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Li H, Chen C, Wang Y, Yi W, Guo P, Yao C, Liu J, Wei Y, Hu K, Shang X, Kang S. A meta-analysis on application and prospect of cell therapy in the treatment of diabetes mellitus. Stem Cell Res Ther 2025; 16:249. [PMID: 40390031 PMCID: PMC12090454 DOI: 10.1186/s13287-025-04377-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 05/02/2025] [Indexed: 05/21/2025] Open
Abstract
OBJECTIVE Diabetes mellitus (DM) is a grave autoimmune disorder because of no insulin self-generation. Currently, mainly clinical methods exist, serious adverse effects leading to stem cell therapy are considered. The mesenchymal stem cells (MSCs), require high differentiation capacity and are judged as crucial in DM treatment. The meta-analysis aimed to systemically analyze the particular types of MSCs which play a more important role in DM and which DM is treated more effectively. METHOD A systematic review was conducted on the published literature, clinical trials and observational studies, utilizing databases such as PubMed, Embase, Cochrane and clinicaltrial.gov. RevMan software was adopted to draw Forest Plot and Funnel Plot, and subgroup analysis were employed to evaluate heterogeneity between different groups. RESULTS We identified the meta-analyses of 34 unique random controlled trials and divided our own systematic reviews into 8 groups. The MSCs were associated with placebo (OR = 2.79, 95% CI [1.63, 4.75]), Standard Clinical Treatment (SCT) (OR = 4.12, 95% CI [2.76, 6.14]), and monocyte (OR = 6.52, 95% CI [3.56, 9.48]). The comparison between Autologous MSCs and Allogenic MSCs (OR = 4.64, 95% CI [3.42, 6.31]), Autologous BMMSCs and other MSCs (OR = 5.28, 95% CI [3.64, 7.66]), Allogenic ASCs and UCMSCs (OR = 3.54, 95% CI [1.83, 6.86]), Type I DM and Type II DM (OR = 3.10, 95% CI [1.79, 5.38]), intravenous injection and other injections (OR = 4.81, 95% CI [3.34, 6.94]), diabetic foot ulcers and diabetic neurological disease (OR = 3.88,,95% CI [2.53,5.95]). CONCLUSION Current evidence suggests that MSCs hold significant potential for treating DM, demonstrating considerably high safety and efficacy. MSCs exhibit higher therapeutic benefits compared to monocytes, with autologous MSCs offering better clinical outcomes than allogenic sources. MSCs (BMMSCs) proved more effective than other types of MSCs. However, no significant differences were observed between adipose-derived MSCs (ASCs) and umbilical cord-derived MSCs (UCMSCs) in the allogeneic setting. Moreover, MSCs show more pronounced therapeutic effects in Type II DM, and the difference among the injection methods is minimally observed. In conclusion, the research scope on DM is relatively limited in this study and further research is necessary to improve the reliability of the estimates.
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Affiliation(s)
- Hanluo Li
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Cheng Chen
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Yuansheng Wang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Wei Yi
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Peipei Guo
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Chenguang Yao
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Jinbiao Liu
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Yanhong Wei
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Kanghong Hu
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Xiaoke Shang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China.
- Wuhan Vickor Medical Technology Co. Ltd., Building 3-3, 3-4, and 3-5, Zhaoshang·High-Tech Network Valley, No. 16, Luzling Third Road, East Lake High-Tech Development Zone, Wuhan (Wuhan Area of the Pilot Free Trade Zone), Wuhan, 430015, China.
| | - Sini Kang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China.
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Costela-Ruiz VJ, González-Vigil E, Espinosa-Ibáñez O, Alcázar – Caballero RM, Melguizo-Rodríguez L, Fernández-López O, Arias-Santiago S. Application of allogeneic adult mesenchymal stem cells in the treatment of venous ulcers: A phase I/II randomized controlled trial protocol. PLoS One 2025; 20:e0323173. [PMID: 40373055 PMCID: PMC12080757 DOI: 10.1371/journal.pone.0323173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 03/26/2025] [Indexed: 05/17/2025] Open
Abstract
OBJECTIVE To evaluate the feasibility, safety and efficacy of the cutaneous application of Bioengineered Artificial Mesenchymal Sheet (BAMS) in venous leg ulcers (VLUs) versus conventional treatment. METHODS This protocol is based on the design of a Phase I/II, multicenter, randomized, controlled, open-label clinical trial investigating the application of a biological dressing supplemented with mesenchymal stem cells (NCT05962931). The clinical trial is being conducted in 2 primary care units within the Granada Metropolitan Health District. A total of 20 patients with VLUs are being randomized (1:1) into 2 intervention arms: a control group and a treatment group. The intervention in the treatment group consists of the local application of 4 doses of BAMS, administered once per week, while the control group receives conventional therapy. Feasibility will be assessed based on the ability to complete the administration of 4 doses in at least 80% of the patients in the treatment group. Safety will be evaluated by analyzing the incidence of adverse effects and serious adverse effects. Efficacy will be assessed in terms of the percentage of wound closure (measured by wound area reduction), macroscopic assessment of the lesion (visual macroscopic analysis and RESVECH 2.0 scale), analysis of growth factors and inflammatory cytokines (ELISA test), pain levels (VAS scale) and quality of life (CIVIQ 20). RESULTS If confirmed, BAMS-based therapy may provide an effective treatment for VLUs, potentially reducing wound closure time and associated complications. This therapy could significantly enhance patients' quality of life due to the regenerative and analgesic properties of the biological dressing. DISCUSSION Given the biological activity of mesenchymal stem cells, an accelerated healing effect is expected in the treatment group. This could lead to shorter healing times for chronic wounds, resulting in significant benefits for patients, healthcare professionals, and overall healthcare costs. TRIAL REGISTRATION NCT05962931.
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Affiliation(s)
- Víctor J. Costela-Ruiz
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain
- Instituto Investigación Biosanitaria, ibs. Granada, Spain
| | - Encarnación González-Vigil
- Andalusian Health Service, Granada Metropolitan Health District, Primary Care Unit of Atarfe (Granada), Granada, Spain
| | - Olga Espinosa-Ibáñez
- Tissue Engineering and Cell Production Unit, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | | | - Lucía Melguizo-Rodríguez
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain
- Instituto Investigación Biosanitaria, ibs. Granada, Spain
| | - Olga Fernández-López
- Andalusian Network for the Design and Translation of Advanced Therapies, Junta de Andalucía, Seville, Spain
| | - Salvador Arias-Santiago
- Instituto Investigación Biosanitaria, ibs. Granada, Spain
- Tissue Engineering and Cell Production Unit, Hospital Universitario Virgen de las Nieves, Granada, Spain
- Dermatology Department, Hospital Universitario Virgen de las Nieves, Granada. Spain
- Dermatology Department, School of Medicine, University of Granada, Granada, Spain
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Ceran F, Bozkurt M, Karakol P. Effectiveness of the combined therapy in the treatment of chronic non-healing wounds in patients with autoimmune diseases. J Plast Reconstr Aesthet Surg 2025; 101:126-133. [PMID: 39731901 DOI: 10.1016/j.bjps.2024.11.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 11/03/2024] [Accepted: 11/19/2024] [Indexed: 12/30/2024]
Abstract
OBJECTIVE Autoimmune diseases are systemic conditions that can have negative effects on wound healing. The objective of the present study was to investigate the efficacy of combining bone marrow-derived mesenchymal stem cells (BM-MSCs), acellular dermal matrix (ADM), split-thickness skin graft (STSG), and negative-pressure wound therapy (NPWT) for treating patients with autoimmune diseases and chronic non-healing wounds. METHODS Thirty-four patients with autoimmune diseases and non-healing chronic wounds of the lower extremities between 2012 and 2023 were included in the study. Among these, 18 patients had Behçet's disease, 8 patients had polyarteritis nodosa, and 8 patients had systemic lupus erythematosus. All patients underwent split-thickness skin grafting in external centers. The wounds were debrided, and BM-MSCs concentrate was injected into the wound base. A suitable ADM was applied to the wound. STSG were adapted onto the ADM. The grafts were closed with NPWT. RESULTS Patients were followed-up for an average of 1.2 years. No necrosis was observed at the wound sites of the post-operative patients. During long-term follow-up, no wounds were observed at the same sites. CONCLUSION Although autoimmune diseases fall within the scope of rheumatology, the treatment of chronic non-healing wounds that accompany such diseases requires a multidisciplinary approach. We demonstrated that the combined use of BM-MSCs, ADM, STSG, and NPWT presents an effective approach in the healing of these types of wounds.
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Affiliation(s)
- Fatih Ceran
- Biruni University Medical Faculty, Department of Plastic, Reconstructive and Aesthetic Surgery, Istanbul, Turkey.
| | - Mehmet Bozkurt
- Bagcilar Training and Research Hospital, Department of Plastic, Reconstructive and Aesthetic Surgery, Istanbul, Turkey
| | - Percin Karakol
- Bagcilar Training and Research Hospital, Department of Plastic, Reconstructive and Aesthetic Surgery, Istanbul, Turkey
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Chavan C, Ray S, Kumar CM. Stem cell therapy approaches for non-malignant diseases & non-haematological diseases in India: A systematic review. Indian J Med Res 2024; 160:411-427. [PMID: 39737504 DOI: 10.25259/ijmr_2141_23] [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: 11/07/2023] [Accepted: 10/01/2024] [Indexed: 01/01/2025] Open
Abstract
Background & objectives Our study aims to provide the diversity of stem cell use for non-malignant, non-haematological diseases in India through the lens of clinical trials. Methods A PRISMA approach was used to evaluate the safety and efficacy of stem cell use for the period 2001-2021 in India. The outcomes were measured using each disease category, types of stem cells, the origin of stem cells, safety, and efficacy. Results Of the 9206 studies screened, 61 studies that were relevant to stem cell use for non-malignant diseases were included for analysis. Autologous stem cells (75%) were used predominantly compared to allogenic stem cells (18.33%), followed by mixed type (6.67%). Use of bone marrow-derived stem cells (51%) was dominant, followed by melanocytes (19%), adipose (7%), haematopoietic (12%), and (11%) other types of stem cells. The study revealed 37 randomized clinical trial studies conducted in the government research hospital compared to the non-government. Interpretation & conclusions Maintaining the gold standard for stem cell therapy requires randomized clinical trials with large sample sizes, control groups, failures, adverse effects, etc. It is important to have a monitoring and regulation system in stem cell clinical research activities with enough preclinical data and repeated exchanges between the bench and the bedside.
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Affiliation(s)
- Chandrashekhar Chavan
- Department of Inclusive Health, CSIR-National Institute of Science Communication and Policy Research, New Delhi, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
| | - Suman Ray
- Department of Inclusive Health, CSIR-National Institute of Science Communication and Policy Research, New Delhi, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
| | - Chandra Mohan Kumar
- Department of Pediatrics, All India Institute of Medical Sciences, Patna, India
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Das P, Pal D, Roy S, Chaudhuri S, Kesh SS, Basak P, Nandi SK. Unveiling advanced strategies for therapeutic stem cell interventions in severe burn injuries: a comprehensive review. Int J Surg 2024; 110:6382-6401. [PMID: 38869979 PMCID: PMC11487052 DOI: 10.1097/js9.0000000000001812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 05/29/2024] [Indexed: 06/15/2024]
Abstract
This comprehensive review explores the complex terrain of stem cell therapies as a potential therapeutic frontier in the healing of complicated burn wounds. Serious tissue damage, impaired healing processes, and possible long-term consequences make burn wounds a complex problem. An in-depth review is required since, despite medical progress, existing methods for treating severe burn wounds have significant limitations. Burn wounds are difficult to heal because they cause extensive tissue damage. The challenges of burn injury-induced tissue regeneration and functional recovery are also the subject of this review. Although there is a lot of promise in current stem cell treatments, there are also some limitations with scalability, finding the best way to transport the cells, and finding consistent results across different types of patients. To shed light on how to improve stem cell interventions to heal severe burn wounds, this review covers various stem cell applications in burn wounds and examines these obstacles. To overcome these obstacles, one solution is to enhance methods of stem cell distribution, modify therapies according to the severity of the burn, and conduct more studies on how stem cell therapy affects individual patients. Novel solutions may also be possible through the combination of cutting-edge technologies like nanotechnology and biotechnology. This review seeks to increase stem cell interventions by analyzing present challenges and suggesting strategic improvements. The goal is to provide a more effective and tailored way to repair serious burn wounds.
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Affiliation(s)
- Pratik Das
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal and Fishery Sciences
- School of Bioscience and Engineering, Jadavpur University
| | - Debajyoti Pal
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal and Fishery Sciences
| | - Sudipta Roy
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal and Fishery Sciences
| | - Shubhamitra Chaudhuri
- Department of Veterinary Clinical Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, India
| | - Shyam S. Kesh
- Department of Veterinary Clinical Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, India
| | - Piyali Basak
- School of Bioscience and Engineering, Jadavpur University
| | - Samit K. Nandi
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal and Fishery Sciences
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Xia Y, Wu P, Chen H, Chen Z. Advances in stem cell therapy for diabetic foot. Front Genet 2024; 15:1427205. [PMID: 39290985 PMCID: PMC11405205 DOI: 10.3389/fgene.2024.1427205] [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: 05/03/2024] [Accepted: 08/14/2024] [Indexed: 09/19/2024] Open
Abstract
Diabetic Foot Ulcers (DFU) represent a grave complication often encountered in the advanced stages of diabetes mellitus. They frequently lead to recurrent hospitalizations and, in severe cases, can result in life-threatening conditions such as infections, gangrene, and even amputation Diabetic foot ulcers (DFU), as a serious complication in the late stage of diabetes mellitus, are prone to lead to repeated hospitalization, and in severe cases, infection, gangrene, and even amputation. Although there are many methods for treating diabetic foot, there is no clear and effective method to reduce the amputation rate of diabetic foot patients. In recent years, advancements in the understanding of stem cell therapy for the treatment of DFU have shed light on its potential as a novel therapeutic approach. In recent years, as the research on stem cell therapy for diabetic foot is gradually deepening, stem cells are expected to become a new therapeutic method for treating DFU in the future. Their therapeutic effects are through promoting angiogenesis, secreting paracrine factors, controlling inflammation, promoting collagen deposition, and regulating immunity, etc. Despite numerous studies confirming the efficacy of stem cell therapy in treating DFU, there is still a need for the establishment of standardized treatment protocols. Although numerous studies have shown that stem cell therapy for DFU is real and effective, there has not yet been a standardized treatment protocol. This article reviews studies related to stem cell therapy for DFU, looking at the mechanism of action, types of stem cells, and modes of administration.
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Affiliation(s)
- Yinfeng Xia
- Department of Burn and Plastic Surgery, Chongqing University Fuling Hospital, Chongqing University, Chongqing, China
| | - Ping Wu
- Department of Burn and Plastic Surgery, Chongqing University Fuling Hospital, Chongqing University, Chongqing, China
| | - Hong Chen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing MedicalUniversity, Chongqing, China
| | - Zhiyong Chen
- Department of Burn and Plastic Surgery, Chongqing University Fuling Hospital, Chongqing University, Chongqing, China
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Tan LT, Mokhtari-Esbuie F, Shababi N, Harmon JW. Stem Cell Therapy for Wound Healing in Ischemic Limbs: Is It Effective? Adv Surg 2024; 58:235-247. [PMID: 39089780 DOI: 10.1016/j.yasu.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
Critical limb ischemia is an important clinical entity due to its association with increased morbidity and mortality. The mortality and amputation-free survival remains poor especially in those where revascularization is not an option. Recently, the role of cellular therapy has emerged as a promising therapeutic measure that may aid in wound healing and revascularization and improve functional outcomes.
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Affiliation(s)
- Li Ting Tan
- Department of Surgery, The Johns Hopkins Hospital, Blalock 658, 600 North Wolfe Street, Baltimore, MD 21287, USA
| | - Farzad Mokhtari-Esbuie
- Department of Surgery, Johns Hopkins University, Surgery A Building 5th Floor, 4940 Eastern Avenue, Baltimore, MD 21224, USA
| | - Niloufar Shababi
- Department of Surgery, Johns Hopkins University, Surgery A Building 5th Floor, 4940 Eastern Avenue, Baltimore, MD 21224, USA
| | - John W Harmon
- Department of Surgery, Johns Hopkins University, Surgery A Building 5th Floor, 4940 Eastern Avenue, Baltimore, MD 21224, USA.
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Wang F, Zhang X, Zhang J, Xu Q, Yu X, Xu A, Yi C, Bian X, Shao S. Recent advances in the adjunctive management of diabetic foot ulcer: Focus on noninvasive technologies. Med Res Rev 2024; 44:1501-1544. [PMID: 38279968 DOI: 10.1002/med.22020] [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: 08/13/2022] [Revised: 12/15/2023] [Accepted: 01/10/2024] [Indexed: 01/29/2024]
Abstract
Diabetic foot ulcer (DFU) is one of the most costly and serious complications of diabetes. Treatment of DFU is usually challenging and new approaches are required to improve the therapeutic efficiencies. This review aims to update new and upcoming adjunctive therapies with noninvasive characterization for DFU, focusing on bioactive dressings, bioengineered tissues, mesenchymal stem cell (MSC) based therapy, platelet and cytokine-based therapy, topical oxygen therapy, and some repurposed drugs such as hypoglycemic agents, blood pressure medications, phenytoin, vitamins, and magnesium. Although the mentioned therapies may contribute to the improvement of DFU to a certain extent, most of the evidence come from clinical trials with small sample size and inconsistent selections of DFU patients. Further studies with high design quality and adequate sample sizes are necessitated. In addition, no single approach would completely correct the complex pathogenesis of DFU. Reasonable selection and combination of these techniques should be considered.
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Affiliation(s)
- Fen Wang
- Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Xiaoling Zhang
- Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Jing Zhang
- Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Qinqin Xu
- Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Xuefeng Yu
- Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Anhui Xu
- Division of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengla Yi
- Division of Trauma Surgery, Tongji Hospital, Tongji Medical College, Wuhan, China
| | - Xuna Bian
- Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Shiying Shao
- Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
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Li J, Liu Y, Zhang R, Yang Q, Xiong W, He Y, Ye Q. Insights into the role of mesenchymal stem cells in cutaneous medical aesthetics: from basics to clinics. Stem Cell Res Ther 2024; 15:169. [PMID: 38886773 PMCID: PMC11184751 DOI: 10.1186/s13287-024-03774-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 05/27/2024] [Indexed: 06/20/2024] Open
Abstract
With the development of the economy and the increasing prevalence of skin problems, cutaneous medical aesthetics are gaining more and more attention. Skin disorders like poor wound healing, aging, and pigmentation have an impact not only on appearance but also on patients with physical and psychological issues, and even impose a significant financial burden on families and society. However, due to the complexities of its occurrence, present treatment options cannot produce optimal outcomes, indicating a dire need for new and effective treatments. Mesenchymal stem cells (MSCs) and their secretomics treatment is a new regenerative medicine therapy that promotes and regulates endogenous stem cell populations and/or replenishes cell pools to achieve tissue homeostasis and regeneration. It has demonstrated remarkable advantages in several skin-related in vivo and in vitro investigations, aiding in the improvement of skin conditions and the promotion of skin aesthetics. As a result, this review gives a complete description of recent scientific breakthroughs in MSCs for skin aesthetics and the limitations of their clinical applications, aiming to provide new ideas for future research and clinical transformation.
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Affiliation(s)
- Junyi Li
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Ye Liu
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Rui Zhang
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Qianyu Yang
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Wei Xiong
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Yan He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, 430030, China.
| | - Qingsong Ye
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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Tabatabaei Hosseini BS, Meadows K, Gabriel V, Hu J, Kim K. Biofabrication of Cellulose-based Hydrogels for Advanced Wound Healing: A Special Emphasis on 3D Bioprinting. Macromol Biosci 2024; 24:e2300376. [PMID: 38031512 DOI: 10.1002/mabi.202300376] [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: 08/17/2023] [Revised: 10/26/2023] [Indexed: 12/01/2023]
Abstract
Even with the current advancements in wound management, addressing most skin injuries and wounds continues to pose a significant obstacle for the healthcare industry. As a result, researchers are now focusing on creating innovative materials utilizing cellulose and its derivatives. Cellulose, the most abundant biopolymer in nature, has unique properties that make it a promising material for wound healing, such as biocompatibility, tunable physiochemical characteristics, accessibility, and low cost. 3D bioprinting technology has enabled the production of cellulose-based wound dressings with complex structures that mimic the extracellular matrix. The inclusion of bioactive molecules such as growth factors offers the ability to aid in promoting wound healing, while cellulose creates an ideal environment for controlled release of these biomolecules and moisture retention. The use of 3D bioprinted cellulose-based wound dressings has potential benefits for managing chronic wounds, burns, and painful wounds by promoting wound healing and reducing the risk of infection. This review provides an up-to-date summary of cellulose-based dressings manufactured by 3D bioprinting techniques by looking into wound healing biology, biofabrication methods, cellulose derivatives, and the existing cellulose bioinks targeted toward wound healing.
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Affiliation(s)
| | - Kieran Meadows
- Department of Biomedical Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
| | - Vincent Gabriel
- Calgary Firefighters Burn Treatment Centre, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
| | - Jinguang Hu
- Department of Petroleum and Chemical Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
| | - Keekyoung Kim
- Department of Biomedical Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
- Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
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Dong Y, Zhang Y, Li F, Tang B, Lv D, Wang H, Luo S. GKT137831 in combination with adipose-derived stem cells alleviates high glucose-induced inflammaging and improves diabetic wound healing. J Leukoc Biol 2024; 115:882-892. [PMID: 37774495 DOI: 10.1093/jleuko/qiad116] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 08/30/2023] [Accepted: 09/05/2023] [Indexed: 10/01/2023] Open
Abstract
Adipose-derived stem cells (ADSCs) have been proven to promote healing in diabetic wounds, which are one of the most serious chronic refractory wounds. However, reactive oxygen species (ROS) induced by high glucose (HG) lead to oxidative stress and aging in ADSCs, which limits the therapeutic effect of ADSCs. In this study, we investigated the role of GKT137831, a NOX1/4 inhibitor that can reduce ROS production, in protecting ADSCs from hyperglycemia and in diabetic wound healing. In vitro, ROS levels and NOX4 expression were increased after HG treatment of ADSCs, while the oxidative stress marker malondialdehyde was increased; mitochondrial membrane potential was decreased; inflammatory aging-related indicators such as p16, p21, matrix metalloproteinase-1 (MMP1), MMP3, interleukin-6, and β-galactosidase were increased; and migration was weakened. In vivo, we constructed a diabetic mouse wound model and found that the combination of ADSCs and GKT137831 synergistically promoted the 21-day wound healing rate, increased the expression of collagen and hydroxyproline, increased the number of blood vessels and the expression of CD31, and reduced the expression of interleukin-6, MMP1, MMP3, and p21. These results suggest that GKT137831 could protect ADSCs from oxidative stress and aging induced by HG and enhance the therapeutic effect of ADSCs on diabetic wounds.
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Affiliation(s)
- Yunxian Dong
- Department of Plastic and Reconstructive Surgery, Guangdong Second Provincial General Hospital, No. 466 Middle Xingang Road, Guangzhou, Guangdong Province 510317, China
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou North Road, Guangzhou, Guangdong Province 510515, China
| | - Youliang Zhang
- Department of Plastic and Reconstructive Surgery, Guangdong Second Provincial General Hospital, No. 466 Middle Xingang Road, Guangzhou, Guangdong Province 510317, China
| | - Fangwei Li
- Department of Plastic and Reconstructive Surgery, Guangdong Second Provincial General Hospital, No. 466 Middle Xingang Road, Guangzhou, Guangdong Province 510317, China
| | - Bing Tang
- Department of Burn Surgery, First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, Guangdong Province 510080, China
| | - Dongming Lv
- Department of Burn Surgery, First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, Guangdong Province 510080, China
| | - Haibin Wang
- Department of Plastic and Reconstructive Surgery, Guangdong Second Provincial General Hospital, No. 466 Middle Xingang Road, Guangzhou, Guangdong Province 510317, China
| | - Shengkang Luo
- Department of Plastic and Reconstructive Surgery, Guangdong Second Provincial General Hospital, No. 466 Middle Xingang Road, Guangzhou, Guangdong Province 510317, China
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12
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Hetta HF, Elsaghir A, Sijercic VC, Akhtar MS, Gad SA, Moses A, Zeleke MS, Alanazi FE, Ahmed AK, Ramadan YN. Mesenchymal stem cell therapy in diabetic foot ulcer: An updated comprehensive review. Health Sci Rep 2024; 7:e2036. [PMID: 38650719 PMCID: PMC11033295 DOI: 10.1002/hsr2.2036] [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: 11/08/2023] [Revised: 02/06/2024] [Accepted: 03/19/2024] [Indexed: 04/25/2024] Open
Abstract
Background Diabetes has evolved into a worldwide public health issue. One of the most serious complications of diabetes is diabetic foot ulcer (DFU), which frequently creates a significant financial strain on patients and lowers their quality of life. Up until now, there has been no curative therapy for DFU, only symptomatic relief or an interruption in the disease's progression. Recent studies have focused attention on mesenchymal stem cells (MSCs), which provide innovative and potential treatment candidates for several illnesses as they can differentiate into various cell types. They are mostly extracted from the placenta, adipose tissue, umbilical cord (UC), and bone marrow (BM). Regardless of their origin, they show comparable features and small deviations. Our goal is to investigate MSCs' therapeutic effects, application obstacles, and patient benefit strategies for DFU therapy. Methodology A comprehensive search was conducted using specific keywords relating to DFU, MSCs, and connected topics in the databases of Medline, Scopus, Web of Science, and PubMed. The main focus of the selection criteria was on English-language literature that explored the relationship between DFU, MSCs, and related factors. Results and Discussion Numerous studies are being conducted and have demonstrated that MSCs can induce re-epithelialization and angiogenesis, decrease inflammation, contribute to immunological modulation, and subsequently promote DFU healing, making them a promising approach to treating DFU. This review article provides a general snapshot of DFU (including clinical presentation, risk factors and etiopathogenesis, and conventional treatment) and discusses the clinical progress of MSCs in the management of DFU, taking into consideration the side effects and challenges during the application of MSCs and how to overcome these challenges to achieve maximum benefits. Conclusion The incorporation of MSCs in the management of DFU highlights their potential as a feasible therapeutic strategy. Establishing a comprehensive understanding of the complex relationship between DFU pathophysiology, MSC therapies, and related obstacles is essential for optimizing therapy outcomes and maximizing patient benefits.
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Affiliation(s)
- Helal F. Hetta
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative MedicineFaculty of Pharmacy, University of TabukTabukSaudi Arabia
- Department of Medical Microbiology and ImmunologyFaculty of Medicine, Assiut UniversityAssiutEgypt
| | - Alaa Elsaghir
- Department of Microbiology and ImmunologyFaculty of Pharmacy, Assiut UniversityAssiutEgypt
| | | | | | - Sayed A. Gad
- Faculty of Medicine, Assiut UniversityAssiutEgypt
| | | | - Mahlet S. Zeleke
- Menelik II Medical and Health Science College, Kotebe Metropolitan UniversityAddis AbabaEthiopia
| | - Fawaz E. Alanazi
- Department of Pharmacology and ToxicologyFaculty of Pharmacy, University of TabukTabukSaudi Arabia
| | | | - Yasmin N. Ramadan
- Department of Microbiology and ImmunologyFaculty of Pharmacy, Assiut UniversityAssiutEgypt
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13
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Burgos-Gutiérrez C, Álvarez-Buylla-Álvarez P, Álvarez-Viejo M, Pérez-López S, Pérez-Basterrechea M, Bea-Muñoz M, Pérez-Arias Á, De-Vicente-Rodríguez JC. Treatment of pressure ulcers in patients with spinal cord injury: Conventional surgery vs. cellular therapy. J Spinal Cord Med 2024; 47:246-254. [PMID: 34982655 PMCID: PMC10885747 DOI: 10.1080/10790268.2021.2014234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
CONTEXT Relapse and recurrence rates of pressure injuries (PIs) are very high in spinal cord injured patients. That is the reason why alternative therapies, such the stem cells derived from bone marrow, have been developed. OBJECTIVE To compare this new technique of infiltration-infusion of mononuclear cells from bone marrow with conventional surgery. DESIGN A retrospective study was carried out in patients with spinal cord injuries who had PIs, category III/IV, in the pelvic area, during a 14-year follow-up period. SETTING One group was treated with conventional surgery and, in the other group, mononuclear cells were infused. PARTICIPANTS One hundred and forty-nine patients were registered, 63 (42.3%) in the conventional surgery group and 86 (57.7%) in the mononuclear cell group. RESULTS A comparative study between these 2 groups was carried out. There were no significant differences in ulcer healing in the first 6 months, but 6 months and one-year post-treatment, they were found. At 6 months, no patient in the conventional surgery group showed dehiscence or fistulization of the wound and, one year after surgery, only 3.17% recurred in the conventional group. In addition, there was a statistically significant relationship between days of hospitalization and the type of bacterial contamination and the intervention group. CONCLUSION Bone marrow mononuclear cell infusion-infiltration is an alternative treatment for PIs and fistula during the first 6 months, instead of conventional surgery. However, in the medium-long term, conventional surgery is more effective.
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Affiliation(s)
| | | | - María Álvarez-Viejo
- Unidad de Terapia Celular y Medicina Regenerativa, Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Silvia Pérez-López
- Unidad de Terapia Celular y Medicina Regenerativa, Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Marcos Pérez-Basterrechea
- Unidad de Terapia Celular y Medicina Regenerativa, Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Manuel Bea-Muñoz
- Servicio de Rehabilitación, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ángel Pérez-Arias
- Servicio de Cirugía Plástica, Hospital Universitario Central de Asturias, Oviedo, Spain
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14
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Mudgal SK, Kumar S, Gaur R, Singh H, Saikia D, Varshney S, Gupta P, Grover A, Varikasuvu SR. Effectiveness of Stem Cell Therapy for Diabetic Foot Ulcers: A Systematic Review and GRADE Compliant Bootstrapped Meta-Analysis of Randomized Clinical Trials. INT J LOW EXTR WOUND 2024:15347346241227530. [PMID: 38298002 DOI: 10.1177/15347346241227530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2024]
Abstract
Diabetic foot (DF) represents a severe complication of diabetes mellitus, imposing substantial psychological and economic burdens on affected individuals. This investigation sought to assess the therapeutic efficacy of stem cell interventions in the management of DF complications. A comprehensive systematic search across PubMed, Embase, CINAHL, Scopus, and the Cochrane library databases was conducted to identify pertinent studies for meta-analysis. Outcome measures encompassed ulcer or wound healing rates, amputation rates, angiogenesis, ankle-brachial index (ABI), and pain-free walking distance. Dichotomous outcomes were expressed as risk differences (RDs) with 95% confidence intervals (CIs), while continuous data were articulated as standardized mean differences (SMDs) with corresponding 95% CIs. Statistical analyses were executed using RevMan 5.3 and Open Meta, with bootstrapped meta-analysis conducted through OpenMEE software. A total of 20 studies, comprising 24 arms and involving 1304 participants, were incorporated into the meta-analysis. The findings revealed that stem cell therapy exhibited superior efficacy compared to conventional interventions in terms of ulcer or wound healing rate [RD = 0.36 (0.28, 0.43)], pain-free walking distance [SMD = 1.27 (0.89, 1.65)], ABI [SMD = 0.61 (0.33, 0.88)], and new vessel development [RD = 0.48 (0.23, 0.78)], while concurrently reducing the amputation rate significantly [RD = -0.19 (-0.25, -0.12)]. Furthermore, no statistically significant difference in adverse events was observed [RD -0.07 (-0.16, 0.02)]. The Grading of Recommendations, Assessment, Development, and Evaluation assessment indicated varying levels of evidence certainty, ranging from very low to moderate, for different outcomes. Bootstrapping analysis substantiated the precision of the results. The meta-analysis underscores the significant superiority of stem cell therapy over conventional approaches in treating DF complications. Future investigations should prioritize large-scale, randomized, double-blind, placebo-controlled, multicenter trials, incorporating rigorous long-term follow-up protocols. These studies are essential for elucidating the optimal cell types and therapeutic parameters that contribute to the most effective treatment strategies for DF management.
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Affiliation(s)
- Shiv Kumar Mudgal
- All India Institute of Medical Sciences (AIIMS), Deoghar, Jharkhand, India
| | - Subodh Kumar
- All India Institute of Medical Sciences (AIIMS), Deoghar, Jharkhand, India
| | - Rakhi Gaur
- All India Institute of Medical Sciences (AIIMS), Deoghar, Jharkhand, India
| | - Harminder Singh
- All India Institute of Medical Sciences (AIIMS), Deoghar, Jharkhand, India
| | - Dibyajyoti Saikia
- All India Institute of Medical Sciences (AIIMS), Guwahati, Assam, India
| | - Saurabh Varshney
- All India Institute of Medical Sciences (AIIMS), Deoghar, Jharkhand, India
| | - Pratima Gupta
- All India Institute of Medical Sciences (AIIMS), Deoghar, Jharkhand, India
| | - Ashoo Grover
- Indian Council of Medical Research (ICMR), Head Quarters, New Delhi, India
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15
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Davis M, Hom D. Current and Future Developments in Wound Healing. Facial Plast Surg 2023; 39:477-488. [PMID: 37308128 PMCID: PMC11121504 DOI: 10.1055/s-0043-1769936] [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] [Indexed: 06/14/2023] Open
Abstract
Poor wound healing on the face and neck can lead to significant morbidity and dissatisfaction in facial plastic surgery. With current advances in wound healing management and commercially available biologic and tissue-engineered products, there are several options available to optimize acute wound healing and treat delayed or chronic wounds. This article summarizes some of the key principals and recent developments in wound healing research in addition to potential future advancements in the field of soft tissue wound healing.
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Affiliation(s)
- Morgan Davis
- Department of Otolaryngology, Head and Neck Surgery, University of California, San Diego, La Jolla, California
| | - David Hom
- Department of Otolaryngology, Head and Neck Surgery, University of California, San Diego, La Jolla, California
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16
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Zhu M, Cao L, Melino S, Candi E, Wang Y, Shao C, Melino G, Shi Y, Chen X. Orchestration of Mesenchymal Stem/Stromal Cells and Inflammation During Wound Healing. Stem Cells Transl Med 2023; 12:576-587. [PMID: 37487541 PMCID: PMC10502569 DOI: 10.1093/stcltm/szad043] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 06/13/2023] [Indexed: 07/26/2023] Open
Abstract
Wound healing is a complex process and encompasses a number of overlapping phases, during which coordinated inflammatory responses following tissue injury play dominant roles in triggering evolutionarily highly conserved principals governing tissue repair and regeneration. Among all nonimmune cells involved in the process, mesenchymal stem/stromal cells (MSCs) are most intensely investigated and have been shown to play fundamental roles in orchestrating wound healing and regeneration through interaction with the ordered inflammatory processes. Despite recent progress and encouraging results, an informed view of the scope of this evolutionarily conserved biological process requires a clear understanding of the dynamic interplay between MSCs and the immune systems in the process of wound healing. In this review, we outline current insights into the ways in which MSCs sense and modulate inflammation undergoing the process of wound healing, highlighting the central role of neutrophils, macrophages, and T cells during the interaction. We also draw attention to the specific effects of MSC-based therapy on different pathological wound healing. Finally, we discuss how ongoing scientific advances in MSCs could be efficiently translated into clinical strategies, focusing on the current limitations and gaps that remain to be overcome for achieving preferred functional tissue regeneration.
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Affiliation(s)
- Mengting Zhu
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People’s Republic of China
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Lijuan Cao
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People’s Republic of China
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Sonia Melino
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Shanghai, People’s Republic of China
| | - Changshun Shao
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People’s Republic of China
| | - Gerry Melino
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Yufang Shi
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People’s Republic of China
| | - Xiaodong Chen
- Wuxi Sinotide New Drug Discovery Institutes, Huishan Economic and Technological Development Zone, Wuxi, Jiangsu, People’s Republic of China
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17
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Peeters JAHM, Peters HAB, Videler AJ, Hamming JF, Schepers A, Quax PHA. Exploring the Effects of Human Bone Marrow-Derived Mononuclear Cells on Angiogenesis In Vitro. Int J Mol Sci 2023; 24:13822. [PMID: 37762125 PMCID: PMC10531254 DOI: 10.3390/ijms241813822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 08/29/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023] Open
Abstract
Cell therapies involving the administration of bone marrow-derived mononuclear cells (BM-MNCs) for patients with chronic limb-threatening ischemia (CLTI) have shown promise; however, their overall effectiveness lacks evidence, and the exact mechanism of action remains unclear. In this study, we examined the angiogenic effects of well-controlled human bone marrow cell isolates on endothelial cells. The responses of endothelial cell proliferation, migration, tube formation, and aortic ring sprouting were analyzed in vitro, considering both the direct and paracrine effects of BM cell isolates. Furthermore, we conducted these investigations under both normoxic and hypoxic conditions to simulate the ischemic environment. Interestingly, no significant effect on the angiogenic response of human umbilical vein endothelial cells (HUVECs) following treatment with BM-MNCs was observed. This study fails to provide significant evidence for angiogenic effects from human bone marrow cell isolates on human endothelial cells. These in vitro experiments suggest that the potential benefits of BM-MNC therapy for CLTI patients may not involve endothelial cell angiogenesis.
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Affiliation(s)
- Judith A. H. M. Peeters
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (J.A.H.M.P.); (H.A.B.P.); (A.J.V.); (J.F.H.); (A.S.)
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Hendrika A. B. Peters
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (J.A.H.M.P.); (H.A.B.P.); (A.J.V.); (J.F.H.); (A.S.)
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Anique J. Videler
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (J.A.H.M.P.); (H.A.B.P.); (A.J.V.); (J.F.H.); (A.S.)
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Jaap F. Hamming
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (J.A.H.M.P.); (H.A.B.P.); (A.J.V.); (J.F.H.); (A.S.)
| | - Abbey Schepers
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (J.A.H.M.P.); (H.A.B.P.); (A.J.V.); (J.F.H.); (A.S.)
| | - Paul H. A. Quax
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (J.A.H.M.P.); (H.A.B.P.); (A.J.V.); (J.F.H.); (A.S.)
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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18
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Alinda MD, Christopher PM, Listiawan MY, Endaryanto A, Suroto H, Rantam FA, Hendradi E, Notobroto HB, Prakoeswa CRS. The efficacy of topical adipose mesenchymal stem cell-conditioned medium versus framycetin gauze dressing in chronic plantar ulcer of leprosy: A randomized controlled trial. Indian J Dermatol Venereol Leprol 2023; 89:656-664. [PMID: 36688887 DOI: 10.25259/ijdvl_784_2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 07/01/2022] [Indexed: 12/13/2022]
Abstract
Background Wound healing shows a unique interaction of several cells, growth factors and cytokines. The healing of chronic plantar ulcer of leprosy is influenced by various factors, one of which is the concentration of growth factors and cytokines related to the pathogenesis of impaired wound healing. Growth factors and cytokines can be found in the secretome of adipose mesenchymal stem cells. Aim To compare the effectiveness of topical adipose mesenchymal stem cell-conditioned medium and framycetin gauze dressing only on the healing of chronic plantar ulcer of leprosy. Methods In this randomised controlled trial, 32 patients with chronic plantar ulcer of leprosy were recruited. After detailed clinical and initial debridement, patients were randomised to two groups to receive either topical adipose mesenchymal stem cell-conditioned medium (n = 16) or framycetin gauze dressing only (n = 16) applied every three days for up to eight weeks, following which the ulcer size, adverse reactions and complications if any were monitored weekly. Results Healing percentage increased each week in all groups. Statistical differences between groups (P < 0.05) were observed from week 2 onwards for ulcer mean size reduction and from week 3 onwards for ulcer mean depth reduction. There were no adverse reactions or complications. Limitations Off-loading on subjects were not performed. Conclusion Adipose mesenchymal stem cell-conditioned medium is a potential therapeutic agent in the management of chronic plantar ulcer of leprosy.
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Affiliation(s)
- Medhi Denisa Alinda
- Post Graduate Doctoral Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Jawa Timur, Indonesia
| | | | | | | | - Heri Suroto
- Department of Cell and Tissue Bank, Faculty of Medicine Universitas Airlangga-Dr. Soetomo General Academic Hospital, Surabaya, Jawa Timur, Indonesia
| | - Fedik Abdul Rantam
- Stem Cell Research and Development Center, Universitas Airlangga, Surabaya, Jawa Timur, Indonesia
| | - Esti Hendradi
- Faculty of Pharmacy Universitas Airlangga, Surabaya, Jawa Timur, Indonesia
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19
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Mills SJ, Kirby GT, Hofma BR, Smith LE, Statham P, Vaes B, Ting AE, Short R, Cowin AJ. Delivery of multipotent adult progenitor cells via a functionalized plasma polymerized surface accelerates healing of murine diabetic wounds. Front Bioeng Biotechnol 2023; 11:1213021. [PMID: 37675407 PMCID: PMC10477914 DOI: 10.3389/fbioe.2023.1213021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/09/2023] [Indexed: 09/08/2023] Open
Abstract
Introduction: Stem cell therapies have been investigated as potential treatment modalities for chronic wounds however there has been limited success to date. Multipotent Adult Progenitor Cells (MAPCs©) have been identified as having potential as an allogenic stem cell product due to their high population doubling number and their characteristic dampening of T-cell proliferation. This helps to prevent autoimmunity and graft/cell rejection. Methods: We have developed a dressing, consisting of medical grade silicone coated with a heptylamine plasma polymer, which supports the growth and transfer of MAPCs to skin. To determine if the dressing can deliver functional stem cells into diabetic wounds, they were loaded with MAPCs and then placed over excisional wounds in both normal and diabetic mice. Results and discussion: Accelerated healing was observed in both the normal and diabetic wounds with wound gape being significantly smaller at day 3 when compared to controls. Wound analysis showed that treatment with the MAPC dressings dampened the inflammatory response with reduced numbers of neutrophils and macrophages observed. Additionally, an increase in pro-angiogenic VEGF and CD31 positive endothelial cells was observed indicating improved new blood vessel formation. The MAPC dressings had no effect on fibrosis with collagen I and III being equally affected in both control and treated wounds. Overall, the functionalized MAPC dressings improve healing responses particularly in diabetic mice with impaired healing responses and therefore, show potential for development as an advanced therapeutic approach for the treatment of chronic diabetic wounds.
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Affiliation(s)
- S. J. Mills
- Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia
- Cooperative Research Centre for Cell Therapy Manufacturing, Adelaide, SA, Australia
| | - G. T. Kirby
- Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia
- Cooperative Research Centre for Cell Therapy Manufacturing, Adelaide, SA, Australia
| | - B. R. Hofma
- Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia
- Cooperative Research Centre for Cell Therapy Manufacturing, Adelaide, SA, Australia
| | - L. E. Smith
- Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia
- Cooperative Research Centre for Cell Therapy Manufacturing, Adelaide, SA, Australia
| | - P. Statham
- Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia
- Cooperative Research Centre for Cell Therapy Manufacturing, Adelaide, SA, Australia
| | - B. Vaes
- ReGenesys BV, Bio-Incubator Leuven, Leuven, Belgium
| | - A. E. Ting
- Athersys Inc., Cleveland, OH, United States
| | - R. Short
- Material Science Institute, Lancaster University, Lancaster, United Kingdom
| | - A. J. Cowin
- Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia
- Cooperative Research Centre for Cell Therapy Manufacturing, Adelaide, SA, Australia
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20
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Jakl V, Popp T, Haupt J, Port M, Roesler R, Wiese S, Friemert B, Rojewski MT, Schrezenmeier H. Effect of Expansion Media on Functional Characteristics of Bone Marrow-Derived Mesenchymal Stromal Cells. Cells 2023; 12:2105. [PMID: 37626914 PMCID: PMC10453497 DOI: 10.3390/cells12162105] [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: 07/19/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
The therapeutic efficacy of mesenchymal stromal cells (MSCs) has been shown to rely on their immunomodulatory and regenerative properties. In order to obtain sufficient numbers of cells for clinical applications, MSCs have to be expanded ex vivo. Expansion media with xenogeneic-free (XF) growth-promoting supplements like human platelet lysate (PL) or serum- and xenogeneic-free (SF/XF) formulations have been established as safe and efficient, and both groups provide different beneficial qualities. In this study, MSCs were expanded in XF or SF/XF media as well as in mixtures thereof. MSCs cultured in these media were analyzed for phenotypic and functional properties. MSC expansion was optimal with SF/XF conditions when PL was present. Metabolic patterns, consumption of growth factors, and secretome of MSCs differed depending on the type and concentration of supplement. The lactate per glucose yield increased along with a higher proportion of PL. Many factors in the supernatant of cultured MSCs showed distinct patterns depending on the supplement (e.g., FGF-2, TGFβ, and insulin only in PL-expanded MSC, and leptin, sCD40L PDGF-AA only in SF/XF-expanded MSC). This also resulted in changes in cell characteristics like migratory potential. These findings support current approaches where growth media may be utilized for priming MSCs for specific therapeutic applications.
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Affiliation(s)
- Viktoria Jakl
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
| | - Tanja Popp
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
| | - Julian Haupt
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
- Clinic for Trauma Surgery and Orthopedics, Army Hospital Ulm, 89081 Ulm, Germany
| | - Matthias Port
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
| | - Reinhild Roesler
- Core Unit of Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany; (R.R.); (S.W.)
| | - Sebastian Wiese
- Core Unit of Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany; (R.R.); (S.W.)
| | - Benedikt Friemert
- Clinic for Trauma Surgery and Orthopedics, Army Hospital Ulm, 89081 Ulm, Germany
| | - Markus T. Rojewski
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, 89081 Ulm, Germany
| | - Hubert Schrezenmeier
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, 89081 Ulm, Germany
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21
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Eom Y, Eom SY, Lee J, Hwang S, Won J, Kim H, Chung S, Kim HJ, Lee MY. Therapeutic Effects and Underlying Mechanism of SOCS-com Gene-Transfected ADMSCs in Pressure Ulcer Mouse Models. Cells 2023; 12:1840. [PMID: 37508509 PMCID: PMC10378383 DOI: 10.3390/cells12141840] [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: 05/24/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
Although the proportion of ulcer patients with medical problems among the elderly has increased with the extension of human life expectancy, treatment efficiency is drastically low, incurring substantial social costs. MSCs have independent regeneration potential, making them useful in clinical trials of difficult-to-treat diseases. In particular, ADMSCs are promising in the stem cell therapy industry as they can be obtained in vast amounts using non-invasive methods. Furthermore, studies are underway to enhance the regeneration potential of ADMSCs using cytokines, growth factors, and gene delivery to generate highly functional ADMSCs. In this study, key regulators of wound healing, SOCS-1, -3, and -5, were combined to maximize the regenerative potential of ADMSCs in pressure ulcer treatments. After transfecting SOCS-1, -3, -5, and SOCS-com into ADMSCs using a non-viral method, the expression of the inflammatory factors TNF-alpha, INF-gamma, and IL-10 was confirmed. ADMSCs transfected with SOCS-com showed decreased overall expression of inflammatory factors and increased expression of anti-inflammatory factors. Based on these results, we implanted ADMSCs transfected with SOCS-com into a pressure ulcer mouse model to observe their subsequent wound-healing effects. Notably, SOCS-com improved wound closure in ulcers, and reconstruction of the epidermis and dermis was observed. The healing mechanism of ADMSCs transfected with SOCS-com was examined by RNA sequencing. Gene analysis results confirmed that expression changes occurred in genes of key regulators of wound healing, such as chemokines, MMP-1, 9, CSF-2, and IL-33, and that such genetic changes enhanced wound healing in ulcers. Based on these results, we demonstrate the potential of ADMSCs transfected with SOCS-com as an ulcer treatment tool.
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Affiliation(s)
- Youngsic Eom
- Department of Medical Science, College of Medical Sciences, Soonchunhyang University, Asan 31538, Republic of Korea
| | - So Young Eom
- School of Mechanical Engineering, Korea University, Seoul 02841, Republic of Korea
| | - Jeonghwa Lee
- Department of Medical Science, College of Medical Sciences, Soonchunhyang University, Asan 31538, Republic of Korea
| | - Saeyeon Hwang
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 34943, Republic of Korea
| | - Jihee Won
- School of Mechanical Engineering, Korea University, Seoul 02841, Republic of Korea
| | - Hyunsoo Kim
- School of Mechanical Engineering, Korea University, Seoul 02841, Republic of Korea
| | - Seok Chung
- School of Mechanical Engineering, Korea University, Seoul 02841, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
- Center for Brain Technology, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Hye Joung Kim
- Institute of Chemical Engineering Convergence System, Korea University, Seoul 02841, Republic of Korea
| | - Mi-Young Lee
- Department of Medical Science, College of Medical Sciences, Soonchunhyang University, Asan 31538, Republic of Korea
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22
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Shirbaghaee Z, Heidari Keshel S, Rasouli M, Valizadeh M, Hashemi Nazari SS, Hassani M, Soleimani M. Report of a phase 1 clinical trial for safety assessment of human placental mesenchymal stem cells therapy in patients with critical limb ischemia (CLI). Stem Cell Res Ther 2023; 14:174. [PMID: 37408043 PMCID: PMC10324209 DOI: 10.1186/s13287-023-03390-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/29/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND Critical limb ischemia (CLI) is associated with increased risk of tissue loss, leading to significant morbidity and mortality. Therapeutic angiogenesis using cell-based treatments, notably mesenchymal stem cells (MSCs), is essential for enhancing blood flow to ischemic areas in subjects suffering from CLI. The objective of this study was to evaluate the feasibility of using placenta-derived mesenchymal stem cells (P-MSCs) in patients with CLI. METHODS This phase I dose-escalation study investigated P-MSCs in nine CLI patients who were enrolled into each of the two dosage groups (20 × 106 and 60 × 106 cells), delivered intramuscularly twice, two months apart. The incidence of treatment-related adverse events was the primary endpoint. The decrease in inflammatory cytokines, improvement in the ankle-brachial pressure index (ABI), maximum walking distance, vascular collateralization, alleviation of rest pain, healing of ulceration, and avoidance of major amputation in the target leg were the efficacy outcomes. RESULTS All dosages of P-MSCs, including the highest tested dose of 60 × 106 cells, were well tolerated. During the 6-month follow-up period, there was a statistically significant decrease in IL-1 and IFN-γ serum levels following P-MSC treatment. The blood lymphocyte profile of participants with CLI did not significantly differ, suggesting that the injection of allogeneic cells did not cause T-cell proliferation in vivo. We found clinically substantial improvement in rest pain, ulcer healing, and maximum walking distance after P-MSC implantation. In patients with CLI, we performed minor amputations rather than major amputations. Angiography was unable to demonstrate new small vessels formation significantly. CONCLUSION The observations from this phase I clinical study indicate that intramuscular administration of P-MSCs is considered safe and well tolerated and may dramatically improve physical performance and minimize inflammatory conditions in patients with CLI. TRIAL REGISTRATION IRCT, IRCT20210221050446N1. Registered May 09, 2021.
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Affiliation(s)
- Zeinab Shirbaghaee
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Heidari Keshel
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Valizadeh
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Saeed Hashemi Nazari
- Prevention of Cardiovascular Disease Research Center, Department of Epidemiology, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassani
- Department of Vascular and Endovascular Surgery, Ayatollah Taleghani Hospital Research Development Committee, Shahid Beheshti University of Medical Sciences, Velenjak St., Shahid Chamran Highway, Tehran, Iran.
| | - Masoud Soleimani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Applied Cell Sciences and Hematology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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23
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Pennington E, Bell S, Hill JE. Should video laryngoscopy or direct laryngoscopy be used for adults undergoing endotracheal intubation in the pre-hospital setting? A critical appraisal of a systematic review. JOURNAL OF PARAMEDIC PRACTICE : THE CLINICAL MONTHLY FOR EMERGENCY CARE PROFESSIONALS 2023; 15:255-259. [PMID: 38812899 PMCID: PMC7616025 DOI: 10.1002/14651858] [Citation(s) in RCA: 2717] [Impact Index Per Article: 1358.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The safety and utility of endotracheal intubation by paramedics in the United Kingdom is a matter of debate. Considering the controversy surrounding the safety of paramedic-performed endotracheal intubation, any interventions that enhance patient safety should be evaluated for implementation based on solid evidence of their effectiveness. A systematic review performed by Hansel and colleagues (2022) sought to assess compare video laryngoscopes against direct laryngoscopes in clinical practice. This commentary aims to critically appraise the methods used within the review by Hansel et al (2022) and expand upon the findings in the context of clinical practice.
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Affiliation(s)
| | - Steve Bell
- Consultant Paramedic, North West Ambulance Service NHS Trust
| | - James E Hill
- University of Central Lancashire, Colne, Lancashire
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24
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Yusuf Aliyu A, Adeleke OA. Nanofibrous Scaffolds for Diabetic Wound Healing. Pharmaceutics 2023; 15:pharmaceutics15030986. [PMID: 36986847 PMCID: PMC10051742 DOI: 10.3390/pharmaceutics15030986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 03/10/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
Chronic wounds are one of the secondary health complications that develop in individuals who have poorly managed diabetes mellitus. This is often associated with delays in the wound healing process, resulting from long-term uncontrolled blood glucose levels. As such, an appropriate therapeutic approach would be maintaining blood glucose concentration within normal ranges, but this can be quite challenging to achieve. Consequently, diabetic ulcers usually require special medical care to prevent complications such as sepsis, amputation, and deformities, which often develop in these patients. Although several conventional wound dressings, such as hydrogels, gauze, films, and foams, are employed in the treatment of such chronic wounds, nanofibrous scaffolds have gained the attention of researchers because of their flexibility, ability to load a variety of bioactive compounds as single entities or combinations, and large surface area to volume ratio, which provides a biomimetic environment for cell proliferation relative to conventional dressings. Here, we present the current trends on the versatility of nanofibrous scaffolds as novel platforms for the incorporation of bioactive agents suitable for the enhancement of diabetic wound healing.
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Affiliation(s)
- Anna Yusuf Aliyu
- College of Pharmacy, Faculty of Health, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Oluwatoyin A Adeleke
- College of Pharmacy, Faculty of Health, Dalhousie University, Halifax, NS B3H 4R2, Canada
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25
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Yu X, Liu P, Li Z, Zhang Z. Function and mechanism of mesenchymal stem cells in the healing of diabetic foot wounds. Front Endocrinol (Lausanne) 2023; 14:1099310. [PMID: 37008908 PMCID: PMC10061144 DOI: 10.3389/fendo.2023.1099310] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Diabetes has become a global public health problem. Diabetic foot is one of the most severe complications of diabetes, which often places a heavy economic burden on patients and seriously affects their quality of life. The current conventional treatment for the diabetic foot can only relieve the symptoms or delay the progression of the disease but cannot repair damaged blood vessels and nerves. An increasing number of studies have shown that mesenchymal stem cells (MSCs) can promote angiogenesis and re-epithelialization, participate in immune regulation, reduce inflammation, and finally repair diabetic foot ulcer (DFU), rendering it an effective means of treating diabetic foot disease. Currently, stem cells used in the treatment of diabetic foot are divided into two categories: autologous and allogeneic. They are mainly derived from the bone marrow, umbilical cord, adipose tissue, and placenta. MSCs from different sources have similar characteristics and subtle differences. Mastering their features to better select and use MSCs is the premise of improving the therapeutic effect of DFU. This article reviews the types and characteristics of MSCs and their molecular mechanisms and functions in treating DFU to provide innovative ideas for using MSCs to treat diabetic foot and promote wound healing.
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Affiliation(s)
- Xiaoping Yu
- School of Medicine and Nursing, Chengdu University, Chengdu, Sichuan, China
| | - Pan Liu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zheng Li
- People’s Hospital of Jiulongpo District, Chongqing, China
| | - Zhengdong Zhang
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Orthopedics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
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26
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Raja JM, Maturana MA, Kayali S, Khouzam A, Efeovbokhan N. Diabetic foot ulcer: A comprehensive review of pathophysiology and management modalities. World J Clin Cases 2023; 11:1684-1693. [PMID: 36970004 PMCID: PMC10037283 DOI: 10.12998/wjcc.v11.i8.1684] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 01/08/2023] [Accepted: 02/17/2023] [Indexed: 03/07/2023] Open
Abstract
Diabetic foot ulcer (DFU) is a debilitating and severe manifestation of uncontrolled and prolonged diabetes that presents as ulceration, usually located on the plantar aspect of the foot. Approximately 15% of individuals with diabetes will eventually develop DFU, and 14%-24% of them will require amputation of the ulcerated foot due to bone infection or other ulcer-related complications. The pathologic mechanisms underlying DFU are comprise a triad: Neuropathy, vascular insufficiency, and secondary infection due to trauma of the foot. Standard local and invasive care along with novel approaches like stem cell therapy pave the way to reduce morbidity, decrease amputations, and prevent mortality from DFU. In this manuscript, we review the current literature with focus on the pathophysiology, preventive options, and definitive management of DFU.
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Affiliation(s)
- Joel M Raja
- Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN 38119, United States
| | - Miguel A Maturana
- Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN 38119, United States
| | - Sharif Kayali
- Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN 38119, United States
| | - Amir Khouzam
- Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN 38119, United States
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27
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Microangiopathy in Rheumatic Diseases. Life (Basel) 2023; 13:life13020491. [PMID: 36836847 PMCID: PMC9965541 DOI: 10.3390/life13020491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/19/2023] [Accepted: 02/03/2023] [Indexed: 02/12/2023] Open
Abstract
Capillaries are part of the microcirculation, which consists of arterioles, capillaries, and venules and are the connecting link between the arterial and venous blood circulation [...].
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28
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Huerta CT, Voza FA, Ortiz YY, Liu ZJ, Velazquez OC. Mesenchymal stem cell-based therapy for non-healing wounds due to chronic limb-threatening ischemia: A review of preclinical and clinical studies. Front Cardiovasc Med 2023; 10:1113982. [PMID: 36818343 PMCID: PMC9930203 DOI: 10.3389/fcvm.2023.1113982] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/12/2023] [Indexed: 02/04/2023] Open
Abstract
Progressive peripheral arterial disease (PAD) can result in chronic limb-threatening ischemia (CLTI) characterized by clinical complications including rest pain, gangrene and tissue loss. These complications can propagate even more precipitously in the setting of common concomitant diseases in patients with CLTI such as diabetes mellitus (DM). CLTI ulcers are cutaneous, non-healing wounds that persist due to the reduced perfusion and dysfunctional neovascularization associated with severe PAD. Existing therapies for CLTI are primarily limited to anatomic revascularization and medical management of contributing factors such as atherosclerosis and glycemic control. However, many patients fail these treatment strategies and are considered "no-option," thereby requiring extremity amputation, particularly if non-healing wounds become infected or fulminant gangrene develops. Given the high economic burden imposed on patients, decreased quality of life, and poor survival of no-option CLTI patients, regenerative therapies aimed at neovascularization to improve wound healing and limb salvage hold significant promise. Cell-based therapy, specifically utilizing mesenchymal stem/stromal cells (MSCs), is one such regenerative strategy to stimulate therapeutic angiogenesis and tissue regeneration. Although previous reviews have focused primarily on revascularization outcomes after MSC treatments of CLTI with less attention given to their effects on wound healing, here we review advances in pre-clinical and clinical studies related to specific effects of MSC-based therapeutics upon ischemic non-healing wounds associated with CLTI.
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Affiliation(s)
- Carlos Theodore Huerta
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Francesca A. Voza
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Yulexi Y. Ortiz
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Zhao-Jun Liu
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States,Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL, United States,*Correspondence: Omaida C. Velazquez, ; Zhao-Jun Liu,
| | - Omaida C. Velazquez
- DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States,Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL, United States,*Correspondence: Omaida C. Velazquez, ; Zhao-Jun Liu,
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29
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Jakl V, Ehmele M, Winkelmann M, Ehrenberg S, Eiseler T, Friemert B, Rojewski MT, Schrezenmeier H. A novel approach for large-scale manufacturing of small extracellular vesicles from bone marrow-derived mesenchymal stromal cells using a hollow fiber bioreactor. Front Bioeng Biotechnol 2023; 11:1107055. [PMID: 36761296 PMCID: PMC9904364 DOI: 10.3389/fbioe.2023.1107055] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 01/09/2023] [Indexed: 01/25/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are promising therapeutic candidates in a variety of diseases due to having immunomodulatory and pro-regenerative properties. In recent years, MSC-derived small extracellular vesicles (sEVs) have attracted increasing interest as a possible alternative to conventional cell therapy. However, translational processes of sEVs for clinical applications are still impeded by inconsistencies regarding isolation procedures and culture conditions. We systematically compared different methods for sEV isolation from conditioned media of ex vivo expanded bone marrow-derived MSCs and demonstrated considerable variability of quantity, purity, and characteristics of sEV preparations obtained by these methods. The combination of cross flow filtration with ultracentrifugation for sEV isolation resulted in sEVs with similar properties as compared to isolation by differential centrifugation combined with ultracentrifugation, the latter is still considered as gold standard for sEV isolation. In contrast, sEV isolation by a combination of precipitation with polyethylene glycol and ultracentrifugation as well as cross flow filtration and size exclusion chromatography resulted in sEVs with different characteristics, as shown by surface antigen expression patterns. The MSC culture requires a growth-promoting supplement, such as platelet lysate, which contains sEVs itself. We demonstrated that MSC culture with EV-depleted platelet lysate does not alter MSC characteristics, and conditioned media of such MSC cultures provide sEV preparations enriched for MSC-derived sEVs. The results from the systematic stepwise evaluation of various aspects were combined with culture of MSCs in a hollow fiber bioreactor. This resulted in a strategy using cross flow filtration with subsequent ultracentrifugation for sEV isolation. In conclusion, this workflow provides a semi-automated, efficient, large-scale-applicable, and good manufacturing practice (GMP)-grade approach for the generation of sEVs for clinical use. The use of EV-depleted platelet lysate is an option to further increase the purity of MSC-derived sEVs.
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Affiliation(s)
- Viktoria Jakl
- Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany
| | - Melanie Ehmele
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, Ulm, Germany
| | - Martina Winkelmann
- Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany
| | - Simon Ehrenberg
- Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany
| | - Tim Eiseler
- Clinic of Internal Medicine I, University Hospital Ulm, Ulm, Germany
| | - Benedikt Friemert
- Clinic for Trauma Surgery and Orthopedics, Army Hospital Ulm, Ulm, Germany
| | - Markus Thomas Rojewski
- Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, Ulm, Germany
| | - Hubert Schrezenmeier
- Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, Ulm, Germany
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30
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Wei Q, Liu X, Su JL, Wang YX, Chu ZQ, Ma K, Huang QL, Li HH, Fu XB, Zhang CP. Small extracellular vesicles from mesenchymal stem cells: A potential Weapon for chronic non-healing wound treatment. Front Bioeng Biotechnol 2023; 10:1083459. [PMID: 36704302 PMCID: PMC9872203 DOI: 10.3389/fbioe.2022.1083459] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
Chronic non-healing wounds have posed a severe threat to patients mentally and physically. Behavior dysregulation of remaining cells at wound sites is recognized as the chief culprit to destroy healing process and hinders wound healing. Therefore, regulating and restoring normal cellular behavior is the core of chronic non-healing wound treatment. In recent years, the therapy with mesenchymal stem cells (MSCs) has become a promising option for chronic wound healing and the efficacy has increasingly been attributed to their exocrine functions. Small extracellular vesicles derived from MSCs (MSC-sEVs) are reported to benefit almost all stages of wound healing by regulating the cellular behavior to participate in the process of inflammatory response, angiogenesis, re-epithelization, and scarless healing. Here, we describe the characteristics of MSC-sEVs and discuss their therapeutic potential in chronic wound treatment. Additionally, we also provide an overview of the application avenues of MSC-sEVs in wound treatment. Finally, we summarize strategies for large-scale production and engineering of MSC-sEVs. This review may possibly provide meaningful guidance for chronic wound treatment with MSC-sEVs.
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Affiliation(s)
- Qian Wei
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Xi Liu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Jian-Long Su
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Ya-Xi Wang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Zi-Qiang Chu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Kui Ma
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
- Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Research Unit of Trauma Care, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China
| | - Qi-Lin Huang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Hai-Hong Li
- Department of Wound Repair, Institute of Wound Repair and Regeneration Medicine, Southern University of Science and Technology Hospital, Southern University of Science and Technology School of Medicine, Shenzhen, China
| | - Xiao-Bing Fu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
- Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Research Unit of Trauma Care, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China
| | - Cui-Ping Zhang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
- Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Research Unit of Trauma Care, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China
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31
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Dama G, Du J, Zhu X, Liu Y, Lin J. Bone marrow-derived mesenchymal stem cells: A promising therapeutic option for the treatment of diabetic foot ulcers. Diabetes Res Clin Pract 2023; 195:110201. [PMID: 36493913 DOI: 10.1016/j.diabres.2022.110201] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 08/31/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022]
Abstract
Chronic wounds fail to heal through the three normal stages of healing (inflammatory, proliferative, and remodelling), resulting in a chronic tissue injury that is not repaired within the average time limit. Patients suffering from type 1 and type 2 diabetes are prone to develop diabetic foot ulcers (DFUs), which commonly develop into chronic wounds that are non treatable with conventional therapies. DFU develops due to various risk factors, such as peripheral neuropathy, peripheral vascular disease, arterial insufficiency, foot deformities, trauma and impaired resistance to infection. DFUs have gradually become a major problem in the health care system worldwide. In this review, we not only focus on the pathogenesis of DFU but also comprehensively summarize the outcomes of preclinical and clinical studies thus far and the potential therapeutic mechanism of bone marrow-derived mesenchymal stem cells (BMSCs) for the treatment of DFU. Based on the published results, BMSC transplantation can contribute to wound healing through growth factor secretion, anti-inflammation, differentiation into tissue-specific cells, neovascularization, re-epithelialization and angiogenesis in DFUs. Moreover, clinical trials showed that BMSC treatment in patients with diabetic ulcers improved ulcer healing and the ankle-brachial index, ameliorated pain scores, and enhanced claudication walking distances with no reported complications. In conclusion, although BMSC transplantation exhibits promising therapeutic potential in DFU treatment, additional studies should be performed to confirm their efficacy and long-term safety in DFU patients.
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Affiliation(s)
- Ganesh Dama
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; Department of Community Health, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Malaysia
| | - Jiang Du
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Medical Engineering, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China
| | - Xinxing Zhu
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Medical Engineering, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China
| | - Yanli Liu
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Life Sciences and Technology, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China.
| | - Juntang Lin
- Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Medical Engineering, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China; College of Life Sciences and Technology, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China.
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Camesi A, Wettstein R, Valido E, Nyfeler N, Stojic S, Glisic M, Stoyanov J, Bertolo A. Advancements in cell-based therapies for the treatment of pressure injuries: A systematic review of interventional studies. J Tissue Eng 2023; 14:20417314231201071. [PMID: 38029017 PMCID: PMC10658773 DOI: 10.1177/20417314231201071] [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: 06/15/2023] [Accepted: 08/29/2023] [Indexed: 12/01/2023] Open
Abstract
The high recurrence and complications associated with severe pressure injuries (PI) necessitate the exploration of advanced treatments, such as cell-based therapies, to facilitate wound healing. Such techniques harness the ability of different cell types to promote angiogenesis, re-epithelialization of the skin, and tissue regeneration. This systematic review explores the efficacy of cell-based therapies and tissue engineering in treating deep PI. We searched for interventional studies using cells in the treatment of PI in adults in four online libraries (PubMed, Embase, Ovid Medline, and Cochrane; latest search 10th June 2023). We found one randomized clinical trial (RCT), two non-RCT, and three pre-post studies, comprising 481 study participants with PI (253 intervention/228 controls). The risk of bias was categorized as moderate due to minimal bias in outcome measurements, or high owing to unclear patient randomization methods, as assessed by the ROBINS-I, NIH, and RoB-2 tools. Four cell types were identified in the context of cell-based therapies of PI: bone marrow mononuclear stem cells (BM-MNCs, n = 2); hematopoietic derived stem cells (HSC, n = 1); macrophages and activated macrophage suspensions (AMS, n = 2); and cryopreserved placental membrane containing viable cells (vCPM, n = 1). Wound healing outcomes were observed in patients undergoing cell-based therapies, including complete wound closure (AMS, vCPM; n = 142), faster healing rate (BM-MNCs, AMS; n = 146), improved granulation tissue formation (HSC, n = 3) and shorter hospitalization time (BM-MNCs; n = 108) compared to standard of care, with no adverse reactions. PI healing rate decreased only in one study with BM-MNC therapy, compared to control (n = 86). Based on the available data, though with limited evidence, it seems that macrophage deployment showed the most favorable outcomes. The results indicate that cell-based therapies offer a potential avenue for enhancing wound healing and tissue repair in PI; however, more extensive research is needed in this domain.
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Affiliation(s)
- Alianda Camesi
- SCI Population Biobanking & Translational Research Group, Swiss Paraplegic Research, Nottwil, Switzerland
| | - Reto Wettstein
- SCI Population Biobanking & Translational Research Group, Swiss Paraplegic Research, Nottwil, Switzerland
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital of Basel, Basel, Switzerland
| | - Ezra Valido
- SCI Population Biobanking & Translational Research Group, Swiss Paraplegic Research, Nottwil, Switzerland
- Department of Health Sciences, University of Lucerne, Lucerne, Switzerland
| | - Nicole Nyfeler
- SCI Population Biobanking & Translational Research Group, Swiss Paraplegic Research, Nottwil, Switzerland
| | - Stevan Stojic
- Cardiometabolic and Respiratory Research, Swiss Paraplegic Research, Nottwil, Switzerland
| | - Marija Glisic
- Cardiometabolic and Respiratory Research, Swiss Paraplegic Research, Nottwil, Switzerland
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - Jivko Stoyanov
- SCI Population Biobanking & Translational Research Group, Swiss Paraplegic Research, Nottwil, Switzerland
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - Alessandro Bertolo
- SCI Population Biobanking & Translational Research Group, Swiss Paraplegic Research, Nottwil, Switzerland
- Department of Orthopaedic Surgery, University of Bern, Bern Inselspital, Bern, Switzerland
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Mahmoudvand G, Karimi Rouzbahani A, Razavi ZS, Mahjoor M, Afkhami H. Mesenchymal stem cell therapy for non-healing diabetic foot ulcer infection: New insight. Front Bioeng Biotechnol 2023; 11:1158484. [PMID: 37122856 PMCID: PMC10133463 DOI: 10.3389/fbioe.2023.1158484] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/31/2023] [Indexed: 05/02/2023] Open
Abstract
Diabetic foot ulcer (DFU) is considered the most catastrophic complication of diabetes mellitus (DM), leading to repeated hospitalizations, infection, gangrene, and finally amputation of the limb. In patients suffering from diabetes mellitus, the wound-healing process is impaired due to various factors such as endothelial dysfunction and synthesis of advanced glycation end-products, hence, conventional therapeutic interventions might not be effective. With increasing therapeutic applications of mesenchymal stem cells (MSCs) in recent years, their potential as a method for improving the wound-healing process has gained remarkable attention. In this field, mesenchymal stem cells exert their beneficial effects through immunomodulation, differentiation into the essential cells at the site of ulcers, and promoting angiogenesis, among others. In this article, we review cellular and molecular pathways through which mesenchymal stem cell therapy reinforces the healing process in non-healing Diabetic foot ulcers.
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Affiliation(s)
- Golnaz Mahmoudvand
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Arian Karimi Rouzbahani
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Zahra Sadat Razavi
- Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohamad Mahjoor
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
- *Correspondence: Hamed Afkhami,
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Yang L, Rong GC, Wu QN. Diabetic foot ulcer: Challenges and future. World J Diabetes 2022; 13:1014-1034. [PMID: 36578870 PMCID: PMC9791573 DOI: 10.4239/wjd.v13.i12.1014] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/07/2022] [Accepted: 11/28/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetic foot ulcers (DFUs) have become one of the important causes of mortality and morbidity in patients with diabetes, and they are also a common cause of hospitalization, which places a heavy burden on patients and society. The prevention and treatment of DFUs requires multidisciplinary management. By controlling various risk factors, such as blood glucose levels, blood pressure, lipid levels and smoking cessation, local management of DFUs should be strengthened, such as debridement, dressing, revascularization, stem cell decompression and oxygen therapy. If necessary, systemic anti-infection treatment should be administered. We reviewed the progress in the clinical practice of treating DFUs in recent years, such as revascularization, wound repair, offloading, stem cell transplantation, and anti-infection treatment. We also summarized and prospectively analyzed some new technologies and measurements used in the treatment of DFUs and noted the future challenges and directions for the development of DFU treatments.
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Affiliation(s)
- Li Yang
- Department of Endocrinology, Dazu Hospital of Chongqing Medical University, The People's Hospital of Dazu, Chongqing 402360, China
| | - Gui-Chuan Rong
- Department of Gynaecology, Dazu Hospital of Chongqing Medical University, The People's Hospital of Dazu, Chongqing 402360, China
| | - Qi-Nan Wu
- Department of Endocrinology, Dazu Hospital of Chongqing Medical University, The People's Hospital of Dazu, Chongqing 402360, China
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Mohamed SA, Duffy A, McInerney V, Krawczyk J, Hayat A, Naughton S, Finnerty A, Holohan M, Liew A, Tubassam M, Walsh SR, O'Brien T, Howard L. Marrow changes and reduced proliferative capacity of mesenchymal stromal cells from patients with "no-option" critical limb ischemia; observations on feasibility of the autologous approach from a clinical trial. Cytotherapy 2022; 24:1259-1267. [PMID: 35999133 DOI: 10.1016/j.jcyt.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/23/2022] [Accepted: 07/07/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND AIMS Approximately 1 in 3 patients with critical limb ischemia (CLI) are not suitable for surgical or endovascular revascularization. Those "no-option" patients are at high risk of amputation and death. Autologous bone marrow mesenchymal stromal cells (MSCs) may provide a limb salvage option. In this study, bone marrow characteristics and expansion potentials of CLI-derived MSCs produced during a phase 1b clinical trial were compared with young healthy donor MSCs to determine the feasibility of an autologous approach. Cells were produced under Good Manufacturing Practice conditions and underwent appropriate release testing. METHODS Five bone marrow aspirates derived from patients with CLI were compared with six young healthy donor marrows in terms of number of colony-forming units-fibroblast (CFUF) and mononuclear cells. The mean population doubling times and final cell yields were used to evaluate expansion potential. The effect of increasing the volume of marrow on the CFUF count and final cell yield was evaluated by comparing 5 CLI-derived MSCs batches produced from a targeted 30 mL of marrow aspirate to five batches produced from a targeted 100 mL of marrow. RESULTS CLI-derived marrow aspirate showed significantly lower numbers of mononuclear cells with no difference in the number of CFUFs when compared with healthy donors' marrow aspirate. CLI-derived MSCs showed a significantly longer population doubling time and reduced final cell yield compared with young healthy donors' MSCs. The poor growth kinetics of CLI MSCs were not mitigated by increasing the bone marrow aspirate from 30 to 100 mL. CONCLUSIONS In addition to the previously reported karyotype abnormalities in MSCs isolated from patients with CLI, but not in cells from healthy donors, the feasibility of autologous transplantation of bone marrow MSCs for patients with no-option CLI is further limited by the increased expansion time and the reduced cell yield.
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Affiliation(s)
- Sara Azhari Mohamed
- Regenerative Medicine Institute, National University of Ireland Galway, Galway, Ireland
| | - Aoife Duffy
- Centre for Cell Manufacturing Ireland, National University of Ireland Galway, Galway, Ireland
| | - Veronica McInerney
- HRB Clinical Research Facility, National University of Ireland Galway, Galway, Ireland
| | - Janusz Krawczyk
- Galway Blood and Tissue Establishment, National University of Ireland Galway, Galway, Ireland
| | - Amjad Hayat
- Galway Blood and Tissue Establishment, National University of Ireland Galway, Galway, Ireland
| | - Sean Naughton
- Galway Blood and Tissue Establishment, National University of Ireland Galway, Galway, Ireland
| | - Andrew Finnerty
- Centre for Cell Manufacturing Ireland, National University of Ireland Galway, Galway, Ireland
| | - Miriam Holohan
- Centre for Cell Manufacturing Ireland, National University of Ireland Galway, Galway, Ireland
| | - Aaron Liew
- School of Medicine, National University of Ireland Galway, Galway, Ireland
| | - Muhammad Tubassam
- Department of Vascular Surgery, University Hospital Galway, Galway, Ireland
| | - Stewart Redmond Walsh
- School of Medicine, National University of Ireland Galway, Galway, Ireland; Department of Vascular Surgery, University Hospital Galway, Galway, Ireland
| | - Timothy O'Brien
- Regenerative Medicine Institute, National University of Ireland Galway, Galway, Ireland; Centre for Cell Manufacturing Ireland, National University of Ireland Galway, Galway, Ireland; School of Medicine, National University of Ireland Galway, Galway, Ireland
| | - Linda Howard
- Regenerative Medicine Institute, National University of Ireland Galway, Galway, Ireland.
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Sharma P, Kumar A, Dey AD. Cellular Therapeutics for Chronic Wound Healing: Future for Regenerative Medicine. Curr Drug Targets 2022; 23:1489-1504. [PMID: 35748548 DOI: 10.2174/138945012309220623144620] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 12/10/2021] [Accepted: 02/01/2022] [Indexed: 01/25/2023]
Abstract
Chronic wounds are associated with significant morbidity and mortality, which demand long-term effective treatment and represent a tremendous financial strain on the global healthcare systems. Regenerative medicines using stem cells have recently become apparent as a promising approach and are an active zone of investigation. They hold the potential to differentiate into specific types of cells and thus possess self-renewable, regenerative, and immune-modulatory effects. Furthermore, with the rise of technology, various cell therapies and cell types such as Bone Marrow and Adipose-derived Mesenchymal Cell (ADMSC), Endothelial Progenitor Cells (EPCs), Embryonic Stem Cells (ESCs), Mesenchymal Stem Cell (MSCs), and Pluripotent Stem Cells (PSCs) are studied for their therapeutic impact on reparative processes and tissue regeneration. Cell therapy has proven to have substantial control over enhancing the quality and rate of skin regeneration and wound restoration. The literature review brings to light the mechanics of wound healing, abnormalities resulting in chronic wounds, and the obstacles wound care researchers face, thus exploring the multitude of opportunities for potential improvement. Also, the review is focused on providing particulars on the possible cell-derived therapeutic choices and their associated challenges in healing, in the context of clinical trials, as solutions to these challenges will provide fresh and better future opportunities for improved study design and therefore yield a substantial amount of data for the development of more specialized treatments.
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Affiliation(s)
- Preety Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.,Government Pharmacy College Kangra, Nagrota Bhagwan, Himachal Pradesh, India
| | - Arun Kumar
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Asmita Deka Dey
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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37
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Platelet-rich plasma: a comparative and economical therapy for wound healing and tissue regeneration. Cell Tissue Bank 2022; 24:285-306. [PMID: 36222966 PMCID: PMC9555256 DOI: 10.1007/s10561-022-10039-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 09/10/2022] [Indexed: 11/17/2022]
Abstract
Rise in the incidences of chronic degenerative diseases with aging makes wound care a socio-economic burden and unceasingly necessitates a novel, economical, and efficient wound healing treatment. Platelets have a crucial role in hemostasis and thrombosis by modulating distinct mechanistic phases of wound healing, such as promoting and stabilizing the clot. Platelet-rich plasma (PRP) contains a high concentration of platelets than naïve plasma and has an autologous origin with no immunogenic adverse reactions. As a consequence, PRP has gained significant attention as a therapeutic to augment the healing process. Since the past few decades, a robust volume of research and clinical trials have been performed to exploit extensive role of PRP in wound healing/tissue regeneration. Despite these rigorous studies and their application in diversified medical fields, efficacy of PRP-based therapies is continuously questioned owing to the paucity of large samplesizes, controlled clinical trials, and standard protocols. This review systematically delineates the process of wound healing and involvement of platelets in tissue repair mechanisms. Additionally, emphasis is laid on PRP, its preparation methods, handling, classification,application in wound healing, and PRP as regenerative therapeutics combined with biomaterials and mesenchymal stem cells (MSCs).
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38
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Bray ER, Kirsner RS, Badiavas EV. Mesenchymal Stem Cell-Derived Extracellular Vesicles as an Advanced Therapy for Chronic Wounds. Cold Spring Harb Perspect Biol 2022; 14:a041227. [PMID: 35817513 PMCID: PMC9524280 DOI: 10.1101/cshperspect.a041227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Chronic wounds are a significant challenge for patients, healthcare providers, and healthcare systems. Chronic wounds develop due to a complex interplay between chronic inflammation, tissue hypoxia, and oxidative stress, often occurring in the setting of advancing age. Ideally, new therapeutics should address all the components of chronic wound pathophysiology. Mesenchymal stem cell (MSC) therapies show significant promise to promote healing of chronic wounds. Extracellular vesicles (EVs) secreted by MSCs mediate many of their beneficial effects. We review the evidence demonstrating that MSC-EVs target the processes leading to chronic wounds. Additionally, we discuss how MSCs can be influenced to generate more potent wound healing EVs. Finally, we highlight the current state of EV clinical trials for wound healing and important preclinical studies that will lead to optimal use of MSC-EVs for patient care.
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Affiliation(s)
- Eric R Bray
- Phillip Frost Department of Dermatology and Cutaneous Surgery
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
| | | | - Evangelos V Badiavas
- Phillip Frost Department of Dermatology and Cutaneous Surgery
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
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Chakraborty R, Borah P, Dutta PP, Sen S. Evolving spectrum of diabetic wound: Mechanistic insights and therapeutic targets. World J Diabetes 2022; 13:696-716. [PMID: 36188143 PMCID: PMC9521443 DOI: 10.4239/wjd.v13.i9.696] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 06/12/2022] [Accepted: 08/18/2022] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus is a chronic metabolic disorder resulting in an increased blood glucose level and prolonged hyperglycemia, causes long term health conse-quences. Chronic wound is frequently occurring in diabetes patients due to compromised wound healing capability. Management of wounds in diabetic patients remains a clinical challenge despite many advancements in the field of science and technology. Increasing evidence indicates that alteration of the biochemical milieu resulting from alteration in inflammatory cytokines and matrix metalloproteinase, decrease in fibroblast and keratinocyte functioning, neuropathy, altered leukocyte functioning, infection, etc., plays a significant role in impaired wound healing in diabetic people. Apart from the current pharmacotherapy, different other approaches like the use of conventional drugs, antidiabetic medication, antibiotics, debridement, offloading, platelet-rich plasma, growth factor, oxygen therapy, negative pressure wound therapy, low-level laser, extracorporeal shock wave bioengineered substitute can be considered in the management of diabetic wounds. Drugs/therapeutic strategy that induce angiogenesis and collagen synthesis, inhibition of MMPs, reduction of oxidative stress, controlling hyperglycemia, increase growth factors, regulate inflammatory cytokines, cause NO induction, induce fibroblast and keratinocyte proliferation, control microbial infections are considered important in controlling diabetic wound. Further, medicinal plants and/or phytoconstituents also offer a viable alternative in the treatment of diabetic wound. The focus of the present review is to highlight the molecular and cellular mechanisms, and discuss the drug targets and treatment strategies involved in the diabetic wound.
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Affiliation(s)
- Raja Chakraborty
- Institute of Pharmacy, Assam Don Bosco University, Kamrup 782402, Assam, India
| | - Pobitra Borah
- School of Pharmacy, Graphic Era Hill University, Dehradun 248002, Uttarakhand, India
| | - Partha Pratim Dutta
- Faculty of Pharmaceutical Science, Assam down town University, Guwahati 781026, Assam, India
| | - Saikat Sen
- Faculty of Pharmaceutical Science, Assam down town University, Guwahati 781026, Assam, India
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Sun Y, Zhao J, Zhang L, Li Z, Lei S. Effectiveness and safety of stem cell therapy for diabetic foot: a meta-analysis update. Stem Cell Res Ther 2022; 13:416. [PMID: 35964145 PMCID: PMC9375292 DOI: 10.1186/s13287-022-03110-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 08/02/2022] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Diabetic foot (DF) is one of the most common and serious complications of diabetes mellitus (DM), which brings great psychological and economic pressure to patients. This study aimed to evaluate the efficacy of stem cells in the treatment of diabetic foot. METHODS All relevant studies in Cochrane, Embase, PubMed, Web of Science, China National Knowledge Infrastructure, and WanFang databases were systematically searched for meta-analysis. The outcomes consisted of ulcer or wound healing rate, amputation rate, new vessels, ankle-brachial index (ABI), transcutaneous oxygen pressure (TcPO2), pain-free walking distance, and rest pain score. Dichotomous outcomes were described as risk ratios (RR) with 95% confidence intervals (CIs), while continuous data were presented as standardized mean differences (SMDs) with 95% CIs. Statistical analysis was performed with RevMan 5.3 software. RESULTS A total of 14 studies with 683 participants were included in the meta-analysis. Meta-analysis showed that stem cell therapy was more effective than conventional therapy in terms of ulcer or wound healing rate [OR = 8.20 (5.33, 12.62)], improvement in lower extremity ischemia(new vessels) [OR = 16.48 (2.88, 94.18)], ABI [MD = 0.13 (0.04, 0.08)], TcO2[MD = 4.23 (1.82, 6.65)], pain-free walking distance [MD = 220.79 (82.10, 359.48)], and rest pain score [MD = - 1.94 (- 2.50, - 1.39)], while the amputation rate was significantly decreased [OR = 0.19 (0.10, 0.36)]. CONCLUSIONS The meta-analysis of the current studies has shown that stem cells are significantly more effective than traditional methods in the treatment of diabetic foot and can improve the quality of life of patients after treatment. Future studies should conduct large-scale, randomized, double-blind, placebo-controlled, multicenter trials with high-quality long-term follow-up to demonstrate the most effective cell types and therapeutic parameters for the treatment of diabetic foot.
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Affiliation(s)
- Yuming Sun
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
| | - Jinhong Zhao
- School of Health Policy and Management, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Lifang Zhang
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
| | - Zhexuan Li
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
| | - Shaorong Lei
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
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Krasilnikova OA, Baranovskii DS, Lyundup AV, Shegay PV, Kaprin AD, Klabukov ID. Stem and Somatic Cell Monotherapy for the Treatment of Diabetic Foot Ulcers: Review of Clinical Studies and Mechanisms of Action. Stem Cell Rev Rep 2022; 18:1974-1985. [PMID: 35476187 DOI: 10.1007/s12015-022-10379-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2022] [Indexed: 02/06/2023]
Abstract
Diabetic foot ulcer (DFU) is one of the most severe complications of diabetes mellitus, often resulting in a limb amputation. A cell-based therapy is a highly promising approach for an effective DFU treatment. However, there is no consensus regarding the most effective cell type for DFU treatment. Various cell types contribute to chronic wound healing via different mechanisms. For example, application of keratinocytes can stimulate migration of native keratinocytes from the wound edge, while mesenchymal stem cells can correct limb ischemia. To assess the effectiveness of a certain cell type, it should be administered as a monotherapy without other substances and procedures that have additional therapeutic effects. In the present review, we described therapeutic effects of various cells and provided an overview of clinical studies in which stem and somatic cell-based therapy was administered as a monotherapy. Topical application of somatic cells contributes to DFU healing only, while injection of mesenchymal stem cells and mononuclear cells can break a pathophysiological chain leading from insufficient blood supply to DFU development. At the same time, the systemic use of mesenchymal stem cells carries greater risks. Undoubtedly, cell therapy is a potent tool for the treatment of DFU. However, it is vital to conduct further high-quality clinical research to determine the most effective cell type, dosage and way of administration for DFU treatment. Ischemia, neuropathy and neuro-ischemia are underlying factors of diabetic foot ulcer. Stem and somatic cells monotherapy can improve chronic wound healing via different mechanisms.
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Affiliation(s)
- O A Krasilnikova
- A. Tsyb Medical Radiological Research Center - branch of the National Medical Research Radiological Center, Obninsk, Russia
| | - D S Baranovskii
- A. Tsyb Medical Radiological Research Center - branch of the National Medical Research Radiological Center, Obninsk, Russia
- Research and Educational Resource Center for Cellular Technologies, Peoples' Friendship University of Russia (RUDN University), Moscow, Russia
| | - A V Lyundup
- Research and Educational Resource Center for Cellular Technologies, Peoples' Friendship University of Russia (RUDN University), Moscow, Russia
| | - P V Shegay
- Department of Regenerative Medicine, National Medical Research Radiological Center, Obninsk, Russia
| | - A D Kaprin
- Research and Educational Resource Center for Cellular Technologies, Peoples' Friendship University of Russia (RUDN University), Moscow, Russia
- Department of Regenerative Medicine, National Medical Research Radiological Center, Obninsk, Russia
| | - I D Klabukov
- Research and Educational Resource Center for Cellular Technologies, Peoples' Friendship University of Russia (RUDN University), Moscow, Russia.
- Department of Regenerative Medicine, National Medical Research Radiological Center, Obninsk, Russia.
- Obninsk Institute for Nuclear Power Engineering of the National Research Nuclear University MEPhI, Obninsk, Russia.
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Abstract
Chronic wounds are characterized by their inability to heal within an expected time frame and have emerged as an increasingly important clinical problem over the past several decades, owing to their increasing incidence and greater recognition of associated morbidity and socio-economic burden. Even up to a few years ago, the management of chronic wounds relied on standards of care that were outdated. However, the approach to these chronic conditions has improved, with better prevention, diagnosis and treatment. Such improvements are due to major advances in understanding of cellular and molecular aspects of basic science, in innovative and technological breakthroughs in treatment modalities from biomedical engineering, and in our ability to conduct well-controlled and reliable clinical research. The evidence-based approaches resulting from these advances have become the new standard of care. At the same time, these improvements are tempered by the recognition that persistent gaps exist in scientific knowledge of impaired healing and the ability of clinicians to reduce morbidity, loss of limb and mortality. Therefore, taking stock of what is known and what is needed to improve understanding of chronic wounds and their associated failure to heal is crucial to ensuring better treatments and outcomes.
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Askø Andersen J, Rasmussen A, Frimodt-Møller M, Engberg S, Steeneveld E, Kirketerp-Møller K, O'Brien T, Rossing P. Novel topical allogeneic bone-marrow-derived mesenchymal stem cell treatment of hard-to-heal diabetic foot ulcers: a proof of concept study. Stem Cell Res Ther 2022; 13:280. [PMID: 35765085 PMCID: PMC9241309 DOI: 10.1186/s13287-022-02951-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/12/2022] [Indexed: 11/10/2022] Open
Abstract
Aim The aim of this study was to investigate safety of treating diabetic foot ulcers with a topically administered mesenchymal stem cell product. Method Individuals with diabetes, peripheral neuropathy, toe blood pressure > 39 mmHg and non-infected foot ulcers with duration of four to fifty-two weeks were screened. Participants were treated with a one-time application of a topically applied allogeneic cellular product containing CD362 enriched mesenchymal stem cells suspended in a collagen solution. Participants were subsequently followed for seven months to gather information on adverse event and serious adverse events. Results/discussion A total of sixteen individuals were screened, of whom two were included. The included participants incurred a total of seven adverse events and one serious adverse event. Increased exudation from the treated diabetic foot ulcer was observed for both participants and a connection to investigational medicinal product was suspected. The increased exudation was resolved within one week after application of investigational medicinal product, without any further complications. The serious adverse event consisted of a hospital admission due to neurological symptoms, which were assumed to be caused by hypoglycemia, with no suspected correlation to the investigational medicinal product. None of the other observed adverse events were suspected to be associated with the investigational medicinal product. Conclusion This study presents data from two individuals with a diabetic foot ulcer treated with a novel topical mesenchymal stem cell product. An adverse event observed for both participants was suspected to be associated to the investigational medicinal product, i.e., increased exudation, which was resolved within one week, did not lead to further complications and can easily be remedied by choosing bandages with higher absorption capacity or increasing frequency of bandage changes. This study lays the groundwork for further large scale randomized clinical studies. Trial registration: EudraCT number 2015-005580-16. Registered 12/06-2018.
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Affiliation(s)
- Jonas Askø Andersen
- Diabetes Complications Research, Steno Diabetes Center Copenhagen, Borgmester Ib Juuls Vej 83, 2730, Herlev, Denmark. .,Orthopedic Department, Nordsjællands Hospital Hilleroed, Dyrehave Vej 2, 3400, Hilleroed, Denmark.
| | - Anne Rasmussen
- Diabetes Complications Research, Steno Diabetes Center Copenhagen, Borgmester Ib Juuls Vej 83, 2730, Herlev, Denmark
| | - Marie Frimodt-Møller
- Diabetes Complications Research, Steno Diabetes Center Copenhagen, Borgmester Ib Juuls Vej 83, 2730, Herlev, Denmark
| | - Susanne Engberg
- Diabetes Complications Research, Steno Diabetes Center Copenhagen, Borgmester Ib Juuls Vej 83, 2730, Herlev, Denmark.,Novo Nordisk A/S, Vandtårnsvej 108, 2860, Søborg, Denmark
| | | | - Klaus Kirketerp-Møller
- Diabetes Complications Research, Steno Diabetes Center Copenhagen, Borgmester Ib Juuls Vej 83, 2730, Herlev, Denmark.,Copenhagen Wound Healing Center Bispebjerg Hospital, Bispebjerg Bakke 23, 2400, Copenhagen, Denmark
| | - Timothy O'Brien
- Regenerative Medicine Institute CURAM, National University of Ireland Galway, Galway, Ireland
| | - Peter Rossing
- Diabetes Complications Research, Steno Diabetes Center Copenhagen, Borgmester Ib Juuls Vej 83, 2730, Herlev, Denmark.,Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen N, Denmark
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El Hage R, Knippschild U, Arnold T, Hinterseher I. Stem Cell-Based Therapy: A Promising Treatment for Diabetic Foot Ulcer. Biomedicines 2022; 10:1507. [PMID: 35884812 PMCID: PMC9312797 DOI: 10.3390/biomedicines10071507] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/17/2022] [Accepted: 06/21/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetic foot ulcer (DFU) is a severe complication of diabetes and a challenging medical condition. Conventional treatments for DFU have not been effective enough to reduce the amputation rates, which urges the need for additional treatment. Stem cell-based therapy for DFU has been investigated over the past years. Its therapeutic effect is through promoting angiogenesis, secreting paracrine factors, stimulating vascular differentiation, suppressing inflammation, improving collagen deposition, and immunomodulation. It is controversial which type and origin of stem cells, and which administration route would be the most optimal for therapy. We reviewed the different types and origins of stem cells and routes of administration used for the treatment of DFU in clinical and preclinical studies. Diabetes leads to the impairment of the stem cells in the diseased patients, which makes it less ideal to use autologous stem cells, and requires looking for a matching donor. Moreover, angioplasty could be complementary to stem cell therapy, and scaffolds have a positive impact on the healing process of DFU by stem cell-based therapy. In short, stem cell-based therapy is promising in the field of regenerative medicine, but more studies are still needed to determine the ideal type of stem cells required in therapy, their safety, proper dosing, and optimal administration route.
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Affiliation(s)
- Racha El Hage
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, Fehrbelliner Str. 38, 16816 Neuruppin, Germany;
| | - Uwe Knippschild
- Department of General and Visceral Surgery, Surgery Center, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany; (U.K.); (T.A.)
| | - Tobias Arnold
- Department of General and Visceral Surgery, Surgery Center, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany; (U.K.); (T.A.)
| | - Irene Hinterseher
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, Fehrbelliner Str. 38, 16816 Neuruppin, Germany;
- Berlin Institute of Health, Vascular Surgery Clinic, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
- Fakultät für Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane und der Brandenburgischen Technischen Universität Cottbus—Senftenberg, Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany
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Søndergaard RH, Højgaard LD, Reese-Petersen AL, Hoeeg C, Mathiasen AB, Haack-Sørensen M, Follin B, Genovese F, Kastrup J, Juhl M, Ekblond A. Adipose-derived stromal cells increase the formation of collagens through paracrine and juxtacrine mechanisms in a fibroblast co-culture model utilizing macromolecular crowding. Stem Cell Res Ther 2022; 13:250. [PMID: 35690799 PMCID: PMC9188050 DOI: 10.1186/s13287-022-02923-y] [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: 11/09/2021] [Accepted: 05/29/2022] [Indexed: 11/24/2022] Open
Abstract
Background Adipose-derived stromal cells (ASCs) possess a multitude of regenerative capabilities, which include immunomodulation, angiogenesis, and stimulation of extracellular matrix (ECM) remodeling. However, the underlying mechanisms leading to ECM remodeling remain largely elusive and highlight the need for functional in vitro models for mode of action studies. Therefore, the purpose of this study was to develop an in vitro co-culture model to investigate the capabilities of ASCs to modulate fibroblasts and ECM. Methods An ECM in vitro model with ASCs and normal human dermal fibroblasts (NHDFs) was established utilizing macromolecular crowding, ascorbic acid, and TGF-β stimulation. Paracrine and juxtacrine co-cultures were created using transwell inserts and cell cultures with direct cell–cell contacts. The cultures were screened using RT2 PCR Profiler Arrays; the protein levels of myofibroblast differentiation marker alpha smooth muscle actin (αSMA) and ECM remodeling enzymes were analyzed using western blot on cell lysates; the formation of collagen type I, III, VI, and fibronectin was investigated using ELISA on culture supernatants; and the deposition of collagens was analyzed using immunocytochemistry. Results TGF-β stimulation of NHDF monocultures increased the expression of 18 transcripts relevant for ECM formation and remodeling, the protein levels of αSMA and matrix metalloproteinase-2 (MMP-2), the formation of collagen type I, III, VI, and fibronectin, and the deposition of collagen type I and VI and decreased the protein levels of MMP-14. Inclusion of ASCs in the ECM co-culture model increased the formation of collagen type I and III through paracrine mechanisms and the formation of collagen type VI through juxtacrine mechanisms. Conclusions The co-culture model provides effective stimulation of NHDF monocultures by TGF-β for enhanced formation and deposition of ECM. In the model, ASCs induce changes in ECM by increasing formation of collagen type I, III and VI. The obtained results could guide further investigations of ASCs’ capabilities and underlying mechanisms related to ECM formation and remodeling. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02923-y.
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Affiliation(s)
- Rebekka Harary Søndergaard
- Cardiology Stem Cell Centre, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Henrik Harpestrengs vej 4C, Dept. 9302, 2100, Copenhagen, Denmark.
| | - Lisbeth Drozd Højgaard
- Cardiology Stem Cell Centre, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Henrik Harpestrengs vej 4C, Dept. 9302, 2100, Copenhagen, Denmark
| | | | - Cecilie Hoeeg
- Cardiology Stem Cell Centre, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Henrik Harpestrengs vej 4C, Dept. 9302, 2100, Copenhagen, Denmark
| | - Anders Bruun Mathiasen
- Department of Cardiology, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Mandana Haack-Sørensen
- Cardiology Stem Cell Centre, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Henrik Harpestrengs vej 4C, Dept. 9302, 2100, Copenhagen, Denmark
| | - Bjarke Follin
- Cardiology Stem Cell Centre, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Henrik Harpestrengs vej 4C, Dept. 9302, 2100, Copenhagen, Denmark
| | - Federica Genovese
- Nordic Bioscience A/S, Herlev Hovedgade 205-207, 2730, Herlev, Denmark
| | - Jens Kastrup
- Cardiology Stem Cell Centre, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Henrik Harpestrengs vej 4C, Dept. 9302, 2100, Copenhagen, Denmark
| | - Morten Juhl
- Cardiology Stem Cell Centre, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Henrik Harpestrengs vej 4C, Dept. 9302, 2100, Copenhagen, Denmark
| | - Annette Ekblond
- Cardiology Stem Cell Centre, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Henrik Harpestrengs vej 4C, Dept. 9302, 2100, Copenhagen, Denmark
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Comparative study of mouse adipose- and bone marrow mesenchymal stem cells in diabetic model with critical limb ischemia. Cell Tissue Bank 2022; 23:923-936. [PMID: 35590084 DOI: 10.1007/s10561-022-10007-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 04/13/2022] [Indexed: 11/02/2022]
Abstract
The aim of this research is to compare the capabilities of Adipose tissue mesenchymal stem cells (AT-MSCs) and bone marrow mesenchymal stem cells (BM-MSCs) in the treatment of diabetic male mice with CLI model. Supernatants were collected from C57BL/6 mice isolated AT-MSCs and BM-MSCs, afterward their effects on human umbilical vein endothelial (HUVEC) migration potential were evaluated. Diabetes mellitus type 1 was induced by streptozotocin injection. Diabetic mice with CLI model were divided into three groups and injected with AT-MSCs, BM-MSCs, or PBS then the efficacy of them was assessed. Survival of MSCs was analysed by SRY-specific gene. The conditioned medium of AT-MSCs and BM-MSCs stimulated HUVECs migration and the donor cells were detected till 21 day in two groups. BM-MSCs and AT-MSCs improved significantly functional recovery and ischemia damage. Neovascularization in ischemic muscle was significantly higher in mice treated with AT-MSCs and BM-MSCs and they improved muscle regeneration. In vivo and in vitro findings show that AT-MSCs and BM-MSCs transplantation could be proposed as a promising therapy to promote angiogenesis and muscle regeneration through secretion of proangiogenic factors, cytokines and growth factors in diabetic mice with CLI model wherein blood supply is insufficient and disrupted.
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Jin L, Wang X, Qiao Z, Deng Y. The safety and efficacy of mesenchymal stem cell therapy in diabetic lower extremity vascular disease: a meta-analysis and systematic review. Cytotherapy 2022; 24:225-234. [PMID: 34656420 DOI: 10.1016/j.jcyt.2021.08.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/11/2021] [Accepted: 08/14/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AIMS Several studies have shown the efficacy of mesenchymal stem cell (MSC) therapy for lower extremity vascular disease (LEVD) in diabetic patients, but the results are not consistent. Therefore, the authors conducted a meta-analysis of randomized controlled trials (RCTs) to examine the safety and efficacy of MSC therapy in diabetic patients with LEVD. METHODS Eight available databases were searched in both English and Chinese to identify RCTs comparing MSC therapy-based conventional treatment with conventional treatment alone in diabetic patients with LEVD. Three investigators independently screened the literature, extracted the data and assessed the risk bias. Meta-analysis was performed using RevMan 5.4.1 and Stata 14.0. RESULTS A total of 10 studies involving 453 patients were included. Compared with conventional treatment only, patients receiving MSC therapy-based conventional treatment had a higher ulcer healing rate, greater number of reduced ulcers and shorter complete healing time. MSC therapy also increased ankle-brachial index and transcutaneous oxygen pressure. In addition, four of the included studies showed that MSC therapy significantly improved the number of new collateral vessels. Moreover, no more adverse events were recorded in the MSC group. CONCLUSIONS This meta-analysis suggests that MSC therapy promotes ulcer healing in diabetic LEVD patients with ulcers, improves blood supply and has a favorable safety profile. More large and well-designed RCTs with long-term follow-up are still needed to explore the safety and efficacy of MSC therapy in diabetic patients with LEVD.
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Affiliation(s)
- Lewei Jin
- Department of Plastic and Aesthetic Surgery and Burns, Second Xiangya Hospital, Central South University, No. 139 Renmin Middle Road, Changsha, P.R China 410011
| | - Xiancheng Wang
- Department of Plastic and Aesthetic Surgery and Burns, Second Xiangya Hospital, Central South University, No. 139 Renmin Middle Road, Changsha, P.R China 410011.
| | - Zhihua Qiao
- Department of Plastic and Aesthetic Surgery and Burns, Second Xiangya Hospital, Central South University, No. 139 Renmin Middle Road, Changsha, P.R China 410011
| | - Yiwen Deng
- Department of Plastic and Aesthetic Surgery and Burns, Second Xiangya Hospital, Central South University, No. 139 Renmin Middle Road, Changsha, P.R China 410011
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Yu Q, Qiao GH, Wang M, Yu L, Sun Y, Shi H, Ma TL. Stem Cell-Based Therapy for Diabetic Foot Ulcers. Front Cell Dev Biol 2022; 10:812262. [PMID: 35178389 PMCID: PMC8844366 DOI: 10.3389/fcell.2022.812262] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic foot ulcer has become a worldwide clinical medical challenge as traditional treatments are not effective enough to reduce the amputation rate. Therefore, it is of great social significance to deeply study the pathogenesis and biological characteristics of the diabetic foot, explore new treatment strategies and promote their application. Stem cell-based therapy holds tremendous promise in the field of regenerative medicine, and its mechanisms include promoting angiogenesis, ameliorating neuroischemia and inflammation, and promoting collagen deposition. Studying the specific molecular mechanisms of stem cell therapy for diabetic foot has an important role and practical clinical significance in maximizing the repair properties of stem cells. In addition, effective application modalities are also crucial in order to improve the survival and viability of stem cells at the wound site. In this paper, we reviewed the specific molecular mechanisms of stem cell therapy for diabetic foot and the extended applications of stem cells in recent years, with the aim of contributing to the development of stem cell-based therapy in the repair of diabetic foot ulcers.
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Affiliation(s)
- Qian Yu
- Department of Hepatology, Songjiang Hospital Affiliated to Nanjing Medical University, Shanghai, China
| | - Guo-Hong Qiao
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Min Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Li Yu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yaoxiang Sun
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Hui Shi
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China.,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Tie-Liang Ma
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
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Biehl C, Biehl L, Tarner IH, Müller-Ladner U, Heiss C, Heinrich M. Microangiopathy in Inflammatory Diseases-Strategies in Surgery of the Lower Extremity. Life (Basel) 2022; 12:200. [PMID: 35207487 PMCID: PMC8876644 DOI: 10.3390/life12020200] [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: 12/18/2021] [Revised: 01/15/2022] [Accepted: 01/27/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Patients with an inflammatory disease frequently develop chronic angiopathy of the capillaries. Due to this pathology, there is an increased rate of complications in lower extremity surgical procedures. It is not uncommon for microangiopathic wound healing disorders to cause deep infections and fistulas, which lead to prolonged courses and hospitalizations. In addition, adhesions and ossifications of the contractile elements occur regularly. This sometimes results in serious limitations of the mobility of the patients. The study aims to present the results of a combination of vacuum and physical therapy. PATIENT AND METHODS A retrospective study of six patients with systemic sclerosis undergoing joint-related procedures of the lower extremity between 2015 and 2020 was performed. In addition to characterization of the patients and therapy, special attention was paid to cutaneous wound healing, affection of the fascia and displacement layers, and sclerosis of the muscle and tendon insertion. RESULTS The characterized structures (skin, tendon, fascia) show pathological changes at the microangiopathic level, which are associated with delayed healing and less physical capacity. Early suture removal regularly results in secondary scar dehiscence. With a stage-adapted vacuum therapy with sanitation of the deep structures and later on a dermal vacuum system, healing with simultaneous mobilization of the patients could be achieved in our patient cohort. CONCLUSION In the case of necessary interventions on the lower extremity, such as trauma surgery, additional decongestive measures in the sense of regular and sustained lymphatic therapy and adapted physiotherapy are indispensable.
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Affiliation(s)
- Christoph Biehl
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Giessen, 35392 Giessen, Germany; (C.H.); (M.H.)
| | - Lotta Biehl
- Medical Faculty Heidelberg, Heidelberg University, 69117 Heidelberg, Germany;
| | - Ingo Helmut Tarner
- Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig-University of Giessen, Benekestr., 61231 Bad Nauheim, Germany; (I.H.T.); (U.M.-L.)
| | - Ulf Müller-Ladner
- Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig-University of Giessen, Benekestr., 61231 Bad Nauheim, Germany; (I.H.T.); (U.M.-L.)
| | - Christian Heiss
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Giessen, 35392 Giessen, Germany; (C.H.); (M.H.)
| | - Martin Heinrich
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Giessen, 35392 Giessen, Germany; (C.H.); (M.H.)
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Immunomodulation of Skin Repair: Cell-Based Therapeutic Strategies for Skin Replacement (A Comprehensive Review). Biomedicines 2022; 10:biomedicines10010118. [PMID: 35052797 PMCID: PMC8773777 DOI: 10.3390/biomedicines10010118] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 12/12/2022] Open
Abstract
The immune system has a crucial role in skin wound healing and the application of specific cell-laden immunomodulating biomaterials emerged as a possible treatment option to drive skin tissue regeneration. Cell-laden tissue-engineered skin substitutes have the ability to activate immune pathways, even in the absence of other immune-stimulating signals. In particular, mesenchymal stem cells with their immunomodulatory properties can create a specific immune microenvironment to reduce inflammation, scarring, and support skin regeneration. This review presents an overview of current wound care techniques including skin tissue engineering and biomaterials as a novel and promising approach. We highlight the plasticity and different roles of immune cells, in particular macrophages during various stages of skin wound healing. These aspects are pivotal to promote the regeneration of nonhealing wounds such as ulcers in diabetic patients. We believe that a better understanding of the intrinsic immunomodulatory features of stem cells in implantable skin substitutes will lead to new translational opportunities. This, in turn, will improve skin tissue engineering and regenerative medicine applications.
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