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Biological Therapies in Regenerative Sports Medicine

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Abstract

Regenerative medicine seeks to harness the potential of cell biology for tissue replacement therapies, which will restore lost tissue functionality. Controlling and enhancing tissue healing is not just a matter of cells, but also of molecules and mechanical forces. We first describe the main biological technologies to boost musculoskeletal healing, including bone marrow and subcutaneous fat-derived regenerative products, as well as platelet-rich plasma and conditioned media. We provide some information describing possible mechanisms of action. We performed a literature search up to January 2016 searching for clinical outcomes following the use of cell therapies for sports conditions, tendons, and joints. The safety and efficacy of cell therapies for tendon conditions was examined in nine studies involving undifferentiated and differentiated (skin fibroblasts, tenocytes) cells. A total of 54 studies investigated the effects of mesenchymal stem-cell (MSC) products for joint conditions including anterior cruciate ligament, meniscus, and chondral lesions as well as osteoarthritis. In 22 studies, cellular products were injected intra-articularly, whereas in 32 studies MSC products were implanted during surgical/arthroscopic procedures. The heterogeneity of clinical conditions, cellular products, and approaches for delivery/implantation make comparability difficult. MSC products appear safe in the short- and mid-term, but studies with a long follow-up are scarce. Although the current number of randomized clinical studies is low, stem-cell products may have therapeutic potential. However, these regenerative technologies still need to be optimized.

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References

  1. Takeda H, Nakagawa T, Nakamura K, et al. Prevention and management of knee osteoarthritis and knee cartilage injury in sports. Br J Sports Med. 2011;45(4):304–9.

    Article  PubMed  Google Scholar 

  2. Andia I, Maffulli N. Muscle and tendon injuries: the role of biological interventions to promote and assist healing and recovery. Arthroscopy. 2015;31(5):999–1015.

    Article  PubMed  Google Scholar 

  3. Burningham S, Ollenberger A, Caulfield T. Commercialization and stem cell research: a review of emerging issues. Stem Cells Dev. 2013;22(Suppl 1):80–4.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Munsie M, Hyun I. A question of ethics: selling autologous stem cell therapies flaunts professional standards. Stem Cell Res. 2014;13(3 Pt B):647–53.

    Article  PubMed  Google Scholar 

  5. Matthews KR, Cuchiara ML. U.S. National Football League athletes seeking unproven stem cell treatments. Stem Cells Dev. 2014;23(Suppl 1):60–4.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Connolly R, O’Brien T, Flaherty G. Stem cell tourism—a web-based analysis of clinical services available to international travellers. Travel Med Infect Dis. 2014;12(6 Pt B):695–701.

    Article  PubMed  Google Scholar 

  7. International Society for Stem Cell Research. Statement on delivery of unproven autologous-cell based interventions to patients. 2013. http://www.isscr.org/docs/default-source/isscr-statements/isscr-acbistatement-091113-fl.pdf. Accessed 10 Jan 2016.

  8. International Society for Stem Cell Research. The guidelines for the clinical translation of stem cells. 2008. http://www.isscr.org/docs/default-source/clin-trans-guidelines/isscrglclinicaltrans.pdf. Accessed 10 Jan 2016.

  9. Wang D, Li J, Zhang Y, et al. Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study. Arthritis Res Ther. 2014;16(2):R79.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Reger RL, Prockop DJ. Should publications on mesenchymal stem/progenitor cells include in-process data on the preparation of the cells? Stem Cells Transl Med. 2014;3(5):632–5.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Rodbell M. Metabolism of isolated fat cells. Effects of hormones on glucose metabolism and lipolysis. J Biol Chem. 1964;239:375–80.

    CAS  PubMed  Google Scholar 

  12. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.

    Article  CAS  PubMed  Google Scholar 

  13. International Federation for Adipose Therapeutics and Science. http://www.ifats.org/. accessed Feb 2016.

  14. Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7(2):211–28.

    Article  CAS  PubMed  Google Scholar 

  15. Choudhery MS, Badowski M, Muise A, et al. Subcutaneous adipose tissue-derived stem cell utility is independent of anatomical harvest site. Biores Open Access. 2015;4(1):131–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schimke MM, Marozin S, Lepperdinger G. Patient specific age: the other side of the coin in advanced mesenchymal stem cell therapies. Front Physiol. 2015;6:362.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.

    Article  CAS  PubMed  Google Scholar 

  18. Russell KC, Phinney DG, Lacey MR, et al. In vitro high-capacity assay to quantify the clonal heterogeneity in trilineage potential of mesenchymal stem cells reveals a complex hierarchy of lineage commitment. Stem Cells. 2010;28(4):788–98.

    Article  CAS  PubMed  Google Scholar 

  19. Chamberlain G, Fox J, Ashton B, et al. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007;25(11):2739–49.

    Article  CAS  PubMed  Google Scholar 

  20. Salmikangas P, Schuessler-Lenz M, Ruiz S, et al. Marketing regulatory oversight of advanced therapy medicinal products (ATMPs) in Europe: the EMA/CAT perspective. Adv Exp Med Biol. 2015;871:103–30.

    Article  PubMed  Google Scholar 

  21. Reddy RL. Mobilization and collection of peripheral blood progenitor cells for transplantation. Transf Apheresis Sci. 2005;32:63–73.

    Article  Google Scholar 

  22. Andia I, Maffulli N. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Nat Rev Rheumatol. 2013;9(12):721–30.

    Article  CAS  PubMed  Google Scholar 

  23. Andia I, Rubio-Azpeitia E, Maffulli N. Platelet-rich plasma modulates the secretion of inflammatory/angiogenic proteins by inflamed tenocytes. Clin Orthop Relat Res. 2015;473(5):1624–34.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kim YS, Choi YJ, Suh DS, et al. Mesenchymal stem cell implantation in osteoarthritic knees: is fibrin glue effective as a scaffold? Am J Sports Med. 2015;43(1):176–85.

    Article  PubMed  Google Scholar 

  25. Nurden AT, Nurden P, Sanchez M, et al. Platelets and wound healing. Front Biosci. 2008;13:3532–48.

    PubMed  Google Scholar 

  26. Dohan Ehrenfest DM, Andia I, Zumstein MA, et al. Classification of platelet concentrates (platelet-rich plasma-PRP, platelet-rich fibrin-PRF) for topical and infiltrative use in orthopedic and sports medicine: current consensus, clinical implications and perspectives. Muscles Ligaments Tendons J. 2014;4(1):3–9.

    PubMed  PubMed Central  Google Scholar 

  27. Rubio-Azpeitia E, Bilbao AM, Sánchez P, et al. The properties of three different plasma formulations and their effects on tendinopathic cells. Am J Sports Med. 2016;44(8):1952–61.

    Article  PubMed  Google Scholar 

  28. Li H, Usas A, Poddar M, et al. Platelet-rich plasma promotes the proliferation of human muscle derived progenitor cells and maintains their stemness. PLoS One. 2013;8(6):e64923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jalowiec JM, D’Este M, Bara JJ, et al. An in vitro investigation of platelet-rich plasma-gel as a cell and growth factor delivery vehicle for tissue engineering. Tissue Eng Part C Methods. 2016;22(1):49–58.

    Article  CAS  PubMed  Google Scholar 

  30. Jeon YR, Kang EH, Yang CE, et al. The effect of platelet-rich plasma on composite graft survival. Plast Reconstr Surg. 2014;134(2):239–46.

    Article  CAS  PubMed  Google Scholar 

  31. D’Esposito V, Passaretti F, Perruolo G, et al. Platelet-rich plasma increases growth and motility of adipose tissue-derived mesenchymal stem cells and controls adipocyte secretory function. J Cell Biochem. 2015;116(10):2408–18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Van Pham P, Bui KH, Ngo DQ, et al. Activated platelet-rich plasma improves adipose-derived stem cell transplantation efficiency in injured articular cartilage. Stem Cell Res Ther. 2013;4(4):91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Maumus M, Jorgensen C, Noël D. Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: role of secretome and exosomes. Biochimie. 2013;95(12):2229–34.

    Article  CAS  PubMed  Google Scholar 

  34. Pawitan JA. Prospect of stem cell conditioned medium in regenerative medicine. BioMed Res Int. 2014;2014:965849.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Rani S, Ryan AE, Griffin MD, et al. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Mol Ther. 2015;23(5):812–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. https://clinicaltrials.gov/ct2/show/NCT02003131?term=NCT+02003131&rank=1<redir.aspx?REF=K6FUxN7V-HmWjkPwWisS6odBg9QHcsGe9whHw5lWHWq1wXmNvTCAFodHRwczovL2NsaW5pY2FsdHJpYWxzmdvdi9jdDIvc2hvdy9OQ1QwMjAwMzEzMT90ZXJtPU5DVCswMjAwMzEzMSZyYW5rPTE.. Accessed 17 Aug 2016.

  37. Eseonu OI, De Bari C. Homing of mesenchymal stem cells: mechanistic or stochastic? Implications for targeted delivery in arthritis. Rheumatology (Oxford). 2015;54(2):210–8.

    Article  PubMed  Google Scholar 

  38. Koga H, Muneta T, Nagase T, et al. Comparison of mesenchymal tissues-derived stem cells for in vivo chondrogenesis: suitable conditions for cell therapy of cartilage defects in rabbit. Cell Tissue Res. 2008;333(2):207–15.

    Article  PubMed  Google Scholar 

  39. Little D, Guilak F, Ruch DS. Ligament-derived matrix stimulates a ligamentous phenotype in human adipose-derived stem cells. Tissue Eng Part A. 2010;16(7):2307–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013;45:e54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Forbes SJ, Rosenthal N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med. 2014;20(8):857–69.

    Article  CAS  PubMed  Google Scholar 

  42. Castagna A, Cesari E, Garofalo R, et al. Matrix metalloproteases and their inhibitors are altered in torn rotator cuff tendons, but also in the macroscopically and histologically intact portion of those tendons. Muscles Ligaments Tendons J. 2013;3(3):132–8.

    PubMed  PubMed Central  Google Scholar 

  43. Zhang K, Asai S, Yu B, et al. IL-1β irreversibly inhibits tenogenic differentiation and alters metabolism in injured tendon-derived progenitor cells in vitro. Biochem Biophys Res Commun. 2015;463(4):667–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98(5):1076–84.

    Article  CAS  PubMed  Google Scholar 

  45. Tran C, Damaser MS. Stem cells as drug delivery methods: application of stem cell secretome for regeneration. Adv Drug Deliv Rev. 2015;82–83:1–11.

    Article  PubMed  CAS  Google Scholar 

  46. Tanaka Y. Human mesenchymal stem cells as a tool for joint repair in rheumatoid arthritis. Clin Exp Rheumatol. 2015;33(4 Suppl 92):S58–62.

    PubMed  Google Scholar 

  47. Oh JY, Ko JH, Lee HJ, et al. Mesenchymal stem/stromal cells inhibit the NLRP3 inflammasome by decreasing mitochondrial reactive oxygen species. Stem Cells. 2014;32(6):1553–63.

    Article  CAS  PubMed  Google Scholar 

  48. Xu Y, Fu M, Li Z, et al. A prosurvival and proangiogenic stem cell delivery system to promote ischemic limb regeneration. Acta Biomater. 2016;31:99–113.

    Article  CAS  PubMed  Google Scholar 

  49. Andia I, Abate M. Platelet-rich plasma: underlying biology and clinical correlates. Regen Med. 2013;8(5):645–58.

    Article  CAS  PubMed  Google Scholar 

  50. Zhou Y, Zhang J, Wu H, et al. The differential effects of leukocyte-containing and pure platelet-rich plasma (PRP) on tendon stem/progenitor cells—implications of PRP application for the clinical treatment of tendon injuries. Stem Cell Res Ther. 2015;6:173.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Zullo JA, Nadel EP, Rabadi MM, et al. The secretome of hydrogel-coembedded endothelial progenitor cells and mesenchymal stem cells instructs macrophage polarization in endotoxemia. Stem Cells Transl Med. 2015;4(7):852–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Walker PA, Harting MT, Jimenez F, et al. Direct intrathecal implantation of mesenchymal stromal cells leads to enhanced neuroprotection via an NFkappaB-mediated increase in interleukin-6 production. Stem Cells Dev. 2010;19(6):867–76.

    Article  CAS  PubMed  Google Scholar 

  53. Platas J, Guillén MI, del Caz MD, et al. Conditioned media from adipose-tissue-derived mesenchymal stem cells downregulate degradative mediators induced by interleukin-1β in osteoarthritic chondrocytes. Mediat Inflamm. 2013;2013:357014.

    Article  CAS  Google Scholar 

  54. Prockop DJ, Oh JY. Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol Ther. 2012;20(1):14–20.

    Article  CAS  Google Scholar 

  55. Lee RH, Yu JM, Foskett AM, et al. TSG-6 as a biomarker to predict efficacy of human mesenchymal stem/progenitor cells (hMSCs) in modulating sterile inflammation in vivo. Proc Natl Acad Sci USA. 2014;111(47):16766–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Fu X, Chen Y, Xie FN, et al. Comparison of immunological characteristics of mesenchymal stem cells derived from human embryonic stem cells and bone marrow. Tissue Eng Part A. 2015;21(3–4):616–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Prockop DJ, Oh JY. Medical therapies with adult stem/progenitor cells (MSCs): a backward journey from dramatic results in vivo to the cellular and molecular explanations. J Cell Biochem. 2012;113(5):1460–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Stochaj U, Kodiha M, Shum-Tim D, et al. Implications of multipotent mesenchymal stromal cell aging. Regen Med. 2013;8(2):211–22.

    Article  CAS  PubMed  Google Scholar 

  59. Siegel G, Kluba T, Hermanutz-Klein U, et al. Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells. BMC Med. 2013;11:146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yan Z, Zhuansun Y, Chen R, et al. Immunomodulation of mesenchymal stromal cells on regulatory T cells and its possible mechanism. Exp Cell Res. 2014;324(1):65–74.

    Article  CAS  PubMed  Google Scholar 

  61. Yan Z, Zhuansun Y, Liu G, et al. Mesenchymal stem cells suppress T cells by inducing apoptosis and through PD-1/B7-H1 interactions. Immunol Lett. 2014;162(1 Pt A):248–255.36.

    Article  CAS  PubMed  Google Scholar 

  62. Li P, Li SH, Wu J, et al. Interleukin-6 downregulation with mesenchymal stem cell differentiation results in loss of immunoprivilege. J Cell Mol Med. 2013;17(9):1136–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Sharma A, Sane H, Gokulchandran N, et al. Autologous bone marrow mononuclear cells intrathecal transplantation in chronic stroke. Stroke Res Treat. 2014;2014:234095.

    PubMed  PubMed Central  Google Scholar 

  64. Oussedik S, Tsitskaris K, Parker D. Treatment of articular cartilage lesions of the knee by microfracture or autologous chondrocyte implantation: a systematic review. Arthroscopy. 2015;31(4):732–44.

    Article  PubMed  Google Scholar 

  65. Laudy AB, Bakker EW, Rekers M, et al. Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis. Br J Sports Med. 2015;49(10):657–72.

    Article  PubMed  Google Scholar 

  66. Fitzpatrick J, Bulsara M, Zheng MH. The effectiveness of platelet-rich plasma in the treatment of tendinopathy: a meta-analysis of randomized controlled clinical trials. Am J Sports Med. 2016. doi:10.1177/0363546516643716.

    Google Scholar 

  67. Connell D, Datir A, Alyas F, et al. Treatment of lateral epicondylitis using skin-derived tenocyte-like cells. Br J Sports Med. 2009;43(4):293–8.

    Article  CAS  PubMed  Google Scholar 

  68. Moon YL, Jo SH, Song CH, et al. Autologous bone marrow plasma injection after arthroscopic debridement for elbow tendinosis. Ann Acad Med Singapore. 2008;37(7):559–63.

    PubMed  Google Scholar 

  69. Singh A, Gangwar DS, Singh S. Bone marrow injection: a novel treatment for tennis elbow. J Nat Sci Biol Med. 2014;5(2):389–91.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Wang A, Mackie K, Breidahl W, et al. Evidence for the durability of autologous tenocyte injection for treatment of chronic resistant lateral epicondylitis: mean 4.5-year clinical follow-up. Am J Sports Med. 2015;43(7):1775–83.

    Article  PubMed  Google Scholar 

  71. Wang A, Breidahl W, Mackie KE, et al. Autologous tenocyte injection for the treatment of severe, chronic resistant lateral epicondylitis: a pilot study. Am J Sports Med. 2013;41(12):2925–32.

    Article  PubMed  Google Scholar 

  72. Centeno CJ, Al-Sayegh H, Bashir J, et al. A prospective multi-site registry study of a specific protocol of autologous bone marrow concentrate for the treatment of shoulder rotator cuff tears and osteoarthritis. J Pain Res. 2015;8:269–76.

    PubMed  PubMed Central  Google Scholar 

  73. Ellera Gomes JL, da Silva RC, Silla LM, et al. Conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells. Knee Surg Sports Traumatol Arthrosc. 2012;20(2):373–7.

    Article  PubMed  Google Scholar 

  74. Clarke AW, Alyas F, Morris T, et al. Skin-derived tenocyte-like cells for the treatment of patellar tendinopathy. Am J Sports Med. 2011;39(3):614–23.

    Article  PubMed  Google Scholar 

  75. Pascual-Garrido C, Rolón A, Makino A. Treatment of chronic patellar tendinopathy with autologous bone marrow stem cells: a 5-year-followup. Stem Cells Int. 2012;2012:953510.

  76. Tate-Oliver K, Alexander RW. Combination of autologous adipose-derived tissue stromal vascular fraction plus high-density platelet rich plasma or bone marrow concentrates in Achilles tendon tears. J Prolotherapy. 2013;5:e895–912.

    Google Scholar 

  77. Centeno CJ, Pitts J, Al-Sayegh H, et al. Anterior cruciate ligament tears treated with percutaneous injection of autologous bone marrow nucleated cells: a case series. J Pain Res. 2015;8:437–47.

    PubMed  PubMed Central  Google Scholar 

  78. Centeno CJ, Freeman MD. Percutaneous injection of autologous, culture-expanded mesenchymal stem cells into carpometacarpal hand joints: a case series with an untreated comparison group. Wien Med Wochenschr. 2014;164(5–6):83–7.

    Article  PubMed  Google Scholar 

  79. Centeno CJ, Schultz JR, Cheever M, et al. Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 2011;6(4):368–78.

    Article  CAS  PubMed  Google Scholar 

  80. Davatchi F, Abdollahi BS, Mohyeddin M, et al. Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis. 2011;14(2):211–5.

    Article  PubMed  Google Scholar 

  81. Emadedin M, Aghdami N, Taghiyar L, et al. Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis. Arch Iran Med. 2012;15(7):422–8.

    PubMed  Google Scholar 

  82. Jo CH, Lee YG, Shin WH, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. 2014;32(5):1254–66.

    Article  CAS  PubMed  Google Scholar 

  83. Kim YS, Kwon OR, Choi YJ, et al. Comparative matched-pair analysis of the injection versus implantation of mesenchymal stem cells for knee osteoarthritis. Am J Sports Med. 2015;43(11):2738–46.

    Article  PubMed  Google Scholar 

  84. Orozco L, Munar A, Soler R, et al. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation. 2013;95(12):1535–41.

    Article  CAS  PubMed  Google Scholar 

  85. Orozco L, Munar A, Soler R, et al. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: two-year follow-up results. Transplantation. 2014;97(11):e66–8.

    Article  PubMed  Google Scholar 

  86. Soler Rich R, Munar A, Soler Romagosa F, et al. Treatment of knee osteoarthritis with autologous expanded bone marrow mesenchymal stem cells: 50 cases clinical and MRI results at one year follow-up. J Stem Cell Res Ther. 2015;5(6):1–7.

    Google Scholar 

  87. Vangsness CT Jr, Farr J 2nd, Boyd J, et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am. 2014;96(2):90–8.

    Article  PubMed  Google Scholar 

  88. Vega A, Martín-Ferrero MA, Del Canto F, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015;99(8):1681–90.

    Article  CAS  PubMed  Google Scholar 

  89. Bui K, Duong T, Nguyen N, et al. Symptomatic knee osteoarthritis treatment using autologous adipose derived stem cells and platelet rich plasma: a clinical study. Biomed Res Therapy. 2014;1(1):2–8.

    Article  Google Scholar 

  90. Centeno CJ, Al-Sayegh H, Bashir J, et al. A dose response analysis of a specific bone marrow concentrate treatment protocol for knee osteoarthritis. BMC Musculoskelet Disord. 2015;16:258.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Centeno C, Pitts J, Al-Sayegh H, et al. Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft. BioMed Res Int. 2014;2014:370621.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Fodor PB, Paulseth SG. Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint. Aesthet Surg J. 2016;36(2):229–36.

    Article  PubMed  Google Scholar 

  93. Gibbs N, Diamond R, Sekyere EO, et al. Management of knee osteoarthritis by combined stromal vascular fraction cell therapy, platelet-rich plasma, and musculoskeletal exercises: a case series. J Pain Res. 2015;8:799–806.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Kim JD, Lee GW, Jung GH, et al. Clinical outcome of autologous bone marrow aspirates concentrate (BMAC) injection in degenerative arthritis of the knee. Eur J Orthop Surg Traumatol. 2014;24(8):1505–11.

    Article  PubMed  Google Scholar 

  95. Koh YG, Jo SB, Kwon OR, et al. Mesenchymal stem cell injections improve symptoms of knee osteoarthritis. Arthroscopy. 2013;29(4):748–55.

    Article  PubMed  Google Scholar 

  96. Koh YG, Choi YJ. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee. 2012;19(6):902–7.

    Article  PubMed  Google Scholar 

  97. Oliver KS, Bayes M, Crane D, et al. Clinical outcome of bone marrow concentrate in osteoarthritis. J Prolotherapy. 2015;7:e937–46.

    Google Scholar 

  98. Pak J, Lee JH, Lee SH. A novel biological approach to treat chondromalacia patellae. PLoS One. 2013;8(5):e64569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Pak J, Chang JJ, Lee JH, et al. Safety reporting on implantation of autologous adipose tissue-derived stem cells with platelet-rich plasma into human articular joints. BMC Musculoskelet Disord. 2013;14:337.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Akgun I, Unlu MC, Erdal OA, et al. Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. Arch Orthop Trauma Surg. 2015;135(2):251–63.

    Article  PubMed  Google Scholar 

  101. Haleem AM, Singergy AA, Sabry D, et al. The clinical use of human culture-expanded autologous bone marrow mesenchymal stem cells transplanted on platelet-rich fibrin glue in the treatment of articular cartilage defects: a pilot study and preliminary results. Cartilage. 2010;1(4):253–61.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Koh YG, Choi YJ, Kwon OR, et al. Second-look arthroscopic evaluation of cartilage lesions after mesenchymal stem cell implantation in osteoarthritic knees. Am J Sports Med. 2014;42(7):1628–37.

    Article  PubMed  Google Scholar 

  103. Lee KB, Wang VT, Chan YH, et al. A novel, minimally-invasive technique of cartilage repair in the human knee using arthroscopic microfracture and injections of mesenchymal stem cells and hyaluronic acid a prospective comparative study on safety and short-term efficacy. Ann Acad Med Singapore. 2012;41:511e7.

    Google Scholar 

  104. Nejadnik H, Hui JH, Feng Choong EP, et al. Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med. 2010;38(6):1110–6.

    Article  PubMed  Google Scholar 

  105. Saw KY, Anz A, Siew-Yoke Jee C, et al. Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: a randomized controlled trial. Arthroscopy. 2013;29(4):684–94.

    Article  PubMed  Google Scholar 

  106. Sekiya I, Muneta T, Horie M, et al. Arthroscopic transplantation of synovial stem cells improves clinical outcomes in knees with cartilage defects. Clin Orthop Relat Res. 2015;473(7):2316–26.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Teo BJ, Buhary K, Tai BC, et al. Cell-based therapy improves function in adolescents and young adults with patellar osteo-chondritis dissecans. Clin Orthop Relat Res. 2013;471:1152.

    Article  PubMed  Google Scholar 

  108. Wong KL, Lee KB, Tai BC, et al. Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years’ follow-up. Arthroscopy. 2013;29(12):2020–8.

    Article  PubMed  Google Scholar 

  109. Buda R, Castagnini F, Cavallo M, et al. “One-step” bone marrow-derived cells transplantation and joint debridement for osteochondral lesions of the talus in ankle osteoarthritis: clinical and radiological outcomes at 36 months. Arch Orthop Trauma Surg. 2016;136:107–16.

    Article  PubMed  Google Scholar 

  110. Buda R, Vannini F, Castagnini F, et al. Regenerative treatment in osteochondral lesions of the talus: autologous chondrocyte implantation versus one-step bone marrow derived cells transplantation. Int Orthop. 2015;39(5):893–900.

    Article  PubMed  Google Scholar 

  111. Buda R, Cavallo M, Castagnini F, et al. Treatment of hemophilic ankle arthropathy with one-step arthroscopic bone marrow-derived cells transplantation. Cartilage. 2015;6(3):150–5.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Buda R, Vannini F, Cavallo M, et al. One-step bone marrow-derived cell transplantation in talar osteochondral lesions: mid-term results. Joints. 2014;1(3):102–7.

    PubMed  PubMed Central  Google Scholar 

  113. Buda R, Vannini F, Cavallo M, et al. Osteochondral lesions of the knee: a new one-step repair technique with bone-marrow-derived cells. J Bone Joint Surg Am. 2010;92(Suppl 2):2–11.

    Article  PubMed  Google Scholar 

  114. Buda R, Vannini F, Cavallo M, et al. One-step arthroscopic technique for the treatment of osteochondral lesions of the knee with bone-marrow-derived cells: three years results. Musculoskelet Surg. 2013;97(2):145–51.

    Article  PubMed  Google Scholar 

  115. Enea D, Cecconi S, Calcagno S, et al. One-step cartilage repair in the knee: collagen-covered microfracture and autologous bone marrow concentrate. A pilot study. Knee. 2015;22(1):30–5.

    Article  CAS  PubMed  Google Scholar 

  116. Giannini S, Buda R, Vannini F, et al. One-step bone marrow-derived cell transplantation in talar osteochondral lesions. Clin Orthop Relat Res. 2009;467(12):3307–20.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Giannini S, Buda R, Battaglia M, et al. One-step repair in talar osteochondral lesions: 4-year clinical results and t2-mapping capability in outcome prediction. Am J Sports Med. 2013;41(3):511–8.

    Article  PubMed  Google Scholar 

  118. Gobbi A, Karnatzikos G, Scotti C, et al. One-step cartilage repair with bone marrow aspirate concentrated cells and collagen matrix in full-thickness knee cartilage lesions: results at 2-year follow-up. Cartilage. 2011;2(3):286–99.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Kasemkijwattana C, Hongeng S, Kesprayura S, et al. Autologous bone marrow mesenchymal stem cells implantation for cartilage defects: two cases report. J Med Assoc Thai. 2011;94(3):395–400.

    PubMed  Google Scholar 

  120. Kim YS, Choi YJ, Koh YG. Mesenchymal stem cell implantation in knee osteoarthritis: an assessment of the factors influencing clinical outcomes. Am J Sports Med. 2015;43(9):2293–301.

    Article  PubMed  Google Scholar 

  121. Kim YS, Choi YJ, Lee SW, et al. Assessment of clinical and MRI outcomes after mesenchymal stem cell implantation in patients with knee osteoarthritis: a prospective study. Osteoarthr Cartil. 2016;24(2):237–45.

    Article  CAS  PubMed  Google Scholar 

  122. Kim YS, Park EH, Kim YC, et al. Clinical outcomes of mesenchymal stem cell injection with arthroscopic treatment in older patients with osteochondral lesions of the talus. Am J Sports Med. 2013;41(5):1090–9.

    Article  PubMed  Google Scholar 

  123. Kim YS, Lee HJ, Choi YJ, et al. Does an injection of a stromal vascular fraction containing adipose-derived mesenchymal stem cells influence the outcomes of marrow stimulation in osteochondral lesions of the talus? A clinical and magnetic resonance imaging study. Am J Sports Med. 2014;42(10):2424–34.

    Article  PubMed  Google Scholar 

  124. Koh YG, Kwon OR, Kim YS, et al. Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone: 2-year follow-up of a prospective randomized trial. Arthroscopy. 2016;32(1):97–109.

    Article  PubMed  Google Scholar 

  125. Koh YG, Choi YJ, Kwon SK, et al. Clinical results and second-look arthroscopic findings after treatment with adipose-derived stem cells for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2015;23(5):1308–16.

    Article  PubMed  Google Scholar 

  126. Koh YG, Kwon OR, Kim YS, et al. Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study. Arthroscopy. 2014;30(11):1453–60.

    Article  PubMed  Google Scholar 

  127. Krych AJ, Nawabi DH, Farshad-Amacker NA, et al. Bone marrow concentrate improves early cartilage phase maturation of a scaffold plug in the knee: a comparative magnetic resonance imaging analysis to platelet-rich plasma and control. Am J Sports Med. 2016;44(1):91–8.

    Article  PubMed  Google Scholar 

  128. Michalek J, Moster R, Lukac L, et al. Autologous adipose tissue-derived stromal vascular fraction cells application in patients with osteoarthritis. Cell Transpl. 2015;. doi:10.3727/096368915X686760.

    Google Scholar 

  129. Saw KY, Anz A, Jee CS, et al. High tibial osteotomy in combination with chondrogenesis after stem cell therapy: a histologic report of 8 cases. Arthroscopy. 2015;31(10):1909–20.

    Article  PubMed  Google Scholar 

  130. Skowroński J, Rutka M. Osteochondral lesions of the knee reconstructed with mesenchymal stem cells—results. Ortop Traumatol Rehabil. 2013;15(3):195–204.

    Article  PubMed  Google Scholar 

  131. Silva A, Sampaio R, Fernandes R, et al. Is there a role for adult non-cultivated bone marrow stem cells in ACL reconstruction? Knee Surg Sports Traumatol Arthrosc. 2014;22(1):66–71.

    Article  PubMed  Google Scholar 

  132. Wakitani S, Imoto K, Yamamoto T, et al. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthr Cartil. 2002;10(3):199–206.

    Article  CAS  PubMed  Google Scholar 

  133. Wakitani S, Okabe T, Horibe S, et al. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med. 2011;5(2):146–50.

    Article  PubMed  Google Scholar 

  134. Geburek F, Mundle K, Conrad S, et al. Tracking of autologous adipose tissue-derived mesenchymal stromal cells with in vivo magnetic resonance imaging and histology after intralesional treatment of artificial equine tendon lesions—a pilot study. Stem Cell Res Ther. 2016;7:21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. McCulloch P, Cook JA, Altman DG, IDEAL Group, et al. IDEAL framework for surgical innovation 1: the idea and development stages. BMJ. 2013;18(346):f3012.

    Article  Google Scholar 

  136. Peeters CM, Leijs MJ, Reijman M, et al. Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review. Osteoarthr Cartil. 2013;21(10):1465–73.

    Article  CAS  PubMed  Google Scholar 

  137. Centeno CJ, Al-Sayegh H, Freeman MD, et al. A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. Int Orthop. 2016 Mar 30. [Epub ahead of print].

  138. https://clinicaltrials.gov/ct2/show/NCT02033525?term=NCT02033525&rank=1<redir.aspx?REF=CDehAp5WnUaaCF04MORaKf_GKqyot7JSK4XAoVNB3Wq1wXmNvTCAFodHRwczovL2NsaW5pY2FsdHJpYWxzmdvdi9jdDIvc2hvdy9OQ1QwMjAzMzUyNT90ZXJtPU5DVDAyMDMzNTI1JnJhbms9MQ.. Accessed 17 Aug 2016.

  139. https://clinicaltrials.gov/ct2/show/NCT02582489?term=NCT02582489&rank=1<redir.aspx?REF=0pcIQhFVYnBesMFmtVDwC2hVufvw_BiztIZg3OKH7nWq1wXmNvTCAFodHRwczovL2NsaW5pY2FsdHJpYWxzLmdvdi9jdDIvc2hvdy9OQ1QwMjU4MjQ4OT90ZXJtPU5DVDAyNTgyNDg5JnJhbm9MQ.. Accessed 17 Aug 2016.

  140. Vadalà A, Iorio R, De Carli A, et al. Platelet-rich plasma: does it help reduce tunnel widening after ACL reconstruction? Knee Surg Sports Traumatol Arthrosc. 2013;21(4):824–9.

    Article  PubMed  Google Scholar 

  141. Saw KY, Anz A, Merican S, et al. Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic acid after arthroscopic subchondral drilling: a report of 5 cases with histology. Arthroscopy. 2011;27(4):493–506.

    Article  PubMed  Google Scholar 

  142. Somoza RA, Welter JF, Correa D, et al. Chondrogenic differentiation of mesenchymal stem cells: challenges and unfulfilled expectations. Eng Part B Rev. 2014;20(6):596–608.

    Article  Google Scholar 

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Authors and Affiliations

  1. Regenerative Medicine Laboratory, BioCruces Health Research Institute, Cruces University Hospital, Pza Cruces 12, 48903, Barakaldo, Spain

    Isabel Andia

  2. Department of Musculoskeletal Disorders, University of Salerno School of Medicine and Dentistry, Salerno, Italy

    Nicola Maffulli

  3. Queen Mary University of London, Barts and the London School of Medicine and Dentistry Centre for Sports and Exercise Medicine, Mile End Hospital, 275 Bancroft Road, London, E1 4DG, England

    Nicola Maffulli

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  1. Isabel Andia
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  2. Nicola Maffulli
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Correspondence to Isabel Andia.

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Nicola Maffulli and Isabel Andia declare that they have no conflicts of interest relevant to the content of this review.

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Andia, I., Maffulli, N. Biological Therapies in Regenerative Sports Medicine. Sports Med 47, 807–828 (2017). https://doi.org/10.1007/s40279-016-0620-z

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