Due to the high-glucose environment of diabetic wounds, a significant proliferation of bacteria at wound site can occur, resulting in an inflammatory response that extends the inflammatory phase of the wound, thereby complicating the healing process in diabetic wounds. Eliminating the proliferation of bacteria plays a crucial role in promoting the healing of diabetic wounds. Under near-infrared (NIR) laser irradiation, l-arginine (L-Arg) -modified natural product puerarin (Pue)-derived carbon nanoparticles (l-Arg-CNP) not only exhibited excellent photothermal effects but also produced reactive oxygen species (ROS) to react with l-Arg for producing Nitric Oxide (NO), thus contributing to a synergistic antibacterial therapy in diabetic wound. At the same time, l-Arg-CNP retained Pue's original characteristics to promote cell proliferation and angiogenesis. Following the loading of l-Arg-CNP into microneedle patches (l-Arg-CNP@MN), it can deliver them into the deeper wound, effectively killing bacteria, reducing inflammatory infiltration, and promoting neovascularization at the wound site. It offers an effective therapeutic strategy for treating diabetic wound healing.

Wound healing in patients with diabetes is challenging because of chronic inflammation, inadequate vascularization, and susceptibility to infection. Current wound dressings often target specific stages of healing and lack comprehensive therapeutic approaches. This study introduces a novel approach using a photodetachable sponge scaffold incorporating carbon nanotubes (CNTs), known for their high photothermal conversion efficiency, electrical conductivity, and water absorption properties. The scaffold incorporated pyrrolidonecarboxylic acid zinc (PC1Z2), a compound with anti-inflammatory and moisturizing properties, which was cross-linked within a network of CNTs and a decellularized dermal matrix. The resulting shape-memory sponge scaffold actively interfaces with endogenous electric fields, facilitating electrical signal transmission to skin cells and accelerating tissue repair. Upon exposure to near-infrared (NIR) light, the PC1Z2 scaffold enhanced antibacterial efficacy (98 %) through photothermal conversion, promoting tissue metabolism at the wound site. Notably, the scaffold absorbed wound exudates and gradually released Zn2+, effectively reducing chronic inflammation in the mice. In a diabetic rat wound model, the PC1Z2 scaffold absorbed exudates, reduced inflammation, and accelerated granulation tissue formation, wound angiogenesis, and re-epithelialization. This innovative PC1Z2 sponge dressing shows promise for enhancing the healing of diabetic wounds.

Diabetic wound healing is constrained by various factors, including chronic inflammation, sustained oxidative stress, impaired angiogenesis, and abnormal wound microenvironments. Exosomes derived from mesenchymal stem cells (MSC-exo) contain a wealth of bioactive substances that play a positive role in promoting diabetic wound healing. Plant-derived exosomes, as a novel therapeutic approach, are continuously being explored. Momordica charantia (MC) has been shown to possess blood glucose-lowering effects, and its exosomes are of significant relevance for treating diabetic wounds. However, direct application of exosomes to wounds faces challenges such as poor stability and short retention time, limiting their therapeutic effectiveness and clinical applicability. Encapsulating exosomes in hydrogels is an effective strategy to preserve their bioactivity. In this study, we fabricated a hydrogel loaded with MSC-exo and MC exosomes (MC-exo) by photopolymerization of methacrylated gelatin (GelMA) and dopamine (MEMC-Gel). The resulting MEMC-Gel exhibited favorable mechanical properties, adhesion, degradability, absorbency, and biocompatibility. In vitro, MEMC-Gel demonstrated the ability to resist inflammation, counter oxidative stress, promote fibroblast migration, support endothelial cell angiogenesis, and regulate macrophage polarization. In a diabetic mouse wound model, MEMC-Gel accelerated wound healing by inhibiting inflammation and oxidative stress, modulating macrophage immune responses and hyperglycemia within the microenvironment, promoting angiogenesis, and enhancing epithelialization. In conclusion, MEMC-Gel is an outstanding hydrogel dressing that synergistically promotes repair by loading MSC-exo and MC-exo, significantly accelerating diabetic wound healing through multiple mechanisms. This multifunctional hydrogel, based on exosomes from two different sources, provides an innovative therapeutic strategy for diabetic wound repair with broad clinical application potential.

Diabetic skin ulcer is a clinical disorder of glucose metabolism that has a long treatment period and is prone to recurrent episodes. Huiyang Shengji decoction (HYSJD) is an effective traditional Chinese medicine for its clinical treatment, but its metabolic effects in patients with diabetic skin ulcers have not been well studied.

Our study aimed to investigate the mechanism of pharmacological treatment of HYSJD in treating diabetic skin ulcers.

The potential mechanism underlying diabetic wound treatment by HYSJD was screened using network pharmacology. Ultra-high performance liquid chromatography-MS/MS metabolomics analysis and correlation analysis were performed to investigate potential target pathways and genes. Furthermore, the db/db diabetic wound tissues and RAW264.7 macrophage inflammation model verified the mechanism using molecular biology experiments.

In network pharmacology, HYSJD played a mainly therapeutic effect by regulating PI3K/AKT signaling pathway, EGFR tyrosine kinase inhibitor resistance, metabolic pathway, and other related metabolic-related pathways. Metabolomics analysis disclosed that L-lysine content increased, while those of linoleic and deoxycholic acids decreased in plasma between the HYSJD-treated group and the control group, participating in biotin metabolism. Among them, PPARγ played an important role. The experiments conducted in db/db mice indicated that HYSJD facilitates VEGF secretion and PPARγ expression. In vitro experiments have revealed that HYSJD inhibits macrophage ROS production, augments mitochondrial ATP production, elevates mitochondrial membrane potential, and diminishes the mitochondrial ECAR rate. Furthermore, these effects culminate in promoting M2 macrophage polarization through PPARγ activation. The molecular docking results revealed that the active compounds from HYSJD were capable of binding to PPARγ protein primarily through hydrogen bonding interactions. Notably, all binding energies were found to be lower than -3 kcal/mol, indicating strong and favorable interactions between the active compounds and the target receptor.

The findings suggested that HYSJD regulates biotin metabolism by reducing excess levels of linoleic and deoxycholic acids and increasing levels of L-lysine, which in turn promotes diabetic wound healing by promoting M2 macrophage polarization through PPARγ up-regulation. These findings indicated that HYSJD is a decoction that can effectively treat diabetic skin ulcers.

Chronic diabetic wounds remain a significant clinical challenge due to persistent bacterial infections, oxidative stress, impaired angiogenesis, and mitochondrial dysfunction. Traditional therapies often fail to address these interrelated pathological factors, highlighting the urgent need for innovative solutions. Here, we present a Mn-ZIF@GOx/BC (MZGB) hydrogel system, where Mn-ZIF@GOx (MZG) nanozymes are successfully integrated into a bacterial cellulose (BC) hydrogel via hydrogen bonding and electrostatic interactions. The MZGB hydrogel lowers wound pH by oxidizing excess glucose into gluconic acid. It exhibits strong ROS scavenging capabilities through its superoxide dismutase and catalase-like activities, while simultaneously providing oxygen. By restoring redox homeostasis, it protects mitochondrial function and enhances cellular energy metabolism. By reprogramming macrophages, MZGB creates a favorable immune microenvironment, significantly promoting angiogenesis through paracrine mechanisms. This facilitates cell-to-cell communication, forming a positive feedback loop. Moreover, MZGB demonstrates ROS-independent antibacterial properties. BC hydrogel ensures adhesion and moisture regulation, forming a protective barrier and maintaining an optimal wound environment. This multifunctional hydrogel represents a promising nanotherapeutic approach for efficiently treating diabetic wounds by precisely regulating the wound microenvironment.

Diabetic wounds (DW) represent a significant clinical challenge due to chronic inflammation, excessive oxidative stress, and impaired angiogenesis, all of which hinder effective tissue regeneration. Existing drug delivery systems often fail to achieve sustained and targeted therapeutic efficacy. In this study, we developed a novel dissolvable dual-layer methacrylated gelatin (GelMA) microneedle (MN) co-loading selenium-doped carbon quantum dots (Se-CQDs) and Astilbin (AST) for enhanced DW treatment. The outer layer, enriched with Se-CQDs, rapidly scavenges reactive oxygen species (ROS), effectively alleviating oxidative stress at the wound site. Sequentially, the inner layer releases AST, exerting potent anti-inflammatory and pro-angiogenic effects. Preliminary findings suggest these effects may involve the modulation of cytoskeletal dynamics and peroxisome function, contributing to endothelial cell migration and angiogenesis. This controlled, sequential release MN establishes a low-oxidative, anti-inflammatory microenvironment, thereby promoting angiogenesis and accelerating wound repair. The pioneering integration of selenium-doped quantum dots and AST-loaded hydrogels offers a synergistic therapeutic strategy, setting a new standard for advanced diabetic wound care with substantial clinical promise.

Although Montgomery T-tube implantation has become an effective method for treating tracheal stenosis, the T-tube needs to be removed as a temporary treatment. At present, there is still a lack of research on the relevant factors affecting T-tube extraction. Therefore, we aimed to explore the clinical characteristics of post-tracheotomy tracheal stenosis (PTTS) disease and the risk factors affecting Montgomery T-tube extraction.

Retrospective analysis of patients who underwent Montgomery T-tube implantation in the Respiratory and Critical Care Medicine of Emergency General Hospital and the Department of Respiratory Medicine at Dongzhimen Hospital from June 2014 to September 2024. They were followed up for at least 6 months. T-tube extraction was used as the main outcome measure. A logarithmic rank test was used to analyze the association between clinical characteristics and T-tube extraction. Kaplan-Meier analysis was performed to analyze the rate of T-tube extraction. Multivariate stepwise Cox regression analysis was used to explore the variables that may affect the association of T-tube extraction.

A total of 49 patients were included, and 18 (36.7%) patients had successful extraction. In the Kaplan-Meier analysis, the rate of extubation was lower in patients with BMI ≥ 24, diabetes mellitus, and a narrow distance of less than or equal to 1 cm from the glottis (P < 0.05). In multivariate Cox regression analysis, cerebrovascular disease (HR 0.341, 95% confidence interval [CI] 0.127-0.918) and diabetes mellitus (HR 0.216, 95% confidence interval [CI] 0.049-0.959) may be independent risk factors for T-tube extraction.

Diabetes mellitus and cerebrovascular diseases are independent risk factors for T-tube extraction, and more attention should be paid to these patients in clinical practice.

This study is a retrospective observational study, and no clinical trial registration number was applied for.

Cyclin-dependent kinase 5 (CDK5) plays a critical role in the inflammatory response. Macrophages are pivotal orchestrators of inflammation, fibrosis, and wound repair. However, the effectiveness of CDK5 in macrophages on cutaneous wound healing remains inadequately characterized. We determined the role of CDK5 signaling pathway in macrophages in mouse cutaneous wound healing through the established macrophage-specific deletion of CDK5 (myeCDK5-/-) mice and the pharmacological CDK5 inhibitor Roscovitine. Phosphorylated proteomics, western blotting, Masson staining, and dualimmunofluorescence staining were performed to investigate the potential mechanisms underlying CDK5-mediated inflammatory regulation in macrophages in wound healing. CDK5 expression and phosphorylation were both elevated significantly in cutaneous wound healing process in mice. Moreover, an accelerated wound healing in myeCDK5-/- mice was exhibited with the reduced pro-inflammatory mediators (IL-1β and iNOS) and the elevated anti-inflammatory markers (IL-10 and CD163) expression significantly. CDK5 deficiency in macrophages enhanced tissue remodeling, evidenced by increased collagen deposition and capillary density (CD31+ cells). Consistently, Roscovitine-treated mice also showed accelerated wound healing, accompanied by decreased pro-inflammatory factors and increased anti-inflammatory markers at the wound site. Mechanistically, the decreased phosphorylation of SIRT1 at the Ser14 and Ser47 sites, as a substrate of CDK5, was confirmed in myeCDK5-/- mice. These data are the first to indicate that CDK5 signaling-dependent regulation of SIRT1 phosphorylation in macrophage-mediated inflammation is required for the wound healing process, warranting consideration of the CDK5-SIRT1 pathway as a therapeutic target for cutaneous wound healing.

In modern society, the need for diabetic wound healing is increasing due to the increase in the number of diabetic patients. In particular, chronic inflammation is a major problem in diabetic wounds due to excessive accumulation of reactive oxygen species (ROS). Therefore, it is essential to remove ROS and promote angiogenesis for effective diabetic wound healing. In this study, we developed a thermo-responsive poly(organophosphazene) hydrogel system (TSP-TP) designed to deliver antioxidants and growth factors for a long period of time. The TSP-TP hydrogel stably loads and continuously releases tannic acid (TA) and platelet-derived growth factor (PDGF) through various physical interactions. Effective ROS scavenging induced macrophage polarization and alleviated chronic inflammation, while the sustained release of PDGF promoted angiogenesis, ultimately maximizing wound healing efficacy in a diabetic mouse model. Based on these results, the proposed TSP-TP hydrogel demonstrates synergistic effects through sustained delivery of antioxidants and growth factors, demonstrating a promising system with high applicability in diabetic wound treatment.

The management of diabetic wound continues to pose significant clinical obstacles, primarily attributed to bacterial infections, excessive inflammation, oxidative stress, and impaired angiogenesis. These pathological factors not only severely affect patient well-being but also create considerable burden on medical services. Current managements often show limited efficacy, necessitating the exploration of alternative therapeutic strategies. Polymeric nanomedicines (PNs), owing to their nanoscale properties, enhanced cellular uptake, stability, bioavailability, and biocompatibility, have been broadly utilized for diabetic wound treatment. PNs demonstrate remarkable capabilities in microbial inhibition, inflammation regulation, oxidative stress mitigation, and vascular network formation, particularly when combined with various agents, including organic substances (eg, exosomes), inorganic substances (eg, metals), and biomaterials (eg, chitosan, hyaluronic acid, and hydrogels). This article systematically examines recent progress in PN-based interventions for diabetic wound recovery, highlighting the pivotal role of PNs in mitigating bacterial infection, modulating inflammatory responses, and promoting cellular regeneration. Additionally, we provide a novel perspective on the multifunctionality of PNs and their potential for overcoming the limitations of conventional therapies. Overall, PNs represent an innovative and promising approach to diabetic wound management, outperforming conventional therapies in stability, targeted delivery, and multifunctionality. In the future, investigations should concentrate on refining PNs formulations and administration strategies so as to enhance biocompatibility, and conducting well-designed clinical trials to validate their therapeutic efficacy.

Elastin and elastin-derived compounds are promising biomaterials due to their biological activity, unique natural crosslinks, and ability to mimic native tissue properties. Solubilized elastin peptides retain the bioactivity of elastin and are more suitable for wound care applications than the insoluble form. Chemically solubilized elastins have shown advantageous effects in skin regeneration in humans. Here, five solubilized elastins were prepared via chemical (stepwise and continuously hydrolyzed with oxalic acid - OxA-st-ELN and OxA-ELN, or with potassium hydroxide - KOH-ELN), enzymatic (Enz-ELN), or combined (Combi-ELN) methods. OxA-st-ELN had the largest molecular weights (MWs) fragments, while Enz-ELN and Combi-ELN yielded the smallest. The effects of elastin preparations were evaluated on primary human cells - dermal fibroblasts and macrophages. In fibroblast assays, Enz-ELN induced elastin, collagen, and fibrillin-2 protein deposition, while other preparations exhibited levels comparable to the control. α-smooth muscle actin (SMA) expression remained low across all conditions. Continuous oxalic acid hydrolysis simplified the traditional stepwise approach while maintaining bioactivity. Macrophage studies showed chemical hydrolysates preserved the M0-like subtype, while Enz-ELN promoted a pro-inflammatory M1-like phenotype, and Combi-ELN had mixed effects. OxA-ELN and KOH-ELN appeared to be the most promising options for developing biomaterial dermal scaffolds that support tissue regeneration in vivo.

Hypoxia, persistent inflammation, excessive reactive oxygen species (ROS), bacterial infection, immune regulation disorder, and impaired angiogenesis are critical factors hindering diabetic wound healing. So far, clinical treatment still lacks comprehensive solutions to address these challenges. The main objective of this study is to develop and evaluate a novel multifunctional nanomaterial (Gen-BioCa/i-ZnPPOPs@HA) for enhancing the treatment of bacterial-infected diabetic wounds through a combination of photodynamic therapy, oxygen self-supply, and acetate supplementation. When infection occurs, Hyaluronic Acid (HA) shells are initially decomposed by hyaluronidase (HAase) secreted by the bacteria, releasing Gen, biomass Calcium peroxide (BioCa) and ionic porphyrin-based polyporous organic polymer (i-ZnPPOPs). BioCa decomposes to oxygen and Ca(OH)2, which alleviates the hypoxia in diabetes wounds and neutralize lactic acid released by the damaged blood vessels. Under NIR irradiation, cationic i-ZnPPOPs combined with Gen showed bacteria-targeting capacity, rapid and high-efficient microbicidal activity. The vitro/vivo experiments results revealed that Gen-BioCa/i-ZnPPOPs@HA could promote macrophages toward M2 polarization, accelerating angiogenesis, collagen deposition and tissues remodeling. In addition, further introduction of acetate supplement shorten the inflammatory period and accelerated wound healing process. This study provides a new strategy for the treatment of chronic bacterial infectious diseases, indicating the important potential of multifunctional nanomaterials in chronic wounds treatment.

Guilongwan (GLW), a representative of traditional Chinese Medicine (TCM) has been utilized to treating diabetic foot ulcer (DFU)-related syndrome including an intolerance of cold with cold limbs, blood circulation disorder, and immune dysfunction for decades. However, the chemical and biological mechanisms of GLW remain unclear. This study aims to discover the biological mechanisms of GLW on DFU by using streptozotocin- and skin-puncher-induced DFU rat models, in vitro macrophage models, and in silico analysis. The alterations in pathology, Notch1 signaling, and macrophage polarization are detected. The results indicated that GLW promoted wound healing, cutaneous cell proliferation, and angiogenesis in DFU rats by inhibiting delta-like (DLL) 4/Notch1 signaling. In addition, GLW inhibited M1 polarization and promoted M2 polarization in diabetic wounds. Seventeen chemical compounds in GLW-medicated serum are identified. In silico analysis and in vitro experiments demonstrated that GLW-medicated serum and its main compounds inhibited the expression of DLL4 in matrix metalloproteinase-9-induced M1 macrophages. In conclusion, GLW ameliorated experimental DFU rats via the inhibition of DLL4/Notch1 signaling in M1 macrophages. This study provided a new biologic mechanism for GLW in the treatment of DFU.

The prevalence of gestational diabetes mellitus (GDM) is currently on the rise globally, which heightens the risk of adverse pregnancy outcomes and subsequently increases the likelihood of cesarean delivery. GDM can induce hyperglycemic conditions in cesarean wounds, leading to delayed wound healing and complications such as itching, pain, and scarring. These complications significantly impact the quality of life and mental health of mothers. Furthermore, there is a lack of effective clinical prevention strategies. Consequently, the need to improve wound healing after cesarean sections in women with GDM is a pressing concern that warrants our attention. To maximize the therapeutic impact and extend the bioavailability of calycosin-7-glucoside (CG), it was integrated into a hybridized hydrogel (GOHA) as a drug carrier to create the GOHACG hydrogel. Bases on our tests, the GOHACG hydrogel demonstrated a strong capacity for water absorption, appropriate pore size, and good biocompatibility to adjust to the in situ surroundings of the wound. GOHACG also promoted epidermal regeneration, collagen deposition, angiogenesis, and the conversion of macrophages from the M1 to M2 phenotype. Indicating a reduction in the inflammatory response, accelerated wound repair, and minimized skin scarring in a postcesarean delivery model involving gestational diabetic mellitus mice. In brief, the GOHACG possesses significant properties that enhance wound healing in GDM model, suggesting its potential effects in treating wound healing of GDM.

Metal oxide nanozymes hold significant potential in combating bacterial infections; however, their ordered crystal structures limit the enhancement of catalytic activity, posing challenges in addressing clinical needs for eliminating intracellularly colonized bacteria. Here, we report the development of an integrated diagnostic-therapeutic microneedle patch incorporates the Res@PtZ-Z nanozyme hybrid. Res@PtZ-Z consists of a ZIF shell loaded with the natural compound resveratrol (Res), encapsulating a Pt-doped zinc oxide (ZnO) nanozyme core (PtZ). The Res component modulates charge distribution on the ZIF shell and attenuates bacterial virulence, thereby promoting the uptake of Res@PtZ-Z by host cells. The PtZ core, doped with Pt4+ to induce sublattice distortion in ZnO, exhibits oxidase-like, peroxidase-like, and catalase-like activities. Under intracellular hypoxic conditions, the cascade of these enzyme-like activities ensures a sustained generation of reactive oxygen species (ROS), enabling robust antibacterial effects. Additionally, Res@PtZ-Z enables real-time infection monitoring by oxidizing the 3,3',5,5'-tetramethylbenzidine (TMB) substrate to produce a distinct colorimetric response. This approach addresses both methicillin-resistant Staphylococcus aureus (MRSA) invasion and intracellular persistence, contributing to improved infection management and promoting wound healing.

Diabetic wound healing poses a significant clinical challenge with limited therapeutic efficacy due to uncontrolled reactive oxygen species (ROS), inflammatory responses, and extracellular matrix (ECM) degradation caused by abnormal macrophage activity in the wound microenvironment. To address these concerns, we propose a novel formulation that combines Tempo-conjugated lipid with the commercially cationic lipid DOTAP to expedite diabetic wound healing through targeted siRNA delivery (cLpT@siRNA) and restoration of the wound microenvironment. The developed cLpT@siRNA nanocomplexes effectively scavenge excessive ROS levels, facilitate polarization of proinflammatory M1 macrophages towards an anti-inflammatory M2 phenotype, and suppress MMP9 gene expression in macrophages. In the ICR mouse model of diabetic wounds, cLpT@siRNA nanocomplexes significantly accelerate wound healing, promoting neovascularization and collagen deposition. Overall, the cLpT@siRNA nanocomplexes based on antioxidant and cationic lipids provide a promising strategy for delivering siRNA in diabetic wound treatment and hold great potential for clinical translation.

Wound healing is a complex biological process and remains a significant challenge due to the lack of effective therapeutic drugs. Cayratia japonica (CJG), a traditional folk medicine, has been widely used for its anti-inflammatory and efficacy in treating traumatic injuries.

This study aimed to investigate the wound-healing effects of CJG and elucidate its underlying mechanism.

First, the phytochemical composition of CJG was identified using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and its potential wound-healing mechanisms were predicated via network pharmacology. Next, in vivo experiments were conducted by dividing subjects into control, CJG (1.5-6 mg/cm2), and bFGF (150 IU/cm2) groups to assess its therapeutic efficacy. Finally, the mechanism of CJG and its key bioactive component, luteolin-7-O-glucoside (LUT-7G), were explained through polymerase chain reaction (PCR), Western blotting, histopathology, immunofluorescence, plasmid transfection, colony formation unit assays, and cellular thermal shift assay (CETSA).

LC-MS/MS identified 15 major constituents of CJG and 102 potential wound healing-related targets. Network pharmacology analysis revealed key enriched pathways, including AMPK, TNF, and metabolic pathways. In vivo, CJG significantly accelerated wound-healing by inhibiting inflammatory responses, promoting angiogenesis, and modulating collagen deposition. In vitro, LUT-7G treatment markedly enhanced the proliferation and migration of HaCaT and HSF cells. Mechanistically, LUT-7G exerted its wound-healing effects by activating the AMPK/CTHRC1/TGF-β1 signaling pathway in HaCaT cells. In conclusion, CJG significantly promotes wound healing by regulating AMPK signaling pathways, indicating its promising clinical application prospects.

The global prevalence of acute and chronic wounds has surged, escalating healthcare burdens and necessitating advanced therapeutic strategies for effective wound management. Electrospun nanofibers have emerged as promising biomimetic platforms for tissue engineering and drug delivery, due to their structural resemblance to the native extracellular matrix (ECM), high porosity, and tunable surface-to-volume ratio. Recent advances in structural design have expanded their applications from conventional two-dimensional (2D) wound dressings to multifunctional three-dimensional (3D) architectures, enabling enhanced mechanical adaptability, bioactive molecule loading, and spatiotemporal control over wound microenvironments. These innovations leverage nanofibers' customizable topography and composition to recapitulate critical ECM cues, thereby fostering cell proliferation, angiogenesis, and immunomodulation during tissue regeneration. This review systematically evaluates cutting-edge strategies focusing on optimizing 2D arrangements and the structural design of multilayered and functionally patterned 3D electrospun nanofibers in wound healing applications. We further present the advantages and limitations of various nanofiber structures, along with the key challenges and future directions for advancing electrospun nanofibers specifically designed for enhanced wound healing.

Wound healing is a highly coordinated biological process encompassing four distinct yet interconnected stages. Notably, microRNA (miRNA) dysregulation is related to non-healing wounds, and miRNAs are considered promising therapeutic targets for wound healing. However, its function and underlying mechanism in wound healing remain incompletely understood. Here, we detected and characterized the miRNA expression patterns during wound healing. Interestingly, miR-301a-5p was significantly downregulated in the initial inflammatory stage and finally peaked in early proliferative phases, suggesting its potential role in modulating phase transition from inflammatory to proliferative phase. Moreover, miR-301a-5p not only promoted the proliferation and migration of macrophages, but also suppressed the excessive inflammatory response, as evidenced by both facilitating the expression of IL-10 and TGF-β and suppressing the pro-inflammatory factors expression. Mechanistically, miR-301a-5p directly targeted inhibitor of κB kinaseβ (IKKβ) and regulated its expression to modulate nuclear factor κB (NF-κB) pathway and macrophage polarization (M1 to M2). Importantly, miR-301a-5p overexpression significantly promoted the regeneration of full-thickness skin wound in mice by regulating NF-κB and macrophage polarization, thereby facilitating epidermal regeneration and collagen deposition. Together, our study found that miR-301a-5p as a novel regulator in the wound healing process transition, and provided potent pro-healing agents for wound healing.

Diabetic wounds represent a significant clinical and economic challenge owing to their chronicity and susceptibility to complications. Dysregulated macrophage function is a key factor in delayed wound healing. Recent studies have emphasized the therapeutic potential of macrophage-derived extracellular vesicles (MDEVs), which are enriched with bioactive molecules such as proteins, lipids, and nucleic acids that mirror the state of their parent cells. MDEVs influence immune modulation, angiogenesis, extracellular matrix remodeling, and intercellular communication. In this review, we summarize and discuss the biological properties and therapeutic mechanisms of MDEVs in diabetic wound healing, highlighting strategies to enhance their efficacy through bioengineering and advanced delivery systems. We also explore the integration of MDEVs into innovative wound care technologies. Addressing current limitations and advancing clinical translation of MDEVs could advance diabetic wound management, offering a precise, effective, and versatile therapeutic option.

Psoriasis and atopic dermatitis (AD) are both chronic inflammatory skin diseases. Their pathogenesis remains incompletely understood. The polarization states of macrophages, as a crucial part of the innate immune system, are influenced by various factors such as cytokines, inflammatory mediators, and epigenetics. Research has demonstrated that macrophages play a "double-edged sword" role in the pathological process of inflammatory skin diseases: they both drive inflammation progression and participate in tissue repair. This article summarizes the roles of macrophages in the inflammatory development and tissue homeostasis of psoriasis and atopic dermatitis. It explores the impact of different factors on macrophages and inflammatory skin diseases. In conclusion, understanding the classification and plasticity of macrophages is crucial for a deeper understanding of the pathogenesis of psoriasis and AD and the development of personalized treatments.

Chronic wounds are challenging to heal due to persistent infection, prolonged inflammation, and impaired angiogenesis, which can ultimately lead to severe disabilities. Current treatment strategies are unable to provide the comprehensive conditions needed for effective chronic wound healing. Herein, we proposed a multifunctional microneedle patch for chronic wound healing, consisting of a needle-like drug-loading gel (DG) constructed with polyethylene glycol (PEG) and a backing hydrogel (BHG) layer constructed with sodium alginate. This design combines the therapeutic effects of drug delivery with the protective benefits of a hydrogel. The needle-like DG layer effectively penetrates the bacterial biofilm, releasing Erythromycin, Vaccarin, Demethylsuberosin, and Cyanidin, agents with synergistic antibacterial, anti-inflammatory, pro-angiogenic, and antioxidant effects in a temperature response-dependent manner. Together, these components address multiple barriers to chronic wound healing. The DG layer also maintains a moist wound environment for the wound. The pH-responsive properties of Cyanidin visually indicate the wound healing status. The multifunctional microneedle patch (DG@BHG) significant enhances healing in both infected and diabetic wounds, leveraging the combined effects of drug action and hydrogel support. This approach presents a novel therapeutic strategy for chronic wound healing by addressing infection, inflammation, and angiogenesis simultaneously.

Diabetic wounds face challenges like infection, prolonged inflammation, and poor vascularization. To address these, we developed an injectable hydrogel for diabetic wound dressing by grafting palmitoyl tetrapeptide-7 (Pal-7) onto chitosan (CS) to form CS/Pal-7 (CP7). Glutaraldehyde (GA) was used to enhance crosslinking between CS, creating the CP7 hydrogel. The hydrogel showed rapid gelation, good mechanical properties, biocompatibility, and strong antibacterial effects. Additionally, stem cells derived from human deciduous teeth (SHED) were loaded into the CP7 hydrogel to form SHED@CP7. This complex promoted human umbilical vein endothelial cell (HUVEC) migration and tube formation, aiding angiogenesis, and induced macrophage polarization toward the M2 phenotype, exerting anti-inflammatory effects. In streptozotocin-induced diabetic mouse wounds, SHED@CP7 significantly improved wound healing with over 95 % wound closure, increased collagen deposition, and reduced tumor necrosis factor-α (TNF-α) expression by approximately 75 % and Interleukin-6 (IL-6) expression by around 81 %. It also increased Interleukin-10 (IL-10) expression by approximately 58 %, modulating the inflammatory microenvironment for regeneration. Moreover, SHED@CP7 enhanced angiogenesis, as shown by a 69 % increase in endothelial cell marker CD31 staining, supporting faster wound healing. These results highlight the potential of SHED@CP7 as an effective treatment for diabetic wounds.

Diabetic wound healing is hindered by oxidative stress, impaired angiogenesis, and inflammation. To address these issues, we developed a novel silver-gallic acid nanoparticle and incorporated it into a methacryloyl silk fibroin hydrogel (Ag@GA/Gel) based on the concept of polyphenol-metal nanoparticle networks for diabetic wound healing. In vitro experiments demonstrated that this hydrogel could promote macrophage polarization toward the M2 phenotype, scavenge reactive oxygen species, and exhibit pro-angiogenic and antibacterial properties. In vivo experiments showed that Ag@GA/Gel enhanced wound healing in diabetic mice, evidenced by a reduction in pro-inflammatory cytokine (IL-6) expression at the wound site. Additionally, levels of the anti-inflammatory factor (TGF-β), the M2 macrophage marker (CD206), and angiogenesis markers (VEGF, CD31) were elevated. The experimental results indicate that Ag@GA/Gel is a promising therapeutic approach for diabetic wound healing.

Photobiomodulation (PBM) has been widely utilized in regenerative medicine, including dermatology, dentistry, and neurology. However, the optimal energy density of PBM for human umbilical cord mesenchymal stem cells (hUC-MSCs) remains underexplored, hindering its development and potential clinical application. This study aims to identify the optimal wavelength and irradiation fluence for promoting the proliferation of hUC-MSCs by comparing the effects of different wavelengths and irradiation fluences. Our results show that green light enhances the anti-inflammatory properties of hUC-MSCs, with the 76s being the most effective in inhibiting IL-6 and GM-CSF. Blue light with 38 s is more effective in promoting angiogenesis, significantly increasing the mRNA and protein secretion of VEGF, HGF, and FGF2 compared to the non-irradiated group. The peak secretion times varied, with VEGF and FGF2 peaking at 72 h and HGF at 24 h. RNA-Seq confirms the significant roles of blue and green light in inhibiting epithelial-mesenchymal transition and inflammation. In vitro co-culture models and conditioned media experiments validate these anti-inflammatory effects. These findings have important implications for accelerating the clinical application of stem cell therapies and provide new references for PBM use in hUC-MSCs.

Diabetic non-healing wounds represent a major complication of diabetes, primarily due to impaired angiogenesis. Ovarian tumor deubiquitinase 1 (OTUD1), a deubiquitinase, has been implicated in vascular pathophysiology; however, its role in endothelial dysfunction and angiogenesis during diabetic wound healing is still poorly understood.

This study explores whether OTUD1 influences angiogenesis and its underlying mechanisms.

We developed OTUD1 knockout mice and induced type 1 and type 2 diabetes mellitus (T1DM and T2DM) by administering streptozotocin (STZ) alone or in combination with a high-fat diet (HFD), respectively. Human umbilical vein endothelial cells (HUVECs) incubated with high glucose and palmitic acid (HG + PA) were utilized to imitate hyperglycemia-induced endothelial dysfunction in vitro. Mass spectrometry combined with immunoprecipitation analysis was used to analyze the interacting proteins of OTUD1. Moreover, we developed endothelial-specific OTUD1 knockdown db/db mice using an adeno-associated virus serotype 2/BI30 (AAV2/BI30) vector.

Increased OTUD1 expressions were observed both in diabetic wound tissues and in HUVECs treated with HG + PA. OTUD1 deficiency promoted angiogenesis and fibrosis in wound tissues of T1DM and T2DM mice and alleviated HG + PA-induced endothelial migration inhibition, tube formation impairment, and oxidative stress in HUVECs. Mechanistically, OTUD1 directly interacted with β-catenin, reducing its K63-linked ubiquitination at residues K496, K508, and K625 via its catalytic site C320. This modification facilitated β-catenin phosphorylation, restricted its nuclear translocation, and downregulated the expression of angiogenesis-related factors. Finally, pharmacological inhibition of β-catenin reversed the improvement of delayed wound healing induced by OTUD1 knockdown in db/db mice.

These findings elucidate the OTUD1-β-catenin pathway's role in endothelial dysfunction-associated angiogenesis and suggest OTUD1 as a promising therapeutic target for diabetic non-healing wounds.

Accurately recognizing and regulating the transition time of macrophages to a pro- (M1-like) or anti-inflammatory (M2-like) state is essential for improving chronic inflammation in pressure injuries (PIs).

This study aimed to evaluate the effectiveness of infrared thermography (IRT) in measuring wound temperature of PIs for the purpose of guiding treatment in regulating chronic inflammation.

The healing process of 21 patients with PIs was monitored using IRT prospectively followed for 30 days. The wound temperature changing pattern of different healing outcomes were analyzed and calculated the optimal wound temperature range to guide the treatment time of anti-inflammation for 100 patients with PIs accurately. Additionally, the molecular mechanisms underlying the observed temperature changes in a mouse model of PI were investigated, and the effect of IRT-guided chronic inflammation targeting ferroptosis modulation on PIs was validated.

The application of IRT to monitor PIs temperatures outside the 36.23 °C to 37.37 °C range is indicative of a potential risk indicator, which allows for the timely guidance of treatment to markedly enhance the efficacy of PIs healing outcomes. This wound temperature change was also observed during the process of PIs healing in mice, as a result of the imbalance of M1-like/M2-like macrophages and the subsequent chronic inflammation. Mechanically, evidence indicates that ferroptosis is hyperactivated in PIs, and the enrichment of M1-like macrophages with iNOS/NO• can enhance their resistance to ferroptosis compared with M2-like macrophages, resulting in the imbalance of M1-like/M2-like macrophages and subsequent alteration of wound temperature.

The modulation of M2-like macrophage resistance to ferroptosis in PIs by NO• donors, suggesting by IRT-monitored temperature changes, has been demonstrated to significantly improve chronic inflammation. This establishes a foundation for the application of IRT to direct a therapeutic strategy for the precise promotion of PIs healing.

The treatment of complex wounds presents a significant clinical challenge due to the limited availability of standardized therapeutic options. Adipose-derived stem cell exosomes (ADSC-Exos) are promising for their capabilities to enhance angiogenesis, mitigate oxidative stress, modulate inflammatory pathways, support skin cell regeneration, and promote epithelialization. These exosomes deliver non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, which facilitate collagen remodeling, reduce scar formation, and expedite wound healing. This study reviews the mechanisms, therapeutic roles, and challenges of non-coding RNA-loaded ADSC-Exos in wound healing and identifies critical directions for future research. It aims to provide insights for researchers into the potential mechanisms and clinical applications of ADSC-Exos non-coding RNAs in wound healing.

Wound healing (WH) poses a significant socio-economic burden due to its high incidence and recurrence rates. Iron overload (IO) could be a factor leading to delayed WH. This study thus analyzed IO-related genes (IORGs) in WH, offering possibilities for developing new therapeutic strategies. Differential gene expression (DEGs) analysis was conducted between the WH group and intact skin (IS) group, intersected with IORGs to obtain differentially expressed IORGs (DE-IORGs). Functional enrichment analysis and potential drug screening were performed on DE-IORGs. A protein-protein interaction (PPI) network of DE-IORGs was constructed, and hub genes were identified using CytoHubba and MCODE methods. ROC curves of hub genes were plotted, and their expression levels in WH and IS groups as well as inter-gene correlations were analyzed. Additionally, immune infiltration variances in WH and IS groups, along with miRNA and TFs of hub genes, were examined. Finally, the effect of EGFR on skin wound healing was verified by scratch healing assay. 39 DE-IORGs were predominantly enriched in signaling pathways like HIF-1 signaling pathway and Th17 cell differentiation. Potential drugs for treating WH (e.g., felbamate, SA-94315, GANT-58, rucaparib) were identified. Three hub genes related to IO in WH were pinpointed (HIF1A, CDKN2A, EGFR) with diagnostic value. Immune infiltration analysis showed higher levels of immune cells like endothelial cells and macrophages in the WH group. Additionally, 55 miRNAs (e.g., hsa-mir-200a-3p, hsa-mir-218-5p) and 2 TFs (L3MBTL2, ZNF76) regulating the three hub genes were predicted. Cell experiments showed that EGFR could promote skin wound healing. The study suggested HIF1A, CDKN2A, and EGFR as potential diagnostic biomarkers for effective WH diagnosis, offering new insights into identifying potenti1al therapeutic targets for WH treatment.

Chronic wound healing is a significant challenge in diabetes. Puerarin is an active compound extracted from the traditional Chinese medicine Pueraria lobata. Puerarin has been used in the treatment of diabetes and derives benefits from its antioxidant, anti-inflammatory, antibacterial, and pro-angiogenesis properties, but its efficacy is hampered by poor water solubility and bioavailability. In this study, we designed a polyvinyl alcohol (PVA)-borax-puerarin (BP) hydrogel system that self-assembled via boronic ester bonds. The BP hydrogel exhibited exceptional physical characteristics, including adaptability, injectability, plasticity, self-healing capabilities, and robust compressive strength, as well as good biocompatibility. In the chronic wound diabetic rats model, the BP hydrogel significantly accelerated wound healing, as evidenced by hematoxylin and eosin (HE) staining, as well as Masson and picrosirius red (PSR) staining. RNA-sequencing and multiple immunohistochemistry (mIHC) analyses revealed that the BP hydrogel exerts a therapeutic effect by modulating macrophage polarization, promoting angiogenesis, and regulating collagen remodeling. Our findings suggest that the BP hydrogel represents a promising wound dressing and holds great potential for clinical applications in acute and chronic wound management.

Excessive oxidative stress, chronic inflammation, and impaired vascularization are the main barriers to diabetic wound repair. A decellularized extracellular matrix (dECM) with a native ECM structure is a promising biomaterial candidate for diabetic wound healing. However, the traditional decellularization process (reagents) can diminish the structural stability, mechanical properties, and bioactive components of dECM. To address these issues, we developed an intrinsically bioactive kelp decellularized scaffold (Im-Gly2) using natural and gentle deep eutectic solvents (DES) for accelerating diabetic wound healing. Im-Gly2 had a stable porous 3D structure (80.7 μm) and suitable mechanical properties, which could support cell growth, proliferation, and migration. Due to the retention of fucoidan, polyphenols (735.3 μg/g), and flavonoids, Im-Gly2 demonstrated intrinsic antioxidant and immunomodulatory effects. It effectively reduced reactive oxygen species (ROS) production in RAW264.7 macrophages and promoted their differentiation into the M2 phenotype. Notably, Im-Gly2 promoted tube formation through paracrine mechanisms by inducing the expression of transforming and proliferative cytokines from the RAW264.7 macrophage. In vivo, Im-Gly2 accelerated the healing of diabetic wounds by alleviating inflammation, angiogenesis, granulation tissue formation, collagen deposition, and re-epithelialization. Taken together, our study provides a novel strategy for fabricating a bioactive kelp dECM without cross-linking with exogenous substances for accelerating chronic diabetic wound healing.

Neonatal hindpaw incision can evoke long-lasting changes in nociceptive processing following repeat injury in adulthood. Studies have focused on the effects and mechanisms in the spinal cord and brain, however changes in inflammation and macrophages in the periphery, especially at the site of early life injury, remain poorly defined. In this paper, we investigated the role of macrophages in the injured tissue in pain hypersensitivity caused by repeat hindpaw incisions and primed by neonatal injury.

Hindpaw incision was performed in anesthetized adult rats. Among them, some had neonatal hindpaw incisions on postnatal day 3. To assess the role of inflammatory response in the priming of adult incision pain, the rats were treated with clodronate liposome, a macrophage depletion agent, and ketorolac tromethamine, the commonly used anti-inflammatory drug following surgery. Their mechanical pain sensitivity was measured via von Frey filaments. Inflammation induced by hindpaw incision was evaluated via Enzyme-linked Immunosorbent Assay, H&E, and immunofluorescence staining. The phenotypes of macrophages were examined by analyzing their surface markers by flow cytometry.

Mechanical pain hypersensitivity caused by the hindpaw incision in the adult rats was enhanced by previous neonatal injury, which also significantly increased microglial activation in the spinal dorsal horn, aggravation of inflammation, and infiltration of both M1 and M2 macrophages in damaged hindpaw tissue after the repeat incision in the adult rats on POD 5. Intraperitoneal injection of clodronate liposome alleviates nociceptive and inflammatory responses in neonatal injured rats. Intramuscular injection of ketorolac tromethamine decreased mechanical hyperalgesia and inflammatory responses primed by prior neonatal injury.

Neonatal tissue injury exacerbated mechanical hypersensitivity, infiltration, and activation of macrophages evoked by repeat hindpaw incision in adulthood.

Diabetic wound-healing difficulties are common for patients with diabetes. Compared to normal wound healing processes, the hyperglycaemic environment in diabetic wounds increases the proportion of M1 macrophages significantly, thereby prolonging the inflammatory phase of wound healing. Consequently, treatment approaches targeting macrophages are gaining increasing attention in both research and clinical practice. 6-Gingerol (6-G), a natural compound derived from ginger, is recognized for its anti-inflammatory, anti-tumour, and antioxidant properties. However, its application in diabetic wound treatment has been limited by poor water solubility and low bioavailability. In this study, we developed a hydrogel microneedle system (6-G@MN) combining 6-G with polyethylene glycol, hyaluronic acid, and gelatin. Our results demonstrated that 6-G@MN effectively promotes angiogenesis and collagen deposition in diabetic wounds while rebalancing macrophage populations in diabetic mice. Additionally, 6-G was shown to inhibit lipopolysaccharide-induced M1 macrophage polarization in vitro and to activate the AMPK/mTOR signalling pathway. In conclusion, we developed 6-G@MN as a novel therapeutic approach that integrates the advantages of the traditional Chinese medicine component 6-G with modern microneedle technology. By targeting macrophage polarization, the system can offer a promising strategy for improving the healing of diabetic wounds.

The healing of bacteria-infected wounds has long posed a significant clinical challenge. Traditional hydrogel wound dressings often lack self-healing properties and effective antibacterial characteristics, making wound healing difficult. In this study, a bioactive small molecule cross-linking agent 4-FPBA/Lys/4-FPBA (FLF) composed of 4-formylphenylboronic acid (4-FPBA) and lysine (Lys) was utilized to cross-link guar gum (GG) and a tannic acid/iron (TA/Fe3+) chelate through multiple dynamic bonds, leading to the formation of a novel self-healing hydrogel dressing GG-FLF/TA/Fe. The hydrogel exhibited excellent stretchability and self-healing ability, which enabled it to adapt to irregular wound sites. Meanwhile, the hydrogel demonstrated remarkable antibacterial efficacy (>99 %) facilitated by the synergistic effects of photothermal properties and aromatic Schiff bases. Additionally, it had adjustable rheological properties, good mechanical characteristics, conductivity, antioxidant characteristics and biocompatibility. Notably, the GG-FLF/TA/Fe hydrogel dressing irradiated with NIR displayed superior therapeutic effects in a mouse wound infection model (wound healing rate: 94.8 %), promoting recovery from bacterially infected wounds by enhancing collagen deposition, facilitating the formation of skin appendages and blood vessels, and regulating inflammatory factors. In summary, this study presented a novel approach to prepare biologically active antibacterial polysaccharide hydrogels and highlighted the substantial potential of this hydrogel as a biomedical antibacterial dressing.

Diabetic wound healing represents a complex biological challenge, often impeded by disrupted cellular processes and dysregulated inflammation, which can lead to chronic and non-healing wounds. Given the significant burden on patients and the healthcare system, there is an urgent need for advanced therapeutic strategies. Hyaluronic acid (HA)-based hydrogels have emerged as a promising solution due to their biocompatibility, biodegradability, and unique physiological functions. This review aims to provide a comprehensive overview of recent advances in HA-based hydrogels, highlighting their potential in addressing diabetic wound complications. Specifically, it examines challenges such as hyperglycemia-induced oxidative stress and impaired cellular signaling within the intricate diabetic wound microenvironment. Moreover, the review explores the composition and properties of HA, including its adhesive capabilities and role in reducing surgical trauma. Various crosslinking strategies and functional modifications are also discussed to endow HA-based hydrogels with antioxidant, antimicrobial, and growth factor-releasing capabilities. By summarizing the latest research and identifying areas for further exploration, this review contributes to the development of more effective HA-based hydrogel formulations for diabetic wound healing.

Chronic diabetic wounds are characterized by prolonged inflammation and excessive accumulation of M1 macrophages, which impede the healing process. Therefore, resolving inflammation promptly and transitioning to the proliferative phase are critical steps for effective diabetic wound healing. Exosomes have emerged as a promising therapeutic strategy. In this study, a smart hydrogel capable of responding to pathological cues in the inflammatory microenvironment to promote the transition from inflammation to proliferation by delivering M2 macrophage-derived exosomes (M2-Exos) is developed. The smart hydrogel is synthesized through the cross-linking of oxidized dextran, a matrix metalloproteinase (MMP)-9-sensitive peptide, and carboxymethyl chitosan containing M2-Exos. In response to elevated MMP-9 concentrations in the inflammatory microenvironment, the hydrogel demonstrates diagnostic logic, adjusting the release kinetics of M2-Exos accordingly. The on-demand release of M2-Exos facilitated macrophage polarization from the M1 to the M2 phenotype, thereby promoting the transition from the inflammatory to the proliferative phase and accelerating diabetic wound healing. The transcriptomic analysis further reveals that the MMP-9-responsive hydrogel with M2-Exos delivery exerts anti-inflammatory and regenerative effects by downregulating inflammation-related pathways. This study introduces an innovative, microenvironment-responsive exosome delivery system that enables precise control of therapeutic agent release, offering a personalized approach for the treatment of chronic diabetic wounds.

Diabetic wounds are a leading cause of disability and mortality in patients with diabetes, and persistent low-grade inflammation plays a significant role in their pathogenesis. Methylglyoxal (MGO), an active product of glucose metabolism, often induces chronic inflammation and is considered a major risk factor in the healing of diabetic wounds. Efferocytosis, the process by which macrophages clear apoptotic cells, is crucial for terminating the inflammatory response and tissue repair. However, the role of MGO in macrophage efferocytosis remains unclear. This study aimed to investigate whether MGO regulates macrophage efferocytosis and the underlying mechanisms. In this study, we observed impaired efferocytosis in diabetic wounds, leading to the accumulation of apoptotic neutrophils and a relative deficiency of M2 macrophages, with MGO being a significant cause. MGO promotes the production of ROS, which not only activates the MAPK p38 pathway, but also upregulates the transcription of the E3 ubiquitin ligase FBXO32, catalyzing the ubiquitination of the transcription factor KLF4 and suppressing the transcription of MerTK mRNA, thereby affecting the phagocytic function of macrophages. Inhibition of the MAPK p38 pathway or knockdown of FBXO32 reduced the ubiquitination and degradation of KLF4, thus mitigating the impairment of efferocytosis caused by oxidative stress. This study reveals the mechanism by which MGO inhibits efferocytosis in diabetic wounds, providing a new target and theoretical basis for the treatment of chronic diabetic wounds.