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Excessive local movement and inflammation are common problems in the process of wound repair, which lead to failure of later repair. In order to solve this problem, inspired by the octopus sucker structure, we successfully developed a photocrosslinked hydrogel that can adsorb skin surface fascia. In addition, extracellular vesicles from human bone marrow mesenchymal stem cells are encapsulated in the octopus like sucker structure. The morphology and structure of extracellular vesicles in bone marrow mesenchymal stem cells were detected by scanning electron microscopy and particle size analysis. Through iTRAQ, we tested the expression of angiogenesis related proteins contained in extracellular vesicles. Design small interfering RNA to verify its impact on angiogenic related genes and proteins. Macrophage polarization was detected by immunofluorescence. The expression of new blood vessels was detected by constructing a skin defect model and injecting microfil contrast agent into the heart. When the sucker is firmly adsorbed on the damaged wound, the sucker will slowly degrade. Using its delivery system, it is observed that the extracellular vesicles are released in the wound. Through iTRAQ, it was found that the angiogenesis regulator (angiopoietin-like 4, angiopoietin-like 3 and aminopeptidase N) released in the extracellular vesicles regulates collagen deposition, angiogenesis, and inhibits macrophage aggregation. In addition, the slowly released extracellular vesicles will further inhibit the polarization of proinflammatory macrophages. This biological behavior can provide an adaptive microenvironment for skin regeneration at an early stage. This new bionic octopus sucker structure gel creates a good microenvironment for wound repair and shortens the wound healing time. Therefore, this hydrogel inspired by the octopus sucker structure may provide a good strategy and commercial value for promoting wound repair treatment in clinical practice.

Diabetic foot ulcers (DFUs) are common chronic wounds and a common complication of diabetes. The foot is the main site of diabetic ulcers, which involve small and medium-sized arteries, peripheral nerves, and microcirculation, among others. DFUs are prone to coinfections and affect many diabetic patients. In recent years, interdisciplinary research combining medicine and material science has been increasing and has achieved significant clinical therapeutic effects, and the application of vacuum sealing drainage (VSD) in the treatment of DFUs is a typical representative of this progress, but the mechanism of action remains unclear. In this review, we integrated bioinformatics and literature and found that ferroptosis is an important signaling pathway through which VSD promotes the healing of DFUs and that System Xc-GSH-GPX4 and NAD(P)H-CoQ10-FSP1 are important axes in this signaling pathway, and we speculate that VSD is most likely to inhibit ferroptosis to promote DFU healing through the above axes. In addition, we found that some classical pathways, such as the TNF, NF-κB, and Wnt/β-catenin pathways, are also involved in the VSD-mediated promotion of DFU healing. We also compiled and reviewed the progress from clinical studies on VSD, and this information provides a reference for the study of VSD in the treatment of DFUs.

The impaired healing of chronic wounds is often attributed to the ischemic and hypoxic microenvironment, leading to increased cell death. Ferroptosis, a novel form of cell death unveiled in recent years, could potentially be linked with the process of wound healing. In this study, we explored the significance and mechanism of ferroptosis in ischemic wounds. Using transmission electron microscopy, Western blot, flow cytometry, immunofluorescence, and glutathione (GSH) assay, we observed that the death of primary mouse skin fibroblasts induced by oxygen and glucose deprivation (OGD) was associated with ferroptosis. Specifically, we observed elevated intracellular Fe2+ and lipid peroxidation levels and decreased GSH levels in vitro, indicative of ferroptosis. Importantly, we found that ferroptosis in OGD-treated skin fibroblasts was dependent on autophagy, as the autophagy inhibitor chloroquine phosphate (CHQ) significantly reduced ferroptosis induced by OGD. Moreover, our study revealed that NCOA4-mediated ferritinophagy significantly contributed to the occurrence of ferroptosis induced by OGD in skin fibroblasts. Additionally, we identified the involvement of YAP in the regulation of ferritinophagy, with YAP suppressing NCOA4 expression in OGD-treated skin fibroblasts, thereby reducing ferroptosis. Furthermore, in ischemic wound models in mice, both inhibitors of ferroptosis and autophagy promoted wound healing, while a YAP inhibitor, verteporfin, delayed wound healing. In conclusion, these findings indicate that ferroptosis, regulated by YAP through ferritinophagy inhibition, presents a novel mechanism responsible for the delayed healing of ischemic wounds. Understanding this process could offer promising therapeutic targets to improve wound healing in ischemic conditions.

Objective: Gongying-Jiedu-Xiji recipe (DDL, batch number Z01080175) reduces body temperature, detoxifies, activates the blood circulation, reduces swelling, and dispels decay and pus. The aim of this study was to investigate the mechanism of action by which DDL functions in the treatment of venous ulcers (VUs).Methods: Normal tissues as well as VU tissues before and after DDL treatment were collected from nine VU patients in the hospital with ethical approval. These three tissues were subjected to Prussian blue iron staining, immunoblotting, immunohistochemistry, immunofluorescence, and quantitative real-time PCR to detect the expression of ferroptosis suppressor protein 1 (FSP1), coenzyme Q (CoQ), 4-hydroxynonenal (4-HNE), and glutathione peroxidase 4 (GPX4). After successful validation of the heme-induced human foreskin fibroblast (HFF) ferroptosis model, lyophilized DDL powder was added to the cells, and the cells were subjected to viability assays, immunoblotting, flow cytometry, glutathione (GSH) and malonaldehyde (MDA) assays, electron microscopy and qPCR assays.Results: Ferroptosis in VU tissues was stronger than that in normal tissues, and ferroptosis in VU tissues after DDL treatment was weaker than that before treatment. Inhibition of CoQ and FSP1 and transfection of FSP1 influenced the effects of DDL.Conclusion: Our results suggest that DDL may promote healing by attenuating ferroptosis in VUs and that DDL may promote VU healing by modulating the CoQ-FSP1 axis.

Abstract Naringenin is a citrus flavonoid with various biological functions and a potential therapeutic agent for skin diseases, such as UV radiation and atopic dermatitis. The present study investigates the therapeutic effect and pharmacological mechanism of naringenin on chronic wounds. Using network pharmacology, we identified 163 potential targets and 12 key targets of naringenin. Oxidative stress was confirmed to be the main biological process modulated by naringenin. The transcription factor p65 (RELA), alpha serine/threonine-protein kinase (AKT1), mitogen-activated protein kinase 1 (MAPK1) and mitogen-activated protein kinase 3 (MAPK3) were identified as common targets of multiple pathways involved in treating chronic wounds. Molecular docking verified that these four targets stably bound naringenin. Naringenin promoted wound healing in mice in vivo by inhibiting wound inflammation. Furthermore, in vitro experiments showed that a low naringenin concentration did not significantly affect normal skin cell viability and cell apoptosis; a high naringenin concentration was cytotoxic and reduced cell survival by promoting apoptosis. Meanwhile, comprehensive network pharmacology, molecular docking and in vivo and in vitro experiments revealed that naringenin could treat chronic wounds by alleviating oxidative stress and reducing the inflammatory response. The underlying mechanism of naringenin in chronic wound therapy involved modulating the RELA, AKT1 and MAPK1/3 signalling pathways to inhibit ROS production and inflammatory cytokine expression.

Abstract Background Skin innervation is crucial for normal wound healing. However, the relationship between nerve receptors and wound healing and the intrinsic mechanism remains to be further identified. In this study, we investigated the role of a calcitonin gene-related peptide (CGRP) receptor component, receptor activity‐modifying protein 1 (RAMP1), in mouse skin fibroblast (MSF) proliferation. Methods In vivo, Western blotting and immunohistochemical (IHC) staining of mouse skin wounds tissue was used to detect changes in RAMP1 expression. In vitro, RAMP1 was overexpressed in MSF cell lines by infection with Tet-On-Flag-RAMP1 lentivirus and doxycycline (DOX) induction. An IncuCyte S3 Live-Cell Analysis System was used to assess and compare the proliferation rate differences between different treatment groups. Total protein and subcellular extraction Western blot analysis, quantitative real-time-polymerase chain reaction (qPCR) analysis, and immunofluorescence (IF) staining analysis were conducted to detect signalling molecule expression and/or distribution. The CUT & RUN assay and dual-luciferase reporter assay were applied to measure protein-DNA interactions. Results RAMP1 expression levels were altered during skin wound healing in mice. RAMP1 overexpression promoted MSF proliferation. Mechanistically, total Yes-associated protein (YAP) and nuclear YAP protein expression was increased in RAMP1-overexpressing MSFs. RAMP1 overexpression increased inhibitory guanine nucleotide-binding protein (G protein) α subunit 3 (Gαi3) expression and activated downstream protein kinase A (PKA), and both elevated the expression of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and activated it, promoting the transcription of YAP, elevating the total YAP level and promoting MSF proliferation. Conclusions Based on these data, we report, for the first time, that changes in the total RAMP1 levels during wound healing and RAMP1 overexpression alone can promote MSF proliferation via the Gαi3-PKA-CREB-YAP axis, a finding critical for understanding RAMP1 function, suggesting that this pathway is an attractive and accurate nerve target for skin wound treatment. Video Abstract

BackgroundSkin innervation plays an important role in wound healing by either direct contact with or indirect secretions that impact skin cells. Many studies in this field have been published; however, there is a lack of bibliometric analyses focusing on the effect of skin innervation on skin wound healing. In this study, we aimed to analyse the research trends, status, and hotspots in this field.MethodsReviews and articles published in English were extracted from the Web of Science Core Collection (WoSCC) database based on subject term searches. Microsoft Office Excel, VOSviewer, and CiteSpace were used to analyse publication date, country or region, institution, author, and author keywords.ResultsA total of 368 papers published between 1959 and 2022 were included in the analysis. Although there was a pulsation during this period, there was an overall upward trend in studies related to the effect of skin innervation on wound healing. The United States, particularly the University of Washington, and Gibran, Nicole S. from the University of Washington, was the most active in this field. Wound Repair and Regeneration published the most relevant literature, and “Calcitonin gene-related peptide: physiology and pathophysiology” had the highest total number of citations. “Diabetic foot ulcer,” “epidermal stem cells,” “mesenchymal stem cells,” and “mast cells” are current and potential future research hotspots.ConclusionThis bibliometric analysis will inform the overall trends in research related to the effect of skin innervation on wound healing, summarise relevant research hotspots, and guide future work.