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Methicillin-resistant Staphylococcus aureus (MRSA) infections pose great challenges to skin wound care due to the severe drug resistance developed in the clinic. There is an urgent need to exploit next-generation bactericidal therapeutics that are both antibiotic-free and multifunctional for enhanced wound healing. Herein, we designed a Ca 2+ -crosslinked alginate hydrogel (EcNSIN@Alg) containing two naturally derived bioactive components, probiotics Escherichia coli Nissle1917 (EcN) and Squid ink nanoparticles (SIN), to treat MRSA-infected wounds. The injectable composite hydrogel displayed excellent biocompatibility, photothermal antibacterial activity, and reactive oxygen species (ROS) scavenging property. Importantly, the probiotic EcN can enhance the photothermal SIN to promote immune regulatory activities, shifting pro-inflammatory macrophages (M1) to anti-inflammatory macrophages (M2). In an MRSA-infected abscess model, EcNSIN@Alg can reduce the expression level of wound inflammatory factors and ROS, increase the number of anti-inflammatory macrophages, accelerate collagen deposition and promote wound healing. This work offers a new perspective on developing safe, antibiotic-free, multifunctional bactericides using fully bioderived materials, with potential applications in clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Skin wound dressings are commonly utilized for the treatment of skin injuries, as they effectively facilitate wound healing and possess anti-inflammatory and antibacterial properties. However, conventional dressings fail to inhibit ROS production and promote vascularization, leading to delayed wound healing. Here, we developed injectable self-crosslinking hydrogels through thiolated hyaluronic acid (HASH/rhCOLIII) with enhancing the ROS inhibitory capacity while preserving the cell adhesion ability of hyaluronic acid. Additionally, recombinant humanized collagen type III (rhCOLIII) is incorporated via electrostatic adsorption to further enhance mechanical strength and angiogenesis properties of the hydrogel. The HASH/rhCOLIII demonstrated excellent biocompatibility, remarkable ROS scavenging ability, as well as hemostatic and angiogenic properties. Cell experiment results show that HASH/rhCOLIII has excellent biocompatibility and can significantly promote angiogenesis. Animal experiments results showed that HASH/rhCOLIII exhibits anti-inflammatory effects, significantly accelerating wound healing in a full-thickness skin defect model. These findings highlight that HASH/rhCOLIII hydrogel holds great promise as an advanced dressing for effective wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Designing materials for wound dressings with superior therapeutic benefits, self-healing and injectable characteristics is important in clinical practice. Herein, a new self-healing injectable hydrogel was prepared via thermal treatment and dynamic Schiff base reaction by mixing oxidized hyaluronic acid (OHA) and hydrazided Salecan (Sal-ADH). The versatility of the wound dressing was confirmed by studying the inherent rheological properties, high swelling rate, sustained-release behavior of the drug, pH/hyaluronidase-dependent biodegradation, in vitro antimicrobial as well as in vivo wound healing performance. The presence of the antimicrobial drug polyhexamethylene biguanide (PHMB) conferred good antimicrobial properties to the Sal-ADH/OHA/PHMB (SOP) hydrogel, which could effectively prevent wound infection (the width of the inhibition circle of SOP-0.20 hydrogel was 4.97 mm, 5.93 mm for Staphylococcus aureus and Escherichia coli, respectively). The findings suggested that SOP hydrogel exhibited remarkable self-healing and injectability properties, as well as excellent hemostasis and biocompatibility. In vivo experiments indicated that the application of SOP hydrogels would obviously accelerate wound healing and attenuate the inflammatory response while increasing collagen deposition and angiogenesis. Altogether, antibacterial SOP hydrogels with moderate mechanical properties, pH-responsive release, excellent injectability, exceptional self-healing ability and anti-inflammatory effects could expand potential applications of injectable hydrogels in the biomedical field., Competing Interests: Declaration of competing interest The authors declare that they have no known financial interests or personal relationships that might influence the work reported here., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Skin wounds are susceptible to infection, leading to severe inflammatory reactions that can progress to chronic wounds, ultimately causing significant physical and mental distress to the patient. In this study, we propose an injectable composite hydrogel achieved through one-pot gelation of oxidized xyloglucan (OXG), cationic polyamide ε-poly-l-lysine (EPL), and surface amino-rich silicon nanoparticles (SiNPs). OXG exhibits commendable anti-inflammatory properties and provides crosslinking sites. SiNPs serve as mechanically reinforced crosslinkers, facilitating the construction of a dynamic Schiff base network. SiNPs significantly reduced the gelation time to 3 s and tripled the storage modulus of the hydrogels. Additionally, the combination of EPL and SiNPs demonstrated synergistic antimicrobial activity against both S. aureus and E. coli. Notably, the hydrogel effectively halted liver bleeding within 30 s. The hydrogel demonstrated outstanding shear-thinning and self-healing properties, crucial considerations for the design of injectable hydrogels. Furthermore, its efficacy was evaluated as a wound dressing in a mouse model with S. aureus infection. The results indicated that, compared to commercial products, the hydrogel exhibited a shorter wound healing time, decreased inflammation, thinner epithelium, increased hair follicles, enhanced neovascularization, and more substantial collagen deposition. These findings strongly suggest the promising potential of the proposed hydrogel as an effective wound dressing for the treatment of infected wounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Surgical resection remains the mainstream treatment for malignant melanoma. However, challenges in wound healing and residual tumor metastasis pose significant hurdles, resulting in high recurrence rates in patients. Herein, a bioactive injectable hydrogel (BG-Mn gel ) formed by crosslinking sodium alginate (SA) with manganese-doped bioactive glass (BG-Mn) is developed as a versatile platform for anti-tumor immunotherapy and postoperative wound healing for melanoma. The incorporation of Mn 2+ within bioactive glass (BG) can activate the cGAS-STING immune pathway to elicit robust immune response for cancer immunotherapy. Furthermore, doping Mn 2+ in BG endows system with excellent photothermal properties, hence facilitating STING activation and reversing the tumor immune-suppressive microenvironment. BG exhibits favorable angiogenic capacity and tissue regenerative potential, and Mn 2+ promotes cell migration in vitro. When combining BG-Mn gel with anti-PD-1 antibody (α-PD-1) for the treatment of malignant melanoma, it shows enhanced anti-tumor immune response and long-term immune memory response. Remarkably, BG-Mn gel can upregulate the expression of genes related to blood vessel formation and promote skin tissue regeneration when treating full-thickness wounds. Overall, BG-Mn Gel serves as an effective adjuvant therapy to regulate tumor metastasis and wound healing for malignant melanoma., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Wound infections, posing a grave risk of severe physical consequences and even mortality, exact a substantial financial toll on society, rendering them among the most formidable challenges confronting our world today. A critical imperative is the development of hydrogel dressings endowed with immune-regulating and antibacterial properties. This study is founded upon the symbiotic physical and efficacious attributes of two small natural molecules. An injectable hydrogel is meticulously crafted by encapsulating puerarin (PUE) into tyramine-modified hyaluronic acid, subsequently introducing rhein (RHE), and catalyzing the formation of inter-phenol crosslinks with H 2 O 2 /horseradish peroxidase (HA-Tyr-R@P). Exhibiting a favorable microenvironmental impact the developed hydrogel attains an antibacterial efficacy exceeding 95 %, coupled with a wound closure rate twice that of the control group. HA-Tyr-R@P hydrogels not only inhibit bacterial growth but also mitigate inflammation, fostering wound healing, owing to their harmonized physicochemical characteristics and synergistic therapeutic effects. This work underscores the creation of a singular, versatile hydrogel platform, negating the complexities and side effects associated with pharmaceutical preparations. Furthermore, it offers new ideas for the formulation of RHE-based hydrogels for wound healing, emphasizing the pivotal role of natural small molecules in advancing biological materials., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Different types of clinical wounds are difficult to treat while infected by bacteria. Wound repair involves multiple cellular and molecular interactions, which is a complicated process. However, wound repair often suffers from abnormal cellular functions or pathways that result in unavoidable side effects, so there is an urgent need for a material that can heal wounds quickly and with few side effects. Based on these needs, hydrogels with injectable properties have been confirmed to be able to undergo self-healing, which provides favorable conditions for wound healing. Notably, as a biopolymer with excellent easy-to-modify properties from a wide range of natural sources, chitosan can be used to prepare injectable hydrogel with multifunction for wound healing because of its outstanding flowability and injectability. Especially, chitosan-based hydrogels with marked biocompatibility, non-toxicity, and bio-adhesion properties are ideal for facilitating wound healing. In this review, the characteristics and healing mechanisms of different wounds are briefly summarized. In addition, the preparation and characterization of injectable chitosan hydrogels in recent years are classified. Additionally, the bioactive properties of this type of hydrogel in vitro and in vivo are demonstrated, and future trend in wound healing is prospected., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

The need for tumor postoperative treatments aimed at recurrence prevention and tissue regeneration have raised wide considerations in the context of the design and functionalization of implants. Herein, an injectable hydrogel system encapsulated with anti-tumor, anti-oxidant dual functional nanoparticles has been developed in order to prevent tumor relapse after surgery and promote wound repair. The utilization of biocompatible gelatin methacryloyl (GelMA) was geared towards localized therapeutic intervention. Zeolitic imidazolate framework-8@ceric oxide (ZIF-8@CeO2, ZC) nanoparticles (NPs) were purposefully devised for their proficiency as reactive oxygen species (ROS) scavengers. Furthermore, injectable GelMA hydrogels loaded with ZC NPs carrying doxorubicin (ZC-DOX@GEL) were tailored as multifunctional postoperative implants, ensuring the efficacious eradication of residual tumor cells and alleviation of oxidative stress. In vitro and in vivo experiments were conducted to substantiate the efficacy in cancer cell elimination and the prevention of tumor recurrence through the synergistic chemotherapy approach employed with ZC-DOX@GEL. The acceleration of tissue regeneration and in vitro ROS scavenging attributes of ZC@GEL were corroborated using rat models of wound healing. The results underscore the potential of the multifaceted hydrogels presented herein for their promising application in tumor postoperative treatments., (© 2024. The Author(s).)

Intraoperative bleeding and delayed postsurgical wound healing caused by persistent inflammation can increase the risk of tumor recurrence after surgical resection. To address these issues, Enteromorpha prolifera polysaccharide (PEP) with intrinsic potentials for hemostasis and wound healing, is chemically modified into aldehyde-PEP and hydrazine-PEP. Thereby, an injectable double-network hydrogel (OPAB) is developed via forming dual dynamic bonding of acylhydrazone bonds between the decorated aldehyde and hydrazine groups and hydrogen bonds between hydroxyl groups between boric acid and PEP skeletons. The OPAB exhibits controllable shape-adaptive gelation (35.0 s), suitable mechanical properties, nonstimulating self-healing (60 s), good wet tissue adhesion (30.9 kPa), and pH-responsive biodegradability. For in vivo models, owing to these properties, OPAB can achieve rapid hemostasis within 30 s for the liver hemorrhage, and readily loading of curcumin nanoparticles to remarkably accelerate surgical wound closure by alleviating inflammation, re-epithelialization, granulation tissue formation, and collagen deposition. Overall, this multifunctional injectable hydrogel is a promising material that facilitates simultaneous intraoperative hemorrhage and postsurgical wound repair, holding significant potential in the clinical managements of bleeding and surgical wounds for tumor resection., (© 2023 Wiley‐VCH GmbH.)

A novel injectable hydrogel dressing (GA@AgNPs-SA) with long-term antimicrobial effect is developed that can accelerate the closure of bacteria-infected wounds. The hydrogel dressing was prepared by cross-linking sodium alginate molecular chains and gallic acid functionalized silver nanoparticles (GA@AgNPs) via calcium ions to form a three-dimensional network. The hydrogel dressing demonstrates excellent biocompatibility and can achieve a sustainable release of silver ions, ensuring a long-term antibacterial activity and inhibiting biofilm formation. Moreover, an in vivo study demonstrates that the GA@AgNPs-SA hydrogel can effectively decrease the expression of IL-6 and TNF-α to alleviate the inflammatory response, and promote angiogenesis by upregulating CD31, α-SMA and VEGF expression, thus significantly accelerating the repair of infected wounds. Given these interesting properties, this antibacterial hydrogel has great potential for application in the clinical care of bacteria-infected wounds., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2023. Published by Elsevier B.V.)

Severe skin injuries are hard to repair and susceptible to bacterial infection. Development of a versatile antimicrobial anti-inflammatory hydrogel dressing that eliminates concern over antibiotic resistance is urgently needed but remains an elusive goal. Our research, described herein, the design and fabrication of a new family of supramolecular hydrogels based on hydroxypropyl chitosan (HPCS) and poly(N-isopropylacrylamide) (PNIPAM) may prove to be that goal. Employing the reversible cross-linking by β-cyclodextrin (β-CD) and adamantyl (AD) pre-assembly, the hydrogels can be formed in a facile one-pot method. Additionally, the structure and performance of the hydrogels can be controlled by a simple adjustment of the AD content. The obtained hydrogels exhibit an abundance of desired properties; they are injectable, thermosensitive, highly ductile, self-healable (will self-heal recurring damage to the hydrogel bandage of up to several millimeters wide), biocompatible, and have antimicrobial activity against Staphylococcus aureus when infused with dipotassium glycyrrhizinate (DG). Using a mouse full-thickness skin defect model, in vivo wound healing evaluations revealed that the DG-loaded hydrogels (HP-3/DG10) applied to the wound resulted in rapid wound closure. The hydrogels promoted efficient tissue remolding, collagen deposition, decreased inflammation and performed better than the control groups of commercial Tegaderm TM film and 3M dressing. Given their multifunctionality and in vivo efficacy, the DG-loaded HP hydrogels hold great potential as a wound dressing for full-thickness skin repair. STATEMENT OF SIGNIFICANCE: Injectable hydrogels are receiving increasing attention as an ideal wound dressing. To the best of our knowledge, however, injectable and wide-crack self-healing hydrogel dressings have been hardly studied. A versatile antimicrobial hydrogel without drug resistance or cytotoxicity is also highly required. Therefore, in the present study, we constructed injectable thermosensitive and wide-crack self-healing hydrogels with antibacterial and anti-inflammatory properties. These hydrogels were developed through novel strategies of the wide-crack self-healing design and the loading of the bioactive antibacterial and anti-inflammatory agent dipotassium glycyrrhizinate. The simple preparation method and multifunctionality of the studied hydrogel composites may provide important insights for the development of future biomaterials for wound dressings and other biomedical applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Self-healing hydrogels with biodegradability have great potential biomedical application in drug loading and delivery, wound dressing and tissue engineering. In this research, biodegradable hydrogels were designed from oxidized CMC (CMC-CHO) and PEO 23 dinaphthoate hydrazide (PEO 23 DNH) with naphthalene structure for potential bio-imaging purpose. Results showed that the gelation time of this self-healing hydrogels was very fit for in situ injectable applications for drug loading and controlled release. The hydrogels also showed excellent biocompatibility because all the components and the acylhydrazone bond are biocompatible. Moreover, the in vitro and in vivo drug release study revealed the CMC-CHO based hydrogels could reduce the acute toxicity of the drugs with a controlled and sustained release manner. The hydrogel also showed hemostatic activity by sealing effect and mEGF loaded hydrogel accelerated the wound repairing efficacy. All above result proved the CMC-CHO/PEO 23 DNH hydrogel with luminescent property have great application property in bioscience and biotechnology., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The wound healing process of the diabetic wound is often hindered by excessive oxygen free radicals and infection. An ideal wound dressing should possess great reactive oxygen species (ROS) scavenging property and considerable antibacterial ability. In this study, we facilely constructed a novel hydrogel dressing with excellent ROS scavenging property and outstanding antibacterial performance by introducing tannic acid (TA) into quaternized chitosan (QCS) matrix. Attributing to the suitable physical crosslinking between TA and QCS, this QCS/TA hydrogel was endowed with injectable and self-healing properties, which could avoid the various external squeezing on the irregular shape by wound dressing. The results showed that it could promote coagulation, suppress inflammation and expedite collagen deposition in the skin defect model of diabetic rats. This study provides a facile and convenient method for constructing injectable hydrogel dressing, which has application potentials in the clinical management of diabetic wounds., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Developing an efficient and available material for improved cutaneous tissue regeneration is a major challenge in healthcare. Inspired by the concept of moist wound healing, the injectable and self-healing adenine-modified chitosan (AC) hydrogels are designed to significantly accelerate wound healing without the addition of therapeutic drugs. A series of AC derivatives with degree of substitution (DS) ranging from 0.21 to 0.55 were synthesized in aqueous solutions, and the AC hydrogels were prepared by a simple heating/cooling process. AC hydrogels presented good self-healing, low swelling rate capacity, biocompatibility, promote cell proliferation and excellent hemostatic effect. The hydrogels displayed excellent antibacterial activities against gram-negative bacteria, gram-positive bacteria, fungi and drug-resistance bacteria. Moreover, the full-thickness skin defect model experiments showed that AC hydrogels could reduce inflammatory cell infiltration and accelerate wound healing significantly. The hydrogel can shed new light on designing of the multifunctional dressings for wound healing., (Copyright © 2021. Published by Elsevier Ltd.)

Traumatic injury of the oral cavity is atypical and often accompanied by uncontrolled bleeding and inflammation. Injectable hydrogels have been considered to be promising candidates for the treatment of oral injuries because of their simple formulation, minimally invasive application technique, and site-specific delivery. Fibrinogen-based hydrogels have been widely explored as effective materials for wound healing in tissue engineering due to their uniqueness. Recently, an injectable foam has taken the spotlight. However, the fibrin component of this biomaterial is relatively stiff. To address these challenges, we created keratin-conjugated fibrinogen (KRT-FIB). This study aimed to develop a novel keratin biomaterial and assess cell-biomaterial interactions. Consequently, a novel injectable KRT-FIB hydrogel was optimized through rheological measurements, and its injection performance, swelling behavior, and surface morphology were investigated. We observed an excellent cell viability, proliferation, and migration/cell-cell interaction, indicating that the novel KRT-FIB-injectable hydrogel is a promising platform for oral tissue regeneration with a high clinical applicability.

Injectable hydrogels have shown therapeutic effects on wound repair, but most of them exhibit poor mechanical strength. The impacts of stiff injectable hydrogels on cell behavior and wound healing remain unclear. Herein, an injectable hydrogel was developed based on thiolated poly(γ-glutamic acid) (γ-PGA-SH) and glycidyl methacrylate-conjuated oxidized hyaluronic acid (OHA-GMA). Thiol-methacrylate Michael chemistry-mediated post-stabilization and increase of polymer concentration were found to improve the mechanical strength of γ-PGA-SH/OHA-GMA hydrogel. Moreover, in vitro studies confirmed its biodegradability, biocompatibility, and self-healing property. Using the mechanically-tunable hydrogel, it further showed that fibroblasts migrated faster on the surface of stiffer hydrogel, but infiltrated slowly inside it compared with softer hydrogel. In animal experiments, the injectable hydrogel could promote wound healing by increasing collagen deposition and vascularization. In summary, γ-PGA-SH/OHA-GMA hydrogel is able to regulate migration and infiltration of fibroblasts by altering stiffness and offers effective in situ forming scaffolds towards skin tissue regeneration., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Biomaterials for effective hemorrhage control are urgently needed in clinics as uncontrolled bleeding is associated with high mortality. Herein, we developed an injectable and in situ photo-crosslinkable hybrid hemostatic hydrogel by combining pectin methacrylate (PECMA) and gelatin methacryloyl (GelMA). This modular material system combines ionic- and photo-crosslinking chemistries to design interpenetrating networks (IPN) exhibiting tunable rheology, highly porous structure, and controllable swelling and mechanical properties. By simply changing the calcium (0-15 mM) and polymer (1.5-7%) content used for the sequential crosslinking of hydrogels via calcium gelation and UV-photopolymerization, it was possible to precisely modulate the injectability, degradation, and swelling ratio. Moreover, it is demonstrated that PECMA/GelMA hydrogels present good cytocompatibility and uniquely synergize the hemostatic properties of calcium ions on PECMA, the amine residues on GelMA, and the highly porous network toward rapid blood absorption and fast coagulation effect. An in vitro porcine skin bleeding model confirmed that the hydrogel could be directly injected into the wound and rapidly photo-crosslinked, circumventing the bleeding and decreasing the coagulation time by 39%. Importantly, the crosslinked hydrogel could be easily removed to prevent secondary wound injury. Overall, this injectable hybrid PECMA/GelMA hydrogel stands as a promising hemostatic material., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Developing effective internal wound dressing materials is important for postoperative tissue regeneration while remains a challenge due to the poor biological environment-adaptability of conventional materials. Here, we report an example of injectable self-healing hydrogel based on gastric environment-adaptive supramolecular assembly, and have explored its application for gastric perforation healing. By leveraging the gastric environment-modulated supramolecular interactions, the self-assembled hydrogel network is orchestrated with sensitive thermo-responsibility, injectability, printability and rapid self-healing capability. The hydrogel dressing can effectively inhibit the attachment of microorganisms and demonstrates outstanding antibiofouling property. In vivo rat model further demonstrates the as-prepared hydrogel dressing simplifies the surgical procedures, reduces postoperative complications as well as enhances the healing process of gastric perforation compared with the conventional treatment. This work provides useful insights into the development of biological environment-adaptive functional materials for various biomedical applications.

Stem cell transplantation is a promising therapy for wound healing, but the low retention and survival of transplanted stem cells limit their application. Injectable hydrogels exert beneficial effects in skin tissue engineering. In this study, an injectable hydrogel composed of sodium alginate (SA) and collagen type I (Col) was synthesized as a tissue scaffold to improve the efficacy of stem cells in a full-thickness excision wound model. Our results showed that SA/Col hydrogel was injectable, biodegradable, and exhibited low immunogenicity, which could promote the retention and survival of hUC-MSCs in vivo. SA/Col loaded with hUC-MSCs showed reduced wound size (p < 0.05). Histological and immunofluorescence results confirmed that SA/Col loaded with hUC-MSCs significantly promoted the formation of granulation, enhanced collagen deposition and angiogenesis, increased VEGF and TGF-β1 expression (p < 0.05), and mitigated inflammation evidenced by lower production of TNF-α and IL-1β and higher release of IL-4 and IL-10 (p < 0.05). Furthermore, SA/Col loaded with hUC-MSCs significantly lowered the expression of NLRP3 inflammasome-related proteins (p < 0.05). Taken together, our results suggest that SA/Col loaded with hUC-MSCs promotes skin wound healing via partly inhibiting NLRP3 pathway, which has potential to the treatment of skin wounds.

Hydrogel can provide a favorable moisture environment for skin wound healing. In this study, a novel in-situ crosslinked injectable hydrogel was prepared using the water-soluble amidated pectin (AP) and oxidized chitosan (OC) through Schiff-base reaction without any chemical crosslinker. The influence of AP content on the properties of the hydrogel was systemically investigated. It showed that gelation time, pore structure, swelling capability and degradability of the hydrogel can be tuned by varying the content of amine and aldehyde groups from AP and OC. All the porous hydrogels with various AP contents (65%, 70%, and 80%) presented desirable gelation time, swelling property, high hemocompatibility and biocompatibility. Particularly, AP-OC-65 hydrogel presented superior swelling capability and better hemo- and bio-compatibility, owing to more residual amine sites in the hydrogel. Therefore, the injectable AP-OC-65 hydrogel has a greater potential for application to wound dressing or skin substitute., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The development of natural polymer-based hydrogels, combining outstanding injectability, self-healing, and tissue adhesion, with mechanical performance, able to facilitate full-thickness skin wound healing, remains challenging. We have developed an injectable micellar hydrogel (AF127/HA-ADH/OHA-Dop) with outstanding adhesive and self-healing properties able to accelerate full-thickness skin wound healing. Dopamine-functionalized oxidized hyaluronic acid (OHA-Dop), adipic acid dihydrazide-modified HA (HA-ADH), and aldehyde-terminated Pluronic F127 (AF127) were employed as polymer backbones. They were cross-linked in situ using Schiff base dynamic covalent bonds (AF127 micelle/HA-ADH network and HA-ADH/OHA-Dop network), hydrogen bonding, and π-π stacking interactions. The resulting multicross-linked double-network design forms a micellar hydrogel. The unique multicross-linked double-network structure endows the hydrogel with both improved injection abilities and mechanical performance while self-healing faster than single-network hydrogels. Inspired by mussel foot adhesive protein, OHA-Dop mimics the catechol groups seen in mussel proteins, endowing hydrogels with robust adhesion properties. We also demonstrate the potential of our hydrogels to accelerate full-thickness cutaneous wound closure and improve skin regeneration with reduced scarring. We anticipate that our hydrogel platform based on a novel multicross-linked double-network design will transform the future development of multifunctional wound dressings.

Injectable hydrogels with the capability to cast a hypoxic microenvironment is of great potentialities to develop novel therapies for tissue regeneration. However, the relative research still remains at the conceptual phase. Herein, we chose diabetic wound as a representative injury model to explore the actual therapeutic results of tissue injury by injectable hypoxia-induced hydrogels. To enhance recovery and widen applicability, the hypoxia-induced system was incorporated with a conductive network by an original sequentially interpenetrating technique based on the combination of a fast "click chemistry" and a slow enzymatic mediated cross-linking. Hyperbranched poly(β-amino ester)-tetraaniline (PBAE-TA) was cross-linked with thiolated hyaluronic acid (HA-SH) via a thiol-ene click reaction, contributing to the rapid formation of the first conductive network, where vanillin-grafted gelatin (Geln-Van) and laccase (Lac) with a slow cross-linking rate were employed in casting a hypoxic microenvironment. The as-prepared injectable hydrogels possessed both suitable conductivity and sustainable hypoxia-inducing capability to upregulate the hypoxia-inducible factor-1α and connexin 43 expressions of the encapsulated adipose-derived stem cells, which enhanced vascular regeneration and immunoregulation and further promoted the reconstruction of blood vessels, hair follicles, and dermal collagen matrix, eventually leading to the recovery of diabetic rat skin wounds and restoration of skin functions. This work provides a promising strategy to broaden the applicability of diverse hydrogels with a long time-consuming gelation process and to integrate different networks with various biological functions for the therapies of diabetic wounds and other complex clinical symptoms.

Injectable hydrogels with high anti-inflammatory and wound-healing properties are highly desirable for clinical application. In the present study, injectable hydrogels were prepared based on carboxymethyl chitosan and oxidized hyaluronic acid. Blueberry anthocyanins (BA), which are known for their antioxidant and antiinflammatory properties, were successfully loaded into the hydrogels. The gelation kinetics and mechanical properties of the hydrogels were investigated. Oxidized hyaluronic acid with an oxidation degree of 38.1% conferred a suitable gelation time (~70 s) and mechanical properties (76.0 kPa compression stress at strain of 80%) of the hydrogel. The injectable BA-loaded hydrogel significantly accelerated the wound healing process in a full-thickness skin wound model in rats, promoted epithelial and tissue regeneration, exerted antiinflammatory effects, and promoted collagen deposition and angiogenesis. Besides, the hydrogel could upregulate the expression of VEGF and IL-10 proteins, downregulate the NF-κB level, and promote macrophage transformation from M1 phenotype to M2. The promotion of the BA-loaded hydrogel on wound healing were mainly realized by its biological effects, including antioxidant and anti-inflammatory effects, and regulation of various wound healing related factors. The results suggested that BA and the hydrogels exert synergistic effects in promoting wound healing. Injectable BA-loaded hydrogels appear to be promising candidates for wound healing application., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Burn wound healing remains a challenging health problem worldwide due to the lack of efficient and precise therapy. Inherent oxidative stress following burn injury is importantly responsible for prolonged inflammation, fibrotic scar, and multiple organ failure. Herein, a bioinspired antioxidative defense system coupling with in situ forming hydrogel, namely, multiresponsive injectable catechol-Fe 3+ coordination hydrogel (MICH) matrix, is engineered to promote burn-wound dermal repair by inhibiting tissue oxidative stress. This MICH matrix serves as the special traits of "Fe-superoxide dismutases," small molecular antioxidant (vitamin E), and extracellular matrix (ECM) in alleviating cellular oxidative damage, which demonstrates precise scavenging on reactive oxygen species (ROS) of different cellular locations, blocking lipid peroxidation and cell apoptosis. In in vivo burn-wound treatment, this MICH promptly integrates with injured surrounding tissue to provide hydration microenvironment and physicochemical ECM for burn wounds. Importantly, the MICH matrix suppresses tissue ROS production, reducing the inflammatory response, prompting re-epithelization and neoangiogenesis during wound healing. Meanwhile, the remodeling skin treated with MICH matrix demonstrates low collagen deposition and normal dermal collagen architecture. Overall, the MICH prevents burn wound progression and enhances skin regeneration, which might be a promising biomaterial for burn-wound care and other disease therapy induced by oxidative stress., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Polysaccharide hydrogels have been widely used as wound dressings because of their biocompatibility and ability to provide moist environment for wound healing. However, bacterial infection often delays the healing process. Herein, a novel thermosensitive and pH-sensitive hydroxypropyl chitin/tannic acid/ferric ion (HPCH/TA/Fe) composite hydrogel was fabricated by a simple assembly. The pre-cooled hydrogel precursor solution can be injected onto the irregular wound area and gel rapidly at physiological temperature. The TA not only acted as a crosslinker to enhance mechanical properties of the hydrogel, but also as an antibacterial agent which could be sustainably released in response to the acidic environment. The composite hydrogel showed excellent broad-spectrum antibacterial activity up to 7 days with negligible cytotoxicity. Moreover, the hydrogel can inhibit bacterial infection and accelerate the wound healing process without scars in the mouse experiment. These results indicate the potential application of this composite hydrogel for the infected wound healing., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In the management of accelerating wound healing, moist environments play an important role. Compared with other scaffolds of various forms, hydrogels can maintain a moist environment in the wound area. They are cross-linked hydrophilic polymeric networks that resemble natural soft tissues and extracellular matrices. Among them, injectable hydrogels have attracted great attention in wound repair, as they can be injected into irregular-shaped skin defects and formed in situ to shape the contour of different dimensions. The excellent compliance makes hydrogels easy to adapt to the wound under different conditions of skin movement. Here, we oxidized hydroxyethyl starch (O-HES) and modified carboxymethyl chitosan (M-CMCS) to fabricate an in situ forming hydrogel with excellent self-recoverable extensibility-compressibility, biocompatibility, biodegradability, and transparency for accelerating wound healing. The oxidation degree of O-HES was 74%. The amino modification degree of M-CMCS was 63%. M-CMCS/O-HES hydrogels were formed through the Schiff base reaction. The physicochemical properties of M-CMCS/O-HES hydrogels with various ratios were investigated, and M-CMCS/O-HES hydrogel with a volume ratio of 5:5 exhibited appropriate gelation time, notable water-retaining capacity, self-recoverable conformal deformation, suitable biodegradability, and good biocompatibility for wound-healing application. Then, skin wound-healing experimental studies were carried out in Sprague-Dawley rats with full-thickness skin defects. Significant outcomes were achieved in the M-CMCS/O-HES hydrogel-treated group including higher wound closure percentage, more granulation tissue formation, faster epithelialization, and decreased collagen deposition. These findings demonstrate that using the obtained M-CMCS/O-HES hydrogels is a promising therapeutic strategy for wound healing.

The regeneration of hyaline articular cartilage remains a major challenge due to the limited potential for cartilage to self-repair. Mesenchymal stem cell and hydrogel scaffold-based cartilage tissue engineering is a promising technique for articular cartilage therapy. The purpose of this study was to investigate the use of rabbit synovial fluid mesenchymal stem cells (rbSF-MSCs) encapsulated in an injectable chitosan-based hydrogel to repair full-thickness cartilage defects in femoral patellar grooves in rabbits. The rbSF-MSCs were obtained from rabbit synovial fluid and the surface markers of rbSF-MSCs were coincidental to the identification criteria of MSCs according to flow cytometry. The rbSF-MSCs were able to differentiate into osteogenic, adipogenic and chondrogenic lineages. In the present study, rbSF-MSCs encapsulated in glycol chitosan (GC) and benzaldehyde capped poly (ethylene oxide) (OHC-PEO-CHO) hydrogel were introduced into rabbits to repair articular cartilage defects. The modulus of the hydrogel could be regulated by the concentrations of GC and OHC-PEO-CHO and the hydrogel has a good biocompatibility to rbSF-MSCs. Assessment of in vivo repair indicates using hydrogel/rbSF-MSCs was superior to using the hydrogel scaffold only and the untreated control based on gross appearance and histological grading and evaluation. These preliminary findings suggest using the injectable chitosan-based hydrogel as a scaffold and rbSF-MSCs as seed cells is an alternative for tissue engineering of in vivo treatments for cartilage defects and these rbSF-MSCs allografts may be promising for use in clinical applications., (Copyright © 2019. Published by Elsevier B.V.)

Diabetic wound is hard to heal mainly because of the difficulty in vascularization in the wound area. Accumulating results have shown that desferrioxamine (DFO) can promote secretion of hypoxia inducible factor-1 (HIF-1α), thereby upregulating the expression of angiogenic growth factors and facilitating revascularization. Our preliminary study has demonstrated that Si ions in bioglass (BG) can upregulate vascular endothelial growth factor (VEGF) expression, thus promoting revascularization. It is hypothesized that the combined use of BG and DFO may have a synergistic effect in promoting VEGF expression and revascularization. To prove this, we first determined DFO concentration range that had no apparent cytotoxicity on human umbilical vein endothelial cells (HUVECs). Then, the optimal concentration of DFO promoting tube formation of HUVECs was determined by cell migration and tube formation assays. In addition, we demonstrated that combination use of BG and DFO improved the migration and tube formation of HUVECs as compared with the use of either BG or DFO alone as BG and DFO could synergistically upregulate VEGF expression. Furthermore, a sodium alginate hydrogel containing both BG and DFO was developed, and this hydrogel better facilitated diabetic skin wound healing than the use of either BG or DFO alone as BG and DFO in the hydrogels worked synergistically in promoting HIF-1α and VEGF expression and subsequently vascularization in the wound sites. Therefore, in this study, the synergistic effect in promoting revascularization between BG and DFO was first demonstrated and an injectable hydrogel simultaneously containing BG and DFO was developed for enhancing repair of diabetic chronic skin defects by taking advantages of the synergistic effects of BG and DFO in promoting revascularization. The study opens up a new prospect for the development of skin repair-promoting biomaterials.

Nanodiamonds (NDs) represent an emerging class of carbon nanomaterials that possess favorable physical and chemical properties to be used as multifunctional carriers for a variety of bioactive molecules. Here we report the synthesis and characterization of a new injectable ND-based nanocomposite hydrogel which facilitates a controlled release of therapeutic molecules for regenerative applications. In particular, we have formulated a thermosensitive hydrogel using gelatin, chitosan and NDs that provides a sustained release of exogenous human vascular endothelial growth factor (VEGF) for wound healing applications. Addition of NDs improved the mechanical properties of the injectable hydrogels without affecting its thermosensitive gelation properties. Biocompatibility of the generated hydrogel was verified by in vitro assessment of apoptotic gene expressions and anti-inflammatory interleukin productions. NDs were complexed with VEGF and the inclusion of this complex in the hydrogel network enabled the sustained release of the angiogenic growth factor. These results suggest for the first time that NDs can be used to formulate a biocompatible, thermosensitive and multifunctional hydrogel platform that can function both as a filling agent to modulate hydrogel properties, as well as a delivery platform for the controlled release of bioactive molecules and growth factors., Statement of Significance: One of the major drawbacks associated with the use of conventional hydrogels as carriers of growth factors is their inability to control the release kinetics of the loaded molecules. In fact, in most cases, a burst release is inevitable leading to diminished therapeutic effects and unsuccessful therapies. As a potential solution to this issue, we hereby propose a strategy of incorporating ND complexes within an injectable hydrogel matrix. The functional groups on the surface of the NDs can establish interactions with the model growth factor VEGF and promote a prolonged release from the polymer network, therefore, providing a longer therapeutic effect. Our strategy demonstrates the efficacy of using NDs as an essential component for the design of a novel injectable nanocomposite system with improved release capabilities., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Tissue-derived extracellular matrix (ECM) biomaterials to regenerate the meniscus have gained increasing attention in treating meniscus injuries and diseases, particularly for aged persons and athletes. However, ECM scaffold has poor cell infiltration and can only be implanted using surgical procedures. To overcome these limitations, we developed an injectable ECM hydrogel material from porcine meniscus via modified decellularization and enzymatic digestion. This meniscus-derived ECM hydrogel exhibited a fibrous morphology with tunable compression and initial modulus. It had a good injectability evidenced by syringe injection into mouse subcutaneous tissue. The hydrogel showed good cellular compatibility by promoting the growth of both bovine chondrocytes and mouse 3T3 fibroblasts encapsulated in the hydrogel for 2 weeks. It also promoted cell infiltration as shown in both in vitro cell culture and in vivo mouse subcutaneous implantation. The in vivo study revealed that the ECM hydrogel possessed good tissue compatibility after 7 days of implantation. The results support the great potential of the newly produced injectable meniscus-derived ECM hydrogel specifically for meniscus repair and regeneration., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Hydrogels have garnered significant interest in the biomedical field owing to their tissue-like properties and capability to incorporate various fillers. Among these, injectable hydrogels have been highlighted for their unique advantages, especially their minimally invasive administration mode for implantable use. These injectable hydrogels can be utilized in their pristine forms or as composites by integrating them with therapeutic filler materials. Given their primary application in implantable platforms, enzymatically crosslinked injectable hydrogels have been actively explored due to their excellent biocompatibility and easily controllable mechanical properties for the desired use. This review introduces the crosslinking mechanisms of such hydrogels, focusing on those mediated by horseradish peroxidase (HRP), transglutaminase (TG), and tyrosinase. Furthermore, several parameters and their relationships with the intrinsic properties of hydrogels are investigated. Subsequently, the representative biomedical applications of enzymatically crosslinked-injectable hydrogels are presented, including those for wound healing, preventing post-operative adhesion (POA), and hemostasis. Furthermore, hydrogel composites containing filler materials, such as therapeutic cells, proteins, and drugs, are analyzed. In conclusion, we examine the scientific challenges and directions for future developments in the field of enzymatically crosslinked-injectable hydrogels, focusing on material selection, intrinsic properties, and filler integration. [ABSTRACT FROM AUTHOR]

Hydrogel stands out as one of the most attractive wound dressings due to its excellent moisturizing properties and capacity to absorb wound exudates. However, conventional hydrogel dressings often lack responsiveness to the microenvironment, merely acting as protective barriers for the wound. Consequently, they exhibit limited effectiveness in preventing infection and facilitating wound repair. To address these problems, we have developed a multifunctional injectable hydrogel, CF/MS@HG, based on peroxidase-like nanozymes, aiming at rapidly healing bacterial-infected wounds. The hydrogel is mainly composed of oxidized sodium alginate, aminated gelatin, and polylysine, encapsulating MIL-101(CuFe) NPs (CF) and manganese selenide nanoparticles (MnSe2 NPs, or MS NPs). After injection, the complex rapidly gelatinizes at the infected wound site through a Schiff base reaction. In vitro experiments have demonstrated the hydrogel's strong adhesion and self-healing capabilities. Moreover, CF exhibiting peroxidase (POD)-like activity, catalyzes in situ hydrogen peroxide (H2O2) to generate highly toxic hydroxyl radicals (·OH) within the wound microenvironment, inducing oxidative damage to bacteria. Meanwhile, MS decomposes into H2Se in the slightly acidic wound microenvironment, disrupting bacterial metabolism and inhibiting proliferation. The addition of polylysine further enhances the hydrogel's antibacterial properties. In vivo experiments have shown that the hydrogel exhibits excellent biological safety and significantly promotes wound healing. This multifunctional smart hydrogel holds great promise for the treatment of bacterial-infected wounds. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer among women worldwide, and adjuvant radiotherapy (RT) following tumor removal is one of the most commonly used treatments for breast cancer. However, the high risk of tumor recurrence and inevitable radiation skin injury after RT remain fatal problems, seriously challenging the patient's postoperative rehabilitation. Herein, a multifunctional poly (lipoic acid)-based hydrogel is constructed through one-step heating the mixture of α-lipoic acid (LA)/arginine (Arg)/silk fibroin (SF), without introducing any non-natural molecules. The multiple synergistic interactions among LA, Arg, and SF not only enhance the solubilization of LA in aqueous systems but also stabilize poly(lipoic acid) through strong salt bridge hydrogen bonds and ionic hydrogen bonds. Intriguingly, the LA-based surfactant induced β-sheet transformation of SF can further modulate the bulk strength of the hydrogel. Regulating the content of LA in hydrogels not only allows efficient control of hydrogel bioactivity but also enables the evolution of hydrogels from injectable forms to adhesive patches. Based on the different biological activities and forms of hydrogels, they can be implanted internally or applied externally on the mice's skin, achieving simultaneous prevention of tumor recurrence post-surgery and assistance in treating radiation-induced skin damage after radiotherapy.

Developing hydrogels with excellent 3D printability, injectability, and mechanical integrity presents an imposing challenge in biomaterials research, especially in the biomedical field where biocompatibility is crucial. This study involved the development of 3D printable and injectable polysaccharide-based hydrogels with inherent self-healing capabilities. Carboxymethyl chitosan and quaternized chitosan (QCS) functioned as polymer backbones, reinforced by dialdehyde-cellulose nanocrystals (DACNC) as a cross-linker. Here, the concentrations of QCS and DACNC were adjusted and optimized for ideal performance. The cross-linking process was orchestrated in situ, integrating dynamic hydrogen bonds and Schiff base covalent bonds to achieve a multi-cross-linked hydrogel network. Comprehensive characterization of the material, including rheological measurements and macroscopic evaluations, demonstrated the hydrogel's admirable injectability, printability, and self-healing attributes. In vitro cell viability assessments on human dermal fibroblasts revealed favorable biocompatibility and minimal cytotoxicity of the hydrogels, properties influenced by the concentrations of QCS. The obtained hydrogels exhibit promising attributes suitable for fabricating 3D printable and injectable hydrogel customized for biomedical applications, particularly wound healing. [ABSTRACT FROM AUTHOR]

[Display omitted] An injectable hydrogel dressing, Zr/Fc-MOF@CuO 2 @FH, was constructed by combing acid-triggered chemodynamic treatment (CDT) with low-temperature photothermal treatment (LT-PTT) to effectively eliminate bacteria without harming the surrounding normal tissues. The Zr/Fc-MOF acts as both photothermal reagent and nanozyme to generate reactive oxygen species (ROS). The CuO 2 nanolayer can be decomposed by the acidic microenvironment of the bacterial infection to release Cu2+ and H 2 O 2 , which not only induces Fenton-like reaction but also enhances the catalytic capability of the Zr/Fc-MOF. The generated heat augments ROS production, resulting in highly efficient bacterial elimination at low temperature. Precisely, injectable hydrogel dressing can match irregular wound sites, which shortens the distance of heat dissipation and ROS diffusion to bacteria, thus improving sterilization efficacy and decreasing non-specific systemic toxicity. Both in vitro and in vivo experiments validated the predominant sterilization efficiency of drug-resistant methicillin-resistant Staphylococcus aureus (MRSA) and kanamycin-resistant Escherichia coli (KREC), presenting great potential for application in clinical therapy. [ABSTRACT FROM AUTHOR]

Bacterial-infected wounds could cause delayed wound healing due to increased inflammation, especially wounds infected by drug-resistant bacteria remain a major clinical problem. However, traditional treatment strategies were gradually losing efficacy, such as the abuse of antibiotics leading to enhanced bacterial resistance. Therefore, there was an urgent need to develop an antibiotic-free multifunctional dressing for bacterially infected wound healing. This study demonstrated the preparation of a multifunctional injectable hydrogel and evaluated its efficacy in treating acute and infected wounds. The hydrogel was prepared by a one-step mixing method, and cross-linked by natural deep eutectic solvent (DES), polyvinyl alcohol (PVA), chitosan (CS), tannic acid (TA), and Cu2+ through non-covalent interactions (hydrogen bonds and metal coordination bonds). PVA/CS/DES/CuTA500 hydrogel has multiple functional properties, including injectability, tissue adhesion, biocompatibility, hemostasis, broad-spectrum antibacterial, anti-inflammatory, and angiogenesis. Most importantly, in the MRSA-infected skin wound model, PVA/CS/DES/CuTA500 hydrogel could ultimately accelerate infected wound healing by killing bacteria, activating M2 polarization, inhibiting inflammation, and promoting angiogenesis. In summary, the PVA/CS/DES/CuTA500 hydrogel showed great potential as a wound dressing for bacterial infected wounds treatment in the clinic.

For various chronic wounds, bacterial infection is one of the important reasons that hinder their healing. Ion‐crosslinked antibacterial hydrogel dressings based on Ag+, Cu2+ and Zn2+, have made progress in clinical application. However, the toxicity of released metal ions cannot be ignored. Therefore, how to ensure the antibacterial performance of hydrogel dressing while reducing the amount of metal ions is a major challenge for the fabrication of metal ion based antibacterial hydrogel. In this study, a general method is proposed to design cationic ion‐crosslinked hydrogel based on thiourea groups. Taking the hydrogel formed by mixing thiourea modified hyaluronic acid (H‐ANCSN) with Ag+ (HA‐NCSN/Ag+ hydrogel) as an example, the characteristics and application potential of this kind of hydrogel are thoroughly explored. Due to the strong cationic chelation characteristics of thiourea groups, HA‐NCSN/Ag+ hydrogel can gel at low Ag+ concentration and achieve long‐term slow release of Ag+ at stable concentration to balance the antibacterial and biocompatible properties. Moreover, this dynamic thiourea‐Ag+ crosslinking also endowed the hydrogel with the property of "gelation and encapsulation first, injection to cover wound when necessary". Then, the mangiferin self‐assembled nanoparticles are loaded into HA‐NCSN/Ag+ hydrogel as the radical oxygen species scavenger. [ABSTRACT FROM AUTHOR]

Abstract Surgical resection remains the mainstream treatment for malignant melanoma. However, challenges in wound healing and residual tumor metastasis pose significant hurdles, resulting in high recurrence rates in patients. Herein, a bioactive injectable hydrogel (BG‐Mngel) formed by crosslinking sodium alginate (SA) with manganese‐doped bioactive glass (BG‐Mn) is developed as a versatile platform for anti‐tumor immunotherapy and postoperative wound healing for melanoma. The incorporation of Mn2+ within bioactive glass (BG) can activate the cGAS‐STING immune pathway to elicit robust immune response for cancer immunotherapy. Furthermore, doping Mn2+ in BG endows system with excellent photothermal properties, hence facilitating STING activation and reversing the tumor immune‐suppressive microenvironment. BG exhibits favorable angiogenic capacity and tissue regenerative potential, and Mn2+ promotes cell migration in vitro. When combining BG‐Mngel with anti‐PD‐1 antibody (α‐PD‐1) for the treatment of malignant melanoma, it shows enhanced anti‐tumor immune response and long‐term immune memory response. Remarkably, BG‐Mngel can upregulate the expression of genes related to blood vessel formation and promote skin tissue regeneration when treating full‐thickness wounds. Overall, BG‐MnGel serves as an effective adjuvant therapy to regulate tumor metastasis and wound healing for malignant melanoma.

This study focuses on synthesizing an injectable hydrogel (IH) using Moringa oleifera gum (MOG) with multi‐aldehyde groups (MOG‐CHO) and carboxymethyl chitosan (CMCh) through a Schiff base reaction at 37 °C. The study includes the optimal concentration of the oxidizing agent to achieve the best content of aldehydes in Moringa oleifera gum. Furthermore, the best oxidized Moringa oleifera gum decides the least gelation time. The physical properties of the optimized IH (IH‐3‐7) are assessed, including color, gel content, porosity, load‐bearing capacity, syringeability, and self‐healing capability. Structural characterization is performed using Fourier transform Infrared spectroscopy (FT‐IR) and nuclear magnetic spectroscopy (1H NMR), while scanning electron microscope (SEM) and rheometer are used to analyze surface morphology and rheological properties. IH‐3‐7 exhibits a porous structure with 35 % porosity and interconnected holes of 1.45 to 4 μm diameter. Higher swelling at pH 5.5 is shown by swelling ratio test conducted in phosphate buffer saline (PBS) at pH 7.4 and pH 5.5. Ciprofloxacin HCl (Cipro) is loaded into IH for release assays, revealing pH‐dependent drug release. In vitro, cytotoxicity assessments on L‐929 fibroblast cell lines show IH′s biocompatibility. Hydrolytic degradation of IH in PBS at pH 7.4 is also evaluated. [ABSTRACT FROM AUTHOR]

Treating the most widespread complication of diabetes: diabetic wounds poses a significant clinical obstacle due to the intricate nature of wound healing in individuals with diabetes. Here a novel approach is proposed using easily applicable injectable gelatin/metal/tea polyphenol double nanonetworks, which effectively remodel the wound microenvironment and accelerates the healing process. The gelatin(Gel) crosslink with metal ions (Zr4+) through the amino acids, imparting advantageous mechanical properties like self‐healing, injectability, and adhesion. The nanonetwork's biological functions are further enhanced by incorporating the tea polyphenol metal nanonetwork through in situ doping of the epigallocatechin gallate (EGCG) with great antibacterial, self‐healing, antioxidant, and anticancer capabilities. The in vitro and in vivo tests show that this double nanonetworks hydrogel exhibits faster cell migration and favorable anti‐inflammatory and antioxidant properties and can greatly reshape the microenvironment of diabetic wounds and accelerate the wound healing rate. In addition, this hydrogel is completely degraded after subcutaneous injection for 7 days, with nondetectable cytotoxicity in H&E staining of major mice organs and the serum level of liver function indicators. Considering the above‐mentioned merits of this hydrogel, it is believed that the injectable gelatin/metal/tea polyphenol double nanonetworks have broad biomedical potential, especially in diabetic wound repair and tissue engineering. [ABSTRACT FROM AUTHOR]

Chronic diabetic wounds are a severe complication of diabetes, often leading to high treatment costs and high amputation rates. Numerous studies have revealed that nitric oxide (NO) therapy is a promising option because it favours wound revascularization. Here, base-paired injectable adhesive hydrogels (CAT) were prepared using adenine- and thymine-modified chitosan (CSA and CST). By further introducing S-nitrosoglutathione (GSNO) and binary l -arginine (bArg), we obtained a NO sustained-release hydrogel (CAT/bArg/GSON) that was more suitable for the treatment of chronic wounds. The results showed that the expression of HIF-1α and VEGF was upregulated in the CAT/bArg/GSON group, and improved blood vessel regeneration was observed, indicating an important role of NO. In addition, the research findings revealed that following treatment with the CAT/bArg/GSON hydrogel, the viability of Staphylococcus aureus and Escherichia coli decreased to 14 ± 2 % and 6 ± 1 %, respectively. Moreover, the wound microenvironment was improved, as evidenced by a 60 ± 1 % clearance of DPPH. In particular, histological examination and immunohistochemical staining results showed that wounds treated with CAT/bArg/GSNO exhibited denser neovascularization, faster epithelial tissue regeneration, and thicker collagen deposition. Overall, this study proposes an effective strategy to prepare injectable hydrogel dressings with dual NO donors. The functionality of CAT/bArg/GSON has been thoroughly demonstrated in research on chronic wound vascular regeneration, indicating that CAT/bArg/GSON could be a potential option for promoting chronic wound healing. This article prepares a chitosan hydrogel utilizing the principle of complementary base pairing, which offers several advantages, including good adhesion, biocompatibility, and flow properties, making it a good material for wound dressings. Loaded GSNO and bArg can steadily release NO and l -arginine through the degradation of the gel. Then, the released l -arginine not only possesses antioxidant properties but can also continue to generate a small amount of NO under the action of NOS. This design achieves a sustained and stable supply of NO at the wound site, maximizing the angiogenesis-promoting and antibacterial effects of NO. More neovascularization and abundant collagen were observed in the regenerated tissues. This study provides an effective repair hydrogel material for diabetic wound. [Display omitted] [ABSTRACT FROM AUTHOR]

Diabetic wound treating remains a challenging due to bacterial infections, oxidative stress, tissue hypoxia, and high glucose levels. Herein, a multi-enzyme-like activities nanocomposite (Mo,Fe/Cu,I-Ag@GOx) was designed and anchored to a multifunctional fluorescence hydrogel. The nanozyme gel, loaded with glucose-oxidase (GOx), exhibits intrinsic GOx, peroxidase (POD)-, oxidase (OXD)-, catalase (CAT)- and superoxide dismutase (SOD)-like activities with pH-switchable glucose-initiated cascade reaction for diabetic wound healing. In the first cascade-reaction, initiated by GOx, the nanozyme gel catalyzes glucose and O 2 into gluconic acid and H 2 O 2 to further generate superoxide anion radical (O 2 ·-) and hydroxyl radicals (·OH) to eradicate bacteria. In the second cascade-reaction, as the wound pH changes alkalescent microenvironment, the nanozyme gel simulates SOD to transform O 2 ·- into O 2 and H 2 O 2 , and then decomposes endogenous and exogenous H 2 O 2 into O 2 via CAT-like activity to reduce oxidative stress and alleviate hypoxia. The gel by calcium ion (Ca2+) cross-linked sodium alginate (SA) and chitosan (CS) containing nanozyme was constructed with injectability, adhesion and fluorescence properties, as well as beneficial biocompatible. Importantly, the water/alcohol solubility of the nanozyme gel allows it to be used as a dressing without causing secondary injury to the wound. The multifunctional fluorescence hydrogel exhibits efficiently promote pro-angiogenesis and bacteria-infected wound healing. A multi-enzyme-like activities nanocomposite (i.e. Mo,Fe/Cu,I-Ag) was designed and anchored onto injectable hydrogels with pH-switchable glucose-initiated cascade reaction to achieve the O 2 self-supplying and the diabetic wound healing. [Display omitted] [ABSTRACT FROM AUTHOR]

The present study aimed at developing an injectable hydrogel based on acacia gum (AG) for wound healing acceleration. The hydrogels were synthetized through metal-ligand coordination mediated by Fe3+ and characterized in terms of gelation time, gel content, initial water content, swelling capacity, water retention ratio, and porosity. Moreover, FTIR, XRD and TGA analyses were performed for the hydrogels and allantoin (Alla) loaded ones. Furthermore, bioadhessiveness, and self-healing as well as antibacterial, toxicity and wound healing potentials of the hydrogels were evaluated. The hydrogels displayed fast gelation time, high swelling, porosity, and bioadhessiveness, as well as antioxidant, self-healing, antibacterial, blood clotting, and injectability properties. FTIR, XRD and TGA analyses confirmed hydrogel synthesis and drug loading. The Alla-loaded hydrogels accelerated wound healing by decreasing the inflammation and increasing the cell proliferation as well as collagen deposition. Hemocompatibility, cell cytotoxicity, and in vivo toxicity experiments were indicative of a high biocompatibility level for the hydrogels. Given the advantages of fast gelation, injectability and beneficial biological properties, the use of Alla-loaded hydrogels could be considered a new remedy for efficient wound healing. [ABSTRACT FROM AUTHOR]

Modulating the inflammatory microenvironment can inhibit the process of inflammatory diseases (IDs). A tri‐cross‐linked inflammatory microenvironment‐responsive hydrogel with ideal mechanical properties achieves triggerable and sustained drug delivery and regulates the inflammatory microenvironment. Here, this study develops an inflammatory microenvironment‐responsive hydrogel (OD‐PP@SeNPs) composed of phenylboronic acid grafted polylysine (PP), oxidized dextran (OD), and selenium nanoparticles (SeNPs). The introduction of SeNPs as initiators and nano‐fillers into the hydrogel results in extra cross‐linking of the polymer network through hydrogen bonding. Based on Schiff base bonds, Phenylboronate ester bonds, and hydrogen bonds, a reactive oxygen species (ROS)/pH dual responsive hydrogel with a triple‐network is achieved. The hydrogel has injectable, self‐healing, adhesion, outstanding flexibility, suitable swelling capacity, optimal biodegradability, excellent stimuli‐responsive active substance release performance, and prominent biocompatibility. Most importantly, the hydrogel with ROS scavenging and pH‐regulating ability protects cells from oxidative stress and induces macrophages into M2 polarization to reduce inflammatory cytokines through PI3K/AKT/NF‐κB and MAPK pathways, exerting anti‐inflammatory effects and reshaping the inflammatory microenvironment, thereby effectively treating typical IDs, including S. aureus infected wound and rheumatoid arthritis in rats. In conclusion, this dynamically responsive injectable hydrogel with a triple‐network structure provides an effective strategy to treat IDs, holding great promise in clinical application. [ABSTRACT FROM AUTHOR]

Bacterial infections and excessive inflammation can impede the healing of wounds. Hydrogels have emerged as a promising approach for dressing bacterial-infected injuries. However, some antibacterial hydrogels are complex, costly, and even require assistance with other instruments such as light, making them unsuitable for routine outdoor injuries. Here, we developed an in-situ generating hydrogel via hybridizing oxidized β -D-glucan with antimicrobial peptide C 8 G 2 through the Schiff base reaction. This hydrogel is easily accessible and actively contributes to the whole healing process of bacterial-infected wounds, demonstrating remarkable antibacterial activity and biological compatibility. The pH-sensitive reversible imine bond enables the hydrogel to self-heal and sustainably release the antibacterial peptide, thereby improving its bioavailability and reducing toxicity. Meanwhile, the immunoregulating β -D-glucan inhibits the release of inflammatory factors while promoting the release of anti-inflammatory factors. In methicillin-resistant Staphylococcus aureus (MRSA)-infected full-thickness skin wound models, the hybrid hydrogel showed superior antibacterial and anti-inflammatory activity, enhanced the M2 macrophage polarization, expedited wound closure, and regenerated epidermis tissue. These features make this hydrogel an appealing wound dressing for treating multi-drug-resistant bacteria-infected wounds. [Display omitted] • The BGA/C 8 G 2 injectable hydrogel can form rapidly in situ. • The hydrogel releases the antibacterial peptide in acidic bacterial infections. • The hydrogel can participate in the entire wound healing process. • The hydrogel accelerates MRSA-infected wound healing without additions. [ABSTRACT FROM AUTHOR]

Abstract Modulating the inflammatory microenvironment can inhibit the process of inflammatory diseases (IDs). A tri‐cross‐linked inflammatory microenvironment‐responsive hydrogel with ideal mechanical properties achieves triggerable and sustained drug delivery and regulates the inflammatory microenvironment. Here, this study develops an inflammatory microenvironment‐responsive hydrogel (OD‐PP@SeNPs) composed of phenylboronic acid grafted polylysine (PP), oxidized dextran (OD), and selenium nanoparticles (SeNPs). The introduction of SeNPs as initiators and nano‐fillers into the hydrogel results in extra cross‐linking of the polymer network through hydrogen bonding. Based on Schiff base bonds, Phenylboronate ester bonds, and hydrogen bonds, a reactive oxygen species (ROS)/pH dual responsive hydrogel with a triple‐network is achieved. The hydrogel has injectable, self‐healing, adhesion, outstanding flexibility, suitable swelling capacity, optimal biodegradability, excellent stimuli‐responsive active substance release performance, and prominent biocompatibility. Most importantly, the hydrogel with ROS scavenging and pH‐regulating ability protects cells from oxidative stress and induces macrophages into M2 polarization to reduce inflammatory cytokines through PI3K/AKT/NF‐κB and MAPK pathways, exerting anti‐inflammatory effects and reshaping the inflammatory microenvironment, thereby effectively treating typical IDs, including S. aureus infected wound and rheumatoid arthritis in rats. In conclusion, this dynamically responsive injectable hydrogel with a triple‐network structure provides an effective strategy to treat IDs, holding great promise in clinical application.

Wound treatment is largely influenced by pre-existing hypoxic microenvironments and biofilms, which can severely diminish the efficacy of phototherapy, suggesting the importance of multifunctional nanoplatforms for synergistic treatment of wound infections. Here, we developed a multifunctional injectable hydrogel (PSPG hydrogel) by loading photothermal sensitive sodium nitroprusside (SNP) into Pt-modified porphyrin metal organic framework (PCN) and in situ modification of gold particles to form a near-infrared (NIR) light-triggered all-in-one phototherapeutic nanoplatform. The Pt-modified nanoplatform exhibits a remarkable catalase-like behavior and promotes the continuous decomposition of endogenous H 2 O 2 into O 2 , thereby enhancing the photodynamic therapy (PDT) effect under hypoxia. Under dual NIR irradiation, PSPG hydrogel can not only produce hyperthermia (η=89.21%) but also generate reactive oxygen species and trigger NO release, contributing jointly to removal of biofilms and disruption of the cell membranes of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli). In vivo experiments demonstrated a 99.9% reduction in bacterial burden on wounds. Additionally, PSPG hydrogel can accelerate MRSA-infected and Pseudomonas aeruginosa -infected (P. aeruginosa -infected) wound healing by promoting angiogenesis, collagen deposition, and suppressing inflammatory responses. Furthermore, in vitro and in vivo experiments revealed that PSPG hydrogel has good cytocompatibility. Overall, we proposed an antimicrobial strategy to eliminate bacteria through the synergistic effects of gas-photodynamic-photothermal killing, alleviating hypoxia in the bacterial infection microenvironment, and inhibiting biofilms, offering a new way against antimicrobial resistance and biofilm-associated infections. The NIR light-triggered multifunctional injectable hydrogel nanoplatform (PSPG hydrogel) based on Pt-decorated gold nanoparticles with sodium nitroprusside (SNP)-loading porphyrin metal organic framework (PCN) as inner templates can efficiently perform photothermal conversion (η=89.21%) to trigger NO release from SNP, while continuously regulating the hypoxic microenvironment at the bacterial infection site through Pt-induced self-oxygenation, achieving efficient sterilization and removal of biofilm by synergistic PDT and PTT phototherapy. In vivo and in vitro experiments demonstrated that the PSPG hydrogel has significant anti-biofilm, antibacterial, and inflammatory regulatory functions. This study proposed an antimicrobial strategy to eliminate bacteria through the synergistic effects of gas-photodynamic-photothermal killing, alleviating hypoxia in the bacterial infection microenvironment, and inhibiting biofilms. [Display omitted] [ABSTRACT FROM AUTHOR]

Overproduction of reactive oxygen species is one of the important reasons of non-healing wounds, such as diabetic wounds. Melatonin is well known as an antioxidant, while the poor solubility limits its use in many areas. In this study, the solubility of melatonin was improved by introducing γ-cyclodextrin to form the composite named MT-γ-CD through ultrasonic process. During this process, the molar ratio of melatonin and γ-cyclodextrin was 2:1, the temperature was set at 30 ℃, and the ultrasonic time was 40 min. The MT-γ-CD showed good antioxidant property in vitro with high free radical scavenging efficiency over 90%. Besides, an injectable self-healing hydrogel was prepared to load with MT-γ-CD to form the wound dressing, here, sodium carboxymethylated cellulose was oxidized to introduce aldehyde groups that could form Schiff base with amino groups in gelatin. This dressing with good biocompatibility could be injected into irregular wounds, suppress the level of reactive oxygen species, and accelerate wound healing of diabetic rats in vivo. Therefore, it has great potential to provide a new treatment strategy for diabetic wounds. [ABSTRACT FROM AUTHOR]

Currently, hydrogels are widely studied for wound dressings. However, wound healing is often hindered by bacterial infection. In this study, in situ cross-linked carboxymethyl chitosan (CMCS)/oxidized dextran (OD)/poly-γ-glutamic acid (γ-PGA) (COP) hydrogel was prepared for antimicrobial and hemostasis of diffuse wounds. In the COP hydrogel, γ-PGA was able to drain the surface moisture of the wound to enhance the surface adhesion. Moreover, γ-PGA could concentrate blood by absorbing plasma, and CMCS could electrostatically adsorb negative RBCs. The antibacterial properties of CMCS and OD endowed the COP hydrogel with certain antibacterial effects. In the inhibition zone experiment, an obvious inhibition zone appeared around the COP hydrogel. In vivo studies showed that the COP hydrogel significantly inhibited bacterial growth and promoted wound healing. In the rat tail diffuse hemorrhage wound model, the COP hydrogel showed superior hemostasis ability. Therefore, the multifunctional COP hydrogel is expected to find different applications in wound hemostasis and healing. [ABSTRACT FROM AUTHOR]

With the development of minimally invasive orthopedics, injectable materials for bone repair are attracted more attention, especially for those wound with a small external mouth and sizeable internal cavity. In this work, the hydrogel with features of thermo-responsiveness, degradability and injectability was designed and fabricated. The hydrogel, named as FHCS, is composed of Pluronic F-127 (F127) loaded with carboxymethyl chitosan/sodium alginate nanoparticles (nCS) and nanohydroxyapatite (nHA). The hydrogel FHCS was non-toxic and good hemocompatible. It can enhance the ALP activity and extracellular matrix calcification of MC3T3-E1 due to the chitosan-based nanoparticle components (nCS). Moreover, FHCS-5 (containing 5 mg/mL nCS) showed relative high expression of osteogenic genes and protein markers. Osteal regeneration was observed treated by FHCS-5 hydrogel in a critical-size rat calvarial bone defect model. CT scanning showed that the whole defect was basically covered by new bone after FHCS-5 hydrogel. The results of H&E staining and Masson's trichrome staining on histological sections further confirmed that FHCS-5 hydrogel promoted new osteal formation and maturation, which up regulated the osteogenic related genes and proteins of ALP, OCN, OPN through BMP/Smad signaling pathway. Hence, this study suggests that FHCS-5 hydrogels have a promising application for non-loading bone regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]