An Injectable Self‐Healing Hydrogel Based on Chain‐Extended PEO‐PPO‐PEO Multiblock Copolymer

Injectable hydrogels have been commonly used as drug‐delivery vehicles and tried in tissue engineering. Injectable self‐healing hydrogels have great advantage over traditional injectable hydrogels because they can be injected as a liquid and then rapidly form bulk gels in situ at the target site under physiological conditions. This study develops an injectable thermosensitive self‐healing hydrogel based on chain‐extended F127 (PEO₉₀‐PPO₆₅‐PEO₉₀) multi‐block copolymer (m‐F127). The rapid sol–gel transition ability under body temperature allows it to be used as injectable hydrogel and the self‐healing property allows it to withstand repeated deformation and quickly recover its mechanical properties and structure through the dynamic covalent bonds. It is hoped that the novel strategy and the fascinating properties of the hydrogel as presented here will provide new opportunities with regard to the design and practical application of injectable self‐healing hydrogels.

     

Biodegradable in situ gel-forming controlled vancomycin delivery system based on a thermosensitive mPEG-PLCPPA hydrogel

In this study, a biodegradable in situ gel-forming controlled drug delivery system based on a thermosensitive methoxy polyethylene glycol-co-poly (lactic acid-co-aromatic anhydride) (mPEG-PLCPPA) hydrogel was studied. The hydrogels were formed by micelle aggregation with rising temperature. The hydrogels underwent a temperature-dependent sol–gel–sol transition, which was a flowing sol at ambient temperature and a non-flowing gel at the physiological body temperature. The residual weight and pH value changes after degradation and the viscosity properties of the hydrogel were investigated. The in vitro release behavior of vancomycin from the mPEG-PLCPPA hydrogels at different concentrations was also investigated. The results showed that the mPEG-PLCPPA amphiphilic copolymer could self-assemble to form micelles at low concentrations, and that the particle sizes gradually increased with increasing temperature. The hydrogel maintained a stable degradation rate and provided a moderate pH microenvironment after degradation for 30 days. Vancomycin sustained a stable release profile from the hydrogel over a 10-day period. Furthermore, good biocompatibility was proven by MTT assay and live and dead test. Therefore, the mPEG-PLCPPA hydrogel shows promise as an injectable local antibiotic delivery system.     

可注射水凝胶在伤口敷料中的研究进展

目前,在伤口治疗中对伤口敷料的选择越来越严格。传统的伤口敷料如纱布、绷带、海绵等在伤口愈合过程中容易诱发细菌感染,延缓伤口愈合,甚至引发慢性并发症。可注射水凝胶具备良好的生物相容性,能够适应伤口的形状以填充伤口,且具备一定的抗菌活性,从而避免伤口感染,相比传统的水凝胶伤口敷料更具备医疗优势,因此在生物医药领域得到广泛关注。本文对天然型可注射水凝胶和复合型可注射水凝胶在伤口愈合中的研究进展进行了综述;也对可注射水凝胶的未来发展趋势进行了展望。     

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.     

A Shear-Thinning,Self-Healing,Dual-Cross Linked Hydrogel Based on Gelatin/Vanillin/Fe3+/AGP-AgNPs: Synthesis,Antibacterial, and Wound-Healing Assessment

A shear-thinning and self-healing hydrogel based on a gelatin biopolymer is synthesized using vanillin and Fe³⁺ as dual crosslinking agents. Rheological studies indicate the formation of a strong gel found to be injectable and exhibit rapid self-healing (within 10 min). The hydrogels also exhibited a high degree of swelling, suggesting potential as wound dressings since the absorption of large amounts of wound exudate, and optimum moisture levels, lead to accelerated wound healing. Andrographolide, an anti-inflammatory natural product is used to fabricate silver nanoparticles, which are characterized and composited with the fabricated hydrogels to imbue them with anti-microbial activity. The nanoparticle/hydrogel composites exhibit activity against Escherichia coli, Staphylococcus aureus, and Burkholderia pseudomallei, the pathogen that causes melioidosis, a serious but neglected disease affecting southeast Asia and northern Australia. Finally, the nanoparticle/hydrogel composites are shown to enhance wound closure in animal models compared to the hydrogel alone, confirming that these hydrogel composites hold great potential in the biomedical field.     

An Injectable Integration of Autologous Bioactive Concentrated Growth Factor and Gelatin Methacrylate Hydrogel with Efficient Growth Factor Release and 3D Spatial Structure for Accelerated Wound Healing

Growth factors are essential for wound healing owing to their multiple reparative effects. Concentrated growth factor (CGF) is a third-generation platelet extract containing various endogenous growth factors. Herein, a CGF extract solution is combined with gelatin methacrylate (GM) by physical blending to produce GM@CGF hydrogels for wound repair. The GM@CGF hydrogels show no immune rejection during autologous transplantation. Compared to CGF, GM@CGF hydrogels not only exhibit excellent plasticity and adhesivity but also prevent rapid release and degradation of growth factors. The GM@CGF hydrogels display good injectability, self-healing, swelling, and degradability along with outstanding cytocompatibility, angiogenic functions, chemotactic functions, and cell migration-promoting capabilities in vitro. The GM@CGF hydrogel can release various effective molecules to rapidly initiate wound repair, stimulate the expressions of type I collagen, transform growth factor β1, epidermal growth factor, and vascular endothelial growth factor, promote the production of granulation tissues, vascular regeneration and reconstruction, collagen deposition, and epidermal cell migration, as well as prevent excessive scar formation. In conclusion, the injectable GM@CGF hydrogel can release various growth factors and provide a 3D spatial structure to accelerate wound repair, thereby providing a foundation for the clinical application and translation of CGF.     

Hyaluronic acid-methacrylic anhydride/polyhexamethylene biguanide hybrid hydrogel with antibacterial and proangiogenic functions for diabetic wound repair

Diabetic wounds lead to a decrease in quality of life and an increase in mortality. Current treatment strategies include preventing bacterial adhesion while improving microcirculation. As a new type of wound dressing that imitates natural skin, hydrogel has gradually emerged with its excellent properties. However, existing hydrogels rarely achieve satisfactory results in promoting wound repair and antibacterial simultaneously. In this case, we prepared methacrylic anhydride chemically modified hyaluronic acid as a hydrogel matrix, added polyhexamethylene biguanide as an antibacterial component, and loaded sodium alginate/salidroside composite microspheres which could sustainably release salidroside and thus promote angiogenesis. Hybrid hydrogel (HAMA/PHMB-Ms) was synthesized via photocrosslinking, and its chemical structure, particle size distribution and microstructure were characterized. The satisfactory antibacterial properties of the HAMA/PHMB(15%)-Ms hydrogel were studied in vitro, and its antibacterial rates against E. coli and S. aureus were 97.85% and 98.56%, respectively. In addition, after demonstrating its good biocompatibility, we verified that the HAMA/PHMB-Ms hydrogel has increased granulation tissue formation, more collagen deposition, more subcutaneous capillary formation, and better wound healing than blank control, HAMA and HAMA/PHMB hydrogel on the back wound model of diabetic mice. The results confirmed that HAMA/PHMB-Ms hydrogel was a promising material for the treatment of the diabetic wounds.     

L-Arginine based polyester amide/hyaluronic acid hybrid hydrogel with dual anti-inflammation and antioxidant functions for accelerated wound healing

Nowadays, there are still many challenges to skin regeneration. As a new type of skin substitute, hydrogel has emerging gradually with its excellent properties. However, it is still a challenge to combine with biological active agents to facilitate skin regeneration. Under the circumstance, we synthesized argininebased poly(ester amide)(Arg-PEA) and hyaluronic acid(HA-MA), and combined them into new hybrid hydrogels via photo-crosslinking. We found that the internal structure and physicochemical...     

pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogels via aza‐michael addition for anticancer drug delivery

A pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogel containing “acetals” as pH‐sensitive groups and “disulfides” as reducible linkages was designed and synthesized via aza‐Michael addition reaction between PAMAM and PEGDA diacrylates. The pore size and swelling ratio of hydrogels was varied from 14 ± 3 to 19 ± 4 μm and 214 ± 13 to 300 ± 19 μm, respectively, with varying ethylene glycol repeating units in diacrylates. The swelling ratio of PEGDA/PAMAM network hydrogel increased with increase in the molecular weight of PEG and with decrease in pH. The presence of different cationizable amino‐functionalities in PEGDA/PAMAM network hydrogel helped to enhance the swelling ability of hydrogel under the acidic conditions. The continuous increase in metabolically active live HeLa cells with time in MTT assay implied biocompatibility/noncytotoxicity of the synthesized PEGDA/PAMAM injectable network hydrogel. Furthermore, the prepared PEGDA/PAMAM hydrogel showed higher degradation at lower pH and at higher concentration of DTT. The burst release of doxorubicin from PEGDA/PAMAM hydrogel under the environment of the lower pH and in presence of DTT compared to the release at normal physiological pH and in absence of DTT suggested the potential ability of this model hydrogel system for targeted and selective anticancer drug release at tumor tissues. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 2080–2095     

Vanillin cross-linked hydrogel membranes interfacial reinforced by carbon nitride nanosheets for enhanced antibacterial activity and mechanical properties

Biopolymer based hydrogels are highly adaptable, compatible and have shown great potential in biological tissues in biomedical applications. However, the development of bio-based hydrogels with high strength and effective antibacterial activity remains challenging. Herein, a series of Vanillin-cross-linked chitosan nanocomposite hydrogel interfacially reinforced by g-C₃N₄ nanosheet carrying starch-caped Ag NPs were prepared for wound healing applications. The study aimed to enhance the strength, sustainability and control release ability of the fabricated membranes. Starch-caped silver nanoparticles were incorporated to enhance the anti-bacterial activities The fabricated membranes were assessed using various characterization techniques such as FT-IR, XRD, SEM, mechanical testing, Gel fraction and porosity alongside traditional biomedical tests i.e., swelling percentage, moisture retention ability, water vapor transmission rate, oxygen permeability, anti-bacterial activity and drug-release of the fabricated membranes. The mechanical strength reached as high as 25.9 ± 0.24 MPa for the best optimized sample. The moisture retention lied between 87–89%, gel fraction 80–85%, and water vapor transmission up to 104 ± 1.9 g/m²h showing great properties of the fabricated membrane. Swelling percentage surged to 225% for blood while porosity fluctuated between 44% ± 2.1% and 52.5% ± 2.3%. Oxygen permeability reached up to 8.02 mg/L showing the breathable nature of fabricated membranes. The nanocomposite membrane shown excellent antibacterial activity for both gram-positive and gram-negative bacteria with a maximum zone of inhibition 30 ± 0.25 mm and 36.23 ± 0.23 mm respectively. Furthermore, nanoparticles maintained sustainable release following non-fickian diffusion. The fabricated membrane demonstrated the application of inorganic filler to enhance the strength of biopolymer hydrogel with superior properties. These results envisage the potential of synthesized membrane to be used as wound dressing, artificial skin and load-bearing scaffolds.     

An injectable chitosan-based hydrogel reinforced by oxidized nanocrystalline cellulose and mineral trioxide aggregate designed for tooth engineering applications

The complex anatomy of teeth limits the accessibility and efficacy of regenerative treatments. Therefore, the application of well-known inducers as injectable hydrogels for the regeneration of the dentin-pulp complex is considered a promising approach. In this regard, this study aimed to develop an injectable hydrogel containing mineral trioxide aggregate (MTA). The injectable chitosan/oxidized-nanocrystalline cellulose/MTA (CS/OCNC/MTA) hydrogels were prepared, and the physicochemical properties of these hydrogels were evaluated by TGA, FTIR, Rheological analysis, and SEM. Moreover, the effect of MTA on the swelling and degradability of scaffolds was assessed. The proliferative effects of synthesized hydrogels were also determined on human dental pulp stem cells (hDPSCs) by MTT assay. For induction of differentiation and biomineralization in these cells, the alkaline phosphatase activity and Alizarin Red S staining tests were performed in the presence of fabricated scaffolds. The proliferation of hDPSCs was significantly increased in the presence of these hydrogels. Moreover, the addition of MTA to hydrogel structure dramatically improved the differentiation of hDPSCs. These results suggested that this novel injectable hydrogel provides appropriate physiochemical properties and can be considered a promising scaffold for regenerative endodontic procedures.

Graphical abstract

     

Thermosensitive and Dissolution Properties in Nanocomposite Polymer Hydrogels

We investigate the phase transition behavior and dissolution resistant properties of thermo‐sensitive nanocomposite hydrogels made from PEO‐PPO‐PEO triblock copolymer (Pluronic F127) and Laponite silicate nanoparticles. The rapid dissolution properties of F127 copolymer hydrogels usually limit their use as sustained release drug carriers. We overcome this limitation by synergistic combination of nanoparticle gelation characteristics with polymer thermo‐sensitivity. We present a proof of concept that the temperature‐dependent phase transitions can be shifted as a function of hydrogel composition and that the dissolution of the polymer hydrogels as well as the release of a model drug, albumin, can be significantly slowed down by addition of nanoparticles. The dissolution resistant properties generated will prove useful in the future formulation, processing and application of our polymer hydrogels for sustained release drug delivery carriers.

     

Injectable and self-healing hydrogels with tissue adhesiveness and antibacterial activity as wound dressings for infected wound healing

The design of wound dressings with excellent self-healing ability, adequate adhesion, good biocompatibility, and potential antibacterial ability is of great significance for the healing of infected wounds arising from human activities. Herein, a series of multi-functional hydrogel dressings, poly(ionized isocyanoethyl methacrylate-glutamine)/poly(hexamethylene guanidine) (iG_x/PHMG_y) hydrogels, were obtained through homopolymerization of fully ionized isocyanoethyl methacrylate-glutamine (iIEM-Gln) in the presence of poly(hexamethylene guanidine) (PHMG), in which strong hydrogen bonds were formed among urea groups in the P (iIEM-Gln) chain to form a stable hydrogel network. The prepared iG_x/PHMG_y hydrogels exhibited adequate self-healing ability and tissue adhesion, which could be firmly adhered to the wound surface and remained intact during application. In addition, the presence of PHMG imparted good antibacterial activity to the hydrogels for the effective promotion of the wound healing in S. aureus infected skin wound on mice. Overall, this multi-functional hydrogel provides a facile and effective strategy for the design of infected wound dressings, and may show great potential in clinical applications.     

Acetate chitosan with CaCO3 doping form tough hydrogel for hemostasis and wound healing

In recent years, chitosan has been applied for wound management due to its properties of biocompatibility, biodegradability, antimicrobial activity, and low immunogenicity. But the poor water solubility in neutral pH limited its further application in clinical wound healing. To overcome this problem, acetate chitosan was developed and approved as commercial products for wound healing. However, the acidity of acetate chitosan was potentially allergenic, and the poor mechanical properties of its formed hydrogels also hindered the therapeutic efficacy in wound care. In this study, CaCO₃ was simply doped into acetate chitosan to form the wound dressing. After absorbing water, the H⁺ of acetate chitosan reacted with CaCO₃ to release Ca²⁺, resulting in acidity decreased. The production of Ca²⁺ and residue of CaCO₃ cross‐linked with chitosan to form a tough hydrogel by electrostatic interaction. The physical characteristics, swelling, mechanical testing, and blood clotting were evaluated. The results in vitro demonstrated that after doping CaCO₃ into acetate chitosan, the mechanical properties and blood clotting of the formed hydrogel were increased. Then, the evaluation of hydrogels in vivo revealed that it can also accelerate the wound healing by promoting re‐epithelization and collagen deposition. This simple way by doping CaCO₃ into acetate chitosan can increase wound healing, and it can also broad the application of acetate chitosan in clinical use.     

Development of Antibacterial,Degradable and pH-Responsive Chitosan/Guar Gum/Polyvinyl Alcohol Blended Hydrogels for Wound Dressing

The present research is based on the fabrication preparation of CS/PVA/GG blended hydrogel with nontoxic tetra orthosilicate (TEOS) for sustained paracetamol release. Different TEOS percentages were used because of their nontoxic behavior to study newly designed hydrogels’ crosslinking and physicochemical properties. These hydrogels were characterized using Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and wetting to determine the functional, surface morphology, hydrophilic, or hydrophobic properties. The swelling analysis in different media, degradation in PBS, and drug release kinetics were conducted to observe their response against corresponding media. The FTIR analysis confirmed the components added and crosslinking between them, and surface morphology confirmed different surface and wetting behavior due to different crosslinking. In various solvents, including water, buffer, and electrolyte solutions, the swelling behaviour of hydrogel was investigated and observed that TEOS amount caused less hydrogel swelling. In acidic pH, hydrogels swell the most, while they swell the least at pH 7 or higher. These hydrogels are pH-sensitive and appropriate for controlled drug release. These hydrogels demonstrated that, as the ionic concentration was increased, swelling decreased due to decreased osmotic pressure in various electrolyte solutions. The antimicrobial analysis revealed that these hydrogels are highly antibacterial against Gram-positive (Staphylococcus aureus and Bacillus cereus) and Gram negative (Pseudomonas aeruginosa and Escherichia coli) bacterial strains. The drug release mechanism was 98% in phosphate buffer saline (PBS) media at pH 7.4 in 140 min. To analyze drug release behaviour, the drug release kinetics was assessed against different mathematical models (such as zero and first order, Higuchi, Baker–Lonsdale, Hixson, and Peppas). It was found that hydrogel (CPG2) follows the Peppas model with the highest value of regression (R² = 0.98509). Hence, from the results, these hydrogels could be a potential biomaterial for wound dressing in biomedical applications.     

Natural okra-based hydrogel for chronic diabetic wound healing

As a representative of chronic wounds, the long-term high levels of oxidative stress and blood sugar in chronic diabetic wounds lead to serious complications, making them the biggest challenge in the research on wound healing. Many edible natural biomaterials rich in terpenes, phenols, and flavonoids can act as efficient antioxidants. In this study, okra extract was selected as the main component of a wound dressing. The okra extracts obtained via different methods comprehensively maintained the bioactivity of multiple molecules. The robust antioxidant properties of okra significantly reduced intracellular reactive oxygen species production, thereby accelerating the wound healing process. The results showed that okra extracts and their hydrogel dressings increased cell migration, angiogenesis, and re-epithelization of the chronic wound area, considerably promoting wound remodeling in diabetic rats. Therefore, okra-based hydrogels are promising candidates for skin regeneration and wider tissue engineering applications.     

Radiation synthesis and characterization of nanosilver/gelatin/carboxymethyl chitosan hydrogel

A series of antibacterial hydrogels were fabricated from an aqueous solution of AgNO₃, gelatin and carboxymethyl chitosan (CM-chitosan) by radiation-induced reduction and crosslinking at ambient temperature. The nanosilver particles were in situ synthesized accompanying with the formation of gelatin/CM-chitosan hydrogel. Transmission Electron Microscope and UV–vis analysis have verified the formation and homogeneous distribution of nanosilver particles in the hydrogel matrix. The nanosilver/gelatin/CM-chitosan hydrogels possessed interconnected porous structure, had a compressive modulus of 44 to 56 kPa, and could absorb 62 to 108 times of deionized water to its dry weight. Furthermore, the hydrogels were found to have sound antibacterial effect on Escherichia coli (E. coli), and their antibacterial ability could be significantly enhanced by the increasing of AgNO₃ content. The comprehensive results of this study suggest that nanosilver/gelatin/CM-chitosan hydrogels have potential as an antibacterial wound dressing.     

Injectable hydrogels

Hydrogels are promising for a variety of medical applications due to their high water content and mechanical similarity to natural tissues. When made injectable, hydrogels can reduce the invasiveness of application, which in turn reduces surgical and recovery costs. Key schemes used to make hydrogels injectable include in situ formation due to physical and/or chemical cross‐linking. Advances in polymer science have provided new injectable hydrogels for applications in drug delivery and tissue engineering. A number of these injectable hydrogel systems have reached the clinic and impact the health care of many patients. However, a significant remaining challenge is translating the ever‐growing family of injectable hydrogels developed in laboratories around the world to the clinic. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2012     

pH‐Modulating Poly(ethylene glycol)/Alginate Hydrogel Dressings for the Treatment of Chronic Wounds

The development of chronic wounds has been frequently associated with alkaline pH values. The application of pH‐modulating wound dressings can, therefore, be a promising treatment option to promote normal wound healing. This study reports on the development and characterization of acidic hydrogel dressings based on interpenetrating poly(ethylene glycol) diacrylate/acrylic acid/alginate networks. The incorporation of ionizable carboxylic acid groups results in high liquid uptake up to 500%. The combination of two separate polymer networks significantly improves the tensile and compressive stability. In a 2D cell migration assay, the application of hydrogels (0% to 1.5% acrylic acid) results in complete “wound” closure; hydrogels with 0.25% acrylic acid significantly increase the cell migration velocity to 19.8 ± 1.9 µm h⁻¹. The most promising formulation (hydrogels with 0.25% acrylic acid) is tested on 3D human skin constructs, increasing keratinocyte ingrowth into the wound by 164%.

     

Synthesis and characterization of a multi-sensitive crosslinked injectable hydrogel based on Pluronic

This paper reports the construction of a novel multi-sensitive chemically crosslinked injectable hydrogel with strong mechanical strength by modifying Pluronic F127 responsive against temperature, pH and redox potential. Crosslinked polymer between benzaldehyde grafted Pluronic (P-A) and amine end capped Pluronic having disulfide linkage (P-B) have been synthesized and characterized with 1H NMR spectroscopy and GPC. The hydrogel under physiological conditions significantly altered sol-gel transition behaviors with much lower critical gelation concentrations and temperatures, compared to Pluronic hydrogels. The rheological characterization demonstrated that the moduli of the hydrogels were able to be tuned depending on molecular weight as well as pH, redox and temperature conditions.