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Cressman A, Le B, Morales D, Yen WS, Wu FJ, Perotti NH, Fury B, Nolta JA, Fierro FA. Investigational New Drug-enabling studies to use genetically modified mesenchymal stromal cells in patients with critical limb ischemia. Stem Cells Transl Med 2025; 14:szae094. [PMID: 40036305 DOI: 10.1093/stcltm/szae094] [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: 08/27/2024] [Accepted: 11/30/2024] [Indexed: 03/06/2025] Open
Abstract
Mesenchymal stromal cells (MSCs) have been tested in multiple clinical trials to treat peripheral artery disease, especially the more severe form called critical limb ischemia. However, MSCs have often not met the expected efficacy endpoints. We developed a more potent therapeutic by genetically modifying MSCs to overexpress Vascular Endothelial Growth Factor (VEGF-A165). Here, we report preclinical studies submitted to the Food and Drug Administration (FDA) as part of our Investigational New Drug submission package. In vitro studies included the characterization of cell banks, transcriptome and secretome analysis, and in vitro potency assays. In vivo studies using immune-deficient NSG mice include dose-finding efficacy studies using a Matrigel plug model, cell retention studies, measurements of circulating VEGF, and toxicology studies to rule out severe adverse events. Our results suggest both the safety and efficacy of MSC/VEGF and support a first-in-human clinical trial to test this new combined cell/gene therapy.
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Affiliation(s)
- Amin Cressman
- Stem Cell Program, University of California at Davis, Sacramento, CA 95817, United States
| | - Bryan Le
- Stem Cell Program, University of California at Davis, Sacramento, CA 95817, United States
| | - David Morales
- Stem Cell Program, University of California at Davis, Sacramento, CA 95817, United States
| | - Won-Shin Yen
- Taiwan Bio Therapeutics, 5F., No. 66, Shengyi 2nd Rd., Zhubei City, Hsinchu County, Taiwan
| | - Fang-Ju Wu
- Taiwan Bio Therapeutics, 5F., No. 66, Shengyi 2nd Rd., Zhubei City, Hsinchu County, Taiwan
| | - Nicholas H Perotti
- GMP Facility, University of California at Davis, Sacramento, CA 95817, United States
| | - Brian Fury
- GMP Facility, University of California at Davis, Sacramento, CA 95817, United States
| | - Jan A Nolta
- Stem Cell Program, University of California at Davis, Sacramento, CA 95817, United States
| | - Fernando A Fierro
- Stem Cell Program, University of California at Davis, Sacramento, CA 95817, United States
- Department of Cell Biology and Human Anatomy, University of California at Davis, Sacramento, CA 95817, United States
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Mirnia K, Bitaraf M, Namakin K, Azimzadeh A, Tanourlouee SB, Zolbin MM, Masoumi A, Kajbafzadeh AM. Enhancing Late Retinopathy of Prematurity Outcomes with Fresh Bone Marrow Mononuclear Cells and Melatonin Combination Therapy. Stem Cell Rev Rep 2025; 21:466-476. [PMID: 39503829 DOI: 10.1007/s12015-024-10819-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2024] [Indexed: 03/04/2025]
Abstract
INTRODUCTION Retinopathy of prematurity (ROP) is a vasoproliferative disease affecting premature neonates with life-lasting impacts. This study aims to investigate the long-term functional outcomes and alterations in neural retina architecture following the intravitreal transplantation of bone marrow mononuclear cells (BMMNC) in the rat models of ROP, and to evaluate the effect of adjunctive therapy with melatonin. METHODS 32 neonate rats were employed. The ROP model was developed in 10 neonatal rats, and two were assigned as control. The ROP models received BMMNC suspension, containing 1.2 × 105 cells, in their right eye, and normal saline in left at p12. Five ROP rats received 12.5 mg/kg melatonin orally for five days (p12 to p17). Optical coherence tomography (OCT) and electroretinography (ERG) were performed on p47. Eyes were then harvested on p47, and after six months for histology, immunofluorescence (anti-calbindin, anti-PKC, and anti-Brn3), and immunohistochemistry (synaptophysin). RESULTS Cell therapy alone and with melatonin increased retinal thickness, and improved oscillatory potentials on ERG. Combination therapy increased horizontal and retinal ganglion cell populations. All treatments improved synaptic maturity in the inner plexiform layer, but only combination therapy was effective on the outer plexiform layer. CONCLUSION Melatonin and BMMNCs combination therapy effectively ameliorates retinal structural and functional deficits at later ROP stages, without causing severe adverse effects. It significantly increases the survival of post-receptor retinal neurons and preserves retinal synaptic structures in the long term, highlighting the promising potential of this novel combination therapy approach to minimize visual deficits in ROP patients.
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Affiliation(s)
- Kayvan Mirnia
- Pediatrics Center of Excellence, Department of Neonatology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Bitaraf
- Pediatric Urology and Regenerative Medicine Research Center, Pediatric Center of Excellence, Gene, Cell & Tissue Research Institute Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Namakin
- Pediatric Urology and Regenerative Medicine Research Center, Pediatric Center of Excellence, Gene, Cell & Tissue Research Institute Tehran University of Medical Sciences, Tehran, Iran
| | - Ashkan Azimzadeh
- Pediatric Urology and Regenerative Medicine Research Center, Pediatric Center of Excellence, Gene, Cell & Tissue Research Institute Tehran University of Medical Sciences, Tehran, Iran
| | - Saman Behboodi Tanourlouee
- Pediatric Urology and Regenerative Medicine Research Center, Pediatric Center of Excellence, Gene, Cell & Tissue Research Institute Tehran University of Medical Sciences, Tehran, Iran.
- Children's Medical Center, Gharib st., Keshavarz blvd., Tehran, 419733151, Iran.
| | - Masoume Majidi Zolbin
- Pediatric Urology and Regenerative Medicine Research Center, Pediatric Center of Excellence, Gene, Cell & Tissue Research Institute Tehran University of Medical Sciences, Tehran, Iran.
- Children's Medical Center, Gharib st., Keshavarz blvd., Tehran, 419733151, Iran.
| | - Ahmad Masoumi
- Ophthalmology Department and Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdol-Mohammad Kajbafzadeh
- Pediatric Urology and Regenerative Medicine Research Center, Pediatric Center of Excellence, Gene, Cell & Tissue Research Institute Tehran University of Medical Sciences, Tehran, Iran
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Scatena A, Apicella M, Mantuano M, Ragghianti B, Silverii A, Miranda C, Monge L, Uccioli L, Scevola G, Stabile E, Gargiulo M, Vermigli C, Monami M. Autologous cell therapy for ischemic diabetic foot: a meta-analysis of randomized controlled trials for the development of the Italian guidelines for the treatment of diabetic foot syndrome. Acta Diabetol 2024:10.1007/s00592-024-02393-z. [PMID: 39545964 DOI: 10.1007/s00592-024-02393-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 10/13/2024] [Indexed: 11/17/2024]
Abstract
AIM To assess the efficacy and safety of autologous cell therapy (ACT) in patients with ischemic diabetic foot ulcers (DFU). The present meta-analysis was designed to support the development of the Italian Guidelines for the Treatment of Diabetic Foot Syndrome (DFS). METHODS A Medline and Embase search were performed up to Feb 1st, 2024 collecting all RCTs including diabetic patients or reporting subgroup analyses on diabetic patients with ischemic foot ulcers comparing ACT with placebo/no therapy/standard of care (SoC), with a duration of at least 26 weeks. Prespecified endpoints were: major amputation (principal) and minor amputation, ulcer healing, time-to-healing, transcutaneous oxygen pressure (TcPO2), ankle-brachial index (ABI), pain, and all-cause mortality (secondary). Any ACT was allowed, irrespective of cell product type and route of administration (intra-arterial and intramuscular). RESULTS Seven studies fulfilled all inclusion criteria, all using intramuscular transplantation as route of administration, but only 2 had a follow-up greater than 26 weeks. Participants treated with ACT had a significantly lower risk of major amputations in comparison with SoC/placebo (MH-OR 0.47 [0.24, 0.92], p = 0.03). ACT was also associated with a significantly higher rate of ulcer healing (MH-OR: 10.1 [3.5, 29.6], p < 0.001), greater increase of TcPO2 and ABI values (WMD: 17.57 [13.02, 22.12], p < 0.001), and reduction of pain (WMD: -1.83 [-2.32, -1.34], p = 0.003). CONCLUSIONS ACT must be considered as a potential therapy for patients with ischemic diabetic foot ulcers. Further studies are needed to better clarify their role in the treatment and management of DFS.
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Affiliation(s)
- Alessia Scatena
- Diabetology Unit, Health Authorities South East Tuscany, San Donato Hospital, Via Pietro Nenni 20, 52100, Arezzo, Italy.
| | - Matteo Apicella
- Diabetology Unit, Health Authorities South East Tuscany, San Donato Hospital, Via Pietro Nenni 20, 52100, Arezzo, Italy
| | - Michele Mantuano
- Diabetology Unit, Health Authorities South East Tuscany, San Donato Hospital, Via Pietro Nenni 20, 52100, Arezzo, Italy
| | - Benedetta Ragghianti
- Azienda Ospedaliero Universitaria Careggi and University of Florence, Florence, Italy
| | - Antonio Silverii
- Azienda Ospedaliero Universitaria Careggi and University of Florence, Florence, Italy
| | | | - Luca Monge
- AMD - Italian Association of Clinical Diabetologists, Rome, Italy
| | - Luigi Uccioli
- Diabetes Section CTO Hospital and dept of Biomedicine and prevention Tor Vergata University of Rome, Rome, Italy
| | | | | | - Mauro Gargiulo
- Vascular Surgery, University of Bologna- DIMEC, Bologna, Italy
| | | | - Matteo Monami
- Azienda Ospedaliero Universitaria Careggi and University of Florence, Florence, Italy
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Чуган ГС, Люндуп АВ, Бондаренко ОН, Галстян ГР. [The application of cell products for the treatment of critical limb ischemia in patients with diabetes mellitus: a review of the literature]. PROBLEMY ENDOKRINOLOGII 2024; 70:4-14. [PMID: 39302860 PMCID: PMC11551799 DOI: 10.14341/probl13481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 07/15/2024] [Indexed: 09/22/2024]
Abstract
The number of patients with diabetes mellitus (DM) has been progressively increasing worldwide over the past decades, and many international organizations consider DM as a public health emergency of the 21st century.Critical limb ischemia (CLI) is the most severe stage of peripheral arterial disease (PAD) in DM and is characterized by a high risk of limb loss without revascularization. Traditional treatment tactics include open and endovascular revascularization surgical techniques. However, in patients not eligible for revascularization and in cases where performed surgical treatment performed has been ineffective, there are almost no therapeutic alternatives, often leading to amputations and death. As of today, one of the newest non-surgical treatment options is cell therapy. Among different cells, mesenchymal stromal cells (MSCs) are potentially one of the most prospective for use in this patient population.This article provides an overview of clinical trials using cell therapy in patients with CLI.To analyze publications, electronic databases PubMed, SCOPUS, ClinicalTrials, and ScienceDirect were searched to identify published data from clinical trials, research studies, and review articles on cell therapy for critical lower extremity ischemia. After the search, 489 results were received.As a result of systematic selection, 22 clinical trials were analyzed.According to the analyzed literature data, the use of cell products in this category of patients is effective and safe. Cell therapy can stimulate the formation of new vessels and enhances collateral circulation; it is also reported improved distal perfusion, increased pain-free walking distance, decreased amputation rates, and increased survival rates.Nevertheless, further study of the potential use of this category of drugs is needed.
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Affiliation(s)
- Г. С. Чуган
- Национальный медицинский исследовательский центр эндокринологии
| | - А. В. Люндуп
- Национальный медицинский исследовательский центр эндокринологии; Научно-образовательный ресурсный центр клеточных технологий, Российский университет дружбы народов им. Патриса Лумумбы (РУДН)
| | | | - Г. Р. Галстян
- Национальный медицинский исследовательский центр эндокринологии
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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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Kyselovic J, Adamičková A, Gažová A, Valášková S, Chomaničová N, Červenák Z, Madaric J. Atorvastatin Treatment Significantly Increased the Concentration of Bone Marrow-Derived Mononuclear Cells and Transcutaneous Oxygen Pressure and Lowered the Pain Scale after Bone Marrow Cells Treatment in Patients with "No-Option" Critical Limb Ischaemia. Biomedicines 2024; 12:922. [PMID: 38672276 PMCID: PMC11048671 DOI: 10.3390/biomedicines12040922] [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: 03/20/2024] [Revised: 04/12/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND The present study investigated the outcomes and possible predictive factors of autologous bone marrow cells (BMCs) therapy in patients with "no-option" critical limb ischaemia (CLI). It was focused on exploring the clinical background and prior statin and renin-angiotensin system (RAS)-acting agents pharmacotherapy related to the therapeutic efficacy of BMCs treatment. METHODS In the present study, we reviewed thirty-three patients (mean age 64.9 ± 10 years; 31 males) with advanced CLI after failed or impossible revascularisation, who were treated with 40 mL of autologous BMCs by local intramuscular application. Patients with limb salvage and wound healing (N = 22) were considered as responders to BMCs therapy, and patients with limb salvage and complete ischemic wound healing (N = 13) were defined as super-responders. Logistic regression models were used to screen and identify the prognostic factors, and a receiver operating characteristics (ROC) curve, a linear regression, and a survival curve were drawn to determine the predictive accuracy, the correlation between the candidate predictors, and the risk of major amputation. RESULTS Based on the univariate regression analysis, baseline C-reactive protein (CRP) and transcutaneous oxygen pressure (TcPO2) values were identified as prognostic factors of the responders, while CRP value, ankle-brachial index (ABI), and bone marrow-derived mononuclear cells (BM-MNCs) concentration were identified as prognostic factors of the super-responders. An area under the ROC curve of 0.768 indicated good discrimination for CRP > 8.1 mg/L before transplantation as a predictive factor for negative clinical response. Linear regression analysis revealed a significant dependence between the levels of baseline CRP and the concentration of BM-MNCs in transplanted bone marrow. Patients taking atorvastatin before BMCs treatment (N = 22) had significantly improved TcPO2 and reduced pain scale after BMCs transplant, compared to the non-atorvastatin group. Statin treatment was associated with reduced risk for major amputation. However, the difference was not statistically significant. Statin use was also associated with a significantly higher concentration of BM-MNCs in the transplanted bone marrow compared to patients without statin treatment. Patients treated with RAS-acting agents (N = 20) had significantly reduced pain scale after BMCs transplant, compared to the non-RAS-acting agents group. Similar results, reduced pain scale and improved TcPO2, were achieved in patients treated with atorvastatin and RAS-acting agents (N = 17) before BMCs treatment. Results of the Spearman correlation showed a significant positive correlation between CLI regression, responders, and previous therapy before BMCs transplant with RAS-acting agents alone or with atorvastatin. CONCLUSIONS CRP and TcPO2 were prognostic factors of the responders, while CRP value, ABI, and BM-MNCs concentration were identified as predictive factors of the super-responders. Atorvastatin treatment was associated with a significantly increased concentration of BM-MNCs in bone marrow concentrate and higher TcPO2 and lower pain scale after BMCs treatment in CLI patients. Similarly, reduced pain scales and improved TcPO2 were achieved in patients treated with atorvastatin and RAS-acting agents before BMCs treatment. Positive correlations between responders and previous treatment before BMCs transplant with RAS-acting agents alone or with atorvastatin were significant.
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Affiliation(s)
- Jan Kyselovic
- 5th Department of Internal Medicine, Faculty of Medicine, Comenius University Bratislava, Špitálska 24, 81372 Bratislava, Slovakia; (J.K.)
- Department of Pharmacology and Toxicology, University of Veterinary Medicine and Pharmacy, 04181 Košice, Slovakia
| | - Adriana Adamičková
- 5th Department of Internal Medicine, Faculty of Medicine, Comenius University Bratislava, Špitálska 24, 81372 Bratislava, Slovakia; (J.K.)
| | - Andrea Gažová
- Institute of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Comenius University Bratislava, Špitálska 24, 81372 Bratislava, Slovakia
| | - Simona Valášková
- International Laser Center, Slovak Centre of Scientific and Technical Information, Lamačská cesta 7315/8A, 84104 Bratislava, Slovakia
| | - Nikola Chomaničová
- International Laser Center, Slovak Centre of Scientific and Technical Information, Lamačská cesta 7315/8A, 84104 Bratislava, Slovakia
| | - Zdenko Červenák
- 5th Department of Internal Medicine, Faculty of Medicine, Comenius University Bratislava, Špitálska 24, 81372 Bratislava, Slovakia; (J.K.)
| | - Juraj Madaric
- Department of Angiology, Faculty of Medicine, Comenius University and National Institute of Cardiovascular Disease, Pod Krásnou Hôrkou 1, 83101 Bratislava, Slovakia;
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Hazrati R, Davaran S, Keyhanvar P, Soltani S, Alizadeh E. A Systematic Review of Stem Cell Differentiation into Keratinocytes for Regenerative Applications. Stem Cell Rev Rep 2024; 20:362-393. [PMID: 37922106 DOI: 10.1007/s12015-023-10636-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2023] [Indexed: 11/05/2023]
Abstract
To improve wound healing or treatment of other skin diseases, and provide model cells for skin biology studies, in vitro differentiation of stem cells into keratinocyte-like cells (KLCs) is very desirable in regenerative medicine. This study examined the most recent advancements in in vitro differentiation of stem cells into KLCs, the effect of biofactors, procedures, and preparation for upcoming clinical cases. A range of stem cells with different origins could be differentiated into KLCs under appropriate conditions. The most effective ways of stem cell differentiation into keratinocytes were found to include the co-culture with primary epithelial cells and keratinocytes, and a cocktail of growth factors, cytokines, and small molecules. KLCs should also be supported by biomaterials for the extracellular matrix (ECM), which replicate the composition and functionality of the in vivo extracellular matrix (ECM) and, thus, support their phenotypic and functional characteristics. The detailed efficient characterization of different factors, and their combinations, could make it possible to find the significant inducers for stem cell differentiation into epidermal lineage. Moreover, it allows the development of chemically known media for directing multi-step differentiation procedures.In conclusion, the differentiation of stem cells to KLCs is feasible and KLCs were used in experimental, preclinical, and clinical trials. However, the translation of KLCs from in vitro investigational system to clinically valuable cells is challenging and extremely slow.
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Affiliation(s)
- Raheleh Hazrati
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soodabeh Davaran
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Peyman Keyhanvar
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somaieh Soltani
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Zhong T, Gao N, Guan Y, Liu Z, Guan J. Co-Delivery of Bioengineered Exosomes and Oxygen for Treating Critical Limb Ischemia in Diabetic Mice. ACS NANO 2023; 17:25157-25174. [PMID: 38063490 PMCID: PMC10790628 DOI: 10.1021/acsnano.3c08088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2023]
Abstract
Diabetic patients with critical limb ischemia face a high rate of limb amputation. Regeneration of the vasculature and skeletal muscles can salvage diseased limbs. Therapy using stem cell-derived exosomes that contain multiple proangiogenic and promyogenic factors represents a promising strategy. Yet the therapeutic efficacy is not optimal because exosomes alone cannot efficiently rescue and recruit endothelial and skeletal muscle cells and restore their functions under hyperglycemic and ischemic conditions. To address these limitations, we fabricated ischemic-limb-targeting stem cell-derived exosomes and oxygen-releasing nanoparticles and codelivered them in order to recruit endothelial and skeletal muscle cells, improve cell survival under ischemia before vasculature is established, and restore cell morphogenic function under high glucose and ischemic conditions. The exosomes and oxygen-releasing nanoparticles, delivered by intravenous injection, specifically accumulated in the ischemic limbs. Following 4 weeks of delivery, the exosomes and released oxygen synergistically stimulated angiogenesis and muscle regeneration without inducing substantial inflammation and reactive oxygen species overproduction. Our work demonstrates that codelivery of exosomes and oxygen is a promising treatment solution for saving diabetic ischemic limbs.
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Affiliation(s)
- Ting Zhong
- Department of Mechanical Engineering & Materials Science, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, United States
| | - Ning Gao
- Institute of Materials Science and Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, United States
| | - Ya Guan
- Institute of Materials Science and Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, United States
| | - Zhongting Liu
- Institute of Materials Science and Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, United States
| | - Jianjun Guan
- Department of Mechanical Engineering & Materials Science, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, United States
- Institute of Materials Science and Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, United States
- Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Soria B, Escacena N, Gonzaga A, Soria-Juan B, Andreu E, Hmadcha A, Gutierrez-Vilchez AM, Cahuana G, Tejedo JR, De la Cuesta A, Miralles M, García-Gómez S, Hernández-Blasco L. Cell Therapy of Vascular and Neuropathic Complications of Diabetes: Can We Avoid Limb Amputation? Int J Mol Sci 2023; 24:17512. [PMID: 38139339 PMCID: PMC10743405 DOI: 10.3390/ijms242417512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/07/2023] [Accepted: 12/13/2023] [Indexed: 12/24/2023] Open
Abstract
Globally, a leg is amputated approximately every 30 seconds, with an estimated 85 percent of these amputations being attributed to complications arising from diabetic foot ulcers (DFU), as stated by the American Diabetes Association. Peripheral arterial disease (PAD) is a risk factor resulting in DFU and can, either independently or in conjunction with diabetes, lead to recurring, slow-healing ulcers and amputations. According to guidelines amputation is the recommended treatment for patients with no-option critical ischemia of the limb (CTLI). In this article we propose cell therapy as an alternative strategy for those patients. We also suggest the optimal time-frame for an effective therapy, such as implanting autologous mononuclear cells (MNCs), autologous and allogeneic mesenchymal stromal cells (MSC) as these treatments induce neuropathy relief, regeneration of the blood vessels and tissues, with accelerated ulcer healing, with no serious side effects, proving that advanced therapy medicinal product (ATMPs) application is safe and effective and, hence, can significantly prevent limb amputation.
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Affiliation(s)
- Bernat Soria
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
- Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain
- CIBERDEM Network Research Center for Diabetes and Associated Metabolic Diseases, Carlos III Health Institute, 28029 Madrid, Spain
| | - Natalia Escacena
- Fresci Consultants, Human Health Innovation, 08025 Barcelona, Spain
| | - Aitor Gonzaga
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
- Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain
| | - Barbara Soria-Juan
- Reseaux Hôpitalieres Neuchatelois et du Jura, 2000 Neuchâtel, Switzerland
| | - Etelvina Andreu
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
- Department of Applied Physics, University Miguel Hernández Elche, 03202 Elche, Spain
| | - Abdelkrim Hmadcha
- Biosanitary Research Institute (IIB-VIU), Valencian International University (VIU), 46002 Valencia, Spain
- Department of Molecular Biology, University Pablo de Olavide, 41013 Sevilla, Spain
| | - Ana Maria Gutierrez-Vilchez
- Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain
- Department of Pharmacology, Pediatrics and Organic Chemistry, University Miguel Hernández, 03202 Elche, Spain
| | - Gladys Cahuana
- Department of Molecular Biology, University Pablo de Olavide, 41013 Sevilla, Spain
| | - Juan R. Tejedo
- CIBERDEM Network Research Center for Diabetes and Associated Metabolic Diseases, Carlos III Health Institute, 28029 Madrid, Spain
- Department of Molecular Biology, University Pablo de Olavide, 41013 Sevilla, Spain
| | | | - Manuel Miralles
- University and Polytechnic Hospital La Fe, 46026 Valencia, Spain
| | | | - Luis Hernández-Blasco
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
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10
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Mohamad Yusoff F, Higashi Y. Mesenchymal Stem/Stromal Cells for Therapeutic Angiogenesis. Cells 2023; 12:2162. [PMID: 37681894 PMCID: PMC10486439 DOI: 10.3390/cells12172162] [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: 07/13/2023] [Revised: 08/18/2023] [Accepted: 08/25/2023] [Indexed: 09/09/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are known to possess medicinal properties to facilitate vascular regeneration. Recent advances in the understanding of the utilities of MSCs in physiological/pathological tissue repair and technologies in isolation, expansion, and enhancement strategies have led to the use of MSCs for vascular disease-related treatments. Various conditions, including chronic arterial occlusive disease, diabetic ulcers, and chronic wounds, cause significant morbidity in patients. Therapeutic angiogenesis by cell therapy has led to the possibilities of treatment options in promoting angiogenesis, treating chronic wounds, and improving amputation-free survival. Current perspectives on the options for the use of MSCs for therapeutic angiogenesis in vascular research and in medicine, either as a monotherapy or in combination with conventional interventions, for treating patients with peripheral artery diseases are discussed in this review.
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Affiliation(s)
- Farina Mohamad Yusoff
- Department of Regenerative Medicine, Division of Radiation Medical Science, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan;
| | - Yukihito Higashi
- Department of Regenerative Medicine, Division of Radiation Medical Science, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan;
- Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima 734-8551, Japan
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11
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Arango-Rodríguez ML, Mateus LC, Sossa CL, Becerra-Bayona SM, Solarte-David VA, Ochoa Vera ME, Viviescas LTG, Berrio AMV, Serrano SE, Vargas O, Isla AC, Benitez A, Rangel G. A novel therapeutic management for diabetes patients with chronic limb-threatening ischemia: comparison of autologous bone marrow mononuclear cells versus allogenic Wharton jelly-derived mesenchymal stem cells. Stem Cell Res Ther 2023; 14:221. [PMID: 37626416 PMCID: PMC10464344 DOI: 10.1186/s13287-023-03427-z] [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: 12/05/2022] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Chronic limb-threatening ischemia (CLTI) represents the final stage of peripheral arterial disease. Approximately one-third of patients with CLTI are not eligible for conventional surgical treatments. Furthermore, patients with advanced stage of CLTI are prone to amputation and death. Thus, an effective therapeutic strategy is urgently needed. In this context, autologous bone marrow mononuclear cell (auto-BM-MNC) and allogeneic mesenchymal stem cells represent a promising therapeutic approach for treating CLTI. In this study, we compared the safety and beneficial therapeutic effect of auto-BM-MNC versus allogeneic Wharton jelly-derived mesenchymal stem cells (allo-WJ-MSCs) in diabetic patients with CLTI. METHODS We performed a randomized, prospective, double-blind and controlled pilot study. Twenty-four diabetic patients in the advanced stage of CLTI (4 or 5 in Rutherford's classification) and a transcutaneous oxygen pressure (TcPO2) below 30 mmHg were randomized to receive 15 injections of (i) auto-BM-MNC (7.197 × 106 ± 2.984 × 106 cells/mL) (n = 7), (ii) allo-WJ-MSCs (1.333 × 106 cells/mL) (n = 7) or (iii) placebo solution (1 mL) (n = 10), which were administered into the periadventitial layer of the arterial walls under eco-Doppler guidance. The follow-up visits were at months 1, 3, 6, and 12 to evaluate the following parameters: (i) Rutherford's classification, (ii) TcPO2, (iii) percentage of wound closure, (iv) pain, (v) pain-free walking distance, (vi) revascularization and limb-survival proportion, and (vii) life quality (EQ-5D questionnaire). RESULTS No adverse events were reported. Patients with CLTI who received auto-BM-MNC and allo-WJ-MSCs presented an improvement in Rutherford's classification, a significant increase in TcPO2 values, a reduction in the lesion size in a shorter time, a decrease in the pain score and an increase in the pain-free walking distance, in comparison with the placebo group. In addition, the participants treated with auto-BM-MNC and allo-WJ-MSCs kept their limbs during the follow-up period, unlike the placebo group, which had a marked increase in amputation. CONCLUSIONS Our results showed that patients with CLTI treated with auto-BM-MNC and allo-WJ-MSCs conserved 100% of their limb during 12 months of the follow-up compared to the placebo group, where 60% of participants underwent limb amputation in different times. Furthermore, we observed a faster improvement in the allo-WJ-MSC group, unlike the auto-BM-MNC group. Trial registration This study was retrospectively registered at ClinicalTrials.gov (NCT05631444).
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Affiliation(s)
- Martha L Arango-Rodríguez
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, 681004, Floridablanca, Colombia.
| | - Ligia C Mateus
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Claudia L Sossa
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
- Programa para el Tratamiento y Estudio de Enfermedades Hematológicas y Oncológicas de Santander (PROTEHOS), 681004153, Floridablanca, Colombia
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Silvia M Becerra-Bayona
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Víctor Alfonso Solarte-David
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
- Facultad de Ingeniería, Universidad Autónoma de Bucaramanga - UNAB, 680003, Bucaramanga, Colombia
| | - Miguel Enrique Ochoa Vera
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Lady T Giratá Viviescas
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, 681004, Floridablanca, Colombia
| | - Ana M Vera Berrio
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, 681004, Floridablanca, Colombia
| | - Sergio Eduardo Serrano
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Oliverio Vargas
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Andrés Catalá Isla
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Alape Benitez
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Germán Rangel
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
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12
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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: 16] [Impact Index Per Article: 8.0] [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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13
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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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14
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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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15
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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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16
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Wu J, Chen LH, Sun SY, Li Y, Ran XW. Mesenchymal stem cell-derived exosomes: The dawn of diabetic wound healing. World J Diabetes 2022; 13:1066-1095. [PMID: 36578867 PMCID: PMC9791572 DOI: 10.4239/wjd.v13.i12.1066] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/04/2022] [Accepted: 11/23/2022] [Indexed: 12/15/2022] Open
Abstract
Chronic wound healing has long been an unmet medical need in the field of wound repair, with diabetes being one of the major etiologies. Diabetic chronic wounds (DCWs), especially diabetic foot ulcers, are one of the most threatening chronic complications of diabetes. Although the treatment strategies, drugs, and dressings for DCWs have made great progress, they remain ineffective in some patients with refractory wounds. Stem cell-based therapies have achieved specific efficacy in various fields, with mesenchymal stem cells (MSCs) being the most widely used. Although MSCs have achieved good feedback in preclinical studies and clinical trials in the treatment of cutaneous wounds or other situations, the potential safety concerns associated with allogeneic/autologous stem cells and unknown long-term health effects need further attention and supervision. Recent studies have reported that stem cells mainly exert their trauma repair effects through paracrine secretion, and exosomes play an important role in intercellular communication as their main bioactive component. MSC-derived exosomes (MSC-Exos) inherit the powerful inflammation and immune modulation, angiogenesis, cell proliferation and migration promotion, oxidative stress alleviation, collagen remodeling imbalances regulation of their parental cells, and can avoid the potential risks of direct stem cell transplantation to a large extent, thus demonstrating promising performance as novel "cell-free" therapies in chronic wounds. This review aimed to elucidate the potential mechanism and update the progress of MSC-Exos in DCW healing, thereby providing new therapeutic directions for DCWs that are difficult to be cured using conventional therapy.
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Affiliation(s)
- Jing Wu
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Li-Hong Chen
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shi-Yi Sun
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yan Li
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xing-Wu Ran
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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17
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Shirbaghaee Z, Hassani M, Heidari Keshel S, Soleimani M. Emerging roles of mesenchymal stem cell therapy in patients with critical limb ischemia. Stem Cell Res Ther 2022; 13:462. [PMID: 36068595 PMCID: PMC9449296 DOI: 10.1186/s13287-022-03148-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/19/2022] [Indexed: 11/25/2022] Open
Abstract
Critical limb ischemia (CLI), the terminal stage of peripheral arterial disease (PAD), is characterized by an extremely high risk of amputation and vascular issues, resulting in severe morbidity and mortality. In patients with severe limb ischemia with no alternative therapy options, such as endovascular angioplasty or bypass surgery, therapeutic angiogenesis utilizing cell-based therapies is vital for increasing blood flow to ischemic regions. Mesenchymal stem cells (MSCs) are currently considered one of the most encouraging cells as a regenerative alternative for the surgical treatment of CLI, including restoring tissue function and repairing ischemic tissue via immunomodulation and angiogenesis. The regenerative treatments for limb ischemia based on MSC therapy are still considered experimental. Despite recent advances in preclinical and clinical research studies, it is not recommended for regular clinical use. In this study, we review the immunomodulatory features of MSC besides the current understanding of different sources of MSC in the angiogenic treatment of CLI subjects and their potential applications as therapeutic agents. Specifically, this paper concentrates on the most current clinical application issues, and several recommendations are provided to improve the efficacy of cell therapy for CLI patients.
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Affiliation(s)
- Zeinab Shirbaghaee
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, 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, Tehran, Iran
| | - Saeed Heidari Keshel
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Applied Cell Science and Hematology Department, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran.
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18
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Xia SL, Ma ZY, Wang B, Gao F, Guo SY, Chen XH. A gene expression profile for the lower osteogenic potent of bone-derived MSCs from osteoporosis with T2DM and the potential mechanism. J Orthop Surg Res 2022; 17:402. [PMID: 36050744 PMCID: PMC9438120 DOI: 10.1186/s13018-022-03291-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 08/17/2022] [Indexed: 11/20/2022] Open
Abstract
Background Osteoporosis (OP) patients complicated with type II diabetes mellitus (T2DM) has a higher fracture risk than the non-diabetic patients, and mesenchymal stem cells (MSCs) from T2DM patients also show a weaker osteogenic potent. The present study aimed to provide a gene expression profile in MSCs from diabetic OP and investigated the potential mechanism. Methods The bone-derived MSC (BMSC) was isolated from OP patients complicated with or without T2DM (CON-BMSC, T2DM-BMSC). Osteogenic differentiation was evaluated by qPCR analysis of the expression levels of osteogenic markers, ALP activity and mineralization level. The differentially expressed genes (DEGs) in T2DM-BMSC was identified by RNA-sequence, and the biological roles of DEGs was annotated by bioinformatics analyses. The role of silencing the transcription factor (TF), Forkhead box Q1 (FOXQ1), on the osteogenic differentiation of BMSC was also investigated. Results T2DM-BMSC showed a significantly reduced osteogenic potent compare to the CON-BMSC. A total of 448 DEGs was screened in T2DM-BMSC, and bioinformatics analyses showed that many TFs and the target genes were enriched in various OP- and diabetes-related biological processes and pathways. FOXQ1 had the highest verified fold change (abs) among the top 8 TFs, and silence of FOXQ1 inhibited the osteogenic differentiation of CON-BMSC. Conclusions Our study provided a comprehensive gene expression profile of BMSC in diabetic OP, and found that downregulated FOXQ1 was responsible for the reduced osteogenic potent of T2DM-BSMC. This is of great importance for the special mechanism researches and the treatment of diabetic OP. Supplementary Information The online version contains supplementary material available at 10.1186/s13018-022-03291-2.
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Affiliation(s)
- Sheng-Li Xia
- Department of Orthopedics, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, China
| | - Zi-Yuan Ma
- Department of Orthopedics, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, China
| | - Bin Wang
- Department of Orthopedics, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, China
| | - Feng Gao
- Department of Orthopedics, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, China
| | - Sheng-Yang Guo
- Department of Orthopedics, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, China
| | - Xu-Han Chen
- Zhoupu Community Health Service Center, 163 Shenmei East Road, Pudong New Area, Shanghai, 201318, China.
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Liu P, Mao Y, Xie Y, Wei J, Yao J. Stem cells for treatment of liver fibrosis/cirrhosis: clinical progress and therapeutic potential. Stem Cell Res Ther 2022; 13:356. [PMID: 35883127 PMCID: PMC9327386 DOI: 10.1186/s13287-022-03041-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
Cost-effective treatment strategies for liver fibrosis or cirrhosis are limited. Many clinical trials of stem cells for liver disease shown that stem cells might be a potential therapeutic approach. This review will summarize the published clinical trials of stem cells for the treatment of liver fibrosis/cirrhosis and provide the latest overview of various cell sources, cell doses, and delivery methods. We also describe the limitations and strengths of various stem cells in clinical applications. Furthermore, to clarify how stem cells play a therapeutic role in liver fibrosis, we discuss the molecular mechanisms of stem cells for treatment of liver fibrosis, including liver regeneration, immunoregulation, resistance to injury, myofibroblast repression, and extracellular matrix degradation. We provide a perspective for the prospects of future clinical implementation of stem cells.
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Affiliation(s)
- Pinyan Liu
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Yongcui Mao
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Ye Xie
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Jiayun Wei
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Jia Yao
- The First Clinical Medical College of Lanzhou University, Lanzhou, China. .,Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China.
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20
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Arango-Rodríguez ML, Solarte-David VA, Becerra-Bayona SM, Callegari E, Paez MD, Sossa CL, Vera MEO, Mateus LC, Eduardo Serrano S, Ardila-Roa AK, Viviescas LTG. Role of mesenchymal stromal cells derivatives in diabetic foot ulcers: a controlled randomized phase 1/2 clinical trial. Cytotherapy 2022; 24:1035-1048. [PMID: 36084965 DOI: 10.1016/j.jcyt.2022.04.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/18/2022] [Accepted: 04/27/2022] [Indexed: 11/28/2022]
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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Affiliation(s)
- Martha L Arango-Rodríguez
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, Floridablanca, Colombia.
| | - Víctor Alfonso Solarte-David
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, Bucaramanga, Colombia; Facultad de Ingeniería, Universidad Autónoma de Bucaramanga - UNAB, Bucaramanga, Colombia 680003
| | - Silvia M Becerra-Bayona
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, Bucaramanga, Colombia
| | - Eduardo Callegari
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA
| | - Maria D Paez
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA
| | - Claudia L Sossa
- Fundación Oftalmológica de Santander Carlos Ardila Lulle Floridablanca, Colombia; Programa para el Tratamiento y Estudio de Enfermedades Hematológicas y Oncológicas de Santander (PROTEHOS), 681004153 Floridablanca, Colombia
| | | | - Ligia C Mateus
- Fundación Oftalmológica de Santander Carlos Ardila Lulle Floridablanca, Colombia
| | - Sergio Eduardo Serrano
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, Bucaramanga, Colombia
| | - Andrea K Ardila-Roa
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, Floridablanca, Colombia
| | - Lady T Giratá Viviescas
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, Floridablanca, Colombia
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21
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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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22
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Khodayari S, Khodayari H, Ebrahimi-Barough S, Khanmohammadi M, Islam MS, Vesovic M, Goodarzi A, Mahmoodzadeh H, Nayernia K, Aghdami N, Ai J. Stem Cell Therapy in Limb Ischemia: State-of-Art, Perspective, and Possible Impacts of Endometrial-Derived Stem Cells. Front Cell Dev Biol 2022; 10:834754. [PMID: 35676930 PMCID: PMC9168222 DOI: 10.3389/fcell.2022.834754] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
As an evidence-based performance, the rising incidence of various ischemic disorders has been observed across many nations. As a result, there is a growing need for the development of more effective regenerative approaches that could serve as main therapeutic strategies for the treatment of these diseases. From a cellular perspective, promoted complex inflammatory mechanisms, after inhibition of organ blood flow, can lead to cell death in all tissue types. In this case, using the stem cell technology provides a safe and regenerative approach for ischemic tissue revascularization and functional cell formation. Limb ischemia (LI) is one of the most frequent ischemic disease types and has been shown to have a promising regenerative response through stem cell therapy based on several clinical trials. Bone marrow-derived mononuclear cells (BM-MNCs), peripheral blood CD34-positive mononuclear cells (CD34+ PB-MNCs), mesenchymal stem cells (MSCs), and endothelial stem/progenitor cells (ESPCs) are the main, well-examined stem cell types in these studies. Additionally, our investigations reveal that endometrial tissue can be considered a suitable candidate for isolating new safe, effective, and feasible multipotent stem cells for limb regeneration. In addition to other teams’ results, our in-depth studies on endometrial-derived stem cells (EnSCs) have shown that these cells have translational potential for limb ischemia treatment. The EnSCs are able to generate diverse types of cells which are essential for limb reconstruction, including endothelial cells, smooth muscle cells, muscle cells, and even peripheral nervous system populations. Hence, the main object of this review is to present stem cell technology and evaluate its method of regeneration in ischemic limb tissue.
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Affiliation(s)
- Saeed Khodayari
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
- Breast Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
- International Center for Personalized Medicine (P7MEDICINE), Düsseldorf, Germany
| | - Hamid Khodayari
- Breast Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
- International Center for Personalized Medicine (P7MEDICINE), Düsseldorf, Germany
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Somayeh Ebrahimi-Barough
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Mehdi Khanmohammadi
- Skull Base Research Center, The Five Senses Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Md Shahidul Islam
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Miko Vesovic
- Department of Mathematics, Statistics, and Computer Science, University of Illinois at Chicago, Chicago, IL, United States
| | - Arash Goodarzi
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
| | | | - Karim Nayernia
- International Center for Personalized Medicine (P7MEDICINE), Düsseldorf, Germany
| | - Nasser Aghdami
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Infectious Diseases and Tropical Medicines, Tehran University of Medical Sciences, Tehran, Iran
- *Correspondence: Jafar Ai, ; Nasser Aghdami,
| | - Jafar Ai
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
- *Correspondence: Jafar Ai, ; Nasser Aghdami,
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23
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Bonanni M, Rehak L, Massaro G, Benedetto D, Matteucci A, Russo G, Esperto F, Federici M, Mauriello A, Sangiorgi GM. Autologous Immune Cell-Based Regenerative Therapies to Treat Vasculogenic Erectile Dysfunction: Is the Immuno-Centric Revolution Ready for the Prime Time? Biomedicines 2022; 10:biomedicines10051091. [PMID: 35625828 PMCID: PMC9138496 DOI: 10.3390/biomedicines10051091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 04/30/2022] [Accepted: 05/02/2022] [Indexed: 02/04/2023] Open
Abstract
About 35% of patients affected by erectile dysfunction (ED) do not respond to oral phosphodiesterase-5 inhibitors (PDE5i) and more severe vasculogenic refractory ED affects diabetic patients. Innovative approaches, such as regenerative therapies, including stem cell therapy (SCT) and platelet-rich plasma (PRP), are currently under investigation. Recent data point out that the regenerative capacity of stem cells is strongly influenced by local immune responses, with macrophages playing a pivotal role in the injury response and as a coordinator of tissue regeneration, suggesting that control of the immune response could be an appealing approach in regenerative medicine. A new generation of autologous cell therapy based on immune cells instead of stem cells, which could change regenerative medicine for good, is discussed. Increasing safety and efficacy data are coming from clinical trials using peripheral blood mononuclear cells to treat no-option critical limb ischemia and diabetic foot. In this review, ongoing phase 1/phase 2 stem cell clinical trials are discussed. In addition, we examine the mechanism of action and rationale, as well as propose a new generation of regenerative therapies, evolving from typical stem cell or growth factor to immune cell-based medicine, based on autologous peripheral blood mononuclear cells (PBMNC) concentrates for the treatment of ED.
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Affiliation(s)
- Michela Bonanni
- Department of Biomedicine and Prevention, Institute of Cardiology, University of Rome Tor Vergata, 00133 Rome, Italy; (M.B.); (G.M.); (D.B.); (A.M.); (G.R.)
| | - Laura Rehak
- Athena Biomedical Innovations, 50126 Florence, Italy;
| | - Gianluca Massaro
- Department of Biomedicine and Prevention, Institute of Cardiology, University of Rome Tor Vergata, 00133 Rome, Italy; (M.B.); (G.M.); (D.B.); (A.M.); (G.R.)
| | - Daniela Benedetto
- Department of Biomedicine and Prevention, Institute of Cardiology, University of Rome Tor Vergata, 00133 Rome, Italy; (M.B.); (G.M.); (D.B.); (A.M.); (G.R.)
| | - Andrea Matteucci
- Department of Biomedicine and Prevention, Institute of Cardiology, University of Rome Tor Vergata, 00133 Rome, Italy; (M.B.); (G.M.); (D.B.); (A.M.); (G.R.)
- Division of Cardiology San Filippo Neri Hospital, 00135 Rome, Italy
| | - Giulio Russo
- Department of Biomedicine and Prevention, Institute of Cardiology, University of Rome Tor Vergata, 00133 Rome, Italy; (M.B.); (G.M.); (D.B.); (A.M.); (G.R.)
| | | | - Massimo Federici
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Alessandro Mauriello
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Giuseppe Massimo Sangiorgi
- Department of Biomedicine and Prevention, Institute of Cardiology, University of Rome Tor Vergata, 00133 Rome, Italy; (M.B.); (G.M.); (D.B.); (A.M.); (G.R.)
- Correspondence:
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24
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Husakova J, Bem R, Jirkovska A, Nemcova A, Fejfarova V, Sutoris K, Kahle M, Jude EB, Dubsky M. Comparison of Three Methods for Preparation of Autologous Cells for Use in Cell Therapy of Chronic Limb-Threatening Ischemia in People with Diabetes. INT J LOW EXTR WOUND 2022:15347346221095954. [PMID: 35466748 DOI: 10.1177/15347346221095954] [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: 02/21/2024]
Abstract
Autologous cell therapy (ACT) is a new therapeutic approach for diabetic patients with no-option chronic limb-threatening ischemia (NO-CLTI). The aim of our study was to quantify cell populations of cell therapy products (CTPs) obtained by three different isolation methods and to correlate their numbers with changes in transcutaneous oxygen pressure (TcPO2). CTPs were separated either from stimulated peripheral blood (PB) (n = 11) or harvested from bone marrow (BM) processed either by Harvest SmartPReP2 (n = 50) or sedimented with succinate gelatin (n = 29). The clinical effect was evaluated by the change in TcPO2 after 1, 3 and 6 months. TcPO2 increased significantly in all three methods at each time point in comparison with baseline values (p < .01) with no significant difference among them. There was no correlation between the change in TcPO2 and the size of injected cell populations. We only observed a weak correlation between the number of injected white blood cells (WBC) and an increase in TcPO2 at 1 and 3 months. Our study showed that all three isolation methods of ACT were similarly relatively efficient in the treatment of NO-CLTI. We observed no correlation of TcPO2 increase with the number of injected monocytes, lymphocytes or CD34+. We observed a weak correlation between TcPO2 increase and the number of injected WBCs.
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Affiliation(s)
- Jitka Husakova
- 360783Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Robert Bem
- 360783Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Alexandra Jirkovska
- 360783Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Andrea Nemcova
- 360783Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Vladimira Fejfarova
- 360783Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Karol Sutoris
- 360783Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Michal Kahle
- 360783Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Edward B Jude
- Diabetes Center, 9386Tameside Hospital NHS Foundation Trust and University of Manchester, Lancashire, UK
| | - Michal Dubsky
- 360783Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- First Faculty of Medicine, Charles University, Prague, Czech Republic
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25
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Yang Y, Lei T, Bi W, Xiao Z, Zhang X, Du H. The combined therapy of mesenchymal stem cell transplantation and resveratrol for diabetes: Future applications and challenges. Life Sci 2022; 301:120563. [PMID: 35460708 DOI: 10.1016/j.lfs.2022.120563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/07/2022] [Accepted: 04/14/2022] [Indexed: 12/22/2022]
Abstract
Diabetes mellitus (DM) is a worldwide chronic epidemic disease of impaired glucose metabolism. Transplantation of mesenchymal stem cells (MSCs) is considered a promising emerging treatment strategy for diabetes. However, the harsh internal environment of DM patients can inhibit the treatment effects of transplanted MSCs. Fortunately, this adverse effect can be reversed by resveratrol (Res). Therefore, we investigated and summarized relevant studies on the combined treatment of diabetes with MSCs and resveratrol. This review presents the therapeutic effects of this combination therapy strategy on DM in glycemic control, anti-inflammatory, anti-oxidative stress and anti-fibrotic. Moreover, this review explained the mechanisms of MSCs and resveratrol in diabetes treatment from 3 aspects, including promoting cell survival and inhibiting apoptosis, inhibiting histiocyte fibrosis, and improving glucose metabolism. These findings help to understand in-depth mechanisms of the treatment of DM and help to propose a potential treatment strategy for DM and its complications.
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Affiliation(s)
- Yanjie Yang
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Tong Lei
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Wangyu Bi
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Zhuangzhuang Xiao
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Xiaoshuang Zhang
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Hongwu Du
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China.
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Liu H, Liu Y, Pan T, Fang Y, Fang G, Jiang X, Chen B, Wei Z, Gu S, Liu P, Fu W, Dong Z. Return to work after cell transplantation in patients with angiitis-induced critical limb ischaemia and factors related: a single-centre retrospective cohort study. Stem Cell Res Ther 2022; 13:139. [PMID: 35365238 PMCID: PMC8972707 DOI: 10.1186/s13287-022-02807-1] [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: 08/30/2021] [Accepted: 12/31/2021] [Indexed: 11/10/2022] Open
Abstract
Background Angiitis-induced critical limb ischaemia (AICLI) patients, who are usually young and have a high amputation rate, always lose their ability to return to the labour force. Return to work (RTW) not only indicates patients’ physical health, showing that they could undertake the work, but also demonstrates their psychological well-being. While cell transplantation showed satisfactory efficacy in limb salvage, few studies of AICLI patients’ RTW after transplantation have been reported. Methods From May 2009 to May 2021, AICLI patients who underwent cell transplantation and completed no less than 12 months of follow-up were retrospectively enrolled. The primary endpoint was RTW. Patient demographics and characteristics of the ischaemic limbs were reviewed to analyse independent risk factors for RTW. Results A total of 171 AICLI patients (170 males) were enrolled with a mean age of 41.9 ± 9.6 years (range: 20–57 years). The 12-month and 24-month RTW cumulative rates were 69.4% (95% confidence interval [CI] 61.6–75.6%) and 70.1% (95% CI 62.3–76.2%), respectively. Age < 40 years (odds ratio [OR] 2.659, 95% CI 1.138–6.719) and preoperative occupation as a mental worker (OR 8.930, 95% CI 2.665–42.847) were identified as independent protective factors for RTW. Perioperative limb infection with ulcer or gangrene (OR 0.250, 95% CI 0.075–0.779) was identified as an independent risk factor. Conclusion AICLI patients who underwent cell transplantation usually had a satisfactory midterm RTW cumulative rate. AICLI patients < 40 years old with preoperative occupation as mental workers were more likely to return to work. Prevention of limb infection during the perioperative period is of great significance to RTW.
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Affiliation(s)
- Hao Liu
- Department of Vascular Surgery of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Yifan Liu
- Department of Vascular Surgery of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Tianyue Pan
- Department of Vascular Surgery of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Yuan Fang
- Department of Vascular Surgery of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Gang Fang
- Department of Vascular Surgery of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Xiaolang Jiang
- Department of Vascular Surgery of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Bin Chen
- Department of Vascular Surgery of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Zheng Wei
- Department of Hematology of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Shiyang Gu
- Department of Hematology of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Peng Liu
- Department of Hematology of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Weiguo Fu
- Department of Vascular Surgery of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Zhihui Dong
- Department of Vascular Surgery of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
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27
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Lin ZH, Wang J, Liang ZH, Pan YC. [Research advances on stem cell therapy for diabetic foot wounds]. ZHONGHUA SHAO SHANG YU CHUANG MIAN XIU FU ZA ZHI 2022; 38:281-286. [PMID: 35325974 DOI: 10.3760/cma.j.cn501120-20210828-00292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Diabetic foot wound repair is a challenging issue in clinical practice. Due to the influence of multiple factors including the damage and regeneration failure of local tissue, the impaired pathways of wound repairing through blood vessels and nerve nutrition, and disorders of a variety of cellular factors, traditional treatment methods are often difficult to achieve good therapeutic effects. Stem cells are a type of cells with potentials of multidirectional differentiation, which also possess functions such as regulating immunity and paracrine to facilitate the comprehensive wound repair, so they have promising application prospect at present for the treatment of diabetic foot wounds. Because the relevant parameters of stem cell treatment are in the exploratory phase, there were no standardized data. This paper reviews the application of stem cells in the research of diabetic foot wound treatment over the past 6 years, analyzing and summarizing the contents in focused aspects including the types and sources of stem cells, effects of donor age and gender on stem cells, mode of administration, transplantation survival rate and safety, which may provide a reference for further application of stem cells in the clinical treatment of diabetic foot wound.
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Affiliation(s)
- Z H Lin
- Department of Burn and Skin Repair, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, China
| | - J Wang
- Department of Burn and Skin Repair, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, China
| | - Z H Liang
- Department of Burn and Skin Repair, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, China
| | - Y C Pan
- Department of Burn and Skin Repair, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, China
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Maksimova NV, Michenko AV, Krasilnikova OA, Klabukov ID, Gadaev IY, Krasheninnikov ME, Belkov PA, Lyundup AV. Mesenchymal stromal cell therapy alone does not lead to complete restoration of skin parameters in diabetic foot patients within a 3-year follow-up period. BIOIMPACTS : BI 2022; 12:51-55. [PMID: 35087716 PMCID: PMC8783077 DOI: 10.34172/bi.2021.22167] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/21/2020] [Accepted: 07/29/2020] [Indexed: 01/07/2023]
Abstract
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Introduction:Mesenchymal stromal cells (MSCs) administration is an effective option for the treatment of diabetic foot ulcers (DFUs). However, to date, studies assessing long-term outcomes and evaluating skin parameters after cell-based therapy are lacking. We presented the clinical outcomes of 3 patients, treated for DFUs with the bone marrow MSCs 3 years earlier.
Methods: Ultrasound examination was used to compare collagen density and epidermal thickness in areas of healed ulcers in comparison with non-affected skin used as a control. Ultrasound and dermatoscopy were used to exclude neoplasm formation, to assess scar contracture and wound recurrence.
Results:In all patients, no ulcer recurrence was detected, which was lower than the expected 60% rate of re-ulceration in diabetic patients in a 3-year period (OD [odds ratio] = 0.095, P = 0.12). No neoplasm formation, no contracture of hypertrophic scar, and adjacent tissue were registered. Collagen ultrasound density was decreased by 57% (P = 0.053) and epidermal thickness was increased by 72% (P = 0.01) in the area of healed ulcers in all patients.
Conclusion:MSCs therapy alone did not result in the complete restoration of the skin parameters within a 3-year period. MSCs may represent important adjuvant to the therapy, however, other novel approaches are required to achieve better results.
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Affiliation(s)
- Nadezhda V Maksimova
- Department of Endocrinology, Sechenov First Moscow State Medical University (Sechenov University), Russia
| | - Anna V Michenko
- Moscow Scientific and Practical Center of Dermatovenerology and Cosmetology, Moscow, Russia
| | - Olga A Krasilnikova
- Department of Regenerative Technologies and Biofabrication, National Medical Research Radiological Center, Obninsk, Russia
| | - Ilya D Klabukov
- Department of Regenerative Technologies and Biofabrication, National Medical Research Radiological Center, Obninsk, Russia
| | - Igor Yu Gadaev
- Chair of Hospital Therapy №1, Sechenov First Moscow State Medical University (Sechenov University), Russia
| | - Michael E Krasheninnikov
- Research and Educational Resource Center for Cellular Technologies, Peoples' Friendship University of Russia, Moscow, Russia
| | | | - Aleksey V Lyundup
- Research and Educational Resource Center for Cellular Technologies, Peoples' Friendship University of Russia, Moscow, Russia
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Modulation of Mesenchymal Stem Cells for Enhanced Therapeutic Utility in Ischemic Vascular Diseases. Int J Mol Sci 2021; 23:ijms23010249. [PMID: 35008675 PMCID: PMC8745455 DOI: 10.3390/ijms23010249] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells are multipotent stem cells isolated from various tissue sources, including but not limited to bone marrow, adipose, umbilical cord, and Wharton Jelly. Although cell-mediated mechanisms have been reported, the therapeutic effect of MSCs is now recognized to be primarily mediated via paracrine effects through the secretion of bioactive molecules, known as the “secretome”. The regenerative benefit of the secretome has been attributed to trophic factors and cytokines that play neuroprotective, anti-angiogenic/pro-angiogenic, anti-inflammatory, and immune-modulatory roles. The advancement of autologous MSCs therapy can be hindered when introduced back into a hostile/disease environment. Barriers include impaired endogenous MSCs function, limited post-transplantation cell viability, and altered immune-modulatory efficiency. Although secretome-based therapeutics have gained popularity, many translational hurdles, including the heterogeneity of MSCs, limited proliferation potential, and the complex nature of the secretome, have impeded the progress. This review will discuss the experimental and clinical impact of restoring the functional capabilities of MSCs prior to transplantation and the progress in secretome therapies involving extracellular vesicles. Modulation and utilization of MSCs–secretome are most likely to serve as an effective strategy for promoting their ultimate success as therapeutic modulators.
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Chiang KJ, Chiu LC, Kang YN, Chen C. Autologous Stem Cell Therapy for Chronic Lower Extremity Wounds: A Meta-Analysis of Randomized Controlled Trials. Cells 2021; 10:3307. [PMID: 34943815 PMCID: PMC8699089 DOI: 10.3390/cells10123307] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 12/15/2022] Open
Abstract
Lower extremity chronic wounds (LECWs) commonly occur in patients with diabetes mellitus (DM) and peripheral arterial disease (PAD). Autologous stem cell therapy (ASCT) has emerged as a promising alternative treatment for those who suffered from LECWs. The purpose of this study was to assess the effects of ASCT on LECWs. Two authors searched three core databases, and independently identified evidence according to predefined criteria. They also individually assessed the quality of the included randomized controlled trials (RCTs), and extracted data on complete healing rate, amputation rate, and outcomes regarding peripheral circulation. The extracted data were pooled using a random-effects model due to clinical heterogeneity among the included RCTs. A subgroup analysis was further performed according to etiology, source of stem cells, follow-up time, and cell markers. A total of 28 RCTs (n = 1096) were eligible for this study. The pooled results showed that patients receiving ASCT had significantly higher complete healing rates (risk ratio (RR) = 1.67, 95% confidence interval (CI) 1.28-2.19) as compared with those without ASCT. In the CD34+ subgroup, ASCT significantly led to a higher complete healing rate (RR = 2.70, 95% CI 1.50-4.86), but there was no significant difference in the CD34- subgroup. ASCT through intramuscular injection can significantly improve wound healing in patients with LECWs caused by either DM or critical limb ischemia. Lastly, CD34+ is an important cell marker for potential wound healing. However, more extensive scale and well-designed studies are necessary to explore the details of ASCT and chronic wound healing.
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Affiliation(s)
- Kuan-Ju Chiang
- School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (K.-J.C.); (L.-C.C.)
| | - Li-Cheng Chiu
- School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (K.-J.C.); (L.-C.C.)
| | - Yi-No Kang
- Department of Health Care Management, College of Health Technology, National Taipei University of Nursing Health Sciences, Taipei 112, Taiwan
- Evidence-Based Medicine Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Research Center of Big Data and Meta-Analysis Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Cochrane Taiwan, Taipei Medical University, Taipei 110, Taiwan
- Institute of Health Policy & Management, College of Public Health, National Taiwan University, Taipei 100, Taiwan
| | - Chiehfeng Chen
- Evidence-Based Medicine Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Cochrane Taiwan, Taipei Medical University, Taipei 110, Taiwan
- Division of Plastic Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
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Burgess JL, Wyant WA, Abdo Abujamra B, Kirsner RS, Jozic I. Diabetic Wound-Healing Science. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:1072. [PMID: 34684109 PMCID: PMC8539411 DOI: 10.3390/medicina57101072] [Citation(s) in RCA: 260] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/28/2021] [Accepted: 10/04/2021] [Indexed: 12/15/2022]
Abstract
Diabetes mellitus is an increasingly prevalent chronic metabolic disease characterized by prolonged hyperglycemia that leads to long-term health consequences. It is estimated that impaired healing of diabetic wounds affects approximately 25% of all patients with diabetes mellitus, often resulting in lower limb amputation, with subsequent high economic and psychosocial costs. The hyperglycemic environment promotes the formation of biofilms and makes diabetic wounds difficult to treat. In this review, we present updates regarding recent advances in our understanding of the pathophysiology of diabetic wounds focusing on impaired angiogenesis, neuropathy, sub-optimal chronic inflammatory response, barrier disruption, and subsequent polymicrobial infection, followed by current and future treatment strategies designed to tackle the various pathologies associated with diabetic wounds. Given the alarming increase in the prevalence of diabetes, and subsequently diabetic wounds, it is imperative that future treatment strategies target multiple causes of impaired healing in diabetic wounds.
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Affiliation(s)
| | | | | | - Robert S. Kirsner
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (J.L.B.); (W.A.W.); (B.A.A.)
| | - Ivan Jozic
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (J.L.B.); (W.A.W.); (B.A.A.)
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32
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Tay S, Abdulnabi S, Saffaf O, Harroun N, Yang C, Semenkovich CF, Zayed MA. Comprehensive Assessment of Current Management Strategies for Patients With Diabetes and Chronic Limb-Threatening Ischemia. Clin Diabetes 2021; 39:358-388. [PMID: 34866779 PMCID: PMC8603325 DOI: 10.2337/cd21-0019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Chronic limb-threatening ischemia (CLTI) is the most severe form of peripheral artery disease. It is estimated that 60% of all nontraumatic lower-extremity amputations performed annually in the United States are in patients with diabetes and CLTI. The consequences of this condition are extraordinary, with substantial patient morbidity and mortality and high socioeconomic costs. Strategies that optimize the success of arterial revascularization in this unique patient population can have a substantial public health impact and improve patient outcomes. This article provides an up-to-date comprehensive assessment of management strategies for patients afflicted by both diabetes and CLTI.
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Affiliation(s)
- Shirli Tay
- Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St. Louis, MO
| | - Sami Abdulnabi
- Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St. Louis, MO
| | - Omar Saffaf
- Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St. Louis, MO
| | - Nikolai Harroun
- Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St. Louis, MO
| | - Chao Yang
- Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St. Louis, MO
| | - Clay F. Semenkovich
- Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO
| | - Mohamed A. Zayed
- Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St. Louis, MO
- Division of Molecular Cell Biology, Washington University School of Medicine, St. Louis, MO
- Department of Biomedical Engineering, Washington University McKelvey School of Engineering, St. Louis, MO
- Veterans Affairs St. Louis Health Care System, St. Louis, MO
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33
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Jiang X, Yuan Y, Ma Y, Zhong M, Du C, Boey J, Armstrong DG, Deng W, Duan X. Pain Management in People with Diabetes-Related Chronic Limb-Threatening Ischemia. J Diabetes Res 2021; 2021:6699292. [PMID: 34046505 PMCID: PMC8128546 DOI: 10.1155/2021/6699292] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 04/19/2021] [Accepted: 05/03/2021] [Indexed: 12/24/2022] Open
Abstract
Management of neuropathic pain in people with diabetes has been widely investigated. However, little attention was paid to address ischemic-related pain in patients with diabetes mellitus who suffered from chronic limb-threatening ischemia (CLTI), the end stage of lower extremity arterial disease (LEAD). Pain management has a tremendous influence on patients' quality of life and prognosis. Poor management of this type of pain owing to the lack of full understanding undermines patients' physical and mental quality of life, which often results in a grim prognosis, such as depression, myocardial infarction, lower limb amputation, and even mortality. In the present article, we review the current strategy in the pain management of diabetes-related CLTI. The endovascular therapy, pharmacological therapies, and other optional methods could be selected following comprehensive assessments to mitigate ischemic-related pain, in line with our current clinical practice. It is very important for clinicians and patients to strengthen the understanding and build intervention strategy in ischemic pain management and possible adverse consequence.
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Affiliation(s)
- Xiaoyan Jiang
- Department of Endocrinology, Diabetic Foot Center, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400014, China
| | - Yi Yuan
- Department of Endocrinology, Diabetic Foot Center, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400014, China
| | - Yu Ma
- Department of Endocrinology, Diabetic Foot Center, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400014, China
| | - Miao Zhong
- Department of Endocrinology, Diabetic Foot Center, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400014, China
| | - Chenzhen Du
- Department of Endocrinology, Diabetic Foot Center, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400014, China
| | - Johnson Boey
- Department of Podiatry, National University of Hospital Singapore, Singapore 169608
| | - David G. Armstrong
- Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
| | - Wuquan Deng
- Department of Endocrinology, Diabetic Foot Center, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400014, China
| | - Xiaodong Duan
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
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Mesenchymal Stem Cell Transplantation for Ischemic Diseases: Mechanisms and Challenges. Tissue Eng Regen Med 2021; 18:587-611. [PMID: 33884577 DOI: 10.1007/s13770-021-00334-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 02/07/2021] [Accepted: 02/16/2021] [Indexed: 12/20/2022] Open
Abstract
Ischemic diseases are conditions associated with the restriction or blockage of blood supply to specific tissues. These conditions can cause moderate to severe complications in patients, and can lead to permanent disabilities. Since they are blood vessel-related diseases, ischemic diseases are usually treated with endothelial cells or endothelial progenitor cells that can regenerate new blood vessels. However, in recent years, mesenchymal stem cells (MSCs) have shown potent bioeffects on angiogenesis, thus playing a role in blood regeneration. Indeed, MSCs can trigger angiogenesis at ischemic sites by several mechanisms related to their trans-differentiation potential. These mechanisms include inhibition of apoptosis, stimulation of angiogenesis via angiogenic growth factors, and regulation of immune responses, as well as regulation of scarring to suppress blood vessel regeneration when needed. However, preclinical and clinical trials of MSC transplantation in ischemic diseases have shown some limitations in terms of treatment efficacy. Such studies have emphasized the current challenges of MSC-based therapies. Treatment efficacy could be enhanced if the limitations were better understood and potentially resolved. This review will summarize some of the strategies by which MSCs have been utilized for ischemic disease treatment, and will highlight some challenges of those applications as well as suggesting some strategies to improve treatment efficacy.
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Holl J, Kowalewski C, Zimek Z, Fiedor P, Kaminski A, Oldak T, Moniuszko M, Eljaszewicz A. Chronic Diabetic Wounds and Their Treatment with Skin Substitutes. Cells 2021; 10:cells10030655. [PMID: 33804192 PMCID: PMC8001234 DOI: 10.3390/cells10030655] [Citation(s) in RCA: 152] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 12/11/2022] Open
Abstract
With the global prevalence of type 2 diabetes mellitus steeply rising, instances of chronic, hard-healing, or non-healing diabetic wounds and ulcers are predicted to increase. The growing understanding of healing and regenerative mechanisms has elucidated critical regulators of this process, including key cellular and humoral components. Despite this, the management and successful treatment of diabetic wounds represents a significant therapeutic challenge. To this end, the development of novel therapies and biological dressings has gained increased interest. Here we review key differences between normal and chronic non-healing diabetic wounds, and elaborate on recent advances in wound healing treatments with a particular focus on biological dressings and their effect on key wound healing pathways.
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Affiliation(s)
- Jordan Holl
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, 15-269 Bialystok, Poland;
| | - Cezary Kowalewski
- Department of Dermatology and Immunodermatology, Medical University of Warsaw, 02-008 Warsaw, Poland;
| | - Zbigniew Zimek
- Institute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland;
| | - Piotr Fiedor
- Department of General and Transplantation Surgery, Medical University of Warsaw, 02-006 Warsaw, Poland;
| | - Artur Kaminski
- Department of Transplantology and Central Tissue Bank, Medical University of Warsaw, 02-091 Warsaw, Poland;
| | - Tomasz Oldak
- Polish Stem Cell Bank (PBKM), 00-867 Warsaw, Poland;
| | - Marcin Moniuszko
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, 15-269 Bialystok, Poland;
- Department of Allergology and Internal Medicine, Medical University of Białystok, 15-276 Białystok, Poland
- Correspondence: (M.M.); (A.E.); Tel.: +48-85-748-59-72 (M.M. & A.E.); Fax: +48-85-748-59-71 (M.M. & A.E.)
| | - Andrzej Eljaszewicz
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, 15-269 Bialystok, Poland;
- Correspondence: (M.M.); (A.E.); Tel.: +48-85-748-59-72 (M.M. & A.E.); Fax: +48-85-748-59-71 (M.M. & A.E.)
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Abstract
Historically, there has been a scarcity of evidence-based topical therapy to hasten the healing of diabetic foot ulcers. But recently new evidence-based treatments have emerged from multicentre, randomised, controlled trials. This article highlights those trials, and describes the current pharmacological management of the diabetic foot ulcer and the advances that have been made in wound therapy to date. It provides an overview of topical and systemic pharmacotherapies in current use and those in development for future use in managing the diabetic foot. For each treatment, proposed mechanisms of action and evidence available to support their clinical use are presented. There is supporting randomised, controlled evidence for sucrose octasulfate in the treatment of neuro-ischaemic ulcers, and multi-layered patch of autologous leucocytes, platelets and fibrin in ulcers with or without ischaemia. There is also evidence for placentally derived products and for topical and systemic oxygen therapy in the healing of diabetic foot ulcers. Growth factors, bio-engineered tissues, stem cell therapy, gene therapy and peptide therapy also have some supporting evidence in the healing of diabetic foot ulcers. Nonsurgical debriding agents may be useful when the optimum approach of sharp debridement is not possible, and immunomodulators may be helpful for their antimicrobial effects, but robust data is still required to strengthen the case for general use. The review does not cover antimicrobials as their primary role are as anti-infectives and not in wound healing. The development of nanotechnology has created a means of prolonging the bioavailability of target molecules at the wound site, with the use of glass/hydrogel nanoparticles, polyethylene glycol and hyaluronic acid. Looking forward, novel therapies, including traction force-activated payloads, local delivery of short-interfering RNA and finally hydrogels incorporating bioactive agents or cells may provide possibilities for pharmacotherapy in the future.
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Affiliation(s)
- Danielle Dixon
- Diabetic Foot Clinic, King's College NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK.
| | - Michael Edmonds
- Diabetic Foot Clinic, King's College NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK
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Ipema J, Roozendaal NC, Bax WA, de Borst GJ, de Vries JPPM, Ünlü Ç. Medical adjunctive therapy for patients with chronic limb-threatening ischemia: a systematic review. THE JOURNAL OF CARDIOVASCULAR SURGERY 2019; 60:642-651. [PMID: 31603294 DOI: 10.23736/s0021-9509.19.11108-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
INTRODUCTION The aim of this article is to systematically review the literature on medical adjunctive therapy for patients with chronic limb-threatening ischemia (CLTI). EVIDENCE ACQUISITION MEDLINE, Embase, and Cochrane Database of Systematic Reviews were searched for studies published between January 1st, 2009, and June 1st, 2019. Articles that studied medical treatment of CLTI patients and reported clinical outcomes were eligible. Main exclusion criteria were case reports <20 patients, incorrect publication type, and CLTI caused by Buerger disease. The primary end point was major amputation (above the ankle) in studies with a follow-up of ≥6 months. Secondary end points were other clinical end points such as death and wound healing. Study quality was assessed according to the Downs and Black checklist. EVIDENCE SYNTHESIS Included were 42 articles: four focused on antiplatelet therapy, five on antihypertensive medication, 6 on lipid-lowering therapy, 16 on stem cell therapy, three on growth factors, five on prostanoids, and one study each on cilostazol, glucose-lowering therapy, spinal cord stimulation, sulodexide, and hemodilution. Calcium channel blockers, iloprost, cilostazol, and hemodilution showed significant improvement of limb salvage, but data are limited. Stem cell therapy showed no significant improvement of limb salvage but could potentially improve wound healing. Antiplatelets, antihypertensives, and statins showed significantly lower cardiovascular events rates but not evident lower major amputation rates. The quality of the studies was fair to good. CONCLUSIONS Certain medical therapies serve to improve limb salvage next to revascularization in CLTI patients, whereas others are important in secondary prevention. Because high quality evidence is limited, further research is needed.
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Affiliation(s)
- Jetty Ipema
- Department of Vascular Surgery, Northwest Clinics, Alkmaar, the Netherlands -
| | - Nicolaas C Roozendaal
- Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Willem A Bax
- Department of Internal Medicine, Northwest Clinics, Alkmaar, the Netherlands
| | - Gert J de Borst
- Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Jean Paul P M de Vries
- Division of Vascular Surgery, Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Çağdaş Ünlü
- Department of Vascular Surgery, Northwest Clinics, Alkmaar, the Netherlands
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