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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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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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Liao Y, Zhang Z, Zhao Y, Zhang S, Zha K, Ouyang L, Hu W, Zhou W, Sun Y, Liu G. Glucose oxidase: An emerging multidimensional treatment option for diabetic wound healing. Bioact Mater 2025; 44:131-151. [PMID: 39484022 PMCID: PMC11525048 DOI: 10.1016/j.bioactmat.2024.10.006] [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: 07/18/2024] [Revised: 10/06/2024] [Accepted: 10/06/2024] [Indexed: 11/03/2024] Open
Abstract
The healing of diabetic skin wounds is a complex process significantly affected by the hyperglycemic environment. In this context, glucose oxidase (GOx), by catalyzing glucose to produce gluconic acid and hydrogen peroxide, not only modulates the hyperglycemic microenvironment but also possesses antibacterial and oxygen-supplying functions, thereby demonstrating immense potential in the treatment of diabetic wounds. Despite the growing interest in GOx-based therapeutic strategies in recent years, a systematic summary and review of these efforts have been lacking. To address this gap, this review article outlines the advancements in the application of GOx and GOx-like nanozymes in the treatment of diabetic wounds, including reaction mechanisms, the selection of carrier materials, and synergistic therapeutic strategies such as multi-enzyme combinations, microneedle structures, and gas therapy. Finally, the article looks forward to the application prospects of GOx in aiding the healing of diabetic wounds and the challenges faced in translating these innovations to clinical practice. We sincerely hope that this review can provide readers with a comprehensive understanding of GOx-based diabetic treatment strategies, facilitate the rigorous construction of more robust multifunctional therapeutic systems, and ultimately benefit patients with diabetic wounds.
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Affiliation(s)
| | | | | | | | - Kangkang Zha
- Wuhan Union Hospital of Tongji Medical College of Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Jianghan District, Wuhan, Hubei, 430022, China
| | - Lizhi Ouyang
- Wuhan Union Hospital of Tongji Medical College of Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Jianghan District, Wuhan, Hubei, 430022, China
| | - Weixian Hu
- Wuhan Union Hospital of Tongji Medical College of Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Jianghan District, Wuhan, Hubei, 430022, China
| | - Wu Zhou
- Wuhan Union Hospital of Tongji Medical College of Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Jianghan District, Wuhan, Hubei, 430022, China
| | - Yun Sun
- Wuhan Union Hospital of Tongji Medical College of Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Jianghan District, Wuhan, Hubei, 430022, China
| | - Guohui Liu
- Wuhan Union Hospital of Tongji Medical College of Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Jianghan District, Wuhan, Hubei, 430022, China
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Huang Y, Xing H, Naud S, Kyriakides TR. Targeting hypoxia and thrombospondin-2 in diabetic wound healing. FASEB J 2024; 38:e70091. [PMID: 39383062 PMCID: PMC11486302 DOI: 10.1096/fj.202302429rrr] [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: 11/26/2023] [Revised: 08/19/2024] [Accepted: 09/23/2024] [Indexed: 10/11/2024]
Abstract
Impaired wound healing in diabetic patients is the leading cause of diabetes-associated hospitalizations and approximately 50% of lower limb amputations. This is due to multiple factors, including elevated glucose, sustained hypoxia, and cell dysfunction. Previously, diabetic wounds were found to contain excessive levels of the matricellular protein thrombospondin-2 (TSP2) and genetic ablation of TSP2 in diabetic mice or treatment of wounds with a hydrogel derived from TSP2-null mouse skin improved healing. Previously, TSP2 has been shown to be repressed by hypoxia, but in the present study we observed sustained hypoxia and overlapping TSP2 deposition in diabetic wounds. We determined this observation was due to the insufficient HIF-1α activation verified by western blot and immunofluorescent analysis of wound tissues and in vitro hypoxia experiments. Application of Dimethyloxalylglycine (DMOG), which can stabilize HIF-1α, inhibited TSP2 expression in diabetic fibroblasts in hypoxic conditions. Therefore, we prepared DMOG-containing TSP2KO hydrogel and applied it to the wounds of diabetic mice. In comparison to empty TSP2KO hydrogel or DMOG treatment, we observed improved wound healing associated with a reduction of TSP2, reduced hypoxia, and increased neovascularization. Overall, our findings shed light on the intricate interplay between hyperglycemia, hypoxia, and TSP2 in the complex environment of diabetic wounds.
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Affiliation(s)
- Yaqing Huang
- Department of Pathology, Yale University, New Haven, CT 06520, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06520, USA
| | - Hao Xing
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06520, USA
| | - Sophie Naud
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06520, USA
| | - Themis R. Kyriakides
- Department of Pathology, Yale University, New Haven, CT 06520, USA
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06520, USA
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Yadav JP, Verma A, Pathak P, Dwivedi AR, Singh AK, Kumar P, Khalilullah H, Jaremko M, Emwas AH, Patel DK. Phytoconstituents as modulators of NF-κB signalling: Investigating therapeutic potential for diabetic wound healing. Biomed Pharmacother 2024; 177:117058. [PMID: 38968797 DOI: 10.1016/j.biopha.2024.117058] [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: 04/15/2024] [Revised: 06/14/2024] [Accepted: 06/26/2024] [Indexed: 07/07/2024] Open
Abstract
The NF-κB pathway plays a pivotal role in impeding the diabetic wound healing process, contributing to prolonged inflammation, diminished angiogenesis, and reduced proliferation. In contrast to modern synthetic therapies, naturally occurring phytoconstituents are well-studied inhibitors of the NF-κB pathway that are now attracting increased attention in the context of diabetic wound healing because of lower toxicity, better safety and efficacy, and cost-effectiveness. This study explores recent research on phytoconstituent-based therapies and delve into their action mechanisms targeting the NF-κB pathway and potential for assisting effective healing of diabetic wounds. For this purpose, we have carried out surveys of recent literature and analyzed studies from prominent databases such as Science Direct, Scopus, PubMed, Google Scholar, EMBASE, and Web of Science. The classification of phytoconstituents into various categorie such as: alkaloids, triterpenoids, phenolics, polyphenols, flavonoids, monoterpene glycosides, naphthoquinones and tocopherols. Noteworthy phytoconstituents, including Neferine, Plumbagin, Boswellic acid, Genistein, Luteolin, Kirenol, Rutin, Vicenin-2, Gamma-tocopherol, Icariin, Resveratrol, Mangiferin, Betulinic acid, Berberine, Syringic acid, Gallocatechin, Curcumin, Loureirin-A, Loureirin-B, Lupeol, Paeoniflorin, and Puerarin emerge from these studies as promising agents for diabetic wound healing through the inhibition of the NF-κB pathway. Extensive research on various phytoconstituents has revealed how they modulate signalling pathways, including NF-κB, studies that demonstrate the potential for development of therapeutic phytoconstituents to assist healing of chronic diabetic wounds.
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Affiliation(s)
- Jagat Pal Yadav
- Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, India; Pharmacology Research Laboratory, Faculty of Pharmaceutical Sciences, Rama University, Kanpur 209217, India; Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, India.
| | - Amita Verma
- Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, India
| | - Prateek Pathak
- Department of Pharmaceutical Analysis, Quality Assurance and Pharmaceutical Chemistry, GITAM School of Pharmacy, GITAM (Deemed to be University), Hyderabad Campus, 502329, India
| | - Ashish R Dwivedi
- Department of Pharmaceutical Analysis, Quality Assurance and Pharmaceutical Chemistry, GITAM School of Pharmacy, GITAM (Deemed to be University), Hyderabad Campus, 502329, India
| | - Ankit Kumar Singh
- Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, India; Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Habibullah Khalilullah
- Department of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Unayzah 51911, Saudi Arabia
| | - Mariusz Jaremko
- Smart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Abdul-Hamid Emwas
- Core Labs, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Dinesh Kumar Patel
- Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, India.
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Wen JP, Ou SJ, Liu JB, Zhang W, Qu YD, Li JX, Xia CL, Yang Y, Qi Y, Xu CP. Global trends in publications regarding macrophages-related diabetic foot ulcers in the last two decades. World J Diabetes 2024; 15:1627-1644. [PMID: 39099825 PMCID: PMC11292333 DOI: 10.4239/wjd.v15.i7.1627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/12/2024] [Accepted: 06/12/2024] [Indexed: 07/08/2024] Open
Abstract
BACKGROUND Diabetic foot ulcers (DFUs) are one of the most severe and popular complications of diabetes. The persistent non-healing of DFUs is the leading cause of ampu-tation, which causes significant mental and financial stress to patients and their families. Macrophages are critical cells in wound healing and perform essential roles in all phases of wound healing. However, no studies have been carried out to systematically illustrate this area from a scientometric point of view. Although there have been some bibliometric studies on diabetes, reports focusing on the investigation of macrophages in DFUs are lacking. AIM To perform a bibliometric analysis to systematically assess the current state of research on macrophage-related DFUs. METHODS The publications of macrophage-related DFUs from January 1, 2004, to December 31, 2023, were retrieved from the Web of Science Core Collection on January 9, 2024. Four different analytical tools: VOSviewer (v1.6.19), CiteSpace (v6.2.R4), HistCite (v12.03.07), and Excel 2021 were used for the scientometric research. RESULTS A total of 330 articles on macrophage-related DFUs were retrieved. The most published countries, institutions, journals, and authors in this field were China, Shanghai Jiao Tong University of China, Wound Repair and Regeneration, and Aristidis Veves. Through the analysis of keyword co-occurrence networks, historical direct citation networks, thematic maps, and trend topics maps, we synthesized the prevailing research hotspots and emerging trends in this field. CONCLUSION Our bibliometric analysis provides a comprehensive overview of macrophage-related DFUs research and insights into promising upcoming research.
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Affiliation(s)
- Jian-Ping Wen
- Department of Orthopaedics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510000, Guangdong Province, China
| | - Shuan-Ji Ou
- Department of Orthopaedics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510000, Guangdong Province, China
| | - Jia-Bao Liu
- Department of Orthopaedics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510000, Guangdong Province, China
| | - Wei Zhang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510000, Guangdong Province, China
| | - Yu-Dun Qu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510000, Guangdong Province, China
| | - Jia-Xuan Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510000, Guangdong Province, China
| | - Chang-Liang Xia
- Department of Orthopaedics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510000, Guangdong Province, China
| | - Yang Yang
- Department of Orthopaedics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510000, Guangdong Province, China
| | - Yong Qi
- Department of Orthopaedics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510000, Guangdong Province, China
| | - Chang-Peng Xu
- Department of Orthopaedics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510000, Guangdong Province, China
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Qin S, Bie F, Chen S, Xu Y, Chen L, Shu B, Yang F, Lu Y, Li J, Zhao J. Targeting S100A12 to Improve Angiogenesis and Accelerate Diabetic Wound Healing. Inflammation 2024:10.1007/s10753-024-02073-8. [PMID: 38954262 DOI: 10.1007/s10753-024-02073-8] [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: 02/24/2024] [Revised: 05/31/2024] [Accepted: 06/02/2024] [Indexed: 07/04/2024]
Abstract
Long-term inflammation and impaired angiogenesis are thought to be the causes of delayed healing or nonhealing of diabetic wounds. S100A12 is an essential pro-inflammatory factor involved in inflammatory reactions and serves as a biomarker for various inflammatory diseases. However, whether high level of S100A12 exists in and affects the healing of diabetic wounds, as well as the underlying molecular mechanisms, remain unclear. In this study, we found that the serum concentration of S100A12 is significantly elevated in patients with type 2 diabetes. Exposure of stratified epidermal cells to high glucose environment led to increased expression and secretion of S100A12, resulting in impaired endothelial function by binding to the advanced glycation endproducts (RAGE) or Toll-like receptor 4 (TLR4) on endothelial cell. The transcription factor Krüpple-like Factor 5 (KLF5) is highly expressed in the epidermis under high glucose conditions, activating the transcriptional activity of the S100A12 and boost its expression. By establishing diabetic wounds model in alloxan-induced diabetic rabbit, we found that local inhibition of S100A12 significantly accelerated diabetic wound healing by promoting angiogenesis. Our results illustrated the novel endothelial-specific injury function of S100A12 in diabetic wounds and suggest that S100A12 is a potential target for the treatment of diabetic wounds.
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Affiliation(s)
- Shitian Qin
- Department of Burns, Wound Repair and Reconstruction, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong Province, 510080, PR China
| | - Fan Bie
- Department of Burns, Wound Repair and Reconstruction, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong Province, 510080, PR China
| | - Shuying Chen
- Department of Burns, Wound Repair and Reconstruction, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong Province, 510080, PR China
| | - Yingbin Xu
- Department of Burns, Wound Repair and Reconstruction, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong Province, 510080, PR China
| | - Lei Chen
- Department of Burns, Wound Repair and Reconstruction, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong Province, 510080, PR China
| | - Bin Shu
- Department of Burns, Wound Repair and Reconstruction, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong Province, 510080, PR China
| | - Fan Yang
- Department of Burns, Wound Repair and Reconstruction, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong Province, 510080, PR China
| | - Yangzhou Lu
- Department of Burns, Wound Repair and Reconstruction, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong Province, 510080, PR China
| | - Jialin Li
- Department of Intensive Care Unit, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong Province, 510080, PR China
| | - Jingling Zhao
- Department of Burns, Wound Repair and Reconstruction, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2 Road, Guangzhou, Guangdong Province, 510080, PR China.
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Su Y, Ye B, Zhang Z, Gao Q, Zeng L, Wan Y, Sun W, Chen S, Quan D, Yu J, Guo X. Photocatalytic oxygen evolution and antibacterial biomimetic repair membrane for diabetes wound repair via HIF1-α pathway. Mater Today Bio 2023; 20:100616. [PMID: 37025556 PMCID: PMC10070145 DOI: 10.1016/j.mtbio.2023.100616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/26/2023] [Accepted: 03/19/2023] [Indexed: 03/31/2023] Open
Abstract
Diabetic wounds always have puzzled patients and caused serious social problems. Due to the lack of local blood vessels, severe hypoxia is generated in the defect area, which is an essential reason for the difficulty of wound healing. We have constructed a photocatalytic oxygen evolution and antibacterial biomimetic repair membrane to solve the problems of wound repair. A scanning electron microscope and transmission electron microscope characterized the biomimetic repair membrane. The oxygen evolution of the biomimetic membrane was tested by an oxygen meter. The excellent antibacterial performance of the biomimetic repair membrane was also verified by co-culture with Staphylococcus aureus and Escherichia coli. It was confirmed that the expression of collagen and HIF1-α in fibroblasts was significantly increased in vitro. And the mitochondrial activity of the vascular and nerve was increased considerably. In vivo, the healing time of diabetes wounds treated with the biomimetic repair membrane was significantly reduced, the collagen and the number of pores were increased considerably, and vascular regeneration was enhanced. The biomimetic repair membrane has an excellent performance in photocatalytic oxygen evolution and antibacterial and can significantly promote the repair of diabetes wounds. This will provide a promising treatment for diabetes wound repair.
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Affiliation(s)
- Yanlin Su
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong Univer sity of Science and Technology, Wuhan, Hubei, 430022, China
| | - Bing Ye
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong Univer sity of Science and Technology, Wuhan, Hubei, 430022, China
| | - Ziming Zhang
- Department of Orthopedics, Zaoyang First People's Hospital, Zaoyang, Hubei, 430022, China
| | - Qing Gao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong Univer sity of Science and Technology, Wuhan, Hubei, 430022, China
| | - Lian Zeng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong Univer sity of Science and Technology, Wuhan, Hubei, 430022, China
| | - Yizhou Wan
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong Univer sity of Science and Technology, Wuhan, Hubei, 430022, China
| | - Wenzhe Sun
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong Univer sity of Science and Technology, Wuhan, Hubei, 430022, China
| | - Siyue Chen
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Daping Quan
- PCFM Lab, School of Chemistry and School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, Guangdong, 510000, China
| | - Jialin Yu
- The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, 430022, China
| | - Xiaodong Guo
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong Univer sity of Science and Technology, Wuhan, Hubei, 430022, China
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Zheng SY, Wan XX, Kambey PA, Luo Y, Hu XM, Liu YF, Shan JQ, Chen YW, Xiong K. Therapeutic role of growth factors in treating diabetic wound. World J Diabetes 2023; 14:364-395. [PMID: 37122434 PMCID: PMC10130901 DOI: 10.4239/wjd.v14.i4.364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/16/2023] [Accepted: 03/21/2023] [Indexed: 04/12/2023] Open
Abstract
Wounds in diabetic patients, especially diabetic foot ulcers, are more difficult to heal compared with normal wounds and can easily deteriorate, leading to amputation. Common treatments cannot heal diabetic wounds or control their many complications. Growth factors are found to play important roles in regulating complex diabetic wound healing. Different growth factors such as transforming growth factor beta 1, insulin-like growth factor, and vascular endothelial growth factor play different roles in diabetic wound healing. This implies that a therapeutic modality modulating different growth factors to suit wound healing can significantly improve the treatment of diabetic wounds. Further, some current treatments have been shown to promote the healing of diabetic wounds by modulating specific growth factors. The purpose of this study was to discuss the role played by each growth factor in therapeutic approaches so as to stimulate further therapeutic thinking.
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Affiliation(s)
- Shen-Yuan Zheng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
| | - Xin-Xing Wan
- Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Piniel Alphayo Kambey
- Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Yan Luo
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Xi-Min Hu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
| | - Yi-Fan Liu
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Jia-Qi Shan
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Yu-Wei Chen
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
- Key Laboratory of Emergency and Trauma, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, Hainan Province, China
- Hunan Key Laboratory of Ophthalmology, Central South University, Changsha 410013, Hunan Province, China
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10
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Li Q, Wang D, Jiang Z, Li R, Xue T, Lin C, Deng Y, Jin Y, Sun B. Advances of hydrogel combined with stem cells in promoting chronic wound healing. Front Chem 2022; 10:1038839. [PMID: 36518979 PMCID: PMC9742286 DOI: 10.3389/fchem.2022.1038839] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/07/2022] [Indexed: 08/15/2023] Open
Abstract
Wounds can be divided into two categories, acute and chronic. Acute wounds heal through the normal wound healing process. However, chronic wounds take longer to heal, leading to inflammation, pain, serious complications, and an economic burden of treatment costs. In addition, diabetes and burns are common causes of chronic wounds that are difficult to treat. The rapid and thorough treatment of chronic wounds, including diabetes wounds and burns, represents a significant unmet medical need. Wound dressings play an essential role in chronic wound treatment. Various biomaterials for wound healing have been developed. Among these, hydrogels are widely used as wound care materials due to their good biocompatibility, moisturizing effect, adhesion, and ductility. Wound healing is a complex process influenced by multiple factors and regulatory mechanisms in which stem cells play an important role. With the deepening of stem cell and regenerative medicine research, chronic wound treatment using stem cells has become an important field in medical research. More importantly, the combination of stem cells and stem cell derivatives with hydrogel is an attractive research topic in hydrogel preparation that offers great potential in chronic wound treatment. This review will illustrate the development and application of advanced stem cell therapy-based hydrogels in chronic wound healing, especially in diabetic wounds and burns.
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Affiliation(s)
- Qirong Li
- Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Ziping Jiang
- Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, China
| | - Rong Li
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Tianyi Xue
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Chao Lin
- School of Grain Science and Technology, Jilin Business and Technology College, Changchun, China
| | - Yongzhi Deng
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Ye Jin
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Baozhen Sun
- Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
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11
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Cutaneous innervation in impaired diabetic wound healing. Transl Res 2021; 236:87-108. [PMID: 34029747 PMCID: PMC8380642 DOI: 10.1016/j.trsl.2021.05.003] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes is associated with several potential comorbidities, among them impaired wound healing, chronic ulcerations, and the requirement for lower extremity amputation. Disease-associated abnormal cellular responses, infection, immunological and microvascular dysfunction, and peripheral neuropathy are implicated in the pathogenesis of the wound healing impairment and the diabetic foot ulcer. The skin houses a dense network of sensory nerve afferents and nerve-derived modulators, which communicate with epidermal keratinocytes and dermal fibroblasts bidirectionally to effect normal wound healing after trauma. However, the mechanisms through which cutaneous innervation modulates wound healing are poorly understood, especially in humans. Better understanding of these mechanisms may provide the basis for targeted treatments for chronic diabetic wounds. This review provides an overview of wound healing pathophysiology with a focus on neural involvement in normal and diabetic wound healing, as well as future therapeutic perspectives to address the unmet needs of diabetic patients with chronic wounds.
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12
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Colak B, Yormaz S, Ece I, Sahin M. Can Intralesional Epidermal Growth Factor Reduce Skin Graft Applications in Patients with Diabetic Foot Ulcer? J Am Podiatr Med Assoc 2021; 111. [PMID: 34861684 DOI: 10.7547/19-027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Diabetic foot ulcer (DFU) is a serious health problem. Major amputation increases the risk of mortality in patients with DFU; therefore, treatment methods other than major amputation come to the fore for these patients. Graft applications create an appropriate environment for the reproduction of epithelial cells. Similarly, epidermal growth factor (EGF) also stimulates epithelization and increases epidermis formation. In this study, we aimed to compare patients with DFU treated with EGF and those treated with a split-thickness skin graft. METHODS Patients who were treated for DFU in the general surgery clinic were included in the study. The patients were evaluated retrospectively according to their demographic characteristics, wound characteristics, duration of treatment, and treatment modalities. RESULTS There were 26 patients in the EGF group and 21 patients in the graft group. The mean duration of treatment was 7 weeks (4-8 weeks) in the EGF group and 5.3 weeks (4-8 weeks) in the graft group (P < .05). In the EGF group, wound healing could not be achieved in one patient during the study period. In the graft group, no recovery was achieved in three patients (14.2%) in the donor site. Graft loss was detected in four patients (19%), and partial graft loss was observed in three patients (14.2%). The DFU of these patients were on the soles (85.7%). These patients have multiple comorbidities. CONCLUSIONS EGF application may be preferred to avoid graft complications in the graft area and the donor site, especially in elderly patients with multiple comorbidities and wounds on the soles.
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13
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Adhenkavil Radhakrishnan R, Joseph Vadakkekuttical R, Radhakrishnan C. Proportion and severity of periodontitis and correlation of periodontal inflamed surface area with glycemic status in patients with type 2 diabetic neuropathy with and without diabetic foot. J Periodontol 2021; 93:687-696. [PMID: 34460108 DOI: 10.1002/jper.21-0174] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/30/2021] [Accepted: 08/23/2021] [Indexed: 11/06/2022]
Abstract
BACKGROUND The association between diabetic neuropathy with and without diabetic foot and periodontitis remains unaddressed in the literature. The present study was conducted to evaluate the frequency of patients with periodontitis and its severity, and to correlate clinical attachment loss (AL) and periodontal inflamed surface area (PISA) with HbA1c in Type 2 Diabetic Neuropathy (T2DN) patients with and without diabetic foot. METHODS In this cross-sectional study 310 patients with type 2 diabetic neuropathy (T2DN) were randomly selected, and the study comprised of 120 patients with T2DN with diabetic foot and 155 patients with T2DN without diabetic foot. All patients were assessed for periodontal parameters (bleeding on probing, probing depth, clinical AL, oral hygiene index-simplified), plaque index, and PISA) and systemic parameters (HbA1c, fasting blood glucose, post prandial blood glucose, urinary albumin creatine ratio, erythrocyte sedimentation rate, and high-sensitivity C-reactive protein).Unpaired t-test and Chi-Square test were used to analyze quantitative data and qualitative data, respectively. RESULTS The frequency of patients with periodontitis in patients with T2DN with and without diabetic foot was 91.7% and 88.4%, respectively. The severity of periodontitis, PISA, and clinical AL were higher in the diabetic foot group. Clinical AL and PISA were significantly related with HbA1c in patients with T2DN with and without diabetic foot. CONCLUSIONS Percentage of patients with periodontitis and the severity of periodontal destruction were high in type 2 diabetic neuropathy with diabetic foot. A significant correlation of PISA, clinical AL with glycemic status was found in patients with T2DN with and without diabetic foot.
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14
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Chantelau EA. A Novel Diagnostic Test for End-Stage Sensory Failure Associated With Diabetic Foot Ulceration: Proof-of-Principle Study. J Diabetes Sci Technol 2021; 15:622-629. [PMID: 31948277 PMCID: PMC8111226 DOI: 10.1177/1932296819900256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Diabetic foot ulceration (DFU) affects only a subgroup of patients with diabetic neuropathy, that is, those with pain-insensitivity due to end-stage sensory failure. Pain perception failure develops insidiously and remains asymptomatic until first DFU. As loss of pain perception is clinically significant, timely detection is mandatory. OBJECTIVES A novel suprathreshold pinprick pain stimulus of 512 mN force made from optical glass-fiber was explored in a prospective cross-sectional diagnostic accuracy study to detect DFU-related end-stage sensory failure. METHODS A total of 116 participants were studied (25 healthy people, 22 patients with diabetes without relevant complications, 19 patients with previous painful foot or leg injuries, and 50 patients with previous or active painless DFU [reference standard]). Palmar and plantar surfaces were stimulated in a standardized fashion. At the feet, the second and third toe skinfolds and the middle of the plantar arch were stimulated. Participants scored stimulated pricking discomfort or pain intensity 0 to 10 on a numerical rating scale. RESULTS At hands, intensity was rated on average 5 (1-10) [median (range)] by 114/116 participants. Per foot, participants without DFU scored 5 (1-10), while those with DFU scored 0 (0-3) (P < .0001). At plantar toe skinfolds, the absence of pinprick pain perception detected DFU-associated sensory failure with an accuracy of 99.5% (sensitivity 99.5%, specificity 99.4%, positive likelihood ratio 248, and negative likelihood ratio 0.005). CONCLUSION In this pilot study, nociceptive stimulation of a plantar toe skinfold with a 512 mN optical glass-fiber pinprick accurately identified DFU-associated end-stage sensory failure.
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Affiliation(s)
- Ernst-Adolf Chantelau
- Heinrich-Heine-University, Düsseldorf,
Germany
- Practice of Endocrinology and
Diabetology PD Dr.Kimmerle, Aachener, Düsseldorf, Germany
- Ernst-Adolf Chantelau, MD, PhD, Holthorster
Weg 16, Bremen 28717, Germany.
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15
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Gkotsoulias E. Split Thickness Skin Graft of the Foot and Ankle Bolstered With Negative Pressure Wound Therapy in a Diabetic Population: The Results of a Retrospective Review and Review of the Literature. Foot Ankle Spec 2020; 13:383-391. [PMID: 31370687 PMCID: PMC7493201 DOI: 10.1177/1938640019863267] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Split thickness skin graft (STSG) is a versatile procedure performed for the treatment of wounds resulting from varying pathology. This remains very useful because of its ability for quick healing and low complication rate. The surface of the foot and ankle is an area frequently affected by severe skin and soft tissue structure infections (SSTIs) whose treatment results in wounds. These infections and resultant surgical wounds are commonly seen patients with diabetes. The objective of the present study was to retrospectively evaluate initial healing and immediate post-operative outcomes following STSG application in a diabetic population when negative pressure wound therapy (NPWT) was used as a bolster. Ten patients were identified, including 11 surgical wounds, who underwent STSG bolstered with NPWT from January 2016 to October 2018. Mean follow-up was 13 months (range 1-33 months) with an average time to heal of 17 days (range 14-30 days) for 11 surgical wounds averaging 57 cm2 (range 6.3 - 91 cm2). Consistent improved outcomes have been demonstrated when compared to alternative bolstering techniques available in the literature making a STSG bolstered with NPWT a powerful tool in the reconstruction of diabetic foot wounds resulting from the treatment of infection.Levels of Evidence: Level IV.
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16
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Nie X, Zhao J, Ling H, Deng Y, Li X, He Y. Exploring microRNAs in diabetic chronic cutaneous ulcers: Regulatory mechanisms and therapeutic potential. Br J Pharmacol 2020; 177:4077-4095. [PMID: 32449793 PMCID: PMC7443474 DOI: 10.1111/bph.15139] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 05/04/2020] [Accepted: 05/07/2020] [Indexed: 12/12/2022] Open
Abstract
Diabetic chronic cutaneous ulcers (DCU) are one of the serious complications of diabetes mellitus, occurring mainly in diabetic patients with peripheral neuropathy. Recent studies have indicated that microRNAs (miRNAs/miRs) and their target genes are essential regulators of cell physiology and pathology including biological processes that are involved in the regulation of diabetes and diabetes-related microvascular complications. in vivo and in vitro models have revealed that the expression of some miRNAs can be regulated in the inflammatory response, cell proliferation, and wound remodelling of DCU. Nevertheless, the potential application of miRNAs to clinical use is still limited. Here, we provide a contemporary overview of the miRNAs as well as their associated target genes and pathways (including Wnt/β-catenin, NF-κB, TGF-β/Smad, and PI3K/AKT/mTOR) related to DCU healing. We also summarize the current development of drugs for DCU treatment and discuss the therapeutic challenges of DCU treatment and its future research directions.
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Affiliation(s)
- Xuqiang Nie
- Key Laboratory of Basic Pharmacology of Ministry of EducationZunyi Medical UniversityZunyiChina
- College of PharmacyZunyi Medical UniversityZunyiChina
- Institute of Materia Medica, College of PharmacyThird Military Medical UniversityChongqingChina
| | - Jiufeng Zhao
- Key Laboratory of Basic Pharmacology of Ministry of EducationZunyi Medical UniversityZunyiChina
| | - Hua Ling
- School of PharmacyGeorgia Campus ‐ Philadelphia College of Osteopathic MedicineSuwaneeGAUSA
| | - Youcai Deng
- Institute of Materia Medica, College of PharmacyThird Military Medical UniversityChongqingChina
| | - Xiaohui Li
- Institute of Materia Medica, College of PharmacyThird Military Medical UniversityChongqingChina
| | - Yuqi He
- Key Laboratory of Basic Pharmacology of Ministry of EducationZunyi Medical UniversityZunyiChina
- College of PharmacyZunyi Medical UniversityZunyiChina
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17
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Çetinkaya ÖA, Çelik SU, Erzincan MB, Hazır B, Uncu H. Intralesional epidermal growth factor application is a potential therapeutic strategy to improve diabetic foot ulcer healing and prevent amputation. Turk J Surg 2020; 36:15-22. [PMID: 32637871 DOI: 10.5578/turkjsurg.4541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 08/27/2019] [Indexed: 12/25/2022]
Abstract
Objectives This study aimed to investigate the efficacy of intralesional epidermal growth factor (EGF) in preventing the extremity from a major amputation and its effects on wound healing in chronic diabetic foot ulcers (DFUs). Material and Methods Thirty-three patients with DFUs were treated with intralesional EGF application between January 2013 and January 2017. The first endpoint was to determine the prevention rate of major amputation within 12 months following treatment. The second endpoints were the recovery of ulcer surface area with ≥ 50% granulation following two months and the healing of ulcer surface area with ≥ 75% granulation following six months after the first application of EGF. Results After three patients were excluded because of major side effects in the remaining 30 patients (48 DFUs), granulation rate of ≥ 50% was achieved in 24 (37 DFUs) patients, and not achieved in 6 (11 DFUs) patients eight weeks following the EGF application. A granulation rate of ≥ 75% was achieved in 21 (31 DFUs) patients after six months. At 12 months following the treatment, one major and seven minor amputations were performed, a total of 10 DFUs in five patients were not healed, and the DFUs in 17 patients completely recovered. Conclusion Intralesional EGF application has positive results in addition to good foot care in DFUs, and promising results can be obtained by protecting the extremity from amputation by using it in patients whose vascular intervention methods are not appropriate and have DFUs that do not heal with conventional wound care treatments.
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Affiliation(s)
- Ömer Arda Çetinkaya
- Department of General Surgery, Ankara University School of Medicine, Ankara, Turkey
| | - Süleyman Utku Çelik
- Clinic of General Surgery, Gulhane Training and Research Hospital, Ankara, Turkey
| | - Miraç Barış Erzincan
- Department of General Surgery, Ankara University School of Medicine, Ankara, Turkey
| | - Barış Hazır
- Department of General Surgery, Ankara University School of Medicine, Ankara, Turkey
| | - Hakan Uncu
- Department of General Surgery, Ankara University School of Medicine, Ankara, Turkey
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18
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Tan JS, Lin CC, Chen GS. Vasomodulation of peripheral blood flow by focused ultrasound potentiates improvement of diabetic neuropathy. BMJ Open Diabetes Res Care 2020; 8:8/1/e001004. [PMID: 32188594 PMCID: PMC7078690 DOI: 10.1136/bmjdrc-2019-001004] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 01/31/2020] [Accepted: 02/22/2020] [Indexed: 01/25/2023] Open
Abstract
OBJECTIVE Effective treatment methods for diabetic peripheral neuropathy are still lacking. Here, a focused ultrasound (FUS) technique was developed to improve blood flow in diabetic peripheral vessels and potentially treat diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS Male adult Sprague-Dawley rats at 4 weeks poststreptozotocin injections were adopted as models for diabetic neuropathic rats. For single FUS treatment, blood perfusion in the skin of the pad of the middle toe was measured before, during, and after the medial and lateral plantar arteries were treated by FUS. For multiple FUS treatments, blood perfusion measurements, von Frey and hot plate testing and nerve conduction velocity measurements were performed before ultrasonic treatment on the first day of each week, and the microvascular and neural fiber densities in the pad of the toe were measured on the first day of the last week. RESULTS The blood perfusion rate significantly increased for 7-10 min in the control and neuropathic rats after a single ultrasound exposure. Multiple ultrasound treatments compared with no treatments significantly increased blood perfusion at the second week and further enhanced perfusion at the third week in the neuropathic rats. Additionally, the paw withdrawal force and latency significantly increased from 34.33±4.55 g and 3.96±0.25 s at the first week to 39.10±5.02 g and 4.77±0.71 s at the second week and to 41.13±2.57 g and 5.24±0.86 s at the third week, respectively. The low nerve conduction velocity in the diabetic rats also improved after the ultrasound treatments. Additionally, ultrasound treatments halted the decrease in microvessel and neural fiber densities in the skin of the diabetic toes. Histologic analysis indicated no damage to the treated arteries or neighboring tissue. CONCLUSIONS FUS treatment can increase upstream arterial blood flow in diabetic feet, ameliorate the decrease in downstream microvessel perfusion and halt neuropathic progression.
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Affiliation(s)
- Joo-Shin Tan
- Department of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan
| | - Chou-Ching Lin
- Department of Neurology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Gin-Shin Chen
- Department of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan
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19
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Sharma S, Schaper N, Rayman G. Microangiopathy: Is it relevant to wound healing in diabetic foot disease? Diabetes Metab Res Rev 2020; 36 Suppl 1:e3244. [PMID: 31845461 DOI: 10.1002/dmrr.3244] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 11/18/2019] [Indexed: 12/15/2022]
Abstract
Chronic diabetic complications - both microvascular and macrovascular - have become serious health issues with their increasing prevalence paralleling the dramatic rise of the diabetic population worldwide. Of these complications, foot disease is a major cause of morbidity and mortality, consuming more health care resource than all other complications combined. Diabetic polyneuropathy and peripheral vascular disease constitute the two main risk factors, with trauma and foot infection being the most important initiating factors and contributors to delayed healing. Intracellular oxidative stress mediated by hyperglycaemia along with hypertension, dyslipidaemia and smoking constitute the main pathological processes in the aetiology of both macrovascular and microvascular disease. Whilst the former remains the major cause of overall mortality in diabetes, the role of microangiopathy in the pathogenesis of diabetes foot disease and its contribution to delayed wound healing in diabetes has yet to be fully understood and indeed continues to be debated. This article will review the key findings to date on structural and functional microvascular abnormalities in the diabetic foot skin and consider their contribution to impaired would healing.
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Affiliation(s)
- Sanjeev Sharma
- Diabetes Research unit, Ipswich Hospital, East Suffolk and North Essex NHS Foundation Trust, Ipswich, UK
| | - Nicolaas Schaper
- Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, Netherlands
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20
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Yang Q, Zhang Y, Yin H, Lu Y. Topical Recombinant Human Epidermal Growth Factor for Diabetic Foot Ulcers: A Meta-Analysis of Randomized Controlled Clinical Trials. Ann Vasc Surg 2020; 62:442-451. [DOI: 10.1016/j.avsg.2019.05.041] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 04/01/2019] [Accepted: 05/18/2019] [Indexed: 01/13/2023]
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21
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Loader J, Khouri C, Taylor F, Stewart S, Lorenzen C, Cracowski JL, Walther G, Roustit M. The continuums of impairment in vascular reactivity across the spectrum of cardiometabolic health: A systematic review and network meta-analysis. Obes Rev 2019; 20:906-920. [PMID: 30887713 DOI: 10.1111/obr.12831] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 01/03/2019] [Accepted: 01/03/2019] [Indexed: 12/12/2022]
Abstract
This study aimed to assess, for the first time, the change in vascular reactivity across the full spectrum of cardiometabolic health. Systematic searches were conducted in MEDLINE and EMBASE databases from their inception to March 13, 2017, including studies that assessed basal vascular reactivity in two or more of the following health groups (aged ≥18 years old): healthy, overweight, obesity, impaired glucose tolerance, metabolic syndrome, or type 2 diabetes with or without complications. Direct and indirect comparisons of vascular reactivity were combined using a network meta-analysis. Comparing data from 193 articles (7226 healthy subjects and 19344 patients), the network meta-analyses revealed a progressive impairment in vascular reactivity (flow-mediated dilation data) from the clinical onset of an overweight status (-0.41%, 95% CI, -0.98 to 0.15) through to the development of vascular complications in those with type 2 diabetes (-4.26%, 95% CI, -4.97 to -3.54). Meta-regressions revealed that for every 1 mmol/l increase in fasting blood glucose concentration, flow-mediated dilation decreased by 0.52%. Acknowledging that the time course of disease may vary between patients, this study demonstrates multiple continuums of vascular dysfunction where the severity of impairment in vascular reactivity progressively increases throughout the pathogenesis of obesity and/or insulin resistance, providing information that is important to enhancing the timing and effectiveness of strategies that aim to improve cardiovascular outcomes.
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Affiliation(s)
- Jordan Loader
- Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Australia.,Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia.,LAPEC EA4278, Avignon Université, Avignon, France
| | - Charles Khouri
- Inserm U1042, Université Grenoble Alpes, Grenoble, France.,Clinical Pharmacology, Grenoble Alpes University Hospital, Grenoble, France
| | - Frances Taylor
- Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia
| | - Simon Stewart
- Hatter Institute for Reducing Cardiovascular Disease in Africa, The University of Cape Town, Cape Town, South Africa
| | - Christian Lorenzen
- School of Exercise Science, Australian Catholic University, Melbourne, Australia
| | - Jean-Luc Cracowski
- Inserm U1042, Université Grenoble Alpes, Grenoble, France.,Clinical Pharmacology, Grenoble Alpes University Hospital, Grenoble, France
| | - Guillaume Walther
- LAPEC EA4278, Avignon Université, Avignon, France.,School of Exercise Science, Australian Catholic University, Melbourne, Australia
| | - Matthieu Roustit
- Inserm U1042, Université Grenoble Alpes, Grenoble, France.,Clinical Pharmacology, Grenoble Alpes University Hospital, Grenoble, France
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22
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Liu T, Wang Z, Chen X, You H, Xue J, Cai D, Zheng Y, Xu Y, Luo D. Low molecular-weight fucoidan protects against hindlimb ischemic injury in type 2 diabetic mice through enhancing endothelial nitric oxide synthase phosphorylation. J Diabetes 2018; 10:820-834. [PMID: 29633569 DOI: 10.1111/1753-0407.12667] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Revised: 02/22/2018] [Accepted: 03/27/2018] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Diabetes mellitus (DM) complications are associated with ischemic injury. Angiogenesis is a therapeutic strategy for diabetic foot. The aim of this study was to investigate the possible angiogenic effect of low molecular weight fucoidan (LMWF) in diabetic peripheral arterial disease (PAD). METHODS Diabetic db/db mice and age-matched C57BL/6 mice underwent femoral artery ligation followed by LMWF (30, 60, 80 mg/kg per day, p.o.) or cilostazol (30 mg/kg/day, p.o.) treatment for 6 weeks. Endothelium-dependent vasodilation and blood flow of the hindlimb were measured. Histological and western blot analyses of CD34, vascular endothelial growth factor (VEGF), eNOS, and inflammatory factors in the gastrocnemius were performed. The effects of LMWF were confirmed in human umbilical vein endothelial cells (HUVEC). RESULTS Diabetic mice with ligation exhibited hindlimb ulceration, hydrosarca, and necrosis, increased expression of inflammatory factors, and decreased levels of VEGF and eNOS phosphorylation. Treatment with LMWF markedly ameliorated foot lesions, suppressed expression of inflammatory factors, and improved plantar perfusion by promoting endothelium-dependent vasodilation and revascularization in diabetic PAD mice. In high-glucose treated HUVEC, LMWF (40 μg/mL) reversed blunted endothelial cell proliferation, migration, and tube formation, and promoted eNOS phosphorylation and VEGF expression, whereas HUVEC pretreatment with 100 μmol/L NG -nitro-l-arginine methyl ester, an eNOS antagonist, markedly inhibited the effects of LMWF. CONCLUSION This study demonstrates that LMWF alleviates hindlimb ischemic damage, at least in part by promoting eNOS phosphorylation, nitric oxide production, and VEGF expression, resulting in enhanced angiogenesis in the ischemic region.
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Affiliation(s)
- Tiantian Liu
- Department of Pharmacology, Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance, Capital Medical University, Beijing, China
| | - Zhiqiang Wang
- Department of Pharmacology, Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance, Capital Medical University, Beijing, China
| | - Xiaoping Chen
- Department of Pharmacology, Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance, Capital Medical University, Beijing, China
| | - Hongjie You
- Department of Pharmacology, Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance, Capital Medical University, Beijing, China
| | - Jingyi Xue
- Department of Pharmacology, Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance, Capital Medical University, Beijing, China
| | - Dayong Cai
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuanyuan Zheng
- Department of Pharmacology, Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance, Capital Medical University, Beijing, China
| | - Yang Xu
- Department of Pharmacology, Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance, Capital Medical University, Beijing, China
| | - Dali Luo
- Department of Pharmacology, Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance, Capital Medical University, Beijing, China
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Laiva AL, O'Brien FJ, Keogh MB. Innovations in gene and growth factor delivery systems for diabetic wound healing. J Tissue Eng Regen Med 2018; 12:e296-e312. [PMID: 28482114 PMCID: PMC5813216 DOI: 10.1002/term.2443] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 04/13/2017] [Accepted: 05/03/2017] [Indexed: 12/22/2022]
Abstract
The rise in lower extremity amputations due to nonhealing of foot ulcers in diabetic patients calls for rapid improvement in effective treatment regimens. Administration of growth factors (GFs) are thought to offer an off-the-shelf treatment; however, the dose- and time-dependent efficacy of the GFs together with the hostile environment of diabetic wound beds impose a major hindrance in the selection of an ideal route for GF delivery. As an alternative, the delivery of therapeutic genes using viral and nonviral vectors, capable of transiently expressing the genes until the recovery of the wounded tissue offers promise. The development of implantable biomaterial dressings capable of modulating the release of either single or combinatorial GFs/genes may offer solutions to this overgrowing problem. This article reviews the state of the art on gene and protein delivery and the strategic optimization of clinically adopted delivery strategies for the healing of diabetic wounds.
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Affiliation(s)
- Ashang Luwang Laiva
- Tissue Engineering Research Group, Department of AnatomyRoyal College of Surgeons in IrelandDublinIreland
- Advanced Materials and Bioengineering Research CentreRoyal College of Surgeons in Ireland and Trinity College DublinIreland
| | - Fergal J. O'Brien
- Tissue Engineering Research Group, Department of AnatomyRoyal College of Surgeons in IrelandDublinIreland
- Trinity Centre for BioengineeringTrinity Biomedical Sciences Institute, Trinity College DublinIreland
- Advanced Materials and Bioengineering Research CentreRoyal College of Surgeons in Ireland and Trinity College DublinIreland
| | - Michael B. Keogh
- Tissue Engineering Research Group, Department of AnatomyRoyal College of Surgeons in IrelandDublinIreland
- Medical University of BahrainAdliyaKingdom of Bahrain
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Asadi MR, Torkaman G, Hedayati M, Mohajeri-Tehrani MR, Ahmadi M, Gohardani RF. Angiogenic effects of low-intensity cathodal direct current on ischemic diabetic foot ulcers: A randomized controlled trial. Diabetes Res Clin Pract 2017; 127:147-155. [PMID: 28371685 DOI: 10.1016/j.diabres.2017.03.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 03/16/2017] [Indexed: 12/27/2022]
Abstract
AIMS This study investigated the effect of low-intensity cathodal direct current (CDC) of electrical stimulation (ES) on the release of hypoxic inducible factor-1α (HIF-1α), nitric oxide (NO), vascular endothelial growth factor (VEGF), and soluble VEGF receptor-2 (sVEGFR-2) in the wound fluid of ischemic diabetic foot ulcers (DFUs). METHODS This study was a randomized, single-blind, placebo-controlled trial. Thirty type 2 diabetes patients with ischemic foot ulcerations were randomly assigned to receive either low-intensity CDC at sensory threshold (ES group, n=15) or placebo treatment (control group, n=15) for 1h/day, 3days/week, for 4weeks (12 sessions). After debridement during the first and twelfth treatment sessions, wound fluid was collected before and after ES application to determine the levels of HIF-1α, NO, VEGF, and sVEGFR-2. Wound surface area (WSA) was measured at the first, sixth, and twelfth sessions. RESULTS At the first session, after ES application, wound-fluid levels of HIF-1α were significantly increased (+61.98pg/mL) compared to the control group (-3.85pg/mL, P=0.01). After ES application at the first and twelfth sessions, wound-fluid levels of VEGF were also significantly increased (+36.77 and +39.57pg/mL, respectively) compared to the control group (+4.15 and +0.15pg/mL, P=0.007 and P=0.019, respectively). There was no significant effect on NO and sVEGFR-2 levels between the groups. CONCLUSIONS Low-intensity CDC has positive effects on the release of HIF-1α and VEGF in the wound area of ischemic DFUs. Furthermore, our results suggest that applying ES to ischemic DFUs can be a promising way to promote angiogenesis and to achieve better outcomes in diabetic wound healing.
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Affiliation(s)
- Mohammad Reza Asadi
- Department of Physical Therapy, School of Rehabilitation Sciences, Hamadan University of Medical Sciences, Hamadan, Iran; Physical Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Giti Torkaman
- Physical Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Mehdi Hedayati
- Cellular and Molecular Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Mousa Ahmadi
- Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
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Van Acker N, Ragé M, Vermeirsch H, Schrijvers D, Nuydens R, Byttebier G, Timmers M, De Schepper S, Streffer J, Andries L, Plaghki L, Cras P, Meert T. NRP-1 Receptor Expression Mismatch in Skin of Subjects with Experimental and Diabetic Small Fiber Neuropathy. PLoS One 2016; 11:e0161441. [PMID: 27598321 PMCID: PMC5012683 DOI: 10.1371/journal.pone.0161441] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 08/07/2016] [Indexed: 12/27/2022] Open
Abstract
The in vivo cutaneous nerve regeneration model using capsaicin is applied extensively to study the regenerative mechanisms and therapeutic efficacy of disease modifying molecules for small fiber neuropathy (SFN). Since mismatches between functional and morphological nerve fiber recovery are described for this model, we aimed at determining the capability of the capsaicin model to truly mimic the morphological manifestations of SFN in diabetes. As nerve and blood vessel growth and regenerative capacities are defective in diabetes, we focused on studying the key regulator of these processes, the neuropilin-1 (NRP-1)/semaphorin pathway. This led us to the evaluation of NRP-1 receptor expression in epidermis and dermis of subjects presenting experimentally induced small fiber neuropathy, diabetic polyneuropathy and of diabetic subjects without clinical signs of small fiber neuropathy. The NRP-1 receptor was co-stained with CD31 vessel-marker using immunofluorescence and analyzed with Definiens® technology. This study indicates that capsaicin application results in significant loss of epidermal NRP-1 receptor expression, whereas diabetic subjects presenting small fiber neuropathy show full epidermal NRP-1 expression in contrast to the basal expression pattern seen in healthy controls. Capsaicin induced a decrease in dermal non-vascular NRP-1 receptor expression which did not appear in diabetic polyneuropathy. We can conclude that the capsaicin model does not mimic diabetic neuropathy related changes for cutaneous NRP-1 receptor expression. In addition, our data suggest that NRP-1 might play an important role in epidermal nerve fiber loss and/or defective regeneration and that NRP-1 receptor could change the epidermal environment to a nerve fiber repellant bed possibly through Sem3A in diabetes.
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Affiliation(s)
- Nathalie Van Acker
- Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- HistoGeneX NV, Antwerp, Belgium
- * E-mail:
| | - Michael Ragé
- Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium
| | | | | | - Rony Nuydens
- Janssen Research and Development, Janssen Pharmaceutics NV, Beerse, Belgium
| | - Geert Byttebier
- Janssen Research and Development, Janssen Pharmaceutics NV, Beerse, Belgium
| | - Maarten Timmers
- Janssen Research and Development, Janssen Pharmaceutics NV, Beerse, Belgium
- Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
| | | | - Johannes Streffer
- Janssen Research and Development, Janssen Pharmaceutics NV, Beerse, Belgium
- Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
| | | | - Léon Plaghki
- Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium
| | - Patrick Cras
- Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Department of Neurology, Antwerp University Hospital, Born Bunge Institute, University of Antwerp, Antwerp, Belgium
| | - Theo Meert
- Janssen Research and Development, Janssen Pharmaceutics NV, Beerse, Belgium
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Ud-Din S, Bayat A. Non-invasive objective devices for monitoring the inflammatory, proliferative and remodelling phases of cutaneous wound healing and skin scarring. Exp Dermatol 2016; 25:579-85. [DOI: 10.1111/exd.13027] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2016] [Indexed: 12/29/2022]
Affiliation(s)
- Sara Ud-Din
- Plastic and Reconstructive Surgery Research; Institute of Inflammation and Repair; University of Manchester; Manchester UK
- University Hospital of South Manchester NHS Foundation Trust; Faculty of Medical and Human Sciences; Manchester Academic Health Science Centre; University of Manchester; Manchester UK
| | - Ardeshir Bayat
- Plastic and Reconstructive Surgery Research; Institute of Inflammation and Repair; University of Manchester; Manchester UK
- University Hospital of South Manchester NHS Foundation Trust; Faculty of Medical and Human Sciences; Manchester Academic Health Science Centre; University of Manchester; Manchester UK
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27
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Neuropathy and Diabetic Foot Syndrome. Int J Mol Sci 2016; 17:ijms17060917. [PMID: 27294922 PMCID: PMC4926450 DOI: 10.3390/ijms17060917] [Citation(s) in RCA: 204] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 05/31/2016] [Accepted: 06/02/2016] [Indexed: 12/15/2022] Open
Abstract
Diabetic foot ulceration is a serious complication of diabetes mellitus worldwide and the most common cause of hospitalization in diabetic patients. The etiology of diabetic foot ulcerations is complex due to their multifactorial nature; in the pathophysiology of diabetic foot ulceration polyneuropathy is important. Proper adherence to standard treatment strategies and interdisciplinary cooperation can reduce the still high rates of major amputations.
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Effects of low level laser therapy on the prognosis of split-thickness skin graft in type 3 burn of diabetic patients: a case series. Lasers Med Sci 2016; 31:497-502. [DOI: 10.1007/s10103-016-1896-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 01/27/2016] [Indexed: 11/25/2022]
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Ud‐Din S, Greaves NS, Sebastian A, Baguneid M, Bayat A. Noninvasive device readouts validated by immunohistochemical analysis enable objective quantitative assessment of acute wound healing in human skin. Wound Repair Regen 2015; 23:901-14. [DOI: 10.1111/wrr.12344] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 06/18/2015] [Indexed: 01/30/2023]
Affiliation(s)
- Sara Ud‐Din
- Plastic and Reconstructive Surgery Research, Manchester Institute of Biotechnology, University of ManchesterManchester United Kingdom
- University Hospital of South Manchester NHS Foundation Trust, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science CentreManchester United Kingdom
| | - Nicholas S. Greaves
- Plastic and Reconstructive Surgery Research, Manchester Institute of Biotechnology, University of ManchesterManchester United Kingdom
- University Hospital of South Manchester NHS Foundation Trust, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science CentreManchester United Kingdom
| | - Anil Sebastian
- Plastic and Reconstructive Surgery Research, Manchester Institute of Biotechnology, University of ManchesterManchester United Kingdom
| | - Mohamed Baguneid
- University Hospital of South Manchester NHS Foundation Trust, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science CentreManchester United Kingdom
| | - Ardeshir Bayat
- Plastic and Reconstructive Surgery Research, Manchester Institute of Biotechnology, University of ManchesterManchester United Kingdom
- University Hospital of South Manchester NHS Foundation Trust, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science CentreManchester United Kingdom
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Zhou K, Ma Y, Brogan MS. Chronic and non-healing wounds: The story of vascular endothelial growth factor. Med Hypotheses 2015; 85:399-404. [PMID: 26138626 DOI: 10.1016/j.mehy.2015.06.017] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 06/01/2015] [Accepted: 06/19/2015] [Indexed: 12/24/2022]
Abstract
The pathophysiology of the chronicity and non-healing status of wounds remains unknown. This paper presents the following hypothesis: abnormal patterns of vascular endothelial growth factor receptors (VEGFRs) are the culprits of wound chronicity and non-healing. More specifically, for patients with poor circulation, the decreased VEGFR-2 level is the cause of poor wound healing; for patients with non-compromised circulation, for example, patients with concurrent chronic wounds and active autoimmune diseases, the increased VEGFR-1 level is related to the non-healing status of wounds. The hypothesis is supported by the following facts. VEGFR-1 is the main contributor for inflammation and VEGFR-2 facilitates angiogenesis; soluble VEGFR-1 (sVEGFR-1) inactivates both VEGFR-1 and VEGFR-2. Patients with auto-immune disease have abnormally increased VEGFR-1 and decreased sVEGFR. Wounds in patients with active autoimmune diseases have poor response to electric stimulation which facilitates chronic wound healing in patients without active autoimmune diseases via increasing vascular endothelial growth factor (VEGF) secretion. Patients with chronic wounds (including diabetic foot ulcers and venous leg ulcers) but no active autoimmune diseases have decreased VEGFR-2 levels. We thus believe that abnormal patterns of VEGFRs are the culprits of wound chronicity and non-healing. For wounds with compromised circulation, VEGFR-2 decrease contributes to its chronicity; whereas for wounds with non-compromised circulation, VEGFR-1 increase is the leading cause of the non-healing status of chronic wounds. Treatments and research in wound care should be tailored to target these changes based on circulation status of wounds. Complete elucidation of changes of VEGFRs in chronic and non-healing wounds will enhance our understandings in tissue healing and thus better our selection of appropriate treatments for chronic and non-healing wounds.
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Affiliation(s)
- Kehua Zhou
- Department of Health Care Studies, Daemen College, Amherst, NY 14226, USA; Daemen College Physical Therapy Wound Care Clinic, Daemen College, Amherst, NY 14226, USA.
| | - Yan Ma
- Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Internal Medicine and Sleep Center, Eye Hospital, China Academy of Chinese Medical Science, Beijing, China.
| | - Michael S Brogan
- Department of Physical Therapy, Daemen College, Amherst, NY 14226, USA.
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Gomez-Villa R, Aguilar-Rebolledo F, Lozano-Platonoff A, Teran-Soto JM, Fabian-Victoriano MR, Kresch-Tronik NS, Garrido-Espíndola X, Garcia-Solis A, Bondani-Guasti A, Bierzwinsky-Sneider G, Contreras-Ruiz J. Efficacy of intralesional recombinant human epidermal growth factor in diabetic foot ulcers in Mexican patients: a randomized double-blinded controlled trial. Wound Repair Regen 2015; 22:497-503. [PMID: 25041620 DOI: 10.1111/wrr.12187] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 04/09/2014] [Indexed: 11/30/2022]
Abstract
The healing process in diabetic foot ulcer (DFU) is hindered by factors such as chronic inflammation, defects in fibroblast function, poor angiogenesis, and lack of cell migration. Recombinant human epidermal growth factor (rhEGF) has been shown to enhance extracellular matrix formation, cellular proliferation, and angiogenesis. Therefore, intralesional application of rhEGF in DFU could accelerate wound healing. Our objective was to determine the efficacy and safety of rhEGF in patients with DFU. A randomized, double-blinded, placebo-controlled study was conducted comparing a thrice-per-week intralesional application of rhEGF (75 μg) or placebo in patients with DFU for 8 weeks. The number of completely healed ulcers, size, and wound bed characteristics were evaluated to determine the efficacy of rhEGF. Adverse events were recorded and analyzed to establish its safety. A total of 34 patients were recruited for the study. After three dropouts, we were able to follow and analyze 16 patients in the placebo group and 15 patients in the rhEGF study to the end of the trial. Baseline testing showed that both groups were similar. Compared to the placebo group, more ulcers achieved complete healing in the rhEGF group (rhEGF, n = 4; placebo, n = 0; p = 0.033); ulcers in the rhEGF group decreased in area size (12.5 cm2 [rhEGF] vs. 5.2 cm2 [placebo]; p = 0.049); and more epithelial islands in the wound bed were present (28% vs. 3%; p = 0.025). Mild transitory dizziness was the only side effect that was more frequently noted in the rhEGF group. Our results showed that in patients with DFU who received standard care, intralesional rhEGF application resulted in complete healing in more patients, promoted the epithelialization of the wound bed, and significantly reduced the area of the DFU treated. Therefore, rhEGF resulted in better outcomes for patients suffering from DFU.
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Affiliation(s)
- Ramiro Gomez-Villa
- Interdisciplinary Wound and Ostomy Care Center, Division of Dermatology, Dr. Manuel Gea Gonzalez General Hospital, Mexico City, Mexico
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Paul DW, Ghassemi P, Ramella-Roman JC, Prindeze NJ, Moffatt LT, Alkhalil A, Shupp JW. Noninvasive imaging technologies for cutaneous wound assessment: A review. Wound Repair Regen 2015; 23:149-62. [PMID: 25832563 DOI: 10.1111/wrr.12262] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 01/22/2015] [Indexed: 02/02/2023]
Abstract
The ability to phenotype wounds for the purposes of assessing severity, healing potential and treatment is an important function of evidence-based medicine. A variety of optical technologies are currently in development for noninvasive wound assessment. To varying extents, these optical technologies have the potential to supplement traditional clinical wound evaluation and research, by providing detailed information regarding skin components imperceptible to visual inspection. These assessments are achieved through quantitative optical analysis of tissue characteristics including blood flow, collagen remodeling, hemoglobin content, inflammation, temperature, vascular structure, and water content. Technologies that have, to this date, been applied to wound assessment include: near infrared imaging, thermal imaging, optical coherence tomography, orthogonal polarization spectral imaging, fluorescence imaging, laser Doppler imaging, microscopy, spatial frequency domain imaging, photoacoustic detection, and spectral/hyperspectral imaging. We present a review of the technologies in use or development for these purposes with three aims: (1) providing basic explanations of imaging technology concepts, (2) reviewing the wound imaging literature, and (3) providing insight into areas for further application and exploration. Noninvasive imaging is a promising advancement in wound assessment and all technologies require further validation.
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Affiliation(s)
- Dereck W Paul
- The Firefighters' Burn and Surgical Research Laboratory, MedStar Health Research Institute, Washington, DC
| | - Pejhman Ghassemi
- Department of Electrical Engineering and Computer Science, The Catholic University of America, Washington, DC
| | - Jessica C Ramella-Roman
- Department of Biomedical Engineering and Herbert Wertheim College of Medicine, Florida International University, Miami, Florida
| | - Nicholas J Prindeze
- The Firefighters' Burn and Surgical Research Laboratory, MedStar Health Research Institute, Washington, DC
| | - Lauren T Moffatt
- The Firefighters' Burn and Surgical Research Laboratory, MedStar Health Research Institute, Washington, DC
| | - Abdulnaser Alkhalil
- The Firefighters' Burn and Surgical Research Laboratory, MedStar Health Research Institute, Washington, DC
| | - Jeffrey W Shupp
- The Firefighters' Burn and Surgical Research Laboratory, MedStar Health Research Institute, Washington, DC
- Department of Surgery, The Burn Center, MedStar Washington Hospital Center, Washington, DC
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Nickerson DS, Rader AJ. Low long-term risk of foot ulcer recurrence after nerve decompression in a diabetes neuropathy cohort. J Am Podiatr Med Assoc 2014; 103:380-6. [PMID: 24072366 DOI: 10.7547/1030380] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Use of nerve decompression in diabetic sensorimotor polyneuropathy is a controversial treatment characterized as being of unknown scientific effectiveness owing to lack of level I scientific studies. METHODS Herein, long-term follow-up data have been assembled on 65 diabetic patients with 75 legs having previous neuropathic foot ulcer and subsequent operative decompression of the common peroneal and tibial nerve branches in the anatomical fibro-osseous tunnels. RESULTS The cohort's previously reported low recurrence risk of less than 5% annually at a mean of 2.49 years of follow-up has persisted for an additional 3 years, and cumulative risk is now 2.6% per patient-year. Nine of 75 operated legs (12%) have developed an ulcer in 4,218 months (351 patient-years) of follow-up. Of the 53 contralateral legs without decompression, 16 (30%) have ulcerated, of which three have undergone an amputation. Fifty-nine percent of patients are known to be alive with intact feet a mean of 60 months after decompression. CONCLUSIONS The prospective, objective, statistically significant finding of a large, long-term diminution of diabetic foot ulcer recurrence risk after operative nerve decompression compares very favorably with the historical literature and the contralateral legs of this cohort, which had no decompression. This finding invites prospective randomized controlled studies for validation testing and reconsideration of the frequency and contribution of unrecognized nerve entrapments in diabetic sensorimotor polyneuropathy and diabetic foot complications.
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Ramanujam CL, Han D, Fowler S, Kilpadi K, Zgonis T. Impact of diabetes and comorbidities on split-thickness skin grafts for foot wounds. J Am Podiatr Med Assoc 2014; 103:223-32. [PMID: 23697729 DOI: 10.7547/1030223] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Split-thickness skin grafts can be used for foot wound closure in diabetic and nondiabetic patients. It is unknown whether this procedure is reliable for all diabetic patients, with or without comorbidities of diabetes, including cardiovascular disease, neuropathy, retinopathy, and nephropathy. METHODS We retrospectively reviewed 203 patients who underwent this procedure to determine significant differences in healing time, postoperative infection, and need for revisional surgery and to create a predictive model to identify diabetic patients who are likely to have a successful outcome. RESULTS Overall, compared with nondiabetic patients, diabetic patients experienced a significantly higher risk of delayed healing time and postoperative complication/infection and, hence, are more likely to require revisional surgery after undergoing the initial split-thickness skin graft procedure. These differences seemed to be related more to the presence of comorbidities than to diabetic status itself. Diabetic patients with preexisting comorbidities experienced a significantly increased risk of delayed healing time and postoperative infection and a higher need for revisional surgery compared with nondiabetic patients or diabetic patients without comorbidities. However, there were no significant differences in outcome between diabetic patients without comorbidities and nondiabetic patients. CONCLUSIONS For individuals with diabetes but without exclusionary comorbidities, split-thickness skin grafting may be considered an effective surgical alternative to other prolonged treatment options currently used in this patient population.
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Affiliation(s)
- Crystal L Ramanujam
- Division of Podiatric Medicine and Surgery, Department of Orthopaedic Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
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Cheng C, Singh V, Krishnan A, Kan M, Martinez JA, Zochodne DW. Loss of innervation and axon plasticity accompanies impaired diabetic wound healing. PLoS One 2013; 8:e75877. [PMID: 24098736 PMCID: PMC3786937 DOI: 10.1371/journal.pone.0075877] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 08/19/2013] [Indexed: 12/26/2022] Open
Abstract
Loss of cutaneous innervation from sensory neuropathy is included among mechanisms for impaired healing of diabetic skin wounds. The relationships between cutaneous axons and their local microenvironment during wound healing are challenged in diabetes. Here, we show that secondary wound closure of the hairy dorsal skin of mice is delayed by diabetes and is associated with not only a pre-existing loss of cutaneous axons but substantial retraction of axons around the wound. At 7d following a 3mm punch wound, a critical period of healing and reinnervation, both intact skin nearby the wound and skin directly at the wound margins had over 30-50% fewer axons and a larger deficit of ingrowing axons in diabetics. These findings contrasted with a pre-existing 10-15% deficit in axons. Moreover, new diabetic ingrowing axons had less evidence of plasticity. Unexpectedly, hair follicles adjacent to the wounds had a 70% reduction in their innervation associated with depleted expression of hair follicular stem cell markers. These impairments were associated with the local upregulation of two established axon regenerative ‘roadblocks’: PTEN and RHOA, potential but thus far unexplored mediators of these changes. The overall findings identify striking and unexpected superimposed cutaneous axon loss or retraction beyond that expected of diabetic neuropathy alone, associated with experimental diabetic skin wounding, a finding that prompts new considerations in diabetic wounds.
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Affiliation(s)
- Chu Cheng
- Department of Clinical Neurosciences and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Vandana Singh
- Department of Clinical Neurosciences and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Anand Krishnan
- Department of Clinical Neurosciences and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Michelle Kan
- Department of Clinical Neurosciences and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Jose A. Martinez
- Department of Clinical Neurosciences and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Douglas W. Zochodne
- Department of Clinical Neurosciences and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
- * E-mail:
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Wukich DK, Armstrong DG, Attinger CE, Boulton AJM, Burns PR, Frykberg RG, Hellman R, Kim PJ, Lipsky BA, Pile JC, Pinzur MS, Siminerio L. Inpatient management of diabetic foot disorders: a clinical guide. Diabetes Care 2013; 36:2862-71. [PMID: 23970716 PMCID: PMC3747877 DOI: 10.2337/dc12-2712] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The implementation of an inpatient diabetic foot service should be the goal of all institutions that care for patients with diabetes. The objectives of this team are to prevent problems in patients while hospitalized, provide curative measures for patients admitted with diabetic foot disorders, and optimize the transition from inpatient to outpatient care. Essential skills that are required for an inpatient team include the ability to stage a foot wound, assess for peripheral vascular disease, neuropathy, wound infection, and the need for debridement; appropriately culture a wound and select antibiotic therapy; provide, directly or indirectly, for optimal metabolic control; and implement effective discharge planning to prevent a recurrence. Diabetic foot ulcers may be present in patients who are admitted for nonfoot problems, and these ulcers should be evaluated by the diabetic foot team during the hospitalization. Pathways should be in place for urgent or emergent treatment of diabetic foot infections and neuropathic fractures/dislocations. Surgeons involved with these patients should have knowledge and interest in limb preservation techniques. Prevention of iatrogenic foot complications, such as pressure sores of the heel, should be a priority in patients with diabetes who are admitted for any reason: all hospitalized diabetic patients require a clinical foot exam on admission to identify risk factors such as loss of sensation or ischemia. Appropriate posthospitalization monitoring to reduce the risk of reulceration and infection should be available, which should include optimal glycemic control and correction of any fluid and electrolyte disturbances.
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Affiliation(s)
- Dane K Wukich
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
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Illigens BMW, Gibbons CH. A human model of small fiber neuropathy to study wound healing. PLoS One 2013; 8:e54760. [PMID: 23382960 PMCID: PMC3561391 DOI: 10.1371/journal.pone.0054760] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Accepted: 12/17/2012] [Indexed: 01/13/2023] Open
Abstract
The aim of this study was to develop a human model of acute wound healing that isolated the effects of small fiber neuropathy on the healing process. Twenty-five healthy subjects had the transient receptor vanilloid 1 agonist capsaicin and placebo creams topically applied to contralateral areas on the skin of the thigh for 48 hours. Subjects had shallow (1.2 millimeter) and deep (>3 millimeter) punch skin biopsies from each thigh on days 1 and 14. Biopsy wound healing was monitored photographically until closure. Intra-epidermal and sweat-gland nerve fiber densities were measured for each biopsy. Shallow wounds in capsaicin-treated sites healed more slowly than in placebo treated skin with biopsies taken on day 1 (P<0.001) and day 14 (P<0.001). Deep biopsies in the capsaicin and placebo areas healed at similar rates at both time points. Nerve fiber densities were reduced only in capsaicin treated regions (P<0.01). In conclusion, topical application of capsaicin causes a small fiber neuropathy and is associated with a delay in healing of shallow, but not deep wounds. This novel human model may prove valuable in the study of wound healing in patients with neuropathy.
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Affiliation(s)
- Ben M. W. Illigens
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Christopher H. Gibbons
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail:
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Diabetic neuropathy and axon reflex-mediated neurogenic vasodilatation in type 1 diabetes. PLoS One 2012; 7:e34807. [PMID: 22529938 PMCID: PMC3328500 DOI: 10.1371/journal.pone.0034807] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 03/08/2012] [Indexed: 11/29/2022] Open
Abstract
Objective Axon reflex-mediated neurogenic vasodilatation in response to cutaneous heating may reflect early, pre-clinical small fibre dysfunction. We aimed to evaluate the distribution of the vascular flare area measured by laser doppler imaging (“LDIFLARE area”) in type 1 diabetes and in healthy volunteers. Research and Methods Concurrent with clinical and electrophysiological examination to classify diabetic sensorimotor polyneuropathy (DSP), LDIFLARE area (cm2) was determined in 89 type 1 diabetes subjects matched to 64 healthy volunteers. We examined the association and diagnostic performance of LDI with clinical and subclinical measures of DSP and its severity. Results Compared to the 64 healthy volunteers, the 56 diabetes controls without DSP had significantly lower LDIFLARE area (p = 0.006). The 33 diabetes cases with DSP had substantially lower LDIFLARE area as compared to controls without DSP (p = 0.002). There was considerable overlap in LDIFLARE area between all groups such that the ROC curve had an AUC of 0.72 and optimal sensitivity of 70% for the detection of clinical DSP. Use of a subclinical definition for DSP, according to subclinical sural nerve impairment, was associated with improved AUC of 0.75 and sensitivity of 79%. In multivariate analysis higher HbA1c and body mass index had independent associations with smaller LDIFLARE area. Conclusions Axon reflex-mediated neurogenic vasodilatation in response to cutaneous heating is a biomarker of early nerve dysfunction in DSP. Its independent association with glycemic exposure in diabetes subjects and both glycemic exposure and BMI in healthy volunteers highlights the existence of small-fibre dysfunction in the natural history of DSP.
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Chan YC, Roy S, Khanna S, Sen CK. Downregulation of endothelial microRNA-200b supports cutaneous wound angiogenesis by desilencing GATA binding protein 2 and vascular endothelial growth factor receptor 2. Arterioscler Thromb Vasc Biol 2012; 32:1372-82. [PMID: 22499991 DOI: 10.1161/atvbaha.112.248583] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE MicroRNAs (miRs) regulate angiogenesis by posttranscriptional silencing of target genes. The significance of angiostatic miR-200b in switching on skin wound angiogenesis was tested. METHODS AND RESULTS Wounding caused imminent and transient downregulation of miR-200b in dermal wound-edge endothelial cells. Derailing this injury response by lentiviral delivery of miR-200b in vivo impaired wound angiogenesis. Computational prediction, target reporter luciferase assay, and Western blot analysis provided first evidence that miR-200b targets globin transcription factor binding protein 2 (GATA2) and vascular endothelial growth factor receptor 2 (VEGFR2). Overexpression of GATA2 or VEGFR2 in endothelial cells rescued the angiostatic effect of miR-200b in vitro. Downregulation of miR-200b derepressed GATA2 and VEGFR2 expression to switch on wound angiogenesis, which was disrupted in diabetic wounds. Treatment of endothelial cells with tumor necrosis factor-α, a proinflammatory cytokine abundant in diabetic wounds, induced miR-200b expression, silenced GATA2 and VEGFR2, and suppressed angiogenesis. These outcomes were attenuated using anti-miR-200b strategy. Neutralization of tumor necrosis factor-α in the diabetic wounds improved wound angiogenesis and closure, which was accompanied by downregulation of miR-200b expression and desilencing of GATA2 and VEGFR2. CONCLUSIONS Injury-induced repression of miR-200b turned on wound angiogenesis. In mice with diabetes mellitus,excessive tumor necrosis factor-α induced miR-200b blunting proangiogenic functions of GATA2 and VEGFR2.
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Affiliation(s)
- Yuk Cheung Chan
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, OH 43210, USA
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Anderson JJ, Wallin KJ, Spencer L. Split thickness skin grafts for the treatment of non-healing foot and leg ulcers in patients with diabetes: a retrospective review. Diabet Foot Ankle 2012; 3:DFA-3-10204. [PMID: 22403742 PMCID: PMC3297411 DOI: 10.3402/dfa.v3i0.10204] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2011] [Revised: 01/01/2012] [Accepted: 01/03/2012] [Indexed: 11/16/2022]
Abstract
We retrospectively reviewed 107 diabetic patients who received a split thickness skin graft (STSG) for treatment of a non-healing diabetic foot or leg ulcer to describe healing times based on patient characteristics, comorbidities or complications. The minimum follow-up was 6 months from the time of STSG application. The mean time to healing among all patients was 5.1 weeks (3 to 16 weeks). The mean healing time for patients with complications was 12.0 weeks (10 to 16 weeks) while the mean healing time for those without complications was 4.9 weeks (3 to 10 weeks). Overall complication rate was 2.8%. Patients with a STSG take of less than 95% had a mean healing time of 7.9 weeks compared to 4.8 weeks for those with a STSG take of 100% (p<0.001). The use of autologous STSG for treatment of non-healing diabetic foot and leg wounds is a viable method for soft tissue closure and may present a low complication rate and a satisfactory rate of healing.
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Affiliation(s)
- John J Anderson
- Alamogordo Orthopedics and Sports Medicine, Alamogordo, New Mexico, USA
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Demidova-Rice TN, Durham JT, Herman IM. Wound Healing Angiogenesis: Innovations and Challenges in Acute and Chronic Wound Healing. Adv Wound Care (New Rochelle) 2012; 1:17-22. [PMID: 24527273 DOI: 10.1089/wound.2011.0308] [Citation(s) in RCA: 125] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2011] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Formation of new blood vessels, by either angiogenesis or vasculogenesis, is critical for normal wound healing. Major processes in neovascularization include (i) growth-promoting or survival factors, (ii) proteolytic enzymes, (iii) activators of multiple differentiated and progenitor cell types, and (iv) permissible microenvironments. A central aim of wound healing research is to "convert" chronic, disease-impaired wounds into those that will heal. THE PROBLEM Reduced ability to re-establish a blood supply to the injury site can ultimately lead to wound chronicity. BASIC/CLINICAL SCIENCE ADVANCES (1) Human fetal endothelial progenitor cells can stimulate wound revascularization and repair following injury, as demonstrated in a novel mouse model of diabetic ischemic healing. (2) Advances in bioengineering reveal exciting alternatives by which wound repair may be facilitated via the creation of vascularized microfluidic networks within organ constructs created ex vivo for wound implantation. (3) A "personalized" approach to regenerative medicine may be enabled by the identification of protein components present within individual wound beds, both chronic and acute. CLINICAL CARE RELEVANCE Despite the development of numerous therapies, impaired angiogenesis and wound chronicity remain significant healthcare problems. As such, innovations in enhancing wound revascularization would lead to significant advances in wound healing therapeutics and patient care. CONCLUSION Insights into endothelial progenitor cell biology together with developments in the field of tissue engineering and molecular diagnostics should not only further advance our understanding of the molecular mechanisms regulating wound repair but also offer innovative solutions to promote the healing of chronic and acute wounds in vivo.
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Affiliation(s)
- Tatiana N. Demidova-Rice
- Department of Radiation Oncology, Edwin L. Steele Laboratory for Tumor Biology, Massachusetts General Hospital, Boston, MA 02114
| | - Jennifer T. Durham
- Department of Molecular Physiology and Pharmacology and the Center for Innovations in Wound Healing Research, Tufts University School of Medicine and Graduate Program in Cellular and Molecular Physiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111
| | - Ira M. Herman
- Department of Molecular Physiology and Pharmacology and the Center for Innovations in Wound Healing Research, Tufts University School of Medicine and Graduate Program in Cellular and Molecular Physiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111
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Haddad PS, Musallam L, Martineau LC, Harris C, Lavoie L, Arnason JT, Foster B, Bennett S, Johns T, Cuerrier A, Coon Come E, Coon Come R, Diamond J, Etapp L, Etapp C, George J, Husky Swallow C, Husky Swallow J, Jolly M, Kawapit A, Mamianskum E, Petagumskum J, Petawabano S, Petawabano L, Weistche A, Badawi A. Comprehensive evidence-based assessment and prioritization of potential antidiabetic medicinal plants: a case study from canadian eastern james bay cree traditional medicine. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2011; 2012:893426. [PMID: 22235232 PMCID: PMC3247006 DOI: 10.1155/2012/893426] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Accepted: 09/09/2011] [Indexed: 01/15/2023]
Abstract
Canadian Aboriginals, like others globally, suffer from disproportionately high rates of diabetes. A comprehensive evidence-based approach was therefore developed to study potential antidiabetic medicinal plants stemming from Canadian Aboriginal Traditional Medicine to provide culturally adapted complementary and alternative treatment options. Key elements of pathophysiology of diabetes and of related contemporary drug therapy are presented to highlight relevant cellular and molecular targets for medicinal plants. Potential antidiabetic plants were identified using a novel ethnobotanical method based on a set of diabetes symptoms. The most promising species were screened for primary (glucose-lowering) and secondary (toxicity, drug interactions, complications) antidiabetic activity by using a comprehensive platform of in vitro cell-based and cell-free bioassays. The most active species were studied further for their mechanism of action and their active principles identified though bioassay-guided fractionation. Biological activity of key species was confirmed in animal models of diabetes. These in vitro and in vivo findings are the basis for evidence-based prioritization of antidiabetic plants. In parallel, plants were also prioritized by Cree Elders and healers according to their Traditional Medicine paradigm. This case study highlights the convergence of modern science and Traditional Medicine while providing a model that can be adapted to other Aboriginal realities worldwide.
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Affiliation(s)
- Pierre S. Haddad
- Canadian Institutes of Health Research Team in Aboriginal Antidiabetic Medicines, Montreal, QC, Canada H3C 317
- Department of Pharmacology, Université de Montréal and Montreal Diabetes Research Center, P.O. Box 6128, Downtown Postal Station, Montreal, QC, Canada H3C 3J7
| | - Lina Musallam
- Canadian Institutes of Health Research Team in Aboriginal Antidiabetic Medicines, Montreal, QC, Canada H3C 317
- Department of Pharmacology, Université de Montréal and Montreal Diabetes Research Center, P.O. Box 6128, Downtown Postal Station, Montreal, QC, Canada H3C 3J7
| | - Louis C. Martineau
- Canadian Institutes of Health Research Team in Aboriginal Antidiabetic Medicines, Montreal, QC, Canada H3C 317
| | - Cory Harris
- Canadian Institutes of Health Research Team in Aboriginal Antidiabetic Medicines, Montreal, QC, Canada H3C 317
- School of Dietetics and Human Nutrition and Center for Indigenous Peoples' Nutrition and Environment, McGill University, Sainte-Anne-de-Bellevue, QC, Canada H9X 3V9
| | - Louis Lavoie
- Canadian Institutes of Health Research Team in Aboriginal Antidiabetic Medicines, Montreal, QC, Canada H3C 317
| | - John T. Arnason
- Canadian Institutes of Health Research Team in Aboriginal Antidiabetic Medicines, Montreal, QC, Canada H3C 317
- Department of Biology, University of Ottawa, Ottawa, ON, Canada K1N 6N5
| | - Brian Foster
- Canadian Institutes of Health Research Team in Aboriginal Antidiabetic Medicines, Montreal, QC, Canada H3C 317
- Department of Cellular and Molecular Medicine, University of Ottawa and Therapeutic Products Directorate, Health Canada, Ottawa, ON, Canada K1A 1B6
| | - Steffany Bennett
- Canadian Institutes of Health Research Team in Aboriginal Antidiabetic Medicines, Montreal, QC, Canada H3C 317
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5
| | - Timothy Johns
- Canadian Institutes of Health Research Team in Aboriginal Antidiabetic Medicines, Montreal, QC, Canada H3C 317
- School of Dietetics and Human Nutrition and Center for Indigenous Peoples' Nutrition and Environment, McGill University, Sainte-Anne-de-Bellevue, QC, Canada H9X 3V9
| | - Alain Cuerrier
- Canadian Institutes of Health Research Team in Aboriginal Antidiabetic Medicines, Montreal, QC, Canada H3C 317
- Plant Biology Research Institute, Université de Montréal and Montreal Botanical Garden, Montreal, QC, Canada H1X 2B2
| | - Emma Coon Come
- Cree Nation of Mistissini, Eeyou Istchii, QC, Canada GOW 1CO
| | - Rene Coon Come
- Cree Nation of Mistissini, Eeyou Istchii, QC, Canada GOW 1CO
| | - Josephine Diamond
- The Crees of Waskaganish First Nation, Eeyou Istchii, QC, Canada JON 1RO
| | - Louise Etapp
- Cree Nation of Mistissini, Eeyou Istchii, QC, Canada GOW 1CO
| | - Charlie Etapp
- Cree Nation of Mistissini, Eeyou Istchii, QC, Canada GOW 1CO
| | - Jimmy George
- Whapmagoostui First Nation, Eeyou Istchii, QC, Canada JOM 1GO
| | | | | | - Mary Jolly
- Cree Nation of Nemaska, Nemaska, QC, Canada JLY 3BO
| | - Andrew Kawapit
- Whapmagoostui First Nation, Eeyou Istchii, QC, Canada JOM 1GO
| | | | | | | | | | - Alex Weistche
- The Crees of Waskaganish First Nation, Eeyou Istchii, QC, Canada JON 1RO
| | - Alaa Badawi
- Office of Biotechnology, Genomics, and Population Health, Public Health Agency of Canada, Toronto, ON, Canada M5V 3L7
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Wukich DK, Joseph A, Ryan M, Ramirez C, Irrgang JJ. Outcomes of ankle fractures in patients with uncomplicated versus complicated diabetes. Foot Ankle Int 2011; 32:120-30. [PMID: 21288410 DOI: 10.3113/fai.2011.0120] [Citation(s) in RCA: 129] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Patients with diabetes who sustain an ankle fracture are at increased risk for complications including higher rates of in hospital mortality, in-hospital postoperative complications, length of stay and non-routine discharges. The purpose of this study was to retrospectively compare the complications associated with operatively treated ankle fractures in a group of patients with uncomplicated diabetes versus a group of patients with complicated diabetes. Complicated diabetes was defined as diabetes associated with end organ damage such as peripheral neuropathy, nephropathy and/or PAD. Uncomplicated diabetes was defined as diabetes without any of these associated conditions. Our hypothesis was that patients with uncomplicated diabetes would experience fewer complications than those patients with complicated diabetes. MATERIALS AND METHODS We compared the complication rates of ankle fracture repair in 46 patients with complicated diabetes and 59 patients with uncomplicated diabetes and calculated odds ratios (OR) for significant findings. RESULTS At a mean followup of 21.4 months we found that patients with complicated diabetes had 3.8 times increased risk of overall complications 3.4 times increased risk of a non-infectious complication (malunion, nonunion or Charcot arthropathy) and 5 times higher likelihood of needing revision surgery/arthrodesis when compared to patients with uncomplicated diabetes. Open ankle fractures in this diabetic population were associated with a three times higher rate of complications and 3.7 times higher rate of infection. CONCLUSION Patients with complicated diabetes have an increased risk of complications after ankle fracture surgery compared to patients with uncomplicated diabetes. Careful preoperative evaluation of the neurovascular status is mandatory, since many patients with diabetes do not recognize that they have neuropathy and/or peripheral artery disease.
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Affiliation(s)
- Dane K Wukich
- UPMC Comprehensive Foot and Ankle Center, Orthopaedic, 2100 Jane St., Pittsburgh, PA 15203, USA.
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Ramanujam CL, Facaros Z, Zgonis T. External fixation for surgical off-loading of diabetic soft tissue reconstruction. Clin Podiatr Med Surg 2011; 28:211-6. [PMID: 21276528 DOI: 10.1016/j.cpm.2010.10.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Early and aggressive treatment of diabetic foot wounds is imperative for the reduction of amputation risk. Whereas sound local wound care is important for successful management; chronic wounds often reach a stagnant point in healing because of diabetic vasculopathy, immunopathy, or neuropathy. The type, size, shape, and location of wound may not always allow primary closure or grafting. In patients with adequate perfusion and in the absence of infection, local advancement flaps are suitable for durable closure. A review and case report demonstrating the use of these flaps with external fixation as an adjunctive therapy for surgical off-loading is presented.
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Affiliation(s)
- Crystal L Ramanujam
- Division of Podiatric Medicine and Surgery, Department of Orthopaedic Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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Ramanujam CL, Stapleton JJ, Kilpadi KL, Rodriguez RH, Jeffries LC, Zgonis T. Split-thickness skin grafts for closure of diabetic foot and ankle wounds: a retrospective review of 83 patients. Foot Ankle Spec 2010; 3:231-40. [PMID: 20631059 DOI: 10.1177/1938640010375114] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The aim of this study was to determine if split-thickness skin grafts could be successfully used for closure of foot and ankle wounds in diabetic patients. The authors retrospectively reviewed the charts of 100 consecutive patients who underwent a soft tissue surgical reconstruction with split-thickness skin grafts to their foot and/or ankle in our institution from 2005 to 2008. After application of inclusion criteria, 83 eligible charts remained. Of the 83 patients, 54 (65%) healed uneventfully, 23 (28%) required regrafting, and 6 (7%) had a complication resolved with conservative management. All patients had a successful surgical outcome, defined as having achieved complete wound closure at the final follow-up. Surgical outcome was not significantly associated with age, gender, race, hemoglobin A1C, wound size, wound location, illicit drug use, amputation history, Charcot history, or preoperative infection. However, postoperative graft complications were significantly associated with current or previous smoking history (P = .016) and the level of previous pedal amputation to which the split-thickness skin graft was applied (P = .009). This study demonstrates that application of split-thickness skin grafts with an appropriate postoperative regimen is a beneficial procedure to achieve foot and ankle wound closure in diabetic patients.
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Affiliation(s)
- Crystal L Ramanujam
- Division of Podiatric Medicine and Surgery, Department of Orthopaedic Surgery, University of Texas Health Science Center at San Antonio, TX 78229, USA
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Green AQ, Krishnan S, Finucane FM, Rayman G. Altered C-fiber function as an indicator of early peripheral neuropathy in individuals with impaired glucose tolerance. Diabetes Care 2010; 33:174-6. [PMID: 20040675 PMCID: PMC2797968 DOI: 10.2337/dc09-0101] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE This study explored the importance of glycemic burden compared with features of the metabolic syndrome in the pathogenesis of diabetic neuropathy by comparing C-fiber function in people with type 1 diabetes to that in people with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS The axon reflex-elicited flare areas (LDIflares) were measured with a laser Doppler imager (LDI) in age-, height-, and BMI-matched groups with IGT (n = 14) and type 1 diabetes (n = 16) and in healthy control subjects (n = 16). RESULTS The flare area was reduced in the IGT group compared with the control (2.78 +/- 1.1 vs. 5.23 +/- 1.7 cm(2), P = 0.0001) and type 1 diabetic (5.16 +/- 2.3 cm(2), P = 0.002) groups, whereas the flare area was similar in the type 1 diabetic and control groups. CONCLUSIONS This technique suggests that small-fiber neuropathy is a feature of IGT. The absence of similar small-fiber neuropathy in those with longstanding type 1 diabetes suggests that glycemia may not be the major determinant of small-fiber neuropathy in IGT.
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Affiliation(s)
- Alistair Q Green
- The Diabetes Research Centre, Ipswich Hospital National Health Service Trust, Suffolk, UK
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Green AQ, Krishnan ST, Rayman G. C-fiber function assessed by the laser doppler imager flare technique and acetylcholine iontophoresis. Muscle Nerve 2009; 40:985-91. [DOI: 10.1002/mus.21333] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Abstract
Abnormal wound healing is a major complication of both type 1 and type 2 diabetes, with nonhealing foot ulcerations leading in the worst cases to lower-limb amputation. Wound healing requires the integration of complex cellular and molecular events in successive phases of inflammation, cell proliferation, cell migration, angiogenesis and re-epithelialisation. A link between wound healing and the nervous system is clinically apparent as peripheral neuropathy is reported in 30-50% of diabetic patients and is the most common and sensitive predictor of foot ulceration. Indeed, a bidirectional connection between the nervous and the immune systems and its role in wound repair has emerged as one of the focal features of the wound-healing dogma. This review provides a broad overview of the mediators of this connection, which include neuropeptides and cytokines released from nerve fibres, immune cells and cutaneous cells. In-depth understanding of the signalling pathways in the neuroimmune axis in diabetic wound healing is vital to the development of successful wound-healing therapies.
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Schaper NC, Huijberts M, Pickwell K. Neurovascular control and neurogenic inflammation in diabetes. Diabetes Metab Res Rev 2008; 24 Suppl 1:S40-4. [PMID: 18442183 DOI: 10.1002/dmrr.862] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Loss of pain perception is currently seen as a key factor in the development of diabetic foot ulcers. However, recent studies suggest that nerves play a central role in tissue homeostasis and can orchestrate complex reparative as well as destructive processes in the feet. Evidence is presented that suggests that denervation can result in altered capillary blood flow (in patients with type 2 diabetes), oxygen delivery, fluid filtration, and inflammatory responses. These processes could render the feet of diabetic patients with neuropathy more susceptible to tissue damage, infection and perhaps, in a subset of patients, to the development of acute Charcot neuro-osteoarthropathy (CN).
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Affiliation(s)
- N C Schaper
- Department of Internal Medicine, Division of Endocrinology, University Hospital Maastricht, The Netherlands.
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