Role of mesenchymal stromal cells derivatives in diabetic foot ulcers: a controlled randomized phase 1/2 clinical trial |
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| Affiliation: | 1. Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, Floridablanca, Colombia;2. Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, Bucaramanga, Colombia;4. Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA;5. Fundación Oftalmológica de Santander Carlos Ardila Lulle Floridablanca, Colombia;1. Department of Hematology, Third Xiangya Hospital of Central South University, Changsha, China;2. Shanghai UniCAR Therapy Biomedicine Technology Co, Ltd, Shanghai, China;3. Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China;4. Department of Gastrointestinal Surgery, Third Xiangya Hospital of Central South University, Changsha, China;1. Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada;2. Schulich School of Medicine, Western University, London, Canada;3. Faculty of Medicine, University of Ottawa, Ottawa, Canada;4. Department of Surgery, University of Ottawa, Ottawa, Canada;5. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada;1. Roper Management Consultants Ltd;2. National Marrow Donor Program/Be The Match;3. Karolinska University Hospital;4. International Council for Commonality in Blood Banking Automation;5. St Jude Children''s Research Hospital;6. Slaper-Cortenbach Biomedical Consultancy;7. Dartmouth-Hitchcock Medical Center;1. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;2. Center for Research and Application of Cellular Therapy, Kyoto University Hospital, Kyoto, Japan;3. Division of Hematology, Department of Internal Medicine, Aichi Medical University, Nagakute, Japan;4. Division of Precision Medicine, Kyusyu University School of Medicine, Fukuoka, Japan;5. Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan;6. Hematology Division, Komagome Hospital, Tokyo Metropolitan Cancer and Infectious Diseases Center, Tokyo, Japan;7. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan;8. Department of Hematology, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan;9. Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan;10. Department of Hematology and Oncology, Osaka University Hospital, Osaka, Japan;11. Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan;12. Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan;13. Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan;14. Division of Hematology and Rheumatology, Department of Internal Medicine, Kindai University Hospital, Osakasayama, Japan;15. Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Japan;p. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan;q. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan;r. Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan;s. Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan |
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| Abstract: | Background: Diabetes-related foot complications have been identified as the most common isolated cause of morbidity among patients with diabetes and the leading cause of amputation. Therefore, new strategies to stimulate skin regeneration may provide a novel therapeutic approach to reduce non-healing ulcer disease. Recently, we demonstrated in proof-of-concept in humans that administration of allogeneic bone marrow mesenchymal stromal cellss derivatives (allo-hBM-MSCDs) is effective in a similar way to the use of allogeneic bone marrow mesenchymal stromal cellss (allo-hBM-MSCs) in grade 2 diabetic foot ulcers (DFUs).Aim: To assess the safety and efficacy profile of the allo-hBM-MSCDs relative to the conventional approach (PolyMen® dressing) in 1/2 clinical trial phases in patients with grade 1 and 2 DFUs.Methods: In the present study, we used 2 doses of allo-hBM-MSCDs (1 mL) or 1 dose of allo-hBM-MSCs (1 × 106 cells) intradermally injected around wounds and assessed their safety and effectiveness, relative to the conventional approach (PolyMem dressing). Allo-hBM-MSCDs and allo-hBM-MSCs were produced in a certified Good Manufacturing Practice-type Laboratory. Patients with grade 1 and 2 DFUs were randomized to receive allo-hBM-MSCDs (n=12), allo-hBM-MSCs (n=6) or conventional treatment (PolyMem dressing) (n=10). The wound-healing process was macroscopically evaluated until the complete closure of the ulcers.Results: No adverse events were reported. Patients with grade 1 and 2 DFUs treated with either allo-hBM-MSCDs or allo-hBM-MSCs, achieved greater percentages of wound closure, enhanced skin regeneration in shorter times and a greater ulcer-free survival relative to the patients who received conventional treatment. Finally, through proteomic analysis, we elucidated the proteins and growth factors that are secreted by allo-hBM-MSCs and relevant to the wound-healing process. In addition, by combining proteomics with Gene Ontology analysis, we comprehensively classified secreted proteins on both biological process and molecular function.Conclusions: In this phase 1/2 trial, our cumulative results suggest that 2 doses of allo-hBM-MSCDs combined with a wound dressing are a safe and effective treatment for grade 1 and 2 DFUs. |
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