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Suppressing persistent multidrug-resistant (MDR) bacterial infections and excessive inflammation is the key for treating chronic wounds. Therefore, developing a microenvironment-responsive material with good biodegradability, drug-loading, anti-infection, and anti-inflammatory properties is desired to boost the chronic wounds healing process; however, using ordinary assembly remains a defect. Herein, we propose a pH/enzyme dual-responsive polymyxin B (PMB) spatiotemporal-release hydrogel (GelMA/OSSA/PMB), namely, the amount of OSSA and PMB released from GelMA/OSSA/PMB was closely related the wound pH and the enzyme concentration changing. The GelMA/OSSA/PMB showed better biosafety than equivalent free PMB, owing to the controlled release of PMB, which helped kill planktonic bacteria and inhibit biofilm activity in vitro. In addition, the GelMA/OSSA/PMB exhibited excellent antibacterial and anti-inflammatory properties. A MDR Pseudomonas aeruginosa caused infection was effectively resolved by the GelMA/OSSA/PMB hydrogel in vivo, thereby significantly boosting wound closure during the inflammatory phase. Furthermore, GelMA/OSSA/PMB accelerated the sequential phases of wound repair. [ABSTRACT FROM AUTHOR]

Microspheres and injectable hydrogels derived from natural biopolymers have been extensively investigated as drug carriers and cell scaffolds. In this study, we report a preparation of composite scaffolds basing microspheres and hydrogel via the Schiff's base reaction. Hybrid gelatin/heparin microspheres loading insulin-like growth factor-1 (IGF-1) with a diameter of 5–10 µm were fabricated using an emulsion cross-linking method. Synchronously, water-soluble carboxymethyl chitosan (CMC) and oxidized chondroitin sulfate (OCS) were prepared for cross-linking of hydrogels, which were embedded with microspheres to produce a composite microspheres/gel scaffold. The mechanism of scaffold cross-linking is attributed to the Schiff's base reaction between amino and aldehyde groups of biopolymers. Currently, gelation rate, morphology, mechanical properties, swelling ratio, weight loss, and IGF-1 release of the composite scaffolds were examined in vitro. The results show that mechanical and bioactive properties of CMC-OCS hydrogel can be significantly improved by embedding gelatin/heparin microspheres containing IGF-1. Compressive modulus of composite gel scaffolds containing 3 wt% of microspheres was 16 kPa, which was higher than the control hydrogel without microspheres. Cumulative release of IGF-1 during 7 days from microspheres embedded hydrogel was 70%, which was significantly lower than those of microspheres and hydrogels. Moreover, the composite microspheres/gel scaffolds exhibited higher swelling ratio and slower degradation rate than the control. Potential of the composite scaffolds was demonstrated by encapsulation of human adipose-derived stem cells (ASCs) in vitro. Cell culture showed that this composite hydrogel could support survival and proliferation of ASCs. These results demonstrate the potential of gelatin/heparin microspheres embedded CMC-OCS hydrogels as an injectable scaffold in soft tissue engineering. [ABSTRACT FROM AUTHOR]

For practical adipose regeneration, the challenge is to dynamically deliver the key adipogenic insulin-like growth factors in hydrogels to induce adipogenesis. In order to achieve dynamic release, smart hydrogels to sense the change in the blood glucose concentration is required when glucose concentration increases. In this study, a heparin-based hydrogel has been developed for use in dynamic delivery of heparin nanospheres containing insulin-like growth factor. The gel scaffold was facilely prepared in physiological conditions by the formation of boronate-maltose ester cross-links between boronate and maltose groups of heparin derivatives. Due to its intrinsic glucose-sensitivity, the exposure of gel scaffold to glucose induces maltose functionalized nanospheres dissociation off hydrogel network and thereby could dynamically move into the microenvironment. The potential of the hydrogel as a cell scaffold was demonstrated by encapsulation of human adipose-derived stem cells (ASCs) within the gel matrix in vitro. Cell culture showed that this dynamic hydrogel could support survival and proliferation of ASCs. This biocompatible coupling chemistry has the advantage that it introduces no potentially cytotoxic groups into injectable gel scaffolds formed and can create a more biomimetic microenvironment for drug and cell delivery, rendering them more suitable for potential in vivo biomedical applications. All these results indicate that this biocompatible gel scaffold can render the formulation of a therapeutically effective platform for diabetes treatment and adipose regeneration. [ABSTRACT FROM AUTHOR]

Although hydrogel contact lens has attracted increasingly concerns as delivery carriers in the field of oculopathy therapy, traditional hydrogel does not show excellent drug encapsulated and controlled properties due to simple hydrophilic polymer chain lacking extra interaction with drug molecule. Herein, functional hydrogels were synthesized in this research to delivery ophthalmic drug for oculopathy therapy. Functional monomer of mono-GMA-β-CD and functional crosslinker of MA-β-CD were incorporated into hydrogel by copolymerization. For hydrogels, equilibrium swelling ratio and contact angle was influenced by mono-GMA-β-CD ratio and MA-β-CD ratio, respectively. All hydrogels exhibited similar water loss behavior and good transparency. Hydrogels had rheological characteristic of typical elastomer. Viscoelasticity and surface morphology of hydrogel were also affected by mono-GMA-β-CD ratio and MA-β-CD ratio. In the aspect of properties, functional hydrogel containing β-CD domain exhibited better protein resistance capacity and significantly higher equilibrium encapsulated drug amount than traditional hydrogel. Besides the performance, drug release behavior of drug encapsulated hydrogel was adjusted by both mono-GMA-β-CD ratio and MA-β-CD ratio. Preliminary in vivo evaluation revealed that functional hydrogel contact lens had better effect and efficacy on lowering intraocular tension than commercial eye drop. It is inferred from all results that functional contact lens has a bright prospect in the application of oculopathy therapy. [ABSTRACT FROM AUTHOR]

Although hydrogel has some outstanding performance, traditional hydrogel still has some drawbacks in the application of drug delivery field. Herein, we attempted to utilize the thiol-yne photopolymerization, which had advantages of high efficiency, mild reaction condition and low toxicity as a type of click chemistry, to realize β-cyclodextrin (β-CD) functionalized hydrogel in order to improve its performance for drug delivery. As a prerequisite, alkynylation was conducted on the per-formed hydrogel. The above-mentioned synthesis was verified by the results of atomic concentration from X-ray Photoelectron Spectroscopy (XPS) characterization and semiquantitative analysis of Fourier-transformed infrared spectroscopy (FTIR) spectra. Similarly, the optimum reaction condition including optimal reaction time and feeding molar ratio were also determined by semiquantitative analysis of FTIR spectra and XPS results. The alkynylation resulted in higher contact angle, lower equilibrium water and coarser surface. Then, β-CD functionalization was beneficial to the hydrophilicity and protein resistant property of hydrogel. With respect to drug delivery performance, an increasing drug concentration and β-CD molecules that grafted onto hydrogel benefited to aggregating orfloxacin molecules in hydrogels. The loading drug concentration as well as β-CD content on hydrogel exerted influences upon drug release behaviors. [ABSTRACT FROM AUTHOR]

Hydrogel contact lenses are ideal drug carriers for ophthalmic drugs delivery. However, some drawbacks of traditional hydrogel restricted their application in the drug delivery field. Herein, we introduced chitosan and β-cyclodextrin (β-CD) into traditional hydrogel in order to improve the properties and control drug release. β-CD functionized and crosslinkable chitosan derivative (CCH) was synthesized and introduced into HEMA/NVP monomers to form HNC tripolymer hydrogel. The introduction of CCH accelerated the polymerization of monomers. Other properties such as equilibrium swelling ratio and oxygen transmissibility of HNC hydrogel were superior to that of HN hydrogel. The capacity of HNC hydrogel to resist the protein absorption was also superior to that of HN hydrogel. Hydrogels exhibited different capacity of drug loading and releasing for different drug. [ABSTRACT FROM AUTHOR]

Abstract: In order to mimic the natural cartilage extracellular matrix, which is composed of core proteins and glycosaminoglycans, a biological hydrogel was synthesized from the biopolymers hyaluronic acid (HA), chondroitin sulfate (CS) and gelatin via click chemistry. HA and CS were modified with 11-azido-3,6,9-trioxaundecan-1-amine (AA) and gelatin was modified with propiolic acid (PA). The molecular structures were verified by 1H nuclear magnetic resonance, infrared spectroscopy and elemental analysis, giving substitution degrees of 29%, 89% and 44% for HA–AA, CS–AA and gelatin–PA (G–PA), respectively. The –N3 groups of HA–AA and CS–AA were reacted with the acetylene groups of G–PA, catalyzed by Cu(I), to form triazole rings, thereby forming a cross-linked hydrogel. The gelation time was decreased monotonically with increasing Cu(I) concentration up to 0.95mgml−1. The hydrogel obtained was in a highly swollen state and showed the characteristics of an elastomer. Incubation in phosphate-buffered saline for 4weeks resulted in a weight loss of up to 45%. Moreover, about 20% gelatin and 10% CS were released from the hydrogel in 2weeks. In vitro cell culture showed that the hydrogel could support the adhesion and proliferation of chondrocytes. [Copyright &y& Elsevier]

Abstract: Hydrogels are more and more attractive in biomedical fields, since they can be used as injectable scaffolds, drugs and gene carriers and smart sensors. The highly hydrated hydrogels, however, generally have low mechanical strength. In this work, a composite chitosan hydrogel was prepared by blending water soluble and crosslinkable chitosan derivative (CML) with poly(lactic-co-glycolic acid) (PLGA) particles whose surfaces were grafted with double carbon bonds containing gelatin (GM), following gelation under UV irradiation. The as-prepared composite hydrogel showed lower swelling ratio than that of the CML hydrogel, and higher elastic stiffness (i.e. storage modulus) than that of the CML hydrogel and the hydrogel filled with the same amount of PLGA particles or gelatin modified PLGA particles. Moreover, the storage modulus of the composite hydrogel was increased with the amount of GM modified PLGA particles. In vitro chondrocyte culture revealed that viability of the cells co-cultured with the GM modified PLGA particles was higher than that of the cells co-cultured with the unmodified PLGA particles. The composite hydrogel blended with the GM modified PLGA particles also showed higher cytoviability than that of the original CML hydrogel after 9d culture. [Copyright &y& Elsevier]

Biopolymer-based hydrogels with sustained drug release capability and antibacterial activity have exhibited great potential in clinical application in drug delivery and wound healing. In this study, a new type of composite wound dressing hydrogel aiming at avoiding wound infection was developed through embedding drug loaded gellan gum microspheres (GMs) into a doubly crosslinked hydrogel, which was constructed by Schiff-base crosslinking of oxidized gellan gum (OG) (pre-crosslinked by calcium ion) and carboxymethyl chitosan (CMCS). The gelation time, swelling index, degradation rate and mechanical properties of the blank hydrogel was optimized by varying the ratios of CMCS/OG (w /w) with fixed OG/calcium (w/w) ratio. The best overall performance of the hydrogel was obtained when CMCS/OG is 16/7 (w/w), with a 139 s gelation time, swelling index remained above 30 after swelling equilibrium, 100.5% degradation rate on the seventh day, and 8.8 KPa compressive modulus. After being embedded with cargo-loaded GMs, the aforementioned performance of the blank hydrogel was improved, and the sustained release of cargoes (antibacterial drugs, tetracycline hydrochloride and silver sulfadiazine) was observed. Moreover, the excellent antibacterial activity of the composite hydrogel was also demonstrated in vitro. These results support the bioactive composite hydrogel can be employed as a promising injectable scaffold for promoting wound regeneration and drug delivery. [ABSTRACT FROM AUTHOR]

In order to broaden the abilities of injectable hydrogel scaffolds, a self-healing chitosan/alginate hydrogel encapsulated with magnetic gelatin microspheres (MGMs) was prepared for anti-cancer drug delivery and soft tissue engineering. The hydrogel was formulated by cross-linking carboxyethyl chitosan (CEC) and oxidized alginate (OAlg) via the Schiff-base reaction. To strengthen the mechanical and biological capabilities of hydrogel, MGMs containing 5-fluorouracil (5-Fu) were prepared by an emulsion cross-linking method. In vitro gelation time, swelling ratio, degradation, compressive modulus and rheological behaviors were tested to monitor the effect of MGMs on the CEC-OAlg hydrogel. With a concentration of 30 mg/mL MGMs, the composite hydrogel provided with the suitable performance and showed excellent self-healing ability under physiological condition. Moreover, this composite hydrogel showed the sustained in vitro drug release compared with control MGMs and CEC-OAlg hydrogel. Our results demonstrated that this magnetic and self-healing CEC-OAlg hydrogel scaffold encapsulated MGMs containing 5-Fu was expected to be a platform for drug delivery and soft tissue engineering. • A self-healing chitosan and alginate gel scaffold was cross-linked via the Schiff-base reaction. • Magnetic gelatin-based microspheres were integrated to improve mechanical properties of the hydrogel. • Hydrogel containing microspheres resulted in a double-barrier system for the sustained release of 5-Fu. [ABSTRACT FROM AUTHOR]

To meet the progressive requirements for bone regeneration purpose, injectable hydrogels have attracted increasing attention in tissue regeneration and local drug delivery applications. In this study, we report a facile method to prepare injectable and degradable polysaccharide-based hydrogels doubly integrated with hydroxyapatite (HAp) nanoparticles and calcium carbonate microspheres (CMs) under physiological condition. The mechanism of cross-linking is attributed to the Schiff-base reaction between amino and aldehyde groups of carboxymethyl chitosan (CMCS) and oxidized alginate (OAlg), respectively. Synchronously, tetracycline hydrochloride (TH) loaded CMs were fabricated by the precipitation reaction with an average diameter of 6.62 μm. To enhance bioactive and mechanical properties, nano-HAp and CMs containing TH were encapsulated into the polysaccharide-based hydrogel to form injectable gel scaffolds for imitation of bone niche. The gelation time, morphology, mechanical properties, swelling ratio and in vitro degradation of the gel scaffolds could be controlled by varying HAp and CMs contents. Moreover, the composite gel scaffolds had good sustained drug release and antibacterial properties, as confirmed by drugs release calculation and antibacterial evaluation. In addition, the gel scaffolds were found to be self-healing due to dynamic equilibrium of the Schiff-base linkages. These results suggested that the prepared composite gel scaffolds hold great potential for drug delivery and regeneration of irregular bone defects. [ABSTRACT FROM AUTHOR]

Injectable hydrogels and microspheres derived from natural polysaccharides have been extensively investigated as drug delivery systems and cell scaffolds. In this study, we report a preparation of covalent hydrogels basing polysaccharides via the Schiff' base reaction. Water soluble carboxymethyl chitosan (CMC) and oxidized chondroitin sulfate (OCS) were prepared for cross-linking of hydrogels. The mechanism of cross-linking is attributed to the Schiff' base reaction between amino and aldehyde groups of polysaccharides. Furthermore, bovine serum albumin (BSA) loaded chitosan-based microspheres (CMs) with a diameter of 3.8–61.6 μm were fabricated by an emulsion cross-linking method, followed by embedding into CMC-OCS hydrogels to produce a composite CMs/gel scaffold. In the current work, gelation rate, morphology, mechanical properties, swelling ratio, in vitro degradation and BSA release of the CMs/gel scaffolds were examined. The results show that mechanical and bioactive properties of gel scaffolds can be significantly improved by embedding CMs. The solid CMs can serve as a filler to toughen the soft CMC-OCS hydrogels. Compressive modulus of composite gel scaffolds containing 20 mg/ml of microspheres was 13 KPa, which was higher than the control hydrogel without CMs. Cumulative release of BSA during 2 weeks from CMs embedded hydrogel was 30%, which was significantly lower than those of CMs and hydrogels. Moreover, the composite CMs/gel scaffolds exhibited lower swelling ratio and slower degradation rate than the control hydrogel without CMs. The potential of the composite hydrogel as an injectable scaffold was demonstrated by encapsulation of bovine articular chondrocytes in vitro. These results demonstrate the potential of CMs embedded CMC-OCS hydrogels as an injectable drug and cell delivery system in cartilage tissue engineering. [ABSTRACT FROM AUTHOR]

An antibacterial and biodegradable composite hydrogel dressing integrated with microspheres is developed for drug delivery and wound healing. The mechanism of gelation is attributed to the Schiff-base reaction between aldehyde and amino groups of oxidized alginate (OAlg) and carboxymethyl chitosan (CMCS). To enhance antibacterial and mechanical properties, tetracycline hydrochloride (TH) loaded gelatin microspheres (GMs) were fabricated by an emulsion cross-linking method, followed by integrating into the OAlg-CMCS hydrogel to produce a composite gel dressing. In vitro gelation time, swelling, degradation, compressive modulus and rheological properties of the gel dressing were investigated as the function of microsphere ratios. With increasing ratios of microspheres from 10 to 40 mg/mL, the composite dressing manifested shorter gelation time and lower swelling ratios, as well as higher mechanical strength. Comparing to other formulations, the gel dressing with 30 mg/mL microspheres showed more suitable stabilities and mechanical properties for wound healing. Also, in vitro drug release results showed that the loaded TH could be sustained release from the composite gel dressing by contrast with pure hydrogels and microspheres. Furthermore, powerful bacteria growth inhibition effects against Escherichia coli and Staphylococcus aureus suggested that the composite gel dressing, especially the one with 30 mg/mL GMs containing TH, has a promising future in treatment of bacterial infection. [ABSTRACT FROM AUTHOR]

Dual-crosslinked alginate/carboxymethyl chitosan (CMC) based hydrogels containing in situ synthesized calcium phosphate (CaP) particles were developed by combining two physical crosslinking, the ionic crosslinking of alginate with divalent cation (Ca2+), and the electrostatic interaction between cation of amino groups on CMC and anion of carboxyl groups on alginate. The calcium phosphate particles were in situ synthesized by using the excess Ca2+ of ionic crosslinking. The developed hydrogels were investigated the rheological properties, swelling behavior, degradation, and drug released performance in both water-soluble and insoluble drug models. The results showed that the viscoelasticity and swelling capacity of dual-crosslinked hydrogels were enhanced comparing the single-crosslinked alginate-based hydrogel. The in situ gelation of the developed hydrogel provided the injectable ability and drug-encapsulated capacity. Beside, calcium phosphate, including hydroxyapatite (HAp) was in situ synthesized during the gelation. Biocompatibility of this injectable hydrogel was studied by encapsulation behavior of human adipose-derived stem cells (ASCs). With these qualities, the developed hydrogel may have potential for medical providers such as hydrogel injections and drug providers. • Dual-crosslinked hydrogels were developed by combining two physical crosslinking. • CaP and HAp nano-particles were in situ synthesized via the ionic crosslinking. • Viscoelasticity and swelling of hydrogels were enhanced by the dual-crosslinking. [ABSTRACT FROM AUTHOR]