Nanoenzyme-Reinforced Injectable Hydrogel for Healing Diabetic Wounds Infected with Multidrug Resistant Bacteria.

Diabetic wound healing remains a critical challenge due to its vulnerability to multidrug-resistant (MDR) bacterial infection, as well as the hyperglycemic and oxidative wound microenvironment. Herein, an injectable multifunctional hydrogel (FEMI) was developed to simultaneously overcome these hurdles. The FEMI hydrogel was fabricated through a Schiff-based reaction between ε-polylysine (EPL)-coated MnO2 nanosheets (EM) and insulin-loaded self-assembled aldehyde Pluronic F127 (FCHO) micelles. Through a synergistic combination of EPL and "nanoknife-like" MnO2 nanosheets, the FEMI hydrogel exhibited extraordinary antimicrobial capacities against MDR bacteria. The MnO2 nanoenzyme reshaped the hostile oxidative wound microenvironment by decomposing the endogenous H2O2 into O2. Meanwhile, the pH/redox dual-responsive FEMI hydrogel achieved a sustained and spatiotemporal controlled release of insulin to regulate the blood glucose. Our FEMI hydrogel demonstrated an accelerated MDR bacteria-infected diabetic wound healing in vivo and represents a versatile strategy for healing a broad range of tissue damages caused by diabetes.

Multifunctional Hydrogels for the Healing of Diabetic Wounds.

The healing of diabetic wounds is hindered by various factors, including bacterial infection, macrophage dysfunction, excess proinflammatory cytokines, high levels of reactive oxygen species, and sustained hypoxia. These factors collectively impede cellular behaviors and the healing process. Consequently, this review presents intelligent hydrogels equipped with multifunctional capacities, which enable them to dynamically respond to the microenvironment and accelerate wound healing in various ways, including stimuli -responsiveness, injectable self-healing, shape -memory, and conductive and real-time monitoring properties. The relationship between the multiple functions and wound healing is also discussed. Based on the microenvironment of diabetic wounds, antibacterial, anti-inflammatory, immunomodulatory, antioxidant, and pro-angiogenic strategies are combined with multifunctional hydrogels. The application of multifunctional hydrogels in the repair of diabetic wounds is systematically discussed, aiming to provide guidelines for fabricating hydrogels for diabetic wound healing and exploring the role of intelligent hydrogels in the therapeutic processes.

Injectable plant-derived polysaccharide hydrogels with intrinsic antioxidant bioactivity accelerate wound healing by promoting epithelialization and angiogenesis.

Skin wound healing is a complex and dynamic process involving hemostasis, inflammatory response, cell proliferation and migration, and angiogenesis. Currently used wound dressings remain unsatisfactory in the clinic due to the lack of adjustable mechanical property for injection operation and bioactivity for accelerating wound healing. In this work, an "all-sugar" hydrogel dressing is developed based on dynamic borate bonding network between the hydroxyl groups of okra polysaccharide (OP) and xyloglucan (XG). Benefiting from the reversible crosslinking network, the resulting composite XG/OP hydrogels exhibited good shear-thinning and fast self-healing properties, which is suitable to be injected at wound beds and filled into irregular injured site. Besides, the proposed XG/OP hydrogels showed efficient antioxidant capacity by scavenging DPPH activity of 73.9 %. In vivo experiments demonstrated that XG/OP hydrogels performed hemostasis and accelerated wound healing with reduced inflammation, enhanced collagen deposition and angiogenesis. This plant-derived dynamic hydrogel offers a facile and effective approach for wound management and has great potential for clinical translation in feature.

Effect of sodium alginate block type on the physicochemical properties and curcumin release behavior of quaternized chitosan-oxidized sodium alginate Schiff base hydrogels.

Controlling bioactive ingredients release by modulating the 3D network structure of cross-linked hydrogels is important for functional food development. Hereby, oxidized sodium alginate (OSA) with varying aldehyde contents was formed by periodate oxidation of sodium alginate (SA) with different ß-d-mannuronic acid (M) and α-l-guluronic acid (G) ratios (M/G = 1:2, 1:1, and 2:1) and its structure was characterized. Moreover, hydrogels were prepared via Schiff base and electrostatic interactions between quaternized chitosan (QCS) and OSA. The properties of hydrogels such as microstructure, thermal stability, swelling and controlled release were investigated. The results showed that OSA with M/G = 1:2 had the highest content of aldehyde groups, and the hydrogel formed by it and QCS had higher thermal stability and a denser network structure with the lowest equilibrium swelling rate, which could better control the release of curcumin. Additionally, it had good self-healing and can recover rapidly after the rupture of its network structure.

Enhanced diabetic wound healing with injectable hydrogel containing self-assembling nanozymes.

To build a smart system in response to the variable microenvironment in infected diabetic wounds, a multifunctional wound dressing was constructed by co-incorporating glucose oxidase (GOx) and a pH-responsive self-assembly Cu2-xSe-BSA nanozyme into a dual-dynamic bond cross-linked hydrogel (OBG). This composite hydrogel (OBG@CG) can adhere to the wound site and respond to the acidic inflammatory environment, initiating the GOx-catalyzed generation of H2O2 and the self-assembly activated peroxidase-like property of Cu2-xSe-BSA nanozymes, resulting in significant hydroxyl radical production to attack the biofilm during the acute infection period and alleviate the high-glucose microenvironment for better wound healing. During the wound recovery phase, Cu2-xSe-BSA aggregates disassembled owing to the elevated pH, terminating catalytic reactive oxygen species generation. Simultaneously, Cu2+ released from the Cu2-xSe-BSA not only promotes the production of mature collagen but also enhances the migration and proliferation of endothelial cells. RNA-seq analysis demonstrated that OBG@CG exerted its antibacterial property by damaging the integrity of the biofilm by inducing radicals and interfering with the energy supply, along with destroying the defense system by disturbing thiol metabolism and reducing transporter activities. This work proposes an innovative glucose consumption strategy for infected diabetic wound management, which may inspire new ideas in the exploration of smart wound dressing.

Adhesive injectable cellulose-based hydrogels with rapid self-healing and sustained drug release capability for promoting wound healing.

Injectable biocompatible hydrogels with multiple functions, including self-healing, adhesion, antibacterial activity, and suitable mechanical properties, are highly desirable for enhancing wound healing. In this study, a new class of multi-functional injectable self-healing cellulose-based hydrogels was synthesised using dynamic covalent acylhydrazone linkages for wound dressing. The carboxymethyl cellulose-graft-adipic dihydrazide (CMC-ADH)/4-Formylbenzoic acid-terminated poly(ethylene glycol) (PEG-FBA) (CMC-ADH/PEG-FBA) hydrogels have adjustable gelation time and excellent self-healing ability. In addition, drug release and in vitro antibacterial activities against Gram-positive and Gram-negative bacteria confirmed the sustained drug-release capacity of the hydrogels. Moreover, haemostasis and wound-healing effects were investigated using an in vivo haemorrhaging liver mouse model and a full-thickness skin defect model, and the results indicated that they not only promoted the wound-healing process but also presented excellent haemostatic effects. The CMC-ADH/PEG-FBA gels also exhibited good adhesion to irregular wounds and significantly enhanced angiogenic ability in vivo. This excellent wound-healing performance occurs because hydrogels can quickly stop bleeding, provide a moist and closed environment for the wound to prevent bacterial invasion, release ciprofloxacin (CIP), reduce inflammatory reactions, and promote wound tissue regeneration. In summary, the synthesised multi-functional gels are ideal candidates for treating haemorrhages and irregular wounds.

Physicochemical and in vitro biological evaluation of an injectable self-healing quaternized chitosan/oxidized pectin hydrogel for potential use as a wound dressing material.

Injectable self-healing hydrogels are attractive materials for use as wound dressings. To prepare such hydrogels, the current study used quaternized chitosan (QCS) to improve the solubility and antibacterial activity and oxidized pectin (OPEC) to introduce aldehyde groups for Schiff's base reaction with the amine groups from QCS. Self-healing hydrogels were made by co-injection of polymer solutions at specific polymer concentrations and reagent ratios that optimized both Schiff's base reactions and ionic interactions. The optimal hydrogel displayed self-healing 30 min after cutting and continuous self-healing during continuous step strain analysis, rapid gelation (< 1 min), a storage modulus of 394 Pa, and hardness of 700 mN, and compressibility of 162 mN s. The adhesiveness of this hydrogel (133 Pa) was within a suitable range for application as a wound dressing. The extraction media from the hydrogel displayed no cytotoxicity to NCTC clone 929 cells and higher cell migration than the control. While the extraction media from the hydrogel was found not to have antibacterial properties, QCS was verified as having MIC50 of 0.04 mg/mL against both E. coli and S. aureus. Therefore, this injectable self-healing QCS/OPEC hydrogel has the potential use as a biocompatible hydrogel material for wound management.

An injectable, self-healing, and antioxidant collagen- and hyaluronic acid-based hydrogel mediated with gallic acid and dopamine for wound repair.

Injectable self-healing hydrogels with antioxidation are required in wound dressings. Because oxidative damage caused by excessive reactive oxygen species (ROS) is a common issue associated with chronic non-healing wounds. Here, collagen (COL) - and hyaluronic acid (HA)-based hydrogel with antioxidant and injectable self-healing mediated with gallic acid (GA) and dopamine (DA) offers unique advantages for wound repair. The hydrogel is constructed by COL-grafted GA (CG), HA-grafted DA (HD) and γ-poly(glutamic acid) (γ-PGA) coupled with 3-aminophenylboric acid (APBA) via the dynamic boronic ester bonds. Rheological measurements and direct visual observation demonstrated the hydrogel's desirable injectability and self-healing properties. Additionally, the hydrogel exhibits tissue adhesion properties. Biocompatibility and cell migration tests showed that the hydrogel promotes cell proliferation and migration. In vitro, antioxidant and intracellular free radical scavenging assays confirmed the hydrogel's antioxidant property and ability to scavenge excess ROS. In vivo wound healing studies have demonstrated that hydrogel can promote angiogenesis, inhibit inflammation, and promote collagen fiber deposition to accelerate wound healing.

Injectable Self-Healing Adhesive pH-Responsive Hydrogels Accelerate Gastric Hemostasis and Wound Healing.

Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are well-established therapeutics for gastrointestinal neoplasias, but complications after EMR/ESD, including bleeding and perforation, result in additional treatment morbidity and even threaten the lives of patients. Thus, designing biomaterials to treat gastric bleeding and wound healing after endoscopic treatment is highly desired and remains a challenge. Herein, a series of injectable pH-responsive self-healing adhesive hydrogels based on acryloyl-6-aminocaproic acid (AA) and AA-g-N-hydroxysuccinimide (AA-NHS) were developed, and their great potential as endoscopic sprayable bioadhesive materials to efficiently stop hemorrhage and promote the wound healing process was further demonstrated in a swine gastric hemorrhage/wound model. The hydrogels showed a suitable gelation time, an autonomous and efficient self-healing capacity, hemostatic properties, and good biocompatibility. With the introduction of AA-NHS as a micro-cross-linker, the hydrogels exhibited enhanced adhesive strength. A swine gastric hemorrhage in vivo model demonstrated that the hydrogels showed good hemostatic performance by stopping acute arterial bleeding and preventing delayed bleeding. A gastric wound model indicated that the hydrogels showed excellent treatment effects with significantly enhanced wound healing with type I collagen deposition, α-SMA expression, and blood vessel formation. These injectable self-healing adhesive hydrogels exhibited great potential to treat gastric wounds after endoscopic treatment.

A physicochemical double cross-linked multifunctional hydrogel for dynamic burn wound healing: shape adaptability, injectable self-healing property and enhanced adhesion.

Burn wounds are one of the most destructive skin traumas that cause more than 180000 deaths each year. Patients with large, irregular burn wounds suffer from slow healing. Dynamic burn wounds have special requirements for hydrogel dressing due to their high frequency movement. To focus on dynamic burn wounds, we designed a novel double cross-linked hydrogel prepared by Schiff base and catechol-Fe3+ chelation bond. The unique double cross-linked structure of the hydrogel resulted in better physicochemical properties and enhanced efficacy. The enhanced physicochemical properties, such as faster gelation time (52 ± 2 s), stronger mechanical property (535 kPa of G'), enhanced adhesive strength (19.3 kPa) and better self-healing property, made the hydrogel suitable for dynamic wounds. The excellent shape adaptability (97.1 ± 1.3% of recovery) made the hydrogel suitable for wounds with irregular shapes. The hydrogel exhibited not only biodegradability during the wound healing process but also superior inherent antibacterial activity (100% killing ratio) and hemostatic property. The results showed that the hydrogel shortened the healing time of burn wounds to 13 days, and accelerated the reconstruction of skin structure and function. This double cross-linked multifunctional hydrogel is a promising candidate as a dynamic burn wound dressing.

NIR/Thermoresponsive Injectable Self-Healing Hydrogels Containing Polydopamine Nanoparticles for Efficient Synergistic Cancer Thermochemotherapy.

Injectable and self-healing hydrogels with thermoresponsiveness as smart hydrogels displayed injectability, automatic healing, and phase and volume changes as well. Here, the thermoresponsive self-healing hydrogel was prepared via the formation of dynamic covalent enamine bonds between the amino groups in polyetherimide (PEI) and the acetoacetate groups in the four-armed star-shaped poly(2-(dimethylamino)ethyl methacrylate-co-2-hydroxyethyl methacrylate) modified with tert-butyl acetoacetate (t-BAA), SP(DMAEMA-co-HEMA-AA). After adding polydopamine nanoparticles (PDA NPs), the SP(DMAEMA-co-HEMA-AA)/PEI/PDA-NP nanocomposite hydrogel presented phase change and volume shrinkage under near-infrared (NIR) irradiation. The thermoresponsive nanocomposite hydrogel loaded with the anticancer drug doxorubicin (DOX) could be injected into the 4T1 tumor by intratumoral injection. After NIR laser irradiation, the temperature of the hydrogel increased because of the photothermal effect of PDA NPs inducing local hyperthermia. Because the hydrophilicity-hydrophobicity transition of the hydrogel occurred, DOX molecules were squeezed out from the hydrogel at temperatures higher than its lower critical solution temperature (LCST) and the tumor cells suffered from internal stress from the shrunk hydrogel. The injectable nanocomposite hydrogel not only demonstrated the synergism of highly efficient thermochemotherapy but also showed the function of improving drug utilization and precise treatment to reduce the side effects of drugs.

Antibacterial adhesive injectable hydrogels with rapid self-healing, extensibility and compressibility as wound dressing for joints skin wound healing.

Designing wound dressing materials with outstanding therapeutic effects, self-healing, adhesiveness and suitable mechanical property has great practical significance in healthcare, especially for joints skin wound healing. Here, we designed a kind of self-healing injectable micelle/hydrogel composites with multi-functions as wound dressing for joint skin damage. By combining the dynamic Schiff base and copolymer micelle cross-linking in one system, a series of hydrogels were prepared by mixing quaternized chitosan (QCS) and benzaldehyde-terminated Pluronic®F127 (PF127-CHO) under physiological conditions. The inherent antibacterial property, pH-dependent biodegradation and release behavior were investigated to confirm multi-functions of wound dressing. The hydrogel dressings showed suitable stretchable and compressive property, comparable modulus with human skin, good adhesiveness and fast self-healing ability to bear deformation. The hydrogels exhibited efficient hemostatic performance and biocompatibility. Moreover, the curcumin loaded hydrogel showed good antioxidant ability and pH responsive release profiles. In vivo experiments indicated that curcumin loaded hydrogels significantly accelerated wound healing rate with higher granulation tissue thickness and collagen disposition and upregulated vascular endothelial growth factor (VEGF) in a full-thickness skin defect model. Taken together, the antibacterial adhesive hydrogels with self-healing and good mechanical property offer significant promise as dressing materials for joints skin wound healing.