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Zhai M, Tan H, Xu A, Wu B, Xie F, Lu Y, Zheng Y. Immunomodulatory hydrogel loaded with PD-L1-expressing exosomes reprograms macrophages and accelerates diabetic wound healing. BIOMATERIALS ADVANCES 2025; 176:214362. [PMID: 40440990 DOI: 10.1016/j.bioadv.2025.214362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 05/06/2025] [Accepted: 05/26/2025] [Indexed: 06/16/2025]
Abstract
Diabetic foot ulcers (DFU), a severe complication of diabetes mellitus, present a global healthcare challenge due to high risks of limb amputation and mortality. This study developed a multifunctional hydrogel dressing, Gelatin Methacryloyl (GelMA) hydrogel loaded with interleukin-4 (IL-4)-engineered exosomes (Exos), designed to synergistically modulate immune responses and enhance angiogenesis for complete diabetic wound repair. The programmed death-ligand 1 (PD-L1)-enriched Exos were engineered via IL-4 overexpression in NIH3T3 fibroblasts. The GelMA hydrogel loaded NIH3T3 fibroblast-derived Exos with IL-4 overexpression (GelMA/ExosIL-4 hydrogel) exhibited favorable physicochemical characteristics, including a three-dimensional porous microstructure, injectability, tissue adhesion, self-healing properties, and sustained moisture retention. In vitro evaluation demonstrated biocompatibility, sustained exosome release, and enhanced viability, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). In a diabetic wound model, the hydrogel significantly accelerated wound closure, promoted re-epithelialization and angiogenesis, and skewed macrophages toward anti-inflammatory M2 polarization while suppressing T-cell proliferation. These findings highlight the dual immunomodulatory and pro-angiogenic efficacy of GelMA/ExosIL-4 hydrogel, offering a promising therapeutic strategy for chronic wound management.
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Affiliation(s)
- Mingzhu Zhai
- Center for Medical Experiments (CME), Shenzhen Guangming District People's Hospital, Shenzhen 518106, China; Department of Clinical Pathology, Jinan University First Affiliated Hospital, Guangzhou 510632, China
| | - Hongxi Tan
- Center for Medical Experiments (CME), Shenzhen Guangming District People's Hospital, Shenzhen 518106, China
| | - Aohong Xu
- Center for Medical Experiments (CME), Shenzhen Guangming District People's Hospital, Shenzhen 518106, China
| | - Benqing Wu
- Benqing Laboratory, Shenzhen Guangming District People's Hospital, Shenzhen 518106, China
| | - Fang Xie
- Nutrition Department, Shenzhen Guangming District People's Hospital, Shenzhen 518106, China.
| | - Yuanzhi Lu
- Department of Clinical Pathology, Jinan University First Affiliated Hospital, Guangzhou 510632, China.
| | - Yi Zheng
- Center for Medical Experiments (CME), Shenzhen Guangming District People's Hospital, Shenzhen 518106, China.
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Su X, Geng X, Li F, Song M, Lv R, Zhang Y, Yuan J, Dong J, Shi Y, Zhao L. Microneedles loaded with l-arginine-modified puerarin-derived carbon nanoparticles improved treatment of diabetic wound via photothermal and nitric oxide-based gas therapy. J Colloid Interface Sci 2025; 691:137353. [PMID: 40127558 DOI: 10.1016/j.jcis.2025.137353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/12/2025] [Accepted: 03/16/2025] [Indexed: 03/26/2025]
Abstract
Due to the high-glucose environment of diabetic wounds, a significant proliferation of bacteria at wound site can occur, resulting in an inflammatory response that extends the inflammatory phase of the wound, thereby complicating the healing process in diabetic wounds. Eliminating the proliferation of bacteria plays a crucial role in promoting the healing of diabetic wounds. Under near-infrared (NIR) laser irradiation, l-arginine (L-Arg) -modified natural product puerarin (Pue)-derived carbon nanoparticles (l-Arg-CNP) not only exhibited excellent photothermal effects but also produced reactive oxygen species (ROS) to react with l-Arg for producing Nitric Oxide (NO), thus contributing to a synergistic antibacterial therapy in diabetic wound. At the same time, l-Arg-CNP retained Pue's original characteristics to promote cell proliferation and angiogenesis. Following the loading of l-Arg-CNP into microneedle patches (l-Arg-CNP@MN), it can deliver them into the deeper wound, effectively killing bacteria, reducing inflammatory infiltration, and promoting neovascularization at the wound site. It offers an effective therapeutic strategy for treating diabetic wound healing.
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Affiliation(s)
- Xiangchen Su
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P R China.
| | - Xinrong Geng
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P R China.
| | - Fang Li
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P R China.
| | - Mingzhu Song
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P R China.
| | - Ruizhen Lv
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P R China.
| | - Yifei Zhang
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P R China.
| | - Jiayu Yuan
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P R China.
| | - Jia Dong
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P R China.
| | - Yijie Shi
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P R China; Collaborative Innovation Center for Age-related Disease, Jinzhou Medical University, Jinzhou, Liaoning, China.
| | - Liang Zhao
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P R China; Collaborative Innovation Center for Age-related Disease, Jinzhou Medical University, Jinzhou, Liaoning, China; Key Laboratory of Neurodegenerative Diseases of Liaoning Province, Jinzhou Medical University, Jinzhou, China.
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Ahmed W, Li S, Liang M, Peng P, Muhammad W, Wang Q, Gao C. Selenium-containing polyurethane nanofibers with MnO 2 nanoparticles and gelsevirine promote diabetic wound healing by modulation of ROS and inflammation. BIOMATERIALS ADVANCES 2025; 173:214289. [PMID: 40158270 DOI: 10.1016/j.bioadv.2025.214289] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/11/2025] [Accepted: 03/18/2025] [Indexed: 04/02/2025]
Abstract
Reactive oxygen species (ROS) and subsequent inflammatory cascades hinder the healing of diabetic wounds, which should be tackled simultaneously when designing wound dressings. In this study, ROS-responsive di‑selenium-containing polyurethane nanofibers (PUF) loaded with manganese dioxide nanoparticles (MnO2 NPs) and gelsevirine (GSV) with an average diameter of 0.6 ± 10 μm, were prepared to specifically target ROS and inflammation control, thereby enhancing healing in diabetic wounds. The resulting nanofibers exhibited a porous architecture and enhanced drug delivery capability. The MnO2/GSV/PUF dressing showed negligible cytotoxicity with cell viability over 80 %, effective ROS-scavenging ability of 87 %, and inhibition of pro-inflammatory cytokine expression. This dual mechanism of ROS-scavenging and inflammation modulation accelerated the healing of diabetic wounds up to 92 % in 14 d in a full-thickness diabetic wound model, as evidenced by reduced cytokine levels, enhanced epithelialization, and uniform collagen deposition with the highest percentage of 60 %.
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Affiliation(s)
- Wajiha Ahmed
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310058, China
| | - Shifen Li
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310058, China
| | - Min Liang
- Center for Healthcare Materials, Shaoxing Institute, Zhejiang University, Shaoxing 312099, China
| | - Pai Peng
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310058, China
| | - Wali Muhammad
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310058, China
| | - Qiaoxuan Wang
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310058, China
| | - Changyou Gao
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310058, China; Center for Healthcare Materials, Shaoxing Institute, Zhejiang University, Shaoxing 312099, China.
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Selby W, Garland P, Mastikhin I. Transient shear wave elastometry using a portable magnetic resonance sensor. Magn Reson Med 2025; 94:373-385. [PMID: 39869494 DOI: 10.1002/mrm.30444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 12/06/2024] [Accepted: 01/13/2025] [Indexed: 01/29/2025]
Abstract
PURPOSE Magnetic resonance elastography (MRE) provides detailed maps of tissue stiffness, helping to diagnose various health conditions, but requires the use of expensive clinical MRI scanners. Our approach utilizes compact, cost-effective portable MR sensors that offer bulk characterization of material properties in a region of interest close to the surface (within 1-2 cm). This accessible instrument could enable routine monitoring and prevention of diseases not readily evaluated with conventional tools. METHODS The method was tested on tissue-mimicking phantoms with varying stiffness. The gels were excited with acoustic pulses (one cycle of a sinusoidal waveform) at a fixed distance from the MR sensor. A series of delays between acoustic excitation and MR signal detection allowed time for the pulse to travel to the sensitive region. RESULTS The "arrival time" of the shear wave, determined by the time-dependent MR signal response, was used to calculate the shear wave speed. MR measurements of shear wave speed were compared with optical sensor measurements and manufacturer-tabulated values, aligning with expected relative differences between samples. CONCLUSION A portable MR-based transient elastometry technique for measuring tissue elasticity was developed and demonstrated on tissue-mimicking phantoms. Future improvements include using a new portable magnet to investigate depth-dependent changes in elasticity in stratified samples and integrating MR relaxation and diffusion measurements for comprehensive tissue analysis. This approach can complement conventional MRE in applications where a portable, affordable, and localized assessment of tissue stiffness is required.
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Affiliation(s)
- William Selby
- MRI Research Centre, Physics, University of New Brunswick, Fredericton, New Brunswick, Canada
| | - Phil Garland
- Mechanical Engineering, University of New Brunswick, Fredericton, New Brunswick, Canada
| | - Igor Mastikhin
- MRI Research Centre, Physics, University of New Brunswick, Fredericton, New Brunswick, Canada
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Ma G, Cheng K, Wang X, Zeng Y, Hu C, He L, Shi Z, Lin H, Zhang T, Sun S, Huang P. Dual oxygen supply system of carbon dot-loaded microbubbles with acoustic cavitation for enhanced sonodynamic therapy in diabetic wound healing. Biomaterials 2025; 318:123145. [PMID: 39874643 DOI: 10.1016/j.biomaterials.2025.123145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/19/2025] [Accepted: 01/24/2025] [Indexed: 01/30/2025]
Abstract
Diabetic wounds present significant treatment challenges due to their complex microenvironment, marked by persistent inflammation from bacterial infections, hypoxia caused by diabetic microangiopathy, and biofilm colonization. Sonodynamic therapy (SDT) offers potential for treating such wounds by targeting deep tissues with antibacterial effects, but its efficacy is limited by hypoxic conditions and biofilm barriers. To overcome these obstacles, we developed a novel approach using oxygen-carrying microbubbles loaded with Mn2+-doped carbon dots (MnCDs@O2MBs) to enhance SDT and disrupt biofilms. Through precursor screening and design, MnCDs are engineered to exhibit tailored properties of sonodynamic activity and enzyme-like catalytic capabilities. This system provides a dual oxygen supply for amplifying the SDT effects: MnCDs, serving as a sonosensitizer, also chemically convert excess H2O2 at infection sites into oxygen, while the O2MBs physically release oxygen through ultrasound-induced cavitation. The cavitation effect also disrupts biofilms, improving the delivery of sonosensitizers and boosting SDT efficacy. In a diabetic wound model, this strategy downregulated TLR, NF-κB, and TNF inflammatory pathways, reduced pro-inflammatory factor secretion, promoted angiogenesis, and accelerated wound healing, thereby acting as a promising treatment approach for diabetic wound healing.
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Affiliation(s)
- Guangrong Ma
- Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China; Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China
| | - Ke Cheng
- International Joint Research Center for Photo-Responsive Molecules and Materials School of Chemical and Material Engineering, Jiangnan University, Wuxi, Jiangsu, 214122, PR China
| | - Xue Wang
- Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China; Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China
| | - Yiqing Zeng
- Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China; Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China
| | - Chenlu Hu
- Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China; Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China
| | - Luying He
- Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China; Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China
| | - Zhan Shi
- Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China; Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China
| | - Hengwei Lin
- International Joint Research Center for Photo-Responsive Molecules and Materials School of Chemical and Material Engineering, Jiangnan University, Wuxi, Jiangsu, 214122, PR China
| | - Tao Zhang
- Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China; Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China.
| | - Shan Sun
- International Joint Research Center for Photo-Responsive Molecules and Materials School of Chemical and Material Engineering, Jiangnan University, Wuxi, Jiangsu, 214122, PR China.
| | - Pintong Huang
- Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China; Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China; Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, No. 66 Dongxin Avenue, Binjiang District, Hangzhou, 310053, PR China.
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Liao Y, Zhang Z, Hu W, Zhang S, Zhao Y, Ouyang L, Yu C, Liu M, Mi B, Liu G. Glucose-regulating hydrogel for immune modulation and angiogenesis through metabolic reprogramming and LARP7-SIRT1 pathway in infected diabetic wounds. Biomaterials 2025; 318:123182. [PMID: 39951832 DOI: 10.1016/j.biomaterials.2025.123182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 02/01/2025] [Accepted: 02/08/2025] [Indexed: 02/16/2025]
Abstract
In diabetic-infected wounds, the local hyperglycemic state leads to unique pathological characteristics of diabetic ulcers, such as secondary chronic infections, abnormal angiogenesis, oxidative stress, and diabetic peripheral neuropathy. Glucose oxidase (GOx) is an enzyme that catalyzes the breakdown of glucose into hydrogen peroxide and gluconic acid, making it a candidate enzyme for regulating the hyperglycemic microenvironment in diabetic wounds. However, multifunctional hydrogel therapeutic systems built around the glucose-lowering capability of GOx have rarely been reported. Here, we loaded stachydrine and Au-FePS3 nanosheets onto a quaternized chitosan (QC) - oxidized dextran (OD) hydrogel to construct a synergistic QC-OD@AF/S hydrogel therapeutic system. In vitro experiments showed that Au-FePS3 possesses GOx-POD cascade catalytic activity, capable of reducing glucose concentration and decomposing generated hydrogen peroxide into reactive oxygen species (ROS). Concurrently, Au-FePS3 exhibits excellent photothermal performance under 808 nm infrared light, synergistically exerting antibacterial capabilities with ROS and quaternary ammonium groups. Stachydrine has been demonstrated to mediate the metabolic reprogramming of macrophages and alleviate high-glucose-induced oxidative stress and impairment of angiogenesis in HUVECs through the LARP7-SIRT1 pathway. In summary, the QC-OD@AF/S hydrogel demonstrates superior capabilities in antibacterial activity, immune modulation, promotion of angiogenesis, and reduction of local glucose concentration, making it a potential clinical therapy.
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Affiliation(s)
- Yuheng Liao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhenhe Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Weixian Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shengming Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yanzhi Zhao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lizhi Ouyang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chenyan Yu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Mengfei Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Bobin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Guohui Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Xiong Y, Hao Y, Ding L, Li J, Cao Y, Fan S, Guan F, He L. Hesperidin-loaded self-assembled supramolecular hydrogel based on quaternized chitosan as efficient photothermal antibacterial dressing for MRSA-infected wound healing. Carbohydr Polym 2025; 359:123577. [PMID: 40306783 DOI: 10.1016/j.carbpol.2025.123577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 03/25/2025] [Accepted: 04/04/2025] [Indexed: 05/02/2025]
Abstract
The management of infected chronic wounds is one of the urgent challenges. Herein, a hesperidin (Hes)-loaded self-assembled supramolecular hydrogel based on quaternized chitosan (CQHP) has been developed as an efficient photothermal antibacterial dressing for MRSA-infected wound healing. Specifically, CQHP hydrogels fabricated through the dynamic noncovalent interactions among CM-β-CD grafted QCS, Hes, proline and Fe3+, exhibited injectable and self-healing behaviors, along with adhesion, antioxidant, hemostatic and protein adsorption performance, satisfying the essential feature as chronic wound dressing. Of note, superior photothermal effect generated from the Hes-Fe3+ has been demonstrated, which endowed the CQHP hydrogels effectively and rapidly eliminate the E. coli, S. aureus and MRSA through photothermal therapy, thereby avoiding the use of antibiotics or photothermal conversion nanomaterials in hydrogels and substantially reducing the biological toxicity. Furtherly, sustained antibacterial performance in the absence of NIR can be achieved through the inherent antibacterial activities of Hes. Importantly, the developed CQHP hydrogels significantly promoted the closure of acute full-thickness scratch wounds, and exhibited remarkable better therapeutic effect on MRSA-infected wound than commercial 3M transparent film, by efficiency and sustained antibacterial activity, reducing inflammation, enhancing angiogenesis and collagen deposition, highlighting its promising application in the MRSA-infected wound healing with high efficiency, quality and security.
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Affiliation(s)
- Yamin Xiong
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yi Hao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Linlin Ding
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Jinjin Li
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yuan Cao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Shuhui Fan
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Fangxia Guan
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Leiliang He
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
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Chen JQ, Chen ZH, Zheng WB, Shen XQ. Correlation of anxiety and depression with pain in patients with diabetic foot ulcers and analysis of risk factors. World J Psychiatry 2025; 15:105334. [DOI: 10.5498/wjp.v15.i6.105334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/24/2025] [Accepted: 04/27/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Pain often predisposes patients with diabetic foot ulcers (DFUs) to negative emotional states, such as anxiety and depression, which can significantly impair treatment outcomes and recovery. However, very few studies have explored the relationship between anxiety, depression, and pain in DFUs, as well as the associated risk factors.
AIM To analyze the correlation between anxiety, depression, and pain in patients with DFUs and to identify the associated risk factors.
METHODS This study included 106 patients diagnosed with DFUs who were admitted to Tiantai County People’s Hospital between March 2022 and March 2024. The patients’ anxiety levels were evaluated using Zung’s self-rating anxiety scale (SAS), depression status was assessed using Zung’s self-rating depression scale (SDS), and pain intensity was assessed using the visual analog scale (VAS). Subsequently, correlations between SAS, SDS, and VAS scores were analyzed. Univariate and multivariate analyses were conducted to explore the risk factors that contributed to anxiety and depression in patients with DFUs.
RESULTS Among the 106 patients, 39.62% exhibited anxiety and 43.40% presented with depression. Most patients experiencing anxiety or depression exhibited mild symptoms, with no severe cases observed. Compared with asymptomatic patients, those with anxiety or depression had significantly higher VAS scores. Correlation analysis indicated a significant positive relationship between both SAS and SDS scores and the VAS score. Univariate analysis identified sex, age, Wagner’s grade, presence of other complications, and smoking history as factors significantly associated with anxiety and depression. Multivariate analysis further confirmed that younger age, higher Wagner’s grade, and higher VAS scores were independent predictors of anxiety and depression.
CONCLUSION This study reveals a significant positive correlation between anxiety, depression, and pain in patients with DFUs. This finding suggests that timely and effective pain intervention may be beneficial in alleviating negative emotions such as anxiety and depression. In addition, younger age (< 50 years), higher Wagner’s grade, and higher VAS scores increase the risk of developing anxiety and depression in this patient population.
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Affiliation(s)
- Jiang-Qiang Chen
- Department of Plastic Surgery, Tiantai County People’s Hospital, Taizhou 317200, Zhejiang Province, China
| | - Zu-Hui Chen
- Department of Plastic Surgery, Tiantai County People’s Hospital, Taizhou 317200, Zhejiang Province, China
| | - Wei-Bin Zheng
- Department of Plastic Surgery, Tiantai County People’s Hospital, Taizhou 317200, Zhejiang Province, China
| | - Xiang-Qian Shen
- Department of Plastic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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Lin SS, Chen CR, Xu WC, Fu J, Xu JQ, Liang ZH. Association between anemia and the risk of diabetic foot ulcer: A meta-analysis. World J Diabetes 2025; 16:105155. [DOI: 10.4239/wjd.v16.i6.105155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/07/2025] [Accepted: 04/23/2025] [Indexed: 06/13/2025] Open
Abstract
BACKGROUND Diabetic foot ulcers (DFUs) are a major complication of diabetes mellitus, and anemia is commonly observed in diabetic patients. However, the relationship between anemia and the risk of developing DFUs remains unclear.
AIM To investigate the relationship between anemia and the risk of DFUs in diabetic patients through a meta-analysis.
METHODS A systematic search was conducted across PubMed, Embase, and Web of Science databases to identify studies that reported the co-occurrence of anemia and DFUs in diabetic patients. The primary outcome was an association between anemia and DFU risk, expressed as odds ratios (ORs). Secondary outcomes included the risk of DFU per 1-g/dL decrease in hemoglobin and the difference in hemoglobin levels between patients with and without DFU. Statistical analyses were performed using random-effects models to account for heterogeneity.
RESULTS Sixteen studies involving 170,949 diabetic patients were included in the analysis. The results indicated a significant association between anemia and an increased risk of DFUs (eight studies, n = 166173, OR: 2.72, 95%CI: 1.73–4.25, P < 0.001; I2 = 93%). Subgroup analyses supported consistent findings across various patient characteristics, analytic models, and study quality scores (P for subgroup differences, all > 0.05). Additionally, each 1-g/dL decrease in hemoglobin was associated with an excess risk of DFUs (four studies, n = 2543, OR: 1.65, 95%CI: 1.21–2.27, P = 0.002; I2 = 68%). Furthermore, diabetic patients with DFUs exhibited significantly lower hemoglobin levels compared to those without DFUs (nine studies, n = 3986, mean difference: -2.13 g/dL, 95%CI: -2.58 to -1.68, P < 0.001; I2 = 90%).
CONCLUSION Anemia can be associated with an increased risk of DFUs in diabetic patients. Monitoring and managing anemia in diabetic population may help mitigate the risk of DFUs, emphasizing the need for early interventions. Further research is required to investigate the underlying mechanisms and potential therapeutic strategies.
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Affiliation(s)
- Shi-Shuai Lin
- Department of Burn and Skin Repair Surgery, Affiliated Hainan Hospital of Hainan Medical University, Hainan General Hospital, Haikou 570311, Hainan Province, China
| | - Cun-Ren Chen
- Department of Endocrinology, Affiliated Hainan Hospital of Hainan Medical University, Hainan General Hospital, Haikou 570311, Hainan Province, China
| | - Wei-Cheng Xu
- Department of Burn and Skin Repair Surgery, Affiliated Clinical College of Hainan Medical University, Haikou 570311, Hainan Province, China
| | - Jia Fu
- Department of Burn and Skin Repair Surgery, Affiliated Clinical College of Hainan Medical University, Haikou 570311, Hainan Province, China
| | - Jia-Qin Xu
- Department of Burn and Skin Repair Surgery, Affiliated Hainan Hospital of Hainan Medical University, Hainan General Hospital, Haikou 570311, Hainan Province, China
| | - Zun-Hong Liang
- Department of Burn and Skin Repair Surgery, Affiliated Hainan Hospital of Hainan Medical University, Hainan General Hospital, Haikou 570311, Hainan Province, China
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Al Madhoun A. Epigenetics and diabetic wound healing: Wilms tumor 1-associated protein as a therapeutic target. World J Diabetes 2025; 16:105615. [DOI: 10.4239/wjd.v16.i6.105615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 04/03/2025] [Accepted: 05/12/2025] [Indexed: 06/13/2025] Open
Abstract
In this editorial, we highlight the study by Xiao et al. Despite progress in the management of diabetic foot ulcers (DFUs), impaired wound healing remains a significant clinical challenge. Recent studies have highlighted the critical role of epigenetic modifications in diabetic wound healing, with particular emphasis on DNA and RNA methylation pathways. This editorial discusses the findings of Xiao et al, who identified the Wilms tumor 1-associated protein (WTAP) - DNA methyltransferase 1 (DNMT1) axis as a pivotal regulator of endothelial dysfunction in DFUs. WTAP, a regulatory subunit of N6-methyladenosine (m6A) methyltransferase, is upregulated under high-glucose conditions and drives the excessive expression of DNMT1 via m6A modification. This contributes to impaired angiogenesis, reduced cell viability, and delayed wound closure. WTAP knockdown restored endothelial function and significantly improved wound healing in a diabetic mouse model. Furthermore, DNMT1 overexpression abrogated the benefits of WTAP suppression, confirming its downstream effector role. Thus, targeting the WTAP-DNMT1 axis provides a new avenue for DFU management. Moreover, epigenetic interventions that modulate both the m6A and RNA methylation pathways could restore endothelial function and enhance tissue repair in patients with diabetes.
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Affiliation(s)
- Ashraf Al Madhoun
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15400, Kuwait
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11
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Wu X, Liu J, Song W, Wu L, Fu Q, Chen J, Li Q. Orthosilicic Acid Promotes Diabetic Wound Healing Through the PI3 K/AKT/mTOR Signaling Pathway. Biol Trace Elem Res 2025:10.1007/s12011-025-04670-6. [PMID: 40517214 DOI: 10.1007/s12011-025-04670-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 05/13/2025] [Indexed: 06/16/2025]
Abstract
Delayed healing of diabetic wounds is one of the major complications of diabetes mellitus, which increases the rate of amputation and mortality in patients. The impairment of vascular endothelial cells in a high-glucose environment is one of the main reasons for the delayed healing of diabetic wounds. Orthosilicic acid (OSA), the primary bioavailable form of silicon, has not yet been investigated for its potential role in the delayed healing of diabetic wounds. The CCK-8 experiment confirmed that 30 μM was the optimal concentration for OSA to affect the proliferation of human umbilical vein endothelial cells (HUVECs). EdU, Transwell, and cell-scratch experiments verified that OSA promoted the proliferation and migration ability of HUVECs under a high-glucose environment. The result of the tube-formation experiment demonstrated that OSA rescued the inhibition of HUVECs angiogenesis caused by a high-glucose environment. TUNEL and flow cytometry revealed that OSA inhibited the apoptosis of HUVECs induced by a high-glucose environment. In vivo experiments revealed that OSA could promote the healing of skin wounds in db/db mice through the PI3K/AKT/mTOR pathway. Our findings suggested that OSA promoted angiogenesis in HUVECs via the PI3K-AKT/mTOR pathway and emphasized that OSA is a potential therapeutic strategy for treating diabetic wounds.
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Affiliation(s)
- Xinhui Wu
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250001, People's Republic of China
- Department of Nephrology, Shandong Electric Power Central Hospital, Jinan, Shandong, 250001, People's Republic of China
| | - Jincheng Liu
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong, 250000, People's Republic of China
| | - Wenting Song
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250001, People's Republic of China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong, 250021, People's Republic of China
| | - Lanxia Wu
- School of Psychology, Shandong Second Medical University, Weifang, Shandong, 261053, People's Republic of China
| | - Qingyang Fu
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong, 250000, People's Republic of China
| | - Junfei Chen
- Department of Pediatric Surgery, Cheeloo College of Medicine, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250000, People's Republic of China.
| | - Qiu Li
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250001, People's Republic of China.
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong, 250021, People's Republic of China.
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12
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Borrelli EP. Estimating the annual cost burden of diabetic peripheral neuropathy in the United States. Endocrine 2025:10.1007/s12020-025-04318-4. [PMID: 40517209 DOI: 10.1007/s12020-025-04318-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 06/04/2025] [Indexed: 06/16/2025]
Abstract
PURPOSE Diabetic peripheral neuropathy (DPN) is one of the leading complications of diabetes. Given the significant growth in prevalence of diabetes and therefore DPN in the United States in recent years, a quantitative analysis is needed to estimate the annual cost burden of DPN. METHODS A cost-of-illness burden model was created to estimate the cost burden on DPN in the United States. A review of the literature was undertaken to identify the most appropriate epidemiologic and economic inputs. One-way sensitivity analyses were conducted for every model input parameter to show the potential variability in the estimated cost-burden. RESULTS There is an estimated prevalence of approximately 13,209,600 patients with DPN in the U.S., with an estimated annual cost burden from DPN of $45,930,580,972. Of the estimated cost burden, $30,859,424,749 was from DPN specific care ($2,389,038,060 for outpatient office visits, $26,830,282,752 for inpatient hospitalizations, and $1,640,103,936 from prescription medications) and $15,071,156,223 from treating incident DPN complications ($12,875,200,000 for diabetic foot ulcers and $2,195,956,223 for diabetic lower limb amputations). CONCLUSIONS DPN is a very costly condition, and the burden is expected to continue to grow in the coming years.
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Affiliation(s)
- Eric P Borrelli
- University of California San Diego, Skaggs School of Pharmacy & Pharmaceutical Sciences, La Jolla, CA, USA.
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13
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Wang F, Yao J, Zuo H, Jiao Y, Wu J, Meng Z. Diverse-Origin Exosomes Therapeutic Strategies for Diabetic Wound Healing. Int J Nanomedicine 2025; 20:7375-7402. [PMID: 40529540 PMCID: PMC12170840 DOI: 10.2147/ijn.s519379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 05/20/2025] [Indexed: 06/20/2025] Open
Abstract
Diabetic wounds represent a pressing clinical challenge in the medical field. Compared to healthy individuals, patients with diabetes present with various complications, including abnormal blood sugar levels, microcirculation disorders, and impaired cellular function. Moreover, they are at a higher risk for skin damage and have a more difficult healing process. In recent years, exosome-based regenerative medicine has provided new strategies for diabetic wound treatment. The bioactive molecules contained in the exosomes, including functional proteins, bioactive lipids, and regulatory RNAs, allow them to suppress inflammation, enhance cell migration, and promote angiogenesis. As exosomes from different sources have different composition and function, the characteristics of their source must be considered when using them. Unlike traditional single source research, this review describes the mechanism of action of exosomes from different sources in diabetic wound-healing process, including mammalian cell-derived exosomes and plant-derived exosome-like nanoparticles. These findings not only provide a theoretical basis for the selection of exosome sources but also lay a foundation for the development of personalized, multimodal treatment plans.
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Affiliation(s)
- Fengyu Wang
- The Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China
| | - Jinling Yao
- Yunnan Province Dai and Yi Medicine Primary Laboratory, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China
| | - Huiling Zuo
- The Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China
| | - Yuhang Jiao
- The Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China
| | - Junzi Wu
- The Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China
| | - Zhuoran Meng
- The Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China
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14
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Suhandi C, Wilar G, Mohammed AFA, Mahmoud SA, Muchtaridi M, Shamsuddin S, Safuan S, Lesmana R, Hasan N, Zulhendri F, Wathoni N. Propolis-Based Nanostructured Lipid Carrier of α-Mangostin for Promoting Diabetic Wound Healing in Alloxan-Induced Mice. J Inflamm Res 2025; 18:7443-7457. [PMID: 40519653 PMCID: PMC12165184 DOI: 10.2147/jir.s525243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 05/31/2025] [Indexed: 06/18/2025] Open
Abstract
Introduction Diabetic wounds present a significant challenge due to delayed healing and susceptibility to infection. Conventional therapies often fall short of achieving complete and timely wound repair. This study investigates the potential of α-mangostin (αM) and its propolis-based nanostructured lipid carrier (NLC-P-αM) formulation as novel therapeutic agents for diabetic wound healing. Purpose To evaluate the release profile, safety, and efficacy of NLC-P-αM in promoting wound repair in an in vitro and in vivo diabetic wound model. Methods The NLC-P-αM formulation was prepared using a melt-emulsification technique with ultrasonication. In vitro release studies were conducted using a dialysis bag method and analyzed using kinetic models. Cytotoxicity was assessed using the WST-8 assay on NIH-3T3 fibroblast cells. In vivo diabetic wound healing was evaluated using alloxan-induced diabetic Swiss Webster mice. The treatments were applied topically for 14 days, and wound closure was monitored quantitatively. Histological analysis was performed to assess the inflammatory cell infiltration, epidermal thickness, and tissue regeneration. Results NLC-P-αM demonstrated a significantly enhanced release profile, with 85.55 ± 4.25% of αM released at 360 min compared to 19.82 ± 6.78% for free αM, following a non-Fickian diffusion mechanism. Both formulations exhibited excellent safety, with cell viabilities of 94.76 ± 4.95% for NLC-P-αM and 102.16 ± 7.98% for αM in NIH-3T3 cells. In vivo, NLC-P-αM achieved the highest wound closure rate (85.83 ± 3.33%) by day 14, outperforming αM and the controls. Histological analysis confirmed reduced inflammation, a thinner epidermis, and advanced tissue regeneration in the NLC-P-αM group, highlighting its superior therapeutic efficacy. Conclusion NLC-P-αM demonstrated enhanced release, excellent safety, and superior efficacy in promoting diabetic wound healing compared to free αM and other controls. This nanoformulation offers a promising therapeutic strategy for accelerating wound repair in diabetic patients.
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Affiliation(s)
- Cecep Suhandi
- Doctoral Program of Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia
| | - Gofarana Wilar
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia
| | | | - Safwat A Mahmoud
- Center for Scientific Research and Entrepreneurship, Northern Border University, Arar, 73213, Saudi Arabia
| | - Muchtaridi Muchtaridi
- Department of Analytical Pharmacy and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia
| | - Shaharum Shamsuddin
- School of Health Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, 16150, Malaysia
| | - Sabreena Safuan
- School of Health Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, 16150, Malaysia
| | - Ronny Lesmana
- Physiology Division, Department of Biomedical Science, Faculty of Medicine, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia
- Biological Activity Division, Central Laboratory, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia
| | - Nurhasni Hasan
- Department of Pharmacy Science and Technology, Faculty of Pharmacy, Universitas Hasanuddin, Makassar, South Sulawesi, 90245, Indonesia
| | - Felix Zulhendri
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia
- Kebun Efi, Karo, North Sumatra, 22171, Indonesia
| | - Nasrul Wathoni
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia
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15
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Jia X, Dou Z, Zhang Y, Yu C, Yang M, Xie H, Lin Y, Liu Z. Application of a novel thermal/pH-responsive antibacterial paeoniflorin hydrogel crosslinked with amino acids for accelerated diabetic foot ulcers healing. Mater Today Bio 2025; 32:101736. [PMID: 40255581 PMCID: PMC12008599 DOI: 10.1016/j.mtbio.2025.101736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 04/01/2025] [Accepted: 04/05/2025] [Indexed: 04/22/2025] Open
Abstract
Diabetic foot ulcers (DFUs), a severe and common complication of diabetes, present significant treatment challenges due to the limitations of conventional dressings, such as poor mechanical properties, bioactivity, and limited functionality, which hinder fast and effective wound healing. To address these issues, we developed a novel natural amino acid-based hydrogel loaded with paeoniflorin (PF@PNMA1) and comprehensively evaluated its properties and functions. The nanogel particles (NGs) were synthesized via emulsion polymerization using N-isopropylacrylamide (NIPAM), methacrylic acid (MAA), and chemically modified arginine (MArg). The poly(NIPAM-co-MAA) (PNM) and poly(NIPAM-co-MAA-co-MArg) (PNMA) gels were prepared by functionalizing the NGs with glycidyl methacrylate (GMA). The different concentrations of amino acids were added to explore the optimal mechanical properties of the gel. Through the rheological measurement, we found that PNMA1 gel has good ductile properties with a critical strain up to about 63 %. At the same time, we also verified its antibacterial activity and found that the viability of bacteria decreased to 47.46 % after 3 h. Preliminary tests using network pharmacology and molecular docking confirmed the therapeutic potential of PF for DFUs. The PF@PNMA1 gel demonstrated excellent biocompatibility, and in vivo experiments revealed its effectiveness in promoting angiogenesis and wound healing. After 10 days, the wound healing rate was 25.6 % higher than that of the control group. The PF@PNMA1 shows great potential as an effective therapy for DFUs treatment.
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Affiliation(s)
- Xintao Jia
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- State Key Laboratory of Component Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Zixuan Dou
- State Key Laboratory of Component Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Ying Zhang
- State Key Laboratory of Component Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Changxiang Yu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- State Key Laboratory of Component Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Mengru Yang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- State Key Laboratory of Component Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Haonan Xie
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- State Key Laboratory of Component Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Yun Lin
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- State Key Laboratory of Component Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Zhidong Liu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- State Key Laboratory of Component Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
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Zhang S, Wang Y, Xiong X, Xing J, Jing K. Mechanistic insights into Hippo-YAP pathway activation for enhanced DFU healing. Am J Physiol Cell Physiol 2025; 328:C1921-C1940. [PMID: 40261295 DOI: 10.1152/ajpcell.01067.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 01/16/2025] [Accepted: 04/10/2025] [Indexed: 04/24/2025]
Abstract
With the increasing prevalence of diabetes, diabetic foot ulcers (DFUs) have become a global health challenge, significantly impacting patients' quality of life and placing a substantial burden on healthcare systems. Among various immune cell subsets, M2-polarized macrophages play a pivotal role in tissue repair and inflammation resolution. This study uses single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing to comprehensively investigate the role of the TFAP2A-LIFR-Hippo-YAP signaling axis in regulating macrophage M2 polarization and its critical function in DFU wound healing. Through scRNA-seq analysis, we identified nine major immune cell subsets in DFU samples, with macrophages emerging as key regulatory cells. In vitro experiments further confirmed that TFAP2A promotes macrophage M2 polarization (evidenced by increased expression of the M2 marker ARG1) and ameliorates endothelial dysfunction by enhancing tube formation, improving migration capacity, and upregulating relevant proteins such as VCAM-1. Moreover, TFAP2A serves as a central regulatory gene for macrophage function in DFU by upregulating LIFR expression and activating the Hippo-YAP signaling pathway, thereby inducing M2 polarization and mitigating endothelial dysfunction. Mouse model experiments further demonstrated that the TFAP2A-LIFR-Hippo-YAP signaling axis accelerates DFU wound healing through the induction of macrophage M2 polarization. This study unveils a novel immunoregulatory role of TFAP2A in DFU and provides a promising therapeutic target for the treatment of chronic diabetic wounds.NEW & NOTEWORTHY This study provides unprecedented insights into diabetic foot ulcer healing by demonstrating the novel immunoregulatory role of the TFAP2A-LIFR-Hippo-YAP signaling axis. Leveraging single-cell and bulk transcriptomics, we identify TFAP2A as a crucial regulator of macrophage M2 polarization, essential for wound healing and angiogenesis. These findings offer valuable mechanistic understanding and present TFAP2A as a promising therapeutic target for improving outcomes in chronic diabetic wounds.
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Affiliation(s)
- Shaochun Zhang
- Department of Orthopedics, The Central Hospital of Ezhou, Ezhou, People's Republic of China
| | - Ye Wang
- Department of Orthopedics, The Central Hospital of Ezhou, Ezhou, People's Republic of China
| | - Xuesong Xiong
- Department of Endocrinology, The Central Hospital of Ezhou, Ezhou, People's Republic of China
| | - Jili Xing
- Department of Gastroenterology, The Central Hospital of Ezhou, Ezhou, People's Republic of China
| | - Ke Jing
- Department of Endocrinology, The Central Hospital of Ezhou, Ezhou, People's Republic of China
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Shawa H, Kaur R, Tchanque-Fossuo C, Lev-Tov H, West K, Lim PS, Yang NT, Dafinone M, Lyle RE, Li CS, Rocke D, Dahle S, Isseroff RR. Cellular Versus Acellular Matrix Products for Diabetic Foot Ulcer Treatment: The Dermagraft and Oasis Longitudinal Comparative Efficacy Study (DOLCE)-A Randomized Clinical Trial. Diabetes Care 2025; 48:966-973. [PMID: 40299441 DOI: 10.2337/dc24-1233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 03/12/2025] [Indexed: 04/30/2025]
Abstract
OBJECTIVE To determine whether cellular matrix (CM) products result in better healing rates than acellular matrix (ACM) products for nonhealing diabetic foot ulcers. RESEARCH DESIGN AND METHODS The Dermagraft and Oasis Longitudinal Comparative Efficacy Study (DOLCE) was a randomized, single-blinded, three-arm controlled trial. Patients (aged ≥18 years) with a full-thickness nonhealing diabetic foot ulcer who met inclusion/exclusion criteria were enrolled. RESULTS Of 169 eligible patients, 138 were enrolled and 117 randomly assigned. For 12 weeks, patients received standard of care (SOC), CM, or ACM. The primary outcome was the percentage of wounds healed by 12 weeks. Of the 117 participants, 41 were in the CM group, 48 in the ACM group, and 28 in the SOC group. There were 21 withdrawals, but seven had reached the first primary end point. Complete re-epithelialization of the ulcer by 12 weeks occurred in 59% of the 117 total participants: 49% in the CM group, 69% in the ACM group, and 57% in the SOC group (P = 0.16 by χ2 test). At 28 weeks, 25 participants (61%) in the CM group, 27 (56%) in the ACM group, and 18 (64%) in the SOC group had healed (P = 0.78). No differences were found in wound recidivism or adverse event occurrence between groups. CONCLUSIONS No difference in efficacy was found between SOC, ACM, and CM, suggesting that SOC can reduce the economic burden of diabetic foot ulcer treatment.
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Affiliation(s)
- Harrison Shawa
- Dermatology Section, VA Northern California Health Care System, Mather, CA
- Kirk Kerkorian School of Medicine, University of Nevada Las Vegas, Las Vegas, NV
| | - Ramanjot Kaur
- Dermatology Section, VA Northern California Health Care System, Mather, CA
- Department of Dermatology, University of California Davis, Sacramento, CA
| | - Catherine Tchanque-Fossuo
- Dermatology Section, VA Northern California Health Care System, Mather, CA
- Department of Dermatology, University of California Davis, Sacramento, CA
| | - Hadar Lev-Tov
- Dermatology Section, VA Northern California Health Care System, Mather, CA
- Department of Dermatology, University of California Davis, Sacramento, CA
| | - Kaitlyn West
- Dermatology Section, VA Northern California Health Care System, Mather, CA
| | - Pallas Sulgi Lim
- Dermatology Section, VA Northern California Health Care System, Mather, CA
| | - Nuen Tsang Yang
- Division of Biostatistics, University of California Davis, Davis, CA
| | - Mirabel Dafinone
- Dermatology Section, VA Northern California Health Care System, Mather, CA
- School of Medicine, University of Nevada Reno, Reno, NV
| | | | - Chin-Shang Li
- Division of Biostatistics, University of California Davis, Davis, CA
| | - David Rocke
- Division of Biostatistics, University of California Davis, Davis, CA
| | - Sara Dahle
- Department of Dermatology, University of California Davis, Sacramento, CA
- Podiatry Section, VA Northern California Health Care System, Mather, CA
| | - Roslyn Rivkah Isseroff
- Dermatology Section, VA Northern California Health Care System, Mather, CA
- Department of Dermatology, University of California Davis, Sacramento, CA
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18
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Wu FF, Wang J, Liu GB. Clinical Effects of Thread-Dragging Therapy on Gangrene of Non-ischemic Diabetic Foot Ulcers. Chin J Integr Med 2025; 31:552-557. [PMID: 39499412 DOI: 10.1007/s11655-024-3912-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/15/2023] [Indexed: 11/07/2024]
Abstract
OBJECTIVE To investigate the clinical effects of thread-dragging therapy on gangrene of non-ischemic diabetic foot ulcers (NIDFU). METHODS A total of 136 patients with NIDFU were recruited from the Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine between June 21, 2021 and February 1, 2023, and randomized into an intervention group and a control group, with 68 cases in each group. Both groups received basic treatment. The intervention group was treated with thread-dragging therapy, while the control group was treated with debridement combined with routine dressing changes after surgery. Both groups were treated continuously for 2 months. The amputation rates and changes in the ulcer area were compared between the groups. The inflammatory response index including peripheral white blood cells (WBCs), neutrophil percentage (NEUT%), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), and interleukin 6 (IL-6) were compared between the two groups. RESULTS After treatment, the ulcer areas in the intervention group were significantly smaller than that of the control group (8.50±3.88 cm2 vs. 10.11±4.61 cm2, P<0.05). The amputation rates of the two groups were not statistically significant (4.4% vs. 5.9%, P>0.05). Differences of WBCs count, CRP, and ESR before and after therapy in the intervention group were better than the control group (P<0.05). However, there were no significant differences in changes of NEUT%, PCT, and IL-6 between the two groups (P>0.05). CONCLUSION Thread-dragging therapy may be effective in the treatment of NIDFU, with the additional advantages of less tissue damage after healing. (Registration No. ChiCTR2100047496).
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Affiliation(s)
- Fang-Fang Wu
- Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jie Wang
- Endocrinology Department of Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Guo-Bin Liu
- Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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19
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Ding Y, Sun Z, Wu Z, Zhang Y, Ma J, Luo H, Cao X. Ceria Centre to Enhance Multi-Active and Photothermal Response Janus Patch for Chronic Wound Senescence Inhibition and Repair. Adv Healthc Mater 2025; 14:e2501042. [PMID: 40231592 DOI: 10.1002/adhm.202501042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/01/2025] [Indexed: 04/16/2025]
Abstract
Bacterial infections and complex microenvironments induce cellular oxidative stress and cellular senescence severely affect chronic wound healing. However, the antibacterial effect of most dressings is single, which is only against the wound-breeding bacteria but cannot resist further invasion of bacteria in the environment into the wound. Few dressings can simultaneously fulfill antibacterial, antifouling, oxidative stress regulation, and cellular protection. Therefore, a Janus patch (SBMA/OHA/GelMA/TA-CeO2@HA (HGT-C@HA)) is prepared, in which the top superhydrophilic SBMA zwitterionic layer resists bacterial adhesion, and CeO2 coated with hyaluronic acid (HA) is loaded into the bottom gel as the functional center. After immersion in tannic acid (TA), Ce-TA chelate formation in situ confers photothermal antimicrobial properties to the hydrogel. It is further validated that HA-coated CeO2 enable the dressing to obtain higher antioxidant properties by regulating the proportion of Ce3+ on the nanoparticle surface, which protects cells from the high glucose and high H2O2 environment and effectively inhibits intracellular DNA damage to mitigate cellular senescence. In vivo experiments illustrate that the material significantly accelerated wound healing and improved the quality of wound healing, demonstrating the significant potential of this dressing in diabetic wound healing.
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Affiliation(s)
- Yilin Ding
- Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), South China University of Technology, Guangzhou, 510006, China
| | - Zhipeng Sun
- Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), South China University of Technology, Guangzhou, 510006, China
| | - Zilin Wu
- Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), South China University of Technology, Guangzhou, 510006, China
| | - Yulin Zhang
- Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), South China University of Technology, Guangzhou, 510006, China
| | - Jiuzhi Ma
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), South China University of Technology, Guangzhou, 510006, China
| | - Huitong Luo
- Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), South China University of Technology, Guangzhou, 510006, China
| | - Xiaodong Cao
- Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), South China University of Technology, Guangzhou, 510006, China
- Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou, 510641, China
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20
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Hu H, Tan G, He H, Zhang Q, Tu J. Hemoglobin-decorated metal polyphenol network platform featuring antibacterial, antioxidant, and oxygen carrying properties for promoting infected diabetic wound healing. Int J Biol Macromol 2025; 311:143695. [PMID: 40315669 DOI: 10.1016/j.ijbiomac.2025.143695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/14/2025] [Accepted: 04/29/2025] [Indexed: 05/04/2025]
Abstract
Chronic wounds have emerged as a formidable challenge in diabetes management, leading to high morbidity and mortality. The diabetic wound healing is often impaired due to recurrent bacterial infections, excessive reactive oxygen species (ROS), and severe hypoxia. Thus, we developed a multifunctional nanoplatform that exhibited remarkable antibacterial activity, ROS scavenging and oxygen-carrying properties. Metal-phenol network (MPN) as core material was synthesized by assembling tannic acid (TA) with Fe2⁺ via coordination and hydrophobic interactions. Subsequently, hemoglobin (Hb) was decorated onto MPN surface through cation-π interactions. MPN protected Hb against oxidation and preserved its physiological function, facilitating oxygen transport. Moreover, MPN-Hb displayed robust and broad-spectrum antioxidant activity that can effectively scavenge ROS and reactive nitrogen species. Under near-infrared (NIR) irradiation, MPN-Hb demonstrated excellent bactericidal activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), effectively eradicated biofilms through hyperthermia. In vivo studies have shown that MPN-Hb with good biocompatibility could effectively eliminate bacteria at the wound site, mitigate the inflammatory response, and promote collagen deposition and angiogenesis, thereby accelerating wound healing. Overall, this multifunctional nanoplatform offers a straightforward, safe, and efficient therapeutic strategy for treating chronic diabetic wounds.
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Affiliation(s)
- Haonan Hu
- State Key Laboratory of Advanced Technology for Material Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, China
| | - Guitao Tan
- State Key Laboratory of Advanced Technology for Material Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, China
| | - Huan He
- College of Resources and Environment, Huazhong Agricultural University, Wuhan 430070, China
| | - Qinqin Zhang
- State Key Laboratory of Advanced Technology for Material Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, China
| | - Jing Tu
- State Key Laboratory of Advanced Technology for Material Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, China.
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21
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Chen J, Qu B, Yang D, Wang Y, Zhu H, Wang Z, Zhang X, Ma H, Zhao N, Zhao L, Zhou L, He X, Li P. Combined metabolomics and network pharmacology to elucidate the mechanisms of Huiyang Shengji decoction in treating diabetic skin ulcer mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156569. [PMID: 40120541 DOI: 10.1016/j.phymed.2025.156569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/17/2025] [Accepted: 02/24/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND Diabetic skin ulcer is a clinical disorder of glucose metabolism that has a long treatment period and is prone to recurrent episodes. Huiyang Shengji decoction (HYSJD) is an effective traditional Chinese medicine for its clinical treatment, but its metabolic effects in patients with diabetic skin ulcers have not been well studied. PURPOSE Our study aimed to investigate the mechanism of pharmacological treatment of HYSJD in treating diabetic skin ulcers. METHODS The potential mechanism underlying diabetic wound treatment by HYSJD was screened using network pharmacology. Ultra-high performance liquid chromatography-MS/MS metabolomics analysis and correlation analysis were performed to investigate potential target pathways and genes. Furthermore, the db/db diabetic wound tissues and RAW264.7 macrophage inflammation model verified the mechanism using molecular biology experiments. RESULTS In network pharmacology, HYSJD played a mainly therapeutic effect by regulating PI3K/AKT signaling pathway, EGFR tyrosine kinase inhibitor resistance, metabolic pathway, and other related metabolic-related pathways. Metabolomics analysis disclosed that L-lysine content increased, while those of linoleic and deoxycholic acids decreased in plasma between the HYSJD-treated group and the control group, participating in biotin metabolism. Among them, PPARγ played an important role. The experiments conducted in db/db mice indicated that HYSJD facilitates VEGF secretion and PPARγ expression. In vitro experiments have revealed that HYSJD inhibits macrophage ROS production, augments mitochondrial ATP production, elevates mitochondrial membrane potential, and diminishes the mitochondrial ECAR rate. Furthermore, these effects culminate in promoting M2 macrophage polarization through PPARγ activation. The molecular docking results revealed that the active compounds from HYSJD were capable of binding to PPARγ protein primarily through hydrogen bonding interactions. Notably, all binding energies were found to be lower than -3 kcal/mol, indicating strong and favorable interactions between the active compounds and the target receptor. CONCLUSIONS The findings suggested that HYSJD regulates biotin metabolism by reducing excess levels of linoleic and deoxycholic acids and increasing levels of L-lysine, which in turn promotes diabetic wound healing by promoting M2 macrophage polarization through PPARγ up-regulation. These findings indicated that HYSJD is a decoction that can effectively treat diabetic skin ulcers.
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Affiliation(s)
- Jia Chen
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China; Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan, 430022, China
| | - Baoquan Qu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Danyang Yang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Yazhuo Wang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Haoyue Zhu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Zhengchun Wang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Xiawei Zhang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Huike Ma
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Ning Zhao
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Li Zhao
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China; Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan, 430022, China
| | - Lijiaming Zhou
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Xiujuan He
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China.
| | - Ping Li
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China.
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22
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Yan J, Zhao Y, Cui C, Zhou L, Xu Y, Bai Z, Zhang K, Tong J, Liu Y, Sun L, Du M, Mi Y, Wang X, Wu X, Li B. Dynamic multistage nanozyme hydrogel reprograms diabetic wound microenvironment: synergistic oxidative stress alleviation and mitochondrial restoration. Mater Today Bio 2025; 32:101780. [PMID: 40290892 PMCID: PMC12032933 DOI: 10.1016/j.mtbio.2025.101780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 04/06/2025] [Accepted: 04/17/2025] [Indexed: 04/30/2025] Open
Abstract
Chronic diabetic wounds remain a significant clinical challenge due to persistent bacterial infections, oxidative stress, impaired angiogenesis, and mitochondrial dysfunction. Traditional therapies often fail to address these interrelated pathological factors, highlighting the urgent need for innovative solutions. Here, we present a Mn-ZIF@GOx/BC (MZGB) hydrogel system, where Mn-ZIF@GOx (MZG) nanozymes are successfully integrated into a bacterial cellulose (BC) hydrogel via hydrogen bonding and electrostatic interactions. The MZGB hydrogel lowers wound pH by oxidizing excess glucose into gluconic acid. It exhibits strong ROS scavenging capabilities through its superoxide dismutase and catalase-like activities, while simultaneously providing oxygen. By restoring redox homeostasis, it protects mitochondrial function and enhances cellular energy metabolism. By reprogramming macrophages, MZGB creates a favorable immune microenvironment, significantly promoting angiogenesis through paracrine mechanisms. This facilitates cell-to-cell communication, forming a positive feedback loop. Moreover, MZGB demonstrates ROS-independent antibacterial properties. BC hydrogel ensures adhesion and moisture regulation, forming a protective barrier and maintaining an optimal wound environment. This multifunctional hydrogel represents a promising nanotherapeutic approach for efficiently treating diabetic wounds by precisely regulating the wound microenvironment.
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Affiliation(s)
| | | | | | | | - Yurong Xu
- Shanxi Medical University School and Hospital of Stomatology and Shanxi Provincial Engineering Research Center for Oral Biomaterials, Taiyuan, 030001, Shanxi, China
| | - Ziyang Bai
- Shanxi Medical University School and Hospital of Stomatology and Shanxi Provincial Engineering Research Center for Oral Biomaterials, Taiyuan, 030001, Shanxi, China
| | - Kaifang Zhang
- Shanxi Medical University School and Hospital of Stomatology and Shanxi Provincial Engineering Research Center for Oral Biomaterials, Taiyuan, 030001, Shanxi, China
| | - Jiahui Tong
- Shanxi Medical University School and Hospital of Stomatology and Shanxi Provincial Engineering Research Center for Oral Biomaterials, Taiyuan, 030001, Shanxi, China
| | - Yingyu Liu
- Shanxi Medical University School and Hospital of Stomatology and Shanxi Provincial Engineering Research Center for Oral Biomaterials, Taiyuan, 030001, Shanxi, China
| | - Lingxiang Sun
- Shanxi Medical University School and Hospital of Stomatology and Shanxi Provincial Engineering Research Center for Oral Biomaterials, Taiyuan, 030001, Shanxi, China
| | - Meijun Du
- Shanxi Medical University School and Hospital of Stomatology and Shanxi Provincial Engineering Research Center for Oral Biomaterials, Taiyuan, 030001, Shanxi, China
| | - Yanling Mi
- Shanxi Medical University School and Hospital of Stomatology and Shanxi Provincial Engineering Research Center for Oral Biomaterials, Taiyuan, 030001, Shanxi, China
| | - Xing Wang
- Shanxi Medical University School and Hospital of Stomatology and Shanxi Provincial Engineering Research Center for Oral Biomaterials, Taiyuan, 030001, Shanxi, China
| | - Xiuping Wu
- Shanxi Medical University School and Hospital of Stomatology and Shanxi Provincial Engineering Research Center for Oral Biomaterials, Taiyuan, 030001, Shanxi, China
| | - Bing Li
- Shanxi Medical University School and Hospital of Stomatology and Shanxi Provincial Engineering Research Center for Oral Biomaterials, Taiyuan, 030001, Shanxi, China
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23
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Zhang Z, Zhang Y, Peng L, Xing Y, Zhou X, Zheng S, Zhang Y, Shao L. Multifunctional dual-layer microneedles loaded with selenium-doped carbon quantum dots and Astilbin for ameliorating diabetic wound healing. Mater Today Bio 2025; 32:101739. [PMID: 40290883 PMCID: PMC12022665 DOI: 10.1016/j.mtbio.2025.101739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 04/02/2025] [Accepted: 04/06/2025] [Indexed: 04/30/2025] Open
Abstract
Diabetic wounds (DW) represent a significant clinical challenge due to chronic inflammation, excessive oxidative stress, and impaired angiogenesis, all of which hinder effective tissue regeneration. Existing drug delivery systems often fail to achieve sustained and targeted therapeutic efficacy. In this study, we developed a novel dissolvable dual-layer methacrylated gelatin (GelMA) microneedle (MN) co-loading selenium-doped carbon quantum dots (Se-CQDs) and Astilbin (AST) for enhanced DW treatment. The outer layer, enriched with Se-CQDs, rapidly scavenges reactive oxygen species (ROS), effectively alleviating oxidative stress at the wound site. Sequentially, the inner layer releases AST, exerting potent anti-inflammatory and pro-angiogenic effects. Preliminary findings suggest these effects may involve the modulation of cytoskeletal dynamics and peroxisome function, contributing to endothelial cell migration and angiogenesis. This controlled, sequential release MN establishes a low-oxidative, anti-inflammatory microenvironment, thereby promoting angiogenesis and accelerating wound repair. The pioneering integration of selenium-doped quantum dots and AST-loaded hydrogels offers a synergistic therapeutic strategy, setting a new standard for advanced diabetic wound care with substantial clinical promise.
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Affiliation(s)
- Zhen Zhang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
| | - Yulin Zhang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
| | - Liang Peng
- The First People's Hospital of Guiyang, Guiyang, 550002, China
| | - Yi Xing
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
| | - Xinru Zhou
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
| | - Shuo Zheng
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
| | - Yanli Zhang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
| | - Longquan Shao
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
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24
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Das P, Maresch M, Dey N, Sulaiman N, Ashour AG, Ammar HM, Basem M, Al Muharraqi MA, McGrath M, Jacob MV, O'Brien FJ, Keogh MB. Programmed wound healing in aged skin may be enhanced by mesenchymal cell loaded gene-activated scaffolds. APL Bioeng 2025; 9:026112. [PMID: 40290726 PMCID: PMC12033048 DOI: 10.1063/5.0240504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 04/15/2025] [Indexed: 04/30/2025] Open
Abstract
Aging can prolong the wound healing and is associated with decline in stem cells, delays in cellular migration, and lower vascularization. Tissue engineering has largely evolved to incorporate advanced three-dimensional wound dressings, scaffolds, and hydrogels that may be seeded with mesenchymal stromal cells (MSCs) to foster an environment conducive to regeneration and enhance the healing process. The effectiveness of stem cell-seeded scaffolds can be improved by incorporating activating agents such as nucleic acids resulting in gene-activated scaffolds (GAS), thereby facilitating targeted wound healing in aged patients. In this study, we assess the in vivo wound healing potential of a promising MSC seeded gene-activated collagen scaffold, containing the anti-fibrotic agent β-klotho and pro-angiogenic stromal derived factor (SDF-1α) in aged male Sprague Dawley rats (20-24 month old). A MSC cell loaded split skin model compared MSC only with the clinical standard dressing +Jelonet, MSCs +gene-free collagen scaffold, and MSCs +SDF-1α/β-klotho dual gene-activated collagen scaffold up to 21 days. Our results showed wound healing in all groups except in MSC +Jelonet which showed scab formation with exudate. MSC only group healed primarily via fibrotic contraction. In contrast, the scaffold groups showed host tissue integration and a redistribution of extracellular matrix proteins, less contraction, and complete re-epithelized wounds at day 21. The dual GAS displayed programmed wound healing with the greatest neo-vascularization CD31 expression. In conclusion, wound healing in aged rats can be effectively modulated when MSCs are loaded on biocompatible collagen scaffolds, particularly when these scaffolds are loaded with anti-fibrotic and pro-angiogenic factors. This approach enhances blood vessel formation while reducing fibrosis, suggesting a promising potential for programmed wound healing strategies in aged chronic wounds.
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Affiliation(s)
- Priya Das
- TERG Bahrain, School of Postgraduate Studies and Research, Royal College of Surgeons in Ireland, Manama, Kingdom of Bahrain
| | | | | | - Noof Sulaiman
- TERG Bahrain, School of Postgraduate Studies and Research, Royal College of Surgeons in Ireland, Manama, Kingdom of Bahrain
| | | | | | | | | | - Matthew McGrath
- Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | | | - Michael B. Keogh
- Present address: Human Biology & Director of Research Laboratories, School of Medicine, RCSI P.O. Box 15503, Adliya, Kingdom of Bahrain. Author to whom correspondence should be addressed:. Tel.: +973 17351450
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25
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Zhou Y, Zhou W, Guo Y, Hu C. Correlation of Wound Prognosis with serum IL-6, ICAM-1 and sST2 in Patients with Diabetic Foot and Construction of a Nomogram Model. INT J LOW EXTR WOUND 2025:15347346251345262. [PMID: 40448331 DOI: 10.1177/15347346251345262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2025]
Abstract
Diabetes foot (DF) is one of the most serious chronic complications of diabetes. This study explored the relationship between serum interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) and soluble suppression of tumorigenicity 2 (sST2) and wound prognosis in 210 DF patients between January 2019 and January 2024. 210 DF patients were divided into the good prognosis (n = 147) and poor prognosis (n = 63) group according to the prognosis. Comparative analysis revealed that levels of serum IL-6, ICAM-1 and sST2 in the poor prognosis group were all higher than those in the good prognosis group significantly (P < .05). Multivariate logistic regression identified these 3 biomarkers as independent risk factors for poor wound healing (P < .05). Positive correlations between serum IL-6 (r = 0.269), ICAM-1 (r = 0.302), sST2 (r = 0.289) levels and poor prognosis were confirmed through Pearson's correlation analysis. A prediction model was established to analyse their predictive value. The training and validation sets ROC curves had AUCs of 0.79 (0.71-0.87) and 0.75 (0.59-0.91) respectively. Calibration curves were plotted to evaluate the consistency of the model, and the results showed that the predictive value of the nomogram model was similar to that of the actual one. Decision curves were plotted, which showed that the nomogram had higher positive net benefit in the range of 20% to 60%. This study suggest that serum IL-6, ICAM-1, and sST2 levels may serve as valuable prognostic indicators for wound healing progression in DF patients, with combined biomarker assessment showing potential clinical utility for outcome prediction. The total sample size (n = 210), with validation set (n = 63) of this study are relatively limited and the representativeness is restricted, which may affect the universality of the research conclusions.
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Affiliation(s)
- Yali Zhou
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
- Clinical Research Division, Changsha Jingyi Pharmaceutical Technology Co., Ltd, Changsha, Hunan, China
| | - Wenhu Zhou
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of The Research and Development of Novel Pharmaceutical Preparations, School of Pharmaceutical Science, Changsha Medical University, Changsha, Hunan, China
| | - Yu Guo
- Department of Plastic Surgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Changping Hu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
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26
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Zhang J, Xu W, Xiao Y, Su D, He Y, Yang H, Xie Y, Wang X, Xu RH, Lei S, Wu D. Accurate Delivery of Mesenchymal Stem Cell Spheroids With Platelet-Rich Fibrin Shield: Enhancing Survival and Repair Functions of Sp-MSCs in Diabetic Wound Healing. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2413430. [PMID: 40433894 DOI: 10.1002/advs.202413430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/27/2025] [Indexed: 05/29/2025]
Abstract
Diabetic wound is a significant clinical challenge, and stem cell therapy has shown great potential. This study explores the role of mesenchymal stem cell (MSC) spheroids (Sp-MSCs) in healing diabetic wounds and the use of autologous plasma-rich platelet fibrin (PRF) as a scaffold for Sp-MSCs. Through activation of the coagulation system, PRF offers a protective fibrin shield for Sp-MSCs to promote the rapid recovery migration and proliferation of MSCs while maintaining the activity of Sp-MSCs in an inflammatory overload environment by activating the related genes of Integrin-β1-vascular endothelial growth factor (VEGF), and Wnt/β-catenin pathways. The inclusion of Sp-MSCs accelerates the gelation of PRF and results in improved mechanical strength. Additionally, PRF enhances the repair function of Sp-MSCs, creating a favorable microenvironment for angiogenesis. In the wound model of diabetic mice, the combination of PRF with Sp-MSCs accelerates wound healing. Results show that this combination significantly promotes wound repair and regulates the immune microenvironment. The study suggests that PRF is a promising bio-derived scaffold for stem cell applications in diabetic wounds, offering new directions for stem cell therapy and biomimetic scaffold material development.
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Affiliation(s)
- Jinglve Zhang
- Department of Plastic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, 410008, China
| | - Wenqing Xu
- Department of Plastic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, 410008, China
| | - Yutian Xiao
- Department of Plastic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, 410008, China
| | - Dingheng Su
- Department of Plastic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, 410008, China
- Xiangya School of Medicine Central South University, Changsha, 410083, China
| | - Yusheng He
- ImStem Biotechnology, Inc., 400 Farmington Avenue R1808, Farmington, CT, 06030, USA
- Zhuhai Hengqin ImStem Biotechnology Co., Ltd, Hengqin New District Huandao Donglu 1889 Building 3, Zhuhai, Guangdong, 519000, China
| | - Huohong Yang
- ImStem Biotechnology, Inc., 400 Farmington Avenue R1808, Farmington, CT, 06030, USA
- Zhuhai Hengqin ImStem Biotechnology Co., Ltd, Hengqin New District Huandao Donglu 1889 Building 3, Zhuhai, Guangdong, 519000, China
| | - Yixin Xie
- ImStem Biotechnology, Inc., 400 Farmington Avenue R1808, Farmington, CT, 06030, USA
- Zhuhai Hengqin ImStem Biotechnology Co., Ltd, Hengqin New District Huandao Donglu 1889 Building 3, Zhuhai, Guangdong, 519000, China
| | - Xiaofang Wang
- ImStem Biotechnology, Inc., 400 Farmington Avenue R1808, Farmington, CT, 06030, USA
- Zhuhai Hengqin ImStem Biotechnology Co., Ltd, Hengqin New District Huandao Donglu 1889 Building 3, Zhuhai, Guangdong, 519000, China
| | - Ren-He Xu
- Ministry of Education Frontiers Science Center for Precision Oncology, Center of Reproduction, Development & Aging, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Shaorong Lei
- Department of Plastic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, 410008, China
| | - Dingyu Wu
- Department of Plastic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, 410008, China
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27
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Mikziński P, Kraus K, Seredyński R, Widelski J, Paluch E. Photocatalysis and Photodynamic Therapy in Diabetic Foot Ulcers (DFUs) Care: A Novel Approach to Infection Control and Tissue Regeneration. Molecules 2025; 30:2323. [PMID: 40509211 PMCID: PMC12156053 DOI: 10.3390/molecules30112323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/30/2025] [Accepted: 05/22/2025] [Indexed: 06/18/2025] Open
Abstract
Photocatalysis and photodynamic therapy have been increasingly used in the management of diabetic foot ulcers (DFUs), and their integration into increasingly innovative treatment protocols enables effective infection control. Advanced techniques such as antibacterial photodynamic therapy (aPDT), liposomal photocatalytic carriers, nanoparticles, and nanomotors-used alone, in combination, or with the addition of antibiotics, lysozyme, or phage enzymes-offer promising solutions for wound treatment. These approaches are particularly effective even in the presence of comorbidities such as angiopathies, neuropathies, and immune system disorders, which are common among diabetic patients. Notably, the use of combination therapies holds great potential for addressing challenges within diabetic foot ulcers, including hypoxia, poor circulation, high glucose levels, increased oxidative stress, and rapid biofilm formation-factors that significantly hinder wound healing in diabetic patients. The integration of modern therapeutic strategies is essential for effective clinical practice, starting with halting infection progression, ensuring its effective eradication, and promoting proper tissue regeneration, especially considering that, according to the WHO, 830 million people worldwide suffer from diabetes.
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Affiliation(s)
- Paweł Mikziński
- Faculty of Medicine, Wroclaw Medical University, Wyb. Pasteura 1, 50-376 Wroclaw, Poland; (P.M.); (K.K.)
| | - Karolina Kraus
- Faculty of Medicine, Wroclaw Medical University, Wyb. Pasteura 1, 50-376 Wroclaw, Poland; (P.M.); (K.K.)
| | - Rafał Seredyński
- Department of Physiology and Pathophysiology, Wroclaw Medical University, Tytusa Chałubińskiego 10, 50-368 Wroclaw, Poland;
| | - Jarosław Widelski
- Department of Pharmacognosy with Medicinal Plants Garden, Lublin Medical University, 20-093 Lublin, Poland;
| | - Emil Paluch
- Department of Microbiology, Faculty of Medicine, Wroclaw Medical University, Tytusa Chalubinskiego 4, 50-376 Wroclaw, Poland
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Yuan J, Li L, Lv Y, Yang W. N4-acetylcytidine modification of LncRNA GFOD1-AS1 promotes high glucose-induced dysfunction in human dermal microvascular endothelial cells through stabilization of DNMT1 protein. Funct Integr Genomics 2025; 25:107. [PMID: 40411601 PMCID: PMC12103335 DOI: 10.1007/s10142-025-01617-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 05/13/2025] [Accepted: 05/14/2025] [Indexed: 05/26/2025]
Abstract
Emerging evidence supports that angiogenesis is essential for the wound healing of diabetic foot ulcer (DFU), and high glucose (HG)-induced dysfunction of human dermal microvascular endothelial cells is a key factor that hinders angiogenesis. However, the underlying mechanisms by which HG leads to the dysfunction of human dermal microvascular endothelial cells has not been fully elucidated. In the present investigation, we discovered a significant upregulation of the long non-coding RNA GFOD1-AS1(GFOD1-AS1) in the ulcer margin samples of patients with DFU and the HG-induced dysfunction model of human dermal microvascular endothelial cells, attributing its dysregulation to the stabilizing effect of NAT10-mediated ac4C modification, as corroborated by an integrated approach of data mining and experimental validation. Subsequently, a series of in vitro functional analyses showed that ectopic expression of GFOD1-AS1 promoted impaired function of human dermal microvascular endothelial cells. In contrast, knockdown of GFOD1-AS1 significantly alleviated the HG-induced functional impairment in human dermal microvascular endothelial cells, as indicated by the enhanced cell proliferation, migration, and tube formation. Mechanistically, GFOD1-AS1 directly interacts with DNA methyltransferase DNMT1 to block its ubiquitin-proteasome degradation, thereby enhancing the protein stability of DNMT1.This stability elevates DNMT1 protein expression, ultimately inducing HG-induced dysfunction in human dermal microvascular endothelial cells. In summary, our results reveal that GFOD1-AS1 serves as a potential therapeutic target for DFU, and highlight the critical role of the NAT10/GFOD1-AS1/DNMT1 axis in the dysfunction of human dermal microvascular endothelial cells in DFU.
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Affiliation(s)
- Jingjing Yuan
- Department of Endocrinology and Metabolism, Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, China
| | - Lusha Li
- Department of Endocrinology and Metabolism, Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, China
| | - Yang Lv
- Department of Biological Sciences and Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Wenjun Yang
- Department of Endocrinology and Metabolism, Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, China.
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Van Netten JJ, Vossen LE, Driebergen FM, Wolthuis D, Merkx MJM, Bus SA. Short-Term Efficacy of a Multi-Modal Intervention Program to Improve Custom-Made Footwear Use in People at High Risk of Diabetes-Related Foot Ulceration. J Clin Med 2025; 14:3635. [PMID: 40507403 PMCID: PMC12155699 DOI: 10.3390/jcm14113635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2025] [Revised: 05/09/2025] [Accepted: 05/17/2025] [Indexed: 06/16/2025] Open
Abstract
Background: Wearing custom-made footwear is key in diabetes-related foot ulcer prevention. However, adhering to wearing footwear is challenging, in particular at home. Evidence-based interventions with proven effect are needed, but scarce. We developed a multi-modal intervention to improve custom-made footwear use, and investigated short-term efficacy. Methods: We used a multidisciplinary multiphase approach to develop a three-modality intervention: structured education, motivational interviewing, and custom-made indoor footwear. To assess efficacy, we measured mean 2-week wearing time of custom-made footwear with a validated sensor, at baseline and after three months (primary outcome), and in the two weeks directly before and after each modality was administered (secondary outcomes). We assessed differences between timepoints using within-subjects paired t-tests. Results: 53 participants with high risk for ulceration were included: 30 with low [<8 h/day] baseline adherence), 17% females, mean age 66 (SD: 10) years, all with peripheral neuropathy and a recent foot ulcer (mean time since healing: 6 (SD: 9) months). Wearing time increased non-significantly from 4.0 (SD: 2.5) at baseline to 5.5 (SD: 4.3) after three months in the low adherence group (p = 0.068); this was 11.9 (SD: 2.3) to 12.0 (SD: 2.8) in the high adherence group (p = 0.898). Following provision of indoor footwear, wearing time increased significantly for low baseline adherence (∆2.7 h/day (95% CI: 1.0-4.4; p = 0.004) and high baseline adherence (∆2.0 h/day (95% CI: 0.5-3.4; p = 0.010). Following structured education, wearing time increased non-significantly in those with low baseline adherence (∆1.0 h/day (95% CI: -0.2-2.2; p = 0.098). Following motivational interviewing, wearing time remained similar in both groups. Conclusions: The multi-modal intervention program combining structured education, motivational interviewing and custom-made indoor footwear did not result in a statistically significant improvement in the wearing time of custom-made footwear after three months. However, significant improvements followed the provision of indoor footwear, and clinically relevant improvements followed structured education in people with low adherence, providing avenues for implementation and research.
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Affiliation(s)
- Jaap J. Van Netten
- Department of Rehabilitation Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.E.V.); (S.A.B.)
- Amsterdam Movement Sciences, Rehabilitation & Development, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Lisa E. Vossen
- Department of Rehabilitation Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.E.V.); (S.A.B.)
- Amsterdam Movement Sciences, Rehabilitation & Development, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Faye M. Driebergen
- Department of Clinical and Development Psychology, University of Amsterdam, 1001 NK Amsterdam, The Netherlands; (F.M.D.); (D.W.); (M.J.M.M.)
| | - Danne Wolthuis
- Department of Clinical and Development Psychology, University of Amsterdam, 1001 NK Amsterdam, The Netherlands; (F.M.D.); (D.W.); (M.J.M.M.)
| | - Maarten J. M. Merkx
- Department of Clinical and Development Psychology, University of Amsterdam, 1001 NK Amsterdam, The Netherlands; (F.M.D.); (D.W.); (M.J.M.M.)
- Mental Care Group, 3447 GN Woerden, The Netherlands
| | - Sicco A. Bus
- Department of Rehabilitation Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.E.V.); (S.A.B.)
- Amsterdam Movement Sciences, Rehabilitation & Development, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
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30
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Chen Z, Chan K, Li X, Gong L, Ma Y, Huang C, Lu Y, Wang L, Piao C. Polymeric Nanomedicines in Diabetic Wound Healing: Applications and Future Perspectives. Int J Nanomedicine 2025; 20:6423-6446. [PMID: 40420911 PMCID: PMC12105632 DOI: 10.2147/ijn.s514000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 04/29/2025] [Indexed: 05/28/2025] Open
Abstract
The management of diabetic wound continues to pose significant clinical obstacles, primarily attributed to bacterial infections, excessive inflammation, oxidative stress, and impaired angiogenesis. These pathological factors not only severely affect patient well-being but also create considerable burden on medical services. Current managements often show limited efficacy, necessitating the exploration of alternative therapeutic strategies. Polymeric nanomedicines (PNs), owing to their nanoscale properties, enhanced cellular uptake, stability, bioavailability, and biocompatibility, have been broadly utilized for diabetic wound treatment. PNs demonstrate remarkable capabilities in microbial inhibition, inflammation regulation, oxidative stress mitigation, and vascular network formation, particularly when combined with various agents, including organic substances (eg, exosomes), inorganic substances (eg, metals), and biomaterials (eg, chitosan, hyaluronic acid, and hydrogels). This article systematically examines recent progress in PN-based interventions for diabetic wound recovery, highlighting the pivotal role of PNs in mitigating bacterial infection, modulating inflammatory responses, and promoting cellular regeneration. Additionally, we provide a novel perspective on the multifunctionality of PNs and their potential for overcoming the limitations of conventional therapies. Overall, PNs represent an innovative and promising approach to diabetic wound management, outperforming conventional therapies in stability, targeted delivery, and multifunctionality. In the future, investigations should concentrate on refining PNs formulations and administration strategies so as to enhance biocompatibility, and conducting well-designed clinical trials to validate their therapeutic efficacy.
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Affiliation(s)
- Zeyao Chen
- Department of Endocrinology, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
| | - Kakei Chan
- Department of Endocrinology, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
| | - Xin Li
- Department of Endocrinology, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
- Department of Gynecology, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
| | - Li Gong
- Department of Diabetes, Shenzhen Bao’an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
| | - Yingjie Ma
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China
| | - Chiwen Huang
- Faculty of Science, The University of Queensland, Brisbane, Queensland, Australia
| | - Yan Lu
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese, Guangzhou, People’s Republic of China
| | - Li Wang
- Department of Endocrinology, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
| | - Chunli Piao
- Department of Endocrinology, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
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Su HY, Chew KY, Graves N, Ou HT. Cost-effectiveness of ON101 with general wound care for diabetic foot ulcers among patients with type 2 diabetes in Singapore: Analysis of a multi-ethnic country in Asia. Diabetes Obes Metab 2025. [PMID: 40396474 DOI: 10.1111/dom.16473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 05/05/2025] [Accepted: 05/06/2025] [Indexed: 05/22/2025]
Abstract
AIMS Diabetic foot ulcers (DFUs) impose a vast health and economic burden on individuals and healthcare systems globally. We assessed the cost-effectiveness of adding ON101, a novel treatment for accelerating wound healing, to general wound care (GWC) versus GWC alone for DFUs in Singapore, a multi-ethnic country with increasing DFU prevalence in a growing type 2 diabetes population. MATERIALS AND METHODS A Markov model was utilized to estimate the healthcare costs and quality-adjusted life years (QALYs) over 5 years from a healthcare sector perspective. Model inputs were mainly derived from the Singapore Wound Registry and published literature. The primary outcome was the incremental cost-effectiveness ratio (ICER). Subgroup analyses stratified by clinically important DFU conditions and scenario analyses were conducted to confirm the study's robustness. RESULTS Compared to GWC alone, adding ON101 yielded greater QALY gained (i.e., 0.15) and lower healthcare costs (i.e., -US$16237) for patients with DFUs. Remarkable cost-savings from the use of ON101 with GWC were observed for patients with complex DFUs, namely ICERs of -US$161 963, -US$181 726 and -US$199 130 per QALY gained for cases with HbA1c ≥ 9%, ulcer duration >6 months and ulcer size >5 cm2, respectively. Scenario analysis comparing ON101 with GWC to negative pressure wound therapy with GWC yielded an ICER of -US$677 243 per QALY gained. CONCLUSIONS Combining ON101 with GWC versus GWC alone was highly cost-effective for DFUs in Singapore. Also, the economic results for complex DFU cases underscore the value of ON101 in addressing DFU treatment challenges for managing complex cases, offering cost-savings alongside clinical benefits.
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Affiliation(s)
- Hsuan-Yu Su
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Khong-Yik Chew
- Department of Plastic, Reconstructive and Aesthetic Surgery, SingHealth, Singapore General Hospital, Singapore
| | - Nicholas Graves
- Health Services and Systems Research, Duke-NUS Medical School, Singapore
| | - Huang-Tz Ou
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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32
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胡 大, 李 梦, 王 鹏. [Frontier progress in complex wound repair: from microenvironment regulation to precision medical practice]. ZHONGHUA SHAO SHANG YU CHUANG MIAN XIU FU ZA ZHI 2025; 41:417-425. [PMID: 40419354 PMCID: PMC12123594 DOI: 10.3760/cma.j.cn501225-20250407-00171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Indexed: 05/28/2025]
Abstract
Complex wounds, with high incidence rate, high disability rate, and high medical costs, have brought huge burdens to patients and medical systems. Traditional treatment methods of complex wounds have limitations, therefore it is necessary to further improve and develop innovative strategies of diagnosis and treatment to address this clinical challenge. This article reviews and discusses important advances in the field of complex wound repair, as well as new concepts in the construction of modern wound management systems. The aim is to provide a reference for clinical medical staff, researchers, and related industry personnel, promote the sustainable development of complex wound repair field, and ultimately achieve comprehensive recovery of function and aesthetics of patients with complex wounds.
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Affiliation(s)
- 大海 胡
- />空军军医大学第一附属医院全军烧伤中心，烧伤与皮肤外科，西安 710032Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
| | - 梦洋 李
- />空军军医大学第一附属医院全军烧伤中心，烧伤与皮肤外科，西安 710032Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
| | - 鹏 王
- />空军军医大学第一附属医院全军烧伤中心，烧伤与皮肤外科，西安 710032Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
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Trujillo-Paez JV, Jacobo-Delgado YM, Felix-Arellano C, Rodriguez-Carlos A, Gonzalez-Curiel I, Gonzalez-Muñiz O, Rivas-Santiago B. Optimizing thrombospondin function through repositioning: Implications for injury and diabetic foot ulcer management. Tissue Cell 2025; 96:102987. [PMID: 40412107 DOI: 10.1016/j.tice.2025.102987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Revised: 05/19/2025] [Accepted: 05/20/2025] [Indexed: 05/27/2025]
Abstract
Diabetic foot ulcer (DFU) is a common and challenging complication of diabetes, characterized by impaired wound healing, chronic inflammation, poor tissue remodeling, and chronic inflammation. Thrombospondin 1 (TSP1) and thrombospondin 4 (TSP4) are key extracellular matrix proteins involved in wound healing. This study aimed to assess the levels and propose inducers of TSP1, TSP4, and SOD3 in diabetic foot ulcer. In this study, we first evaluated the expression of TSP1, TSP4, and superoxide dismutase 3 (SOD3) in DFU tissues using real-time PCR and immunohistochemistry. In DFU tissues using real-time PCR we found that TSP-4 expression was significantly reduced and confirmed by immunohistochemistry. TSP1 expression did not show similar alterations. Additionally, while SOD3 expression was decreased at the mRNA level in the diabetic population, no changes were observed in the protein levels by immunohistochemistry. To explore potential therapeutic approaches, we performed pharmacological repositioning and identified three drugs riboflavin, desloratadine, and chenodeoxycholic acid that selectively increased TSP-4 expression. These findings suggest that riboflavin, desloratadine, and chenodeoxycholic acid may promote wound healing in DFU by specifically upregulating TSP4, potentially enhancing tissue remodeling and angiogenesis.
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Affiliation(s)
- Juan Valentin Trujillo-Paez
- CONAHCYT-Biomedical Research Unit Zacatecas-IMSS, Instituto Mexicano del Seguro Social, Zacatecas, Mexico; Biomedical Research Unit Zacatecas-IMSS, Instituto Mexicano del Seguro Social, Zacatecas, Mexico
| | - Yolanda M Jacobo-Delgado
- Biomedical Research Unit Zacatecas-IMSS, Instituto Mexicano del Seguro Social, Zacatecas, Mexico
| | - Camelia Felix-Arellano
- Biomedical Research Unit Zacatecas-IMSS, Instituto Mexicano del Seguro Social, Zacatecas, Mexico
| | - Adrian Rodriguez-Carlos
- Biomedical Research Unit Zacatecas-IMSS, Instituto Mexicano del Seguro Social, Zacatecas, Mexico
| | - Irma Gonzalez-Curiel
- Laboratorio de Inmunotoxicología, Unidad Académica de Ciencias Químicas, Universidad Autónoma de Zacatecas, Campus UAZ siglo XXI, Carretera Zacatecas-Guadalajara km 6, Col. Ejido La Escondida, Zacatecas 98160, Mexico
| | - Oscar Gonzalez-Muñiz
- Biomedical Research Unit Zacatecas-IMSS, Instituto Mexicano del Seguro Social, Zacatecas, Mexico
| | - Bruno Rivas-Santiago
- Biomedical Research Unit Zacatecas-IMSS, Instituto Mexicano del Seguro Social, Zacatecas, Mexico.
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Tian L, Wang Z, Chen S, Guo K, Hao Y, Ma L, Ma K, Chen J, Liu X, Li L, Fu X, Zhang C. Ellagic Acid-Loaded sEVs Encapsulated in GelMA Hydrogel Accelerate Diabetic Wound Healing by Activating EGFR on Skin Repair Cells. Cell Prolif 2025:e70064. [PMID: 40384373 DOI: 10.1111/cpr.70064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/25/2025] [Accepted: 05/06/2025] [Indexed: 05/20/2025] Open
Abstract
Delayed diabetic wound healing is partially attributed to the functional disorder of skin repair cells caused by high glucose (HG). Small extracellular vehicles (sEVs) loaded with small-molecule drugs represent a highly promising therapeutic strategy. This study aims to evaluate the therapeutic efficacy of ellagic acid-encapsulated small extracellular vesicles (EA-sEVs) in diabetic wound regeneration and to unravel related mechanisms. Cytotoxicity tests of ellagic acid (EA) as liposomal small molecules (LSMs) were performed with the CCK8 assay. EA was incorporated into sEVs obtained from chorionic plate-mesenchymal stem cells (CP-MSCs) to construct EA-engineered sEVs. The protective effects of EA-sEVs on human dermal fibroblasts (HDFs) and human epidermal keratinocytes (HEKs) induced by high glucose (HG) were assessed through the evaluation of their proliferative, migrative and differentiative capabilities. Furthermore, to illustrate the underlying mechanism, the specific biological targets of EA were predicted and confirmed. Finally, EA-sEVs were encapsulated in GelMA hydrogel for investigating the pro-healing effects on diabetic wounds. EA was harmless to cell viability, increasing the possibility and safety of drug development. EA-engineered sEVs were fabricated by loading EA in sEVs. In vitro, EA-sEVs promoted the proliferation, migration, and transdifferentiation of HG-HDFs and the proliferation and migration of HG-HEKs. Mechanism analysis elucidated that epidermal growth factor receptor (EGFR) was the specific biological target of EA. EA interacting with EGFR was responsible for the functional improvement of HG-HDFs and HG-HEKs. In vivo, EA-sEVs encapsulated in GelMA promoted the healing of diabetic wounds by improving re-epithelialisation, collagen formation and the expression of EGFR. Gel-EA-sEVs promoted diabetic wound healing by improving biological functions of HDFs and HEKs. EGFR was first identified as the specific biological target of EA and was responsible for the functional improvement of HG-HDFs and HG-HEKs by Gel-EA-sEVs. Hence, Gel-EA-sEVs can serve as a new promising active dressing for diabetic wound treatment.
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Affiliation(s)
- Lige Tian
- College of Graduate, Tianjin Medical University, Tianjin, China
- Medical Innovation Research Department, PLA General Hospital, Beijing, China
| | - Zihao Wang
- Medical Innovation Research Department, PLA General Hospital, Beijing, China
- Chinese PLA Medical School, Beijing, China
| | - Shengqiu Chen
- Medical Innovation Research Department, PLA General Hospital, Beijing, China
- Innovation Research Center for Diabetic Foot, West China Hospital, Sichuan University, Chengdu, China
| | - Kailu Guo
- College of Graduate, Tianjin Medical University, Tianjin, China
- Medical Innovation Research Department, PLA General Hospital, Beijing, China
| | - Yaying Hao
- Medical Innovation Research Department, PLA General Hospital, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine, Beijing, China
| | - Liqian Ma
- Medical Innovation Research Department, PLA General Hospital, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine, Beijing, China
| | - Kui Ma
- Medical Innovation Research Department, PLA General Hospital, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine, Beijing, China
| | - Junli Chen
- Medical Innovation Research Department, PLA General Hospital, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine, Beijing, China
| | - Xi Liu
- Medical Innovation Research Department, PLA General Hospital, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine, Beijing, China
| | - Linlin Li
- Beijing Key Laboratory of Micro-Nano Energy and Sensor, Center for High-Entropy Energy and Systems, Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences, Beijing, China
| | - Xiaobing Fu
- Medical Innovation Research Department, PLA General Hospital, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine, Beijing, China
| | - Cuiping Zhang
- Medical Innovation Research Department, PLA General Hospital, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine, Beijing, China
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Liu L, Ding Z, Huang Y, Zou J. Magnesium Ion/Gallic Acid MOF-Laden Multifunctional Acellular Matrix Hydrogels for Diabetic Wound Healing. ACS APPLIED BIO MATERIALS 2025; 8:3811-3823. [PMID: 40317115 DOI: 10.1021/acsabm.4c01979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2025]
Abstract
The main objective for diabetic wound treatment is the design of a functional dressing that scavenges free radicals, alleviates inflammation, and is antibacterial while promoting neovascularization. Herein, a multifunctional acellular matrix hydrogel was prepared with the antimicrobial peptide jelleine-1 and a magnesium ion/gallic acid metal framework to exhibit antioxidant, anti-inflammatory, and proangiogenesis effects in diabetic wounds. The prepared hydrogel termed Gel-J-MOF efficiently released gallic acid in the acidic microenvironment of the diabetic wound, scavenged excess free radicals in vitro, and effectively reduced the levels of inflammation by regulating M2 macrophage polarization in vivo. The antimicrobial peptide jelleine-1 in the composite hydrogel effectively inhibited S. aureus and E. coli in vitro, promoting a suitable microenvironment for wound healing. In the later stage of wound healing, the composite hydrogel stimulated angiogenesis, accelerating the re-epithelialization and collagen deposition in the wound. In conclusion, this multifunctional composite hydrogel provides a regulated microenvironment for treating diabetic wounds and, therefore, has significant potential application promise in the treatment of chronic diabetic wounds.
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Affiliation(s)
- Lutong Liu
- Department of General Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241000, China
- Beijing Allgens Medical Science and Technology Co., Ltd., Beijing 100176, China
| | - Zhaozhao Ding
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, China
| | - Yong Huang
- Department of General Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241000, China
| | - Junwei Zou
- Department of General Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241000, China
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36
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Zhou Y, Zhou Y, Chen H, Zhang L, Bi S. Potential Role of CD99 Signaling Pathway in Schwann Cell Dysfunction in Diabetic Foot Ulcers Based on Single-Cell Transcriptome Analysis. J Diabetes Res 2025; 2025:9935400. [PMID: 40420926 PMCID: PMC12103954 DOI: 10.1155/jdr/9935400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 04/24/2025] [Indexed: 05/28/2025] Open
Abstract
Background: Schwann cell (SC) dysfunction contributes to the delayed healing of diabetic foot ulcers (DFUs). However, the underlying molecular mechanism regarding the unregulated SC function is poorly understood. Thus, we examined the single-cell transcriptome data from different DFU states focusing on SC characteristics. Methods: The single-cell RNA sequencing (scRNA-seq) data of DFU was obtained from the Gene Expression Omnibus (GEO) database, covering foot skin samples from nondiabetic patients, diabetic patients without DFU, DFU healers, and DFU nonhealers. After scRNA-seq data processing, downscaling, and cell cluster identification, cell communication analysis was performed by the CellChat package. Furthermore, we subclustered SC populations and ran the trajectory inference and pseudotime analysis to investigate the dynamic changes in SC. Finally, the significant pathways were validated with a db/db mouse wound model. Results: scRNA-seq analysis revealed different SC percentages and gene markers across the DFU groups. We identified that the CD99 signaling pathway was upregulated in the DFU nonhealer group. In the db/db mouse wound model, we observed that CD99 was highly expressed in the demyelinated area of the peripheral nerve fibers. Conclusion: Our study elucidated that the CD99 pathway activation may play a crucial role in SC dysfunction of DFU, providing insights into the peripheral glia regulation mechanism and potential therapeutic target of DFU.
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Affiliation(s)
- Yannan Zhou
- Department of Burn and Plastic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yaxin Zhou
- Department of Medical Ultrasound, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Haohan Chen
- Department of Burn and Plastic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Zhang
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Siwei Bi
- Department of Burn and Plastic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
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Valsami EA, Chu G, Guan M, Gilman J, Theocharidis G, Veves A. The Role of Omics Techniques in Diabetic Wound Healing: Recent Insights into the Application of Single-Cell RNA Sequencing, Bulk RNA Sequencing, Spatial Transcriptomics, and Proteomics. Adv Ther 2025:10.1007/s12325-025-03212-9. [PMID: 40381157 DOI: 10.1007/s12325-025-03212-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 03/10/2025] [Indexed: 05/19/2025]
Abstract
Diabetic foot ulcers (DFUs) are a devastating complication of diabetes mellitus (DM) that affect millions of people worldwide every year. They have a long-term impact on patients' quality of life and pose a significant challenge for both patients and clinicians, alongside negative economic implications on affected individuals. The current therapeutic approaches are costly and, in many cases, ineffective, highlighting the urgent need to develop novel, affordable, more efficient, and personalized treatments. Recent advances in high-throughput omics technologies, including proteomics, bulk RNA sequencing (bulk RNA-seq), single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics in both preclinical animal and human clinical studies, have enhanced our understanding of the molecular function and mechanisms of DFUs, thereby offering potential for targeted therapies. Additionally, these technologies provide valuable insights behind the mechanism of action of novel wound dressings and treatments. In this review, we outline the latest application of omics technologies in DFU preclinical animal and human clinical research on diabetic wound healing, and spotlight recent findings.A graphical abstract is available with this article.
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Affiliation(s)
- Eleftheria-Angeliki Valsami
- The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Palmer 321A, One Deaconess Rd, Boston, MA, 02215, USA
| | - Guangyu Chu
- The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Palmer 321A, One Deaconess Rd, Boston, MA, 02215, USA
| | - Ming Guan
- The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Palmer 321A, One Deaconess Rd, Boston, MA, 02215, USA
| | - Jessica Gilman
- The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Palmer 321A, One Deaconess Rd, Boston, MA, 02215, USA
| | - Georgios Theocharidis
- The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Palmer 321A, One Deaconess Rd, Boston, MA, 02215, USA
| | - Aristidis Veves
- The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Palmer 321A, One Deaconess Rd, Boston, MA, 02215, USA.
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He L, Li Z, Wang J, Wu Z, Li X, Li Z, Hu Z. Innovative Self-Powered Electrically Stimulated Fabric Dressing for Enhanced Diabetic Wound Healing. ACS APPLIED MATERIALS & INTERFACES 2025. [PMID: 40377115 DOI: 10.1021/acsami.5c03857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2025]
Abstract
Electrical stimulation (ES) therapy has emerged as a promising method for improving wound healing by mimicking the body's natural electric fields. However, traditional ES devices often fall short in practical applications due to their bulkiness and inefficiency. Current tools for electrical stimulation are hindered by issues such as poor sustainability, limited flexibility, and inadequate biocompatibility. To address these challenges, we have developed a novel self-powered electrical stimulation fabric dressing (SESFD). This innovative dressing employs advanced electrochemical deposition technology to integrate fiber electrodes seamlessly into the fabric using standard textile manufacturing methods. Additionally, we incorporated a gel electrolyte infused with antimicrobial agents to enhance protection against bacterial infections during electrical stimulation. To evaluate the effectiveness of the SESFD in promoting healing for chronic diabetic wounds, we conducted rigorous in vivo studies. The results demonstrated that the SESFD significantly improved cell proliferation and migration within the wound tissue while effectively reducing bacterial growth. These enhancements contributed to faster wound closure, decreased inflammatory response, increased collagen deposition, and improved angiogenesis. Furthermore, the SESFD displayed excellent mechanical properties, extended discharge durability, and stable voltage output even under mechanical deformation. These attributes greatly enhance user experience and comfort for patients throughout the healing process. This study positions the SESFD as a groundbreaking solution that combines electrical stimulation with antimicrobial treatment for diabetic wound care. It represents a sustainable, flexible, and biocompatible approach to accelerating wound healing and improving treatment outcomes.
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Affiliation(s)
- Lin He
- College of Textiles and Clothing, XinJiang University, Urumqi, Xinjiang 830046, China
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Zihan Li
- Beijing Institute of Radiation Medicine, Beijing 100850, China
- Key Laboratory of Polyoxometalate and Reticular Material Chemistry of Ministry of Education, National and Local United Engineering Laboratory for Power Batteries, Key Laboratory of Nanobiosensing and Nanobioanalysis at Universities of Jilin Province, Analysis and Testing Center, Department of Chemistry, Northeast Normal University, Changchun, Jilin 130024, China
| | - Junping Wang
- Beijing Institute of Radiation Medicine, Beijing 100850, China
- School of Mechanical Engineering, Nanjing University of Science and Technology, 200 Xiaolingwei Street, Nanjing 210094, China
| | - Zhongdong Wu
- Beijing Institute of Radiation Medicine, Beijing 100850, China
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China
| | - Xinyu Li
- Beijing Institute of Radiation Medicine, Beijing 100850, China
- Key Laboratory of Hunan Province for Advanced Carbon-Based Functional Materials, School of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang, Hunan 414006, China
| | - Zhihui Li
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Zongqian Hu
- Beijing Institute of Radiation Medicine, Beijing 100850, China
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Choi S, Kim M, Kim M, Kim SH. Advances in oxygenation nanozymes for overcoming diabetic ulcers. Biomater Sci 2025. [PMID: 40370002 DOI: 10.1039/d5bm00340g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
Diabetic ulcers, affecting 15-25% of diabetes patients worldwide, are characterized by localized hypoxia that impedes healing. This review explores the emerging field of in situ oxygen-generating nanozymes as a promising approach to diabetic ulcer treatment. Nanozymes, synthetic nanoparticles mimicking natural enzyme activities, have shown potential in generating oxygen in situ, scavenging reactive oxygen species, and modulating the wound microenvironment. Materials such as manganese dioxide, cerium dioxide, platinum nanoparticles, and molybdenum-based quantum dots have demonstrated efficacy in preclinical studies, often exhibiting multiple enzyme-like activities. These nanozymes have shown accelerated wound closure, enhanced angiogenesis, and improved tissue regeneration in animal models. However, challenges remain, including optimizing nanozyme-hydrogel interactions, addressing the potential toxicity of metal-based nanomaterials, and determining optimal oxygen concentrations for various wound conditions. Future research directions include developing biocompatible nanozymes, enhancing delivery systems, and exploring combination therapies. This review underscores the potential of nanozyme-based therapies to revolutionize the treatment of diabetic ulcers and potentially other hypoxia-related conditions.
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Affiliation(s)
- Sumi Choi
- School of Integrative Engineering, Chung-Ang University, Seoul, 06974, Republic of Korea.
| | - Minjeong Kim
- School of Integrative Engineering, Chung-Ang University, Seoul, 06974, Republic of Korea.
| | - Minjin Kim
- School of Integrative Engineering, Chung-Ang University, Seoul, 06974, Republic of Korea.
| | - Su-Hwan Kim
- School of Integrative Engineering, Chung-Ang University, Seoul, 06974, Republic of Korea.
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Chen Y, Liu KM, Zhou LX, An JY, Feng S, Wu MY, Yu XQ. H 2S Donor Functionalized Molecular Machine for Combating Multidrug-Resistant Bacteria Infected Chronic Wounds. Angew Chem Int Ed Engl 2025:e202507833. [PMID: 40375364 DOI: 10.1002/anie.202507833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2025] [Revised: 05/14/2025] [Accepted: 05/15/2025] [Indexed: 05/18/2025]
Abstract
Chronic wounds are a worldwide medical challenge due to the complex and multifaceted etiologies, including bacterial infection, persistent inflammation, and impaired angiogenesis. Developing a comprehensive strategy integrating antibiosis and anti-inflammation to promote revascularization and accelerate wound healing is highly desirable. Nevertheless, current therapeutic methods still face two major challenges: 1) how to combat bacterial drug resistance, 2) how to achieve spatiotemporal control over bacterial elimination and inflammation reduction. To address these issues, a novel H2S donor functionalized molecular machine (MM), ACR-DM-HS, was developed. It selectively binds to and disturbs the bacterial membrane through a light-active vibronic-driven mechanochemical action (VDA), which synergizes with photodynamic therapy (PDT) to efficiently eradicate multidrug-resistant bacteria and biofilms, and conquers the evolution of bacterial resistance. Furthermore, it releases H2S in infected tissues to scavenge excess reactive oxygen species (ROS), inhibit the secretion of inflammatory factors, promote angiogenesis, and accelerate the healing of diabetic wounds in vivo. This work provides an integrated strategy combining antibiotics and anti-inflammation to treat with multidrug resistance bacterial-infected chronic wounds.
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Affiliation(s)
- Yuan Chen
- School of Biomedical Engineering, Sichuan University, Chengdu, 610065, P.R. China
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P.R. China
| | - Kun-Mei Liu
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P.R. China
| | - Ling-Xiao Zhou
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P.R. China
| | - Jin-Yu An
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P.R. China
| | - Shun Feng
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P.R. China
| | - Ming-Yu Wu
- School of Biomedical Engineering, Sichuan University, Chengdu, 610065, P.R. China
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P.R. China
| | - Xiao-Qi Yu
- School of Biomedical Engineering, Sichuan University, Chengdu, 610065, P.R. China
- Asymmetric Synthesis and Chiral Technology, Key Laboratory of Sichuan Province, Department of Chemistry, Xihua University, Chengdu, 610039, P.R. China
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41
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Xiong L, Huang YX, Mao L, Xu Y, Deng YQ. Targeting gut microbiota and its associated metabolites as a potential strategy for promoting would healing in diabetes. World J Diabetes 2025; 16:98788. [DOI: 10.4239/wjd.v16.i5.98788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 01/03/2025] [Accepted: 03/05/2025] [Indexed: 04/25/2025] Open
Abstract
Impaired healing of diabetic wounds is one of the most important complications of diabetes, often leading to lower limb amputations and incurring significant economic and psychosocial costs. Unfortunately, there are currently no effective prevention or treatment strategies available. Recent research has reported that an imbalance in the gut microbiota, known as dysbiosis, was linked to the onset of type 2 diabetes, as well as the development and progression of diabetic complications. Indeed, the gut microbiota has emerged as a promising therapeutic approach for treating type 2 diabetes and related diseases. However, there is few of literatures specifically discussing the relationship between gut microbiota and diabetic wounds. This review aims to explore the potential role of the gut microbiota, especially probiotics, and its associated byproducts such as short chain fatty acids, bile acids, hydrogen sulfide, and tryptophan metabolites on wound healing to provide fresh insights and novel perspectives for the treatment of chronic wounds in diabetes.
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Affiliation(s)
- Ling Xiong
- Department of Dermatology & STD, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Ya-Xin Huang
- Department of Dermatology & STD, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Lan Mao
- Department of Dermatology & STD, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Yong Xu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Yong-Qiong Deng
- Department of Dermatology & STD, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu 610000, Sichuan Province, China
- Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, Sichuan Province, China
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42
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Mengru Z, Qinyi W, Zimo Y, Bingqing G, Zhongyu X, Xu J. MXenes in the application of diabetic foot: mechanisms, therapeutic implications and future perspectives. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2025; 36:42. [PMID: 40374863 PMCID: PMC12081522 DOI: 10.1007/s10856-025-06895-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 04/22/2025] [Indexed: 05/18/2025]
Abstract
Diabetic foot represents a significant healthcare challenge, accounting for a substantial portion of diabetes-related hospitalizations and amputations globally. The complexity of diabetic foot management stems from the interplay of poor glycemic control, neuropathy, and peripheral vascular disease, which hinder wound healing processes. The high incidence, recurrence, and amputation rates associated with diabetic foot underscore the urgency for innovative treatment strategies. Recent advancements in nanotechnology, particularly the emergence of MXenes (two-dimensional transition metal carbides and/or nitrides), have shown promising potential in addressing these challenges by offering unique physicochemical and biological properties suitable for various biomedical applications. It is a novel potential strategy for diabetic foot wound healing in the future. This review comprehensively summarizes current knowledge, unique characteristics, and underlying mechanisms of MXenes in the context of diabetic foot management. Additionally, we propose the potential application of MXenes-based therapeutic strategies in diabetes foot. Furthermore, we also provide an overview of their current challenges and the future perspectives in related fields of diabetic wound healing.
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Affiliation(s)
- Zhang Mengru
- Department of Orthopaedics, Changzhou Hospital Affiliated to Nanjing University of Chinese Medicine, Changzhou, Jiangsu Province, China
| | - Wu Qinyi
- Department of Orthopaedics, Changzhou Hospital Affiliated to Nanjing University of Chinese Medicine, Changzhou, Jiangsu Province, China
| | - Yao Zimo
- The Fourth Clinical School of Nanjing Medical University, Nanjing City, Jiangsu Province, China
| | - Guo Bingqing
- Department of Orthopaedics, Changzhou Hospital Affiliated to Nanjing University of Chinese Medicine, Changzhou, Jiangsu Province, China
| | - Xia Zhongyu
- Department of Orthopaedics, Changzhou Hospital Affiliated to Nanjing University of Chinese Medicine, Changzhou, Jiangsu Province, China.
| | - Jianda Xu
- Department of Orthopaedics, Changzhou Hospital Affiliated to Nanjing University of Chinese Medicine, Changzhou, Jiangsu Province, China.
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He L, Zhao N, Chen X, Zhang W, Lv K, Xu Y. Platelet-rich plasma-derived exosomes accelerate the healing of diabetic foot ulcers by promoting macrophage polarization toward the M2 phenotype. Clin Exp Med 2025; 25:163. [PMID: 40372505 PMCID: PMC12081558 DOI: 10.1007/s10238-025-01651-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 03/25/2025] [Indexed: 05/16/2025]
Abstract
Diabetic foot ulcers (DFUs) impose a significant clinical and socioeconomic burden on patients and healthcare systems. Although platelet-rich plasma (PRP) and platelet-rich plasma-derived exosomes (PRP-Exos) have emerged as promising therapeutic agents in tissue regeneration, the mechanisms underlying the immunomodulatory effects of PRP and PRP-Exos-particularly their role in macrophage polarization-remain poorly understood. In this study, we isolated and characterized PRP-Exos and systematically evaluated their therapeutic potential in diabetic wound healing via comprehensive in vivo and in vitro experiments. Our results revealed that both PRP-gel and PRP-Exos significantly enhanced diabetic wound healing by promoting macrophage polarization toward the anti-inflammatory M2 phenotype. These findings suggest that PRP-Exos represent a novel and effective therapeutic strategy for DFUs, providing a robust rationale for future clinical translation.
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Affiliation(s)
- Ling He
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230000, Anhui, China
- Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution (Wannan Medical College), Wuhu, 241001, Anhui, China
- Blood transfusion department of Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, Anhui, China
| | - Nan Zhao
- Academy of Laboratory Medicine, Wannan Medical College, Wuhu, 241001, Anhui, China
| | - Xiaoling Chen
- Blood transfusion department of Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, Anhui, China
| | - Wenjie Zhang
- Blood transfusion department of Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, Anhui, China
| | - Kun Lv
- Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution (Wannan Medical College), Wuhu, 241001, Anhui, China.
- Central Laboratory, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, Anhui, China.
| | - Yuanhong Xu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230000, Anhui, China.
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Riza SM, Porosnicu AL, Sinescu RD. A Comprehensive Literature Review on the Therapeutic Potential of Platelet-Rich Plasma for Diabetic Foot Management: Insights from a Case of a Neglected Deep Plantar Abscess. Healthcare (Basel) 2025; 13:1130. [PMID: 40427966 PMCID: PMC12110965 DOI: 10.3390/healthcare13101130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/22/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Diabetic foot ulcers (DFUs) remain a major complication of diabetes, characterized by impaired wound healing, high infection risk, and an increased likelihood of limb amputation. Platelet-rich plasma (PRP) has emerged as a promising adjunctive therapy due to its regenerative properties, promoting angiogenesis, modulating inflammation, and accelerating tissue repair. Methods: This literature review explores the current evidence regarding the use of PRP in the management of DFUs. It was conducted using the PubMed database to evaluate the efficacy of PRP in DFUs. The search was restricted to studies published in the last 10 years, including randomized controlled trials, meta-analyses, and systematic reviews. The inclusion criteria focused on studies assessing PRP as a standalone treatment or in combination with other wound care strategies, evaluating key clinical outcomes such as wound healing rates, infection control, tissue regeneration, and amputation prevention. Results: A total of 35 studies met the inclusion criteria, including 11 meta-analyses, 15 review articles, and 9 clinical trials. PRP demonstrated potential benefits in accelerating wound healing, reducing inflammation, and promoting granulation tissue formation. Additionally, PRP combined with negative-pressure wound therapy (NPWT) showed superior outcomes in reducing amputation rates. However, findings varied based on patient characteristics, PRP preparation techniques, and treatment protocols. Conclusions: PRP represents a valuable adjunct in DFU management, contributing to improved healing outcomes and reduced complications. However, the lack of standardized protocols and variability in clinical results highlight the need for further large-scale, multicenter studies to establish its definitive role in diabetic wound care.
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Affiliation(s)
- Stefania-Mihaela Riza
- Department of Plastic Surgery and Reconstructive Microsurgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (S.-M.R.); (R.D.S.)
- Department of Plastic Surgery and Reconstructive Microsurgery, Elias Emergency University Hospital, 011461 Bucharest, Romania
| | - Andrei-Ludovic Porosnicu
- Department of Plastic Surgery and Reconstructive Microsurgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (S.-M.R.); (R.D.S.)
- Department of Plastic Surgery and Reconstructive Microsurgery, Elias Emergency University Hospital, 011461 Bucharest, Romania
| | - Ruxandra Diana Sinescu
- Department of Plastic Surgery and Reconstructive Microsurgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (S.-M.R.); (R.D.S.)
- Department of Plastic Surgery and Reconstructive Microsurgery, Elias Emergency University Hospital, 011461 Bucharest, Romania
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Xiong Y, Wu Q, Zhang P, Liao J, Hu H, Shahbazi MA, Zhao Y, Mi B. Immune-Vascular Synergy: A Photodynamic Hydrogel Activating ALDH2 to Combat Inflammation and Enhance Angiogenesis in Diabetic Wound Healing. SMALL METHODS 2025:e2500391. [PMID: 40364604 DOI: 10.1002/smtd.202500391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/21/2025] [Indexed: 05/15/2025]
Abstract
Infected diabetic wounds present serious therapeutic challenges, primarily due to persistent infections, impaired immune responses, and insufficient vascularization. Excessive secretion of neutrophil extracellular traps (NETs) is increasingly recognized as a key driver of inflammation in diabetic wounds. Single-cell sequencing analysis of clinical specimens reveals a deficiency in aldehyde dehydrogenase 2 (ALDH2) within wound tissues, which plays a critical role in sustaining inflammation and hindering vascular regeneration. Unlike conventional treatments that focus on either infection control or vascular repair, a photodynamic hydrogel with a dual-function strategy is developed, uniquely integrating ALDH2 activation with immune-vascular modulation to address these multifaceted challenges. The hydrogel-mediated activation of ALDH2 effectively reduces NET formation and mitigates chronic inflammation, while promoting macrophage polarization from the pro-inflammatory M1 phenotype to the reparative M2 phenotype. This transition fosters an anti-inflammatory microenvironment that not only facilitates tissue repair but also enhances angiogenesis by stimulating endothelial cell activity, improving vascularization at the wound site. In contrast to existing therapeutics, the approach directly targets the interplay between immune regulation and vascular regeneration, offering a synergistic mechanism to enhance wound healing outcomes. The findings introduce an immune-vascular synergy-based therapeutic strategy, emphasizing the translational potential of this hydrogel technology for chronic wound management.
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Affiliation(s)
- Yuan Xiong
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Qipeng Wu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Peng Zhang
- Department of Orthopedics, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, 215153, China
| | - Jiewen Liao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hui Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Mohammad-Ali Shahbazi
- Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, Groningen, 9713 AV, The Netherlands
| | - Yanli Zhao
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Bobin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
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Lu Y, Duan Y, Dai Y, Ni X, Li J, Zeng X, Cai P, Li S. Decoding the pharmacodynamics of Fufang Tongye Shaoshang You: A promising ethnomedicine for diabetic ulcer healing. JOURNAL OF ETHNOPHARMACOLOGY 2025; 347:119727. [PMID: 40187623 DOI: 10.1016/j.jep.2025.119727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 03/15/2025] [Accepted: 03/30/2025] [Indexed: 04/07/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Fufang Tongye Shaoshang You (TYY) is an ethnomedicine derived from the traditional folk formula of the Tujia people in Hunan Province, which consists of Paulownia leaf and sesame oil, has shown promising potential in promoting diabetic ulcer (DU) healing. However, its pharmacological substance and mechanism of action require further elucidation. AIMS OF THE STUDY This study was designed to assess the healing effect of TYY on DU wounds in mice, and to explore systematically its potential mechanisms and pharmacodynamic material basis. METHODS The combination of high-fat, high-sugar diet and streptozotocin injection was used to induce C57BL/6 J mouse diabetic model, and the ulcer was surgically introduced. After TYY treatment, the skin lesions of diabetic mice were observed by H&E, Masson staining and transmission electron microscopy over a period of time. The wound tissues were collected. Transcriptomics were used to predict the potential mechanism of TYY, and then immunohistochemistry, immunofluorescence, ELISA, Western blotting, and qRT-PCR were used to detect the expression levels of key proteins and mRNA in related signaling pathways. The effect of TYY on tight junction proteins was evaluated by Western blotting. The chemical components of 10 batches of TYY were analyzed by multivariate analysis, and the iconic components of TYY were screened by molecular docking and dynamics simulation. HMEC-1 cells were induced by lipopolysaccharide and high glucose concentrations to simulate a DU microenvironment and construct an endothelial cell injury model. Scratch test and RT-qPCR were used to evaluate the effects of TYY active ingredients on the endothelial cell injury model, finally determining the pharmacodynamic material basis of TYY. RESULTS The study has demonstrated that TYY can not only effectively repair the skin barrier, but also regulate the IL-17-mediated NF-κB/AP-1 signaling pathway, inhibit the exacerbation of inflammation, and accelerate wound healing in DU mice. In addition, we further discovered the key active ingredients of TYY: maslinic acid, corosolic acid, oleanolic acid, ursolic acid and sesamin. CONCLUSION This study provides scientific evidence for TYY as a potential drug to repair DU, and also provides a theoretical basis for its further clinical application and drug development.
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Affiliation(s)
- Yuting Lu
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Engineering Technology Research Center for Bioactive Substance Discovery of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Province Sino-US International Joint Research Center for Therapeutic Drugs of Senile Degenerative Diseases, Changsha, Hunan, 410208, China; School of Medicine, Guangxi University of Science and Technology, Liuzhou, Guangxi, 545005, China; Guangxi College Key Laboratory of Innovation Research on Medical and Engineering Integration & Liuzhou Key Laboratory of Guizhong Characteristic Medicinal Resources Development, Liuzhou, Guangxi, 545005, China.
| | - Yan Duan
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Engineering Technology Research Center for Bioactive Substance Discovery of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Province Sino-US International Joint Research Center for Therapeutic Drugs of Senile Degenerative Diseases, Changsha, Hunan, 410208, China.
| | - Yuping Dai
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Engineering Technology Research Center for Bioactive Substance Discovery of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Province Sino-US International Joint Research Center for Therapeutic Drugs of Senile Degenerative Diseases, Changsha, Hunan, 410208, China.
| | - Xiaoting Ni
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Engineering Technology Research Center for Bioactive Substance Discovery of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Province Sino-US International Joint Research Center for Therapeutic Drugs of Senile Degenerative Diseases, Changsha, Hunan, 410208, China.
| | - Juan Li
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Engineering Technology Research Center for Bioactive Substance Discovery of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Province Sino-US International Joint Research Center for Therapeutic Drugs of Senile Degenerative Diseases, Changsha, Hunan, 410208, China.
| | - Xinliang Zeng
- Xiangxi Hongcheng Pharmaceutical Co., Ltd., Xiangxi, Hunan, 416000, China.
| | - Pei Cai
- Hunan Engineering Technology Research Center for Bioactive Substance Discovery of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Province Sino-US International Joint Research Center for Therapeutic Drugs of Senile Degenerative Diseases, Changsha, Hunan, 410208, China; Pharmaceutical Department, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, 410008, China.
| | - Shunxiang Li
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Engineering Technology Research Center for Bioactive Substance Discovery of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Province Sino-US International Joint Research Center for Therapeutic Drugs of Senile Degenerative Diseases, Changsha, Hunan, 410208, China; National Key Laboratory Cultivation Base of Chinese Medicinal Powder & Innovative Medicinal Jointly Established by Province and Ministry, Changsha, Hunan, 410208, China.
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Zhou R, Zou X, Yu J, Wang Z, Lu W, Li X, Wei C, Li X, Wang F. KDELR3 and YOD1 proteins as critical endoplasmic reticulum stress mediators and potential therapeutic targets in diabetic foot ulcers: An integrated bioinformatics analysis. Int J Biol Macromol 2025; 312:144095. [PMID: 40354856 DOI: 10.1016/j.ijbiomac.2025.144095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Revised: 05/06/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Diabetic foot ulcers (DFU) represent one of the most severe complications of diabetes mellitus and are closely associated with persistent hyperglycemia. Endoplasmic reticulum stress response proteins play critical roles in the development and progression of DFU, highlighting the urgent need for further research to identify novel biomarkers and therapeutic strategies. METHOD This study utilized DFU datasets from the GEO database and employed bioinformatics approaches to identify differentially expressed genes encoding endoplasmic reticulum stress (ERS) response proteins. Key regulatory proteins NCCRP1, KDELR3, BOK, and YOD1 were screened using WGCNA, machine learning algorithms, and molecular docking techniques, followed by an evaluation of their correlation with the immune microenvironment. Additionally, single-cell RNA sequencing and Mendelian randomization analysis were applied to investigate the structural and functional characteristics of these proteins in DFU pathogenesis. The expression levels of key protein biomarkers were validated using qRT-PCR. RESULT A total of 32 differentially expressed endoplasmic reticulum stress-related proteins associated with DFU were identified. Machine learning algorithms confirmed that NCCRP1, KDELR3, BOK, and YOD1 proteins demonstrated significant diagnostic potential as biomarkers. Immune analysis revealed associations between these stress-response proteins and immune cell infiltration, while molecular docking identified metronidazole as a promising therapeutic candidate targeting the KDELR3 and YOD1 protein structures. Experimental validation confirmed the differential expression of KDELR3 and YOD1 proteins in DFU tissues, and Mendelian randomization analysis suggested that BOK protein may be a potential causal factor in DFU development due to its structural interactions with ERS pathways. CONCLUSION Our study characterized specific ERS response proteins with significant diagnostic potential for DFU. These findings enhance the understanding of protein-mediated DFU pathogenesis and lay the foundation for improving diagnostic and therapeutic strategies targeting these biological macromolecules.
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Affiliation(s)
- Rongbin Zhou
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning 530021, Guangxi, China; Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, University Engineering Research Center of Digital Medicine and Healthcare, Guangxi Medical University, Nanning 530021, Guangxi, China; Department of Urology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Xiaochong Zou
- Department of Urology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Guangxi 530021, China
| | - Jiayin Yu
- Department of Urology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Guangxi 530021, China
| | - Zuheng Wang
- Department of Urology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Guangxi 530021, China
| | - Wenhao Lu
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning 530021, Guangxi, China; Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, University Engineering Research Center of Digital Medicine and Healthcare, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Xiao Li
- School of Life Sciences, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Chunmeng Wei
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, University Engineering Research Center of Digital Medicine and Healthcare, Guangxi Medical University, Nanning 530021, Guangxi, China; Department of Urology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Guangxi 530021, China
| | - Xing Li
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
| | - Fubo Wang
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning 530021, Guangxi, China; Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, University Engineering Research Center of Digital Medicine and Healthcare, Guangxi Medical University, Nanning 530021, Guangxi, China; Department of Urology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Guangxi 530021, China; School of Life Sciences, Guangxi Medical University, Nanning 530021, Guangxi, China; Department of Urology, Affiliated Tumor Hospital of Guangxi Medical University, Guangxi Medical University, Nanning 530021, Guangxi, China; School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China.
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Melamed E, Dabbah J, Israel T, Kan I, Pinzur MS, Roth T, Borkow G. Noninferiority of Copper Dressings Than Negative Pressure Wound Therapy in Healing Diabetic Wounds: A Randomized Clinical Trial. Adv Wound Care (New Rochelle) 2025. [PMID: 40338200 DOI: 10.1089/wound.2024.0273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2025] Open
Abstract
Objective: To evaluate if treatment of diabetic wounds by copper oxide impregnated dressings (COD) is noninferior to negative pressure wound therapy (NPWT). Approach: Following the CONSORT guidelines, patients with diabetes mellitus (type 1 or type 2) and noninfected wounds eligible for treatment with NPWT were randomized into two groups. One group received NPWT followed by standard wound care dressings, whereas the other was treated exclusively with COD. The primary outcome was wound size reduction, measured blindly using a 3D wound-imaging system. Secondary outcomes included patient and caregiver convenience (assessed via visual analog scores), cost, and additional wound parameters. Results: COD showed statistically significant noninferiority to NPWT in wound size reduction throughout the study (p < 0.01). The percentage of wounds that closed was 47.83% (11/23) and 34.78% (8/23) in the COD and NPWT arms, respectively (p > 0.05). The average time to wound closure, adjusted to potential confounders, such as gender, age, body mass index, diabetes, and smokers, was similar in both arms (p > 0.05). COD were found to be more convenient than NPWT for both patients (p < 0.001) and caregivers (p = 0.003), with a significantly shorter application time (p < 0.001). The COD cost was 14% of NPWT cost ($470 compared with $3,360). Innovation: COD may be considered as the first line of treatment for diabetic foot wounds when NPWT seems indicated. Conclusions: Using copper dressings as a first line of treatment of diabetic wounds, when NPWT is indicated, is expected to reduce health costs, improve convenience, and increase compliance without compromising the final outcome.
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Affiliation(s)
- Eyal Melamed
- Foot and Ankle Service, Division of Orthopedics, Rambam Health Care Campus, Haifa, Israel
| | - Jihad Dabbah
- Foot and Ankle Service, Division of Orthopedics, Rambam Health Care Campus, Haifa, Israel
| | - Talia Israel
- Foot and Ankle Service, Division of Orthopedics, Rambam Health Care Campus, Haifa, Israel
| | - Ilana Kan
- Foot and Ankle Service, Division of Orthopedics, Rambam Health Care Campus, Haifa, Israel
| | | | - Tohar Roth
- MedCu Technologies Ltd., Herzliya, Israel
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Liao X, Jiang Z, Fu Z, Liu M, Guo G. LncRNA SNHG14 Drives NLRP3 Inflammasome Activation in Diabetic Foot Ulcers: Mechanistic Insights and Diagnostic Implications. INT J LOW EXTR WOUND 2025:15347346251339713. [PMID: 40329710 DOI: 10.1177/15347346251339713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
BackgroundDiabetic foot (DF), a severe complication of diabetes mellitus (DM), poses significant challenges in early diagnosis and mechanistic understanding. This study investigates the expression patterns and clinical relevance of long non-coding RNA SNHG14 (lncRNA SNHG14) and the NLRP3 inflammasome in DF pathogenesis.MethodsA total of 176 DM patients (88 DF cases vs 88 Non-DF controls) admitted between September 2022 and February 2024 were enrolled. Serum SNHG14 and NLRP3 levels were quantified via qRT-PCR, while DF severity was categorized using the Wagner grading system. Pearson's correlation assessed SNHG14-NLRP3 interactions, Spearman's rank correlation evaluated their associations with Wagner grades, logistic regression identified independent risk factors, and ROC analysis determined diagnostic efficacy.ResultsDF patients exhibited significantly prolonged diabetes duration, elevated HbA1c%, FPG, and upregulated SNHG14/NLRP3 expression compared to Non-DF controls (P < 0.05). A robust positive correlation was observed between SNHG14 and NLRP3 (r = 0.7006, P < 0.0001). Multivariate logistic regression revealed diabetes duration (OR = 7.423, P < 0.0001), HbA1c (OR = 19.478, P = 0.002), SNHG14 overexpression (OR = 5941.653, P < 0.001), and NLRP3 upregulation (OR = 529.864, P = 0.036) as independent DF risk factors. Both SNHG14 (r = 0.5953) and NLRP3 (r = 0.5554) positively correlated with Wagner grades (P < 0.0001). ROC analysis demonstrated high diagnostic accuracy for SNHG14 (AUC = 0.8688) and NLRP3 (AUC = 0.8074), with combined detection further improving performance (AUC = 0.8773, sensitivity = 77.27%, specificity = 93.18%).ConclusionOverexpression of SNHG14 and NLRP3 is intricately linked to DF progression, metabolic dysregulation, and ulcer severity. Their combined use synergistically enhances diagnostic precision, highlighting transformative potential in DF management.
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Affiliation(s)
- Xincheng Liao
- Department of Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Zhengying Jiang
- Department of Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Zhonghua Fu
- Department of Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Mingzhuo Liu
- Department of Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Guanghua Guo
- Department of Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
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Wang H, Wu S, Bai X, Pan D, Ning Y, Wang C, Guo L, Guo J, Gu Y. Mesenchymal Stem Cell-Derived Exosomes Hold Promise in the Treatment of Diabetic Foot Ulcers. Int J Nanomedicine 2025; 20:5837-5857. [PMID: 40351704 PMCID: PMC12065540 DOI: 10.2147/ijn.s516533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/11/2025] [Indexed: 05/14/2025] Open
Abstract
Diabetic foot ulcers (DFU) represent one of the most common side effects of diabetes, significantly impacting patients' quality of life and imposing considerable financial burdens on families and society at large. Despite advancements in therapies targeting lower limb revascularization and various medications and dressings, outcomes for patients with severe lesions remain limited. A recent breakthrough in DFU treatment stems from the development of mesenchymal stem cells (MSCs). MSCs have shown promising results in treating various diseases and skin wounds due to their ability for multidirectional differentiation and immunomodulation. Recent studies highlight that MSCs primarily repair tissue through their paracrine activities, with exosomes playing a crucial role as the main biologically active components. These exosomes transport proteins, mRNA, DNA, and other substances, facilitating DFU treatment through immunomodulation, antioxidant effects, angiogenesis promotion, endothelial cell migration and proliferation, and collagen remodeling. Mesenchymal stem cell-derived exosomes (MSC-Exo) not only deliver comparable therapeutic effects to MSCs but also mitigate adverse reactions like immune rejection associated with MSCs transplantation. This article provides an overview of DFU pathophysiology and explores the mechanisms and research progress of MSC-Exo in DFU therapy.
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Affiliation(s)
- Hui Wang
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Sensen Wu
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Xinyu Bai
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin Province, 130033, People’s Republic of China
| | - Dikang Pan
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Yachan Ning
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Cong Wang
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Lianrui Guo
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Jianming Guo
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
| | - Yongquan Gu
- Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China
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