Chronic Diabetic Wound Healing Research Articles

A novel pectic polysaccharide-based hydrogel derived from okra (Abelmoschus esculentus L. Moench) for chronic diabetic wound healing

Hydrogels based on natural polysaccharides represent a growing group of suitable biomaterials for the elaboration of effective wound healing dressings, especially for the treatment of chronic wounds. This work was intended to prepare a polysaccharide-based hydrogel for diabetic wound healing which would help maintain the well-being of diabetes and improve their quality of life. For this purpose, a pectic polysaccharide (OPS) was extracted and purified, for the first time, from Tunisian okra pods and its physicochemical and rheological features, antioxidant and in vivo and in vitro wound healing activities were investigated. OPS, an acidic polysaccharide with a molecular weight of 3.28 × 106 Da and a polydispersity index of 1.03, was mainly composed of galactose (24.45 %), galacturonic acid (24.6 %) and rhamnose (18.25 %). Combined with FT-IR and NMR analyses, it consisted of a pectic rhamnogalacturonan I (RG-I) structure with galactan side chains. The OPS demonstrated antioxidant potential, gelling ability, cytocompatibility properties, non-cytotoxicity and cell migration and proliferation promoting activities, which met the requirements for wound dressings. Then, the in vivocutaneous wound healing effect of OPS-based hydrogel was investigated using an alloxan-induced diabetic rat model, and results showed that it significantly accelerated the wound healing process by acting in the acceleration of the recovery of the dermis and inducing moreblood vessels formationand tissue granulation.Overall, these results provide new insights into the development of a promising and effective okra pectin-based hydrogel for the treatment of chronic diabetic wounds.

Collagen scaffolds derived from bovine skin loaded with MSC optimized M1 macrophages remodeling and chronic diabetic wounds healing.

Owing to the persistent inflammatory microenvironment and unsubstantial dermal tissues, chronic diabetic wounds do not heal easily and their recurrence rate is high. Therefore, a dermal substitute that can induce rapid tissue regeneration and inhibit scar formation is urgently required to address this concern. In this study, we established biologically active dermal substitutes (BADS) by combining novel animal tissue-derived collagen dermal-replacement scaffolds (CDRS) and bone marrow mesenchymal stem cells (BMSCs) for the healing and recurrence treatments of chronic diabetic wounds. The collagen scaffolds derived from bovine skin (CBS) displayed good physicochemical properties and superior biocompatibility. CBS loaded with BMSCs (CBS-MCSs) could inhibit M1 macrophage polarization in vitro. Decreased MMP-9 and increased Col3 at the protein level were detected in CBS-MSCs-treated M1 macrophages, which may be attributed to the suppression of the TNF-α/NF-κB signaling pathway (downregulating phospho-IKKα/β/total IKKα/β, phospho-IκB/total IκB, and phospho-NFκB/total NFκB) in M1 macrophages. Moreover, CBS-MSCs could benefit the transformation of M1 (downregulating iNOS) to M2 (upregulating CD206) macrophages. Wound-healing evaluations demonstrated that CBS-MSCs regulated the polarization of macrophages and the balance of inflammatory factors (pro-inflammatory: IL-1β, TNF-α, and MMP-9; anti-inflammatory: IL-10 and TGF-β3) in db/db mice. Furthermore, CBS-MSCs facilitated the noncontractile and re-epithelialized processes, granulation tissue regeneration, and neovascularization of chronic diabetic wounds. Thus, CBS-MSCs have a potential value for clinical application in promoting the healing of chronic diabetic wounds and preventing the recurrence of ulcers.

Single-cell RNA-Seq analysis of diabetic wound macrophages in STZ-induced mice

The crucial role of macrophages in the healing of chronic diabetic wounds is widely known, but previous in vitro classification and marker genes of macrophages may not be fully applicable to cells in the microenvironment of chronic wounds. The heterogeneity of macrophages was studied and classified at the single-cell level in a chronic wound model. We performed single-cell sequencing of CD45 + immune cells within the wound edge and obtained 17 clusters of cells, including 4 clusters of macrophages. One of these clusters is a previously undescribed population of macrophages possessing osteoclast gene expression, for which analysis of differential genes revealed possible functions. We also analysed the differences in gene expression between groups of macrophages in the control and diabetic wound groups at different sampling times. We described the differentiation profile of mononuclear macrophages, which has provided an important reference for the study of immune-related mechanisms in diabetic chronic wounds.Graphical

Chiral Supramolecular Hydrogel Loaded with Dimethyloxalyglycine to Accelerate Chronic Diabetic Wound Healing by Promoting Cell Proliferation and Angiogenesis.

Chronic refractory wounds are one of the most serious complications of diabetes, and the effects of common treatments are limited. Chiral hydrogel combined with dimethyloxalyglycine (DMOG) as a dressing is a promising strategy for the treatment of chronic wounds. In this research, we have developed a DMOG-loaded supramolecular chiral amino-acid-derivative hydrogel for wound dressings for full-thickness skin regeneration of chronic wounds. The properties of the materials, the ability of sustained release drugs, and the ability to promote angiogenesis were tested in vitro, and the regeneration rate and repair ability of full-thickness skin were tested in vivo. The chiral hydrogel had the ability to release drugs slowly. It can effectively promote cell migration and angiogenesis in vitro, and promote full-thickness skin regeneration and angiogenesis in vivo. This work offers a new approach for repairing chronic wounds completely through a supramolecular chiral hydrogel loaded with DMOG.

Bioactive Injectable Hydrogel Dressings for Bacteria-Infected Diabetic Wound Healing: A "Pull-Push" Approach.

Chronic diabetic wound healing remains a challenge due to the existence of excessive danger molecules and bacteria in the inflammatory microenvironment. There is an urgent need for advanced wound dressings that target both inflammation and infection. Here, a bioactive hydrogel without loading any anti-inflammatory ingredients is rationally designed to achieve a "Pull-Push" approach for efficient and safe bacteria-infected diabetic wound healing by integrating danger molecule scavenging (Pull) with antibiotic delivery (Push) in the inflammatory microenvironment. The cationic hydrogel, termed the OCMC-Tob/PEI hydrogel, is fabricated by the conjugation of polyethylenimine (PEI) and tobramycin (Tob) on an oxidized carboxymethyl cellulose (OCMC) backbone via the Schiff base reaction with injectable, self-healing, and biocompatible properties. The OCMC-Tob/PEI hydrogel not only displays the remarkable capability of capturing multiple negatively charged danger molecules (e.g., cell-free DNA, lipopolysaccharides, and tumor necrosis factor-α) to ameliorate anti-inflammation effects but also achieves controllable long-term antibacterial activity by the pH-sensitive release of Tob. Consequently, this multifunctional hydrogel greatly expedites the wound closure rate with combined anti-inflammation and anti-infection effects on Pseudomonas aeruginosa-infected diabetic wounds. Our work provides a highly versatile treatment approach for chronic diabetic wounds and a promising dressing for regenerative medicine.

Glucose/ROS cascade-responsive ceria nanozymes for diabetic wound healing.

Diabetic wounds have an extremely complex microenvironment of hyperglycemia, hypoxia and high reactive oxygen species (ROS). Therefore, the regulation and management of this microenvironment may provide a new and improved treatment method for chronic diabetic wound healing. Herein, a glucose/ROS cascade-responsive nanozyme (CHA@GOx) was developed for diabetic wound treatment based on Ce-driven coassembly by a special dual ligand (alendronic acid and 2-methylimidazole) and glucose oxidase (GOx). It possesses superoxide dismutase and catalase mimic activities, which effectively remove excess ROS. In particular, it can catalyze excessive hydrogen peroxide generated by the glucose oxidation reaction to produce oxygen, regulate the oxygen balance of the wound, and reduce the toxic side effects of GOx, thus achieving the purpose of synergistically repairing diabetic wounds. In vitro experiments show that CHA@GOx assists mouse fibroblast migration and promotes human umbilical vein endothelial cell tube formation. In vivo, it can induce angiogenesis, collagen deposition, and re-epithelialization during wound healing in diabetic mice. Taken together, this study indicates that the coassembly of multifunctional nanozymes has implications in diabetic wound healing.

HUC-MSCs lyophilized powder loaded polysaccharide ulvan driven functional hydrogel for chronic diabetic wound healing

In this study, we used the polysaccharide ulvan from the green macroalgae Ulva fenestrata to prepare the hydrogel for chronic diabetic wound healing. A natural polysaccharide-based hydrogel matrix (UC-DPA-Ag hydrogel) was prepared using ulvan dialdehyde, chitosan, dopamine (DPA) and silver nanoparticles (Ag NPs). Human umbilical cord mesenchymal stem cell lyophilized powder (hUC-MSCs) was loaded into the hydrogel to develop a novel chronic diabetic wound healing material (UC-DPA-Ag@hUC-MSCs). The resulting hydrogel features adequate mechanical properties, swelling capability, adhesiveness, antioxidant, antibacterial ability, and promoting cell proliferation and migration. In vivo wound healing in type II diabetic mellitus mouse wound model showed that hUC-MSCs loaded UC-DPA-Ag hydrogel could accelerate wound healing effectively. This advanced hydrogel provides a facile and effective way for diabetic chronic wound management. Furthermore, it offers a new route for the utilizing Ulva as a valuable biomaterial for the global and large-scale production of valued added biomaterials.

Dual Spinneret Electrospun Polyurethane/PVA-Gelatin Nanofibrous Scaffolds Containing Cinnamon Essential Oil and Nanoceria for Chronic Diabetic Wound Healing: Preparation, Physicochemical Characterization and In-Vitro Evaluation.

In this study, a dual spinneret electrospinning technique was applied to fabricate a series of polyurethane (PU) and polyvinyl alcohol–gelatin (PVA/Gel) nanofibrous scaffolds. The study aims to enhance the properties of PU/PVA-Gel NFs loaded with a low dose of nanoceria through the incorporation of cinnamon essential oil (CEO). The as-prepared nCeO2 were embedded into the PVA/Gel nanofibrous layer, where the cinnamon essential oil (CEO) was incorporated into the PU nanofibrous layer. The morphology, thermal stability, mechanical properties, and chemical composition of the produced NF mats were investigated by STEM, DSC, and FTIR. The obtained results showed improvement in the mechanical, and thermal stability of the dual-fiber scaffolds by adding CEO along with nanoceria. The cytotoxicity evaluation revealed that the incorporation of CEO to PU/PVA-Gel loaded with a low dose of nanoceria could enhance the cell population compared to using pure PU/PVA-Gel NFs. Moreover, the presence of CEO could inhibit the growth rate of S. aureus more than E. coli. To our knowledge, this is the first time such nanofibrous membranes composed of PU and PVA-Gel have been produced. The first time was to load the nanofibrous membranes with both CEO and nCeO2. The obtained results indicate that the proposed PU/PVA-Gel NFs represent promising platforms with CEO and nCeO2 for effectively managing diabetic wounds.

Potential Use of Topical Insulin in Chronic Diabetic Wound Healing

Wound healing disturbances that occur in chronic diabetic wounds result in various complications and cause a significant burden. With the increasing prevalence of diabetes mellitus, it is estimated that the numbers of chronic diabetic wounds and their complications will also continue to increase. One of the latest managements using growth factors for chronic diabetic wounds gives satisfactory results, but their use is still limited because of the high costs. This study aims to explore the effectiveness of using topical insulin as a cheaper and effective alternative therapy in chronic diabetic wounds. The method of this study is a literature review sourced from Google Scholar and ProQuest search engine. Eight articles were obtained that are relevant to be discussed in this study. According to studies conducted so far, topical insulin can improve wound healing through the modulation of inflammation and insulin signaling pathways. In conclusion, there is improved wound healing in diabetic chronic wounds patients that were given topical insulin. Therefore topical insulin should be considered as part of chronic diabetic wounds management.
 Keywords: wound healing; chronic diabetic wounds; growth factors; topical insulin

A multifunctional antibacterial and self-healing hydrogel laden with bone marrow mesenchymal stem cell-derived exosomes for accelerating diabetic wound healing

Chronic diabetic wound injury is a serious syndrome of diabetes, and the treatment of this syndrome is of great significance. Owing to metabolic abnormalities, diabetic wounds are difficult to heal due to chronic inflammation, immune dysfunction, impaired angiogenesis and bacterial reproduction. However, most traditional treatments can only play a limited role in dealing with unhealed wounds, and the overall healing effect is not ideal. We designed a novel bone marrow mesenchymal stem cell-derived exosome (MSC-Exo)-loaded carboxyethyl chitosan (CEC)-dialdehyde carboxymethyl cellulose (DCMC) hydrogel (MSC-Exos@CEC-DCMC HG) for chronic diabetic wound healing. The results demonstrated that CEC can be cross-linked with DCMC through Schiff base reactions to form antibacterial and self-healing hydrogels. The inherent MSC-Exos not only promoted angiogenesis but also enhanced the transformation of M1-type macrophages to the M2 type to reduce inflammatory effects. Finally, MSC-Exos@CEC-DCMC HG, as an effective therapeutic agent, synergistically adjusted the wound inflammation microenvironment, promoted neovascularization, and accelerated wound healing in type 1 diabetic rats.

Novel dopamine-modified oxidized sodium alginate hydrogels promote angiogenesis and accelerate healing of chronic diabetic wounds

Herein, the dopamine (DA) was grafted with oxidized sodium alginate (OSA) via Schiff base reduction reaction, aiming to fabricate novel DA-grafted OSA (OSA-DA) hydrogels with enhanced biocompatibility and suitable adhesion for clinical applications. The chemical structures of OSA-DA were characterized via UV–Vis, FTIR and 1H NMR spectroscopy analysis. The hydrogel characteristics, biocompatibility, as well as the chronic diabetic wound healing efficacy were investigated. Our results demonstrated that DA was grafted with OSA successfully with highest grafting rate of 7.50%. Besides, OSA-DA hydrogels possessed suitable swelling ratio and appropriate adhesion characteristics. Additionally, OSA-DA exhibited satisfactory cytocompatibility and cell affinity in L-929 cells, and superior biocompatibility in SD rats. Moreover, OSA-DA exerted remarkable promoting effects on migration and tube formation of human umbilical vein endothelial cells (HUVECs). Studies on full-thickness excision chronic diabetic wounds further revealed that OSA-DA hydrogels could accelerate healing via promoting angiogenesis, reducing inflammation response, and stimulating collagen deposition. Overall, our studies would provide basis for SA-based hydrogels as clinical wound dressings.

Glucose and MMP-9 dual-responsive hydrogel with temperature sensitive self-adaptive shape and controlled drug release accelerates diabetic wound healing.

Chronic diabetic wounds are an important healthcare challenge. High concentration glucose, high level of matrix metalloproteinase-9 (MMP-9), and long-term inflammation constitute the special wound environment of diabetic wounds. Tissue necrosis aggravates the formation of irregular wounds. All the above factors hinder the healing of chronic diabetic wounds. To solve these issues, a glucose and MMP-9 dual-response temperature-sensitive shape self-adaptive hydrogel (CBP/GMs@Cel&INS) was designed and constructed with polyvinyl alcohol (PVA) and chitosan grafted with phenylboric acid (CS-BA) by encapsulating insulin (INS) and gelatin microspheres containing celecoxib (GMs@Cel). Temperature-sensitive self-adaptive CBP/GMs@Cel&INS provides a new way to balance the fluid-like mobility (self-adapt to deep wounds quickly, approximately 37 °C) and solid-like elasticity (protect wounds against external forces, approximately 25 °C) of self-adaptive hydrogels, while simultaneously releasing insulin and celecoxib on-demand in the environment of high-level glucose and MMP-9. Moreover, CBP/GMs@Cel&INS exhibits remodeling and self-healing properties, enhanced adhesion strength (39.65 ± 6.58 kPa), down-regulates MMP-9, and promotes cell proliferation, migration, and glucose consumption. In diabetic full-thickness skin defect models, CBP/GMs@Cel&INS significantly alleviates inflammation and regulates the local high-level glucose and MMP-9 in the wounds, and promotes wound healing effectively through the synergistic effect of temperature-sensitive shape-adaptive character and the dual-responsive system.

Exosome/Metformin-Loaded Self-Healing Conductive Hydrogel Rescues Microvascular Dysfunction and Promotes Chronic Diabetic Wound Healing by Inhibiting Mitochondrial Fission

Exosome/Metformin-Loaded Self-Healing Conductive Hydrogel Rescues Microvascular Dysfunction and Promotes Chronic Diabetic Wound Healing by Inhibiting Mitochondrial Fission

Macrophage polarization in diabetic wound healing.

Impaired wound healing is one of the severe complications of diabetes. Macrophages have been shown to play a vital role in wound healing. In different wound environments, macrophages are classified into two phenotypes: classically activated macrophages and alternatively activated macrophages. Dysregulation of macrophage phenotypes leads to severely impaired wound healing in diabetes. Particularly, uncontrolled inflammation and abnormal macrophage phenotype are important reasons hindering the closure of diabetic wounds. This article reviews the functions of macrophages at various stages of wound healing, the relationship between macrophage phenotypic dysregulation and diabetic wound healing and the mechanism of macrophage polarization in diabetic wound healing. New therapeutic drugs targeting phagocyte polarization to promote the healing of diabetic wounds might provide a new strategy for treating chronic diabetic wound healing.

Synergistic Effects of Photobiomodulation Therapy with Combined Wavelength on Diabetic Wound Healing In Vitro and In Vivo.

Objective: The difficulty in chronic diabetic wound healing remains the focus of clinical research. Photobiomodulation therapy (PBMT) with different wavelengths could exert different effects on wound healing, but the effects of combined red and blue light (BL) remained unclear. Methods: Diabetic rat wound model and diabetic wounded endothelial cell model were established to observe possible effects of PBMT using combined wavelengths for wound healing. Cells and animals were separated into four groups exposed to red and/or BL. Cell viability, apoptosis, and migration, as well as the expression level of nitric oxide (NO), vascular endothelial growth factor, interleukin-6, and tumor necrosis factor-α were measured in vitro. Diabetic rats were evaluated for wound closure rates, collagen deposition, inflammation intensity, and density of neovascularization after light irradiation. Results: PBMT using combined wavelengths significantly sped up the healing process with increasing angiogenesis density, collagen deposition, and alleviating inflammation in vivo. Moreover, combined wavelength irradiation promoted cell proliferation and migration, and NO production, as well as reduced reactive oxygen species and inflammation in vitro. Conclusions: PBMT using combined wavelengths performed a synergistic effect for promoting diabetic wound healing and would be helpful to explore a more efficient pattern toward chronic wound healing.

Ultrashort Peptides and Hyaluronic Acid-Based Injectable Composite Hydrogels for Sustained Drug Release and Chronic Diabetic Wound Healing.

Peptide hydrogels are widely used for biomedical applications owing to their good biocompatibility and unique advantages in terms of amino acid-based structures and functions. However, the exploration of the peptide/saccharide composite hydrogels as potential biomaterials for chronic diabetic wound healing is still limited. Herein, hyaluronic acid (HA) was incorporated into diphenylalanine (FF) conjugated with different aromatic moieties by a one-pot reaction. Our results showed that the dipeptide derivatives modified by benzene (B), naphthalene (N), and pyrene (P) self-assembled into composite hydrogels with uniform distribution and good mechanical properties in the presence of HA. The obtained N-FF/HA composite hydrogel exhibited greatly improved self-healing properties via injection syringe needle operation and good biocompatibility on human skin fibroblast (HSF) cells. Besides, the structure of thinner nanofibers and honeycomb networks inside the composite hydrogel allowed for a longer sustained release of curcumin, a hydrophobic drug for anti-inflammation and wound healing. The curcumin-loaded N-FF/HA composite hydrogels could promote chronic wound healing in the streptozotocin-induced type I diabetic mouse model. The results suggested that our developed saccharide-peptide hydrogels could serve as very promising synthetic biomaterials for applications in both drug delivery and wound healing in the future.

An NIR-Triggered Au Nanocage Used for Photo-Thermo Therapy of Chronic Wound in Diabetic Rats Through Bacterial Membrane Destruction and Skin Cell Mitochondrial Protection.

Bacterial infection and its severe oxidative stress reaction will cause damage to skin cell mitochondria, resulting in long-lasting wound healing and great pain to patients. Thus, delayed wound healing in diabetic patients with Staphylococcus aureus infection is a principal challenge worldwide. Therefore, novel biomaterials with multifunction of bacterial membrane destruction and skin cell mitochondrial protection are urgently needed to be developed to address this challenge. In this work, novel gold cage (AuNCs) modified with epigallocatechin gallate (EGCG) were prepared to treat delayed diabetic wounds. The results showed that Au-EGCG had a high and stable photothermal conversion efficiency under near-infrared irradiation, and the scavenging rate of Au-EGCG for S. aureus could reach 95%. The production of large amounts of reactive oxygen species (ROS) leads to the disruption of bacterial membranes, inducing bacterial lysis and apoptosis. Meanwhile, Au-EGCG fused into hydrogel (Au-EGCG@H) promoted the migration and proliferation of human umbilical cord endothelial cells, reduced cellular mitochondrial damage and oxidative stress in the presence of infection, and significantly increased the basic fibroblast growth factor expression and vascular endothelial growth factor. In addition, animal studies showed that wound closure was 97.2% after 12 days of treatment, and the healing of chronic diabetic wounds was significantly accelerated. Au-EGCG nanoplatforms were successfully prepared to promote cell migration and angiogenesis in diabetic rats while removing S. aureus, reducing oxidative stress in cells, and restoring impaired mitochondrial function. Au-EGCG provides an effective, biocompatible, and multifunctional therapeutic strategy for chronic diabetic wounds.

Peptide Inhibitor of Complement C1, RLS-0071, Reduces Zosteriform Spread of Herpes Simplex Virus Type 1 Skin Infection and Promotes Survival in Infected Mice.

Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen primarily transmitted through skin-to-skin contact, especially on and around mucosal surfaces where there is contact with contaminated saliva during periods of viral shedding. It is estimated that 90% of adults worldwide have HSV-1 antibodies. Cutaneous HSV-1 infections are characterized by a sensation of tingling or numbness at the initial infection site followed by an eruption of vesicles and then painful ulcers with crusting. These symptoms can take ten days to several weeks to heal, leading to significant morbidity. Histologically, infections cause ballooning degeneration of keratinocytes and formation of multinucleated giant cells, ultimately resulting in a localized immune response. Commonly prescribed treatments against HSV-1 infections are nucleoside analogs, such as acyclovir (ACV). However, the emergence of ACV-resistant HSV (ACVR-HSV) clinical isolates has created an urgent need for the development of compounds to control symptoms of cutaneous infections. RLS-0071, also known as peptide inhibitor of complement C1 (PIC1), is a 15-amino-acid anti-inflammatory peptide that inhibits classical complement pathway activation and modulates neutrophil activation. It has been previously shown to aid in the healing of chronic diabetic wounds by inhibiting the excessive activation of complement component C1 and infiltration of leukocytes. Here, we report that treatment of cutaneous infections of HSV-1 and ACVR-HSV-1 in BALB/cJ mice with RLS-0071 significantly reduced the rate of mortality, decreased zosteriform spread, and enhanced the healing of the infection-associated lesions compared to control-treated animals. Therefore, RLS-0071 may work synergistically with other antiviral drugs to aid in wound healing of HSV-1 cutaneous infection and may potentially aid in rapid wound healing of other pathology not limited to HSV-1.

Bioinspired Conductive Silk Microfiber Integrated Bioelectronic for Diagnosis and Wound Healing in Diabetes

AbstractIdeal epidermal bioelectronics can be used not only for long‐term detection of physiological signals for disease diagnosis but also for chronic disease treatment. Silk, an animal‐derived fiber with good biocompatibility and skin‐affinity, is widely used in flexible bioelectronics. However, silk fibers are insulating. In this study, ultralong conductive silk microfibers (mSFs) are fabricated by extracting mSF from raw silk using a bioinspired extraction‐protection process with the assistance of polydopamine, followed by deposition of poly(3,4‐ethylenedioxythiophene) (PEDOT) on its surface. The conductive mSFs are produced and used to fabricate a conductive flexible silk fibroin patch, which is used as a conformable bioelectronic for monitoring physiological signals. In addition, as the conductive mSF possessed anti‐oxidative activity, the patch exhibits excellent performance in chronic diabetic wound healing by reducing inflammation and regulating oxidative stress. Thus, this bioinspired strategy produces conductive silk fibers that can be used as biocompatible building blocks, opening new avenues for employing passive silk as an active component in the design of epidermal wound repair biomaterials and next‐generation flexible epidermal bioelectronics.

Dual-crosslinked mussel-inspired smart hydrogels with enhanced antibacterial and angiogenic properties for chronic infected diabetic wound treatment via pH-responsive quick cargo release

The healing of chronic diabetic wounds remains a key challenge due to its susceptibility to bacterial infection, the inflammatory wound microenvironment, and difficulty in angiogenesis. Herein, a pH-responsive, mussel-inspired, double-crosslinking injectable, and adhesive smart hydrogel formula was exploited to overcome these obstacles simultaneously. The multifunctional double-crosslinking hydrogel was developed through the formation of catechol-catechol adducts and a Schiff-based reaction between amino groups (−NH2) in chitosan quaternary ammonium salt (HTCC) and aldehyde groups (–CHO) in oxidized dextran-dopamine (OD-DA). The double-crosslinking mechanism gave the hydrogels great mechanical properties. Most importantly, via the effective encapsulation of silver nanoparticles (AgNPs) and pro-angiogenic drug deferoxamine (DFO), the hydrogel was given with antibacterial and angiogenic features respectively. At the infected diabetic wound area, the double Schiff base bonds (DA and OD; HTCC and OD-DA) in the hydrogels could quickly achieve pH-response and accomplish a sustained and controlled release of drugs to accelerate wound healing. Through the combination of AgNPs and HTCC, the hydrogel exhibited antimicrobial capacities to gram-positive bacteria (S. aureus) and gram-negative bacteria (E. coli), it did not cause toxic side effects and avoided drug resistance. The DFO released at the infected diabetic wound area promoted angiogenesis by enhancing the expression of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF). We elucidated the mechanisms by which the designed hydrogels accelerated the healing of bacterial infected diabetic wounds in vitro and in vivo, and our hydrogels represented a general strategy for the healing of a wide range of tissue injuries.