Hongyi Li, Huiyun Wen, He Zhang, Xiang Cao, Li Li, Xiaowen Hu, Yanmei Zhang, Xinkun Shen, Quazi T H Shubhra, Hong Yang, Xiaojun Cai
Background The management of chronic diabetic wounds remains a formidable challenge in clinical practice. Persistent hyperglycemia triggers vasculopathy, neuropathy, and immune dysfunction, critically impeding wound repair. We developed a multifunctional hydrogel (DPFI) engineered for sequential therapeutic actions, including antibacterial, anti-inflammatory, antioxidant, pro-vascularization/epithelialization, and glycemic-regulating properties, to address these complications. Methods DPFI hydrogels were prepared by encapsulating dihydromyricetin (DMY) into aldehyde-functionalized Pluronic F127 micelles (DMY@PF127-CHO), followed by a Schiff base reaction with amine-rich polyethyleneimine (PEI), resulting in the formation of a hydrogel for controlled drug release. The antimicrobial, antioxidant, anti-inflammatory, pro-cellular proliferative, and angiogenic properties of the hydrogels were evaluated using various techniques, including structural characterization, bacterial live/dead staining, reactive oxygen species (ROS) assays, antioxidant enzyme assays, reverse transcription–polymerase chain reaction (RT–PCR), cellular immunofluorescence staining, scratch wound healing assays, and angiogenesis assays. In vivo, the effects of the hydrogel on wound healing and glycemic control were assessed in MRSA-infected mice with streptozotocin-induced diabetes. Results The hydrogel exhibits exceptional injectability, bioadhesion, and self-healing properties, facilitating the controlled, sustained release of DMY, which synergistically enhances antimicrobial effects in combination with PEI. The antioxidant activity of DMY is remarkable; it effectively scavenges reactive oxygen species (ROS) and induces the expression of antioxidant enzymes while promoting the phenotypic switch of M1 macrophages to M2 macrophages to mitigate inflammation. Critically, DPFI also contributes to glycemic regulation, reducing hyperglycemia-associated complications and creating a microenvironment conducive to wound repair. Comprehensive in vitro and in vivo analyses corroborate the multifaceted therapeutic capabilities of DPFI, including its antibacterial activity and abilities to clear ROS, reduce inflammation, promote angiogenesis, promote epithelialization, and modulate blood glucose levels. Conclusions DPFI represents a promising, integrative strategy for enhanced diabetic wound management, meriting further exploration for clinical application.
{"title":"A multifunctional Dihydromyricetin-loaded hydrogel for the sequential modulation of diabetic wound healing and Glycemic control","authors":"Hongyi Li, Huiyun Wen, He Zhang, Xiang Cao, Li Li, Xiaowen Hu, Yanmei Zhang, Xinkun Shen, Quazi T H Shubhra, Hong Yang, Xiaojun Cai","doi":"10.1093/burnst/tkaf024","DOIUrl":"https://doi.org/10.1093/burnst/tkaf024","url":null,"abstract":"Background The management of chronic diabetic wounds remains a formidable challenge in clinical practice. Persistent hyperglycemia triggers vasculopathy, neuropathy, and immune dysfunction, critically impeding wound repair. We developed a multifunctional hydrogel (DPFI) engineered for sequential therapeutic actions, including antibacterial, anti-inflammatory, antioxidant, pro-vascularization/epithelialization, and glycemic-regulating properties, to address these complications. Methods DPFI hydrogels were prepared by encapsulating dihydromyricetin (DMY) into aldehyde-functionalized Pluronic F127 micelles (DMY@PF127-CHO), followed by a Schiff base reaction with amine-rich polyethyleneimine (PEI), resulting in the formation of a hydrogel for controlled drug release. The antimicrobial, antioxidant, anti-inflammatory, pro-cellular proliferative, and angiogenic properties of the hydrogels were evaluated using various techniques, including structural characterization, bacterial live/dead staining, reactive oxygen species (ROS) assays, antioxidant enzyme assays, reverse transcription–polymerase chain reaction (RT–PCR), cellular immunofluorescence staining, scratch wound healing assays, and angiogenesis assays. In vivo, the effects of the hydrogel on wound healing and glycemic control were assessed in MRSA-infected mice with streptozotocin-induced diabetes. Results The hydrogel exhibits exceptional injectability, bioadhesion, and self-healing properties, facilitating the controlled, sustained release of DMY, which synergistically enhances antimicrobial effects in combination with PEI. The antioxidant activity of DMY is remarkable; it effectively scavenges reactive oxygen species (ROS) and induces the expression of antioxidant enzymes while promoting the phenotypic switch of M1 macrophages to M2 macrophages to mitigate inflammation. Critically, DPFI also contributes to glycemic regulation, reducing hyperglycemia-associated complications and creating a microenvironment conducive to wound repair. Comprehensive in vitro and in vivo analyses corroborate the multifaceted therapeutic capabilities of DPFI, including its antibacterial activity and abilities to clear ROS, reduce inflammation, promote angiogenesis, promote epithelialization, and modulate blood glucose levels. Conclusions DPFI represents a promising, integrative strategy for enhanced diabetic wound management, meriting further exploration for clinical application.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"183 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Foot ulcerations in patients with diabetes are common and severe, typically caused by infection and chronic inflammation. Poor blood circulation and neuropathy impair the body's ability to heal wounds effectively, creating a conducive environment for ulcers. Excessive reactive oxygen species contribute to ulcer development by damaging cellular structures and hindering wound healing. The administration of antioxidants can protect cells from oxidative damage and promote wound recovery. Antioxidants such as epidermal growth factors, flavonoid hesperidin, alpha-lipoic acid, and N-acetylcysteine effectively reduce oxidative stress. Encapsulating various drugs into nanoparticles and targeting carriers such as hydrogels, metal–organic frameworks, and nanohydrogels can improve their therapeutic effects. Nanotechnologies have been shown to boost tissue regeneration by modifying biomaterial properties, modulating signal release, and targeting key factors. Here, we describe the occurrence and development of diabetic foot ulcers (DFUs), emphasizing the role of oxidative damage in these processes. This review summarizes the strategy for targeting oxidative damage in DFUs using nanotechnology-loaded antioxidant drugs. This review advocates for the use of personalized biomaterials in treating DFUs and provides a theoretical basis for their potential clinical and translational applications.
{"title":"Targeting oxidative damage in diabetic foot ulcers: integrative strategies involving antioxidant drugs and nanotechnologies","authors":"Runze Wang, Bowen Li, Mengchao Dong, Huili Zhu, Ping Jin, Yingying Zou","doi":"10.1093/burnst/tkaf020","DOIUrl":"https://doi.org/10.1093/burnst/tkaf020","url":null,"abstract":"Foot ulcerations in patients with diabetes are common and severe, typically caused by infection and chronic inflammation. Poor blood circulation and neuropathy impair the body's ability to heal wounds effectively, creating a conducive environment for ulcers. Excessive reactive oxygen species contribute to ulcer development by damaging cellular structures and hindering wound healing. The administration of antioxidants can protect cells from oxidative damage and promote wound recovery. Antioxidants such as epidermal growth factors, flavonoid hesperidin, alpha-lipoic acid, and N-acetylcysteine effectively reduce oxidative stress. Encapsulating various drugs into nanoparticles and targeting carriers such as hydrogels, metal–organic frameworks, and nanohydrogels can improve their therapeutic effects. Nanotechnologies have been shown to boost tissue regeneration by modifying biomaterial properties, modulating signal release, and targeting key factors. Here, we describe the occurrence and development of diabetic foot ulcers (DFUs), emphasizing the role of oxidative damage in these processes. This review summarizes the strategy for targeting oxidative damage in DFUs using nanotechnology-loaded antioxidant drugs. This review advocates for the use of personalized biomaterials in treating DFUs and provides a theoretical basis for their potential clinical and translational applications.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"10 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wei Dai, Haowei Zhou, Jincheng Du, Ruozu Xiao, Junwei Su, Zhe Liu, Rong Huang, Yuqian Li, Jing Li
Background Diabetic wounds present persistent clinical challenges characterized by disrupted extracellular matrix (ECM) homeostasis, which critically impedes tissue regeneration. While bone marrow-derived mesenchymal stem cells (BMSCs) exhibit therapeutic potential through ECM remodeling, conventional transplantation strategies are limited by suboptimal cell retention and transient therapeutic effects. Methods BMSCs cultured on Flexcell plates were subjected to programmable mechanical stretching using a custom-built spherical cell-stretching system. Strain rate- and duration-dependent effects on paracrine signaling and ECM secretion were longitudinally assessed through Western blotting and ELISA. The optimized mechanical parameters (15% deformation, 1440 cycles, 5-s vertex residence time) were subsequently applied to generate BMSC sheets. Comparative analyses of biological activity and mechanical properties were performed between non-stretched controls and mechanically optimized groups. In vivo therapeutic efficacy was evaluated in diabetic rat models through wound closure kinetics, Masson’s trichrome staining, and immunofluorescence detection of neovascularization markers. Mechanistic insights were obtained via transcriptomic profiling of stretch-activated signaling pathways. Results Mechanical stretching significantly upregulated type I collagen, type III collagen, vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-β) secretion in BMSCs. The optimized stretching parameters (15% deformation, 1440 cycles, and 5 s vertex residence time) promoted BMSC proliferation while reducing apoptosis without compromising stemness. Mechanical stretching facilitated the formation of layered cell sheets with more organized collagen deposition and higher mechanical strength, expediting wound healing in diabetic rats through enhanced re-epithelialization and neovascularization. RNA sequencing analysis revealed that mechanical stretching significantly upregulated mechanosensitive molecules, mechanical stimulation signaling pathways, and cellular behavior regulatory pathways, particularly those associated with mechanical stimuli response, integrin binding, ECM secretion, and intercellular adhesion. Conclusions Mechanically stretched BMSC cell sheets can promote diabetic wound healing by enhancing cellular activity, paracrine of growth factors, and ECM components.
{"title":"Mechanical stretching enhances the cellular and paracrine effects of bone marrow mesenchymal stem cells on diabetic wound healing","authors":"Wei Dai, Haowei Zhou, Jincheng Du, Ruozu Xiao, Junwei Su, Zhe Liu, Rong Huang, Yuqian Li, Jing Li","doi":"10.1093/burnst/tkaf022","DOIUrl":"https://doi.org/10.1093/burnst/tkaf022","url":null,"abstract":"Background Diabetic wounds present persistent clinical challenges characterized by disrupted extracellular matrix (ECM) homeostasis, which critically impedes tissue regeneration. While bone marrow-derived mesenchymal stem cells (BMSCs) exhibit therapeutic potential through ECM remodeling, conventional transplantation strategies are limited by suboptimal cell retention and transient therapeutic effects. Methods BMSCs cultured on Flexcell plates were subjected to programmable mechanical stretching using a custom-built spherical cell-stretching system. Strain rate- and duration-dependent effects on paracrine signaling and ECM secretion were longitudinally assessed through Western blotting and ELISA. The optimized mechanical parameters (15% deformation, 1440 cycles, 5-s vertex residence time) were subsequently applied to generate BMSC sheets. Comparative analyses of biological activity and mechanical properties were performed between non-stretched controls and mechanically optimized groups. In vivo therapeutic efficacy was evaluated in diabetic rat models through wound closure kinetics, Masson’s trichrome staining, and immunofluorescence detection of neovascularization markers. Mechanistic insights were obtained via transcriptomic profiling of stretch-activated signaling pathways. Results Mechanical stretching significantly upregulated type I collagen, type III collagen, vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-β) secretion in BMSCs. The optimized stretching parameters (15% deformation, 1440 cycles, and 5 s vertex residence time) promoted BMSC proliferation while reducing apoptosis without compromising stemness. Mechanical stretching facilitated the formation of layered cell sheets with more organized collagen deposition and higher mechanical strength, expediting wound healing in diabetic rats through enhanced re-epithelialization and neovascularization. RNA sequencing analysis revealed that mechanical stretching significantly upregulated mechanosensitive molecules, mechanical stimulation signaling pathways, and cellular behavior regulatory pathways, particularly those associated with mechanical stimuli response, integrin binding, ECM secretion, and intercellular adhesion. Conclusions Mechanically stretched BMSC cell sheets can promote diabetic wound healing by enhancing cellular activity, paracrine of growth factors, and ECM components.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"37 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143570443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Linyang Liu, Eugenia Spessot, Khoon Lim, Ziyu Wang, Suzanne Mithieux, Devid Maniglio, Antonella Motta, Anthony S Weiss
Bioprinting has emerged as a promising technology for fabricating vascularized skin substitutes. The availability of functional skin tissue constructs is critical for the surgical treatment of various wounds, including ulcers and burns. Integrating functional vascular networks within engineered skin constructs is indispensable for ensuring adequate nutrient perfusion and overall tissue viability. This review undertakes a comprehensive exploration of the application of 3D bioprinting for fabricating vascularized skin tissue constructs. It encompasses an examination of the printing modalities, ink formulations, and cell-sourcing strategies currently prevalent in the field. The design and formulation of suitable inks are crucial steps in the successful bioprinting of vascularized skin constructs, and various ink components such as biomaterials, cells, growth factors, and bioactive molecules are particularly considered, with a focus on their roles in promoting angiogenesis and blood vessel formation within the printed constructs.
{"title":"Bioprinting vascularized skin analogs: a stepwise approach","authors":"Linyang Liu, Eugenia Spessot, Khoon Lim, Ziyu Wang, Suzanne Mithieux, Devid Maniglio, Antonella Motta, Anthony S Weiss","doi":"10.1093/burnst/tkaf018","DOIUrl":"https://doi.org/10.1093/burnst/tkaf018","url":null,"abstract":"Bioprinting has emerged as a promising technology for fabricating vascularized skin substitutes. The availability of functional skin tissue constructs is critical for the surgical treatment of various wounds, including ulcers and burns. Integrating functional vascular networks within engineered skin constructs is indispensable for ensuring adequate nutrient perfusion and overall tissue viability. This review undertakes a comprehensive exploration of the application of 3D bioprinting for fabricating vascularized skin tissue constructs. It encompasses an examination of the printing modalities, ink formulations, and cell-sourcing strategies currently prevalent in the field. The design and formulation of suitable inks are crucial steps in the successful bioprinting of vascularized skin constructs, and various ink components such as biomaterials, cells, growth factors, and bioactive molecules are particularly considered, with a focus on their roles in promoting angiogenesis and blood vessel formation within the printed constructs.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"23 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To preserve functionality, bone is an active tissue that can constantly reconstruct itself through modeling and remodeling. It plays critical roles in the body, including maintaining mineral homeostasis, serving as the adult human body's core site of hematopoiesis, and supporting the structures of the body's soft tissues. It possesses the natural regeneration capacity, but large and complex lesions often require surgical intervention. Multiple omics integrate proteomics, metabolomics, genomics, and transcriptomics to provide a comprehensive understanding of biological processes like bone tissue injury and healing in bone tissue regeneration and engineering. Recently, bone tissue engineering and regenerative medicines have offered promising tools for bone regeneration using a multi-omic approach. Thus, this article will highlight the role of multiple omics in understanding bone tissue Injury and healing. It will discuss the role of bone tissue engineering (BTE) in developing bone substitutes that can replace translational medicine. Lastly, new developments in bone tissue engineering and regenerative medicine, along with multi-omic approaches, offer promising tools for bone regeneration.
{"title":"Multi-omics insights into bone tissue injury and healing: bridging Orthopedic trauma and regenerative medicine","authors":"Liyu Yang, Zhijie Xu, Jie Liu, Xiyue Chang, Zhaozhou Ren, Wan'an Xiao","doi":"10.1093/burnst/tkaf019","DOIUrl":"https://doi.org/10.1093/burnst/tkaf019","url":null,"abstract":"To preserve functionality, bone is an active tissue that can constantly reconstruct itself through modeling and remodeling. It plays critical roles in the body, including maintaining mineral homeostasis, serving as the adult human body's core site of hematopoiesis, and supporting the structures of the body's soft tissues. It possesses the natural regeneration capacity, but large and complex lesions often require surgical intervention. Multiple omics integrate proteomics, metabolomics, genomics, and transcriptomics to provide a comprehensive understanding of biological processes like bone tissue injury and healing in bone tissue regeneration and engineering. Recently, bone tissue engineering and regenerative medicines have offered promising tools for bone regeneration using a multi-omic approach. Thus, this article will highlight the role of multiple omics in understanding bone tissue Injury and healing. It will discuss the role of bone tissue engineering (BTE) in developing bone substitutes that can replace translational medicine. Lastly, new developments in bone tissue engineering and regenerative medicine, along with multi-omic approaches, offer promising tools for bone regeneration.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"91 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In recent years, significant progress has been made in the development of organoids, which offer promising opportunities for developmental and translational research. With advances in cell biology and bioengineering techniques, skin models are evolving from conventional multilayered structures to appendage-bearing spheroids or 3D biomimetic models. This comprehensive review aims to provide an in-depth understanding of organoid models of the skin, covering topics such as skin development, construction strategies and key elements, types of organoid models, biomedical applications, and challenges. Embryonic skin development is briefly introduced to provide a foundational understanding of construction principles. Current engineering strategies are outlined, highlighting key elements such as cell sources, bioengineering techniques, 3D scaffolds, and crucial signaling pathways. Furthermore, recent advances in generating organoids with structural and functional parallels to native skin are meticulously summarized. These developments facilitate the utilization of organoids in diverse applications, such as modeling skin disorders, developing regenerative solutions, and understanding skin development. Finally, the challenges and prospects in the field are discussed. The integration of state-of-the-art bioengineering techniques with a deep understanding of skin biology is promoting the production and biomedical application of these organoid models.
{"title":"Advances in engineered organoid models of skin for biomedical research","authors":"Dongao Zeng, Shikai Li, Fangzhou Du, Yuchen Xia, Jingzhong Zhang, Shuang Yu, Jianhua Qin","doi":"10.1093/burnst/tkaf016","DOIUrl":"https://doi.org/10.1093/burnst/tkaf016","url":null,"abstract":"In recent years, significant progress has been made in the development of organoids, which offer promising opportunities for developmental and translational research. With advances in cell biology and bioengineering techniques, skin models are evolving from conventional multilayered structures to appendage-bearing spheroids or 3D biomimetic models. This comprehensive review aims to provide an in-depth understanding of organoid models of the skin, covering topics such as skin development, construction strategies and key elements, types of organoid models, biomedical applications, and challenges. Embryonic skin development is briefly introduced to provide a foundational understanding of construction principles. Current engineering strategies are outlined, highlighting key elements such as cell sources, bioengineering techniques, 3D scaffolds, and crucial signaling pathways. Furthermore, recent advances in generating organoids with structural and functional parallels to native skin are meticulously summarized. These developments facilitate the utilization of organoids in diverse applications, such as modeling skin disorders, developing regenerative solutions, and understanding skin development. Finally, the challenges and prospects in the field are discussed. The integration of state-of-the-art bioengineering techniques with a deep understanding of skin biology is promoting the production and biomedical application of these organoid models.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"67 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Poor wound healing is a refractory process that places an enormous medical and financial burden on diabetic patients. Exosomes have recently been recognized as crucial players in the healing of diabetic lesions. They have excellent stability, homing effects, biocompatibility, and reduced immunogenicity as novel cell-free therapies. In addition to transporting cargos to target cells to enhance intercellular communication, exosomes are beneficial in nearly every phase of diabetic wound healing. They participate in modulating the inflammatory response, accelerating proliferation and reepithelization, increasing angiogenesis, and regulating extracellular matrix remodeling. Accumulating evidence indicates that hydrogels or dressings in conjunction with exosomes can prolong the duration of exosome residency in diabetic wounds. This review provides an overview of the mechanisms, delivery, clinical application, engineering, and existing challenges of the use of exosomes in diabetic wound repair. We also propose future directions for biomaterials incorporating exosomes: 2D or 3D scaffolds, biomaterials loaded with wound healing-promoting gases, intelligent biomaterials, and the prospect of systematic application of exosomes. These findings may might shed light on future treatments and enlighten some studies to improve quality of life among diabetes patients.
{"title":"Advances of exosomes in diabetic wound healing","authors":"Weixue Jin, Yi Li, Meirong Yu, Danyang Ren, Chunmao Han, Songxue Guo","doi":"10.1093/burnst/tkae078","DOIUrl":"https://doi.org/10.1093/burnst/tkae078","url":null,"abstract":"Poor wound healing is a refractory process that places an enormous medical and financial burden on diabetic patients. Exosomes have recently been recognized as crucial players in the healing of diabetic lesions. They have excellent stability, homing effects, biocompatibility, and reduced immunogenicity as novel cell-free therapies. In addition to transporting cargos to target cells to enhance intercellular communication, exosomes are beneficial in nearly every phase of diabetic wound healing. They participate in modulating the inflammatory response, accelerating proliferation and reepithelization, increasing angiogenesis, and regulating extracellular matrix remodeling. Accumulating evidence indicates that hydrogels or dressings in conjunction with exosomes can prolong the duration of exosome residency in diabetic wounds. This review provides an overview of the mechanisms, delivery, clinical application, engineering, and existing challenges of the use of exosomes in diabetic wound repair. We also propose future directions for biomaterials incorporating exosomes: 2D or 3D scaffolds, biomaterials loaded with wound healing-promoting gases, intelligent biomaterials, and the prospect of systematic application of exosomes. These findings may might shed light on future treatments and enlighten some studies to improve quality of life among diabetes patients.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"85 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background Diabetic foot ulcer (DFU) is one of the most common and complex complications of diabetes, but the underlying pathophysiology remains unclear. Single-cell RNA sequencing (scRNA-seq) has been conducted to explore novel cell types or molecular profiles of DFU from various perspectives. This study aimed to comprehensively analyse the potential mechanisms underlying impaired reepithelization of DFU in a single-cell perspective. Methods We conducted scRNA-seq on tissues from human normal skin (NS), acute wound (AW) and DFU to investigate the potential mechanisms underlying impaired epidermal differentiation and the pathological microenvironment. Pseudo-time and lineage inference analyses revealed the distinct states and transition trajectories of epidermal cells under different conditions. Transcription factor analysis revealed the potential regulatory mechanism of key subtypes of keratinocytes. Cell–cell interaction analysis revealed the regulatory network between the proinflammatory microenvironment and epidermal cells. Laser-capture microscopy coupled with RNA sequencing (LCM-seq) and multiplex immunohistochemistry (mIHC) were used to validate the expression and location of key subtypes of keratinocytes. Results Our research provided a comprehensive map of the phenotypic and dynamic changes that occur during epidermal differentiation, alongside the corresponding regulatory networks in DFU. Importantly, we identified two subtypes of keratinocytes: basal cells (BC-2) and diabetes-associated keratinocytes (DAK) that might play crucial roles in the impairment of epidermal homeostasis. BC-2 and DAK showed a marked increase in DFU, with an inactive state and insufficient motivation for epidermal differentiation. BC-2 was involved in the cellular response and apoptosis processes, with high expression of TXNIP, IFITM1 and IL1R2. Additionally, the pro-differentiation transcription factors (TFs) were downregulated in BC-2 in DFU, indicating that the differentiation process might be inhibited in BC-2 in DFU. DAK was associated with cellular glucose homeostasis. Furthermore, increased CCL2 + CXCL2+ fibroblasts, VWA1+ vascular endothelial cells and GZMA+CD8+ T cells were detected in DFU. These changes in the wound microenvironment could regulate the fate of epidermal cells through the TNFSF12-TNFRSF12A, IFNG-IFNGR1/2 and IL-1B-IL1R2 pathways, which might result in persistent inflammation and impaired epidermal differentiation in DFU. Conclusions Our findings offer novel insights into the pathophysiology of DFU and present potential therapeutic targets that could improve wound care and treatment outcomes for diabetic patients.
{"title":"Single-cell RNA sequencing reveals the impaired epidermal differentiation and pathological microenvironment in diabetic foot ulcer","authors":"Yiling Liu, Peng Wang, Jingting Li, Lei Chen, Bin Shu, Hanwen Wang, Hengdeng Liu, Shixin Zhao, Junli Zhou, Xiaodong Chen, Julin Xie","doi":"10.1093/burnst/tkae065","DOIUrl":"https://doi.org/10.1093/burnst/tkae065","url":null,"abstract":"Background Diabetic foot ulcer (DFU) is one of the most common and complex complications of diabetes, but the underlying pathophysiology remains unclear. Single-cell RNA sequencing (scRNA-seq) has been conducted to explore novel cell types or molecular profiles of DFU from various perspectives. This study aimed to comprehensively analyse the potential mechanisms underlying impaired reepithelization of DFU in a single-cell perspective. Methods We conducted scRNA-seq on tissues from human normal skin (NS), acute wound (AW) and DFU to investigate the potential mechanisms underlying impaired epidermal differentiation and the pathological microenvironment. Pseudo-time and lineage inference analyses revealed the distinct states and transition trajectories of epidermal cells under different conditions. Transcription factor analysis revealed the potential regulatory mechanism of key subtypes of keratinocytes. Cell–cell interaction analysis revealed the regulatory network between the proinflammatory microenvironment and epidermal cells. Laser-capture microscopy coupled with RNA sequencing (LCM-seq) and multiplex immunohistochemistry (mIHC) were used to validate the expression and location of key subtypes of keratinocytes. Results Our research provided a comprehensive map of the phenotypic and dynamic changes that occur during epidermal differentiation, alongside the corresponding regulatory networks in DFU. Importantly, we identified two subtypes of keratinocytes: basal cells (BC-2) and diabetes-associated keratinocytes (DAK) that might play crucial roles in the impairment of epidermal homeostasis. BC-2 and DAK showed a marked increase in DFU, with an inactive state and insufficient motivation for epidermal differentiation. BC-2 was involved in the cellular response and apoptosis processes, with high expression of TXNIP, IFITM1 and IL1R2. Additionally, the pro-differentiation transcription factors (TFs) were downregulated in BC-2 in DFU, indicating that the differentiation process might be inhibited in BC-2 in DFU. DAK was associated with cellular glucose homeostasis. Furthermore, increased CCL2 + CXCL2+ fibroblasts, VWA1+ vascular endothelial cells and GZMA+CD8+ T cells were detected in DFU. These changes in the wound microenvironment could regulate the fate of epidermal cells through the TNFSF12-TNFRSF12A, IFNG-IFNGR1/2 and IL-1B-IL1R2 pathways, which might result in persistent inflammation and impaired epidermal differentiation in DFU. Conclusions Our findings offer novel insights into the pathophysiology of DFU and present potential therapeutic targets that could improve wound care and treatment outcomes for diabetic patients.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"1 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-17eCollection Date: 2025-01-01DOI: 10.1093/burnst/tkae086
Ugo Lancien, Maria Sbeih, Alexandra Poinas, Pierre Perrot, Selim Aractingi, Amir Khammari, Brigitte Dréno
{"title":"An easy and reproducible method for a large-zone deep partial-thickness burn model in the mini-pig.","authors":"Ugo Lancien, Maria Sbeih, Alexandra Poinas, Pierre Perrot, Selim Aractingi, Amir Khammari, Brigitte Dréno","doi":"10.1093/burnst/tkae086","DOIUrl":"10.1093/burnst/tkae086","url":null,"abstract":"","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"13 ","pages":"tkae086"},"PeriodicalIF":6.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background Ischemic injury is a primary cause of distal flap necrosis. Previous studies have shown that Flufenamic acid (FFA) can reduce inflammation, decrease oxidative stress (OS), and promote angiogenesis, suggesting its potential role in protecting flaps from ischemic damage. This study investigated the effects and mechanisms of FFA in enhancing the survival of ischemic flaps. Methods The viability of ischemic flaps was evaluated using laser doppler blood flow (LDBF) and survival rates. We examined levels of pyroptosis, OS, transcription factor E3 (TFE3)-induced autophagy, and elements of the AMPK-TRPML1-Calcineurin pathway through western blotting (WB), immunofluorescence (IF), molecular docking (MD), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR). Results The findings suggest that FFA significantly enhances the viability of ischemic flaps. The improvement in flap survival associated with FFA can be attributed to increased autophagy, diminished OS, and the suppression of pyroptosis. Notably, the promotion of autophagy flux and an augmented resistance to OS are instrumental in curbing pyroptosis in these flaps. Activation of TFE3 by FFA promoted autophagy and diminished oxidative damage. The therapeutic effects of FFA were negated when TFE3 levels were decreased using adeno-associated virus (AAV)-TFE3shRNA. Additionally, FFA modified TFE3 activity through the AMPK-TRPML1-Calcineurin pathway. Conclusions FFA promotes ischemic flap survival via induction of autophagy and suppression of oxidative stress by activation of the AMPK-TRPML1-Calcineurin-TFE3 signaling pathway. These findings could have therapeutic implications.
{"title":"Flufenamic acid inhibits pyroptosis in ischemic flaps via the AMPK-TRPML1-Calcineurin signaling pathway","authors":"Liang Chen, Ningning Yang, Kongbin Chen, Yingying Huang, Xian Liu, Gaoxiang Yu, Fulin Wang, Yong Gou, Yi Wang, Xiaolang Lu, Yuqi Wang, Lipeng Zhu, Weiyang Gao, Jian Ding","doi":"10.1093/burnst/tkaf007","DOIUrl":"https://doi.org/10.1093/burnst/tkaf007","url":null,"abstract":"Background Ischemic injury is a primary cause of distal flap necrosis. Previous studies have shown that Flufenamic acid (FFA) can reduce inflammation, decrease oxidative stress (OS), and promote angiogenesis, suggesting its potential role in protecting flaps from ischemic damage. This study investigated the effects and mechanisms of FFA in enhancing the survival of ischemic flaps. Methods The viability of ischemic flaps was evaluated using laser doppler blood flow (LDBF) and survival rates. We examined levels of pyroptosis, OS, transcription factor E3 (TFE3)-induced autophagy, and elements of the AMPK-TRPML1-Calcineurin pathway through western blotting (WB), immunofluorescence (IF), molecular docking (MD), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR). Results The findings suggest that FFA significantly enhances the viability of ischemic flaps. The improvement in flap survival associated with FFA can be attributed to increased autophagy, diminished OS, and the suppression of pyroptosis. Notably, the promotion of autophagy flux and an augmented resistance to OS are instrumental in curbing pyroptosis in these flaps. Activation of TFE3 by FFA promoted autophagy and diminished oxidative damage. The therapeutic effects of FFA were negated when TFE3 levels were decreased using adeno-associated virus (AAV)-TFE3shRNA. Additionally, FFA modified TFE3 activity through the AMPK-TRPML1-Calcineurin pathway. Conclusions FFA promotes ischemic flap survival via induction of autophagy and suppression of oxidative stress by activation of the AMPK-TRPML1-Calcineurin-TFE3 signaling pathway. These findings could have therapeutic implications.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"12 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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