Glucose oxidase (GOx) with unique catalytic properties and inherent biocompatibility can effectively oxidize both endogenous and exogenous glucose with oxygen (O2) into gluconic acid and hydrogen peroxide (H2O2). Accordingly, the GOx-based catalytic chemistry offers new possibilities for designing and constructing multimodal synergistic antibacterial systems. The consumption of glucose permanently downregulates bacterial cell metabolism by blocking essential energy supplies, inhibiting their growth and survival. Additionally, the production of gluconic acid could downregulates the pH within the bacterial infection microenvironment, enhancing the production of hydroxyl radicals (∙OH) from H2O2 via enhanced Fenton or Fendon-like reactions and triggering the pH-responsive release of drugs. Furthermore, the generated H2O2 in situ avoids the addition of exogenous hydrogen peroxide. Therefore, it is possible to design GOx-based multimodal antibacterial synergistic therapies by combining GOx-instructed cascade reactions with other therapeutic approaches such as chemodynamic therapies (CDT), hypoxia-activated prodrugs, photosensitizers, and stimuli-responsive drug release. Such multimodal strategies are expected to exhibit better therapeutic effects than single therapeutic modes. This tutorial review highlights recent advancements in GOx-instructed multimodal synergistic antibacterial systems, focusing on design philosophy and construction strategies. Current challenges and future prospects for advancing GOx-based multimodal antibacterial synergistic therapies are discussed.

Diabetic wounds are open lesions that can develop on any part of the body of diabetic patients. Importantly, melatonin (Mel) exerts promotional effects on wound healing. Accordingly, this study explored the mechanism of Mel in diabetic wound healing by mediating mitochondrial function in endothelial cells.

Human umbilical vein vascular endothelial cells (HUVECs) were exposed to high glucose (HG) to mimic a diabetic environment in vitro, followed by Mel treatment. Cell viability, invasion and angiogenic capacity were evaluated with CCK-8, Transwell, and tube formation assays, respectively. CD31 protein expression was determined with Western blot. Wound healing ability was evaluated in vitro, and the levels of adenosine triphosphate (ATP), reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and apoptosis-related proteins (Bcl-2/Bax/CytC) were also detected. To verify the role of the AMPK/SIRT1/HIF-1α pathway in diabetic wound healing, HG-induced HUVECs treated with Mel were subjected to treatment with sh-HIF-1α, AMPK inhibitor (compound c), or SIRT1 inhibitor (Nicotinamide).

HG impaired the proliferation, invasion, angiogenesis, and wound healing ability of HUVEC, increased ROS, Bax, and CytC levels, and decreased MMP and the levels of ATP and Bcl-2. Mel facilitated viability, angiogenesis, and wound healing ability while ameliorating mitochondrial dysfunction in HG-treated HUVECs. Mel activated the AMPK/SIRT1 pathway to upregulate HIF-1α in HG-treated HUVECs. HIF-1α knockdown, CC, or Nicotinamide negated the effect of Mel on HG-treated HUVECs.

Mel fosters angiogenesis and represses mitochondrial dysfunction in endothelial cells by activating the AMPK/SIRT1/HIF-1α pathway, thereby promoting diabetic wound healing.

The chronic inflammation and matrix metalloprotease (MMP)-induced tissue degradation significantly disrupt re-epithelization and delay the healing process of diabetic wounds. To address these issues, we produced nanofibrils from Antheraea pernyi (Ap) silk fibers via a facile and green treatment of swelling and shearing. The integrin receptors on the cytomembrane could specifically bind to the Ap nanofibrils (ApNFs) due to their inherent Arg-Gly-Asp (RGD) motifs, which activated platelets to accelerate coagulation and promoted fibroblast migration, adhesion and spreading. These degradable nanofibrils served as effective competitive substrates to reduce MMP-induced tissue degradation. ApNFs and their enzymatic hydrolysates could modulate macrophage polarization due to their RGD motifs. RNA sequencing further revealed that ApNFs treatment activated the JAK2-STAT5b and PI3K-Akt signaling pathways while suppressed the NF-κB, IL-17 and TNF signaling pathways in macrophages. The full-thickness skin wound experiments confirmed that ApNFs significantly accelerated wound healing in both diabetic and non-diabetic rats. Notably, in diabetic wound, ApNFs and their enzymatic hydrolysates polarized the accumulated M1-type macrophages into M2-type, which promoted the wound to get rid of the inflammatory stage and transition to the following proliferative stage, improving the wound healing percentage on day 14 from 74.9 % to 93.2 % by facilitating collagen deposition, angiogenesis and re-epithelization. These results demonstrate that ApNFs are promising drug-free diabetic wound dressings with favorable inherent immunoregulatory properties for biomedical translation.

In diabetic-infected wounds, the local hyperglycemic state leads to unique pathological characteristics of diabetic ulcers, such as secondary chronic infections, abnormal angiogenesis, oxidative stress, and diabetic peripheral neuropathy. Glucose oxidase (GOx) is an enzyme that catalyzes the breakdown of glucose into hydrogen peroxide and gluconic acid, making it a candidate enzyme for regulating the hyperglycemic microenvironment in diabetic wounds. However, multifunctional hydrogel therapeutic systems built around the glucose-lowering capability of GOx have rarely been reported. Here, we loaded stachydrine and Au-FePS3 nanosheets onto a quaternized chitosan (QC) - oxidized dextran (OD) hydrogel to construct a synergistic QC-OD@AF/S hydrogel therapeutic system. In vitro experiments showed that Au-FePS3 possesses GOx-POD cascade catalytic activity, capable of reducing glucose concentration and decomposing generated hydrogen peroxide into reactive oxygen species (ROS). Concurrently, Au-FePS3 exhibits excellent photothermal performance under 808 nm infrared light, synergistically exerting antibacterial capabilities with ROS and quaternary ammonium groups. Stachydrine has been demonstrated to mediate the metabolic reprogramming of macrophages and alleviate high-glucose-induced oxidative stress and impairment of angiogenesis in HUVECs through the LARP7-SIRT1 pathway. In summary, the QC-OD@AF/S hydrogel demonstrates superior capabilities in antibacterial activity, immune modulation, promotion of angiogenesis, and reduction of local glucose concentration, making it a potential clinical therapy.

Recent studies have identified an essential role of macrophage polarization imbalance in the impaired diabetic wound healing process. Macrophages are key players in wound healing, and their transition from the pro-inflammatory M1 phenotype to the anti-inflammatory and reparative M2 phenotype is crucial for effective wound repair. However, in diabetic conditions, this balance is disrupted, leading to prolonged M1 activation and reduced M2 functionality, which hinders the healing process. Exosomes, known for their role in intercellular communication, have garnered significant interest for their diverse functions in immune modulation, angiogenesis, inflammation regulation, and tissue regeneration. Research has demonstrated the ability of exosomes to modulate macrophage polarization, facilitating the shift from M1 to M2 phenotypes, ameliorating the inflammatory milieu, and thereby promoting tissue repair and regeneration. However, the specific mechanisms underlying exosome-mediated regulation of macrophage phenotypic transitions in diabetic wounds remain inadequately elucidated. Moreover, exosomes, serving as novel drug delivery vehicles, present advantages such as enhanced targeting, reduced immunogenicity, and prolonged drug presence, offering considerable promise for diabetic wound management. This review comprehensively outlines advancements in understanding how exosomes influence macrophage polarization in diabetic wound healing, emphasizing the pathophysiological processes of diabetic wounds, the dysregulation of macrophage polarization, and their interactions with exosomes. It also assesses current research limitations and clinical challenges while proposing future research directions, thereby introducing novel theoretical perspectives and potential strategies for diabetic wound therapy.

Chronic wound healing, particularly in diabetic wounds, remains a global challenge. The delayed or even stagnant healing process imposes a substantial burden on both society and individuals. A critical challenge lies in effectively reducing inflammatory levels and promoting vascular remodeling. As an adipokine, C1QTNF9 (CTRP9) has been demonstrated to suppress inflammatory responses under various pathological conditions. In diabetic wound healing, CTRP9 facilitates the proliferation, differentiation, and migration of keratinocytes, yet its specific regulatory mechanisms on local inflammation remain unclear. Transcriptomic analysis of diabetic wounds revealed significantly reduced CTRP9 transcription levels in non-healing wounds. Animal experiments showed lower CTRP9 expression in the skin tissues of diabetic mice compared to normal mice, suggesting a close association between CTRP9 and wound healing. Subsequent local supplementation of CTRP9 in diabetic mouse wounds significantly accelerated healing to near-normal levels. Notably, SLC7A11 (also known as xCT)-a key protein linked to impaired efferocytosis in dendritic cells at diabetic wounds-was downregulated by CTRP9, while CTRP9 enhanced efferocytic efficiency. ATF3, a transcriptional repressor of SLC7A11 involved in ferroptosis regulation, has not been previously explored in dendritic cell efferocytosis. This study found that ATF3 knockdown upregulated SLC7A11 expression and attenuated CTRP9-mediated efferocytosis enhancement, indicating ATF3 as a critical pathway through which CTRP9 regulates SLC7A11. Furthermore, CTRP9 enhances glycolysis to produce lactate, thereby providing energy support for dendritic cell efferocytosis. In summary, this study demonstrates that CTRP9, as an anti-inflammatory factor, promotes diabetic wound healing by enhancing dendritic cell efferocytosis and reducing local inflammation, offering a promising therapeutic strategy.

This review comprehensively examines the biological and molecular mechanisms underlying wound healing, focusing on inflammation, signaling pathways, and microenvironmental imbalances. By comparing traditional and emerging therapies, we highlight innovative approaches such as gene editing, stem cell therapy, and nanotechnology, which offer new perspectives for enhancing wound treatment outcomes. This study underscores the integration of modern medicine with traditional practices, providing a robust theoretical foundation for future clinical applications.

Diabetic wounds (DW) are one of the complications of diabetes. They are difficult to repair and current treatment options are limited. In this study, we employed a network pharmacology approach to investigate the therapeutic potential of Apigenin (API) in the treatment of DW. We used TCMSP, ETCM and SwissTargetPrediction to identify API's drug targets and DisGeNET, GeneCards, TTD, and OMIN for DW-related targets, yielding a set of intersecting genes. Then, we constructed the PPI network by STRING and visualized with Cytoscape software. Further refinement through relevant algorithms of Cytohubba identified nine core genes: HSP90AA1, ACTB, AKT1, BCL2, EGFR, SRC, CCND1, ESR1, and JUN. GO/KEGG analysis were conducted using the DAVID database. The results show that the targets are enriched in biological processes related to cell and smooth muscle movement and migration, as well as pathways associated with anti-inflammatory, diabetes, and inflammatory stimuli. Moreover, the binding affinity of API to identified core targets was confirmed through molecular docking using Autodock software. We further carried out Molecular docking simulations to verify that API exhibits significant binding affinities towards these core targets, suggesting a robust interaction profile. Finally, the experimental validation further confirmed the regulatory effect of API on PI3K-AKT signaling and cell apoptotic pathway. Our research elucidated that API holds significant promise as a therapeutic agent for the treatment of DWs.

Treatment for deep diabetic foot ulcers (DFUs) and infections (DFIs) includes debridement of any dead/infected non-viable tissue, systemic antibiotics, and surgical drainage to avoid exudate stasis. Surgical drainage can cause extended incisions leading to long scars which expose these sites to ulcer recurrence and inadequate rehabilitation. In order to treat the negative impact of stasis on wound healing, we have designed an easy, minimally invasive surgical drainage technique which allows adequate ulcer cleansing by daily irrigation of any drained tract. A probe is passed along the ulcer's infected recesses until the end and pushed against the skin, which is incised and pierced. A small 6 Fr-size silastic tube is then anchored to the probe and pulled backwards. The two ends of the tube are tied together to construct an ulcer-piercing drainage (UPD) ring. The UPD ring is designed to keep any tract open for irrigation with a syringe through both sides of the skin opening. The UPD procedure is easy and safe. The constructed blocked ring of tubing the system avoids the possibility for drainage displacement or accidental removal and can be easily utilized by any home caregiver. The UPD and irrigation are useful to provide any recess cleansing, reduce critical and negative ulcer bioburden and bacterial load, and it could avoid unnecessary and untimely extended surgical incisions leading to long uncomfortable scars, inadequate rehabilitation, relapses, or distal amputations.

Elastin is a connective tissue protein, produced from the ELN gene, that provides elasticity and recoil to tissues that stretch, such as the large arteries of the body, lung parenchyma, skin, ligaments and elastic cartilages. It is produced as a soluble monomer, tropoelastin, that when cross-linked in the extracellular space generates a polymer that is extraordinarily stable, with a predicted half-life of >70 years. Although data suggest ongoing elastin transcription, it is rare to see new elastin deposited outside of its tight developmental window. Consequently, elastin-related disease comes about primarily in one of three scenarios: (1) inadequate elastin deposition, (2) production of poor-quality elastic fibers, or (3) increased destruction of previously deposited elastin. By understanding the pathways controlling elastin production and maintenance, we can design new therapeutics to thwart those abnormal processes. In this review, we will summarize the diseases arising from genetic and environmental alteration of elastin (Williams syndrome, supravalvar aortic stenosis, autosomal dominant cutis laxa, and ELN-related vascular and connective tissue dysfunction) and then describe the mechanisms controlling elastin production and maintenance that might be manipulated to generate novel therapeutics aimed at these conditions. We will end by summarizing existing therapeutic strategies targeting these disease mechanisms before outlining future approaches that may better solve the challenges associated with elastin based regenerative medicine.

Diabetes mellitus is a chronic disease that has become more prevalent worldwide because of lifestyle changes. It leads to serious complications, including increased atherosclerosis, protein glycosylation, endothelial dysfunction, and vascular denervation. These complications impair neovascularization and wound healing, resulting in delayed recovery from injuries and an elevated risk of infections. The present study aimed to investigate the effect of lipoic acid (LA) on the key mediators involved in the wound healing process, specifically CD4 + CD25 + T cell subsets, CD4 + CD25 + Foxp3 + regulatory T (Treg) cells, T-helper-17 (Th17) cells that generate IL-17 A, glucocorticoid-induced tumor necrosis factor receptor (GITR) expressing cells, as well as cytokines such as IL-2, IL-1β, IL-6, and TNF-α and IFN-γ. These mediators play crucial roles in epidermal and dermal proliferation, hypertrophy, and cell migration.

We divided mice into 5 groups: the non-diabetic (normal control; NC), wounded non-diabetic mice (N + W), wounded diabetic mice (D + W), wounded diabetic mice treated with 50 mg/kg lipoic acid (D + W + L50) for 14 days, and wounded diabetic mice treated with 100 mg/kg lipoic acid (D + W + L100) for 14 days.

Flow cytometric analysis indicated that lipoic acid-treated mice exhibited a significant decrease in the frequency of intracellular cytokines (IL-17 A, TNF-α and IFN-γ) in CD4 + T cells, as well as a reduction in the number of GITR-expressing cells. Conversely, a significant upregulation in the number CD4+, CD25+, FOXp3 + and CD4 + CD25 + Foxp3 + regulatory T (Treg) cells was observed in this group compared to both the normal + wounded (N + W) and diabetic + wounded (D + W) groups. Additionally, the mRNA Levels of inflammatory mediators (IL-2, IL-1β, IL-6, and TNF-α) were downregulated in lipoic acid-treated mice compared to other groups. T thereby he histological findings of diabetic skin wounds treated with lipoic acid showed well-healed surgical wounds.

These findings support the beneficial role of lipoic acid in fine-tuning the balance between anti-inflammatory and pro-inflammatory cytokines, influencing both their release and gene expression.

Functional hydrogel dressings offer a promising therapeutic approach, and optimizing their formulations is crucial for improving diabetic foot ulcers (DFUs) outcomes. This study explores the comparative efficacy of different functional hydrogel dressings in DFUs treatment.

We conducted a systematic review and Bayesian network meta-analysis of randomized controlled trials evaluating functional hydrogel dressings for DFUs treatment. A comprehensive search was performed across PubMed, Embase, CENTRAL, CNKI and Web of Science from inception to June 2024. Bayesian network meta-analysis was employed to synthesize and compare the relative efficacy of hydrogel interventions, defined as the number of patients with complete wound closure.

In total, 23 studies involving 1671 patients with DFUs were included. The analysis revealed that immuno-regulating hydrogels (IRHs) had the highest effect estimate (2.2, 95% CI: 1.6, 3.2), compared with anti-bacterial hydrogels (ABHs) ranked last (1.3, 95% CI: 0.78, 2.3). Multi-functional hydrogels (MFHs) and proliferation-promoting hydrogels (PPHs) displayed intermediate effects (1.7, 95% CI: 1.2, 2.4). The relative efficacy ranking was IRH > MFH/PPH > ABH > placebo. The risk of adverse events was lower in functional hydrogel groups relative to placebo (0.75, 95% CI: 0.56, 0.96). Node-splitting analysis confirmed the consistency between direct and indirect evidence for IRH versus ABH. A funnel plot analysis indicated no significant publication bias, affirming the robustness of our findings.

This study provides a comprehensive evaluation of functional hydrogel dressings for DFUs treatment, highlighting the potential of IRH as the most effective option. These insights will guide future research and clinical applications to improve DFUs management.

Chronic consequences of diabetes that are most commonly encountered are diabetic foot ulcers (DFUs), driven by microbiota-immune system dyshomeostasis, eventually leading to delayed wound healing. Available therapies, such as systemic or topical administration of anti-inflammatory or antimicrobial agents, are limited due to antibiotic resistance and immune dysfunction. Herein, a hybrid hydrogel dressing is developed as the artificial bioadhesive barrier at wound sites to maintain microbial and immunological homeostasis locally and have potent anti-inflammatory effects. Specifically, Zero-valent selenium nanoparticles are synthesized and encapsulated into the alginate-polyacrylamide interpenetrating hydrogel networks, during which trehalose is adopted to modify the network defects. Besides, as an anti-adhesion agent, trehalose has shown the ability to prevent immune degradation by reducing bacteria binding to HUVECs. The obtained hybrid hydrogel dressing serves as a physical barrier against microbiome invasion, further regulates the composition of the wound microbiome to restore microbial immune homeostasis at the wound site, and cooperatively relieves DFU-associated symptoms. Meanwhile, the hydrogel dressing can synthesize selenoproteins in situ based on biochemical strategies and significantly reduce the secretion of proinflammatory cytokines. The proposed biochemical strategy based on the hybrid hydrogel dressings can efficiently restore microbiota-immune homeostasis in the wounds, presenting a promising approach for DFU therapy in clinics.

Collagen is widely used as a scaffold for full-thickness epithelial defects but has poor biostability and often induces hypertrophic scarring. Silk, especially silk derived from germ-free silkworms (SGFS), has high biocompatibility and controllable durability. Therefore, SGFS is possibly for medicine. Herein, we evaluated the effects of SGFS as a scaffold in the wound healing of full-thickness epithelial defects. Epithelial defects were made in the dorsal skin of C57BL/6 J mice, and an SGFS or a collagen sheet was applied to each defect and compared. On days 1, 3, 7, and 14 after surgery, re-epithelialization, inflammatory responses, and granulation tissue formation of each wound were assessed and compared between the groups. Re-epithelialization was observed in the SGFS group on day 3 but no re-epithelialization occurred in the collagen group. Histopathological examination showed less granulation tissue formation in the SGFS group than in the collagen group. IL-6 expression was significantly higher in the SGFS group than in the collagen group on day 1. TGF-β1 expression in the SGFS group was significantly lower than that in the collagen sheet group on days 7 and 14. Based on these results, SGFS promoted re-epithelialization and reduced hypertrophic scarring in the wound healing process compared with collagen.

A diabetic wound (DW) is an alteration in the highly orchestrated physiological sequence of wound healing especially, the inflammatory phase. These alterations result in the generation of oxidative stress and inflammation at the injury site. This further leads to the impairment in the angiogenesis, extracellular matrix, collagen deposition, and re-epithelialization. Additionally, in DW there is the presence of microbial load which makes the wound worse and impedes the wound healing cycle. There are several treatment strategies which have been employed by the researchers to mitigate the aforementioned challenges. However, they failed to address the multifactorial pathogenic nature of the disease. Looking at the severity of the disease researchers have explored snail mucus and its components such as achacin, allantoin, elastin, collagen, and glycosaminoglycan due to its multiple therapeutic potentials; however, glycosaminoglycan (GAGs) is very important among all because they accelerate the wound-healing process by promoting reepithelialization, vascularization, granulation, and angiogenesis at the site of injury. Despite its varied applications, the field of snail mucus in wound healing is still underexplored. The present review aims to highlight the role of snail mucus in diabetic wound healing, the advantages of snail mucus over conventional treatments, the therapeutic potential of snail mucus, and the application of snail mucus in DW. Additionally, clinical trials, patents, structural variations, and advancements in snail mucus characterization have been covered in the article.

The current study assessed the wound healing potential of Bergenia ciliata (BC) extract, BC-loaded Salvia hispanica hydrogel (CH-BC) and Bergenia ciliata nanoparticles (NPs)-loaded Salvia hispanica hydrogel (CH-BC AgNPs/NPs-loaded hydrogel) using in vitro and in vivo studies. The prepared hydrogel and its components were analyzed using UV-visible spectrophotometry (UV-vis), scanning electron microscopy (SEM), dynamic light scattering (DLS) analysis/particle size analyzer (PSA), zeta potential, fourier transform infrared spectrometry (FT-IR), and x-ray diffraction (XRD). Peaks and peak shifts at 450-460, 250-260, and 270-280 nm in UV-vis and FT-IR (500-4000 cm-1) confirmed extract loading and various functional group presence. DLS confirmed the nanometric size of BC AgNP while zeta potential indicated the slightly negative charge of prepared hydrogel. SEM assessed the average size and topography of Bergenia ciliata-mediated nanoparticles (BC AgNPs) and BC AgNPs loaded hydrogel (CH-BC AgNPs), and XRD peaks at various 2ϴ (10-70) confirmed the topographical and crystalline and porous nature of materials. Bergenia ciliata extract showed higher radical scavenging (74.19% ± 1.84%) and iron chelation activity (93.70 ± 2.20) at 50 and 25 μL/mL, respectively, while CH-BC AgNPs produced the lowest (48.97% ± 3.0%) at 25 and 75 μL/mL (54.35 ± 3.24). Moreover, Chia hydrogel (CH) synergistically enhanced (1.30%) DPPH scavenging. The wound contraction percentage augmented the CH-BC AgNPs as the potent candidate for wound healing (14th day). These findings were further supported by a significant (p < 0.001) restoration of MMP2 (184.6 ± 11.7 pg/mL), TIMPs (184.8 ± 15.7 pg/mL), GPx (153.4 ± 11.5 pg/mL), and IL-6 (10 ± 1 pg/mL) levels as compared to those of diabetic negative control. The normal reepithelization, angiogenesis, and maturation of wounds in treatment groups after histological analysis further strengthened the supposed rationale that CH, along with the BC extract and CH-BC AgNPs, can act synergistically to improve therapeutic results. Hence, CH-BC appeared as a sustainable, biocompatible, and nontoxic agent for wound healing and paved the way for futuristic biomedical investigations.

The microenvironment of diabetic wounds is complicated and characterized by hyperglycemia, hyperinflammation, persistent infection, hypoxia, and ischemia, making wound restoration and healing extremely challenging. Therefore, functional hydrogel dressings with the ability to regulate the microenvironment of diabetic wounds are a promising strategy for the treatment of diabetic wounds. In this study, a pH/glucose dual-responsive hydrogel based on phenylboric acid-modified carboxymethyl chitosan (CMCSPBA), aldehyde-terminated polyethylene glycol (PEGCHO), and polyvinyl alcohol (PVA) has been developed for diabetic wound treatment via Schiff base and phenylboric ester interactions. Glucose oxidase (GOX), catalase (CAT), and deferoxamine mesylate (DFO) are incorporated into the hydrogel to endow it with multi-functionality. In the hyperglycemic environment of diabetic wounds, a benign feedback loop is formed through the synergistic action of each component of the hydrogel, which enables the reshaping of the microenvironment of diabetic wounds by adjusting the pH and glucose, alleviating oxidative stress and hypoxia, regulating the inflammatory response, inhibiting bacterial infection, and promoting angiogenesis, thus accelerating diabetic wound healing in streptozotocin (STZ)-induced diabetic mice.

BackgroundDiabetic wounds are difficult to heal due to long-term chronic ulcers, thus lacking effective treatment methods. Some antimicrobial peptides are known to have biological functions that promote wound healing, but the effects of the antimicrobial peptide Buforin-I on diabetic wound healing and the mechanisms underlying these effects are not yet elucidated.MethodsThis project investigated the effects of Buforin-I on the healing rate of foot wounds in streptozotocin (STZ)-induced diabetic mice and the antioxidant reactions in wound tissues. Histological staining with HE and Masson, as well as biochemical assays with immunohistochemistry (IHC), were applied to assess tissue chemistry markers. The activity levels of SOD, GSH, and reactive oxygen species (ROS) were measured to evaluate oxidative stress levels. TUNEL analysis was carried out to detect the apoptosis rate. The levels of VEGF, TGF-β1, and Nrf2 were measured by enzyme-linked immunosorbent assay (ELISA) and western blot (WB). In addition, the in vitro effects of Buforin-I on cell proliferation, apoptosis, migration, and oxidative stress levels under high glucose conditions were analyzed on HaCaT cells. Cell viability was measured using an MTT assay, and cell migration was assessed through the wound healing experiment.ResultsBuforin-I treatment accelerated the healing of foot wounds in STZ-induced diabetic mice, with increased fibroblast proliferation and collagen deposition in the wound tissue and decreased Nrf2-mediated oxidative stress levels. Furthermore, Buforin-I facilitated the proliferation and migration as well as reduced apoptosis of HaCaT cells under high glucose conditions, thus enhancing the antioxidant capacity of HaCaT cells.ConclusionIn conclusion, this study confirmed the promoting effect of Buforin-I on diabetic wound healing through the regulation of oxidative stress, highlighting the potential application of Buforin-I in diabetic wound healing.

The advancement of biomaterials utilization in biomedical and tissue regenerative applications has emerged progressively. Hydrogels are three-dimensional, hydrophilic polymeric networks that replicate the natural extracellular matrix (ECM), establishing a hydrated porous milieu that emulates biological functions such as proliferation and differentiation of cellular components. The application of biological macromolecules, particularly Heparin-based hydrogel, has garnered considerable interest owing to various intrinsic biological and mechanical properties. This comprehensive review paper is designed to elucidate the derivation of heparin and its purification method for biomedical uses. The article briefly outlines the diverse physiochemical and biological properties of heparin derivative-based hydrogels/scaffolds and emphasizes their significance as vehicles for growth factors, genes, and cells in complex biomedical and tissue engineering applications. This publication also summarizes the potential concerns associated with heparin-based derivatives, efforts to address these issues, and current clinical perspectives. This represents the inaugural instance of an extensive summarization of heparin-based hydrogels in biomedical applications, emphasizing pre-clinical and clinical investigations, which will further assist the scientific community in addressing the challenges associated with heparin-based hydrogels in biomedical contexts.

Diabetic wounds, especially diabetic foot ulcers, present a major clinical challenge due to delayed healing and prolonged inflammation. Macrophage-fibroblast interactions are essential for wound repair, yet this crosstalk is disrupted in diabetic wounds due to hyperglycemia and bacterial infection. This study investigates the dysfunctional communication between macrophages and fibroblasts, focusing on autocrine, paracrine, and juxtacrine signaling in simulated diabetic environments. Using monoculture and co-culture models of THP-1-derived macrophages and primary human dermal fibroblasts, we simulated conditions of normal glucose, LPS-induced infection, high glucose (with AGEs), and combined high glucose (with AGEs) and LPS. Macrophages in hyperglycemic and LPS-infected environments exhibited a pro-inflammatory M1 phenotype with elevated expression of CD80, and STAT1 and increased production of IL-1β, TNF-α, and MMP9. Fibroblast migration was significantly impaired under high glucose conditions, particularly in paracrine model. Secretome profiling showed heightened pro-inflammatory cytokines and proteases, with reduced anti-inflammatory markers (IL-10 and VEGF-A) under hyperglycemic conditions. Paracrine signaling exacerbated the inflammatory response, while juxtacrine signaling showed more moderate effects, conducive to healing. These findings highlight the pathological macrophage-fibroblast crosstalk in diabetic wounds, particularly under hyperglycemic and LPS-infected conditions, offering insights for potential immunomodulatory therapies aimed at restoring effective signaling and improving wound healing outcomes.

Background/Objectives: A sustainable inflammatory response is a significant obstacle for diabetic wound care. In this study, the pH-sensitive multifunctional hydrogel ODex/BSA-Zn was fabricated via a Schiff base and coordination force for the first time. Methods: The hydrogel consisted of oxidized dextran (ODex), bovine serum albumin (BSA), and zinc ions (Zn2+) in the absence of an additional crosslinking agent. Results: The hydrogel showed excellent mechanical stability, fast self-healing ability, and significant anti-inflammatory effects, as demonstrated by the formation of dynamic covalent bonds between the aldehyde group (-CHO) of ODex and the amino group (-NH2) of BSA via the Schiff base reaction, as well as the metal-ion coordination reaction of Zn2+ with the imidazole ring of BSA. In a diabetic mouse full-thickness cutaneous defect wound model, the ODex/BSA-Zn hydrogel could effectively inhibit the inflammatory response and increase collagen deposition, thereby accelerating the transition of macrophage M1 to M2 and promoting wound closure. This study offers a promising therapeutic approach for managing long-term diabetic ulcers.

Despite current medicine's fast-paced advances, many acute and chronic illnesses still lack truly effective and safe therapies. Cancer treatments often lead to off-target healthy tissue damage and poor therapeutic outcomes, wound standard treatments generally demonstrate poor healing efficacy and increased susceptibility to infection, and bone tissue engineering and myocardial tissue engineering can result in immunological rejection and limited availability. To tackle these issues, injectable hydrogels have emerged, and through the incorporation of nanoparticles, nanocomposite hydrogels have appeared as versatile platforms, offering improved biocompatibility, mechanical strength, stability, and precise controlled drug release, as well as targeted delivery with increased drug retention at the site of action, reducing systemic drug distribution to non-target sites. With the ability to deliver a diverse range of therapeutic entities, including low molecular weight drugs, proteins, antibodies, and even isolated cells, injectable nanocomposite hydrogels have revolutionized current therapies, working as multifunctional platforms capable of improving efficacy and safety in cancer treatment, including in chemotherapy, immunotherapy, photothermal therapy, magnetic hyperthermia, photodynamic therapy, chemodynamic therapy, radiotherapy, molecularly targeted therapy, and after tumor surgical removal, and in general, chronic diabetic or tumor-induced wound healing, as well as in bone tissue engineering and myocardial tissue engineering. This review provides a thorough summary and critical insight of current advances on injectable nanocomposite hydrogels as an innovative approach that could bring substantial contributions to biomedical research and clinical practice, with a focus on their applications in cancer therapy, wound healing management, and tissue engineering.

Dysregulation of growth factor expression causes impaired healing of diabetic foot ulcer (DFU). Platelet-derived growth factor (PDGF)-containing gel has been clinically applied for topical treatment of DFU. Recruitment of neutrophils stimulated by PDGF favors the wound healing of DFU. However, overactivation of neutrophils induced by hyperglycemia causes massive generation and long-term persistence of neutrophil extracellular traps (NETs), ultimately leading to unexpected skin damage and delayed wound repair. Here, we engineer a hierarchically-assembled hydrogel to achieve local release of the growth factor, PDGF-BB and the NET scavenger, deoxyribonuclease (DNase) I with distinct kinetics for enhanced healing of DFU. The hydrogel is constructed by crosslinking of anti-bacterial quaternized chitosan and hypochlorite-degradable nanogel via a copper-free click reaction, in which PDGF-BB is loaded in the hydrogel matrix while DNase I is encapsulated in the inner nanogel. Programmable release of combinatorial therapeutics is implemented by the hydrogel in response to the wound microenvironment. We show that the hierarchical hydrogel co-loaded with PDGF-BB and DNase I promotes neutrophil recruitment, increases endothelial cell migration, degrades excess NETs, and prevents wound infection for accelerating the wound closure in the diabetic mouse wound models.

Delayed diabetic wound regeneration can be attributed to multiple underlying factors, including bacterial infection, endogenous reactive oxygen species (ROS), impaired angiogenesis and exaggerated inflammatory response. Here, a bilayer electrospun nanofibrous membrane (ENM) was fabricated through sequential electrospinning to accelerate diabetic wound healing by addressing aforementioned challenges. For the purpose, nano Zinc Oxide was mixed into chitosan as the bottom layer of ENM (CS/ZnO NPs), while astaxanthin (AST) was encapsulated in a composite nanofibrous membrane of polyvinyl alcohol, chitosan and Ti3C2TX MXene (PVA/CS/MXene) as the upper layer, thus preparing the bilayer CZ/PCM@AST ENM, which reflected the therapeutic properties of spatial structure distribution and time series on diabetic wounds. The bilayer CZ/PCM@AST ENM was verified to possess sufficient biocompatibility and effective antibacterial properties on E. coli and S. aureus. Furthermore, the ENM facilitated sustained AST release at inflammatory sites, effectively scavenging excessive ROS and inhibiting inflammatory responses, ultimately accelerating diabetic wound healing, as demonstrated through both in vitro and in vivo evaluations. In summary, the multi-effect combination strategy improved complicated pathological microenvironment of wound sites, thereby presenting a promising method in diabetic wound treatment.

The skin acts as a vital barrier against external threats and regulates moisture levels. The skin's repair and rejuvenation encompass complex molecular and cellular mechanisms, constituting an essential yet intricate process to preserve skin integrity following trauma or surgical intervention. Acute wound repair unfolds through different interrelated stages, whereas chronic wounds pose significant healthcare challenges, often linked to conditions like diabetes and vascular diseases. Understanding of wound physiology is crucial for developing effective treatments. Chronic wounds require more comprehensive treatments, including surgical debridement, glycemic control, and antibiotic therapy. Ascorbic acid (AA) emerges as a promising wound-healing agent because it facilitates collagen synthesis, enhances antioxidant defense, promotes re-epithelialization and angiogenesis, regulates pH, and exhibits antimicrobial properties. Research outcomes on applying AA-based formulations on wound environment demonstrated its potential to accelerate wound closure and tissue regeneration, offering hope for improved wound management and reduced healthcare burdens associated with chronic wounds. The application of AA, which often utilizes innovative delivery methods and synergistic combinations with other actives, shows promise in preclinical studies for superior efficacy, biocompatibility, and controlled release profiles. Overall, AA-based therapies represent a significant avenue for advancing wound care and addressing the challenges of chronic wounds in healthcare systems.

Reduced fibroblast activity is a critical factor in the progression of diabetic ulcers. CD248, a transmembrane glycoprotein prominently expressed in activated fibroblasts, plays a pivotal role in wound healing. However, the role of CD248 in diabetic wound healing and the CD248 regulatory pathway remains largely unexplored. Our study shows that CD248 expression is significantly reduced in skin wounds from both patients and mice with diabetes. Single-cell transcriptome data analyses reveal a marked reduction of CD248-enriched secretory-reticular fibroblasts in diabetic wounds. We identify IGF-1 as a key regulator of CD248 expression through the protein kinase B/mTOR signaling pathway and the SP1 transcription factor. Overexpression of CD248 enhances fibroblast motility, elucidating the under-representation of CD248-enriched fibroblasts in diabetic wounds. Immunohistochemical staining of diabetic wound samples further confirms low SP1 expression and fewer CD248-positive secretory-reticular fibroblasts. Further investigation reveals that elevated TNFα levels in diabetic environment promotes IGF-1 resistance, and inhibiting IGF-1 induced CD248 expression. In summary, our findings underscore the critical role of the IGF1-SP1-CD248 axis in activating reticular fibroblasts during wound-healing processes. Targeting this axis in fibroblasts could help develop a therapeutic regimen for diabetic ulcers.

The most common complication of diabetes is chronic non-healing wound, which can lead to amputation in severe cases. Therefore, identifying new and effective therapies is crucial. This study extracted, isolated, and purified a homogeneous polysaccharide named BSP1-1 from Bletilla striata. The yield of BSP1-1 was 2.17 %, with a molecular weight of 2.265 × 104 Da. The monosaccharide components were identified as mannose and glucose. Using a diabetic rat wound model to study the effects of BSP1-1 on wound healing. The results showed that the wound healing rate increased in a dose-dependent manner after treatment with BSP1-1. On the 15th day after administration, the wound healing rates of the low-, medium-, and high-dose groups increased by 11.2 %, 14.6 %, and 18.9 % compared with the control group, respectively. Histological analysis showed that BSP1-1 promoted angiogenesis and collagen deposition. In the high-dose group, the collagen content increased by 11.84 % compared with the control group, and the CD31 positive cell rate increased by 7.66 %. Furthermore, compared to the DM group, BSP1-1 treatment reduced malondialdehyde (MDA) content and increased superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels (P < 0.05). It was concluded that, BSP1-1 might alleviate oxidative stress and promote wound healing through up-regulation of Nrf2 and its downstream antioxidant factor, HO-1. In summary, this study demonstrates that Bletilla striata polysaccharide can effectively accelerate diabetic wound healing.

The incidence and burden of skin wounds, especially chronic and complex wounds, have a profound impact on healthcare. Effective wound healing strategies require a multidisciplinary approach, and advances in materials science and bioengineering have paved the way for the development of novel wound healing dressing. In this context, electrospun nanofibers can mimic the architecture of the natural extracellular matrix and provide new opportunities for wound healing. Inspired by the bioelectric phenomena in the human body, electrospun nanofibrous scaffolds with electroactive characteristics are gaining widespread attention and gradually emerging. To this end, this review first summarizes the basic process of wound healing, the causes of chronic wounds, and the current status of clinical treatment, highlighting the urgency and importance of wound dressings. Then, the biological effects of electric fields, the preparation materials, and manufacturing techniques of electroactive electrospun nanofibrous (EEN) scaffolds are discussed. The latest progress of EEN scaffolds in enhancing skin wound healing is systematically reviewed, mainly including treatment and monitoring. Finally, the importance of EEN scaffold strategies to enhance wound healing is emphasized, and the challenges and prospects of EEN scaffolds are summarized.

Diabetic wound healing critically depends on functional endothelial cells for angiogenesis, yet the hyperglycemic microenvironment induces endothelial dysfunction through oxidative stress, inflammation, and senescence. Although ferroptosis has been recognized as a critical pathological factor contributing to impaired diabetic wound healing, the therapeutic potential of resveratrol (Res), a natural polyphenol with well-documented antioxidant and anti-ferroptotic properties, remains underexplored in this context. This study aimed to investigate the protective effects of Res on endothelial cells and elucidate its underlying mechanisms in diabetic wound healing. In vitro experiments systematically evaluated Res's impact on cellular inflammatory responses, senescence levels, and angiogenic capacity. Subsequent in vivo studies assessed Res's therapeutic potential by monitoring diabetic wound healing progression and analyzing associated histological changes. To clarify the mechanisms underlying Res's promotion of diabetic wound healing, we conducted comprehensive analyses measuring intracellular reactive oxygen species, lipid peroxidation levels, mitochondrial membrane potential and morphology, ferroptosis-related marker expression, and upstream signaling pathway regulation. Res significantly reduced HG-induced inflammatory responses and cellular senescence in human umbilical vein endothelial cells while enhancing their angiogenic potential in vitro. In vivo results showed that Res not only markedly accelerated diabetic wound healing but also demonstrated multiple beneficial effects, including effective suppression of cellular senescence, decreased ferroptosis levels, and significantly promoted angiogenesis. Mechanistic investigations confirmed that Res achieves these effects by inhibiting ferroptosis through activation of the PI3K-AKT-Nrf2 signaling axis. Our results demonstrate that Res protects endothelial cells from HG-induced ferroptosis by activating PI3K-AKT-Nrf2 signaling, thereby promoting angiogenesis and diabetic wound healing. These findings highlight Res as a promising therapeutic candidate for impaired diabetic wound repair and justify further clinical investigation.

Hypoxia, excessive reactive oxygen species (ROS), and an impaired inflammatory microenvironment are key barriers to diabetic wound healing, collectively hindering cell migration, proliferation, and neovascularization, ultimately leading to failure in the healing process. Therefore, developing an effective therapeutic strategy capable of simultaneously addressing these challenges remains a critical clinical need. In this study, we developed CeS-Gel, an advanced hydrogel dressing integrating live microalgae and CeO₂ nanoparticles within a dual-crosslinked silk hydrogel network. By harnessing photosynthesis, CeS-Gel provided a continuous and reliable oxygen supply, significantly enhancing cell migration and proliferation. Additionally, CeS-Gel exhibited potent ROS-scavenging properties, effectively mitigating oxidative stress-induced cellular damage while directly promoting M2 macrophage polarization, thereby modulating the inflammatory response. In vivo experiments demonstrated that CeS-Gel markedly accelerated wound healing in diabetic mice, achieving a 93.2 % wound closure rate. Furthermore, CeS-Gel effectively alleviated hypoxia, promoted neovascularization, and exhibited anti-inflammatory and immunoregulatory effects. This living microalgae-silk gel represents a promising approach for improving chronic diabetic wound healing with great potential for clinical application.

Diabetic or diabetic infectious wounds pose a global challenge, marked by delayed healing and high amputation/mortality rates. This study of participating transcriptomes and their regulators unveils critical alterations.

Transcriptome data from GEO analyzed DEGs in diabetic foot ulcers vs. controls using RNA-Seq, limma, STRINGdb, Cytoscape, and clusterProfiler for PPI networks and functional enrichment. TRRUST database was used to predict transcriptional factors (TFs). Adverse molecular pathology in different models of wounds (non-diabetic, acute diabetic, diabetic infectious wounds) was validated by RT-PCR, Western blotting, oxidative stress markers, cytokines, and histological analysis.

RNA-Seq dataset 'GSE199939' was analyzed after normalization to identify DEGs (total 47 DEG, 31 upregulated, 16 downregulated) in diabetic wound healing using limma. PPI networks revealed seven hub genes which were further processed for functional enrichment and highlighted oxidative stress, ECM remodeling, AGE-RAGE, and IL-17 signaling in diabetic wound pathology. Additionally, 17 key TFs were identified as hub gene regulators. The healing rate was significantly impaired in diabetic wounds, with delayed contraction, elevated pro-inflammatory cytokines, oxidative stress, reduced anti-inflammatory cytokines, antioxidants, angiogenesis, collagen deposition, and re-epithelialization. Further, RT-PCR and Western blot analysis validated the expression of target genes including the overexpression of HSPA1B, FOS, and down-expression of SOD2, COL1A1, and CCL2, whereas TFs including upregulation of RELA, NFKB1, STAT3, and downregulation of SP1 and JUN in diabetic and diabetic infectious wounds.

Molecular analyses reveal disrupted oxidative stress, ECM remodeling, and inflammatory signaling in diabetic and diabetic infectious, emphasizing impaired healing dynamics and identifying therapeutic targets.

Type 2 Diabetes (T2D) is a complex metabolic disorder that affects multiple organs, leading to severe complications in the pancreas, kidneys, liver, and heart. Prolonged hyperglycemia, along with oxidative stress and chronic inflammation, plays a crucial role in accelerating tissue damage, significantly increasing the risk of diabetic complications such as nephropathy, hepatopathy, and cardiovascular disease. This review evaluates the protective effects of various antidiabetic treatments on organ tissues affected by T2D, based on findings from experimental animal models. Metformin, a first-line antidiabetic agent, has been widely recognized for its ability to reduce inflammation and oxidative stress, thereby mitigating diabetes-induced organ damage. Its protective role extends beyond glucose regulation, offering benefits such as improved mitochondrial function and reduced fibrosis in affected tissues. In addition to traditional therapies, new classes of antidiabetic drugs, including sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists not only improve glycemic control but also exhibit nephroprotective and cardioprotective properties by reducing glomerular hyperfiltration, oxidative stress, and inflammation. Similarly, GLP-1 receptor agonists have been associated with reduced hepatic steatosis and enhanced cardiovascular function. Preclinical studies suggest that tirzepatide, a dual GLP-1/gastric inhibitory polypeptide receptor agonist may offer superior metabolic benefits compared to conventional GLP-1 agonists by improving β-cell function, enhancing insulin sensitivity, and reducing fatty liver progression. Despite promising preclinical results, differences between animal models and human physiology pose a challenge. Further clinical research is needed to confirm these effects and refine treatment strategies. Future T2D management aims to go beyond glycemic control, emphasizing organ protection and long-term disease prevention.

A myriad of physical, psychosocial and environmental sequelae are associated with limb loss. However, there is a paucity of empirical South African data, which focusses on these sequelae, how they interface with the amputee's quality of life as well as the challenges they experience following amputation.

This study sought to explore the biopsychosocial effects of amputation and how it affected the quality of life of transtibial amputees.

A qualitative approach guided this study. Data were collected using one-on-one interviews with 14 unilateral transtibial amputees. Data were analysed thematically.

Five broad themes emerged from the inquiry, which captured amputees' experiences of phantom limb pain, body image disturbances and their challenges related to adapting to daily activities. Participants also expressed the salience of familial support as well as the importance of psychological interventions to cope.

The findings suggested that support networks and professional psychological intervention are imperative in facilitating successful adjustment to the amputation experience. Raising awareness of limb loss, in both rural and urban settings, may help reduce the stigma attached to it.

Quality of life comprises several domains, namely physical, psychological, environmental and social. However, limited local and international data exists regarding the environmental and social effects. This study brought to the fore the positive and negative effects of amputation in each domain, as well as various strategies, which facilitate successful adjustment to amputation.

Mesenchymal stromal cell-derived small extracellular vesicles (MSC-sEVs) have shown great promise in promoting tissue repair, including skin wound healing, but challenges like rapid degradation and short retention have limited their clinical application. Hydrogels have emerged as effective carriers for sustained EV release. Three-dimensional printing enables the development of personalized skin substitutes tailored to the wound size and shape. This study aimed to develop 3D bioprinted gelatin-genipin hydrogels incorporating human umbilical cord MSC-sEVs (hUCMSC-sEVs) for future skin wound healing applications. Gelatin hydrogels (8% and 10% w/v) were crosslinked with 0.3% genipin (GECL) to improve stability. The hydrogels were evaluated for their suitability for extrusion-based 3D bioprinting and physicochemical properties, such as the swelling ratio, hydrophilicity, enzymatic degradation, and water vapor transmission rate (WVTR). Chemical characterization was performed using EDX, XRD, and FTIR. The hUCMSC-sEVs were isolated via centrifugation and tangential flow filtration (TFF) and characterized. The crosslinked hydrogels were successfully 3D bioprinted and demonstrated superior properties, including high hydrophilicity, a swelling ratio of ~500%, slower degradation, and optimal WVTR. hUCMSC-sEVs, ranging from 50 to 200 nm, were positive for surface and cytosolic markers. Adding 75 μg/mL of hUCMSC-EVs into 10% GECL hydrogels significantly improved the biocompatibility. These hydrogels offer ideal properties for 3D bioprinting and wound healing, demonstrating their potential as biomaterial scaffolds for skin tissue regeneration applications.

Accelerating wound healing is a crucial objective in surgical and regenerative medicine. The wound healing process involves three key stages: inflammation, cell proliferation, and tissue repair. Mesenchymal stem cells (MSCs) have demonstrated significant therapeutic potential in promoting tissue regeneration, particularly by enhancing epidermal cell migration and proliferation. However, the precise molecular mechanisms underlying MSC-mediated wound healing remain unclear. This review highlights the pivotal role of MSCs and their exosomes in wound repair, with a specific focus on critical signaling pathways, including PI3K/Akt, WNT/β-catenin, Notch, and MAPK. These pathways regulate essential cellular processes such as proliferation, differentiation, and angiogenesis. Moreover, in vitro and in vivo studies reveal that MSCs accelerate wound closure, enhance collagen deposition, and modulate immune responses, contributing to improved tissue regeneration. Understanding these mechanisms provides valuable insights into MSC-based therapeutic strategies for enhancing wound healing.

A traditional preparation of Ya-Samarn-Phlae (T-YaSP) consists of Garcinia mangostana L., Oryza sativa L., Curcuma longa L., and Areca catechu L. and has been used in Thai medicine as an infused oil for treating chronic and diabetic wounds. It is reputed for its antibacterial, antioxidant, and wound-healing properties. Despite its traditional use, scientific validation of the mechanisms underlying diabetic wound healing remains limited.

This study aims to develop a novel gauze dressing impregnated with an ointment containing T-YaSP (YaSP) to enhance its practical application and elucidate the mechanisms of action in promoting wound healing in both non-diabetic and type 2 diabetic wounds of this ointment.

YaSP was developed and tested for stability and dermal irritation. Changes in chemical markers during storage were measured both qualitatively and quantitatively. Its anti-inflammatory activity was assessed using the carrageenan-induced rat paw edema model. The effect of YaSP on levels of nitric oxide (NO), myeloperoxidase (MPO), malondialdehyde (MDA), inflammatory cytokines (TNF-α, IL-1β, and PGE2), and pro-inflammatory enzymes (iNOS and COX-2) was measured. The wound-healing effects of YaSP were assessed using full-thickness (6 mm diameter) wound models in both non-diabetic Wistar rats and type 2 diabetic Goto-Kakizaki rats. In addition to evaluating wound closure on days 0, 3, 5, 7, 9, and 11, the influence on TGF-β1, VEGF, and the production of collagen types I and III, which indicate the inflammatory, proliferative, and remodeling phases, was measured.

During the 6-month storage period, the α-mangostin content measured in YaSP did not decrease; however, the curcumin level showed a significant reduction. Topical treatment with YaSP demonstrated strong anti-inflammatory activity and alleviated oxidative stress and inflammatory markers. YaSP improved wound closure rates in both diabetic and non-diabetic models. Levels of TGF-β1 and VEGF increased, indicating the promotion of angiogenesis and granulation tissue formation during the proliferation phase on the seventh day. Additionally, TGF-β1 levels dropped on the 11th day, aligning with diminished inflammation and enhanced remodeling. The treatment balanced collagen synthesis, increasing type III collagen in the early stages and type I collagen in the later stages of wound healing. Histological analysis confirmed reduced inflammation, enhanced neovascularization, and increased collagen production.

A gauze dressing impregnated with YaSP provides a practical solution for diabetic wound management and demonstrates strong wound-healing properties by modulating excess inflammation, promoting angiogenesis during the proliferation phase, and regulating collagen synthesis throughout the remodeling phase. This discovery reveals, for the first time, the underlying mechanisms of action of this traditional formulation, highlighting its potential as a cost-effective alternative for managing chronic wounds in resource-limited settings.

Amyloid fibrils have emerged as excellent templates and building blocks for the development of ordered functional materials with considerable potential in biomedical applications. Here, lysozyme amyloid fibrils (Lys-AFs) are employed as templates for the in situ synthesis of ceria nanozymes (Lys-AFs-Ceria) with ultrafine dimensions, an optimized Ce3+/Ce4+ ratio, and uniform distribution on the fibril surface, addressing the challenges of low catalytic efficiency and high susceptibility to aggregation typical of traditional methods. As a proof of concept, it is further applied Lys-AFs-Ceria to develop hydrogel/microneedle for treating bacteria-infected diabetic wounds via non-covalent interactions between polyphenols and amyloid fibrils incorporating glucose oxidase (GOX). The hydrogel/microneedle facilitates superoxide dismutase and catalase cascade catalysis by Lys-AFs-Ceria, and integrates GOX-mediated glucose consumption, synergistically achieving glucose reduction, reactive oxygen species elimination, and hypoxia alleviation in the diabetic wound infection microenvironment. In addition to antibacterial properties and tissue regeneration promotion of Lys-AFs scaffold, Lys-AFs-Ceria regulates macrophages polarization toward an anti-inflammatory M2 state. Collectively, these attributes contribute to the enhanced efficacy of diabetic wound healing, with in vivo studies demonstrating increased healing efficiency following a single application, and more in general an effective strategy toward high-catalytic and stable nanozymes.

Delayed wound healing is among the major peripheral complications of diabetes. Synergistic treatment of diabetic wounds (DW) with phytochemicals and non-invasive techniques has shown promising results. The synergistic effect of vanillin and photobiomodulation (PBM) on DW healing, and their modulatory effect on oxidative stress and glucose metabolism was investigated in DW fibroblast cells (WS1). DW cells were treated with vanillin and vanillin + PBM. Control consisted of WS1 cells, untreated DW cells, and DW cells treated with PBM. Diabetes was induced by repeated growth in complete MEM containing high D-glucose (22.6 mM/L). Wounds were induced by central scratching. Cells were treated with vanillin at various concentrations for 2 h prior to PBM at 660 nm with a fluence of 5 J/cm2 for an irradiation time of 780 s, followed by 24 h incubation. Induction of DW led to a decreased glutathione level, and decreased superoxide dismutase, catalase, glutathione reductase, glyoxalase, and Na/K-ATPase activities, while concomitantly increasing the activities of fructose-1,6-bisphosphatase, glucose 6-phosphatase, E-NTPDase, and 5-lipoxygenase. These levels and activities were reversed following treatment with 12 μg/mL vanillin, and 6 μg/mL vanillin + PBM having the best effects. However, treatment with 24 μg/mL vanillin and vanillin + PBM showed no significant effects. Except for cells treated with 24 μg/mL vanillin and vanillin + PBM, morphological analysis indicated wound closures compared to the controls. These results indicate the synergistic therapeutic effect of vanillin + PBM on the management of diabetic wounds, with 6 μg/mL vanillin + PBM displaying the best effect.

Delayed diabetic wound (DBW) healing is a severe complication of diabetes, characterized notably by peripheral sensory neuropathy. The underlying mechanism of sensory nerves and DBW remain unclear. Here, we demonstrate the role of calcitonin gene-related peptide (CGRP) in regulating epithelialization and angiogenesis in DBW. Subsequently, we design and synthesis a gelatin methacryloyl (GelMA-CGRP) hydrogel that slowly releases CGRP, and evaluated its effect on promoting DBW healing. The results show that CGRP is abnormally downregulated in DBW, and CGRP ablation further delays DBW healing. This is due to the reduced M2 polarization and decreased angiogenesis in the absence of CGRP, whereas local application of GelMA-CGRP accelerates DBW healing. Mechanistic studies indicate that CGRP promotes M2 macrophage polarization by inhibiting the p53 signaling pathway and enhances endothelial cell function, thereby accelerating DBW healing. These findings suggest that CGRP could provide a novel therapeutic approach for diabetic wound treatment. STATEMENT OF SIGNIFICANCE: Current methods for treating diabetic wounds have many limitations. Compared to conventional dressings, hydrogels combined with drugs or biological factors to promote diabetic wound healing have become an important research direction in recent years. This study reveals the key role of CGRP in the pathogenesis of diabetic wounds. The research found that CGRP promotes M2 macrophage polarization and angiogenesis by inhibiting the p53 signaling pathway, thereby promoting diabetic wound healing. We further utilized the carrier properties of GelMA hydrogel to develop a GelMA-CGRP hydrogel material that slowly delivers CGRP and effectively treats diabetic wounds. This material demonstrates strong biocompatibility and antimicrobial properties, offering a novel approach for the treatment of diabetic wounds.