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Zhao RN, Ke YY, Sun HY, Quan C, Xu Q, Li J, Guan JQ, Zhang YM. Achievements and challenges in glucose oxidase-instructed multimodal synergistic antibacterial applications. Microbiol Res 2025; 297:128149. [PMID: 40187057 DOI: 10.1016/j.micres.2025.128149] [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: 08/22/2024] [Revised: 02/26/2025] [Accepted: 03/17/2025] [Indexed: 04/07/2025]
Abstract
Glucose oxidase (GOx) with unique catalytic properties and inherent biocompatibility can effectively oxidize both endogenous and exogenous glucose with oxygen (O2) into gluconic acid and hydrogen peroxide (H2O2). Accordingly, the GOx-based catalytic chemistry offers new possibilities for designing and constructing multimodal synergistic antibacterial systems. The consumption of glucose permanently downregulates bacterial cell metabolism by blocking essential energy supplies, inhibiting their growth and survival. Additionally, the production of gluconic acid could downregulates the pH within the bacterial infection microenvironment, enhancing the production of hydroxyl radicals (∙OH) from H2O2 via enhanced Fenton or Fendon-like reactions and triggering the pH-responsive release of drugs. Furthermore, the generated H2O2 in situ avoids the addition of exogenous hydrogen peroxide. Therefore, it is possible to design GOx-based multimodal antibacterial synergistic therapies by combining GOx-instructed cascade reactions with other therapeutic approaches such as chemodynamic therapies (CDT), hypoxia-activated prodrugs, photosensitizers, and stimuli-responsive drug release. Such multimodal strategies are expected to exhibit better therapeutic effects than single therapeutic modes. This tutorial review highlights recent advancements in GOx-instructed multimodal synergistic antibacterial systems, focusing on design philosophy and construction strategies. Current challenges and future prospects for advancing GOx-based multimodal antibacterial synergistic therapies are discussed.
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Affiliation(s)
- Rui-Nan Zhao
- College of Life Science, Dalian Minzu University, Economical and Technological Development Zone, Dalian 116600, China; Key Laboratory of Biotechnology and Bioresources Utilization (Dalian Minzu University), Ministry of Education, China
| | - Yi-Yin Ke
- College of Life Science, Dalian Minzu University, Economical and Technological Development Zone, Dalian 116600, China; Key Laboratory of Biotechnology and Bioresources Utilization (Dalian Minzu University), Ministry of Education, China
| | - Hui-Yan Sun
- College of Life Science, Dalian Minzu University, Economical and Technological Development Zone, Dalian 116600, China; Key Laboratory of Biotechnology and Bioresources Utilization (Dalian Minzu University), Ministry of Education, China
| | - Chunshan Quan
- College of Life Science, Dalian Minzu University, Economical and Technological Development Zone, Dalian 116600, China; Key Laboratory of Biotechnology and Bioresources Utilization (Dalian Minzu University), Ministry of Education, China
| | - Qingsong Xu
- College of Life Science, Dalian Minzu University, Economical and Technological Development Zone, Dalian 116600, China; Key Laboratory of Biotechnology and Bioresources Utilization (Dalian Minzu University), Ministry of Education, China
| | - Jun Li
- State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Science, P. O. Box 110, Dalian 116023, China.
| | - Jing-Qi Guan
- Institute of Physical Chemistry, College of Chemistry, Jilin University, 2519 Jiefang Road, Changchun 130021, China.
| | - Yan-Mei Zhang
- College of Life Science, Dalian Minzu University, Economical and Technological Development Zone, Dalian 116600, China; Key Laboratory of Biotechnology and Bioresources Utilization (Dalian Minzu University), Ministry of Education, China.
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Yu Z, Wang J, Li T, Gao L. Melatonin promotes diabetic wound healing by mediating mitochondrial function in endothelial cells through the AMPK/SIRT1/HIF-1α pathway. Tissue Cell 2025; 95:102884. [PMID: 40233668 DOI: 10.1016/j.tice.2025.102884] [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: 12/19/2024] [Revised: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 04/17/2025]
Abstract
OBJECTIVE Diabetic wounds are open lesions that can develop on any part of the body of diabetic patients. Importantly, melatonin (Mel) exerts promotional effects on wound healing. Accordingly, this study explored the mechanism of Mel in diabetic wound healing by mediating mitochondrial function in endothelial cells. METHODS Human umbilical vein vascular endothelial cells (HUVECs) were exposed to high glucose (HG) to mimic a diabetic environment in vitro, followed by Mel treatment. Cell viability, invasion and angiogenic capacity were evaluated with CCK-8, Transwell, and tube formation assays, respectively. CD31 protein expression was determined with Western blot. Wound healing ability was evaluated in vitro, and the levels of adenosine triphosphate (ATP), reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and apoptosis-related proteins (Bcl-2/Bax/CytC) were also detected. To verify the role of the AMPK/SIRT1/HIF-1α pathway in diabetic wound healing, HG-induced HUVECs treated with Mel were subjected to treatment with sh-HIF-1α, AMPK inhibitor (compound c), or SIRT1 inhibitor (Nicotinamide). RESULTS HG impaired the proliferation, invasion, angiogenesis, and wound healing ability of HUVEC, increased ROS, Bax, and CytC levels, and decreased MMP and the levels of ATP and Bcl-2. Mel facilitated viability, angiogenesis, and wound healing ability while ameliorating mitochondrial dysfunction in HG-treated HUVECs. Mel activated the AMPK/SIRT1 pathway to upregulate HIF-1α in HG-treated HUVECs. HIF-1α knockdown, CC, or Nicotinamide negated the effect of Mel on HG-treated HUVECs. CONCLUSIONS Mel fosters angiogenesis and represses mitochondrial dysfunction in endothelial cells by activating the AMPK/SIRT1/HIF-1α pathway, thereby promoting diabetic wound healing.
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Affiliation(s)
- Zeyang Yu
- Department of Orthopedic, Capital Medical University Affiliated Beijing Shijitan Hospital, No.10 Yangfangdian Tieyi Road, Haidian District, Beijing 100038, China
| | - Jiangning Wang
- Department of Orthopedic, Capital Medical University Affiliated Beijing Shijitan Hospital, No.10 Yangfangdian Tieyi Road, Haidian District, Beijing 100038, China
| | - Tianbo Li
- Department of Orthopedic, Capital Medical University Affiliated Beijing Shijitan Hospital, No.10 Yangfangdian Tieyi Road, Haidian District, Beijing 100038, China
| | - Lei Gao
- Department of Orthopedic, Capital Medical University Affiliated Beijing Shijitan Hospital, No.10 Yangfangdian Tieyi Road, Haidian District, Beijing 100038, China.
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Duan L, Liu G, Liao F, Xie C, Shi J, Yang X, Zheng F, Reis RL, Kundu SC, Xiao B. Antheraea pernyi silk nanofibrils with inherent RGD motifs accelerate diabetic wound healing: A novel drug-free strategy to promote hemostasis, regulate immunity and improve re-epithelization. Biomaterials 2025; 318:123127. [PMID: 39879843 DOI: 10.1016/j.biomaterials.2025.123127] [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: 11/26/2024] [Revised: 01/16/2025] [Accepted: 01/23/2025] [Indexed: 01/31/2025]
Abstract
The chronic inflammation and matrix metalloprotease (MMP)-induced tissue degradation significantly disrupt re-epithelization and delay the healing process of diabetic wounds. To address these issues, we produced nanofibrils from Antheraea pernyi (Ap) silk fibers via a facile and green treatment of swelling and shearing. The integrin receptors on the cytomembrane could specifically bind to the Ap nanofibrils (ApNFs) due to their inherent Arg-Gly-Asp (RGD) motifs, which activated platelets to accelerate coagulation and promoted fibroblast migration, adhesion and spreading. These degradable nanofibrils served as effective competitive substrates to reduce MMP-induced tissue degradation. ApNFs and their enzymatic hydrolysates could modulate macrophage polarization due to their RGD motifs. RNA sequencing further revealed that ApNFs treatment activated the JAK2-STAT5b and PI3K-Akt signaling pathways while suppressed the NF-κB, IL-17 and TNF signaling pathways in macrophages. The full-thickness skin wound experiments confirmed that ApNFs significantly accelerated wound healing in both diabetic and non-diabetic rats. Notably, in diabetic wound, ApNFs and their enzymatic hydrolysates polarized the accumulated M1-type macrophages into M2-type, which promoted the wound to get rid of the inflammatory stage and transition to the following proliferative stage, improving the wound healing percentage on day 14 from 74.9 % to 93.2 % by facilitating collagen deposition, angiogenesis and re-epithelization. These results demonstrate that ApNFs are promising drug-free diabetic wound dressings with favorable inherent immunoregulatory properties for biomedical translation.
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Affiliation(s)
- Lian Duan
- State Key Laboratory of Resource Insects, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, 400715, China
| | - Ga Liu
- State Key Laboratory of Resource Insects, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, 400715, China
| | - Fuying Liao
- State Key Laboratory of Resource Insects, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, 400715, China
| | - Chunyu Xie
- State Key Laboratory of Resource Insects, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, 400715, China
| | - Jiahao Shi
- State Key Laboratory of Resource Insects, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, 400715, China
| | - Xiao Yang
- State Key Laboratory of Resource Insects, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, 400715, China
| | - Fan Zheng
- State Key Laboratory of Resource Insects, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, 400715, China.
| | - Rui L Reis
- 3Bs Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimaraes, 4805-017, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga, 4800-058, Portugal
| | - Subhas C Kundu
- 3Bs Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimaraes, 4805-017, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga, 4800-058, Portugal
| | - Bo Xiao
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, 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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Ganjibakhsh M, Tkachenko Y, Knutsen RH, Kozel BA. Toward a rational therapeutic for elastin related disease: Key considerations for elastin based regenerative medicine strategies. Matrix Biol 2025; 138:8-21. [PMID: 40158781 DOI: 10.1016/j.matbio.2025.03.003] [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: 01/04/2025] [Revised: 03/07/2025] [Accepted: 03/23/2025] [Indexed: 04/02/2025]
Abstract
Elastin is a connective tissue protein, produced from the ELN gene, that provides elasticity and recoil to tissues that stretch, such as the large arteries of the body, lung parenchyma, skin, ligaments and elastic cartilages. It is produced as a soluble monomer, tropoelastin, that when cross-linked in the extracellular space generates a polymer that is extraordinarily stable, with a predicted half-life of >70 years. Although data suggest ongoing elastin transcription, it is rare to see new elastin deposited outside of its tight developmental window. Consequently, elastin-related disease comes about primarily in one of three scenarios: (1) inadequate elastin deposition, (2) production of poor-quality elastic fibers, or (3) increased destruction of previously deposited elastin. By understanding the pathways controlling elastin production and maintenance, we can design new therapeutics to thwart those abnormal processes. In this review, we will summarize the diseases arising from genetic and environmental alteration of elastin (Williams syndrome, supravalvar aortic stenosis, autosomal dominant cutis laxa, and ELN-related vascular and connective tissue dysfunction) and then describe the mechanisms controlling elastin production and maintenance that might be manipulated to generate novel therapeutics aimed at these conditions. We will end by summarizing existing therapeutic strategies targeting these disease mechanisms before outlining future approaches that may better solve the challenges associated with elastin based regenerative medicine.
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Affiliation(s)
- Meysam Ganjibakhsh
- Institute of Genomic Medicine, Abigail Wexler Research Institute, Nationwide Children's Hospital, OH 43205, USA
| | - Yanina Tkachenko
- Institute of Genomic Medicine, Abigail Wexler Research Institute, Nationwide Children's Hospital, OH 43205, USA
| | - Russell H Knutsen
- Institute of Genomic Medicine, Abigail Wexler Research Institute, Nationwide Children's Hospital, OH 43205, USA
| | - Beth A Kozel
- Institute of Genomic Medicine, Abigail Wexler Research Institute, Nationwide Children's Hospital, OH 43205, USA; Department of Pediatrics, The Ohio State University, OH 43210, USA.
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Zoheir KMA, Ali NI, Ashour AE, Kishta MS, Othman SI, Rudayni HA, Rashad AA, Allam AA. Lipoic acid improves wound healing through its immunomodulatory and anti-inflammatory effects in a diabetic mouse model. J Diabetes Metab Disord 2025; 24:56. [PMID: 39868353 PMCID: PMC11759746 DOI: 10.1007/s40200-025-01559-y] [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: 05/03/2024] [Accepted: 10/28/2024] [Indexed: 01/28/2025]
Abstract
Objectives Diabetes mellitus is a chronic disease that has become more prevalent worldwide because of lifestyle changes. It leads to serious complications, including increased atherosclerosis, protein glycosylation, endothelial dysfunction, and vascular denervation. These complications impair neovascularization and wound healing, resulting in delayed recovery from injuries and an elevated risk of infections. The present study aimed to investigate the effect of lipoic acid (LA) on the key mediators involved in the wound healing process, specifically CD4 + CD25 + T cell subsets, CD4 + CD25 + Foxp3 + regulatory T (Treg) cells, T-helper-17 (Th17) cells that generate IL-17 A, glucocorticoid-induced tumor necrosis factor receptor (GITR) expressing cells, as well as cytokines such as IL-2, IL-1β, IL-6, and TNF-α and IFN-γ. These mediators play crucial roles in epidermal and dermal proliferation, hypertrophy, and cell migration. Methods We divided mice into 5 groups: the non-diabetic (normal control; NC), wounded non-diabetic mice (N + W), wounded diabetic mice (D + W), wounded diabetic mice treated with 50 mg/kg lipoic acid (D + W + L50) for 14 days, and wounded diabetic mice treated with 100 mg/kg lipoic acid (D + W + L100) for 14 days. Results Flow cytometric analysis indicated that lipoic acid-treated mice exhibited a significant decrease in the frequency of intracellular cytokines (IL-17 A, TNF-α and IFN-γ) in CD4 + T cells, as well as a reduction in the number of GITR-expressing cells. Conversely, a significant upregulation in the number CD4+, CD25+, FOXp3 + and CD4 + CD25 + Foxp3 + regulatory T (Treg) cells was observed in this group compared to both the normal + wounded (N + W) and diabetic + wounded (D + W) groups. Additionally, the mRNA Levels of inflammatory mediators (IL-2, IL-1β, IL-6, and TNF-α) were downregulated in lipoic acid-treated mice compared to other groups. T thereby he histological findings of diabetic skin wounds treated with lipoic acid showed well-healed surgical wounds. Conclusions These findings support the beneficial role of lipoic acid in fine-tuning the balance between anti-inflammatory and pro-inflammatory cytokines, influencing both their release and gene expression.
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Affiliation(s)
- Khairy M. A. Zoheir
- Cell Biology Department, Biotechnology Research Institute, National Research Centre, Dokki, Giza 12622 Egypt
| | - Neama I. Ali
- Cell Biology Department, Biotechnology Research Institute, National Research Centre, Dokki, Giza 12622 Egypt
| | - Abdelkader E. Ashour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Salman International University, Ras Sudr, South Sinai Egypt
| | - Mohamed S. Kishta
- Hormones Department, Medical Research and Clinical Studies Institute, and Stem Cell Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Cairo, 12622 Egypt
| | - Sarah I. Othman
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. BOX 84428, 11671 Riyadh, Saudi Arabia
| | - Hassan A. Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, 11623 Saudi Arabia
| | - Ahmed A. Rashad
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829 Egypt
| | - Ahmed A. Allam
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, 11623 Saudi Arabia
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Zhou X, Chen S, Savitz B, Yu N, Perdikis G, Duckworth K, Dean Y, Long X, Lineaweaver W. Comparative efficacy of different functional hydrogel dressings in healing diabetic foot ulcer: A systematic review and network meta-analysis. Diabetes Obes Metab 2025; 27:3431-3441. [PMID: 40197692 DOI: 10.1111/dom.16367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/05/2025] [Accepted: 03/13/2025] [Indexed: 04/10/2025]
Abstract
AIMS Functional hydrogel dressings offer a promising therapeutic approach, and optimizing their formulations is crucial for improving diabetic foot ulcers (DFUs) outcomes. This study explores the comparative efficacy of different functional hydrogel dressings in DFUs treatment. MATERIALS AND METHODS We conducted a systematic review and Bayesian network meta-analysis of randomized controlled trials evaluating functional hydrogel dressings for DFUs treatment. A comprehensive search was performed across PubMed, Embase, CENTRAL, CNKI and Web of Science from inception to June 2024. Bayesian network meta-analysis was employed to synthesize and compare the relative efficacy of hydrogel interventions, defined as the number of patients with complete wound closure. RESULTS In total, 23 studies involving 1671 patients with DFUs were included. The analysis revealed that immuno-regulating hydrogels (IRHs) had the highest effect estimate (2.2, 95% CI: 1.6, 3.2), compared with anti-bacterial hydrogels (ABHs) ranked last (1.3, 95% CI: 0.78, 2.3). Multi-functional hydrogels (MFHs) and proliferation-promoting hydrogels (PPHs) displayed intermediate effects (1.7, 95% CI: 1.2, 2.4). The relative efficacy ranking was IRH > MFH/PPH > ABH > placebo. The risk of adverse events was lower in functional hydrogel groups relative to placebo (0.75, 95% CI: 0.56, 0.96). Node-splitting analysis confirmed the consistency between direct and indirect evidence for IRH versus ABH. A funnel plot analysis indicated no significant publication bias, affirming the robustness of our findings. CONCLUSION This study provides a comprehensive evaluation of functional hydrogel dressings for DFUs treatment, highlighting the potential of IRH as the most effective option. These insights will guide future research and clinical applications to improve DFUs management.
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Affiliation(s)
- Xiaozhen Zhou
- Peking Union Medical College Hospital, Beijing, China
| | - Shida Chen
- Peking Union Medical College Hospital, Beijing, China
| | - Benjamin Savitz
- Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Nanze Yu
- Peking Union Medical College Hospital, Beijing, China
| | - Galen Perdikis
- Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kylie Duckworth
- Medical University of South Carolina College of Medicine, Charleston, South Carolina, USA
| | - Yomna Dean
- Alexandria University, Alexandria, Egypt
| | - Xiao Long
- Peking Union Medical College Hospital, Beijing, China
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Liu X, Wang W, Wang Y, Duan W, Liu C, Quan P, Xiao J, Zhang Y, Hao Y, Fang L, Song Y, Zhang W. Biochemical strategy-based hybrid hydrogel dressing-mediated in situ synthesis of selenoproteins for DFU immunity-microbiota homeostasis regulation. Biomaterials 2025; 317:123114. [PMID: 39854881 DOI: 10.1016/j.biomaterials.2025.123114] [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: 06/21/2024] [Revised: 01/14/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025]
Abstract
Chronic consequences of diabetes that are most commonly encountered are diabetic foot ulcers (DFUs), driven by microbiota-immune system dyshomeostasis, eventually leading to delayed wound healing. Available therapies, such as systemic or topical administration of anti-inflammatory or antimicrobial agents, are limited due to antibiotic resistance and immune dysfunction. Herein, a hybrid hydrogel dressing is developed as the artificial bioadhesive barrier at wound sites to maintain microbial and immunological homeostasis locally and have potent anti-inflammatory effects. Specifically, Zero-valent selenium nanoparticles are synthesized and encapsulated into the alginate-polyacrylamide interpenetrating hydrogel networks, during which trehalose is adopted to modify the network defects. Besides, as an anti-adhesion agent, trehalose has shown the ability to prevent immune degradation by reducing bacteria binding to HUVECs. The obtained hybrid hydrogel dressing serves as a physical barrier against microbiome invasion, further regulates the composition of the wound microbiome to restore microbial immune homeostasis at the wound site, and cooperatively relieves DFU-associated symptoms. Meanwhile, the hydrogel dressing can synthesize selenoproteins in situ based on biochemical strategies and significantly reduce the secretion of proinflammatory cytokines. The proposed biochemical strategy based on the hybrid hydrogel dressings can efficiently restore microbiota-immune homeostasis in the wounds, presenting a promising approach for DFU therapy in clinics.
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Affiliation(s)
- Xueling Liu
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Weidi Wang
- Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Yali Wang
- Department of Chemistry, College of Pharmacy, North China University of Science and Technology, Tangshan, 063000, China
| | - Wenyuan Duan
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Chao Liu
- Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Peng Quan
- Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Jiali Xiao
- Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Yunning Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Yu Hao
- Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Liang Fang
- Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Yilin Song
- Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
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Tosaka R, Eguchi T, Ishizuka T, Kawaguchi K, Nagashima T, Nakayama R, Hamada Y. The effects of silk sheets derived from germ-free silkworms on wound healing of full-thickness epithelial defects. Burns 2025; 51:107470. [PMID: 40327970 DOI: 10.1016/j.burns.2025.107470] [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: 12/25/2024] [Revised: 02/24/2025] [Accepted: 03/24/2025] [Indexed: 05/08/2025]
Abstract
Collagen is widely used as a scaffold for full-thickness epithelial defects but has poor biostability and often induces hypertrophic scarring. Silk, especially silk derived from germ-free silkworms (SGFS), has high biocompatibility and controllable durability. Therefore, SGFS is possibly for medicine. Herein, we evaluated the effects of SGFS as a scaffold in the wound healing of full-thickness epithelial defects. Epithelial defects were made in the dorsal skin of C57BL/6 J mice, and an SGFS or a collagen sheet was applied to each defect and compared. On days 1, 3, 7, and 14 after surgery, re-epithelialization, inflammatory responses, and granulation tissue formation of each wound were assessed and compared between the groups. Re-epithelialization was observed in the SGFS group on day 3 but no re-epithelialization occurred in the collagen group. Histopathological examination showed less granulation tissue formation in the SGFS group than in the collagen group. IL-6 expression was significantly higher in the SGFS group than in the collagen group on day 1. TGF-β1 expression in the SGFS group was significantly lower than that in the collagen sheet group on days 7 and 14. Based on these results, SGFS promoted re-epithelialization and reduced hypertrophic scarring in the wound healing process compared with collagen.
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Affiliation(s)
- Ryo Tosaka
- Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan.
| | - Takanori Eguchi
- Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan.
| | - Tadatoshi Ishizuka
- Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan.
| | - Koji Kawaguchi
- Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan.
| | - Takayuki Nagashima
- Department of Human Animal Relations, Yamazaki University of Animal Health Technology, 4-7-2, Minami-Osawa, Hachioji-shi, Tokyo 192-0364, Japan.
| | - Ryoko Nakayama
- Department of Pathology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan.
| | - Yoshiki Hamada
- Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan.
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10
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Mishra R, Singh TG, Bhatia R, Awasthi A. Unveiling the therapeutic journey of snail mucus in diabetic wound care. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:6531-6560. [PMID: 39869187 DOI: 10.1007/s00210-024-03657-9] [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: 10/01/2024] [Accepted: 11/19/2024] [Indexed: 01/28/2025]
Abstract
A diabetic wound (DW) is an alteration in the highly orchestrated physiological sequence of wound healing especially, the inflammatory phase. These alterations result in the generation of oxidative stress and inflammation at the injury site. This further leads to the impairment in the angiogenesis, extracellular matrix, collagen deposition, and re-epithelialization. Additionally, in DW there is the presence of microbial load which makes the wound worse and impedes the wound healing cycle. There are several treatment strategies which have been employed by the researchers to mitigate the aforementioned challenges. However, they failed to address the multifactorial pathogenic nature of the disease. Looking at the severity of the disease researchers have explored snail mucus and its components such as achacin, allantoin, elastin, collagen, and glycosaminoglycan due to its multiple therapeutic potentials; however, glycosaminoglycan (GAGs) is very important among all because they accelerate the wound-healing process by promoting reepithelialization, vascularization, granulation, and angiogenesis at the site of injury. Despite its varied applications, the field of snail mucus in wound healing is still underexplored. The present review aims to highlight the role of snail mucus in diabetic wound healing, the advantages of snail mucus over conventional treatments, the therapeutic potential of snail mucus, and the application of snail mucus in DW. Additionally, clinical trials, patents, structural variations, and advancements in snail mucus characterization have been covered in the article.
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Affiliation(s)
- Ritika Mishra
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Rohit Bhatia
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Ankit Awasthi
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
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11
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Summer M, Ali S, Muhammad G, Riaz A. Evaluating the Wound Healing Potential of Characterized Bergenia ciliata-Loaded Salvia hispanica Hydrogel in Diabetic Mice. Microsc Res Tech 2025; 88:1917-1934. [PMID: 40014652 DOI: 10.1002/jemt.24826] [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: 09/30/2024] [Revised: 01/13/2025] [Accepted: 02/09/2025] [Indexed: 03/01/2025]
Abstract
The current study assessed the wound healing potential of Bergenia ciliata (BC) extract, BC-loaded Salvia hispanica hydrogel (CH-BC) and Bergenia ciliata nanoparticles (NPs)-loaded Salvia hispanica hydrogel (CH-BC AgNPs/NPs-loaded hydrogel) using in vitro and in vivo studies. The prepared hydrogel and its components were analyzed using UV-visible spectrophotometry (UV-vis), scanning electron microscopy (SEM), dynamic light scattering (DLS) analysis/particle size analyzer (PSA), zeta potential, fourier transform infrared spectrometry (FT-IR), and x-ray diffraction (XRD). Peaks and peak shifts at 450-460, 250-260, and 270-280 nm in UV-vis and FT-IR (500-4000 cm-1) confirmed extract loading and various functional group presence. DLS confirmed the nanometric size of BC AgNP while zeta potential indicated the slightly negative charge of prepared hydrogel. SEM assessed the average size and topography of Bergenia ciliata-mediated nanoparticles (BC AgNPs) and BC AgNPs loaded hydrogel (CH-BC AgNPs), and XRD peaks at various 2ϴ (10-70) confirmed the topographical and crystalline and porous nature of materials. Bergenia ciliata extract showed higher radical scavenging (74.19% ± 1.84%) and iron chelation activity (93.70 ± 2.20) at 50 and 25 μL/mL, respectively, while CH-BC AgNPs produced the lowest (48.97% ± 3.0%) at 25 and 75 μL/mL (54.35 ± 3.24). Moreover, Chia hydrogel (CH) synergistically enhanced (1.30%) DPPH scavenging. The wound contraction percentage augmented the CH-BC AgNPs as the potent candidate for wound healing (14th day). These findings were further supported by a significant (p < 0.001) restoration of MMP2 (184.6 ± 11.7 pg/mL), TIMPs (184.8 ± 15.7 pg/mL), GPx (153.4 ± 11.5 pg/mL), and IL-6 (10 ± 1 pg/mL) levels as compared to those of diabetic negative control. The normal reepithelization, angiogenesis, and maturation of wounds in treatment groups after histological analysis further strengthened the supposed rationale that CH, along with the BC extract and CH-BC AgNPs, can act synergistically to improve therapeutic results. Hence, CH-BC appeared as a sustainable, biocompatible, and nontoxic agent for wound healing and paved the way for futuristic biomedical investigations.
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Affiliation(s)
- Muhammad Summer
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, Lahore, Pakistan
| | - Shaukat Ali
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, Lahore, Pakistan
| | - Gulzar Muhammad
- Department of Chemistry, Government College University, Lahore, Lahore, Pakistan
| | - Anfah Riaz
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, Lahore, Pakistan
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12
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Mantry S, Das PK, Sankaraiah J, Panda S, Silakabattini K, Reddy Devireddy AK, Barik CS, Khalid M. Advancement on heparin-based hydrogel/scaffolds in biomedical and tissue engineering applications: Delivery carrier and pre-clinical implications. Int J Pharm 2025:125733. [PMID: 40398669 DOI: 10.1016/j.ijpharm.2025.125733] [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: 02/06/2025] [Revised: 05/12/2025] [Accepted: 05/14/2025] [Indexed: 05/23/2025]
Abstract
The advancement of biomaterials utilization in biomedical and tissue regenerative applications has emerged progressively. Hydrogels are three-dimensional, hydrophilic polymeric networks that replicate the natural extracellular matrix (ECM), establishing a hydrated porous milieu that emulates biological functions such as proliferation and differentiation of cellular components. The application of biological macromolecules, particularly Heparin-based hydrogel, has garnered considerable interest owing to various intrinsic biological and mechanical properties. This comprehensive review paper is designed to elucidate the derivation of heparin and its purification method for biomedical uses. The article briefly outlines the diverse physiochemical and biological properties of heparin derivative-based hydrogels/scaffolds and emphasizes their significance as vehicles for growth factors, genes, and cells in complex biomedical and tissue engineering applications. This publication also summarizes the potential concerns associated with heparin-based derivatives, efforts to address these issues, and current clinical perspectives. This represents the inaugural instance of an extensive summarization of heparin-based hydrogels in biomedical applications, emphasizing pre-clinical and clinical investigations, which will further assist the scientific community in addressing the challenges associated with heparin-based hydrogels in biomedical contexts.
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Affiliation(s)
- Shubhrajit Mantry
- Department of Pharmacy, Sarala Birla University, Birla Knowledge City, P.O.- Mahilong, Purulia Road, Ranchi 835103 Jharkhand, India.
| | - Prabhat Kumar Das
- Department of Pharmacology, GRY Institute of Pharmacy, Borawan, Khargone, MP, India
| | - Jonna Sankaraiah
- Department of Process Development, Medytox Inc., 102, Osongsaengmyeong 4-ro, Osong-eup, Heugdeok-gu, Cheongju-si, Chungcheongbuk-do, South Korea
| | - Satyajit Panda
- Department of Pharmaceutics, Institute of Pharmacy and Technology, Salipur, Cuttack, Odisha 754202, India.
| | - Kotaiah Silakabattini
- Department of Pharmacognosy, Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Chandramoulipuram, Chowdavaram, Guntur 522019 Andhra Pradesh, India
| | - Ashok Kumar Reddy Devireddy
- Department of Pharmacology, A M Reddy Memorial College of Pharmacy, Petlurivaripalem, Narasaraopet, Palnadu (Dt), A.P 522601, India
| | - Chandra Sekhar Barik
- Department of Pharmacology, School of Pharmacy, DRIEMS University, Kotasahi, Kairapari, Tangi, Cuttack, Odisha 754022, India
| | - Mohammad Khalid
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University Alkharj, Saudi Arabia
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13
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Sharma S, Kishen A. Dysfunctional crosstalk between macrophages and fibroblasts under LPS-infected and hyperglycemic environment in diabetic wounds. Sci Rep 2025; 15:17233. [PMID: 40383800 PMCID: PMC12086240 DOI: 10.1038/s41598-025-00673-4] [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: 10/21/2024] [Accepted: 04/29/2025] [Indexed: 05/20/2025] Open
Abstract
Diabetic wounds, especially diabetic foot ulcers, present a major clinical challenge due to delayed healing and prolonged inflammation. Macrophage-fibroblast interactions are essential for wound repair, yet this crosstalk is disrupted in diabetic wounds due to hyperglycemia and bacterial infection. This study investigates the dysfunctional communication between macrophages and fibroblasts, focusing on autocrine, paracrine, and juxtacrine signaling in simulated diabetic environments. Using monoculture and co-culture models of THP-1-derived macrophages and primary human dermal fibroblasts, we simulated conditions of normal glucose, LPS-induced infection, high glucose (with AGEs), and combined high glucose (with AGEs) and LPS. Macrophages in hyperglycemic and LPS-infected environments exhibited a pro-inflammatory M1 phenotype with elevated expression of CD80, and STAT1 and increased production of IL-1β, TNF-α, and MMP9. Fibroblast migration was significantly impaired under high glucose conditions, particularly in paracrine model. Secretome profiling showed heightened pro-inflammatory cytokines and proteases, with reduced anti-inflammatory markers (IL-10 and VEGF-A) under hyperglycemic conditions. Paracrine signaling exacerbated the inflammatory response, while juxtacrine signaling showed more moderate effects, conducive to healing. These findings highlight the pathological macrophage-fibroblast crosstalk in diabetic wounds, particularly under hyperglycemic and LPS-infected conditions, offering insights for potential immunomodulatory therapies aimed at restoring effective signaling and improving wound healing outcomes.
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Affiliation(s)
- Shivam Sharma
- The Kishen Lab, Dental Research Institute, University of Toronto, Toronto, Canada
- Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, ON, M5G 1G6, Canada
| | - Anil Kishen
- The Kishen Lab, Dental Research Institute, University of Toronto, Toronto, Canada.
- Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, ON, M5G 1G6, Canada.
- Department of Dentistry, Mount Sinai Hospital, Toronto, Canada.
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14
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Sun X, Li Y, Wang H, Meng Y, Dai X, Du L, Li L. Construction of pH-Sensitive Multifunctional Hydrogel with Synergistic Anti-Inflammatory Effect for Treatment of Diabetic Wounds. Pharmaceutics 2025; 17:644. [PMID: 40430935 PMCID: PMC12114684 DOI: 10.3390/pharmaceutics17050644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2025] [Revised: 05/05/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: A sustainable inflammatory response is a significant obstacle for diabetic wound care. In this study, the pH-sensitive multifunctional hydrogel ODex/BSA-Zn was fabricated via a Schiff base and coordination force for the first time. Methods: The hydrogel consisted of oxidized dextran (ODex), bovine serum albumin (BSA), and zinc ions (Zn2+) in the absence of an additional crosslinking agent. Results: The hydrogel showed excellent mechanical stability, fast self-healing ability, and significant anti-inflammatory effects, as demonstrated by the formation of dynamic covalent bonds between the aldehyde group (-CHO) of ODex and the amino group (-NH2) of BSA via the Schiff base reaction, as well as the metal-ion coordination reaction of Zn2+ with the imidazole ring of BSA. In a diabetic mouse full-thickness cutaneous defect wound model, the ODex/BSA-Zn hydrogel could effectively inhibit the inflammatory response and increase collagen deposition, thereby accelerating the transition of macrophage M1 to M2 and promoting wound closure. This study offers a promising therapeutic approach for managing long-term diabetic ulcers.
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Affiliation(s)
| | | | | | | | | | | | - Lei Li
- College of Chemical Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
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15
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Pereira AR, Pires PC, Hameed H, Lopes D, Lopes J, Sousa-Oliveira I, Babaie S, Mazzola P, Veiga F, Paiva-Santos AC. Injectable nanocomposite hydrogels for targeted intervention in cancer, wound healing, and bone and myocardial tissue engineering. Drug Deliv Transl Res 2025:10.1007/s13346-025-01864-2. [PMID: 40358831 DOI: 10.1007/s13346-025-01864-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2025] [Indexed: 05/15/2025]
Abstract
Despite current medicine's fast-paced advances, many acute and chronic illnesses still lack truly effective and safe therapies. Cancer treatments often lead to off-target healthy tissue damage and poor therapeutic outcomes, wound standard treatments generally demonstrate poor healing efficacy and increased susceptibility to infection, and bone tissue engineering and myocardial tissue engineering can result in immunological rejection and limited availability. To tackle these issues, injectable hydrogels have emerged, and through the incorporation of nanoparticles, nanocomposite hydrogels have appeared as versatile platforms, offering improved biocompatibility, mechanical strength, stability, and precise controlled drug release, as well as targeted delivery with increased drug retention at the site of action, reducing systemic drug distribution to non-target sites. With the ability to deliver a diverse range of therapeutic entities, including low molecular weight drugs, proteins, antibodies, and even isolated cells, injectable nanocomposite hydrogels have revolutionized current therapies, working as multifunctional platforms capable of improving efficacy and safety in cancer treatment, including in chemotherapy, immunotherapy, photothermal therapy, magnetic hyperthermia, photodynamic therapy, chemodynamic therapy, radiotherapy, molecularly targeted therapy, and after tumor surgical removal, and in general, chronic diabetic or tumor-induced wound healing, as well as in bone tissue engineering and myocardial tissue engineering. This review provides a thorough summary and critical insight of current advances on injectable nanocomposite hydrogels as an innovative approach that could bring substantial contributions to biomedical research and clinical practice, with a focus on their applications in cancer therapy, wound healing management, and tissue engineering.
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Affiliation(s)
- Ana Rita Pereira
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal
| | - Patrícia C Pires
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal.
- REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000 - 548, Coimbra, Portugal.
- Department of Medical Sciences, Faculty of Health Sciences, RISE-Health, University of Beira Interior, Av. Infante D. Henrique, 6200 - 506, Covilhã, Portugal.
| | - Huma Hameed
- Faculty of Pharmaceutical Sciences, University of Central Punjab (UCP), Lahore, 54000, Pakistan
| | - Daniela Lopes
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal
- REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000 - 548, Coimbra, Portugal
| | - Joana Lopes
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal
- REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000 - 548, Coimbra, Portugal
| | - Inês Sousa-Oliveira
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal
- REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000 - 548, Coimbra, Portugal
| | - Soraya Babaie
- Physical Medicine and Rehabilitation Research Center, Tabriz University of Medical Sciences, Tabriz, 51368, Iran
| | - Priscila Mazzola
- Faculty of Pharmaceutical Sciences, Universidade Estadual de Campinas, Campinas, SP, 13083 - 970, Brazil
| | - Francisco Veiga
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal
- REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000 - 548, Coimbra, Portugal
| | - Ana Cláudia Paiva-Santos
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000 - 548, Coimbra, Portugal.
- REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000 - 548, Coimbra, Portugal.
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16
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Zhang Y, Lin S, Xu X, Yao Y, Feng S, Jiang S, Wang Y, He W, Mo R. Programmable hierarchical hydrogel dressing for sequential release of growth factor and DNase to accelerate diabetic wound healing. J Control Release 2025; 383:113825. [PMID: 40339657 DOI: 10.1016/j.jconrel.2025.113825] [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: 12/04/2024] [Revised: 04/30/2025] [Accepted: 05/05/2025] [Indexed: 05/10/2025]
Abstract
Dysregulation of growth factor expression causes impaired healing of diabetic foot ulcer (DFU). Platelet-derived growth factor (PDGF)-containing gel has been clinically applied for topical treatment of DFU. Recruitment of neutrophils stimulated by PDGF favors the wound healing of DFU. However, overactivation of neutrophils induced by hyperglycemia causes massive generation and long-term persistence of neutrophil extracellular traps (NETs), ultimately leading to unexpected skin damage and delayed wound repair. Here, we engineer a hierarchically-assembled hydrogel to achieve local release of the growth factor, PDGF-BB and the NET scavenger, deoxyribonuclease (DNase) I with distinct kinetics for enhanced healing of DFU. The hydrogel is constructed by crosslinking of anti-bacterial quaternized chitosan and hypochlorite-degradable nanogel via a copper-free click reaction, in which PDGF-BB is loaded in the hydrogel matrix while DNase I is encapsulated in the inner nanogel. Programmable release of combinatorial therapeutics is implemented by the hydrogel in response to the wound microenvironment. We show that the hierarchical hydrogel co-loaded with PDGF-BB and DNase I promotes neutrophil recruitment, increases endothelial cell migration, degrades excess NETs, and prevents wound infection for accelerating the wound closure in the diabetic mouse wound models.
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Affiliation(s)
- Ying Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Shiqi Lin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Xiao Xu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Yufan Yao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Shufan Feng
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Sida Jiang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Yuqian Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Wei He
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Ran Mo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China.
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17
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Zhan Y, Sun H, Zhang Z, Chen X, Xu Z, He Y, Tao S, Fan L, Tan J. Chitosan and polyvinyl alcohol-based bilayer electrospun nanofibrous membrane incorporated with astaxanthin promotes diabetic wound healing by addressing multiple factors. Int J Biol Macromol 2025; 311:143921. [PMID: 40324499 DOI: 10.1016/j.ijbiomac.2025.143921] [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: 12/09/2024] [Revised: 04/27/2025] [Accepted: 05/02/2025] [Indexed: 05/07/2025]
Abstract
Delayed diabetic wound regeneration can be attributed to multiple underlying factors, including bacterial infection, endogenous reactive oxygen species (ROS), impaired angiogenesis and exaggerated inflammatory response. Here, a bilayer electrospun nanofibrous membrane (ENM) was fabricated through sequential electrospinning to accelerate diabetic wound healing by addressing aforementioned challenges. For the purpose, nano Zinc Oxide was mixed into chitosan as the bottom layer of ENM (CS/ZnO NPs), while astaxanthin (AST) was encapsulated in a composite nanofibrous membrane of polyvinyl alcohol, chitosan and Ti3C2TX MXene (PVA/CS/MXene) as the upper layer, thus preparing the bilayer CZ/PCM@AST ENM, which reflected the therapeutic properties of spatial structure distribution and time series on diabetic wounds. The bilayer CZ/PCM@AST ENM was verified to possess sufficient biocompatibility and effective antibacterial properties on E. coli and S. aureus. Furthermore, the ENM facilitated sustained AST release at inflammatory sites, effectively scavenging excessive ROS and inhibiting inflammatory responses, ultimately accelerating diabetic wound healing, as demonstrated through both in vitro and in vivo evaluations. In summary, the multi-effect combination strategy improved complicated pathological microenvironment of wound sites, thereby presenting a promising method in diabetic wound treatment.
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Affiliation(s)
- Yuhang Zhan
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Huixuan Sun
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, 430070, China
| | - Zhihan Zhang
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Xi Chen
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Zhengping Xu
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, 430070, China
| | - Yifeng He
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Shengxiang Tao
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
| | - Lihong Fan
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, 430070, China.
| | - Jinhai Tan
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
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18
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Jha B, Majie A, Roy K, Gorain B. Functional and molecular insights in topical wound healing by ascorbic acid. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04180-1. [PMID: 40317316 DOI: 10.1007/s00210-025-04180-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 04/11/2025] [Indexed: 05/07/2025]
Abstract
The skin acts as a vital barrier against external threats and regulates moisture levels. The skin's repair and rejuvenation encompass complex molecular and cellular mechanisms, constituting an essential yet intricate process to preserve skin integrity following trauma or surgical intervention. Acute wound repair unfolds through different interrelated stages, whereas chronic wounds pose significant healthcare challenges, often linked to conditions like diabetes and vascular diseases. Understanding of wound physiology is crucial for developing effective treatments. Chronic wounds require more comprehensive treatments, including surgical debridement, glycemic control, and antibiotic therapy. Ascorbic acid (AA) emerges as a promising wound-healing agent because it facilitates collagen synthesis, enhances antioxidant defense, promotes re-epithelialization and angiogenesis, regulates pH, and exhibits antimicrobial properties. Research outcomes on applying AA-based formulations on wound environment demonstrated its potential to accelerate wound closure and tissue regeneration, offering hope for improved wound management and reduced healthcare burdens associated with chronic wounds. The application of AA, which often utilizes innovative delivery methods and synergistic combinations with other actives, shows promise in preclinical studies for superior efficacy, biocompatibility, and controlled release profiles. Overall, AA-based therapies represent a significant avenue for advancing wound care and addressing the challenges of chronic wounds in healthcare systems.
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Affiliation(s)
- Bhawana Jha
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India
| | - Ankit Majie
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India
| | - Kankan Roy
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India
| | - Bapi Gorain
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India.
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19
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Ku YC, Lee YC, Hong YK, Lo YL, Kuo CH, Wang KC, Hsu CK, Yu CH, Lin SW, Wu HL. Deciphering the Dysregulating IGF-1-SP1-CD248 Pathway in Fibroblast Functionality during Diabetic Wound Healing. J Invest Dermatol 2025; 145:1180-1195. [PMID: 39293711 DOI: 10.1016/j.jid.2024.07.035] [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: 02/26/2024] [Revised: 07/08/2024] [Accepted: 07/31/2024] [Indexed: 09/20/2024]
Abstract
Reduced fibroblast activity is a critical factor in the progression of diabetic ulcers. CD248, a transmembrane glycoprotein prominently expressed in activated fibroblasts, plays a pivotal role in wound healing. However, the role of CD248 in diabetic wound healing and the CD248 regulatory pathway remains largely unexplored. Our study shows that CD248 expression is significantly reduced in skin wounds from both patients and mice with diabetes. Single-cell transcriptome data analyses reveal a marked reduction of CD248-enriched secretory-reticular fibroblasts in diabetic wounds. We identify IGF-1 as a key regulator of CD248 expression through the protein kinase B/mTOR signaling pathway and the SP1 transcription factor. Overexpression of CD248 enhances fibroblast motility, elucidating the under-representation of CD248-enriched fibroblasts in diabetic wounds. Immunohistochemical staining of diabetic wound samples further confirms low SP1 expression and fewer CD248-positive secretory-reticular fibroblasts. Further investigation reveals that elevated TNFα levels in diabetic environment promotes IGF-1 resistance, and inhibiting IGF-1 induced CD248 expression. In summary, our findings underscore the critical role of the IGF1-SP1-CD248 axis in activating reticular fibroblasts during wound-healing processes. Targeting this axis in fibroblasts could help develop a therapeutic regimen for diabetic ulcers.
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Affiliation(s)
- Ya-Chu Ku
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yao-Chou Lee
- Division of Plastic and Reconstructive Surgery, Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Yi-Kai Hong
- Department of Dermatology, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Yung-Ling Lo
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Cheng-Hsiang Kuo
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kuan-Chieh Wang
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Chao-Kai Hsu
- Department of Dermatology, National Cheng Kung University Hospital, Tainan, Taiwan; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
| | - Chien-Hung Yu
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shu-Wha Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
| | - Hua-Lin Wu
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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20
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Li Y, Hao Y, Yang X, Zhao J, Chang R, Wang B, Zhan X. Structure characterization of a Bletilla striata homogeneous polysaccharide and its effects on reducing oxidative stress and promoting wound healing in diabetic rats. Int J Biol Macromol 2025; 307:141904. [PMID: 40064269 DOI: 10.1016/j.ijbiomac.2025.141904] [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: 09/10/2024] [Revised: 02/11/2025] [Accepted: 03/07/2025] [Indexed: 03/20/2025]
Abstract
The most common complication of diabetes is chronic non-healing wound, which can lead to amputation in severe cases. Therefore, identifying new and effective therapies is crucial. This study extracted, isolated, and purified a homogeneous polysaccharide named BSP1-1 from Bletilla striata. The yield of BSP1-1 was 2.17 %, with a molecular weight of 2.265 × 104 Da. The monosaccharide components were identified as mannose and glucose. Using a diabetic rat wound model to study the effects of BSP1-1 on wound healing. The results showed that the wound healing rate increased in a dose-dependent manner after treatment with BSP1-1. On the 15th day after administration, the wound healing rates of the low-, medium-, and high-dose groups increased by 11.2 %, 14.6 %, and 18.9 % compared with the control group, respectively. Histological analysis showed that BSP1-1 promoted angiogenesis and collagen deposition. In the high-dose group, the collagen content increased by 11.84 % compared with the control group, and the CD31 positive cell rate increased by 7.66 %. Furthermore, compared to the DM group, BSP1-1 treatment reduced malondialdehyde (MDA) content and increased superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels (P < 0.05). It was concluded that, BSP1-1 might alleviate oxidative stress and promote wound healing through up-regulation of Nrf2 and its downstream antioxidant factor, HO-1. In summary, this study demonstrates that Bletilla striata polysaccharide can effectively accelerate diabetic wound healing.
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Affiliation(s)
- Yuanlin Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yinxue Hao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xiaoqi Yang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jiahui Zhao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Ruiying Chang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Bo Wang
- Hubei Institute for Drug Control, Wuhan 430012, China; NMPA Key Laboratory of Quality Control of Chinese Medicine(HuBei), Wuhan 430075, China.
| | - Xueyan Zhan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China; Beijing Key Laboratory for Production Process Control and Quality Evaluation of Traditional Chinese Medicine, Beijing 100029, China.
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21
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Zhang Y, Zheng Z, Zhu S, Xu L, Zhang Q, Gao J, Ye M, Shen S, Xing J, Wu M, Xu RX. Electroactive Electrospun Nanofibrous Scaffolds: Innovative Approaches for Improved Skin Wound Healing. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2416267. [PMID: 40190057 PMCID: PMC12079356 DOI: 10.1002/advs.202416267] [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] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 03/05/2025] [Indexed: 05/16/2025]
Abstract
The incidence and burden of skin wounds, especially chronic and complex wounds, have a profound impact on healthcare. Effective wound healing strategies require a multidisciplinary approach, and advances in materials science and bioengineering have paved the way for the development of novel wound healing dressing. In this context, electrospun nanofibers can mimic the architecture of the natural extracellular matrix and provide new opportunities for wound healing. Inspired by the bioelectric phenomena in the human body, electrospun nanofibrous scaffolds with electroactive characteristics are gaining widespread attention and gradually emerging. To this end, this review first summarizes the basic process of wound healing, the causes of chronic wounds, and the current status of clinical treatment, highlighting the urgency and importance of wound dressings. Then, the biological effects of electric fields, the preparation materials, and manufacturing techniques of electroactive electrospun nanofibrous (EEN) scaffolds are discussed. The latest progress of EEN scaffolds in enhancing skin wound healing is systematically reviewed, mainly including treatment and monitoring. Finally, the importance of EEN scaffold strategies to enhance wound healing is emphasized, and the challenges and prospects of EEN scaffolds are summarized.
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Affiliation(s)
- Yang Zhang
- Department of RehabilitationThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
- Department of Precision Machinery and InstrumentationSchool of Engineering ScienceUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
| | - Zhiyuan Zheng
- Department of Precision Machinery and InstrumentationSchool of Engineering ScienceUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
| | - Shilu Zhu
- School of Biomedical EngineeringDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
- Suzhou Institute for Advanced ResearchUniversity of Science and Technology of ChinaSuzhou215000China
| | - Liang Xu
- School of Biomedical EngineeringDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
- Suzhou Institute for Advanced ResearchUniversity of Science and Technology of ChinaSuzhou215000China
| | - Qingdong Zhang
- Department of Precision Machinery and InstrumentationSchool of Engineering ScienceUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
- School of Biomedical EngineeringDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
- Suzhou Institute for Advanced ResearchUniversity of Science and Technology of ChinaSuzhou215000China
| | - Jie Gao
- School of Biomedical EngineeringDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
- Suzhou Institute for Advanced ResearchUniversity of Science and Technology of ChinaSuzhou215000China
| | - Min Ye
- School of Biomedical EngineeringDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
- Suzhou Institute for Advanced ResearchUniversity of Science and Technology of ChinaSuzhou215000China
| | - Shuwei Shen
- School of Biomedical EngineeringDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
- Suzhou Institute for Advanced ResearchUniversity of Science and Technology of ChinaSuzhou215000China
| | - Jinyu Xing
- Department of Precision Machinery and InstrumentationSchool of Engineering ScienceUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
| | - Ming Wu
- Department of RehabilitationThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
| | - Ronald X. Xu
- Department of Precision Machinery and InstrumentationSchool of Engineering ScienceUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
- School of Biomedical EngineeringDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui230027P. R. China
- Suzhou Institute for Advanced ResearchUniversity of Science and Technology of ChinaSuzhou215000China
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Pan Y, Xia M, Luo J, Lu S. Resveratrol Promotes Wound Healing by Enhancing Angiogenesis via Inhibition of Ferroptosis. Food Sci Nutr 2025; 13:e70254. [PMID: 40330211 PMCID: PMC12053223 DOI: 10.1002/fsn3.70254] [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: 12/18/2024] [Revised: 04/04/2025] [Accepted: 04/24/2025] [Indexed: 05/08/2025] Open
Abstract
Diabetic wound healing critically depends on functional endothelial cells for angiogenesis, yet the hyperglycemic microenvironment induces endothelial dysfunction through oxidative stress, inflammation, and senescence. Although ferroptosis has been recognized as a critical pathological factor contributing to impaired diabetic wound healing, the therapeutic potential of resveratrol (Res), a natural polyphenol with well-documented antioxidant and anti-ferroptotic properties, remains underexplored in this context. This study aimed to investigate the protective effects of Res on endothelial cells and elucidate its underlying mechanisms in diabetic wound healing. In vitro experiments systematically evaluated Res's impact on cellular inflammatory responses, senescence levels, and angiogenic capacity. Subsequent in vivo studies assessed Res's therapeutic potential by monitoring diabetic wound healing progression and analyzing associated histological changes. To clarify the mechanisms underlying Res's promotion of diabetic wound healing, we conducted comprehensive analyses measuring intracellular reactive oxygen species, lipid peroxidation levels, mitochondrial membrane potential and morphology, ferroptosis-related marker expression, and upstream signaling pathway regulation. Res significantly reduced HG-induced inflammatory responses and cellular senescence in human umbilical vein endothelial cells while enhancing their angiogenic potential in vitro. In vivo results showed that Res not only markedly accelerated diabetic wound healing but also demonstrated multiple beneficial effects, including effective suppression of cellular senescence, decreased ferroptosis levels, and significantly promoted angiogenesis. Mechanistic investigations confirmed that Res achieves these effects by inhibiting ferroptosis through activation of the PI3K-AKT-Nrf2 signaling axis. Our results demonstrate that Res protects endothelial cells from HG-induced ferroptosis by activating PI3K-AKT-Nrf2 signaling, thereby promoting angiogenesis and diabetic wound healing. These findings highlight Res as a promising therapeutic candidate for impaired diabetic wound repair and justify further clinical investigation.
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Affiliation(s)
- Yujie Pan
- Department of Traumatic OrthopedicsThe Affiliated Hospital of Guizhou Medical UniversityGuiyangGuizhouChina
- School of Clinical Medicine, Guizhou Medical UniversityGuiyangGuizhouChina
| | - Mingyan Xia
- Department of AnatomySchool of Basic Medicine Science, Guizhou Medical UniversityGuiyangChina
| | - Jin Luo
- Department of Traumatic OrthopedicsThe Affiliated Hospital of Guizhou Medical UniversityGuiyangGuizhouChina
| | - Shuai Lu
- Department of BiologySchool of Basic Medical Science, Guizhou Medical UniversityGuiyangChina
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23
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Chen L, Li Y, Zhang N, Chen T, Li F, Han J, Wang Z, Kannan PR, Sun Z, Fu F, Cheng L, Lu J, Kong X. Injectable dual-cross-linked microalgae-silk gel ameliorates diabetic wound healing by promoting oxygenation and ROS clearance and lessening inflammation. Int J Biol Macromol 2025; 309:142897. [PMID: 40203918 DOI: 10.1016/j.ijbiomac.2025.142897] [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: 01/13/2025] [Revised: 04/01/2025] [Accepted: 04/05/2025] [Indexed: 04/11/2025]
Abstract
Hypoxia, excessive reactive oxygen species (ROS), and an impaired inflammatory microenvironment are key barriers to diabetic wound healing, collectively hindering cell migration, proliferation, and neovascularization, ultimately leading to failure in the healing process. Therefore, developing an effective therapeutic strategy capable of simultaneously addressing these challenges remains a critical clinical need. In this study, we developed CeS-Gel, an advanced hydrogel dressing integrating live microalgae and CeO₂ nanoparticles within a dual-crosslinked silk hydrogel network. By harnessing photosynthesis, CeS-Gel provided a continuous and reliable oxygen supply, significantly enhancing cell migration and proliferation. Additionally, CeS-Gel exhibited potent ROS-scavenging properties, effectively mitigating oxidative stress-induced cellular damage while directly promoting M2 macrophage polarization, thereby modulating the inflammatory response. In vivo experiments demonstrated that CeS-Gel markedly accelerated wound healing in diabetic mice, achieving a 93.2 % wound closure rate. Furthermore, CeS-Gel effectively alleviated hypoxia, promoted neovascularization, and exhibited anti-inflammatory and immunoregulatory effects. This living microalgae-silk gel represents a promising approach for improving chronic diabetic wound healing with great potential for clinical application.
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Affiliation(s)
- Liuting Chen
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China; Zhejiang-Mauritius Joint Research Center for Biomaterials and Tissue Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Yao Li
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China; Zhejiang-Mauritius Joint Research Center for Biomaterials and Tissue Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China.
| | - Na Zhang
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Tianshuang Chen
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Feiyan Li
- Zhejiang-Mauritius Joint Research Center for Biomaterials and Tissue Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Jiayi Han
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Zihang Wang
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Perumal Ramesh Kannan
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China; Zhejiang-Mauritius Joint Research Center for Biomaterials and Tissue Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Zeyue Sun
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Feiya Fu
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Ling Cheng
- Luoxi Medical Technology (Hangzhou) Co., Ltd., Hangzhou 310018, China
| | - Jiaju Lu
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China; International Scientific and Technological Cooperation Base of Intelligent Biomaterials and Functional Fibers of Zhejiang Province, Hangzhou 310018, China.
| | - Xiangdong Kong
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China; Zhejiang-Mauritius Joint Research Center for Biomaterials and Tissue Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China; International Scientific and Technological Cooperation Base of Intelligent Biomaterials and Functional Fibers of Zhejiang Province, Hangzhou 310018, China.
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24
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Sharma V, Singh J, Kumar Y, Kumar A, Venkatesan K, Mukherjee M, Sharma AK. Integrated insights into gene expression dynamics and transcription factor roles in diabetic and diabetic-infectious wound healing using rat model. Life Sci 2025; 368:123508. [PMID: 40015667 DOI: 10.1016/j.lfs.2025.123508] [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: 12/20/2024] [Revised: 02/08/2025] [Accepted: 02/22/2025] [Indexed: 03/01/2025]
Abstract
BACKGROUND Diabetic or diabetic infectious wounds pose a global challenge, marked by delayed healing and high amputation/mortality rates. This study of participating transcriptomes and their regulators unveils critical alterations. METHODS Transcriptome data from GEO analyzed DEGs in diabetic foot ulcers vs. controls using RNA-Seq, limma, STRINGdb, Cytoscape, and clusterProfiler for PPI networks and functional enrichment. TRRUST database was used to predict transcriptional factors (TFs). Adverse molecular pathology in different models of wounds (non-diabetic, acute diabetic, diabetic infectious wounds) was validated by RT-PCR, Western blotting, oxidative stress markers, cytokines, and histological analysis. RESULTS RNA-Seq dataset 'GSE199939' was analyzed after normalization to identify DEGs (total 47 DEG, 31 upregulated, 16 downregulated) in diabetic wound healing using limma. PPI networks revealed seven hub genes which were further processed for functional enrichment and highlighted oxidative stress, ECM remodeling, AGE-RAGE, and IL-17 signaling in diabetic wound pathology. Additionally, 17 key TFs were identified as hub gene regulators. The healing rate was significantly impaired in diabetic wounds, with delayed contraction, elevated pro-inflammatory cytokines, oxidative stress, reduced anti-inflammatory cytokines, antioxidants, angiogenesis, collagen deposition, and re-epithelialization. Further, RT-PCR and Western blot analysis validated the expression of target genes including the overexpression of HSPA1B, FOS, and down-expression of SOD2, COL1A1, and CCL2, whereas TFs including upregulation of RELA, NFKB1, STAT3, and downregulation of SP1 and JUN in diabetic and diabetic infectious wounds. CONCLUSION Molecular analyses reveal disrupted oxidative stress, ECM remodeling, and inflammatory signaling in diabetic and diabetic infectious, emphasizing impaired healing dynamics and identifying therapeutic targets.
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Affiliation(s)
- Vikash Sharma
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University, Gurugram, Haryana- 122413, India; Amity Institute of Biotechnology, Amity University, Gurugram, Haryana- 122413, India
| | - Jitender Singh
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University, Gurugram, Haryana- 122413, India
| | - Yash Kumar
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University, Gurugram, Haryana- 122413, India
| | - Ashish Kumar
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University, Gurugram, Haryana- 122413, India
| | - Kumar Venkatesan
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Monalisa Mukherjee
- Molecular Sciences and Engineering Laboratory, Amity Institute of Click Chemistry Research and Studies, Amity University, Noida, Uttar Pradesh 201303, India.
| | - Arun K Sharma
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University, Gurugram, Haryana- 122413, India.
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25
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Tartau CG, Boboc IKS, Mititelu-Tartau L, Bogdan M, Buca BR, Pavel LL, Amalinei C. Exploring the Protective Effects of Traditional Antidiabetic Medications and Novel Antihyperglycemic Agents in Diabetic Rodent Models. Pharmaceuticals (Basel) 2025; 18:670. [PMID: 40430489 PMCID: PMC12114790 DOI: 10.3390/ph18050670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/29/2025] Open
Abstract
Type 2 Diabetes (T2D) is a complex metabolic disorder that affects multiple organs, leading to severe complications in the pancreas, kidneys, liver, and heart. Prolonged hyperglycemia, along with oxidative stress and chronic inflammation, plays a crucial role in accelerating tissue damage, significantly increasing the risk of diabetic complications such as nephropathy, hepatopathy, and cardiovascular disease. This review evaluates the protective effects of various antidiabetic treatments on organ tissues affected by T2D, based on findings from experimental animal models. Metformin, a first-line antidiabetic agent, has been widely recognized for its ability to reduce inflammation and oxidative stress, thereby mitigating diabetes-induced organ damage. Its protective role extends beyond glucose regulation, offering benefits such as improved mitochondrial function and reduced fibrosis in affected tissues. In addition to traditional therapies, new classes of antidiabetic drugs, including sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists not only improve glycemic control but also exhibit nephroprotective and cardioprotective properties by reducing glomerular hyperfiltration, oxidative stress, and inflammation. Similarly, GLP-1 receptor agonists have been associated with reduced hepatic steatosis and enhanced cardiovascular function. Preclinical studies suggest that tirzepatide, a dual GLP-1/gastric inhibitory polypeptide receptor agonist may offer superior metabolic benefits compared to conventional GLP-1 agonists by improving β-cell function, enhancing insulin sensitivity, and reducing fatty liver progression. Despite promising preclinical results, differences between animal models and human physiology pose a challenge. Further clinical research is needed to confirm these effects and refine treatment strategies. Future T2D management aims to go beyond glycemic control, emphasizing organ protection and long-term disease prevention.
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Affiliation(s)
- Cosmin Gabriel Tartau
- Department of Morphofunctional Sciences I, Faculty of Medicine, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania; (C.G.T.); (C.A.)
| | - Ianis Kevyn Stefan Boboc
- Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Liliana Mititelu-Tartau
- Department of Pharmacology, Faculty of Medicine, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.M.-T.); (B.R.B.)
| | - Maria Bogdan
- Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Beatrice Rozalina Buca
- Department of Pharmacology, Faculty of Medicine, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.M.-T.); (B.R.B.)
| | - Liliana Lacramioara Pavel
- Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800010 Galati, Romania;
| | - Cornelia Amalinei
- Department of Morphofunctional Sciences I, Faculty of Medicine, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania; (C.G.T.); (C.A.)
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26
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Chetty R, Bhagwan R, Govender N. The biopsychosocial effects of transtibial amputation: A South African perspective. Afr J Disabil 2025; 14:1404. [PMID: 40357351 PMCID: PMC12067012 DOI: 10.4102/ajod.v14i0.1404] [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: 01/31/2024] [Accepted: 12/15/2024] [Indexed: 05/15/2025] Open
Abstract
Background A myriad of physical, psychosocial and environmental sequelae are associated with limb loss. However, there is a paucity of empirical South African data, which focusses on these sequelae, how they interface with the amputee's quality of life as well as the challenges they experience following amputation. Objectives This study sought to explore the biopsychosocial effects of amputation and how it affected the quality of life of transtibial amputees. Method A qualitative approach guided this study. Data were collected using one-on-one interviews with 14 unilateral transtibial amputees. Data were analysed thematically. Results Five broad themes emerged from the inquiry, which captured amputees' experiences of phantom limb pain, body image disturbances and their challenges related to adapting to daily activities. Participants also expressed the salience of familial support as well as the importance of psychological interventions to cope. Conclusion The findings suggested that support networks and professional psychological intervention are imperative in facilitating successful adjustment to the amputation experience. Raising awareness of limb loss, in both rural and urban settings, may help reduce the stigma attached to it. Contribution Quality of life comprises several domains, namely physical, psychological, environmental and social. However, limited local and international data exists regarding the environmental and social effects. This study brought to the fore the positive and negative effects of amputation in each domain, as well as various strategies, which facilitate successful adjustment to amputation.
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Affiliation(s)
- Riyona Chetty
- Department of Medical Orthotics and Prosthetics, Faculty of Health Sciences, Durban University of Technology, Durban, South Africa
| | - Raisuyah Bhagwan
- Department of Community Health Studies, Faculty of Health Sciences, Durban University of Technology, Durban, South Africa
| | - Nalini Govender
- Department of Basic Medical Sciences, Faculty of Health Sciences, Durban University of Technology, Durban, South Africa
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27
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Taghdi MH, Al-Masawa ME, Muttiah B, Fauzi MB, Law JX, Zainuddin AA, Lokanathan Y. Three-Dimensional Bioprinted Gelatin-Genipin Hydrogels Enriched with hUCMSC-Derived Small Extracellular Vesicles for Regenerative Wound Dressings. Polymers (Basel) 2025; 17:1163. [PMID: 40362948 PMCID: PMC12073717 DOI: 10.3390/polym17091163] [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: 03/25/2025] [Revised: 04/17/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025] Open
Abstract
Mesenchymal stromal cell-derived small extracellular vesicles (MSC-sEVs) have shown great promise in promoting tissue repair, including skin wound healing, but challenges like rapid degradation and short retention have limited their clinical application. Hydrogels have emerged as effective carriers for sustained EV release. Three-dimensional printing enables the development of personalized skin substitutes tailored to the wound size and shape. This study aimed to develop 3D bioprinted gelatin-genipin hydrogels incorporating human umbilical cord MSC-sEVs (hUCMSC-sEVs) for future skin wound healing applications. Gelatin hydrogels (8% and 10% w/v) were crosslinked with 0.3% genipin (GECL) to improve stability. The hydrogels were evaluated for their suitability for extrusion-based 3D bioprinting and physicochemical properties, such as the swelling ratio, hydrophilicity, enzymatic degradation, and water vapor transmission rate (WVTR). Chemical characterization was performed using EDX, XRD, and FTIR. The hUCMSC-sEVs were isolated via centrifugation and tangential flow filtration (TFF) and characterized. The crosslinked hydrogels were successfully 3D bioprinted and demonstrated superior properties, including high hydrophilicity, a swelling ratio of ~500%, slower degradation, and optimal WVTR. hUCMSC-sEVs, ranging from 50 to 200 nm, were positive for surface and cytosolic markers. Adding 75 μg/mL of hUCMSC-EVs into 10% GECL hydrogels significantly improved the biocompatibility. These hydrogels offer ideal properties for 3D bioprinting and wound healing, demonstrating their potential as biomaterial scaffolds for skin tissue regeneration applications.
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Affiliation(s)
- Manal Hussein Taghdi
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (M.H.T.); (M.E.A.-M.); (B.M.); (M.B.F.); (J.X.L.)
- Department of Anesthesia and Intensive Care, Faculty of Medical Technology, University of Tripoli, Tripoli P.O. Box 13932, Libya
| | - Maimonah Eissa Al-Masawa
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (M.H.T.); (M.E.A.-M.); (B.M.); (M.B.F.); (J.X.L.)
| | - Barathan Muttiah
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (M.H.T.); (M.E.A.-M.); (B.M.); (M.B.F.); (J.X.L.)
| | - Mh Busra Fauzi
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (M.H.T.); (M.E.A.-M.); (B.M.); (M.B.F.); (J.X.L.)
- Advance Bioactive Materials-Cells UKM Research Group, Universiti Kebangsaan Malaysia, Bangi 43600, Malaysia
| | - Jia Xian Law
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (M.H.T.); (M.E.A.-M.); (B.M.); (M.B.F.); (J.X.L.)
| | - Ani Amelia Zainuddin
- Department of Obstetrics and Gynecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia;
| | - Yogeswaran Lokanathan
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (M.H.T.); (M.E.A.-M.); (B.M.); (M.B.F.); (J.X.L.)
- Advance Bioactive Materials-Cells UKM Research Group, Universiti Kebangsaan Malaysia, Bangi 43600, Malaysia
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Rybka M, Mazurek Ł, Jurak J, Laskowska A, Zajdel M, Czuwara J, Sulejczak D, Szudzik M, Samborowska E, Schwartz RA, Dziadek M, Salagierski S, Drapała A, Ufnal M, Konop M. Keratin-TMAO dressing accelerates full-thickness skin wound healing in diabetic rats via M2-macrophage polarization and the activation of PI3K/AKT/mTOR signaling pathway. Int J Biol Macromol 2025; 310:143313. [PMID: 40274140 DOI: 10.1016/j.ijbiomac.2025.143313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 04/14/2025] [Accepted: 04/16/2025] [Indexed: 04/26/2025]
Affiliation(s)
- Mateusz Rybka
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research (CePT), Medical University of Warsaw, Warsaw, Poland.
| | - Łukasz Mazurek
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research (CePT), Medical University of Warsaw, Warsaw, Poland
| | - Jan Jurak
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research (CePT), Medical University of Warsaw, Warsaw, Poland
| | - Anna Laskowska
- Department of Pharmaceutical Microbiology and Bioanalysis, Centre for Preclinical Research and Technology (CePT), Faculty of Pharmacy, Medical University of Warsaw, Poland
| | - Mikołaj Zajdel
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research (CePT), Medical University of Warsaw, Warsaw, Poland
| | - Joanna Czuwara
- Department of Dermatology, Medical University of Warsaw, Warsaw, Poland
| | - Dorota Sulejczak
- Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Mateusz Szudzik
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research (CePT), Medical University of Warsaw, Warsaw, Poland
| | - Emilia Samborowska
- Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Robert A Schwartz
- Department of Dermatology and Pathology, Rutgers New Jersey Medical School, Newark, United States of America
| | - Michał Dziadek
- Department of Glass Technology and Amorphous Coatings, AGH University of Krakow, Krakow, Poland; Department of Materials Engineering, University of British Columbia, Vancouver, British Columbia, Canada
| | - Szymon Salagierski
- Department of Glass Technology and Amorphous Coatings, AGH University of Krakow, Krakow, Poland
| | - Adrian Drapała
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research (CePT), Medical University of Warsaw, Warsaw, Poland
| | - Marcin Ufnal
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research (CePT), Medical University of Warsaw, Warsaw, Poland
| | - Marek Konop
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research (CePT), Medical University of Warsaw, Warsaw, Poland.
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Zhou Y, Dai F, Zhao S, Li Z, Liang H, Wang X, Zhao L, Tan H. pH and Glucose Dual-Responsive Hydrogels Promoted Diabetic Wound Healing by Remodeling the Wound Microenvironment. Adv Healthc Mater 2025:e2500810. [PMID: 40237168 DOI: 10.1002/adhm.202500810] [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: 02/13/2025] [Revised: 04/02/2025] [Indexed: 04/18/2025]
Abstract
The microenvironment of diabetic wounds is complicated and characterized by hyperglycemia, hyperinflammation, persistent infection, hypoxia, and ischemia, making wound restoration and healing extremely challenging. Therefore, functional hydrogel dressings with the ability to regulate the microenvironment of diabetic wounds are a promising strategy for the treatment of diabetic wounds. In this study, a pH/glucose dual-responsive hydrogel based on phenylboric acid-modified carboxymethyl chitosan (CMCSPBA), aldehyde-terminated polyethylene glycol (PEGCHO), and polyvinyl alcohol (PVA) has been developed for diabetic wound treatment via Schiff base and phenylboric ester interactions. Glucose oxidase (GOX), catalase (CAT), and deferoxamine mesylate (DFO) are incorporated into the hydrogel to endow it with multi-functionality. In the hyperglycemic environment of diabetic wounds, a benign feedback loop is formed through the synergistic action of each component of the hydrogel, which enables the reshaping of the microenvironment of diabetic wounds by adjusting the pH and glucose, alleviating oxidative stress and hypoxia, regulating the inflammatory response, inhibiting bacterial infection, and promoting angiogenesis, thus accelerating diabetic wound healing in streptozotocin (STZ)-induced diabetic mice.
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Affiliation(s)
- Yifan Zhou
- School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Fanjia Dai
- School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211, China
- Infectious Diseases Department, Shenzhen Children's Hospital, Shenzhen, Guangdong, 518038, China
| | - Sifang Zhao
- School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Zelong Li
- School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Hongze Liang
- School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Xiao Wang
- Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Lingling Zhao
- School of Materials Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Hui Tan
- Infectious Diseases Department, Shenzhen Children's Hospital, Shenzhen, Guangdong, 518038, China
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Kananivand M, Nouri F, Yousefi MH, Pajouhi A, Ghorbani H, Afkhami H, Razavi ZS. Mesenchymal stem cells and their exosomes: a novel approach to skin regeneration via signaling pathways activation. J Mol Histol 2025; 56:132. [PMID: 40208456 DOI: 10.1007/s10735-025-10394-7] [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: 12/01/2024] [Accepted: 03/06/2025] [Indexed: 04/11/2025]
Abstract
Accelerating wound healing is a crucial objective in surgical and regenerative medicine. The wound healing process involves three key stages: inflammation, cell proliferation, and tissue repair. Mesenchymal stem cells (MSCs) have demonstrated significant therapeutic potential in promoting tissue regeneration, particularly by enhancing epidermal cell migration and proliferation. However, the precise molecular mechanisms underlying MSC-mediated wound healing remain unclear. This review highlights the pivotal role of MSCs and their exosomes in wound repair, with a specific focus on critical signaling pathways, including PI3K/Akt, WNT/β-catenin, Notch, and MAPK. These pathways regulate essential cellular processes such as proliferation, differentiation, and angiogenesis. Moreover, in vitro and in vivo studies reveal that MSCs accelerate wound closure, enhance collagen deposition, and modulate immune responses, contributing to improved tissue regeneration. Understanding these mechanisms provides valuable insights into MSC-based therapeutic strategies for enhancing wound healing.
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Affiliation(s)
- Maryam Kananivand
- Medical Department, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Nouri
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University (SRBIAU), Tehran, Iran
| | - Mohammad Hasan Yousefi
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Student Research Committee, Qom University of Medical Sciences, Qom, Iran
| | - Ali Pajouhi
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Hakimeah Ghorbani
- Department of Sciences, Faculty of Biological Sciences, Tabriz University of Sciences, Tabriz, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran.
- Student Research Committee, Qom University of Medical Sciences, Qom, Iran.
| | - Zahra Sadat Razavi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Sanpinit S, Issuriya A, Sakulkeo O, Wetchakul P, Limsuwan S, Na-Phatthalung P, Kantisin S, Tang J, Chusri S. Mechanisms underlying the wound healing and tissue regeneration properties of a novel gauze dressing impregnated with traditional herbal medicine (Ya-Samarn-Phlae) in type 2 diabetic Goto-Kakizaki (GK) rats. Front Pharmacol 2025; 16:1574715. [PMID: 40271074 PMCID: PMC12015241 DOI: 10.3389/fphar.2025.1574715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Accepted: 04/01/2025] [Indexed: 04/25/2025] Open
Abstract
Ethnopharmacological relevance A traditional preparation of Ya-Samarn-Phlae (T-YaSP) consists of Garcinia mangostana L., Oryza sativa L., Curcuma longa L., and Areca catechu L. and has been used in Thai medicine as an infused oil for treating chronic and diabetic wounds. It is reputed for its antibacterial, antioxidant, and wound-healing properties. Despite its traditional use, scientific validation of the mechanisms underlying diabetic wound healing remains limited. Aim This study aims to develop a novel gauze dressing impregnated with an ointment containing T-YaSP (YaSP) to enhance its practical application and elucidate the mechanisms of action in promoting wound healing in both non-diabetic and type 2 diabetic wounds of this ointment. Materials and methods YaSP was developed and tested for stability and dermal irritation. Changes in chemical markers during storage were measured both qualitatively and quantitatively. Its anti-inflammatory activity was assessed using the carrageenan-induced rat paw edema model. The effect of YaSP on levels of nitric oxide (NO), myeloperoxidase (MPO), malondialdehyde (MDA), inflammatory cytokines (TNF-α, IL-1β, and PGE2), and pro-inflammatory enzymes (iNOS and COX-2) was measured. The wound-healing effects of YaSP were assessed using full-thickness (6 mm diameter) wound models in both non-diabetic Wistar rats and type 2 diabetic Goto-Kakizaki rats. In addition to evaluating wound closure on days 0, 3, 5, 7, 9, and 11, the influence on TGF-β1, VEGF, and the production of collagen types I and III, which indicate the inflammatory, proliferative, and remodeling phases, was measured. Results During the 6-month storage period, the α-mangostin content measured in YaSP did not decrease; however, the curcumin level showed a significant reduction. Topical treatment with YaSP demonstrated strong anti-inflammatory activity and alleviated oxidative stress and inflammatory markers. YaSP improved wound closure rates in both diabetic and non-diabetic models. Levels of TGF-β1 and VEGF increased, indicating the promotion of angiogenesis and granulation tissue formation during the proliferation phase on the seventh day. Additionally, TGF-β1 levels dropped on the 11th day, aligning with diminished inflammation and enhanced remodeling. The treatment balanced collagen synthesis, increasing type III collagen in the early stages and type I collagen in the later stages of wound healing. Histological analysis confirmed reduced inflammation, enhanced neovascularization, and increased collagen production. Conclusion A gauze dressing impregnated with YaSP provides a practical solution for diabetic wound management and demonstrates strong wound-healing properties by modulating excess inflammation, promoting angiogenesis during the proliferation phase, and regulating collagen synthesis throughout the remodeling phase. This discovery reveals, for the first time, the underlying mechanisms of action of this traditional formulation, highlighting its potential as a cost-effective alternative for managing chronic wounds in resource-limited settings.
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Affiliation(s)
- Sineenart Sanpinit
- Department of Applied Thai Traditional Medicine, School of Medicine, Walailak University, Thasala, Nakhon Si Thammarat, Thailand
| | - Acharaporn Issuriya
- Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Songkhla, Thailand
| | - Oraphan Sakulkeo
- Traditional Thai Medical Research and Innovation Center, Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Palika Wetchakul
- Department of Applied Thai Traditional Medicine, School of Medicine, Walailak University, Thasala, Nakhon Si Thammarat, Thailand
| | - Surasak Limsuwan
- Traditional Thai Medical Research and Innovation Center, Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Pinanong Na-Phatthalung
- Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Siriwan Kantisin
- Unit for Area-Based Research and Innovation in Cross-Border Health Care and Occupational Health and Safety Department, School of Health Science, Mae Fah Luang University, Chiang Rai, Thailand
| | - Jian Tang
- School of Chinese Medicine, Bozhou University, Bozhou, China
| | - Sasitorn Chusri
- School of Health Science and Biomedical Technology Research Group for Vulnerable Populations, Mae Fah Luang University, Chiang Rai, Thailand
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Xuan Q, Cai J, Gao Y, Qiao X, Jin T, Peydayesh M, Zhou J, Sun Q, Zhan L, Liu B, Wang P, Li H, Chen C, Mezzenga R. Amyloid-Templated Ceria Nanozyme Reinforced Microneedle for Diabetic Wound Treatments. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2417774. [PMID: 39995378 PMCID: PMC12004906 DOI: 10.1002/adma.202417774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 02/15/2025] [Indexed: 02/26/2025]
Abstract
Amyloid fibrils have emerged as excellent templates and building blocks for the development of ordered functional materials with considerable potential in biomedical applications. Here, lysozyme amyloid fibrils (Lys-AFs) are employed as templates for the in situ synthesis of ceria nanozymes (Lys-AFs-Ceria) with ultrafine dimensions, an optimized Ce3+/Ce4+ ratio, and uniform distribution on the fibril surface, addressing the challenges of low catalytic efficiency and high susceptibility to aggregation typical of traditional methods. As a proof of concept, it is further applied Lys-AFs-Ceria to develop hydrogel/microneedle for treating bacteria-infected diabetic wounds via non-covalent interactions between polyphenols and amyloid fibrils incorporating glucose oxidase (GOX). The hydrogel/microneedle facilitates superoxide dismutase and catalase cascade catalysis by Lys-AFs-Ceria, and integrates GOX-mediated glucose consumption, synergistically achieving glucose reduction, reactive oxygen species elimination, and hypoxia alleviation in the diabetic wound infection microenvironment. In addition to antibacterial properties and tissue regeneration promotion of Lys-AFs scaffold, Lys-AFs-Ceria regulates macrophages polarization toward an anti-inflammatory M2 state. Collectively, these attributes contribute to the enhanced efficacy of diabetic wound healing, with in vivo studies demonstrating increased healing efficiency following a single application, and more in general an effective strategy toward high-catalytic and stable nanozymes.
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Affiliation(s)
- Qize Xuan
- Institute for Environmental Pollution and Health, School of Environmental and Chemical EngineeringShanghai UniversityShanghai200444P. R. China
- Department of Health Sciences and TechnologyETH ZürichSchmelzbergstrasse 9Zürich8092Switzerland
- State Key Laboratory of Bioreactor Engineering Center, School of BiotechnologyEast China University of Science and TechnologyShanghai200237China
| | - Jiazhe Cai
- Institute for Environmental Pollution and Health, School of Environmental and Chemical EngineeringShanghai UniversityShanghai200444P. R. China
| | - Yuan Gao
- Institute for Environmental Pollution and Health, School of Environmental and Chemical EngineeringShanghai UniversityShanghai200444P. R. China
| | - Xinchi Qiao
- Institute for Environmental Pollution and Health, School of Environmental and Chemical EngineeringShanghai UniversityShanghai200444P. R. China
| | - Tonghui Jin
- Department of Health Sciences and TechnologyETH ZürichSchmelzbergstrasse 9Zürich8092Switzerland
| | - Mohammad Peydayesh
- Department of Health Sciences and TechnologyETH ZürichSchmelzbergstrasse 9Zürich8092Switzerland
| | - Jiangtao Zhou
- Department of Health Sciences and TechnologyETH ZürichSchmelzbergstrasse 9Zürich8092Switzerland
| | - Qiyao Sun
- Department of Health Sciences and TechnologyETH ZürichSchmelzbergstrasse 9Zürich8092Switzerland
| | - Lijian Zhan
- Institute for Biomedical EngineeringETH ZürichZürich8092Switzerland
| | - Bin Liu
- Department of Health Sciences and TechnologyETH ZürichSchmelzbergstrasse 9Zürich8092Switzerland
| | - Ping Wang
- Department of Bioproducts and Biosystems EngineeringUniversity of MinnesotaSt PaulMN55108USA
| | - Hui Li
- Institute for Environmental Pollution and Health, School of Environmental and Chemical EngineeringShanghai UniversityShanghai200444P. R. China
| | - Chao Chen
- Institute for Environmental Pollution and Health, School of Environmental and Chemical EngineeringShanghai UniversityShanghai200444P. R. China
- State Key Laboratory of Bioreactor Engineering Center, School of BiotechnologyEast China University of Science and TechnologyShanghai200237China
| | - Raffaele Mezzenga
- Department of Health Sciences and TechnologyETH ZürichSchmelzbergstrasse 9Zürich8092Switzerland
- Department of MaterialsETH ZürichWolfgang‐Pauli‐Strasse 10Zürich8049Switzerland
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Erukainure OL, Houreld NN. Vanillin Enhances Photobiomodulation Wound Healing by Modulating Glyco-Oxidative Stress and Glucose Dysmetabolism in Diabetic Wounded Fibroblast Cells. J Cell Mol Med 2025; 29:e70537. [PMID: 40194982 PMCID: PMC11975505 DOI: 10.1111/jcmm.70537] [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: 07/15/2024] [Revised: 03/20/2025] [Accepted: 03/24/2025] [Indexed: 04/09/2025] Open
Abstract
Delayed wound healing is among the major peripheral complications of diabetes. Synergistic treatment of diabetic wounds (DW) with phytochemicals and non-invasive techniques has shown promising results. The synergistic effect of vanillin and photobiomodulation (PBM) on DW healing, and their modulatory effect on oxidative stress and glucose metabolism was investigated in DW fibroblast cells (WS1). DW cells were treated with vanillin and vanillin + PBM. Control consisted of WS1 cells, untreated DW cells, and DW cells treated with PBM. Diabetes was induced by repeated growth in complete MEM containing high D-glucose (22.6 mM/L). Wounds were induced by central scratching. Cells were treated with vanillin at various concentrations for 2 h prior to PBM at 660 nm with a fluence of 5 J/cm2 for an irradiation time of 780 s, followed by 24 h incubation. Induction of DW led to a decreased glutathione level, and decreased superoxide dismutase, catalase, glutathione reductase, glyoxalase, and Na/K-ATPase activities, while concomitantly increasing the activities of fructose-1,6-bisphosphatase, glucose 6-phosphatase, E-NTPDase, and 5-lipoxygenase. These levels and activities were reversed following treatment with 12 μg/mL vanillin, and 6 μg/mL vanillin + PBM having the best effects. However, treatment with 24 μg/mL vanillin and vanillin + PBM showed no significant effects. Except for cells treated with 24 μg/mL vanillin and vanillin + PBM, morphological analysis indicated wound closures compared to the controls. These results indicate the synergistic therapeutic effect of vanillin + PBM on the management of diabetic wounds, with 6 μg/mL vanillin + PBM displaying the best effect.
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Affiliation(s)
- Ochuko L. Erukainure
- Laser Research CentreFaculty of Health Sciences, University of JohannesburgDoornfonteinSouth Africa
| | - Nicolette N. Houreld
- Laser Research CentreFaculty of Health Sciences, University of JohannesburgDoornfonteinSouth Africa
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Li X, Yi M, Song Z, Ni T, Tu L, Yu M, Zhang L, Shi J, Gao W, Zhang Q, Yan W. A calcitonin gene-related peptide co-crosslinked hydrogel promotes diabetic wound healing by regulating M2 macrophage polarization and angiogenesis. Acta Biomater 2025; 196:109-122. [PMID: 40020959 DOI: 10.1016/j.actbio.2025.02.046] [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: 11/18/2024] [Revised: 02/07/2025] [Accepted: 02/21/2025] [Indexed: 03/03/2025]
Abstract
Delayed diabetic wound (DBW) healing is a severe complication of diabetes, characterized notably by peripheral sensory neuropathy. The underlying mechanism of sensory nerves and DBW remain unclear. Here, we demonstrate the role of calcitonin gene-related peptide (CGRP) in regulating epithelialization and angiogenesis in DBW. Subsequently, we design and synthesis a gelatin methacryloyl (GelMA-CGRP) hydrogel that slowly releases CGRP, and evaluated its effect on promoting DBW healing. The results show that CGRP is abnormally downregulated in DBW, and CGRP ablation further delays DBW healing. This is due to the reduced M2 polarization and decreased angiogenesis in the absence of CGRP, whereas local application of GelMA-CGRP accelerates DBW healing. Mechanistic studies indicate that CGRP promotes M2 macrophage polarization by inhibiting the p53 signaling pathway and enhances endothelial cell function, thereby accelerating DBW healing. These findings suggest that CGRP could provide a novel therapeutic approach for diabetic wound treatment. STATEMENT OF SIGNIFICANCE: Current methods for treating diabetic wounds have many limitations. Compared to conventional dressings, hydrogels combined with drugs or biological factors to promote diabetic wound healing have become an important research direction in recent years. This study reveals the key role of CGRP in the pathogenesis of diabetic wounds. The research found that CGRP promotes M2 macrophage polarization and angiogenesis by inhibiting the p53 signaling pathway, thereby promoting diabetic wound healing. We further utilized the carrier properties of GelMA hydrogel to develop a GelMA-CGRP hydrogel material that slowly delivers CGRP and effectively treats diabetic wounds. This material demonstrates strong biocompatibility and antimicrobial properties, offering a novel approach for the treatment of diabetic wounds.
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Affiliation(s)
- Xiangyu Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Min Yi
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Ziyan Song
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Tianyi Ni
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Liying Tu
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Miao Yu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Lantian Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Jingping Shi
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China
| | - Weicheng Gao
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China.
| | - Qian Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China.
| | - Wei Yan
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, PR China.
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Ye P, Yang Y, Liu M, Meng J, Zhao J, Zhao J, Wang J, Lu Q, Liu J, Wang L, Lei J, Wang C. Co-Delivery of Morphologically Switchable Au Nanowire and Hemoglobin-Resveratrol Nanoparticles in the Microneedle for Diabetic Wound Healing Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2419430. [PMID: 40066484 DOI: 10.1002/adma.202419430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/25/2025] [Indexed: 04/24/2025]
Abstract
Diabetic wounds are a common complication of diabetes and pose a significant threat to human health. High glucose concentration in the wound remains a major obstacle, necessitating effective strategies to achieve sustained glucose consumption for synergistic diabetic wound therapy. In this study, an Au-based nanomaterial is developed that can adjust its morphology in different therapeutic processes. The prepared Au nanowire (ANW) can be converted into Au nanospheres (AS) under ultrasonic conditions by adjusting the amount of polyethylene glycol (PEG) on its surface for convenient delivery. Intriguingly, AS is depolymerized into ANW again in the wound area, prolonging the retention time, and ensuring continuous consumption of glucose. After constructing the morphologically switchable Au nanowire, a polyvinyl alcohol (PVA) is applied it to microneedle and co-delivered it with hemoglobin (Hb)-resveratrol (RES) nanoparticles for synergistic diabetic wound therapy. In a streptozotocin (STZ)-induced diabetic mouse model, the microneedle degraded gradually, and the Hb-RES nanoparticles synergistically ameliorated hypoxia, scavenged ROS, and inhibited macrophage differentiation into pro-inflammatory M1 phenotypes. During this process, ANW continuously catalyzed glucose through its inherent glucose oxidase activity. Thus, this study provides novel insights into the long-term management of glucose concentration during synergistic diabetic wound healing.
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Affiliation(s)
- Peng Ye
- Beijing Key Laboratory of Lignocellulosic Chemistry, College of Material Science and Technology, Beijing Forestry University, Beijing, 100083, China
- State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China
| | - Yuan Yang
- State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China
| | - Mengzhe Liu
- Beijing Key Laboratory of Lignocellulosic Chemistry, College of Material Science and Technology, Beijing Forestry University, Beijing, 100083, China
| | - Jiaqi Meng
- State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China
| | - Jingyang Zhao
- Beijing Key Laboratory of Lignocellulosic Chemistry, College of Material Science and Technology, Beijing Forestry University, Beijing, 100083, China
- State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China
| | - Jiawei Zhao
- State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China
| | - Jinghui Wang
- State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China
- Department of Gastroenterology Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China
| | - Qianyun Lu
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Jing Liu
- Beijing Key Laboratory of Lignocellulosic Chemistry, College of Material Science and Technology, Beijing Forestry University, Beijing, 100083, China
| | - Luying Wang
- Beijing Key Laboratory of Lignocellulosic Chemistry, College of Material Science and Technology, Beijing Forestry University, Beijing, 100083, China
| | - Jiandu Lei
- Beijing Key Laboratory of Lignocellulosic Chemistry, College of Material Science and Technology, Beijing Forestry University, Beijing, 100083, China
| | - Changlong Wang
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, China
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Yin Y, Guo W, Chen Q, Tang Z, Liu Z, Lin R, Pan T, Zhan J, Ren L. A Single H 2S-Releasing Nanozyme for Comprehensive Diabetic Wound Healing through Multistep Intervention. ACS APPLIED MATERIALS & INTERFACES 2025; 17:18134-18149. [PMID: 40088144 DOI: 10.1021/acsami.5c00889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/17/2025]
Abstract
Diabetic wound healing presents a significant medical challenge and requires multistep interventions due to comprehensive wound environments, such as hyperglycemia, bacterial infection, and impaired angiogenesis. However, current multistep interventions are complicated and need on-demand sequential release and synergy of multicomponents. Herein, a H2S-releasing cascade nanozyme (FeS@Au), which is composed of ultrasmall gold nanocluster (AuNC) loaded on ferrous sulfide nanoparticle (FeSNP), is developed as a single component to regulate glucose level, eliminate infection, and promote angiogenesis, achieving multistep interventions for comprehensive diabetic wound treatment. The glucose oxidase-like activity of AuNC catalyzes glucose into gluconic acid and H2O2, which not only lowers the local glucose level but also decreases the local pH and increases H2O2 level to boost the peroxidase-like activity of FeSNP to generate abundant hydroxyl radical (reactive oxygen species, ROS), inducing ferroptosis-like death in drug-resistant bacteria. Additionally, FeSNP release H2S in the acidified environment to upregulate hypoxia-inducible factor-1 to enhance vascularization through upregulating the expression of vascular endothelial growth factor (VEGF) and other angiogenesis-related genes, reducing the damage to endothelial cells caused by excessive ROS produced by the nanozyme. In a full-thickness MRSA-infected diabetic rat model, FeS@Au significantly eliminates bacteria, enhances angiogenesis, promotes collagen deposition, and accelerates wound healing. This work presents a single nanozyme with H2S-release for multistep interventions, providing a versatile strategy for healing extensive tissue damage caused by diabetes.
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Affiliation(s)
- Ying Yin
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou 510006, China
| | - Wentai Guo
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou 510006, China
| | - Qiangyu Chen
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou 510006, China
| | - Zhimin Tang
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou 510006, China
| | - Zheng Liu
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou 510006, China
| | - Ruibin Lin
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou 510006, China
| | - Ting Pan
- Institute of Nanophotonics, College of Physics & Optoelectronic Engineering, Jinan University, 511443 Guangzhou, China
| | - Jiezhao Zhan
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou 510006, China
| | - Li Ren
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou 510006, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education and Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, China
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Zhang S, Shao Y, Jin R, Ma B. Combining Network Pharmacology, Molecular Docking, Molecular Dynamics Simulation, and Experimental Validation to Uncover the Efficacy and Mechanisms of Si-Miao-Yong-An Decoction in Diabetic Wound Healing. J Inflamm Res 2025; 18:4087-4101. [PMID: 40129870 PMCID: PMC11930845 DOI: 10.2147/jir.s506739] [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: 11/29/2024] [Accepted: 02/21/2025] [Indexed: 03/26/2025] Open
Abstract
Purpose Si-Miao-Yong-An (SMYA) Decoction, a traditional Chinese herbal mixture, shows promise for managing diabetic complications. Up to this point, no reports have explored the effects of SMYA on diabetic wounds or the underlying mechanisms. This study aimed to investigate the therapeutic potential of SMYA in promoting diabetic wound healing and to elucidate the underlying molecular mechanisms. Methods The wound healing effects of SMYA were evaluated in db/db diabetic mice by measuring wound closure rates and histological characteristics, including epidermal thickness and collagen deposition. Network pharmacology was utilized to identify active ingredients and corresponding therapeutic targets of SMYA, followed by validation through molecular docking and molecular dynamics simulations. KEGG and GO enrichment analyses were conducted to elucidate the relevant biological processes and pathways. In vitro studies involving high-glucose-treated HUVECs assessed the effects of SMYA-containing serum on cellular migration and angiogenesis. Finally, the expression of inflammatory factors and RAGE in the wound tissue was detected by qRT-PCR. Results SMYA significantly accelerated wound closure in db/db mice, as evidenced by improved epidermal thickness, tissue morphology, and collagen deposition. Network pharmacology identified 140 overlapping genes involved in angiogenesis and inflammation, with the AGE-RAGE signaling pathway playing a central role. Molecular docking and dynamics simulations revealed strong binding stability of quercetin and kaempferol to inflammation-related hub targets, including IL-6, TNF, and IL-1β. In vitro, SMYA-containing serum alleviated high-glucose-induced impairments in HUVEC migration and angiogenesis. Furthermore, qRT-PCR analysis showed that SMYA significantly downregulated Tnf, Il1b, Il6, and Rage expression in wound tissues, supporting its anti-inflammatory effect. Conclusion SMYA promotes diabetic wound healing by modulating the inflammatory microenvironment and inhibiting the AGE-RAGE signaling pathway. These findings provide robust evidence for SMYA's therapeutic potential and lay a foundation for its future clinical application in treating diabetic wounds.
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Affiliation(s)
- Shujuan Zhang
- Department of Laboratory Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Yiming Shao
- Center of Stem Cell and Regenerative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Ranran Jin
- Center of Stem Cell and Regenerative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Baodong Ma
- Center of Stem Cell and Regenerative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People’s Republic of China
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Li H, Yu L, Li Z, Li S, Liu Y, Qu G, Chen K, Huang L, Li Z, Ren J, Wu X, Huang J. A Narrative Review of Bioactive Hydrogel Microspheres: Ingredients, Modifications, Fabrications, Biological Functions, and Applications. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025:e2500426. [PMID: 40103506 DOI: 10.1002/smll.202500426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 03/02/2025] [Indexed: 03/20/2025]
Abstract
Hydrogel microspheres are important in regenerative medicine and tissue engineering, acting as cargos of cells, drugs, growth factors, bio-inks for 3D printing, and medical devices. The antimicrobial and anti-inflammatory characteristics of hydrogel microspheres are good for treating injured tissues. However, the biological properties of hydrogel microspheres should be modified for optimal treatment of various body parts with different physiological and biochemical environments. In addition, specific preparation methods are required to produce customized hydrogel microspheres with different shapes and sizes for various clinical applications. Herein, the advances in hydrogel microspheres for biomedical applications are reviewed. Synthesis methods for hydrogel precursor solutions, manufacturing methods, and strategies for enhancing the biological functions of these hydrogel microspheres are described. The involvement of bioactive hydrogel microspheres in tissue repair is also discussed. This review anticipates fostering more insights into the design, production, and application of hydrogel microspheres in biomedicine.
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Affiliation(s)
- Haohui Li
- Research Institute of General Surgery, Jinling Hospital, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Lili Yu
- Research Institute of General Surgery, Jinling Hospital, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ze Li
- School of Medicine, Nanjing University, Nanjing, 210093, China
| | - Sicheng Li
- School of Medicine, Nanjing University, Nanjing, 210093, China
| | - Ye Liu
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Guiwen Qu
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Kang Chen
- Research Institute of General Surgery, Jinling Hospital, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Luqiao Huang
- Research Institute of General Surgery, Jinling Hospital, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zongan Li
- Jiangsu Key Laboratory of 3D Printing Equipment and Manufacturing, NARI School of Electrical and Automation Engineering, Nanjing Normal University, Nanjing, 210042, China
| | - Jianan Ren
- Research Institute of General Surgery, Jinling Hospital, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xiuwen Wu
- Research Institute of General Surgery, Jinling Hospital, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jinjian Huang
- Research Institute of General Surgery, Jinling Hospital, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- School of Medicine, Nanjing University, Nanjing, 210093, China
- School of Medicine, Southeast University, Nanjing, 210009, China
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Li Y, Yu S, Zeng J, Zhou S, Cui X, Zhou J, Zhang P. Corilagin enhances wound healing by modulating the macrophage phenotype in diabetic mice. FASEB J 2025; 39:e70439. [PMID: 40052815 DOI: 10.1096/fj.202403085rr] [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: 12/03/2024] [Revised: 02/18/2025] [Accepted: 02/24/2025] [Indexed: 05/13/2025]
Abstract
Excessive inflammation is a prominent issue in diabetic wounds, leading to delayed healing or amputation. Corilagin (Cori) is a natural polyphenolic compound with diverse pharmacological activities, particularly its anti-inflammatory properties. The aim of this study was to evaluate the anti-inflammatory effect of Cori on diabetic wounds and to explore the potential underlying mechanisms. The impact of Cori on wound healing was assessed in streptozotocin (STZ)-induced diabetic mice through morphological observation, histological staining, and gene expression analysis. Flow cytometry, qRT-PCR, western blot analysis, and RNA sequencing were conducted to elucidate the underlying mechanisms in RAW264.7 cells. The results demonstrated that Cori accelerated wound healing, inhibited excessive inflammation, and regulated macrophage polarization in diabetic mice. In Vitro, Cori decreased M1 polarization and inhibited the expression of pro-inflammatory mediators in RAW264.7 cells. Sequencing analysis revealed that Cori exerts anti-inflammatory effects on RAW 264.7 cells through multiple targeted mechanisms. Moreover, in LPS-induced macrophages, Cori dramatically decreased the activation of TLR4, MyD88, and NF-κB. Additionally, Cori enhanced M2 polarization by promoting fatty acid oxidation. In conclusion, the findings suggest that Cori modulates macrophage polarization through various targeted mechanisms, effectively suppressing inflammation and accelerating diabetic wound healing.
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Affiliation(s)
- Yun Li
- Department of Burns and Reconstructive Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
| | - Site Yu
- Department of Burns and Reconstructive Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
| | - Jizhang Zeng
- Department of Burns and Reconstructive Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
| | - Situo Zhou
- Department of Burns and Reconstructive Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
| | - Xu Cui
- Department of Burns and Reconstructive Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
| | - Jie Zhou
- Department of Burns and Reconstructive Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
| | - Pihong Zhang
- Department of Burns and Reconstructive Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
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Wang H, Wei B, WuLan H, Qu B, Li H, Ren J, Han Y, Guo L. Conditioned medium of engineering macrophages combined with soluble microneedles promote diabetic wound healing. PLoS One 2025; 20:e0316398. [PMID: 40072964 PMCID: PMC11902060 DOI: 10.1371/journal.pone.0316398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 12/10/2024] [Indexed: 03/14/2025] Open
Abstract
Diabetic wounds have a profound effect on both the physical and psychological health of patients, highlighting the urgent necessity for novel treatment strategies and materials. Macrophages are vital contributors to tissue repair mechanisms. Macrophage conditioned medium contains various proteins and cytokines related to wound healing, indicating its potential to improve recovery from diabetic wound. Engineering macrophages may enable a further improvement in their tissue repair capacity. Fibroblast growth factor 2 (FGF2) is a crucial growth factor that plays an integral role in wound healing process. And in this study, a stable macrophage cell line (engineered macrophages) overexpressing FGF2 was successfully established by engineering modification of macrophages. Proteomic analysis indicated that conditioned medium derived from FGF2 overexpressed macrophages may promote wound healing by enhancing the level of vascularization. Additionally, cellular assays demonstrated that this conditioned medium promotes endothelial cell migration in vitro. For the convenience of drug delivery and wound application, we prepared soluble hyaluronic acid microneedles to load the conditioned medium. These soluble microneedles exhibited excellent mechanical properties and biocompatibility while effectively releasing their contents in vivo. The microneedles significantly accelerated wound healing, leading to a marked increase in vascular proliferation and improved collagen deposition within a full thickness skin defect diabetic mouse model. In summary, we developed a type of hyaluronic acid microneedle loaded with conditioned medium of engineered macrophages. These microneedles have been demonstrated to enhance tissue vascularization and facilitate diabetic wound healing. This might potentially serve as a highly promising therapeutic approach for diabetic wounds.
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Affiliation(s)
- HongYu Wang
- Medical School of Chinese PLA, Department of Plastic and Reconstructive Surgery, First Medical Center of Chinese PLA General Hospital, Beijing, China
- Department of Burn and Plastic Surgery, PLA No.983 Hospital, Tianjin, China
| | - BaoHua Wei
- Medical School of Chinese PLA, Department of Plastic and Reconstructive Surgery, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Hasi WuLan
- Medical School of Chinese PLA, Department of Plastic and Reconstructive Surgery, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Bin Qu
- Department of Burn Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, China
| | - HuiLong Li
- College of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jing Ren
- Medical School of Chinese PLA, Department of Plastic and Reconstructive Surgery, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yan Han
- Medical School of Chinese PLA, Department of Plastic and Reconstructive Surgery, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - LingLi Guo
- Medical School of Chinese PLA, Department of Plastic and Reconstructive Surgery, First Medical Center of Chinese PLA General Hospital, Beijing, China
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Tian M, Wu J, Du Q, Han J, Yang M, Li X, Li M, Ding X, Song Y. Revealing the Mechanisms of Shikonin Against Diabetic Wounds: A Combined Network Pharmacology and In Vitro Investigation. J Diabetes Res 2025; 2025:4656485. [PMID: 40225010 PMCID: PMC11986939 DOI: 10.1155/jdr/4656485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 01/29/2025] [Indexed: 04/15/2025] Open
Abstract
Background: Shikonin (SHK) possesses extensive pharmacological effects including antimicrobial and anti-inflammatory properties for diabetic wound (DW), while its molecular mechanism remains to be clarified. In this study, we investigated the potential mechanisms of SHK in treating DW by combining network pharmacology and in vitro experiments. Methods: We obtained potential targets for SHK and DW from the publicly available database. Based on the interaction network and conducting GO and KEGG pathway enrichment analysis, we constructed a target pathway network to explore the relationship between SHK and DW. To validate the mechanism of SHK, we established an in vitro experimental model. Results: Sixty intersecting targets between SHK and DW were obtained, and the top 10 targets of the protein-protein interaction (PPI) network included AKT1, SRC, EGFR, CASP3, MMP9, PPARG, ESR1, ANXA5, MMP2, and JAK2. Based on target-pathway networks, the PI3K-AKT signaling pathway was found to be a signaling pathway with low p value in enrichment analysis. In vitro experiments revealed that SHK significantly promoted angiogenesis. Meanwhile, SHK could inhibit the high glucose-induced human umbilical vein endothelial cell dysfunction through regulating the PI3K-AKT pathway. Conclusion: This study initially revealed the molecular mechanism of SHK in DW by multitarget and multipathway. The PI3K-AKT signaling pathway, MAPK signaling pathway, and AGE-RAGE signaling pathways may be the main pathways of SHK in treating DW.
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Affiliation(s)
- Meng Tian
- First College of Clinical Medical, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Junchao Wu
- Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qian Du
- Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jiale Han
- Stomatology Hospital Affiliated to Tongji University, Tongji University, Shanghai, China
| | - Meng Yang
- Department of Cosmetic Dermatology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Xiang Li
- Department of Emergency Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Mingzhu Li
- First College of Clinical Medical, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Xiaofeng Ding
- Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yeqiang Song
- First College of Clinical Medical, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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Jing Y, Liu X, Zhu Y, Wu L, Nong W. Metal-organic framework microneedles for precision transdermal drug delivery: design strategy and therapeutic potential. NANOSCALE 2025; 17:5571-5604. [PMID: 39918280 DOI: 10.1039/d4nr03898c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/08/2025]
Abstract
Metal-organic frameworks (MOFs) are porous materials renowned for their high porosity, large specific surface area, biocompatibility, and biodegradability. Hydrogel microneedles (MNs) is an emerging technology that minimally disrupts the skin or mucosal membranes, bypassing gastrointestinal absorption and the rapid metabolism typical of oral drug delivery. Over the past few decades, both MOFs and MNs have found applications across a range of fields. However, MOFs alone cannot penetrate the skin or mucosal barrier to deliver drugs effectively, and MNs have limited direct loading capacity. When combined, MOFs enhance the loading efficiency of therapeutic agents in hydrogel MNs and optimize their release kinetics. Additionally, the incorporation of MOFs improves the mechanical properties of hydrogel MNs, increasing their permeability to the skin. In turn, hydrogel MNs enable MOFs-whether therapeutically active or drug-loaded-to bypass the skin or mucosal barrier and deliver active compounds directly to the target site for localized treatment. This review discusses the structural features and preparation methods of MOFs and MOF-based MNs, explores their synergistic potential, and highlights strategies for integrating MOFs with MNs to enhance transdermal drug delivery in applications such as wound healing, scar management, acne treatment, and tumor suppression. Finally, we examine the challenges and future potential of MOF-based MNs and offer insights into their role in advancing transdermal therapies.
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Affiliation(s)
- Yutong Jing
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China.
| | - Xueting Liu
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China.
| | - Yajing Zhu
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China.
| | - Lichuan Wu
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China.
| | - Wenqian Nong
- Institute of Oncology, Guangxi Academy of Medical Sciences and the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China.
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Kaleva MD, Kermedchiev M, Velkova L, Zaharieva MM, Dolashki A, Todorova M, Guncheva M, Dolashka P, Najdenski HM. Synergistic Antibacterial Effect of Mucus Fraction from Cornu aspersum and Cirpofloxacin Against Pathogenic Bacteria Isolated from Wounds of Diabetic Patients. Antibiotics (Basel) 2025; 14:260. [PMID: 40149071 PMCID: PMC11939354 DOI: 10.3390/antibiotics14030260] [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: 12/28/2024] [Revised: 02/13/2025] [Accepted: 02/21/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: The treatment of diabetic foot ulcers (DFU) is a challenging medical problem of extreme clinical and social importance, as a consequence of the emerging antibiotic resistance and decreased quality of life of diabetic patients due to impaired wound healing. One of the current trends in world science is the search for biologically active substances derived from living organisms. Biologically active peptides from snail mucus attract considerable scientific interest because of their pleiotropic pharmacological properties. The aim of our study was to evaluate the activity of a combination between a snail mucus protein fraction (MW > 20 kDa) obtained from the garden snail Cornu aspersum and the clinically applied antibacterial chemotherapeutic ciprofloxacin on pathogenic bacterial strains isolated from DFU. Results: The test bacterial strains were characterized as multidrug resistant. The combination between ciprofloxacin and the snail mucus fraction of interest led to additive or synergistic effects depending on the test strain. The mucus fraction exerted a well-pronounced wound-healing effect and no cytotoxicity on normal human fibroblasts and keratinocytes. Methods: The snail mucus was obtained by a patented technology (BG Utility model 2097/2015) and its electrophoretic profile was presented by SDS-PAGE. The bacterial strains were identified and tested for antimicrobial susceptibility (BD Phoenix M50 and Kirby-Bauer assay). The in vitro cytotoxicity of the mucus was evaluated by ISO 10995-5. The antimicrobial activity and combination effects were tested through ISO 20776/1 and the Checkerboard assay. Conclusions: The obtained results are promising and open new horizons for the development of novel combination treatment schemas for healing of infected DFU.
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Affiliation(s)
- Mila Dobromirova Kaleva
- Department of Infectious Microbiology, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 26 Acad. G. Bonchev Str., 1113 Sofia, Bulgaria; (M.D.K.); (M.M.Z.)
| | - Momchil Kermedchiev
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 9, 1113 Sofia, Bulgaria; (M.K.); (L.V.); (A.D.); (M.T.); (M.G.); or (P.D.)
| | - Lyudmila Velkova
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 9, 1113 Sofia, Bulgaria; (M.K.); (L.V.); (A.D.); (M.T.); (M.G.); or (P.D.)
| | - Maya Margaritova Zaharieva
- Department of Infectious Microbiology, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 26 Acad. G. Bonchev Str., 1113 Sofia, Bulgaria; (M.D.K.); (M.M.Z.)
| | - Aleksandar Dolashki
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 9, 1113 Sofia, Bulgaria; (M.K.); (L.V.); (A.D.); (M.T.); (M.G.); or (P.D.)
| | - Maria Todorova
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 9, 1113 Sofia, Bulgaria; (M.K.); (L.V.); (A.D.); (M.T.); (M.G.); or (P.D.)
| | - Maya Guncheva
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 9, 1113 Sofia, Bulgaria; (M.K.); (L.V.); (A.D.); (M.T.); (M.G.); or (P.D.)
| | - Pavlina Dolashka
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 9, 1113 Sofia, Bulgaria; (M.K.); (L.V.); (A.D.); (M.T.); (M.G.); or (P.D.)
- Centre of Competence “Clean Technologies for Sustainable Environment—Waters, Waste, Energy for a Circular Economy”, 1000 Sofia, Bulgaria
| | - Hristo Miladinov Najdenski
- Department of Infectious Microbiology, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 26 Acad. G. Bonchev Str., 1113 Sofia, Bulgaria; (M.D.K.); (M.M.Z.)
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Xiao Y, Xu K, Zhao P, Ji L, Hua C, Jia X, Wu X, Diao L, Zhong W, Lyu G, Xing M. Microgels sense wounds' temperature, pH and glucose. Biomaterials 2025; 314:122813. [PMID: 39270627 DOI: 10.1016/j.biomaterials.2024.122813] [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: 06/07/2024] [Revised: 08/23/2024] [Accepted: 09/02/2024] [Indexed: 09/15/2024]
Abstract
Wound healing concerns almost all bed-side related diseases. With our increasing comprehension of healing nature, the physical and chemical natures behind the wound microenvironment have been decoupled. Wound care demands timely screening and prompt diagnosis of wound complications such as infection and inflammation. Biosensor by the way of exhaustive collection, delivery, and analysis of data, becomes indispensable to arrive at an ideal healing upshot and controlling complications by capturing in-situ wound status. Electrochemical based sensors carry some potential unstable performance subjected to the electrical circuitry and power access and contamination. The colorimetric sensors are free from those concerns. We report that microsensors designed from O/W/O of capillary fluids can continuously monitor wound temperature, pH and glucose concentration. We combined three different types of microgels to encapsulate liquid crystals of cholesterol, nontoxic fuel litmus and two glucose-sensitizing enzymes. A smartphone applet was then developed to convert wound healing images to RGB of digitalizing data. The microgel dressing effectively demonstrates the local temperature change, pH and glucose levels of the wound in high resolution where a microgel is a 'pixel'. They are highly responsive, reversible and accurate. Monitoring multiple physicochemical and physiological indicators provides tremendous potential with insight into healing processing.
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Affiliation(s)
- Yuqin Xiao
- Burn & Trauma Treatment Center, The Affiliated Hospital of Jiangnan University, Wuxi 214000, China; Wuxi School of Medicine, Jiangnan University, Wuxi 214000, China
| | - Kaige Xu
- Department of Mechanical Engineering, University of Manitoba, Winnipeg, R3T 2N2, Canada
| | - Peng Zhao
- Burn & Trauma Treatment Center, The Affiliated Hospital of Jiangnan University, Wuxi 214000, China
| | - Leilei Ji
- Burn & Trauma Treatment Center, The Affiliated Hospital of Jiangnan University, Wuxi 214000, China; Wuxi School of Medicine, Jiangnan University, Wuxi 214000, China
| | - Chao Hua
- Medical School of Nantong University, Nantong, 226019, China
| | - Xiaoli Jia
- Burn & Trauma Treatment Center, The Affiliated Hospital of Jiangnan University, Wuxi 214000, China; Wuxi School of Medicine, Jiangnan University, Wuxi 214000, China
| | - Xiaozhuo Wu
- Department of Mechanical Engineering, University of Manitoba, Winnipeg, R3T 2N2, Canada
| | - Ling Diao
- Burn & Trauma Treatment Center, The Affiliated Hospital of Jiangnan University, Wuxi 214000, China
| | - Wen Zhong
- Department of Biosystems Engineering, University of Manitoba, Winnipeg, R3T 2N2, Canada
| | - Guozhong Lyu
- Burn & Trauma Treatment Center, The Affiliated Hospital of Jiangnan University, Wuxi 214000, China; Wuxi School of Medicine, Jiangnan University, Wuxi 214000, China; Medical School of Nantong University, Nantong, 226019, China; National Research Center for Emergency Medicine, Beijing, China.
| | - Malcolm Xing
- Department of Mechanical Engineering, University of Manitoba, Winnipeg, R3T 2N2, Canada.
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Tibatan MA, Katana D, Yin CM. The emerging role of nanoscaffolds in chronic diabetic wound healing: a new horizon for advanced therapeutics. JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION 2025; 36:513-544. [PMID: 39291361 DOI: 10.1080/09205063.2024.2402148] [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: 07/15/2024] [Accepted: 09/04/2024] [Indexed: 09/19/2024]
Abstract
Non-healing or chronic wounds in extremities that lead to amputations in patients with Type II diabetes (hyperglycemia) are among the most serious and common health problems in the modern world. Over the past decade, more efficient solutions for diabetic ulcers have been developed. Nanofibers and/or composite materials capable of drug delivery, moisture control, and antibacterial effectiveness are increasingly utilized in the formulation of wound dressings, with a particular focus on the biofunctionalization of polymeric and hydrogel materials. Natural products, including plant extracts, honey, antibacterial agents, nanozymes, and metal nanoparticles, are now commonly and effectively implemented to enhance the functionality of wound dressings. Due to the complicated and dysfunctional physiological structure of the chronic wound sites in the extremities of diabetic patients, formulated nanoscaffold or hydrogel components are becoming more intricate and versatile. This study aimed to investigate the development of wound dressing materials over the years while demonstrating their progressively enhanced complexity in effectively targeting, treating, and managing chronic wounds. The mechanisms of action and bio-functionality of wound dressing technologies were elucidated based on findings from 290 studies conducted over the last decade. A notable observation that emerged from these studies is the evolution of wound dressing development technology, which has led to significant advancements in the operational range of smart systems. These include, but are not limited to, self-healing, self-oxygenation, and adaptable mimicry of human tissue.
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Affiliation(s)
| | - Dzana Katana
- Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Casey M Yin
- Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
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Bahadoran Z, Mirmiran P, Hosseinpanah F, Kashfi K, Ghasemi A. Nitric oxide-based treatments improve wound healing associated with diabetes mellitus. Med Gas Res 2025; 15:23-35. [PMID: 39436167 PMCID: PMC11515056 DOI: 10.4103/mgr.medgasres-d-24-00020] [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: 03/12/2024] [Revised: 04/16/2024] [Accepted: 06/27/2024] [Indexed: 10/23/2024] Open
Abstract
Non-healing wounds are long-term complications of diabetes mellitus (DM) that increase mortality risk and amputation-related disability and decrease the quality of life. Nitric oxide (NO·)-based treatments (i.e., use of both systemic and topical NO· donors, NO· precursors, and NO· inducers) have received more attention as complementary approaches in treatments of DM wounds. Here, we aimed to highlight the potential benefits of NO·-based treatments on DM wounds through a literature review of experimental and clinical evidence. Various topical NO·-based treatments have been used. In rodents, topical NO·-based therapy facilitates wound healing, manifested as an increased healing rate and a decreased half-closure time. The wound healing effect of NO·-based treatments is attributed to increasing local blood flow, angiogenesis induction, collagen synthesis and deposition, re-epithelization, anti-inflammatory and anti-oxidative properties, and potent broad-spectrum antibacterial effects. The existing literature lacks human clinical evidence on the safety and efficacy of NO·-based treatments for DM wounds. Translating experimental favors of NO·-based treatments of DM wounds into human clinical practice needs conducting clinical trials with well-predefined effect sizes, i.e., wound reduction area, rate of wound healing, and hospital length of stay.
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Affiliation(s)
- Zahra Bahadoran
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parvin Mirmiran
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farhad Hosseinpanah
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Wang Z, Zhang D, Liu N, Wang J, Zhang Q, Zheng S, Zhang Z, Zhang W. A review on recent advances in polymeric microneedle loading cells: Design strategies, fabrication technologies, transdermal application and challenges. Int J Biol Macromol 2025; 297:138885. [PMID: 39719236 DOI: 10.1016/j.ijbiomac.2024.138885] [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: 06/24/2024] [Revised: 12/11/2024] [Accepted: 12/16/2024] [Indexed: 12/26/2024]
Abstract
Microneedle systems (MNs) loading living cells are a powerful platform to treat various previously incurable diseases in the era of precision medicine. Herein, an overview of recent advances in MN-based strategies for cell delivery is summarized, including material selection, design of morphological structures, and processing methods. We also systematically outlined the law of microstructural design relative to the structure-effective/function relationship in transdermal delivery or precision medicine and the design principles of cell microneedle (CMN). Furthermore, the representative works of precision treatments focusing on inflammatory skin diseases were tracked and discussed using CMN. Indeed, it highlights a practical path to solving the dilemma of cell therapy and raising the hope of precision medicine. However, there are still some challenges in developing CMN since they need multi-dimensional comprehensive properties, including mechanical properties, cell viability preservation, release, therapeutic effect, etc. The manuscript could provide insights into developing an innovative fit-to-purpose vehicle in cell therapy for interested researchers.
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Affiliation(s)
- Zixin Wang
- School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China
| | - Dongmei Zhang
- School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China; Collaborative Innovation Center of Fragrance Flavour and Cosmetics, School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China.
| | - Ningning Liu
- School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China
| | - Jiayi Wang
- School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China
| | - Qianjie Zhang
- School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China; Collaborative Innovation Center of Fragrance Flavour and Cosmetics, School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China
| | - Shilian Zheng
- School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China
| | - Zijia Zhang
- School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China
| | - Wanping Zhang
- School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China; Collaborative Innovation Center of Fragrance Flavour and Cosmetics, School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China.
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Ou S, Sima C, Liu Z, Li X, Chen B. Facilitation of diabetic wound healing by far upstream element binding protein 1 through augmentation of dermal fibroblast activity. Acta Diabetol 2025; 62:353-365. [PMID: 39412701 DOI: 10.1007/s00592-024-02360-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 08/08/2024] [Indexed: 03/04/2025]
Abstract
AIMS Diabetes mellitus (DM) often leads to wound healing complications, partly attributed to the accumulation of advanced glycosylation end products (AGEs) that impair fibroblast function. Far Upstream Element Binding Protein 1 (FUBP1) regulates cell proliferation, migration, and collagen synthesis. However, the impact of FUBP1 on diabetic wound healing remains unknown. This study is designed to explore the function and mechanisms of FUBP1 in diabetic wound healing. METHODS Eighteen Sprague-Dawley rats (weighing 220-240 g) were randomly assigned to three groups (n = 6): a control group (NC) of healthy rats, a model group (DM) of untreated diabetic rats, and a treatment group (DM + FUBP1) of diabetic rats accepting FUBP1 treatment. A 10 mm diameter circular full-thickness skin defect was created on the back of each rat. On days 1 and 7, rats in the treatment group received local injections of 5 µg FUBP1 protein at the wound site, whereas the control group and model group were administered saline. Wound healing was documented on days 0, 3, 7, 10, and 14, with tissue samples from the wound areas collected on day 14 for histological analysis, including H&E staining, Masson's trichrome staining, and immunohistochemistry. Western blot analysis was utilized to assess the expression of GSK-3β, Wnt3a, and β-catenin. In vitro, the effects of various concentrations of AGEs on cell viability and FUBP1 expression were examined in human dermal fibroblasts (HDF). Cells were genetically modified to overexpress FUBP1 using lentiviral vectors and were cultured for 48 h in media with or without AGEs. The impacts on fibroblast proliferation, migration, and Wnt/β-catenin signaling were evaluated using CCK-8, scratch assays, and Western blot analysis. RESULTS Animal investigation revealed that from day 7 onwards, the wound healing rate of the treatment group was higher than that of the model group but lower than the control group. On day 14, the wound healing rates were as follows: control group (0.97 ± 0.01), model group (0.84 ± 0.03), and treatment group (0.93 ± 0.01). These differences were statistically significant. Histological analysis indicates that FUBP1 promotes granulation tissue formation, re-epithelialization, and collagen deposition in treatment group. Additionally, FUBP1 protein expression decreased in dermal fibroblasts when exposed to AGEs. Overexpression of FUBP1 significantly enhanced fibroblast proliferation and migration, activating the Wnt/β-catenin pathway and mitigating the inhibitory effects of AGEs. CONCLUSIONS Our results suggest that FUBP1 can be a promising therapeutic target for diabetic wound healing, potentially counteracting the detrimental effects of AGEs on dermal fibroblasts through the Wnt/β-catenin pathway.
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Affiliation(s)
- Shali Ou
- Department of Burns and Plastic Surgery, Guangzhou Red Cross Hospital of Jinan University, No 369, Tongfu Middle Road, Guangzhou, Guangdong, China
- Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Chao Sima
- Department of Burns and Plastic Surgery, Guangzhou Red Cross Hospital of Jinan University, No 369, Tongfu Middle Road, Guangzhou, Guangdong, China
| | - Zhihe Liu
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Xiaojian Li
- Department of Burns and Plastic Surgery, Guangzhou Red Cross Hospital of Jinan University, No 369, Tongfu Middle Road, Guangzhou, Guangdong, China
| | - Bing Chen
- Department of Burns and Plastic Surgery, Guangzhou Red Cross Hospital of Jinan University, No 369, Tongfu Middle Road, Guangzhou, Guangdong, China.
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Wang X, Liu M, Wu Y, Sun J, Liu L, Pan Z. Gentiopicroside targeting AKT1 activates HIF-1α/VEGF axis promoting diabetic ulcer wound healing. Front Pharmacol 2025; 16:1506499. [PMID: 40078292 PMCID: PMC11897484 DOI: 10.3389/fphar.2025.1506499] [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: 10/05/2024] [Accepted: 02/10/2025] [Indexed: 03/14/2025] Open
Abstract
Backgound Gentiopicroside (GSP) have been proven to accelerate the healing of diabetic ulcers (DU), but the underlying molecular mechanisms remain unclear. This study aims to explore the mechanism by which GSP accelerates the healing of DU. Method The targets of GSP were firstly predicted using the SuperPred, SwissTargetPrediction, and Pharmmapper databases; DU-related transcriptome data were obtained from the GEO database, including GSE147890, GSE68183, and GSE199939; differential expression analysis was conducted using the Limma package, and DU-related targets were identified after summarization and de-duplication. Then, Potential targets for GSP treatment of DU were screened by Venn analysis; core targets for GSP treatment of DU were selected by constructing a protein-protein interaction (PPI) network; the mechanism of GSP treatment of DU was predicted by GO and KEGG enrichment analysis. Finally, the target binding of GSP to core targets was evaluated by molecular docking and CETSA assay, and in vitro experiments were conducted using L929 cells to validate the findings. Result A total of 538 targets of GSP and 10795 DU-related targets were predicted; Venn analysis identified 215 potential targets for GSP to accelerate DU wound healing; PPI network analysis suggested that AKT1 may be core targets for GSP treatment of DU; GO and KEGG enrichment analysis showed that pathways such as HIF-1 and VEGF are closely related to the treatment of DU with GSP, and it also participates in the regulation of various biological processes such as small molecule catabolism and leukocyte migration to exert its therapeutic effect on DU. Molecular docking and CETSA detection indicated that GSP can target bind to AKT1. The experimental results confirmed that GSP can significantly promote the proliferation and migration of L929 cells. Westen Blot results showed that GSP can accelerate DU wound healing via AKT1/HIF-1α/VEGF axis. Conclusion GSP target binding to AKT1 accelerates DU wound healing via the regulation of HIF-1α/VEGF axis.
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Affiliation(s)
- Xinxia Wang
- Department of Pharmacy, Shanghai Jiahui International Hospital Pharmacy, Shanghai, China
| | - Mingyan Liu
- Department of Opreating Room, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Yao Wu
- Department of Otolaryngology, 980th Hospital of The Joint Logistics Support Force, Shijiazhuang, Hebei, China
| | - Jianguo Sun
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Li Liu
- Department of Opreating Room, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Zheng Pan
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
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Deng Q, Du F, Pan S, Xia Y, Zhu Y, Zhang J, Li C, Yu S. Activation of angiopoietin-1 signaling with engineering mesenchymal stem cells promoted efficient angiogenesis in diabetic wound healing. Stem Cell Res Ther 2025; 16:75. [PMID: 39985096 PMCID: PMC11846275 DOI: 10.1186/s13287-025-04207-7] [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: 11/13/2024] [Accepted: 01/29/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Vascular insufficiency is associated with the pathogenesis and therapeutic outcomes of diabetic foot ulcers (DFU). While mesenchymal stem cells (MSCs) hold potential for DFU treatment, further enhancement in promoting angiogenesis in the challenging DFU wounds is imperative. METHODS The differential expression of pro- and anti-angiogenic factors during both normal and diabetic wound healing was compared using quantitative PCR. MSCs derived from the umbilical cord was prepared, and the engineered MSC (MSCANG1) overexpressing both the candidate pro-angiogenic gene, angiopoietin-1 (ANG1), and green fluorescent protein (GFP) was constructed using a lentiviral system. The pro-vascular stabilizing effects of MSCANG1 were assessed in primary endothelial cell cultures. Subsequently, MSCANG1 was transplanted into streptozotocin (STZ)-induced diabetic wound models to evaluate therapeutic effects on angiogenesis and wound healing. The underlying mechanisms were further examined both in vitro and in vivo. RESULTS The comprehensive analysis of the temporal expression of pro- and anti-angiogenic factors revealed a consistent impairment in ANG1 expression throughout diabetic wound healing. MSCANG1 exhibited robust EGFP expression in 80% of cells, with overexpression and secretion of the ANG1 protein. MSCANG1 notably enhanced the survival and tubulogenesis of endothelial cells and promoted the expression of junction proteins, facilitating the establishment of functional vasculature with improved vascular leakage. Although MSCANG1 did not enhance the survival of engrafted MSCs in diabetic wounds, it significantly promoted angiogenesis in diabetic wound healing, fostering the establishment of stable vasculature during the healing process. Activation of the protein kinase B (Akt) pathway and suppression of proto-oncogene tyrosine kinase Src (Src) activity in MSCANG1-treated diabetic wounds confirmed efficient angiogenesis process. Consequently, epidermal and dermal reconstruction, as well as skin appendage regeneration were markedly accelerated in MSCANG1-treated diabetic wounds compared to MSC-treated wounds. CONCLUSION Treatment with MSCs alone promotes angiogenesis and DFU healing, while the engineering of MSCs with ANG1 provides substantial additional benefits to this therapeutic process. The engineering of MSCs with ANG1 presents a promising avenue for developing innovative strategies in managing DFU.
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Affiliation(s)
- Qiong Deng
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu, China
| | - Fangzhou Du
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu, China
| | - Shenzhen Pan
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu, China
- Department of Vascular Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yuchen Xia
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu, China
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yuxin Zhu
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu, China
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Jingzhong Zhang
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu, China.
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
- Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Chenglong Li
- Department of Vascular Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Shuang Yu
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu, China.
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
- Xuzhou Medical University, Xuzhou, Jiangsu, China.
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