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Bioactive Materials 2023年第6期24卷 463-476页

作者： Pei Wang Jiayingzi Wu Haiyan Yang Hengke Liu Tianyu Yao Chang Liu Yan Gong Mingsong Wang Guangyu Ji Peng Huang Xiansong Wang Department of Thoracic Surgery Shanghai Key Laboratory of Tissue EngineeringShanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai200011China Marshall Laboratory of Biomedical Engineering International Cancer CenterLaboratory of Evolutionary Theranostics(LET)School of Biomedical EngineeringShenzhen University Medical SchoolShenzhen518060China Center of Hydrogen Science Shanghai Jiao Tong UniversityShanghai200240China

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.

关键词： Microneedle patch Magnesium hydride Hydrogen Magnesium ion diabetic wound healing

wound microenvironment self-adaptive hydrogel with efficient angiogenesis for promoting diabetic wound healing

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Bioactive Materials 2023年第2期20卷 561-573页

作者： Zijian Shao Tianyu Yin Jinbo Jiang Yang He Tao Xiang Shaobing Zhou Key Laboratory of Advanced Technologies of Materials Ministry of EducationSchool of Materials Science and EngineeringSouthwest Jiaotong UniversityChengdu610031PR China

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.

关键词： wound microenvironment Self-adaptive hydrogel MMP-9 responsive Angiogenesis diabetic wound healing

Glucose and MMP-9 dual-responsive hydrogel with temperature sensitive self-adaptive shape and controlled drug release accelerates diabetic wound healing

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Bioactive Materials 2022年第11期7卷 1-17页

作者： Wanyi Zhou Zhiguang Duan Jing Zhao Rongzhan Fu Chenhui Zhu Daidi Fan Shaanxi Key Laboratory of Degradable Biomedical Materials School of Chemical EngineeringNorthwest UniversityXi’an710069ShaanxiChina Shaanxi R&D Center of Biomaterials and Fermentation Engineering School of Chemical EngineeringNorthwest UniversityXi’an710069ShaanxiChina Biotech.&Biomed.Research Institute Northwest UniversityXi’an710069ShaanxiChina

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.

关键词： Dual-responsive Temperature-sensitive Shape self-adaptive hydrogels diabetic wound healing

Near-field electrospun PCL fibers/GelMA hydrogel composite dressing with controlled deferoxamine-release ability and retiform surface for diabetic wound healing

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Nano Research 2023年第1期16卷 599-612页

作者： Huiling Zhong Jun Huang Moucheng Luo Yifei Fang Xinchen Zeng Jun Wu Jianhang Du Medical Research Center The Eighth Affiliated Hospital of Sun Yat-sen UniversityShenzhen 518033China School of Biomedical Engineering Sun Yat-sen UniversityGuangzhou 510006China Institute of Biological and Medical Engineering Guangdong Academy of SciencesGuangzhou 510316China Department of Liver Surgery The Third People’s Hospital of ShenzhenShenzhen 518112China NHC Key Laboratory of Assisted Circulation Sun Yat-sen UniversityGuangzhou 510080China

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.

关键词： diabetic wound healing near field electrospinning hydrogel large pore

Porous nanofibrous dressing enables mesenchymal stem cell spheroid formation and delivery to promote diabetic wound healing

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CHINESE JOURNAL OF CHEMICAL ENGINEERING 2024年第4期68卷 156-164页

作者： Zhang, Kexin Zhang, Wenmin An, Heng Huang, Zhe Wen, Yanzhen Jiao, Xiangyu Wen, Yongqiang Taiyuan Univ Sci & Technol Coll Chem Engn & Technol Taiyuan 030024 Peoples R China Univ Sci & Technol Beijing Daxing Res Inst Sch Chem & Biol Engn Beijing Key Lab Bioengn & Sensing Technol Beijing 100083 Peoples R China

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. (c) 2024 The Chemical Industry and Engineering Society of China, and Chemical Industry Press Co., Ltd. All rights reserved.

关键词： Electrospinning Homogenization Biomedical engineering Nanomaterials Stem cell spheroids diabetic wound healing STRATEGIES HYDROGELS

Chlorella sp.-ameliorated undesirable microenvironment promotes diabetic wound healing

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Acta Pharmaceutica Sinica B 2023年第1期13卷 410-424页

作者： Hangyi Wu Pei Yang Aiqin Li Xin Jin Zhenhai Zhang HuiXia Lv Department of Pharmaceutics China Pharmaceutical UniversityNanjing 211198China The Affiliated Suqian First People's Hospital of Nanjing Medical University Suqian 223800China Jiangsu Province Academy of Traditional Chinese Medicine Nanjing 210023China Affiliated Hospital of Integrated Traditional Chinese and Western Medicine Nanjing University of Chinese MedicineNanjing 210028China

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.

关键词： Chlorella sp. diabetic wound healing Oxygen production Glucose consumption ROS depletion Nutrition supplement Anti-inflammation

Sustained delivery of rhMG53 promotes diabetic wound healing and hair follicle development

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Bioactive Materials 2022年第12期7卷 104-115页

作者： Hong Niu Haichang Li Ya Guan Xin Zhou Zhongguang Li Serana Li Zhao Peng Chen Tao Tan Hua Zhu Valerie Bergdall Xuehong Xu Jianjie Ma Jianjun Guan Department of Mechanical Engineering and Materials Science Washington University in St.LouisSt.LouisMO63130USA Institute of Materials Science and Engineering Washington University in St.LouisSt.LouisMO63130USA Department of Surgery Davis Heart and Lung Research InstituteThe Ohio State UniversityColumbusOH43210USA Laboratory of Cell Genetics and Developmental Biology Shaanxi Normal University College of Life SciencesXi’an710062China Department of Veterinary Preventive Medicine University Laboratory Animals ResourcesThe Ohio State UniversityColumbusOH43210USA

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.

关键词： diabetic wound healing hair follicle stem cell MG53 ROS-Scavenging hydrogel Controlled drug delivery

Single-cell sequencing technology in diabetic wound healing:New insights into the progenitors-based repair strategies

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World Journal of Stem Cells 2024年第5期16卷 462-466页

作者： Zhen Xiang Rui-Peng Cai Yang Xiao Yong-Can Huang Shenzhen Engineering Laboratory of Orthopaedic Regenerative Technologies Department of Spine SurgeryPeking University Shenzhen HospitalShenzhen 518036Guangdong ProvinceChina Department of Breast and Thyroid Surgery Peking University Shenzhen HospitalShenzhen 518036Guangdong ProvinceChina

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.

关键词： Single-cell sequencing diabetic wound healing Cell subpopulations Heterogeneity Pathogenesis Progenitor cells

GnRH impairs diabetic wound healing through enhanced NETosis

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Cellular & Molecular Immunology 2020年第8期17卷 856-864页

作者： Yun Sang Lee Sung Un Kang Myung-Hoon Lee Haeng-Jun Kim Chang-Hak Han Ho-Ryun Won Young Uk Park Chul-Ho Kim Department of Otolaryngology School of MedicineAjou UniversitySuwonRepublic of Korea Department of Molecular Science and Technology Ajou UniversitySuwonRepublic of Korea Department of Otolaryngology School of MedicineChungnam National UniversityDaejeonRepublic of Korea Department of Orthopedic Surgery Ajou UniversitySuwonRepublic of Korea

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.

关键词： Neutrophils GnRH diabetic wound healing NETosis

Antioxidant biocompatible composite collagen dressing for diabetic wound healing in rat model

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Regenerative Biomaterials 2021年第2期8卷 74-84页

作者： Bei Qian Jialun Li Ke Guo Nengqiang Guo Aimei Zhong Jie Yang Jiecong Wang Peng Xiao Jiaming Sun Lingyun Xiong Department of Plastic Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhan 430022China Wuhan Clinical Research Center for Superficial Organ Reconstruction Wuhan 430022China

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.

关键词： collagen graphene oxide N-acetylcysteine sustained release diabetic wound healing