engineering and therapeutics.Cucurbit[n]uril(CB [n])-mediated reversible crosslinking of polysaccharides possess intrinsic stimuliresponsiveness towards competitive guests and have been extensively investigated to fabricate various particles and hydrogels for multiple stimuli-re sponsive drug release by incorpo ration with other stimuli including photo,redox,and enzyme.Through host-guest interactions between CB[6] and aliphatic diamines,functional tags covalently connected with CB[6] can be readily anchored into polysaccharidebased hydrogels,realizing multiple functionalization.The rheological prope rty and drug release profile of polysaccharide-based supramolecular hydrogels can be facilely tuned through CB [8]-mediated dyna mic homo or hetero crosslinking of polysaccharides and/or other polymers.In this review,we introduce and summarize recent progress regarding polysaccharide-based supramolecular drug delivery systems mediated via host-guest interactions of CB[6] and CB[8],covering both bulk hydrogels and particular systems.At the end,possible utilization of CB[7]-based host-guest interactions in constructing polysaccharide-based drug delivery systems and future perspectives of this research direction are also discussed.     

Protein encapsulation and release from degradable sugar based hydrogels

Acid labile sugar based hydrogels have been synthesized using a commercially available acid sensitive cross-linker, 3,9-divinyl-2,4,8,10-tetraoxaspiro-[5,5]-undecane. The monomers used for polymerization are N-isopropylacrylamide (NIPAM) and d-gluconamidoethyl methacrylate (GAMA), which when polymerized in the presence of the acid labile cross-linker yield hydrogels that can swell and degrade under acidic conditions, making them ideal for drug delivery. The hydrogels are synthesized using either a photo-initiator, Irgacure-2959 or a conventional initiator, potassium persulfate. The hydrogels obtained by photo-polymerization exhibit defined and unique microstructures, when analyzed by scanning electron microscopy (SEM). The swelling capacity and protein release from the hydrogels as a function of pH is studied. The protein release from the hydrogels is found to be dependent upon the degree of cross-linking and the pH of the environment.     

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.     

Microfabrication of an asymmetric, multi-layered microdevice for controlled release of orally delivered therapeutics

The creation of an oral drug delivery platform to administer chemotherapeutic agents effectively can not only increase patient compliance, but also potentially diminish drug toxicity. A microfabricated device offers advantages over conventional drug delivery technology. Here we describe the development of a multi-layered polymeric drug-loaded microfabricated device (microdevice) for the oral delivery of therapeutics, which offers unidirectional release of multiple therapeutics. The imaging and release of therapeutics from the multi-layered device was performed with three different fluorescently labeled albumins. The release of insulin and chemotherapeutic camptothecin was also observed to be released in a controlled manner over the course of 180 min in vitro. Furthermore, asymmetric delivery was shown to concentrate drug at the device/cell interface, wherein 10 times more drug permeated an intestinal epithelial cell monolayer, compared to unprotected drug-loaded hydrogels. The bioactivity of the released chemotherapeutic was shown with cytostasis of colorectal adenocarcinoma cells. Cytostasis of drug loaded hydrogels was significantly higher than control empty hydrogel laden microdevices. Our results conclude that microfabrication of a hydrogel laden microdevice leads to a viable oral delivery platform for chemotherapeutics.     

Injectable Graphene Oxide/Graphene Composite Supramolecular Hydrogel for Delivery of Anti-Cancer Drugs

Injectable hydrogels have attracted a lot of attention in drug delivery, however, their capacity to deliver water-insoluble or hydrophobic anti-cancer drugs is limited. Here, we developed injectable graphene oxide/graphene composite supramolecular hydrogels to deliver anti-cancer drugs. Pluronic F-127 was used to stabilize graphene oxide (GO) and reduced graphene oxide (RGO) in solution, which was mixed with α-cyclodextrin (α-CD) solution to form hydrogels. Native hydrogel was used as control. GO or RGO slightly shortened gelation time. The storage and loss moduli of the hydrogels were tracked by dynamic force measurement. The storage modulus of GO or RGO composite hydrogels was larger than that of the native hydrogel. Hydrogels were unstable in solution and eroded gradually. GO or RGO in Pluronic F-127 solution could potentially improve the solubility of the water-insoluble anti-cancer drug camptothecin (CPT), especially with large drug-loaded CPT amount. Drug release behaviors from solutions and hydrogels were characterized. The nanocomponents (GO or RGO) were able to bind more drug molecules either for CPT or for doxorubicin hydrochloride (DXR) in solution. Therefore, GO or RGO composite hydrogel could potentially enable better controlled and gentler drug release (for both CPT and DXR) than native hydrogel.     

Nanoscopic Characterization of Stearic Acid Release from Bovine Serum Albumin Hydrogels

The release behavior of 16‐doxyl stearic acid (16‐DSA) from hydrogels made from bovine serum albumin (BSA) is characterized. 16‐DSA serves as a model tracer molecule for amphiphilic drugs. Various hydrogel preparation procedures are tested and the fatty acid release from the different gels is compared in detail. These comparisons reach from the macroscopic level, the viscoelastic behavior via rheological characterization to changes on the nanoscopic level concerning the secondary structure of the protein during gelation through infrared (ATR‐IR) spectroscopy. 16‐DSA‐BSA interaction via continuous wave electron paramagnetic resonance (CW EPR) spectroscopy in addition gives a nanoscopic view of small molecule–hydrogel interaction. The combined effects of fatty acid concentration, hydrogel incubation time, and gelation procedures on release behavior are studied via CW EPR spectroscopy and dynamic light scattering (DLS) measurements, which provide deep insight on the interaction of 16‐DSA with BSA hydrogels and the nature and size of the released components, respectively. It is found that the release rate of the fatty acid from BSA hydrogels depends on and can thus be tuned through its loading percentage, duration of hydrogel formation and the type of gelation methods. All of the results confirm the potential of these gels as delivery hosts in pharmaceutical applications allowing the sustained release of drug.     

Synthesis,Characterization and Application of Cellulose Based Nano-Biocomposite Hydrogels

Nano-hydroxyapatite/cellulose-graft-polyacrylamide biocomposite hydrogels of different molar ratios were prepared to examine their potential application as a carrier for colon targeted drug delivery in vitro. The particle size of the synthesized nano-hydroxyapatite was found to be 122 nm. The swelling behavior of the composite hydrogels was observed in acidic and basic aqueous solution that simulated lower small intestine, colon and stomach fluids. The hydrogel could be applied in drug-delivery systems and acetylsalicylic acid was used as a model compound to test such a possibility. Finally, the synthesized biocomposite hydrogels with the 96.97% maximum encapsulation and 85.67% release efficiency in the basic medium were found to be a suitable candidate to carry and release of colon-targeted drugs.     

Design and preparation of pH-responsive curdlan hydrogels as a novel protein delivery vector

New pH-responsive saccharide hydrogels were designed and prepared using curdlan derivatives(curdlan-Bochistidine, CUR-HIS). The CUR-HIS hydrogels possessed highly porous structures. The swelling ratios of CUR-HIS hydrogels increased with the degree of substitution of Boc-histidine groups. And the addition of 0.5 mol/L Na Cl provoked a sharp reduction of swelling ratio of CUR-HIS hydrogels. Bovine serum albumin(BSA) can be efficiently encapsulated into CUR-HIS hydrogels. Moreover, the release profiles of BSA at different p H values from CUR-HIS hydrogels were significantly different. These hydrogels showed good biocompatibility in the cytotoxicity assays. The CUR-HIS hydrogels are of great potential in biomedical applications such as protein delivery systems.     

Controlled and targeted delivery of diclofenac sodium to the intestine from pH-Responsive chitosan/poly(vinyl alcohol) interpenetrating polymeric network hydrogels

pH-Responsive hydrogels comprised of chitosan and poly(vinyl alcohol) were explored for the controlled delivery of diclofenac sodium (DS) to the intestine. To regulate the drug delivery, preformed solid inclusion complex of DS with ß-cyclodextrin (ß-CD) was added into the hydrogels. Negligible drug release was observed in the simulated gastric fluid and sustained release in the intestinal fluid. The preliminary kinetics revealed that the drug release follows anomalous transport mechanism which is influenced by the presence of ß-CD. The pH-specific release behavior of these hydrogels suggests them to be ideal candidates for oral controlled delivery of DS to the intestine.     

Preparation and Characterization of a Novel Drug Delivery System: Biodegradable Nanoparticles in Thermosensitive Chitosan/Gelatin Blend Hydrogels

A novel injectable in situ gelling drug delivery system (DDS) consisting of biodegradable N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) nanoparticles and thermosensitive chitosan/gelatin blend hydrogels was developed for prolonged and sustained controlled drug release. Four different HTCC nanoparticles, prepared based on ionic process of HTCC and oppositely charged molecules such as sodium tripolyphosphate, sodium alginate and carboxymethyl chitosan, were incorporated physically into thermosensitive chitosan/gelatin blend solutions to form the novel DDSs. Resulting DDSs interior morphology was evaluated by scanning electron microscopy. The effect of nanoparticles composition on both the gel process and the gel strength was investigated from which possible hydrogel formation mechanisms were inferred. Finally, bovine serum albumin (BSA), used as a model protein drug, was loaded into four different HTCC nanoparticles to examine and compare the effects of controlled release of these novel DDSs. The results showed that BSA could be sustained and released from these novel DDSs and the release rate was affected by the properties of nanoparticle: the slower BSA release rate was observed from DDS containing nanoparticles with a positive charge than with a negative charge. The described injectable drug delivery systems might have great potential application for local and sustained delivery of protein drugs.