Frontiers of Medicine

, Volume 12, Issue 2, pp 139–152 | Cite as

Platelet-rich plasma: combinational treatment modalities for musculoskeletal conditions



Current research on common musculoskeletal problems, including osteoarticular conditions, tendinopathies, and muscle injuries, focuses on regenerative translational medicine. Platelet-rich plasma therapies have emerged as a potential approach to enhance tissue repair and regeneration. Platelet-rich plasma application aims to provide supraphysiological concentrations of platelets and optionally leukocytes at injured/pathological tissues mimicking the initial stages of healing. However, the efficacy of platelet-rich plasma is controversial in chronic diseases because patients’ outcomes show partial improvements. Platelet-rich plasma can be customized to specific conditions by selecting the most appropriate formulation and timing for application or by combining platelet-rich plasma with synergistic or complementary treatments. To achieve this goal, researchers should identify and enhance the main mechanisms of healing. In this review, the interactions between platelet-rich plasma and healing mechanisms were addressed and research opportunities for customized treatment modalities were outlined. The development of combinational platelet-rich plasma treatments that can be used safely and effectively to manipulate healing mechanisms would be valuable and would provide insights into the processes involved in physiological healing and pathological failure.


regenerative medicine joint conditions muscle injuries platelet rich plasma tendinopathy healing mechanisms 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Andia I, Abate M. Platelet-rich plasma: underlying biology and clinical correlates. Regen Med 2013; 8(5): 645–658PubMedGoogle Scholar
  2. 2.
    Andia I, Latorre PM, Gomez MC, Burgos-Alonso N, Abate M, Maffulli N. Platelet-rich plasma in the conservative treatment of painful tendinopathy: a systematic review and meta-analysis of controlled studies. Br Med Bull 2014; 110(1): 99–115PubMedGoogle Scholar
  3. 3.
    Moraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JC. Platelet-rich therapies for musculoskeletal soft tissue injuries. Cochrane Database Syst Rev 2014; (4): CD010071Google Scholar
  4. 4.
    Fitzpatrick J, Bulsara M, Zheng MH. The effectiveness of plateletrich plasma in the treatment of tendinopathy: a meta-analysis of randomized controlled clinical trials. Am J Sports Med 2017; 45(1): 226–233PubMedGoogle Scholar
  5. 5.
    Meheux CJ, McCulloch PC, Lintner DM, Varner KE, Harris JD. Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: a systematic review. Arthroscopy 2016; 32(3): 495–505PubMedGoogle Scholar
  6. 6.
    Zumstein MA, Rumian A, Thélu CÉ, Lesbats V, O’Shea K, Schaer M, Boileau P. SECEC Research Grant 2008 II: Use of platelet- and leucocyte-rich fibrin (L-PRF) does not affect late rotator cuff tendon healing: a prospective randomized controlled study. J Shoulder Elbow Surg 2016; 25(1): 2–11PubMedGoogle Scholar
  7. 7.
    Laudy AB, Bakker EW, Rekers M, Moen MH. Efficacy of plateletrich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis. Br J Sports Med 2015; 49(10): 657–672PubMedGoogle Scholar
  8. 8.
    Keene DJ, Alsousou J, Willett K. How effective are platelet rich plasma injections in treating musculoskeletal soft tissue injuries? BMJ 2016; 352: i517PubMedGoogle Scholar
  9. 9.
    Sánchez M, Anitua E, Delgado D, Sanchez P, Prado R, Goiriena JJ, Prosper F, Orive G, Padilla S. A new strategy to tackle severe knee osteoarthritis: combination of intra-articular and intraosseous injections of platelet rich plasma. Expert Opin Biol Ther 2016; 16(5): 627–643PubMedGoogle Scholar
  10. 10.
    Kelc R, Trapecar M, Gradisnik L, Rupnik MS, Vogrin M. Plateletrich plasma, especially when combined with a TGF-β inhibitor promotes proliferation, viability and myogenic differentiation of myoblasts in vitro. PLoS One 2015; 10(2): e0117302PubMedPubMedCentralGoogle Scholar
  11. 11.
    Li H, Hicks JJ, Wang L, Oyster N, Philippon MJ, Hurwitz S, Hogan MV, Huard J. Customized platelet-rich plasma with transforming growth factor β1 neutralization antibody to reduce fibrosis in skeletal muscle. Biomaterials 2016; 87: 147–156PubMedGoogle Scholar
  12. 12.
    Andia I, Maffulli N. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Nat Rev Rheumatol 2013; 9(12): 721–730PubMedGoogle Scholar
  13. 13.
    Yang H, Yuan C,Wu C, Qian J, Shi Q, Li X, Zhu X, Zou J. The role of TGF-β1/Smad2/3 pathway in platelet-rich plasma in retarding intervertebral disc degeneration. J Cell Mol Med 2016; 20(8): 1542–1549PubMedPubMedCentralGoogle Scholar
  14. 14.
    Ghasemzadeh M, Kaplan ZS, Alwis I, Schoenwaelder SM, Ashworth KJ, Westein E, Hosseini E, Salem HH, Slattery R, McColl SR, Hickey MJ, Ruggeri ZM, Yuan Y, Jackson SP. The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi. Blood 2013; 121(22): 4555–4566PubMedPubMedCentralGoogle Scholar
  15. 15.
    Stålman A, Bring D, Ackermann PW. Chemokine expression of CCL2, CCL3, CCL5 and CXCL10 during early inflammatory tendon healing precedes nerve regeneration: an immunohistochemical study in the rat. Knee Surg Sports Traumatol Arthrosc 2015; 23(9): 2682–2689PubMedGoogle Scholar
  16. 16.
    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): 1624–1634PubMedPubMedCentralGoogle Scholar
  17. 17.
    Gleissner CA, Shaked I, Little KM, Ley K. CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages. J Immunol 2010; 184(9): 4810–4818PubMedPubMedCentralGoogle Scholar
  18. 18.
    Vasina EM, Cauwenberghs S, Feijge MA, Heemskerk JW, Weber C, Koenen RR. Microparticles from apoptotic platelets promote resident macrophage differentiation. Cell Death Dis 2011; 2(11): e233PubMedCentralGoogle Scholar
  19. 19.
    Vasina EM, Cauwenberghs S, Staudt M, Feijge MA, Weber C, Koenen RR, Heemskerk JW. Aging- and activation-induced platelet microparticles suppress apoptosis in monocytic cells and differentially signal to proinflammatory mediator release. Am J Blood Res 2013; 3(2): 107–123PubMedPubMedCentralGoogle Scholar
  20. 20.
    Hudgens JL, Sugg KB, Grekin JA, Gumucio JP, Bedi A, Mendias CL. Platelet-rich plasma activates proinflammatory signaling pathways and induces oxidative stress in tendon fibroblasts. Am J Sports Med 2016; 44(8): 1931–1940PubMedPubMedCentralGoogle Scholar
  21. 21.
    Roh YH, Kim W, Park KU, Oh JH. Cytokine-release kinetics of platelet-rich plasma according to various activation protocols. Bone Joint Res 2016; 5(2): 37–45PubMedPubMedCentralGoogle Scholar
  22. 22.
    Frelinger AL, 3rdGerrits AJ, Garner AL, Torres AS, Caiafa A, Morton CA, Berny-Lang MA, Carmichael SL, Neculaes VB, Michelson AD. Modification of pulsed electric field conditions results in distinct activation profiles of platelet-rich plasma. PLoS One 2016; 11(8): e0160933PubMedPubMedCentralGoogle Scholar
  23. 23.
    Bendinelli P, Matteucci E, Dogliotti G, Corsi MM, Banfi G, Maroni P, Desiderio MA. Molecular basis of anti-inflammatory action of platelet-rich plasma on human chondrocytes: mechanisms of NF-kB inhibition via HGF. J Cell Physiol 2010; 225(3): 757–766PubMedGoogle Scholar
  24. 24.
    Zhang J, Middleton KK, Fu FH, Im HJ, Wang JH. HGF mediates the anti-inflammatory effects of PRP on injured tendons. PLoS One 2013; 8(6): e67303PubMedPubMedCentralGoogle Scholar
  25. 25.
    Coudriet GM, He J, Trucco M, Mars WM, Piganelli JD. Hepatocyte growth factor modulates interleukin-6 production in bone marrow derived macrophages: implications for inflammatory mediated diseases. PLoS One 2010; 5(11): e15384PubMedPubMedCentralGoogle Scholar
  26. 26.
    Wang CC, Lee CH, Peng YJ, Salter DM, Lee HS. Platelet-rich plasma attenuates 30-kDa fibronectin fragment-induced chemokine and matrix metalloproteinase expression by meniscocytes and articular chondrocytes. Am J Sports Med 2015; 43(10): 2481–2489PubMedGoogle Scholar
  27. 27.
    Lee HR, Shon OJ, Park SI, Kim HJ, Kim S, Ahn MW, Do SH. Platelet-rich plasma increases the levels of catabolic molecules and cellular dedifferentiation in the meniscus of a rabbit model. Int J Mol Sci 2016; 17(1): E120PubMedGoogle Scholar
  28. 28.
    van Buul GM, Koevoet WL, Kops N, Bos PK, Verhaar JA, Weinans H, Bernsen MR, van Osch GJ. Platelet-rich plasma releasate inhibits inflammatory processes in osteoarthritic chondrocytes. Am J Sports Med 2011; 39(11): 2362–2370PubMedGoogle Scholar
  29. 29.
    Anitua E, Sánchez M, Nurden AT, Zalduendo MM, de la Fuente M, Azofra J, Andía I. Platelet-released growth factors enhance the secretion of hyaluronic acid and induce hepatocyte growth factor production by synovial fibroblasts from arthritic patients. Rheumatology (Oxford) 2007; 46(12): 1769–1772Google Scholar
  30. 30.
    Denapoli PM, Stilhano RS, Ingham SJ, Han SW, Abdalla RJ. Platelet-rich plasma in a murine model: leukocytes, growth factors, Flt-1, and muscle healing. Am J Sports Med 2016; 44(8): 1962–1971PubMedGoogle Scholar
  31. 31.
    Peterson JE, Zurakowski D, Italiano JE Jr, Michel LV, Fox L, Klement GL, Folkman J. Normal ranges of angiogenesis regulatory proteins in human platelets. Am J Hematol 2010; 85(7): 487–493PubMedGoogle Scholar
  32. 32.
    Kakudo N, Morimoto N, Kushida S, Ogawa T, Kusumoto K. Platelet-rich plasma releasate promotes angiogenesis in vitro and in vivo. Med Mol Morphol 2014; 47(2): 83–89PubMedGoogle Scholar
  33. 33.
    Guo J, Chan KM, Zhang JF, Li G. Tendon-derived stem cells undergo spontaneous tenogenic differentiation. Exp Cell Res 2016; 341(1): 1–7PubMedGoogle Scholar
  34. 34.
    Mammoto T, Jiang A, Jiang E, Mammoto A. Platelet rich plasma extract promotes angiogenesis through the angiopoietin1-Tie2 pathway. Microvasc Res 2013; 89: 15–24PubMedGoogle Scholar
  35. 35.
    Mammoto T, Chen Z, Jiang A, Jiang E, Ingber DE, Mammoto A. Acceleration of lung regeneration by platelet-rich plasma extract through the low-density lipoprotein receptor-related protein 5-Tie2 pathway. Am J Respir Cell Mol Biol 2016; 54(1): 103–113PubMedPubMedCentralGoogle Scholar
  36. 36.
    Kang J, Hur J, Kang JA, Yun JY, Choi JI, Ko SB, Lee CS, Lee J, Han JK, Kim HK, Kim HS. Activated platelet supernatant can augment the angiogenic potential of human peripheral blood stem cells mobilized from bone marrow by G-CSF. J Mol Cell Cardiol 2014; 75: 64–75PubMedGoogle Scholar
  37. 37.
    Moser B, Wolf M, Walz A, Loetscher P. Chemokines: multiple levels of leukocyte migration control. Trends Immunol 2004; 25 (2): 75–84PubMedGoogle Scholar
  38. 38.
    Kobayashi Y, Saita Y, Nishio H, Ikeda H, Takazawa Y, Nagao M, Takaku T, Komatsu N, Kaneko K. Leukocyte concentration and composition in platelet-rich plasma (PRP) influences the growth factor and protease concentrations. J Orthop Sci 2016; 21(5):683–689PubMedGoogle Scholar
  39. 39.
    Pifer MA, Maerz T, Baker KC, Anderson K. Matrix metalloproteinase content and activity in low-platelet, low-leukocyte and high-platelet, high-leukocyte platelet rich plasma (PRP) and the biologic response to PRP by human ligament fibroblasts. Am J Sports Med 2014; 42(5): 1211–1218PubMedGoogle Scholar
  40. 40.
    Kawase T, Tanaka T, Okuda K, Tsuchimochi M, Oda M, Hara T. Quantitative single-cell motility analysis of platelet-rich plasmatreated endothelial cells in vitro. Cytoskeleton (Hoboken) 2015; 72 (5): 246–255Google Scholar
  41. 41.
    Sönmez TT, Vinogradov A, Zor F, Kweider N, Lippross S, Liehn EA, Naziroglu M, Hölzle F,Wruck C, Pufe T, Tohidnezhad M. The effect of platelet rich plasma on angiogenesis in ischemic flaps in VEGFR2-luc mice. Biomaterials 2013; 34(11): 2674–2682PubMedGoogle Scholar
  42. 42.
    Enomoto H, Inoki I, Komiya K, Shiomi T, Ikeda E, Obata K, Matsumoto H, Toyama Y, Okada Y. Vascular endothelial growth factor isoforms and their receptors are expressed in human osteoarthritic cartilage. Am J Pathol 2003; 162(1): 171–181PubMedPubMedCentralGoogle Scholar
  43. 43.
    Gilbert RW, Vickaryous MK, Viloria-Petit AM. Signaling by transforming growth factor β isoforms in wound healing and tissue regeneration. J Dev Biol 2016; 4(2): 21PubMedCentralGoogle Scholar
  44. 44.
    Hinz B. Tissue stiffness, latent TGF-β1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr Rheumatol Rep 2009; 11(2): 120–126PubMedGoogle Scholar
  45. 45.
    Dohan Ehrenfest DM, Andia I, Zumstein MA, Zhang CQ, Pinto NR, Bielecki T. 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): 3–9PubMedPubMedCentralGoogle Scholar
  46. 46.
    Oh JH, Kim W, Park KU, Roh YH. Comparison of the cellular composition and cytokine-release kinetics of various platelet-rich plasma preparations. Am J Sports Med 2015; 43(12): 3062–3070PubMedGoogle Scholar
  47. 47.
    Boswell SG, Schnabel LV, Mohammed HO, Sundman EA, Minas T, Fortier LA. Increasing platelet concentrations in leukocytereduced platelet-rich plasma decrease collagen gene synthesis in tendons. Am J Sports Med 2014; 42(1): 42–49PubMedGoogle Scholar
  48. 48.
    Cross JA, Cole BJ, Spatny KP, Sundman E, Romeo AA, Nicholson GP,Wagner B, Fortier LA. Leukocyte-reduced platelet-rich plasma normalizes matrix metabolism in torn human rotator cuff tendons. Am J Sports Med 2015; 43(12): 2898–2906PubMedGoogle Scholar
  49. 49.
    Jo CH, Kim JE, Yoon KS, Shin S. Platelet-rich plasma stimulates cell proliferation and enhances matrix gene expression and synthesis in tenocytes from human rotator cuff tendons with degenerative tears. Am J Sports Med 2012; 40(5): 1035–1045PubMedGoogle Scholar
  50. 50.
    McCarrel TM1, Minas T, Fortier LA. Optimization of leukocyte concentration in platelet-rich plasma for the treatment of tendinopathy. J Bone Joint Surg Am 2012;94(19):e143(1–8)Google Scholar
  51. 51.
    Rubio-Azpeitia E, Bilbao AM, Sánchez P, Delgado D, Andia I. The Properties of 3 different plasma formulations and their effects on tendinopathic cells. Am J Sports Med 2016; 44(8): 1952–1961PubMedGoogle Scholar
  52. 52.
    Zhang L, Chen S, Chang P, Bao N, Yang C, Ti Y, Zhou L, Zhao J. Harmful effects of leukocyte-rich platelet-rich plasma on rabbit tendon stem cells in vitro. Am J Sports Med 2016; 44(8): 1941–1951PubMedGoogle Scholar
  53. 53.
    Zhou Y, Zhang J, Wu H, Hogan MV, Wang JH. 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(1): 173PubMedPubMedCentralGoogle Scholar
  54. 54.
    Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, Li L, Leet AI, Seo BM, Zhang L, Shi S, Young MF. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med 2007; 13(10): 1219–1227PubMedGoogle Scholar
  55. 55.
    Guo Y, Yu H, Yuan L, Yao S, Yu H, Wang P, Lv H, Li W, Sun S. Treatment of knee osteoarthritis with platelet-rich plasma plus hyaluronic acid in comparison with platelet-rich plasma only. Int J Clin Exp Med 2016; 9(6): 12085–12090Google Scholar
  56. 56.
    Assirelli E, Filardo G, Mariani E, Kon E, Roffi A, Vaccaro F, Marcacci M, Facchini A, Pulsatelli L. Effect of two different preparations of platelet-rich plasma on synoviocytes. Knee Surg Sports Traumatol Arthrosc 2015; 23(9): 2690–2703PubMedGoogle Scholar
  57. 57.
    Braun HJ, Kim HJ, Chu CR, Dragoo JL. The effect of platelet-rich plasma formulations and blood products on human synoviocytes: implications for intra-articular injury and therapy. Am J Sports Med 2014; 42(5): 1204–1210PubMedPubMedCentralGoogle Scholar
  58. 58.
    Cavallo C, Filardo G, Mariani E, Kon E, Marcacci M, Pereira Ruiz MT, Facchini A, Grigolo B. Comparison of platelet-rich plasma formulations for cartilage healing: an in vitro study. J Bone Joint Surg Am 2014; 96(5): 423–429PubMedGoogle Scholar
  59. 59.
    Freymann U, Metzlaff S, Krüger JP, Hirsh G, Endres M, Petersen W, Kaps C. Effect of human serum and 2 different types of platelet concentrates on human meniscus cell migration, proliferation, and matrix formation. Arthroscopy 2016; 32(6): 1106–1116PubMedGoogle Scholar
  60. 60.
    Jalowiec JM, D’Este M, Bara JJ, Denom J, Menzel U, Alini M, Verrier S, Herrmann M. 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): 49–58PubMedGoogle Scholar
  61. 61.
    Kreuz PC, Krüger JP, Metzlaff S, Freymann U, Endres M, Pruss A, Petersen W, Kaps C. Platelet-rich plasma preparation types show impact on chondrogenic differentiation, migration, and proliferation of human subchondral mesenchymal progenitor cells. Arthroscopy 2015; 31(10): 1951–1961PubMedGoogle Scholar
  62. 62.
    Osterman C, McCarthy MB, Cote MP, Beitzel K, Bradley J, Polkowski G, Mazzocca AD. Platelet-rich plasma increases antiinflammatory markers in a human coculture model for osteoarthritis. Am J Sports Med 2015; 43(6): 1474–1484PubMedGoogle Scholar
  63. 63.
    Ríos DL, López C, Carmona JU. Evaluation of the antiinflammatory effects of two platelet-rich gel supernatants in an in vitro system of cartilage inflammation. Cytokine 2015; 76(2): 505–513PubMedGoogle Scholar
  64. 64.
    Mariani E, Canella V, Cattini L, Kon E, Marcacci M, Di Matteo B, Pulsatelli L, Filardo G. Leukocyte-rich platelet-rich plasma injections do not up-modulate intra-articular pro-inflammatory cytokines in the osteoarthritic knee. PLoS One 2016; 11(6): e0156137PubMedPubMedCentralGoogle Scholar
  65. 65.
    Filardo G, Kon E, Pereira Ruiz MT, Vaccaro F, Guitaldi R, Di Martino A, Cenacchi A, Fornasari PM, Marcacci M. Platelet-rich plasma intra-articular injections for cartilage degeneration and osteoarthritis: single- versus double-spinning approach. Knee Surg Sports Traumatol Arthrosc 2012; 20(10): 2082–2091PubMedGoogle Scholar
  66. 66.
    Yoshida R, Murray MM. Peripheral blood mononuclear cells enhance the anabolic effects of platelet-rich plasma on anterior cruciate ligament fibroblasts. J Orthop Res 2013; 31(1): 29–34PubMedGoogle Scholar
  67. 67.
    Nami N, Feci L, Napoliello L, Giordano A, Lorenzini S, Galeazzi M, Rubegni P, Fimiani M. Crosstalk between platelets and PBMC: new evidence in wound healing. Platelets 2016; 27(2): 143–148PubMedGoogle Scholar
  68. 68.
    Mazzocca AD, McCarthy MB, Chowaniec DM, Dugdale EM, Hansen D, Cote MP, Bradley JP, Romeo AA, Arciero RA, Beitzel K. The positive effects of different platelet-rich plasma methods on human muscle, bone, and tendon cells. Am J Sports Med 2012; 40 (8): 1742–1749PubMedGoogle Scholar
  69. 69.
    Hosny N, Goubran F, BadrEldin Hasan B, Kamel N. Assessment of vascular endothelial growth factor in fresh versus frozen platelet rich plasma. J Blood Transfus 2015;2015:706903PubMedPubMedCentralGoogle Scholar
  70. 70.
    Roffi A, Filardo G, Assirelli E, Cavallo C, Cenacchi A, Facchini A, Grigolo B, Kon E, Mariani E, Pratelli L, Pulsatelli L, Marcacci M. Does platelet-rich plasma freeze-thawing influence growth factor release and their effects on chondrocytes and synoviocytes? Biomed Res Int 2014;2014:692913PubMedPubMedCentralGoogle Scholar
  71. 71.
    Sonker A, Dubey A. Determining the effect of preparation and storage: an effort to streamline platelet components as a source of growth factors for clinical application. Transfus Med Hemother 2015; 42(3): 174–180PubMedPubMedCentralGoogle Scholar
  72. 72.
    Pan L, Yong Z, Yuk KS, Hoon KY, Yuedong S, Xu J. Growth factor release from lyophilized porcine platelet-rich plasma: quantitative analysis and implications for clinical applications. Aesthetic Plast Surg 2016; 40(1): 157–163PubMedGoogle Scholar
  73. 73.
    Salini V, Vanni D, Pantalone A, Abate M. Platelet rich plasma therapy in non-insertional achilles tendinopathy: the efficacy is reduced in 60-years old people compared to young and middle-age individuals. Front Aging Neurosci 2015; 7: 228PubMedPubMedCentralGoogle Scholar
  74. 74.
    Perez-Zabala E, Basterretxea A, Larrazabal A, Perez-Del-Pecho K, Rubio-Azpeitia E, Andia I. Biological approach for the management of non-healing diabetic foot ulcers. J Tissue Viability 2016; 25(2): 157–163PubMedGoogle Scholar
  75. 75.
    Tobita M, Tajima S, Mizuno H. Adipose tissue-derived mesenchymal stem cells and platelet-rich plasma: stem cell transplantation methods that enhance stemness. Stem Cell Res Ther 2015; 6(1): 215PubMedPubMedCentralGoogle Scholar
  76. 76.
    Abate M, Schiavone C, Salini V, Andia I. Occurrence of tendon pathologies in metabolic disorders. Rheumatology (Oxford) 2013; 52(4): 599–608Google Scholar
  77. 77.
    Andia I, Rubio-Azpeitia E, Maffulli N. Hyperuricemic PRP in tendon cells. Biomed Res Int 2014;2014:926481PubMedPubMedCentralGoogle Scholar
  78. 78.
    Sung CM, Hah YS, Kim JS, Nam JB, Kim RJ, Lee SJ, Park HB. Cytotoxic effects of ropivacaine, bupivacaine, and lidocaine on rotator cuff tenofibroblasts. Am J Sports Med 2014; 42(12): 2888–2896PubMedGoogle Scholar
  79. 79.
    Breu A, Scheidhammer I, Kujat R, Graf B, Angele P. Local anesthetic cytotoxicity on human mesenchymal stem cells during chondrogenic differentiation. Knee Surg Sports Traumatol Arthrosc 2015; 23(4): 937–945PubMedGoogle Scholar
  80. 80.
    Dean BJ, Lostis E, Oakley T, Rombach I, Morrey ME, Carr AJ. The risks and benefits of glucocorticoid treatment for tendinopathy: a systematic review of the effects of local glucocorticoid on tendon. Semin Arthritis Rheum 2014; 43(4): 570–576PubMedGoogle Scholar
  81. 81.
    Durant TJ, Dwyer CR, McCarthy MB, Cote MP, Bradley JP, Mazzocca AD. Protective nature of platelet-rich plasma against chondrocyte death when combined with corticosteroids or local anesthetics. Am J Sports Med 2017; 45(1): 218–225PubMedGoogle Scholar
  82. 82.
    Abate M, Schiavone C, Salini V, Andia I. Clinical benefits and drawbacks of local corticosteroids injections in tendinopathies. Exp Opin Drug Safety 2017;16(3):341–349Google Scholar
  83. 83.
    Zargar Baboldashti N, Poulsen RC, Franklin SL, Thompson MS, Hulley PA. Platelet-rich plasma protects tenocytes from adverse side effects of dexamethasone and ciprofloxacin. Am J Sports Med 2011; 39(9): 1929–1935PubMedGoogle Scholar
  84. 84.
    Carofino B, Chowaniec DM, McCarthy MB, Bradley JP, Delaronde S, Beitzel K, Cote MP, Arciero RA, Mazzocca AD. Corticosteroids and local anesthetics decrease positive effects of platelet-rich plasma: an in vitro study on human tendon cells. Arthroscopy 2012; 28(5): 711–719PubMedGoogle Scholar
  85. 85.
    Schippinger G, Prüller F, Divjak M, Mahla E, Fankhauser F, Rackemann S, Raggam RB. Autologous platelet-rich plasma preparations: influence of nonsteroidal anti-inflammatory drugs on platelet function. Orthop J Sports Med 2015; 3(6): 26665098Google Scholar
  86. 86.
    Finnoff JT, Fowler SP, Lai JK, Santrach PJ,Willis EA, Sayeed YA, Smith J. Treatment of chronic tendinopathy with ultrasoundguided needle tenotomy and platelet-rich plasma injection. PM R 2011; 3(10): 900–911PubMedGoogle Scholar
  87. 87.
    Andia I, Maffulli N. Biological therapies in regenerative sports medicine. Sports Med 2017; 47(5): 807–828PubMedGoogle Scholar
  88. 88.
    Clarke AW, Alyas F, Morris T, Robertson CJ, Bell J, Connell DA. Skin-derived tenocyte-like cells for the treatment of patellar tendinopathy. Am J Sports Med 2011; 39(3): 614–623PubMedGoogle Scholar
  89. 89.
    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–e912Google Scholar
  90. 90.
    Barbosa D, de Souza RA, de Carvalho WR, Xavier M, de Carvalho PK, Cunha TC, Arisawa EÂ, Silveira L Jr, Villaverde AB. Lowlevel laser therapy combined with platelet-rich plasma on the healing calcaneal tendon: a histological study in a rat model. Lasers Med Sci 2013; 28(6): 1489–1494PubMedGoogle Scholar
  91. 91.
    Allahverdi A, Sharifi D, Takhtfooladi MA, Hesaraki S, Khansari M, Dorbeh SS. Evaluation of low-level laser therapy, platelet-rich plasma, and their combination on the healing of Achilles tendon in rabbits. Lasers Med Sci 2015; 30(4): 1305–1313PubMedGoogle Scholar
  92. 92.
    Schnabel LV, Lynch ME, van der Meulen MC, Yeager AE, Kornatowski MA, Nixon AJ. Mesenchymal stem cells and insulinlike growth factor-I gene-enhanced mesenchymal stem cells improve structural aspects of healing in equine flexor digitorum superficialis tendons. J Orthop Res 2009; 27(10): 1392–1398PubMedGoogle Scholar
  93. 93.
    Witte TH, Yeager AE, Nixon AJ. Intralesional injection of insulinlike growth factor-I for treatment of superficial digital flexor tendonitis in thoroughbred racehorses: 40 cases (2000–2004). J Am Vet Med Assoc 2011; 239(7): 992–997PubMedGoogle Scholar
  94. 94.
    Hansen M, Boesen A, Holm L, Flyvbjerg A, Langberg H, Kjaer M. Local administration of insulin-like growth factor-I (IGF-I) stimulates tendon collagen synthesis in humans. Scand J Med Sci Sports 2013; 23(5): 614–619PubMedGoogle Scholar
  95. 95.
    Boesen AP, Dideriksen K, Couppé C, Magnusson SP, Schjerling P, Boesen M, Kjaer M, Langberg H. Tendon and skeletal muscle matrix gene expression and functional responses to immobilisation and rehabilitation in young males: effect of growth hormone administration. J Physiol 2013; 591(23): 6039–6052PubMedPubMedCentralGoogle Scholar
  96. 96.
    Sampson S, Smith J, Vincent H, Aufiero D, Zall M, Botto-van- Bemden A. Intra-articular bone marrow concentrate injection protocol: short-term efficacy in osteoarthritis. Regen Med 2016; 11 (6): 511–520PubMedGoogle Scholar
  97. 97.
    Rubio-Azpeitia E, Andia I. Partnership between platelet-rich plasma and mesenchymal stem cells: in vitro experience. Muscles Ligaments Tendons J 2014; 4(1): 52–62PubMedPubMedCentralGoogle Scholar
  98. 98.
    Van Pham P, Bui KH, Ngo DQ, Vu NB, Truong NH, Phan NL, Le DM, Duong TD, Nguyen TD, Le VT, Phan NK. Activated plateletrich plasma improves adipose-derived stem cell transplantation efficiency in injured articular cartilage. Stem Cell Res Ther 2013; 4 (4): 91PubMedPubMedCentralGoogle Scholar
  99. 99.
    Gibbs N, Diamond R, Sekyere EO, Thomas WD. 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: 799–806PubMedPubMedCentralGoogle Scholar
  100. 100.
    Koh YG, Choi YJ. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee 2012; 19(6): 902–907PubMedGoogle Scholar
  101. 101.
    Koh YG, Jo SB, Kwon OR, Suh DS, Lee SW, Park SH, Choi YJ. Mesenchymal stem cell injections improve symptoms of knee osteoarthritis. Arthroscopy 2013; 29(4): 748–755PubMedGoogle Scholar
  102. 102.
    Pak J, Lee JH, Lee SH. A novel biological approach to treat chondromalacia patellae. PLoS One 2013; 8(5): e64569PubMedPubMedCentralGoogle Scholar
  103. 103.
    Pak J, Chang JJ, Lee JH, Lee SH. Safety reporting on implantation of autologous adipose tissue-derived stem cells with platelet-rich plasma into human articular joints. BMC Musculoskelet Disord 2013; 14(1): 337PubMedPubMedCentralGoogle Scholar
  104. 104.
    Pak J, Lee JH, Park KS, Jeong BC, Lee SH. Regeneration of cartilage in human knee osteoarthritis with autologous adipose tissue-derived stem cells and autologous extracellular matrix. Biores Open Access 2016; 5(1):192–200PubMedPubMedCentralGoogle Scholar
  105. 105.
    Bui KH-T, Duong TD, Nguyen NT, Nguyen TD, Le VT, Mai VT, Phan NL-C, Le DM, Ngoc NK, Van Pham P. Symptomatic knee osteoarthritis treatment using autologous adipose derived stem cells and platelet rich plasma: a clinical study. Biomed Res Therapy 2014; 1(1): 02–08Google Scholar
  106. 106.
    Russo F, D’Este M, Vadalà G, Cattani C, Papalia R, Alini M, Denaro V. Platelet rich plasma and hyaluronic acid blend for the treatment of osteoarthritis: rheological and biological evaluation. PLoS One 2016; 11(6): e0157048PubMedPubMedCentralGoogle Scholar
  107. 107.
    Andia I, Abate M. Knee osteoarthritis: hyaluronic acid, plateletrich plasma or both in association? Expert Opin Biol Ther 2014; 14 (5): 635–649PubMedGoogle Scholar
  108. 108.
    Chen WH, Lin CM, Huang CF, Hsu WC, Lee CH, Ou KL, Dubey NK, Deng WP. Functional recovery in osteoarthritic chondrocytes through hyaluronic acid and platelet-rich plasma-inhibited infrapatellar fat pad adipocytes. Am J Sports Med 2016; 44(10): 2696–2705PubMedGoogle Scholar
  109. 109.
    Abate M, Verna S, Schiavone C, Di Gregorio P, Salini V. Efficacy and safety profile of a compound composed of platelet-rich plasma and hyaluronic acid in the treatment for knee osteoarthritis (preliminary results). Eur J Orthop Surg Traumatol 2015; 25(8): 1321–1326PubMedGoogle Scholar
  110. 110.
    Dallari D, Stagni C, Rani N, Sabbioni G, Pelotti P, Torricelli P, Tschon M, Giavaresi G. Ultrasound-guided injection of plateletrich plasma and hyaluronic acid, separately and in combination, for hip osteoarthritis: a randomized controlled study. Am J Sports Med 2016; 44(3): 664–671PubMedGoogle Scholar
  111. 111.
    Lana JFSD, Weglein A, Sampson SE, Vicente EF, Huber SC, Souza CV, Ambach MA, Vincent H, Urban-Paffaro A, Onodera CM, Annichino-Bizzacchi JM, Santana MH, Belangero WD. Randomized controlled trial comparing hyaluronic acid, plateletrich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee. J Stem Cells Regen Med 2016; 12(2): 69–78PubMedPubMedCentralGoogle Scholar
  112. 112.
    Reurink G, Goudswaard GJ, Moen MH, Weir A, Verhaar JA, Bierma-Zeinstra SM, Maas M, Tol JL. Dutch Hamstring Injection Therapy (HIT) Study Investigators. Platelet-rich plasma injections in acute muscle injury. N Engl J Med 2014; 370(26): 2546–2547PubMedGoogle Scholar
  113. 113.
    A Hamid MS, Mohamed Ali MR, Yusof A, George J, Lee LP. Platelet-rich plasma injections for the treatment of hamstring injuries: a randomized controlled trial. Am J Sports Med 2014; 42 (10): 2410–2418PubMedGoogle Scholar
  114. 114.
    Martinez-Zapata MJ, Orozco L, Balius R, Soler R, Bosch A, Rodas G, Til L, Peirau X, Urrútia G, Gich I, Bonfill X. PRP-RICE group. Efficacy of autologous platelet-rich plasma for the treatment of muscle rupture with haematoma: a multicentre, randomised, double-blind, placebo-controlled clinical trial. Blood Transfus 2016; 14(2): 245–254PubMedPubMedCentralGoogle Scholar
  115. 115.
    Hamilton B, Tol JL, Almusa E, Boukarroum S, Eirale C, Farooq A, Whiteley R, Chalabi H. Platelet-rich plasma does not enhance return to play in hamstring injuries: a randomised controlled trial. Br J Sports Med 2015; 49(14): 943–950PubMedGoogle Scholar
  116. 116.
    Rossi LA, Molina Rómoli AR, Bertona Altieri BA, Burgos Flor JA, Scordo WE, Elizondo CM. Does platelet-rich plasma decrease time to return to sports in acute muscle tear? A randomized controlled trial. Knee Surg Sports Traumatol Arthrosc 2016 Apr 16. [Epub ahead of print] 4129-7Google Scholar
  117. 117.
    Bosurgi L, Manfredi AA, Rovere-Querini P. Macrophages in injured skeletal muscle: a perpetuum mobile causing and limiting fibrosis, prompting or restricting resolution and regeneration. Front Immunol 2011; 2(62): 62PubMedPubMedCentralGoogle Scholar
  118. 118.
    Andia I, Abate M. Platelet-rich plasma in the treatment of skeletal muscle injuries. Expert Opin Biol Ther 2015; 15(7): 987–999PubMedGoogle Scholar
  119. 119.
    Akhurst RJ, Hata A. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov 2012; 11(10): 790–811PubMedPubMedCentralGoogle Scholar
  120. 120.
    Carlson ME, Conboy MJ, Hsu M, Barchas L, Jeong J, Agrawal A, Mikels AJ, Agrawal S, Schaffer DV, Conboy IM. Relative roles of TGF-β1 and Wnt in the systemic regulation and aging of satellite cell responses. Aging Cell 2009; 8(6): 676–689PubMedPubMedCentralGoogle Scholar
  121. 121.
    Reed NI, Jo H, Chen C, Tsujino K, Arnold TD, DeGrado WF, Sheppard D. The avβ1 integrin plays a critical in vivo role in tissue fibrosis. Sci Transl Med 2015; 7(288): 288ra79PubMedPubMedCentralGoogle Scholar
  122. 122.
    Terada S, Ota S, Kobayashi M, Kobayashi T, Mifune Y, Takayama K, Witt M, Vadalà G, Oyster N, Otsuka T, Fu FH, Huard J. Use of an antifibrotic agent improves the effect of platelet-rich plasma on muscle healing after injury. J Bone Joint Surg Am 2013; 95(11): 980–988PubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany 2018

Authors and Affiliations

  1. 1.Regenerative Medicine Laboratory, BioCruces Health Research InstituteCruces University HospitalBarakaldoSpain
  2. 2.Department of Medicine and Science of AgingUniversity G. d’Annunzio, Chieti-PescaraChieti ScaloItaly

Personalised recommendations