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      Comparison of efficacy and safety of single versus repeated intra-articular injection of allogeneic neonatal mesenchymal stem cells for treatment of osteoarthritis of the metacarpophalangeal/metatarsophalangeal joint in horses: A clinical pilot study

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          Abstract

          The purpose of this prospective study was to evaluate the effects of single and repeated intra-articular administration of allogeneic, umbilical cord-derived, neonatal mesenchymal stem cells (MSC) in horses with lameness due to osteoarthritis (OA) of a metacarpophalangeal joint (MPJ).

          Twenty-eight horses were included. Horses were divided into two groups. Horses in group MSC1 received an MSC injection at M0 and a placebo injection at M1 (1 month after M0). Horses in group MSC2 received MSC injections at M0 and at M1. Joint injections were performed with a blinded syringe. Clinical assessment was performed by the treating veterinarian at M1, M2 and M6 (2 and 6 months after M0), including lameness evaluation, palpation and flexion of the joint. Radiographic examination of the treated joints was performed at inclusion and repeated at M6. Radiographs were anonymized and assessed by 2 ECVDI LA associate members. Short term safety assessment was performed by owner survey. A 2-month rehabilitation program was recommended to veterinarians. There was a significant improvement of the total clinical score for horses in both groups. There was no significant difference in the total clinical score between groups MSC1 and MSC2 at any time point in the study. There was no significant difference in the total radiographic OA score, osteophyte score, joint space width score and subchondral bone score between inclusion and M6. Owner-detected adverse effects to MSC injection were recorded in 18% of the horses. Lameness caused by OA improved significantly over the 6-month duration of the study after treatment with allogeneic neonatal umbilical cord-derived MSCs combined with 8 weeks rest and rehabilitation. There is no apparent clinical benefit of repeated intra-articular administration of MSCs at a 1-month interval in horses with MPJ OA when compared to the effect of a single injection.

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          Umbilical Cord‐Derived Mesenchymal Stromal Cells (MSCs) for Knee Osteoarthritis: Repeated MSC Dosing Is Superior to a Single MSC Dose and to Hyaluronic Acid in a Controlled Randomized Phase I/II Trial

          Abstract Knee osteoarthritis (OA) is a leading cause of pain and disability. Although conventional treatments show modest benefits, pilot and phase I/II trials with bone marrow (BM) and adipose‐derived (AD) mesenchymal stromal cells (MSCs) point to the feasibility, safety, and occurrence of clinical and structural improvement in focal or diffuse disease. This study aimed to assess the safety and efficacy of the intra‐articular injection of single or repeated umbilical cord‐derived (UC) MSCs in knee OA. UC‐MSCs were cultured in an International Organization for Standardization 9001:2015 certified Good Manufacturing Practice‐type Laboratory. Patients with symptomatic knee OA were randomized to receive hyaluronic acid at baseline and 6 months (HA, n = 8), single‐dose (20 × 106) UC‐MSC at baseline (MSC‐1, n = 9), or repeated UC‐MSC doses at baseline and 6 months (20 × 106 × 2; MSC‐2, n = 9). Clinical scores and magnetic resonance images (MRIs) were assessed throughout the 12 months follow‐up. No severe adverse events were reported. Only MSC‐treated patients experienced significant pain and function improvements from baseline (p = .001). At 12 months, Western Ontario and Mc Master Universities Arthritis Index (WOMAC‐A; pain subscale) reached significantly lower levels of pain in the MSC‐2‐treated group (1.1 ± 1.3) as compared with the HA group (4.3 ± 3.5; p = .04). Pain Visual Analog scale was significantly lower in the MSC‐2 group versus the HA group (2.4 ± 2.1 vs. 22.1 ± 9.8, p = .03) at 12 months. For total WOMAC, MSC‐2 had lower scores than HA at 12 months (4.2 ± 3.9 vs. 15.2 ± 11, p = .05). No differences in MRI scores were detected. In a phase I/II trial (NCT02580695), repeated UC‐MSC treatment is safe and superior to active comparator in knee OA at 1‐year follow‐up. stem cells translational medicine 2019;8:215&224
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            Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon.

            Mesenchymal stem (progenitor; stromal) cell (MSC) therapy has gained popularity for the treatment of equine tendon injuries but without reports of long-term follow-up. To evaluate the safety and reinjury rate of racehorses after intralesional MSC injection in a large study of naturally occurring superficial digital flexor tendinopathy and to compare these data with those published for other treatments. Safety was assessed clinically, ultrasonographically, scintigraphically and histologically in a cohort of treated cases: 141 client-owned treated racehorses followed-up for a minimum of 2 years after return to full work. Reinjury percentages were compared to 2 published studies of other treatments with similar selection criteria and follow-up. The number of race starts, discipline, age, number of MSCs injected and interval between injury and treatment were analysed. There were no adverse effects of the treatment with no aberrant tissue on histological examination. The reinjury percentage of all racehorses with follow-up (n = 113) undergoing MSC treatment was 27.4%, with the rate for flat (n = 8) and National Hunt (n = 105) racehorses being 50 and 25.7%, respectively. This was significantly less than published for National Hunt racehorses treated in other ways. No relationship between outcome and age, discipline, number of MSCs injected or injury to implantation interval was found. Whilst recognising the limitations of historical controls, this study has shown that MPC implantation is safe and appears to reduce the reinjury rate after superficial digital flexor tendinopathy, especially in National Hunt racehorses. This study has provided evidence for the long-term efficacy of MSC treatment for tendinopathy in racehorses and provides support for translation to human tendon injuries. © 2011 EVJ Ltd.
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              Concentrated bone marrow aspirate improves full-thickness cartilage repair compared with microfracture in the equine model.

              The purpose of this study was to compare the outcomes of treatment with bone marrow aspirate concentrate, a simple, one-step, autogenous, and arthroscopically applicable method, with the outcomes of microfracture with regard to the repair of full-thickness cartilage defects in an equine model. Extensive (15-mm-diameter) full-thickness cartilage defects were created on the lateral trochlear ridge of the femur in twelve horses. Bone marrow was aspirated from the sternum and centrifuged to generate the bone marrow concentrate. The defects were treated with bone marrow concentrate and microfracture or with microfracture alone. Second-look arthroscopy was performed at three months, and the horses were killed at eight months. Repair was assessed with use of macroscopic and histological scoring systems as well as with quantitative magnetic resonance imaging. No adverse reactions due to the microfracture or the bone marrow concentrate were observed. At eight months, macroscopic scores (mean and standard error of the mean, 9.4 + or - 1.2 compared with 4.4 + or - 1.2; p = 0.009) and histological scores (11.1 + or - 1.6 compared with 6.4 + or - 1.2; p = 0.02) indicated improvement in the repair tissue in the bone marrow concentrate group compared with that in the microfracture group. All scoring systems and magnetic resonance imaging data indicated that delivery of the bone marrow concentrate resulted in increased fill of the defects and improved integration of repair tissue into surrounding normal cartilage. In addition, there was greater type-II collagen content and improved orientation of the collagen as well as significantly more glycosaminoglycan in the bone marrow concentrate-treated defects than in the microfracture-treated defects. Delivery of bone marrow concentrate can result in healing of acute full-thickness cartilage defects that is superior to that after microfracture alone in an equine model. Delivery of bone marrow concentrate to cartilage defects has the clinical potential to improve cartilage healing, providing a simple, cost-effective, arthroscopically applicable, and clinically effective approach for cartilage repair.
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                Author and article information

                Contributors
                Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Investigation
                Role: ConceptualizationRole: Methodology
                Role: ConceptualizationRole: Methodology
                Role: InvestigationRole: MethodologyRole: Resources
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                29 August 2019
                2019
                : 14
                : 8
                : e0221317
                Affiliations
                [1 ] Clinéquine, VetAgro Sup, Campus Vétérinaire de Lyon, Marcy l’Etoile, France
                [2 ] Vetbiobank SAS, Campus Vétérinaire de Lyon, Marcy l’Etoile, France
                [3 ] Azurvet, Cagnes-sur-Mer, France
                [4 ] Clinique équine vétérinaire de Meheudin, Ecouché, France
                [5 ] Clinique équine Areda, Bex, Switzerland
                [6 ] Clinique équine de Grosbois, Marolles-en-Brie, France
                Children's Hospital Boston, UNITED STATES
                Author notes

                Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: SM is a current and principal shareholder of Vetbiobank. MF, FL, NS, are employees of Vetbiobank. There is no commercial or financial connection between Vetbiobank and the seven co-authors (CM, MS, EC, IF, AL, DA, AM). EC is shareholder of Azurvet. The product used in this study is developed for commercial use in France and Europe. There are no patents associated with this research to declare. These commercial affiliations do not alter adherence of all authors to all PLOS ONE policies on sharing data and materials. MS and CM are current employees of the National Veterinary School Of Lyon, Vetagro Sup in France.

                ‡ These authors also contributed equally to this work.

                Author information
                http://orcid.org/0000-0003-1854-149X
                Article
                PONE-D-19-16694
                10.1371/journal.pone.0221317
                6715221
                31465445
                6ac4b076-81b6-47db-8630-1d55f3389a8c
                © 2019 Magri et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 June 2019
                : 2 August 2019
                Page count
                Figures: 2, Tables: 2, Pages: 16
                Funding
                Azurvet provided support in the form of salary for author EC. Vetbiobank provided support in the form of salaries for authors (MF, FL, NS) and contributed to the study design, data collection and analysis, decision to publish and preparation of the manuscript. The specific roles of these authors are articulated in the 'Authors Contribution Section’.
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Equines
                Horses
                Medicine and Health Sciences
                Rheumatology
                Arthritis
                Osteoarthritis
                Biology and Life Sciences
                Anatomy
                Musculoskeletal System
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                Medicine and Health Sciences
                Anatomy
                Musculoskeletal System
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                Biology and Life Sciences
                Cell Biology
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                Mesenchymal Stem Cells
                Biology and Life Sciences
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                Immunology
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