Diabetic Wound Research Articles

Chitin-Assisted Synthesis of CuS Composite Sponge for Bacterial Capture and Near-Infrared-Promoted Healing of Infected Diabetic Wounds.

Diabetic wounds are prone to recurrent infections, often leading to delayed healing. To address this challenge, we developed a chitin-copper sulfide (CuS@CH) composite sponge, which combines bacterial trapping with near-infrared (NIR) activated phototherapy for treating infected diabetic wounds. CuS nanoparticles were synthesized and incorporated in situ within the sponge using a chitin assisted biomineralization strategy. The positively charged chitin surface effectively adhered bacteria, while NIR irradiation of CuS generated reactive oxygen species (ROS) heat and Cu2+ to rapidly damage the trapped bacteria. This synergistic effect resulted in an exceptional antibacterial performance against E. coli (∼99.9%) and S. aureus (∼99.3%). The bactericidal mechanism involved NIR-induced glutathione oxidation, membrane lipid peroxidation, and increased membrane permeability. In diabetic mouse models, the CuS@CH sponge accelerated the wound healing of S. aureus infected wounds by facilitating collagen deposition and reducing inflammation. Furthermore, the sponge demonstrated good biocompatibility. This dual-functional platform integrating bacterial capture and NIR-triggered phototherapy shows promise as an antibacterial wound dressing to promote healing of infected diabetic wound.

Single-cell RNA-seq in diabetic foot ulcer wound healing.

Diabetic foot ulcer (DFU) is a chronic and serious complication of diabetes mellitus. It is mainly caused by hyperglycaemia, diabetic peripheral vasculopathy and diabetic peripheral neuropathy. These conditions result in ulceration of foot tissues and chronic wounds. If left untreated, DFU can lead to amputation or even endanger the patient's life. Single-cell RNA sequencing (scRNA-seq) is a technique used to identify and characterise transcriptional subpopulations at the single-cell level. It provides insight into cellular function and the molecular drivers of disease. The objective of this paper is to examine the subpopulations, genes and molecules of cells associated with chronic wounds of diabetic foot by using scRNA-seq. The paper aims to explore the wound-healing mechanism of DFU from three aspects: inflammation, angiogenesis and extracellular matrix remodelling. The goal is to gain a better understanding of the mechanism of DFU wound healing and identify possible DFU therapeutic targets, providing new insights for the application of DFU personalised therapy.

Hyaluronic Acid/Gelatin-Based Multifunctional Bioadhesive Hydrogel Loaded with a Broad-Spectrum Bacteriocin for Enhancing Diabetic Wound Healing.

The development of multifunctional wound adhesives is critical in clinical settings due to the scarcity of dressings with effective adhesive properties while protecting against infection by drug-resistant bacteria. Polysaccharide and gelatin-based hydrogels, known for their biocompatibility and bioactivity, assist in wound healing. This study introduces a multifunctional bioadhesive hydrogel developed through dynamic covalent bonding and light-triggered covalent bonding, comprising oxidized hyaluronic acid, methacrylated gelatin, and the bacteriocin recently discovered by our lab, named jileicin (JC). The adhesion strength of the hydrogel, measured at 180 kPa, was 4.35 times higher than that of the fibrin glue. Furthermore, the hydrogel demonstrated robust platelet adhesion, procoagulant activity, and outstanding hemostatic properties in a mouse liver injury model. Incorporating JC significantly enhanced the phagocytosis and bactericidal capabilities of the macrophages. This immunomodulatory function on host cells, coupled with its potent bacterial membrane-disrupting ability, makes JC an effective killer against methicillin-resistant Staphylococcus aureus. In wound repair experiments on diabetic mice with infected full-thickness skin defects, the hydrogel treatment group showed a notable reduction in bacterial load, accelerated M2-type macrophage polarization, diminished inflammation, and hastened wound healing. Owing to its outstanding biocompatibility, antibacterial activity, and controlled adhesion, this hydrogel presents a promising therapeutic option for treating infected skin wounds.

Non-releasing poly (ionic liquid) based hydrogel accelerates diabetic wound healing

Persistent bacterial colonization, abnormal inflammatory responses, and impaired angiogenesis pose significant challenges to effective wound repair, particularly in diabetic wounds. Employing exogenous bioactive substances in wound dressings is a recognized approach to dynamically respond to the wound microenvironment and accelerate the repair process. However, this strategy can lead to the development of drug resistance and induce further tissue damage. To address these challenges, we are synthesizing a novel hydrogel for diabetic wound treatment using functional poly (ionic liquid) and modified dextran. The hydrogel is characterized by its excellent tissue adhesion, exceptional self-healing capacity, and substantial compressive deformation. It exhibits broad antibacterial activity, reduces the expression of pro-inflammatory cytokines and enhances the healing in diabetic wounds. Its efficacy is superior to that of the positive control group. This innovative non-releasing hydrogel presents as a promising alternative to conventional antibiotics, offering significant potential for the treatment and healing of diabetic chronic wounds.

Modulatory Effects of 830 nm on Diabetic Wounded Fibroblast Cells: An In Vitro Study on Inflammatory Cytokines.

Background:After skin damage, a complicated set of processes occur for epidermal and dermal wound healing. This process is hindered under diabetic conditions, resulting in nonhealing diabetic ulcers. In diabetes there is an increase in inflammation and proinflammatory cytokines. Modulating cells using photobiomodulation (PBM) may have an effect on inflammation and cell viability, which are crucial for the healing of wounds. Objective: This study explored the impact of PBM in the near-infrared spectrum (830 nm; 5 J/cm2) on inflammation in diabetic wound healing. Materials and Methods: Five cell models, namely normal, wounded, diabetic, diabetic wounded, and wounded with d-galactose were used. Cell morphology and migration rate were assessed, while cellular response measures included viability (Trypan blue and adenosine triphosphate), apoptosis (annexin-V/PI), proinflammatory cytokines interleukin-6, tumor necrosis factor-alpha (TNF-α), and cyclooxygenase-2, nuclear translocation of nuclear factor kappa B (NF-κB), and gene expression of advanced glycation end product receptor (AGER). Results: PBM resulted in increased levels of TNF-α, supported by activation of NF-κB. PBM stimulated translocation of NF-κB and upregulation of AGER. Conclusions: PBM modulates diabetic wound healing in vitro at 830 nm through stimulated NF-κB signaling activated by TNF-α.

Multifunctional Silver‐Enzyme Nanogels Assembly with Efficient Trienzyme Cascades for Synergistic Diabetic Wound Healing

AbstractDiabetic wound healing presents a persistent clinical challenge, often characterized by prolonged healing times, and can be particularly difficult to achieve in a hyperglycemic environment. In this study, a multi‐functional silver‐enzyme nanogels assembly (Ag‐nGHC) is designed by focusing on the complex diabetic wound environment. Glucose oxidase (GOX), horseradish peroxidase (HRP), and catalase (CAT) are modified within polymeric nanogel layers and assembled into a large enzyme cluster with silver ions. The close attachment of three enzymes ensures fast and continuous consumption of a high level of glucose, generation of oxygen, and hydroxyl radicals (•OH) around the wound site. Meanwhile, the silver ions within the Ag‐nGHC assembly act as an effective agent to kill bacteria. This cascade enzyme system significantly improves the microenvironment of the wound site by reducing bacterium infection and alleviating hypoxia as well as hyperglycemia. Sequentially, the improved environment facilitates the later processes including anti‐inflammatory, re‐epithelialization, and angiogenesis, evidenced by enhancing polarization toward M2 macrophages and increasing CD31 signals in this study. Overall, the Ag‐nGHC materials are proven to achieve multifunctional properties toward complicated diabetic wound healing processes (attributes such as adaptability, hypoxia‐alleviated, anti‐hyperglycemic, antimicrobial, anti‐inflammatory, and angiogenic) and showed great potential for the treatment of chronic diabetic wound.

Photothermal and Antibacterial PDA@Ag/SerMA Microneedles for Promoting Diabetic Wound Repair.

Diabetic foot ulcer (DFU) is a common and severe complication of diabetes characterized by wound neuropathy, ischemia, and susceptibility to infection, making its treatment difficult. Dressings are commonly used in treating diabetic wounds; however, they have disadvantages, including lack of flexibility and mechanical strength, lack of coagulation activity, resistance to biodegradation, and low drug delivery efficiency. Developing more effective strategies for diabetic wound treatment has become a new focus. Microneedles (MN) can be used as a drug delivery platform for DFU wounds, allowing safe, effective, painless and minimally invasive medication administration through the skin. Herein, PDA@Ag/SerMA microneedles were prepared by combining the photothermal properties of polydopamine (PDA), the antimicrobial properties of argentum (Ag), and the ability of sericin methacryloyl (SerMA) to promote cell mitosis to accelerate wound healing and treat diabetic ulcer wounds. The results revealed that PDA@Ag/SerMA microneedles exhibited approximately 100% antimicrobial efficacy against Staphylococcus aureus and Escherichia coli under 808 nm near-infrared (NIR) irradiation. Furthermore, the wound healing rate of mice reached 95% within 12 days, which demonstrated the excellent antibacterial properties and wound healing efficacy of PDA@Ag/SerMA microneedles at cellular and animal levels, providing a potential solution for treating DFU.

Ultrasound-Responsive HBD Peptide Hydrogel with Antibiofilm Capability for Fast Diabetic Wound Healing.

Despite advancements in therapeutic agents for diabetic chronic wounds, challenges such as suboptimal bioavailability, intricate disease milieus, and inadequate delivery efficacy have impeded treatment outcomes. Here, ultrasound-responsive hydrogel incorporated with heparin-binding domain (HBD) peptide nanoparticles is developed to promote diabetic wound healing. HBD peptide, derived from von Willebrand Factor with angiogenic activity, are first engineered to self-assemble into nanoparticles with enhanced biostability and bioavailability. Ultrasound responsive cargo release and hydrogel collapses are first verified through breakage of crosslinking. In addition, desired antioxidant and antibacterial activity of such hydrogel is observed. Moreover, the degradation of hydrogel under ultrasound stimulation into smaller fragments facilitated the deeper wound penetration of ≈400 µm depth. Complete wound closure is observed from diabetic mice with chronic wounds after being treated with the proposed hydrogel. In detail, in vivo studies revealed that hydrogels loaded with HBD peptide nanoparticles increased the levels of angiogenesis-related growth factors (VEGF-A, CD31, and α-SMA) to effectively accelerate wound repair. Overall, this study demonstrates that ultrasound-responsive HBD peptide hydrogel provides a synergistic therapeutic strategy for external biofilm elimination and internal effective delivery for diabetic wounds with biofilm infection.

Combination Strategy of Two Hydrogels Loaded with Prussian Blue Nanoparticles and Calcium Peroxide Separately for Diabetic Wound Repair

Combination Strategy of Two Hydrogels Loaded with Prussian Blue Nanoparticles and Calcium Peroxide Separately for Diabetic Wound Repair

Bioinspired Collagen Scaffold Loaded with bFGF-Overexpressing Human Mesenchymal Stromal Cells Accelerating Diabetic Skin Wound Healing via HIF-1 Signal Pathway Regulated Neovascularization.

The healing of severe chronic skin wounds in chronic diabetic patients is still a huge clinical challenge due to complex regeneration processes and control signals. Therefore, a single approach is difficult in obtaining satisfactory therapeutic efficacy for severe diabetic skin wounds. In this study, we adopted a composite strategy for diabetic skin wound healing. First, we fabricated a collagen-based biomimetic skin scaffold. The human basic fibroblast growth factor (bFGF) gene was electrically transduced into human umbilical cord mesenchymal stromal cells (UC-MSCs), and the stable bFGF-overexpressing UC-MSCs (bFGF-MSCs) clones were screened out. Then, an inspired collagen scaffold loaded with bFGF-MSCs was applied to treat full-thickness skin incision wounds in a streptozotocin-induced diabetic rat model. The mechanism of skin damage repair in diabetes mellitus was investigated using RNA-Seq and Western blot assays. The bioinspired collagen scaffold demonstrated good biocompatibility for skin-regeneration-associated cells such as human fibroblast (HFs) and endothelial cells (ECs). The bioinspired collagen scaffold loaded with bFGF-MSCs accelerated the diabetic full-thickness incision wound healing including cell proliferation enhancement, collagen deposition, and re-epithelialization, compared with other treatments. We also showed that the inspired skin scaffold could enhance the in vitro tube formation of ECs and the early angiogenesis process of the wound tissue in vivo. Further findings revealed enhanced angiogenic potential in ECs stimulated by bFGF-MSCs, evidenced by increased AKT phosphorylation and elevated HIF-1α and HIF-1β levels, indicating the activation of HIF-1 pathways in diabetic wound healing. Based on the superior biocompatibility and bioactivity, the novel bioinspired skin healing materials composed of the collagen scaffold and bFGF-MSCs will be promising for healing diabetic skin wounds and even other refractory tissue regenerations. The bioinspired collagen scaffold loaded with bFGF-MSCs could accelerate diabetic wound healing via neovascularization by activating HIF-1 pathways.

Analysis of Biogenic Amines and Small Molecule Metabolites in Human Diabetic Wound Ulcer Exudate.

Diabetic foot ulcers (DFUs) pose a significant challenge in wound care due to their chronic nature and impaired healing processes. This study examines the biogenic amines and small molecule metabolites present in DFU wound exudates to identify their potential roles in wound healing. Under an IRB-approved protocol, wound fluid samples were collected from 25 diabetic patients and analyzed using ultrahigh-pressure liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry. The analysis identified 721 metabolites, with 402 confirmed through stringent criteria. Key metabolites significantly contributing to the wound exudates include betaine, lactic acid, carnitine, choline, creatine, and metformin (a widely used first-line treatment for type 2 diabetes). These molecules are known to influence wound healing processes, such as collagen synthesis, angiogenesis, inflammation modulation, and energy metabolism. Notably, the presence of drugs such as metformin and beclomethasone in the exudates suggests significant pharmacodynamic interactions that could influence wound healing. Specifically, we discovered that the combined use of insulin and metformin administered systemically significantly increased the concentration of metformin in the wound exudates (from 0.3% ± 0.0 to 3.1% ± 3.4; p = 0.00 49). This study highlights the complexity of DFU exudate composition and underscores the potential for targeted metabolic profiling to develop personalized wound care strategies.

The role of SLC7A11 in diabetic wound healing: novel insights and new therapeutic strategies.

Diabetic wounds are a severe complication of diabetes, characterized by persistent, non-healing ulcers due to disrupted wound-healing mechanisms in a hyperglycemic environment. Key factors in the pathogenesis of these chronic wounds include unresolved inflammation and antioxidant defense imbalances. The cystine/glutamate antiporter SLC7A11 (xCT) is crucial for cystine import, glutathione production, and antioxidant protection, positioning it as a vital regulator of diabetic wound healing. Recent studies underscore the role of SLC7A11 in modulating immune responses and oxidative stress in diabetic wounds. Moreover, SLC7A11 influences critical processes such as insulin secretion and the mTOR signaling pathway, both of which are implicated in delayed wound healing. This review explores the mechanisms regulating SLC7A11 and its impact on immune response, antioxidant defenses, insulin secretion, and mTOR pathways in diabetic wounds. Additionally, we highlight the current advancements in targeting SLC7A11 for treating related diseases and conceptualize its potential applications and value in diabetic wound treatment strategies, along with the challenges encountered in this context.

Polyphenol hydroxytyrosol present olive oil improves skin wound healing of diabetic mice.

The imbalance in oxidant production and chronic inflammation are the main mechanisms that lead to the detrimental effects of diabetes on skin wound healing. Thus, administration of antioxidants could improve diabetic wound healing. This study aimed to understand the effects of extra virgin olive oil (EVOO) or hydroxytyrosol (HT) in skin wound healing under diabetic conditions. Skin wounds in streptozotocin-induced diabetic mice were topically treated with HT. Some diabetic animals were fed with a diet rich in EVOO. Wounds were harvested 7 days later. In in vitro assays, fibroblasts and macrophages were treated with high levels of glucose and HT. The EVOO or HT promoted wound closure and collagen deposition in diabetic mouse wounds. The EVOO or HT reduced the number of infiltrated neutrophils, tumour necrosis factor-α, lipid peroxidation, and nuclear factor erythroid 2-related factor 2 in diabetic mouse wounds. The EVOO or HT also increased the number of macrophages with anti-inflammatory phenotype and interleukin-10 in diabetic mouse wounds. In the in vitro assays, HT promoted the fibroblast migration, collagen gel contraction, and switched macrophages to an anti-inflammatory phenotype under high glucose conditions. In conclusion, the diet supplementation with EVOO or topical application of HT promotes skin wound healing under diabetic conditions and can be a possible therapeutic tool for the treatment of those lesions.

PCL-gelatin honey scaffolds promote Staphylococcus aureus agrA expression in biofilms with Pseudomonas aeruginosa.

Bacterial infection and biofilm formation contribute to impaired healing in chronic diabetic wounds. Staphylococcus aureus and Pseudomonas aeruginosa are found in human diabetic wound biofilms. They may develop antibiotic resistance, increasing the urgency for alternative or complementary therapies. Diabetic wound healing may be improved with the use of biomedically engineered scaffolds, which can also serve as delivery systems for antibacterial compounds. Manuka honey is a potent antibacterial and wound care agent due to its high osmolarity, low pH, and constituents (such as methylglyoxal). Honey exhibits bacteriostatic and bactericidal effects, modulates the expression of biofilm forming genes, and restores antibiotic susceptibility in previously drug resistant pathogens. In this study, we created a dermal regeneration template (DRT) composed of polycaprolactone-gelatin (PCL-gelatin) and Manuka honey to retain honey in the wound and also provide a scaffold for tissue regeneration. Soluble Manuka honey inhibited the planktonic and biofilm growth of both S. aureus (UWH3) and P. aeruginosa (PA14) co-cultures. Manuka honey embedded PCL-gelatin scaffolds did not exhibit bacteriostatic or bactericidal effects on cocultures of UHW3 and PA14; however, they promoted the expression of AgrA, a gene associated with dispersal of S. aureus biofilms.

A modified hyaluronic acid hydrogel with strong bacterial capture and killing capabilities for drug-resistant bacteria-infected diabetic wound healing

Management of diabetic wounds becomes increasingly challenging as bacterial infections intensify the inflammation. Employing polysaccharide hydrogels with inherent antibacterial qualities can significantly reduce the need for antibiotics to manage infections in diabetic wounds. The typical approach to achieving antibacterial outcomes with hydrogels relies on the penetration of bacteria into their porous architecture. Such penetration not only takes time but can also prolong inflammation, thus impeding the healing of wounds. Hence, the quick capture and eradication of bacteria are essential for optimizing the hydrogel's antibacterial performance. Herein, we introduce a multifunctional polysaccharide hydrogel dressing—designated as HAQ—created for managing bacterial infections in diabetic wounds. This dressing is based on hyaluronic acid, which is modified with methacrylic anhydride, and special functional groups are added to the modified hyaluronic acid matrix: phenylboronic acid for capturing bacteria and quaternary ammonium chitosan for bacterial destruction. As expected, the HAQ system exhibits robust antibacterial effectiveness against both methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa in vitro and in vivo. Consequently, HAQ stands as a promising hydrogel dressing with intrinsic antibacterial capabilities and offers significant potential for managing diabetic wounds infected by drug-resistant bacteria.

Endogenous electric field coupling Mxene sponge for diabetic wound management: haemostatic, antibacterial, and healing

Improper management of diabetic wound effusion and disruption of the endogenous electric field can lead to passive healing of damaged tissue, affecting the process of tissue cascade repair. This study developed an extracellular matrix sponge scaffold (K1P6@Mxene) by incorporating Mxene into an acellular dermal stroma-hydroxypropyl chitosan interpenetrating network structure. This scaffold is designed to couple with the endogenous electric field and promote precise tissue remodelling in diabetic wounds. The fibrous structure of the sponge closely resembles that of a natural extracellular matrix, providing a conducive microenvironment for cells to adhere grow, and exchange oxygen. Additionally, the inclusion of Mxene enhances antibacterial activity(98.89%) and electrical conductivity within the scaffold. Simultaneously, K1P6@Mxene exhibits excellent water absorption (39 times) and porosity (91%). It actively interacts with the endogenous electric field to guide cell migration and growth on the wound surface upon absorbing wound exudate. In in vivo experiments, the K1P6@Mxene sponge reduced the inflammatory response in diabetic wounds, increased collagen deposition and arrangement, promoted microvascular regeneration, Facilitate expedited re-epithelialization of wounds, minimize scar formation, and accelerate the healing process of diabetic wounds by 7 days. Therefore, this extracellular matrix sponge scaffold, combined with an endogenous electric field, presents an appealing approach for the comprehensive repair of diabetic wounds.

Glycyrrhizic acid and glycyrrhetinic acid loaded cyclodextrin MOFs with enhanced antibacterial and anti-inflammatory effects for accelerating diabetic wound healing

A water stable cyclodextrin MOF (Cu-SD) was synthesized with γ-cyclodextrin derivative as organic ligand and Cu2+ as metal center to co-crystallizely load glycyrrhizic acid (GL) and glycyrrhetinic acid (GA). Cu-SD has a high drug loading capacity for GL (499.91 μg/mg) and GA (112.37 μg/mg), and the drug-loaded materials had a controlled release in different meadiums. In addition, Cu-SD and its drug loaded materials demonstrated better inhibiting α-glucosidase activity than the control drug acarbose. Furthermore, Cu-SD presented excellent antibacterial activity, and the antibacterial activity was significantly enhanced after GA and GL being encapsulated by Cu-SD. Moreover, both free and drug-loaded materials had good anti-inflammatory activities, and the anti-inflammatory effects of GL@Cu-SD and GA@Cu-SD were superior to those of their corresponding free drugs. Cu-SD, GL@Cu-SD and GA@Cu-SD demonstrated good biocompatibility and were applied to treat the wounds of diabetic rats. The experimental results showed that GL@Cu-SD and GA@Cu-SD had good promoting effects on the recovery of chronic diabetic wounds by suppressing wound inflammation.

Unlocking the role of wound microbiome in diabetic, burn, and germ-free wound repair treated by natural and synthetic scaffolds

In current clinical practice, various dermal templates and skin substitutes are used to enhance wound healing. However, the role of wound commensal microbiome in regulating scaffold performance and the healing process remains unclear. In this study, we investigated the influence of both natural and synthetic scaffolds on the wound commensal microbiome and wound repair in three distinct models including diabetic wounds, burn injuries, and germ-free (GF) wounds. Remarkably, synthetic electrospun polycaprolactone (PCL) scaffolds were observed to positively promote microbiome diversity, leading to enhanced diabetic wound healing compared to the natural scaffolds Integra® (INT) and MatriDerm® (MAD). In contrast, both natural and synthetic scaffolds exhibited comparable effects on the diversity of the microbiome and the healing of burn injuries. In GF wounds with no detectable microorganisms, a reversed healing rate was noted showing natural scaffold (MAD) accelerated wound repair compared to the open or the synthetic scaffold (PCL) treatment. Furthermore, the response of the wound commensal microbiome to PCL scaffolds appears pivotal in promoting anti-inflammatory factors during diabetic wound healing. Our results emphasize that the wound commensal microbiome, mediated by different scaffolds plays an important role in the wound healing process.

A Living Microecological Hydrogel with Microbiota Remodeling and Immune Reinstatement for Diabetic Wound Healing.

Dysregulated skin microbiota and compromised immune responses are the major etiological factors for non-healing diabetic wounds. Current antibacterial strategies fail to orchestrate immune responses and indiscriminately eradicate bacteria at the wound site, exacerbating the imbalance of microbiota. Drawing inspiration from the beneficial impacts that probiotics possess on microbiota, a living microecological hydrogel containing Lactobacillus plantarum and fructooligosaccharide (LP/FOS@Gel) is formulated to remodel dysregulated skin microbiota and reinstate compromised immune responses, cultivating a conducive environment for optimal wound healing. LP/FOS@Gel acts as an "evocator," skillfully integrating the skin microecology, promoting the proliferation of Lactobacillus, Ralstonia, Muribaculum, Bacillus, and Allobaculum, while eradicating colonized pathogenic bacteria. Concurrently, LP/FOS@Gel continuously generates lactic acid to elicit a reparative macrophage response and impede the activation of the nuclear factor kappa-B pathway, effectively alleviating inflammation. As an intelligent microecological system, LP/FOS@Gel reinstates the skin's sovereignty during the healing process and effectively orchestrates the harmonious dialogue between the host immune system and microorganisms, thereby fostering the healing of diabetic infectious wounds. These remarkable attributes render LP/FOS@Gel highly advantageous for pragmatic clinical applications.

In Situ Triggered Self-Contraction Bioactive Microgel Assembly Accelerates Diabetic Skin Wound Healing by Activating Mechanotransduction and Biochemical Pathway.

Chronic nonhealing skin wounds, characterized by reduced tissue contractility and inhibited wound cell survival under hyperglycemia and hypoxia, present a significant challenge in diabetic care. Here, an advanced self-contraction bioactive core-shell microgel assembly with robust tissue-adhesion (SMART-EXO) is introduced to expedite diabetic wound healing. The SMART-EXO dressing exhibits strong, reversible adhesion to damaged tissue due to abundant hydrogen and dynamic coordination bonds. Additionally, the core-shell microgel components and dynamic coordination bonds provide moderate rigidity, customizable self-contraction, and an interlinked porous architecture. The triggered in situ self-contraction of the SMART-EXO dressing enables active, tunable wound contraction, activating mechanotransduction in the skin and promoting the optimal fibroblast-to-myofibroblast conversion, collagen synthesis, and angiogenesis. Concurrently, the triggered contraction of SMART-EXO facilitates efficient loading and on-demand release of bioactive exosomes, contributing to re-epithelialization and wound microenvironment regulation in diabetic mice. RNA-seq results reveal the activation of critical signaling pathways associated with mechanosensing and exosome regulation, highlighting the combined biomechanical and biochemical mechanisms. These findings underscore SMART-EXO as a versatile, adaptable solution to the complex challenges of diabetic wound care.