Delayed and nonhealing of diabetic wounds imposes substantial economic burdens and physical pain on patients.Mesenchymal stem cells(MSCs)promote diabetic wound healing.Particularly when MSCs aggregate into multicellul...Delayed and nonhealing of diabetic wounds imposes substantial economic burdens and physical pain on patients.Mesenchymal stem cells(MSCs)promote diabetic wound healing.Particularly when MSCs aggregate into multicellular spheroids,their therapeutic effect is enhanced.However,traditional culture platforms are inadequate for the efficient preparation and delivery of MSC spheroids,resulting in inefficiencies and inconveniences in MSC spheroid therapy.In this study,a three-dimensional porous nanofibrous dressing(NFD)is prepared using a combination of electrospinning and homogeneous freeze-drying.Using thermal crosslinking,the NFD not only achieves satisfactory elasticity but also maintains notable cytocompatibility.Through the design of its structure and chemical composition,the NFD allows MSCs to spontaneously form MSC spheroids with controllable sizes,serving as MSC spheroid delivery systems for diabetic wound sites.Most importantly,MSC spheroids cultured on the NFD exhibit improved secretion of vascular endothelial growth factor,basic fibroblast growth factor,and hepatocyte growth factor,thereby accelerating diabetic wound healing.The NFD provides a competitive strategy for MSC spheroid formation and delivery to promote diabetic wound healing.展开更多
Diabetic wounds,characterized by prolonged inflammation and impaired vascularization,are a serious complication of diabetes.This study aimed to design a gelatin methacrylate(GelMA)hydrogel for the sustained release of...Diabetic wounds,characterized by prolonged inflammation and impaired vascularization,are a serious complication of diabetes.This study aimed to design a gelatin methacrylate(GelMA)hydrogel for the sustained release of netrin-1 and evaluate its potential as a scaffold to promote diabetic wound healing.The results showed that netrin-1 was highly expressed during the inflammation and proliferation phases of normal wounds,whereas it synchronously exhibited aberrantly low expression in diabetic wounds.Neutralization of netrin-1 inhibited normal wound healing,and the topical application of netrin-1 accelerated diabetic wound healing.Mechanistic studies demonstrated that netrin-1 regulated macrophage heterogeneity via the A2bR/STAT/PPARγsignaling pathway and promoted the function of endothelial cells,thus accelerating diabetic wound healing.These data suggest that netrin-1 is a potential therapeutic target for diabetic wounds.展开更多
Diabetes mellitus(DM),an increasingly prevalent chronic metabolic disease,is characterised by prolonged hyperglycaemia,which leads to long-term health consequences.Although much effort has been put into understanding ...Diabetes mellitus(DM),an increasingly prevalent chronic metabolic disease,is characterised by prolonged hyperglycaemia,which leads to long-term health consequences.Although much effort has been put into understanding the pathogenesis of diabetic wounds,the underlying mechanisms remain unclear.The advent of single-cell RNA sequencing(scRNAseq)has revolutionised biological research by enabling the identification of novel cell types,the discovery of cellular markers,the analysis of gene expression patterns and the prediction of develop-mental trajectories.This powerful tool allows for an in-depth exploration of pathogenesis at the cellular and molecular levels.In this editorial,we focus on progenitor-based repair strategies for diabetic wound healing as revealed by scRNAseq and highlight the biological behaviour of various healing-related cells and the alteration of signalling pathways in the process of diabetic wound healing.ScRNAseq could not only deepen our understanding of the complex biology of diabetic wounds but also identify and validate new targets for inter-vention,offering hope for improved patient outcomes in the management of this challenging complication of DM.展开更多
In this editorial,we discuss the article by Wen et al published.Diabetic foot ulcers are prevalent and serious complications of diabetes,significantly impacting patients’quality of life and often leading to disabilit...In this editorial,we discuss the article by Wen et al published.Diabetic foot ulcers are prevalent and serious complications of diabetes,significantly impacting patients’quality of life and often leading to disability or death,thereby placing a heavy burden on society.Effective diabetic wound healing is hindered by an imbalance in macrophage polarization;many macrophages fail to transition from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype,which is crucial for tissue remodelling and repair.The wound healing process is both dynamic and complex.Healthy M1 macrophages,which have strong phagocytic abilities,are vital during the inflammatory phase of diabetic wound healing.However,the failure to transition to M2 macrophages during the proliferative phase hinders wound healing.We anticipate the development of new therapies that can repair damaged M1 macrophages during the inflammatory phase and promote M2 macrophage polarization during the proliferative phase,thereby enhancing the overall healing process.展开更多
Delayed or non-healing of diabetic wounds is a significant complication,often attributed to high glucose-induced M1 macrophage accumulation,impaired angiogenesis,and reactive oxygen species(ROS)buildup.Addressing this...Delayed or non-healing of diabetic wounds is a significant complication,often attributed to high glucose-induced M1 macrophage accumulation,impaired angiogenesis,and reactive oxygen species(ROS)buildup.Addressing this,we introduced a strontium polyphenol network microneedle patch(SrC-MPNs@MN-PP)for percutaneous drug delivery.This patch,formulated with polymer poly(γ-glutamic acid)(γ-PGA)and epsilon-poly-l-lysine(ε-PLL),incorporates strontium polyphenol networks(SrC-MPNs).The release of chlorogenic acid(CGA)from SrC-MPNs not only neutralizes ROS,but strontium ions also foster angiogen-esis.Consequently,SrC-MPNs@MN-PP can ameliorate the diabetic wound microenvironment and expedite healing.展开更多
Diabetic wounds, as a complication of diabetes, are slow to heal and seriously affect the quality of life of patients. Functional hydrogel dressing is an effective approach to improve diabetic wound healing. Electrica...Diabetic wounds, as a complication of diabetes, are slow to heal and seriously affect the quality of life of patients. Functional hydrogel dressing is an effective approach to improve diabetic wound healing. Electrical stimulation (ES) therapy is conducive to promoting cell migration and wound healing. In this work, a multifunctional PPTZ hydrogel wound dressing was developed by freeze-thaw method with polyvinyl alcohol (PVA), phytic acid (PA), tannic acid (TA), and Zinc chloride. The obtained PPTZ hydrogel has good mechanical properties (stress and strain of 700.03 kPa and 575.08%), light transmittance (close to 100%) and antibacterial rate (over 75%). With good biocompatibility, antioxidant abilities and conductivity, the PPTZ hydrogel could effectively promote the healing of diabetic wounds with two weeks under the action of electric field, which provides an auxiliary treatment strategy for diabetic patients.展开更多
Diabetic wounds are a difficult medical challenge.Excessive secretion of matrix metalloproteinase-9(MMP-9)in diabetic wounds further degrades the extracellular matrix and growth factors and causes severe vascular dama...Diabetic wounds are a difficult medical challenge.Excessive secretion of matrix metalloproteinase-9(MMP-9)in diabetic wounds further degrades the extracellular matrix and growth factors and causes severe vascular damage,which seriously hinders diabetic wound healing.To solve these issues,a double-network porous hydrogel composed of poly(methyl methacrylate-co-acrylamide)(p(MMA-co-AM))and polyvinyl alcohol(PVA)was constructed by the high internal phase emulsion(HIPE)technique for the delivery of potassium sucrose octasulfate(PSO),a drug that can inhibit MMPs,increase angiogenesis and improve microcirculation.The hydrogel possessed a typical polyHIPE hierarchical microstructure with interconnected porous morphologies,high porosity,high specific surface area,excellent mechanical properties and suitable swelling properties.Meanwhile,the p(MMA-co-AM)/PVA@PSO hydrogel showed high drug-loading performance and effective PSO release.In addition,both in vitro and in vivo studies showed that the p(MMA-co-AM)/PVA@PSO hydrogel had good biocompatibility and significantly accelerated diabetic wound healing by inhibiting excessive MMP-9 in diabetic wounds,increasing growth factor secretion,improving vascularization,increasing collagen deposition and promoting re-epithelialization.Therefore,this study provided a reliable therapeutic strategy for diabetic wound healing,some theoretical basis and new insights for the rational design and preparation of wound hydrogel dressings with high porosity,high drug-loading performance and excellent mechanical properties.展开更多
Healing of chronic diabetic wounds is challenging due to complications of severe inflammatory microenvironment,bacterial infection and poor vascular formation.Herein,a novel injectable polyvinyl alcohol-hyaluronic aci...Healing of chronic diabetic wounds is challenging due to complications of severe inflammatory microenvironment,bacterial infection and poor vascular formation.Herein,a novel injectable polyvinyl alcohol-hyaluronic acid-based composite hydrogel was developed,with tannic acid(TA)and silicate functionalization to fabricate an‘all-in-one’hydrogel PTKH.On one hand,after being locally injected into the wound site,the hydrogel underwent a gradual sol-gel transition in situ,forming an adhesive and protective dressing for the wound.Manipulations of rheological characteristics,mechanical properties and swelling ability of PTKH could be performed via regulating TA and silicate content in hydrogel.On the other hand,PTKH was capable of eliminating reactive oxygen species overexpression,combating infection and generating a cell-favored microenvironment for wound healing acceleration in vitro.Subsequent animal studies demonstrated that PTKH could greatly stimulate angiogenesis and epithelization,accompanied with inflammation and infection risk reduction.Therefore,in consideration of its impressive in vitro and in vivo outcomes,this‘all-in-one’multifunctional hydrogel may hold promise for chronic diabetic wound treatment.展开更多
Diabetes mellitus,an epidemic with a rapidly increasing number of patients,always leads to delayed wound healing associated with consistent pro-inflammatory M1 polarization,decreased angiogenesis and increased reactiv...Diabetes mellitus,an epidemic with a rapidly increasing number of patients,always leads to delayed wound healing associated with consistent pro-inflammatory M1 polarization,decreased angiogenesis and increased reactive oxygen species(ROS)in the microenvironment.Herein,a poly(lactic-co-glycolic acid)(PLGA)-based microneedle patch loaded with magnesium hydride(MgH_(2))(MN-MgH_(2))is manufactured for defeating diabetic wounds.The application of microneedle patch contributes to the transdermal delivery and the prolonged release of MgH_(2) that can generate hydrogen(H_(2))and magnesium ions(Mg^(2+))after reaction with body fluids.The released H_(2) reduces the production of ROS,transforming the pathological microenvironment induced by diabetes mellitus.Meanwhile,the released Mg^(2+)promotes the polarization of pro-healing M2 macrophages.Consequently,cell proliferation and migration are improved,and angiogenesis and tissue regeneration are enhanced.Such intelligent microneedle patch provides a novel way for accelerating wound healing through steadily preserving and releasing of H_(2) and Mg^(2+)locally and sustainably.展开更多
Chronic diabetic wound healing remains a formidable challenge due to susceptibility to bacterial infection,excessive oxidative stress,and poor angiogenesis.To address these issues,a sodium alginate(SA)based phototherm...Chronic diabetic wound healing remains a formidable challenge due to susceptibility to bacterial infection,excessive oxidative stress,and poor angiogenesis.To address these issues,a sodium alginate(SA)based photothermal hydrogel dressing with multifunction was fabricated to facilitate wound treatment.Ceria nanoparticles(CeO_(2)NPs)was synthesized,and their antibacterial performance by near-infrared light triggered photothermal effects was first studied and verified in this work.In addition,to release CeO_(2)NPs to achieve antioxidation and pro-vascularization,thermosensitive gelatin(Gel)was utilized to embed the nanoparticles in advance and then composited in SA hydrogel networks.SA network was finally strengthened by acid soaking to form partially crystalline regions to act as natural crosslinkers.Results showed that the Gel/SA/CeO_(2)hydrogel displayed temperature-responsive release of CeO_(2)NPs,significant antibacterial and antioxidative activity,as well as the ability to remove without injury and promote infected diabetic wound healing with low cytotoxicity,according to antibacterial investigations,cell studies,and in vivo animal studies.This research offers not only a successful method for quickening the healing of diabetic wounds but also a fresh approach to the general use of CeO_(2)NPs.展开更多
Chronic diabetic wound remains a critical challenge suffering from the complicated negative microenvironments,such as high-glucose,excessive reactive oxygen species(ROS),hypoxia and malnutrition.Unfortunately,few stra...Chronic diabetic wound remains a critical challenge suffering from the complicated negative microenvironments,such as high-glucose,excessive reactive oxygen species(ROS),hypoxia and malnutrition.Unfortunately,few strategies have been developed to ameliorate the multiple microenvironments simultaneously.In this study,Chlorella sp.(Chlorella)hydrogels were prepared against diabetic wounds.In vitro experiments demonstrated that living Chlorella could produce dissolved oxygen by photosynthesis,actively consume glucose and deplete ROS with the inherent antioxidants,during the daytime.At night,Chlorella was inactivated in situ by chlorine dioxide with human-body harmless concentration to utilize its abundant contents.It was verified in vitro that the inactivated-Chlorella could supply nutrition,relieve inflammation and terminate the oxygen-consumption of Chlorella-respiration.The advantages of living Chlorella and its contents were integrated ingeniously.The abovementioned functions were proven to accelerate cell proliferation,migration and angiogenesis in vitro.Then,streptozotocininduced diabetic mice were employed for further validation.The in vivo outcomes confirmed that Chlorella could ameliorate the undesirable microenvironments,including hypoxia,high-glucose,excessiveROS and chronic inflammation,thereby synergistically promoting tissue regeneration.Given the results above,Chlorella is considered as a tailor-made therapeutic strategy for diabetic wound healing.展开更多
Neovascularization is critical to improve the diabetic microenvironment,deliver abundant nutrients to the wound and promote wound closure.However,the excess of oxidative stress impedes the healing process.Herein,a sel...Neovascularization is critical to improve the diabetic microenvironment,deliver abundant nutrients to the wound and promote wound closure.However,the excess of oxidative stress impedes the healing process.Herein,a self-adaptive multifunctional hydrogel with self-healing property and injectability is fabricated through a boronic ester-based reaction between the phenylboronic acid groups of the 3-carboxyl-4-fluorophenylboronic acid-grafted quaternized chitosan and the hydroxyl groups of the polyvinyl alcohol,in which pro-angiogenic drug of desferrioxamine(DFO)is loaded in the form of gelatin microspheres(DFO@G).The boronic ester bonds of the hydrogel can self-adaptively react with hyperglycemic and hydrogen peroxide to alleviate oxidative stress and release DFO@G in the early phase of wound healing.A sustained release of DFO is then realized by responding to overexpressed matrix metalloproteinases.In a full-thickness diabetic wound model,the DFO@G loaded hydrogel accelerates angiogenesis by upregulating expression of hypoxia-inducible factor-1 and angiogenic growth factors,resulting in collagen deposition and rapid wound closure.This multifunctional hydrogel can not only self-adaptively change the microenvironment to a pro-healing state by decreasing oxidative stress,but also respond to matrix metalloproteinases to release DFO.The self-adaptive multifunctional hydrogel has a potential for treating diabetic wounds.展开更多
Wound ulceration caused by diabetes is a typical chronic wound wherein healing the local tissue is difficult due to lack of blood vessels and tissue necrosis caused by the long-term accumulation of free radicals.Near-...Wound ulceration caused by diabetes is a typical chronic wound wherein healing the local tissue is difficult due to lack of blood vessels and tissue necrosis caused by the long-term accumulation of free radicals.Near-field electrospinning(NFES)is an innovative technology used to produce micro-nano-scaled,controllable sequencing fibers.In this study,we constructed a novel wound dressing based on the NFES polycaprolactone(PCL)fiber network and modified gelatin with methacrylic anhydride(GelMA)hydrogel to promote angiogenesis and the re-epithelialization of diabetic wounds.An angiogenic and antioxidant drug named deferoxamine(DFO)was encapsulated in a GelMA hydrogel to achieve a slow-release effect that is more suitable for chronic wounds.The cell adhesion experiment showed that the cells could attach to the fibers in the dressing group having a network of PCL fibers on the surface and grow along the direction of the fibers,which in turn,effectively regulates cell behavior from the physical structure.Additionally,the large pore size(~500μm)of the network allowed the cells to penetrate the pores and enter the surface of the hydrogel without being blocked out.Besides,the composite dressing had a notable effect on angiogenesis.Furthermore,antioxidation experiments confirmed that the DFO-loaded hydrogel exhibited antioxidant activity.Experimental animal models of diabetes showed that rats treated with the PCL-GelMA-DFO(PGD)hydrogel had faster ability of hemostasis,scab formation,and wound healing.In conclusion,the PGD hydrogel effectively promoted the repair of chronic wounds.展开更多
Background:Diabetic wounds are one of the most common and serious complications of diabetes mellitus,characterized by the dysfunction of wound-healing-related cells in quantity and quality.Our previous studies reveale...Background:Diabetic wounds are one of the most common and serious complications of diabetes mellitus,characterized by the dysfunction of wound-healing-related cells in quantity and quality.Our previous studies revealed that human amniotic epithelial cells(hAECs)could promote diabetic wound healing by paracrine action.Interestingly,numerous studies demonstrated that exosomes derived from stem cells are the critical paracrine vehicles for stem cell therapy.However,whether exosomes derived from hAECs(hAECs-Exos)mediate the effects of hAECs on diabetic wound healing remains unclear.This study aimed to investigate the biological effects of hAECs-Exos on diabetic wound healing and preliminarily elucidate the underlying mechanism.Methods:hAECs-Exos were isolated by ultracentrifugation and identified by transmission electron microscopy,dynamic light scattering and flow cytometry.A series of in vitro functional analyses were performed to assess the regulatory effects of hAECs-Exos on human fibroblasts(HFBs)and human umbilical vein endothelial cells(HUVECs)in a high-glycemic microenvironment.Highthroughput sequencing and bioinformatics analyses were conducted to speculate the related mechanisms of actions of hAECs-Exos on HFBs and HUVECs.Subsequently,the role of the candidate signaling pathway of hAECs-Exos in regulating the function of HUVECs and HFBs,as well as in diabetic wound healing,was assessed.Results:hAECs-Exos presented a cup-or sphere-shaped morphology with a mean diameter of 105.89±10.36 nm,were positive for CD63 and TSG101 and could be internalized by HFBs and HUVECs.After that,hAECs-Exos not only significantly promoted the proliferation and migration of HFBs,but also facilitated the angiogenic activity of HUVECs in vitro.High-throughput sequencing revealed enriched miRNAs of hAECs-Exos involved in wound healing.Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses have shown that the target genes of the top 15 miRNAs were highly enriched in the PI3K-AKT pathway.Further functional studies demonstrated that the PI3K-AKT-mTOR pathway was necessary for the induced biological effects of hAECs-Exos on HFBs and HUVECs,as well as on wound healing,in diabetic mice.Conclusions:Our findings demonstrated that hAECs-Exos represent a promising,novel strategy for diabetic wound healing by promoting angiogenesis and fibroblast function via activation of the PI3K-AKT-mTOR pathway.展开更多
Chronic diabetic wounds are an important healthcare challenge. High concentration glucose, high level of matrix metalloproteinase-9 (MMP-9), and long-term inflammation constitute the special wound environment of diabe...Chronic diabetic wounds are an important healthcare challenge. High concentration glucose, high level of matrix metalloproteinase-9 (MMP-9), and long-term inflammation constitute the special wound environment of diabetic wounds. Tissue necrosis aggravates the formation of irregular wounds. All the above factors hinder the healing of chronic diabetic wounds. To solve these issues, a glucose and MMP-9 dual-response temperature-sensitive shape self-adaptive hydrogel (CBP/GMs@Cel&INS) was designed and constructed with polyvinyl alcohol (PVA) and chitosan grafted with phenylboric acid (CS-BA) by encapsulating insulin (INS) and gelatin microspheres con-taining celecoxib (GMs@Cel). Temperature-sensitive self-adaptive CBP/GMs@Cel&INS provides a new way to balance the fluid-like mobility (self-adapt to deep wounds quickly, approximately 37 ◦C) and solid-like elasticity (protect wounds against external forces, approximately 25 ◦C) of self-adaptive hydrogels, while simultaneously releasing insulin and celecoxib on-demand in the environment of high-level glucose and MMP-9. Moreover, CBP/ GMs@Cel&INS exhibits remodeling and self-healing properties, enhanced adhesion strength (39.65 ± 6.58 kPa), down-regulates MMP-9, and promotes cell proliferation, migration, and glucose consumption. In diabetic full-thickness skin defect models, CBP/GMs@Cel&INS significantly alleviates inflammation and regulates the local high-level glucose and MMP-9 in the wounds, and promotes wound healing effectively through the synergistic effect of temperature-sensitive shape-adaptive character and the dual-responsive system.展开更多
Prolonged,intense inflammation and excessive oxidative stress hinder diabetic wounds from healing normally,leading to disorders downstream including the postponement of re-epithelialization and extracellular matrix(EC...Prolonged,intense inflammation and excessive oxidative stress hinder diabetic wounds from healing normally,leading to disorders downstream including the postponement of re-epithelialization and extracellular matrix(ECM)formation.Herein,we report a hyaluronic acid(HA)and chitosan based hydrogel(OHA-CMC)with inherent antibacterial and hemostatic activities fabricated via Schiff base reaction.By encapsulating nanotechnologically-modified curcumin(CNP)and epidermal growth factor(EGF)into the hydrogel,OHA-CMC/CNP/EGF exhibited extraordinary antioxidant,anti-inflammatory,and migration-promoting effects in vitro.Meanwhile,OHA-CMC/CNP/EGF presented on-demand drug release in synchrony with the phases of the wound healing process.Specifically,curcumin was rapidly and constantly released to alleviate inflammation and oxidative stress in the early phase of wound healing,while a more gradual and sustained release of EGF supported late proliferation and ECM remodeling.In a diabetic full-thickness skin defect model,OHA-CMC/CNP/EGF dramatically improved wound healing with ideal re-epithelialization,granulation tissue formation,and skin appendage regeneration,highlighting the enormous therapeutic potential this biomaterial holds as a diabetic wound dressing.展开更多
It has been reported that neutrophil extracellular traps(NETs)impair wound healing in diabetes and that inhibiting NET generation(NETosis)improves wound healing in diabetic mice.Gonadotropin-releasing hormone(GnRH)ago...It has been reported that neutrophil extracellular traps(NETs)impair wound healing in diabetes and that inhibiting NET generation(NETosis)improves wound healing in diabetic mice.Gonadotropin-releasing hormone(GnRH)agonists are associated with a greater risk of diabetes.However,the role of GnRH in diabetic wound healing is unclear.We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing.A mouse model of diabetes was established using five injections with streptozotocin.Mice with blood glucose levels>250 mg/dL were then used in the experiments.GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice.In contrast,GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing.The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients.In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate(PMA)-induced NETosis in mouse and human neutrophils.Furthermore,GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis,which were increased by GnRH treatment.These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds.Thus,inhibition of GnRH might be a novel treatment of diabetic foot ulcers.展开更多
Nano Research volume 13,pages2268–2279(2020)Cite this article 131 Accesses 1 Altmetric Metrics details Abstract Insufficient angiogenesis in the chronic wound of the diabetic is one of the most important causes that ...Nano Research volume 13,pages2268–2279(2020)Cite this article 131 Accesses 1 Altmetric Metrics details Abstract Insufficient angiogenesis in the chronic wound of the diabetic is one of the most important causes that making the wound unable to heal itself.In this work,a cobalt-based metal–organic framework(ZIF-67)was introduced as a carrier for loading a pro-angiogenic small molecular drug(dimethyloxalylglycine,DMOG).To achieve a long-term angiogenic therapy on the diabetic wound beds,a dual cooperative controllable release system has been designed by incorporating the drug-loaded ZIF-67 nanoparticles into the micro-patterned PLLA/Gelatin nanofibrous scaffolds.The results showed that DMOG was incorporated into ZIF-67 with a high loading ratio(359.12 mg/g),and the drug-loaded ZIF-67 nanoparticles were well embedded in the circular patterned scaffold.Notably,the DMOG as well as Co ions could continuously release from the scaffold for more than 15 days.The in vitro studies showed that the released Co ions and DMOG from the micropatterned nanofibrous scaffolds could synergistically promote the proliferation,migration and tube formation of the human umbilical vein endothelial cells(HUVECs)by inducing a hypoxia response and upregulating the expression of angiogenesis-related genes such as HIF-1α,VEGF and e-NOS.Furthermore,the in vivo results demonstrated that the composite scaffolds could significantly enhance angiogenesis,collagen deposition and eliminate inflammation in the diabetes wounds.These results indicate that the cobalt-based metal–organic framework as a dual cooperative controllable release system provides a new strategy for enhancing angiogenesis and promoting diabetic wound healing.展开更多
MG53 is an essential component of the cell membrane repair machinery,participating in the healing of dermal wounds.Here we develop a novel delivery system using recombinant human MG53(rhMG53)protein and a reactive oxy...MG53 is an essential component of the cell membrane repair machinery,participating in the healing of dermal wounds.Here we develop a novel delivery system using recombinant human MG53(rhMG53)protein and a reactive oxygen species(ROS)-scavenging gel to treat diabetic wounds.Mice with ablation of MG53 display defective hair follicle structure,and topical application of rhMG53 can promote hair growth in the mg53/mice.Cell lineage tracing studies reveal a physiological function of MG53 in modulating the proliferation of hair follicle stem cells(HFSCs).We find that rhMG53 protects HFSCs from oxidative stress-induced apoptosis and stimulates differentiation of HSFCs into keratinocytes.The cytoprotective function of MG53 is mediated by STATs and MAPK signaling in HFSCs.The thermosensitive ROS-scavenging gel encapsulated with rhMG53 allows for sustained release of rhMG53 and promotes healing of chronic cutaneous wounds and hair follicle development in the db/db mice.These findings support the potential therapeutic value of using rhMG53 in combination with ROS-scavenging gel to treat diabetic wounds.展开更多
Associated with persistent oxidative stress,altered inflammatory responses,poor angiogenesis and epithelization,wound healing in diabetic patients is impaired.N-acetylcysteine(NAC)is reported to resist excess reactive...Associated with persistent oxidative stress,altered inflammatory responses,poor angiogenesis and epithelization,wound healing in diabetic patients is impaired.N-acetylcysteine(NAC)is reported to resist excess reactive oxygen species(ROS)production,prompt angiogenesis and maturation of the epidermis.Studies have revealed that graphene oxide(GO)can regulate cellular behavior and form cross-links with naturally biodegradable polymers such as collagen(COL)to construct composite scaffolds.Here,we reported a COL-based implantable scaffold containing a mixture of GO capable of the sustained delivery of NAC to evaluate the wound healing in diabetic rats.The morphological,physical characteristics,biocompatibility and NAC release profile of the GO-COL-NAC(GCN)scaffold were evaluated in vitro.Wound healing studies were performed on a 20mm dorsal full-skin defect of streptozotocin(STZ)-induced diabetic rats.The injured skin tissue was removed at the 18th day post-surgery for histological analysis and determination of glutathione peroxidase(GPx),catalase(CAT)and superoxide dismutase(SOD)activity.In diabetic rats,we confirmed that the GCN scaffold presented a beneficial effect in enhancing the wound healing process.Additionally,due to the sustained release of NAC,the scaffold may potentially induce the antioxidant defense system,upregulating the expression levels of the antioxidant enzymes in the wound tissue.The findings revealed that the antioxidant biocompatible composite collagen dressing could not only deliver NAC in situ for ROS inhibition but also promote the wound healing process.This scaffold with valuable therapy potential might enrich the approaches for surgeon in diabetic wound treatment in the future.展开更多
基金supported by Fundamental Research Program of Shanxi Province(202203021222199)the Taiyuan University of Science and Technology Scientific Research Initial Funding(20222090)the National Natural Science Foundation of China(21975019).
文摘Delayed and nonhealing of diabetic wounds imposes substantial economic burdens and physical pain on patients.Mesenchymal stem cells(MSCs)promote diabetic wound healing.Particularly when MSCs aggregate into multicellular spheroids,their therapeutic effect is enhanced.However,traditional culture platforms are inadequate for the efficient preparation and delivery of MSC spheroids,resulting in inefficiencies and inconveniences in MSC spheroid therapy.In this study,a three-dimensional porous nanofibrous dressing(NFD)is prepared using a combination of electrospinning and homogeneous freeze-drying.Using thermal crosslinking,the NFD not only achieves satisfactory elasticity but also maintains notable cytocompatibility.Through the design of its structure and chemical composition,the NFD allows MSCs to spontaneously form MSC spheroids with controllable sizes,serving as MSC spheroid delivery systems for diabetic wound sites.Most importantly,MSC spheroids cultured on the NFD exhibit improved secretion of vascular endothelial growth factor,basic fibroblast growth factor,and hepatocyte growth factor,thereby accelerating diabetic wound healing.The NFD provides a competitive strategy for MSC spheroid formation and delivery to promote diabetic wound healing.
基金supported by 173 plan project of Military Science and Technology(2019-JCJQ-ZD-359-00)the National Key R&D Program of China(2019YFA0110503,2019YFA0110501)+5 种基金the National Nature Science Foundation of China(82072170,82372512,82172201,82372513,81930057 and 81701905)Shanghai Rising Star Program(22QA1411700)Basic medical research project of Changhai Hospital(2023YQ02)Changhong talent plan of Changhai HospitalYouth Medical Talents-Specialist ProgramChinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2019-I2M-5-076).
文摘Diabetic wounds,characterized by prolonged inflammation and impaired vascularization,are a serious complication of diabetes.This study aimed to design a gelatin methacrylate(GelMA)hydrogel for the sustained release of netrin-1 and evaluate its potential as a scaffold to promote diabetic wound healing.The results showed that netrin-1 was highly expressed during the inflammation and proliferation phases of normal wounds,whereas it synchronously exhibited aberrantly low expression in diabetic wounds.Neutralization of netrin-1 inhibited normal wound healing,and the topical application of netrin-1 accelerated diabetic wound healing.Mechanistic studies demonstrated that netrin-1 regulated macrophage heterogeneity via the A2bR/STAT/PPARγsignaling pathway and promoted the function of endothelial cells,thus accelerating diabetic wound healing.These data suggest that netrin-1 is a potential therapeutic target for diabetic wounds.
基金Supported by Shenzhen Science and Technology Program,No.GJHZ20210705142543019Guangdong Basic and Applied Basic Research Foundation,No.2023A1515220074.
文摘Diabetes mellitus(DM),an increasingly prevalent chronic metabolic disease,is characterised by prolonged hyperglycaemia,which leads to long-term health consequences.Although much effort has been put into understanding the pathogenesis of diabetic wounds,the underlying mechanisms remain unclear.The advent of single-cell RNA sequencing(scRNAseq)has revolutionised biological research by enabling the identification of novel cell types,the discovery of cellular markers,the analysis of gene expression patterns and the prediction of develop-mental trajectories.This powerful tool allows for an in-depth exploration of pathogenesis at the cellular and molecular levels.In this editorial,we focus on progenitor-based repair strategies for diabetic wound healing as revealed by scRNAseq and highlight the biological behaviour of various healing-related cells and the alteration of signalling pathways in the process of diabetic wound healing.ScRNAseq could not only deepen our understanding of the complex biology of diabetic wounds but also identify and validate new targets for inter-vention,offering hope for improved patient outcomes in the management of this challenging complication of DM.
基金Supported by Key Project of the Huzhou City Science and Technology Plan,No.2023GZ83.
文摘In this editorial,we discuss the article by Wen et al published.Diabetic foot ulcers are prevalent and serious complications of diabetes,significantly impacting patients’quality of life and often leading to disability or death,thereby placing a heavy burden on society.Effective diabetic wound healing is hindered by an imbalance in macrophage polarization;many macrophages fail to transition from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype,which is crucial for tissue remodelling and repair.The wound healing process is both dynamic and complex.Healthy M1 macrophages,which have strong phagocytic abilities,are vital during the inflammatory phase of diabetic wound healing.However,the failure to transition to M2 macrophages during the proliferative phase hinders wound healing.We anticipate the development of new therapies that can repair damaged M1 macrophages during the inflammatory phase and promote M2 macrophage polarization during the proliferative phase,thereby enhancing the overall healing process.
基金supported by the National Natural Science Foundation of China(No.31971271)The Natural Science Foundation of Fujian Province of China(No.2022J01794)The Science and Technology Plan Project of Quanzhou(No.2021N033S).
文摘Delayed or non-healing of diabetic wounds is a significant complication,often attributed to high glucose-induced M1 macrophage accumulation,impaired angiogenesis,and reactive oxygen species(ROS)buildup.Addressing this,we introduced a strontium polyphenol network microneedle patch(SrC-MPNs@MN-PP)for percutaneous drug delivery.This patch,formulated with polymer poly(γ-glutamic acid)(γ-PGA)and epsilon-poly-l-lysine(ε-PLL),incorporates strontium polyphenol networks(SrC-MPNs).The release of chlorogenic acid(CGA)from SrC-MPNs not only neutralizes ROS,but strontium ions also foster angiogen-esis.Consequently,SrC-MPNs@MN-PP can ameliorate the diabetic wound microenvironment and expedite healing.
基金supported by the National key Research and development program of China(No.2022YFC2106100)the National Natural Science Foundation of China(Nos.22078265,and 21908179)the Natural Science Foundation of Shaanxi Province,China(No.218JQ2052).
文摘Diabetic wounds, as a complication of diabetes, are slow to heal and seriously affect the quality of life of patients. Functional hydrogel dressing is an effective approach to improve diabetic wound healing. Electrical stimulation (ES) therapy is conducive to promoting cell migration and wound healing. In this work, a multifunctional PPTZ hydrogel wound dressing was developed by freeze-thaw method with polyvinyl alcohol (PVA), phytic acid (PA), tannic acid (TA), and Zinc chloride. The obtained PPTZ hydrogel has good mechanical properties (stress and strain of 700.03 kPa and 575.08%), light transmittance (close to 100%) and antibacterial rate (over 75%). With good biocompatibility, antioxidant abilities and conductivity, the PPTZ hydrogel could effectively promote the healing of diabetic wounds with two weeks under the action of electric field, which provides an auxiliary treatment strategy for diabetic patients.
基金supported by the National Key Research and Development Program of China(2022YFB4601402)the National Natural Science Foundation of China(32201109,51772233,82072446)+3 种基金the Guangdong Basic and Applied Basic Research Foundation(2022B1515120052,2021A1515110557)the Key Basic Research Program of Shenzhen(JCYJ20200109150218836)the Chaozhou Branch of Chemistry and Chemical Engineering Guangdong Laboratory(HJL202202A002)the Trauma Microsurgery Clinical Medical Research Center of Hubei Province and the Health Commission of Hubei Province Medical Leading Talent Project(LJ20200405).
文摘Diabetic wounds are a difficult medical challenge.Excessive secretion of matrix metalloproteinase-9(MMP-9)in diabetic wounds further degrades the extracellular matrix and growth factors and causes severe vascular damage,which seriously hinders diabetic wound healing.To solve these issues,a double-network porous hydrogel composed of poly(methyl methacrylate-co-acrylamide)(p(MMA-co-AM))and polyvinyl alcohol(PVA)was constructed by the high internal phase emulsion(HIPE)technique for the delivery of potassium sucrose octasulfate(PSO),a drug that can inhibit MMPs,increase angiogenesis and improve microcirculation.The hydrogel possessed a typical polyHIPE hierarchical microstructure with interconnected porous morphologies,high porosity,high specific surface area,excellent mechanical properties and suitable swelling properties.Meanwhile,the p(MMA-co-AM)/PVA@PSO hydrogel showed high drug-loading performance and effective PSO release.In addition,both in vitro and in vivo studies showed that the p(MMA-co-AM)/PVA@PSO hydrogel had good biocompatibility and significantly accelerated diabetic wound healing by inhibiting excessive MMP-9 in diabetic wounds,increasing growth factor secretion,improving vascularization,increasing collagen deposition and promoting re-epithelialization.Therefore,this study provided a reliable therapeutic strategy for diabetic wound healing,some theoretical basis and new insights for the rational design and preparation of wound hydrogel dressings with high porosity,high drug-loading performance and excellent mechanical properties.
基金supported by the National Natural Science Foundation of China(82025025)Natural Science Foundation of Hebei Province of China(H2022202007)+3 种基金Full-time Talents Program of Hebei Province of China(2020HBQZYC012)Natural Science Foundation of Tianjin of China(21JCYBJC01030,21JCZDJC01110)The Scientific Research Project of Tianjin Education Commission(2022KJ096)Academician Expert Workstation of Yunnan Province of China(202205AF150025).
文摘Healing of chronic diabetic wounds is challenging due to complications of severe inflammatory microenvironment,bacterial infection and poor vascular formation.Herein,a novel injectable polyvinyl alcohol-hyaluronic acid-based composite hydrogel was developed,with tannic acid(TA)and silicate functionalization to fabricate an‘all-in-one’hydrogel PTKH.On one hand,after being locally injected into the wound site,the hydrogel underwent a gradual sol-gel transition in situ,forming an adhesive and protective dressing for the wound.Manipulations of rheological characteristics,mechanical properties and swelling ability of PTKH could be performed via regulating TA and silicate content in hydrogel.On the other hand,PTKH was capable of eliminating reactive oxygen species overexpression,combating infection and generating a cell-favored microenvironment for wound healing acceleration in vitro.Subsequent animal studies demonstrated that PTKH could greatly stimulate angiogenesis and epithelization,accompanied with inflammation and infection risk reduction.Therefore,in consideration of its impressive in vitro and in vivo outcomes,this‘all-in-one’multifunctional hydrogel may hold promise for chronic diabetic wound treatment.
文摘Diabetes mellitus,an epidemic with a rapidly increasing number of patients,always leads to delayed wound healing associated with consistent pro-inflammatory M1 polarization,decreased angiogenesis and increased reactive oxygen species(ROS)in the microenvironment.Herein,a poly(lactic-co-glycolic acid)(PLGA)-based microneedle patch loaded with magnesium hydride(MgH_(2))(MN-MgH_(2))is manufactured for defeating diabetic wounds.The application of microneedle patch contributes to the transdermal delivery and the prolonged release of MgH_(2) that can generate hydrogen(H_(2))and magnesium ions(Mg^(2+))after reaction with body fluids.The released H_(2) reduces the production of ROS,transforming the pathological microenvironment induced by diabetes mellitus.Meanwhile,the released Mg^(2+)promotes the polarization of pro-healing M2 macrophages.Consequently,cell proliferation and migration are improved,and angiogenesis and tissue regeneration are enhanced.Such intelligent microneedle patch provides a novel way for accelerating wound healing through steadily preserving and releasing of H_(2) and Mg^(2+)locally and sustainably.
基金supported by the National Key Research and Development Project(grant no.2019YFD0901905).
文摘Chronic diabetic wound healing remains a formidable challenge due to susceptibility to bacterial infection,excessive oxidative stress,and poor angiogenesis.To address these issues,a sodium alginate(SA)based photothermal hydrogel dressing with multifunction was fabricated to facilitate wound treatment.Ceria nanoparticles(CeO_(2)NPs)was synthesized,and their antibacterial performance by near-infrared light triggered photothermal effects was first studied and verified in this work.In addition,to release CeO_(2)NPs to achieve antioxidation and pro-vascularization,thermosensitive gelatin(Gel)was utilized to embed the nanoparticles in advance and then composited in SA hydrogel networks.SA network was finally strengthened by acid soaking to form partially crystalline regions to act as natural crosslinkers.Results showed that the Gel/SA/CeO_(2)hydrogel displayed temperature-responsive release of CeO_(2)NPs,significant antibacterial and antioxidative activity,as well as the ability to remove without injury and promote infected diabetic wound healing with low cytotoxicity,according to antibacterial investigations,cell studies,and in vivo animal studies.This research offers not only a successful method for quickening the healing of diabetic wounds but also a fresh approach to the general use of CeO_(2)NPs.
基金financially supported by the National Natural Science Foundation of China(81673830)Six Talent Peaks Project in Jiangsu Province(YY053,China)+1 种基金Major Project and Double firstclass innovative team(CPU2018GY28,China)National Science and Technology Major Project(2017zx09101001005,China)。
文摘Chronic diabetic wound remains a critical challenge suffering from the complicated negative microenvironments,such as high-glucose,excessive reactive oxygen species(ROS),hypoxia and malnutrition.Unfortunately,few strategies have been developed to ameliorate the multiple microenvironments simultaneously.In this study,Chlorella sp.(Chlorella)hydrogels were prepared against diabetic wounds.In vitro experiments demonstrated that living Chlorella could produce dissolved oxygen by photosynthesis,actively consume glucose and deplete ROS with the inherent antioxidants,during the daytime.At night,Chlorella was inactivated in situ by chlorine dioxide with human-body harmless concentration to utilize its abundant contents.It was verified in vitro that the inactivated-Chlorella could supply nutrition,relieve inflammation and terminate the oxygen-consumption of Chlorella-respiration.The advantages of living Chlorella and its contents were integrated ingeniously.The abovementioned functions were proven to accelerate cell proliferation,migration and angiogenesis in vitro.Then,streptozotocininduced diabetic mice were employed for further validation.The in vivo outcomes confirmed that Chlorella could ameliorate the undesirable microenvironments,including hypoxia,high-glucose,excessiveROS and chronic inflammation,thereby synergistically promoting tissue regeneration.Given the results above,Chlorella is considered as a tailor-made therapeutic strategy for diabetic wound healing.
基金supported by the National Natural Science Foundation of China(Nos.52103186,51725303,52033007)the Fundamental Research Funds for the Central Universities(Nos.2682020ZT84,2682021ZTPY008).
文摘Neovascularization is critical to improve the diabetic microenvironment,deliver abundant nutrients to the wound and promote wound closure.However,the excess of oxidative stress impedes the healing process.Herein,a self-adaptive multifunctional hydrogel with self-healing property and injectability is fabricated through a boronic ester-based reaction between the phenylboronic acid groups of the 3-carboxyl-4-fluorophenylboronic acid-grafted quaternized chitosan and the hydroxyl groups of the polyvinyl alcohol,in which pro-angiogenic drug of desferrioxamine(DFO)is loaded in the form of gelatin microspheres(DFO@G).The boronic ester bonds of the hydrogel can self-adaptively react with hyperglycemic and hydrogen peroxide to alleviate oxidative stress and release DFO@G in the early phase of wound healing.A sustained release of DFO is then realized by responding to overexpressed matrix metalloproteinases.In a full-thickness diabetic wound model,the DFO@G loaded hydrogel accelerates angiogenesis by upregulating expression of hypoxia-inducible factor-1 and angiogenic growth factors,resulting in collagen deposition and rapid wound closure.This multifunctional hydrogel can not only self-adaptively change the microenvironment to a pro-healing state by decreasing oxidative stress,but also respond to matrix metalloproteinases to release DFO.The self-adaptive multifunctional hydrogel has a potential for treating diabetic wounds.
基金We sincerely acknowledge the funding from the Science and Technology Planning Project of Shenzhen Municipality(Nos.JCYJ20180306174831458 and JCYJ20190807155801657)the National Natural Science Foundation of China(Nos.51973243 and 52173150)+3 种基金Guangdong Innovative and Entrepreneurial Research Team Program(No.2016ZT06S029)Key international(regional)cooperative research projects of the National Natural Science Foundation of China(No.5181001045)The International Science and technology cooperation project of Shenzhen Municipality(No.GJHZ20200731095008026)Public welfare project of Futian District Health Bureau(No.FTWS2021001).
文摘Wound ulceration caused by diabetes is a typical chronic wound wherein healing the local tissue is difficult due to lack of blood vessels and tissue necrosis caused by the long-term accumulation of free radicals.Near-field electrospinning(NFES)is an innovative technology used to produce micro-nano-scaled,controllable sequencing fibers.In this study,we constructed a novel wound dressing based on the NFES polycaprolactone(PCL)fiber network and modified gelatin with methacrylic anhydride(GelMA)hydrogel to promote angiogenesis and the re-epithelialization of diabetic wounds.An angiogenic and antioxidant drug named deferoxamine(DFO)was encapsulated in a GelMA hydrogel to achieve a slow-release effect that is more suitable for chronic wounds.The cell adhesion experiment showed that the cells could attach to the fibers in the dressing group having a network of PCL fibers on the surface and grow along the direction of the fibers,which in turn,effectively regulates cell behavior from the physical structure.Additionally,the large pore size(~500μm)of the network allowed the cells to penetrate the pores and enter the surface of the hydrogel without being blocked out.Besides,the composite dressing had a notable effect on angiogenesis.Furthermore,antioxidation experiments confirmed that the DFO-loaded hydrogel exhibited antioxidant activity.Experimental animal models of diabetes showed that rats treated with the PCL-GelMA-DFO(PGD)hydrogel had faster ability of hemostasis,scab formation,and wound healing.In conclusion,the PGD hydrogel effectively promoted the repair of chronic wounds.
基金funded by the National Key R&D Program of China(2019YFA0110503)the National Nature Science Foundation of China(81701905,81930057,81772076,81871559,81571897)+5 种基金the Shanghai Pujiang Program(17PJD043)the Clinical Key Discipline Project of Shanghai and Chinathe Shanghai Health System Excellent Talent Training Program(2017BR037)the Fujian Burn Medical Center([2017]171)the Key Clinical Specialty Discipline Construction Programme of Fujian,China([2012]149)the Fujian Provincial Key Laboratory of Burn and Trauma,China.
文摘Background:Diabetic wounds are one of the most common and serious complications of diabetes mellitus,characterized by the dysfunction of wound-healing-related cells in quantity and quality.Our previous studies revealed that human amniotic epithelial cells(hAECs)could promote diabetic wound healing by paracrine action.Interestingly,numerous studies demonstrated that exosomes derived from stem cells are the critical paracrine vehicles for stem cell therapy.However,whether exosomes derived from hAECs(hAECs-Exos)mediate the effects of hAECs on diabetic wound healing remains unclear.This study aimed to investigate the biological effects of hAECs-Exos on diabetic wound healing and preliminarily elucidate the underlying mechanism.Methods:hAECs-Exos were isolated by ultracentrifugation and identified by transmission electron microscopy,dynamic light scattering and flow cytometry.A series of in vitro functional analyses were performed to assess the regulatory effects of hAECs-Exos on human fibroblasts(HFBs)and human umbilical vein endothelial cells(HUVECs)in a high-glycemic microenvironment.Highthroughput sequencing and bioinformatics analyses were conducted to speculate the related mechanisms of actions of hAECs-Exos on HFBs and HUVECs.Subsequently,the role of the candidate signaling pathway of hAECs-Exos in regulating the function of HUVECs and HFBs,as well as in diabetic wound healing,was assessed.Results:hAECs-Exos presented a cup-or sphere-shaped morphology with a mean diameter of 105.89±10.36 nm,were positive for CD63 and TSG101 and could be internalized by HFBs and HUVECs.After that,hAECs-Exos not only significantly promoted the proliferation and migration of HFBs,but also facilitated the angiogenic activity of HUVECs in vitro.High-throughput sequencing revealed enriched miRNAs of hAECs-Exos involved in wound healing.Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses have shown that the target genes of the top 15 miRNAs were highly enriched in the PI3K-AKT pathway.Further functional studies demonstrated that the PI3K-AKT-mTOR pathway was necessary for the induced biological effects of hAECs-Exos on HFBs and HUVECs,as well as on wound healing,in diabetic mice.Conclusions:Our findings demonstrated that hAECs-Exos represent a promising,novel strategy for diabetic wound healing by promoting angiogenesis and fibroblast function via activation of the PI3K-AKT-mTOR pathway.
基金This work was supported by the National key Research and devel-opment program of China(2019YFA0905200)the National Natural Science Foundation of China(21878247,21808184)Key Program of the National Natural Science Foundation of China(21838009).
文摘Chronic diabetic wounds are an important healthcare challenge. High concentration glucose, high level of matrix metalloproteinase-9 (MMP-9), and long-term inflammation constitute the special wound environment of diabetic wounds. Tissue necrosis aggravates the formation of irregular wounds. All the above factors hinder the healing of chronic diabetic wounds. To solve these issues, a glucose and MMP-9 dual-response temperature-sensitive shape self-adaptive hydrogel (CBP/GMs@Cel&INS) was designed and constructed with polyvinyl alcohol (PVA) and chitosan grafted with phenylboric acid (CS-BA) by encapsulating insulin (INS) and gelatin microspheres con-taining celecoxib (GMs@Cel). Temperature-sensitive self-adaptive CBP/GMs@Cel&INS provides a new way to balance the fluid-like mobility (self-adapt to deep wounds quickly, approximately 37 ◦C) and solid-like elasticity (protect wounds against external forces, approximately 25 ◦C) of self-adaptive hydrogels, while simultaneously releasing insulin and celecoxib on-demand in the environment of high-level glucose and MMP-9. Moreover, CBP/ GMs@Cel&INS exhibits remodeling and self-healing properties, enhanced adhesion strength (39.65 ± 6.58 kPa), down-regulates MMP-9, and promotes cell proliferation, migration, and glucose consumption. In diabetic full-thickness skin defect models, CBP/GMs@Cel&INS significantly alleviates inflammation and regulates the local high-level glucose and MMP-9 in the wounds, and promotes wound healing effectively through the synergistic effect of temperature-sensitive shape-adaptive character and the dual-responsive system.
基金X.Zhang acknowledges the financial support from the Interdisciplinary Program of Shanghai Jiao Tong University(project number ZH2018ZDA36(19X190020006))Shanghai Jiao Tong University Scientific and Technological Innovation Funds(2019TPA10)the Foundation of National Facility for Translational Medicine(Shanghai)(TMSK-2020-008).
文摘Prolonged,intense inflammation and excessive oxidative stress hinder diabetic wounds from healing normally,leading to disorders downstream including the postponement of re-epithelialization and extracellular matrix(ECM)formation.Herein,we report a hyaluronic acid(HA)and chitosan based hydrogel(OHA-CMC)with inherent antibacterial and hemostatic activities fabricated via Schiff base reaction.By encapsulating nanotechnologically-modified curcumin(CNP)and epidermal growth factor(EGF)into the hydrogel,OHA-CMC/CNP/EGF exhibited extraordinary antioxidant,anti-inflammatory,and migration-promoting effects in vitro.Meanwhile,OHA-CMC/CNP/EGF presented on-demand drug release in synchrony with the phases of the wound healing process.Specifically,curcumin was rapidly and constantly released to alleviate inflammation and oxidative stress in the early phase of wound healing,while a more gradual and sustained release of EGF supported late proliferation and ECM remodeling.In a diabetic full-thickness skin defect model,OHA-CMC/CNP/EGF dramatically improved wound healing with ideal re-epithelialization,granulation tissue formation,and skin appendage regeneration,highlighting the enormous therapeutic potential this biomaterial holds as a diabetic wound dressing.
基金This study was supported by the National Research Foundation of Korea grant funded by the Korean government(MSIP)(No.2011-0030043(SRC)),(2017M3A9F7079339)the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT,and Future Planning(2018R1A2B3009008).
文摘It has been reported that neutrophil extracellular traps(NETs)impair wound healing in diabetes and that inhibiting NET generation(NETosis)improves wound healing in diabetic mice.Gonadotropin-releasing hormone(GnRH)agonists are associated with a greater risk of diabetes.However,the role of GnRH in diabetic wound healing is unclear.We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing.A mouse model of diabetes was established using five injections with streptozotocin.Mice with blood glucose levels>250 mg/dL were then used in the experiments.GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice.In contrast,GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing.The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients.In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate(PMA)-induced NETosis in mouse and human neutrophils.Furthermore,GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis,which were increased by GnRH treatment.These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds.Thus,inhibition of GnRH might be a novel treatment of diabetic foot ulcers.
基金This work was supported by the Natural Science Foundation of Shanghai(No.19ZR1437800).
文摘Nano Research volume 13,pages2268–2279(2020)Cite this article 131 Accesses 1 Altmetric Metrics details Abstract Insufficient angiogenesis in the chronic wound of the diabetic is one of the most important causes that making the wound unable to heal itself.In this work,a cobalt-based metal–organic framework(ZIF-67)was introduced as a carrier for loading a pro-angiogenic small molecular drug(dimethyloxalylglycine,DMOG).To achieve a long-term angiogenic therapy on the diabetic wound beds,a dual cooperative controllable release system has been designed by incorporating the drug-loaded ZIF-67 nanoparticles into the micro-patterned PLLA/Gelatin nanofibrous scaffolds.The results showed that DMOG was incorporated into ZIF-67 with a high loading ratio(359.12 mg/g),and the drug-loaded ZIF-67 nanoparticles were well embedded in the circular patterned scaffold.Notably,the DMOG as well as Co ions could continuously release from the scaffold for more than 15 days.The in vitro studies showed that the released Co ions and DMOG from the micropatterned nanofibrous scaffolds could synergistically promote the proliferation,migration and tube formation of the human umbilical vein endothelial cells(HUVECs)by inducing a hypoxia response and upregulating the expression of angiogenesis-related genes such as HIF-1α,VEGF and e-NOS.Furthermore,the in vivo results demonstrated that the composite scaffolds could significantly enhance angiogenesis,collagen deposition and eliminate inflammation in the diabetes wounds.These results indicate that the cobalt-based metal–organic framework as a dual cooperative controllable release system provides a new strategy for enhancing angiogenesis and promoting diabetic wound healing.
文摘MG53 is an essential component of the cell membrane repair machinery,participating in the healing of dermal wounds.Here we develop a novel delivery system using recombinant human MG53(rhMG53)protein and a reactive oxygen species(ROS)-scavenging gel to treat diabetic wounds.Mice with ablation of MG53 display defective hair follicle structure,and topical application of rhMG53 can promote hair growth in the mg53/mice.Cell lineage tracing studies reveal a physiological function of MG53 in modulating the proliferation of hair follicle stem cells(HFSCs).We find that rhMG53 protects HFSCs from oxidative stress-induced apoptosis and stimulates differentiation of HSFCs into keratinocytes.The cytoprotective function of MG53 is mediated by STATs and MAPK signaling in HFSCs.The thermosensitive ROS-scavenging gel encapsulated with rhMG53 allows for sustained release of rhMG53 and promotes healing of chronic cutaneous wounds and hair follicle development in the db/db mice.These findings support the potential therapeutic value of using rhMG53 in combination with ROS-scavenging gel to treat diabetic wounds.
基金This study received financial support by the National Key R&D Program of China(2019YFA0110500)the National Natural Science Foundation of China(82020108020,81873941 and 81701922).
文摘Associated with persistent oxidative stress,altered inflammatory responses,poor angiogenesis and epithelization,wound healing in diabetic patients is impaired.N-acetylcysteine(NAC)is reported to resist excess reactive oxygen species(ROS)production,prompt angiogenesis and maturation of the epidermis.Studies have revealed that graphene oxide(GO)can regulate cellular behavior and form cross-links with naturally biodegradable polymers such as collagen(COL)to construct composite scaffolds.Here,we reported a COL-based implantable scaffold containing a mixture of GO capable of the sustained delivery of NAC to evaluate the wound healing in diabetic rats.The morphological,physical characteristics,biocompatibility and NAC release profile of the GO-COL-NAC(GCN)scaffold were evaluated in vitro.Wound healing studies were performed on a 20mm dorsal full-skin defect of streptozotocin(STZ)-induced diabetic rats.The injured skin tissue was removed at the 18th day post-surgery for histological analysis and determination of glutathione peroxidase(GPx),catalase(CAT)and superoxide dismutase(SOD)activity.In diabetic rats,we confirmed that the GCN scaffold presented a beneficial effect in enhancing the wound healing process.Additionally,due to the sustained release of NAC,the scaffold may potentially induce the antioxidant defense system,upregulating the expression levels of the antioxidant enzymes in the wound tissue.The findings revealed that the antioxidant biocompatible composite collagen dressing could not only deliver NAC in situ for ROS inhibition but also promote the wound healing process.This scaffold with valuable therapy potential might enrich the approaches for surgeon in diabetic wound treatment in the future.
