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A systematic review of the concept and clinical applications of bone marrow aspirate concentrate in tendon pathology

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      Tendon pathologies are a group of musculoskeletal conditions frequently seen in clinical practice. They can be broadly classified into traumatic, degenerative and overuse-related tendinopathies. Rotator cuff tears, Achilles tendinopathy and tennis elbow are common examples of these conditions. Conventional treatments have shown inconsistent outcomes and might fail to provide satisfactory clinical improvement. With the growing trend towards the use of mesenchymal stem cells (MSCs) in other branches of medicine, there is an increasing interest in treating tendon pathologies using the bone marrow MSC. In this article, we provide a systematic literature review documenting the current status of the use of bone marrow aspirate concentrate (BMAC) for the treatment of tendon pathologies. We also asked the question on the safety of BMAC and whether there are potential complications associated with BMAC therapy. Our hypothesis is that the use of BMAC provides safe clinical benefit when used for the treatment of tendinopathy or as a biological augmentation of tendon repair. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist while preparing this systematic review. A literature search was carried out including the online databases of PubMed, EMBASE, and the Cochrane Library from 1960 to the end of May 2015. Relevant studies were selected and critically appraised. Data from eligible studies were extracted and classified per type of tendon pathology. We included 37 articles discussing the application and use of BMAC for the treatment of tendon pathologies. The Critical Appraisal Skills Program (CASP) appraisal confirmed a satisfactory standard of 37 studies. Studies were sub-categorised into: techniques of extraction, processing and microscopic examination of BMAC ( n = 18), where five studies looked at the evaluation of aspiration techniques ( n = 5), augmentation of rotator cuff tears ( n = 5), augmentation of tendo-achilles tendon ( n = 1), treatment of gluteal tendon injuries ( n = 1), management of elbow epicondylitis ( n = 2), management of patellar tendinopathy ( n = 1) and complications related to BMAC ( n = 5). Multiple experimental studies investigated the use of BMAC for tendon repair; nonetheless, there are only limited clinical studies available in this field. Unfortunately, due to the scarcity of studies, which were mainly case series, the current level of evidence is weak. We strongly recommend further future randomised controlled studies in this field to allow scientists and clinicians make evidence-based conclusions.

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      Most cited references 63

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      Multilineage potential of adult human mesenchymal stem cells.

      Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.
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        Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche.

        The repair of injured tendons remains a great challenge, largely owing to a lack of in-depth characterization of tendon cells and their precursors. We show that human and mouse tendons harbor a unique cell population, termed tendon stem/progenitor cells (TSPCs), that has universal stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity. The isolated TSPCs could regenerate tendon-like tissues after extended expansion in vitro and transplantation in vivo. Moreover, we show that TSPCs reside within a unique niche predominantly comprised of an extracellular matrix, and we identify biglycan (Bgn) and fibromodulin (Fmod) as two critical components that organize this niche. Depletion of Bgn and Fmod affects the differentiation of TSPCs by modulating bone morphogenetic protein signaling and impairs tendon formation in vivo. Our results, while offering new insights into the biology of tendon cells, may assist in future strategies to treat tendon diseases.
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          Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation.

          Recent studies have demonstrated the existence of a subset of cells in human bone marrow capable of differentiating along multiple mesenchymal lineages. Not only do these mesenchymal stem cells (MSCs) possess multilineage developmental potential, but they may be cultured ex vivo for many passages without overt expression of a differentiated phenotype. The goals of the current study were to determine the growth kinetics, self-renewing capacity and the osteogenic potential of purified MSCs during extensive subcultivation and following cryopreservation. Primary cultures of MSCs were established from normal iliac crest bone marrow aspirates, an aliquot was cryopreserved and thawed, and then both frozen and unfrozen populations were subcultivated in parallel for as many as 15 passages. Cells derived from each passage were assayed for their kinetics of growth and their osteogenic potential in response to an osteoinductive medium containing dexamethasone. Spindle-shaped human MSCs in primary culture exhibit a lag phase of growth, followed by a log phase, finally resulting in a growth plateau state. Passaged cultures proceed through the same stages, however, the rate of growth in log phase and the final number of cells after a fixed period in culture diminishes as a function of continued passaging. The average number of population doublings for marrow-derived adult human MSCs was determined to be 38 +/- 4, at which time the cells finally became very broad and flattened before degenerating. The osteogenic potential of cells was conserved throughout every passage as evidenced by the significant increase in APase activity and formation of mineralized nodular aggregates. Furthermore, the process of cryopreserving and thawing the cells had no effect on either their growth or osteogenic differentiation. Importantly, these studies demonstrate that replicative senescence of MSCs is not a state of terminal differentiation since these cells remain capable of progressing through the osteogenic lineage. The use of population doubling potential as a measure of biological age suggests that MSCs are intermediately between embryonic and adult tissues, and as such, may provide an in situ source for mesenchymal progenitor cells throughout an adult's lifetime.

            Author and article information

            [1 ] Department of Trauma and Orthopaedics, Faculty of Medicine, Suez Canal University Circular road Ismailia 41111 Egypt
            [2 ] The Royal Orthopaedic Hospital Birmingham B31 2AP UK
            [3 ] Birmingham University Birmingham B15 2TT UK
            [4 ] St George Hospital London SW17 0QT UK
            [5 ] Faculty of Medicine, Zagzig University 44519 Zagzig Egypt
            [6 ] Department of Orthopaedics, Balgrist University Hospital, University of Zurich Forchstrasse 340 8008 Zürich Switzerland
            [7 ] Ashford and St Peters Hospitals Chertsey KT16 0PZ UK
            [8 ] Regenerative Medicine, Aston University, Aston Triangle Birmingham B4 7ET UK
            Author notes
            [* ]Corresponding author: mohamed.imam@
            SICOT J
            SICOT J
            EDP Sciences
            09 October 2017
            : 3
            : ( publisher-idID: sicotj/2017/01 )
            28990575 5632955 10.1051/sicotj/2017039 sicotj170063 10.1051/sicotj/2017039
            © The Authors, published by EDP Sciences, 2017

            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 work is properly cited.

            Figures: 1, Tables: 1, Equations: 0, References: 57, Pages: 9
            Special Issue: "Orthobiologics: role of platelet-rich plasma in orthopaedic clinical practice" Guest Editor: Vijay D. Shetty
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