Biologic Treatment in Tendon and Muscle Injuries

  • Moises Cohen
  • Gustavo Gonçalves Arliani
  • Camila Cohen Kaleka


In the last decades, we have observed a great increase in the number of people practicing sports around the world. However, these beneficial effects must be balanced with injuries that are to some extent unavoidable. Muscle and tendon injuries are very common in sports practice. Despite the enormous advances in medicine in recent decades, the treatment of muscle injuries has changed little. Some biological treatments have been studied with promising initial results: platelet-rich plasma (PRP), mesenchymal cells, losartan, prolotherapy, and gene therapy. But further investigations are required to better define indication techniques, modalities, safety, and cost-effectiveness.


Biological treatment Tendon injuries Muscle Injuries Athletic injuries Sports medicine 


  1. 1.
    Arliani GG, Astur DC, Yamada RK, Yamada AF, da Rocha Correa Fernandes A, Ejnisman B, et al. Professional football can be considered a healthy sport? Knee Surg Sports Traumatol Arthrosc. 2016;24(12):3907–11.CrossRefGoogle Scholar
  2. 2.
    Maffulli N, Longo UG, Gougoulias N, Caine D, Denaro V. Sport injuries: a review of outcomes. Br Med Bull. 2011;97:47–80.CrossRefGoogle Scholar
  3. 3.
    Nicholl JP, Coleman P, Williams BT. The epidemiology of sports and exercise related injury in the United Kingdom. Br J Sports Med. 1995;29(4):232–8.CrossRefGoogle Scholar
  4. 4.
    Lindqvist KS, Timpka T, Bjurulf P. Injuries during leisure physical activity in a Swedish municipality. Scand J Soc Med. 1996;24(4):282–92.CrossRefGoogle Scholar
  5. 5.
    Galer BS, Rowbotham M, Perander J, Devers A, Friedman E. Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial. J Pain Symptom Manage. 2000;19(4):287–94.CrossRefGoogle Scholar
  6. 6.
    Jarvinen TA, Jarvinen TL, Kaariainen M, Aarimaa V, Vaittinen S, Kalimo H, et al. Muscle injuries: optimising recovery. Best Pract Res Clin Rheumatol. 2007;21(2):317–31.CrossRefGoogle Scholar
  7. 7.
    Ekstrand J, Hagglund M, Walden M. Epidemiology of muscle injuries in professional football (soccer). Am J Sports Med. 2011;39(6):1226–32.CrossRefGoogle Scholar
  8. 8.
    Woods C, Hawkins R, Hulse M, Hodson A. The Football Association Medical Research Programme: an audit of injuries in professional football-analysis of preseason injuries. Br J Sports Med. 2002;36(6):436–41; discussion 41.CrossRefGoogle Scholar
  9. 9.
    Manning MR, Levy RS. Soccer. Phys Med Rehabil Clin N Am. 2006;17(3):677–95, vii.CrossRefGoogle Scholar
  10. 10.
    Huard J, Lu A, Mu X, Guo P, Li Y. Muscle injuries and repair: what’s new on the horizon! Cells Tissues Organs. 2016;202(3–4):227–36.CrossRefGoogle Scholar
  11. 11.
    Andrade BM, Baldanza MR, Ribeiro KC, Porto A, Pecanha R, Fortes FS, et al. Bone marrow mesenchymal cells improve muscle function in a skeletal muscle re-injury model. PLoS One. 2015;10(6):e0127561.CrossRefGoogle Scholar
  12. 12.
    Filardo G, Kon E, Roffi A, Di Matteo B, Merli ML, Marcacci M. Platelet-rich plasma: why intra-articular? A systematic review of preclinical studies and clinical evidence on PRP for joint degeneration. Knee Surg Sports Traumatol Arthrosc. 2015;23(9):2459–74.CrossRefGoogle Scholar
  13. 13.
    Malanga G, Abdelshahed D, Jayaram P. Orthobiologic interventions using ultrasound guidance. Phys Med Rehabil Clin N Am. 2016;27(3):717–31.CrossRefGoogle Scholar
  14. 14.
    Andia I, Abate M. Platelet-rich plasma in the treatment of skeletal muscle injuries. Expert Opin Biol Ther. 2015;15(7):987–99.CrossRefGoogle Scholar
  15. 15.
    Vidal B, Serrano AL, Tjwa M, Suelves M, Ardite E, De Mori R, et al. Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway. Genes Dev. 2008;22(13):1747–52.CrossRefGoogle Scholar
  16. 16.
    Dohan Ehrenfest DM, Rasmusson L, Albrektsson T. Classification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF). Trends Biotechnol. 2009;27(3):158–67.CrossRefGoogle Scholar
  17. 17.
    DeLong JM, Russell RP, Mazzocca AD. Platelet-rich plasma: the PAW classification system. Arthroscopy. 2012;28(7):998–1009.CrossRefGoogle Scholar
  18. 18.
    Delos D, Leineweber MJ, Chaudhury S, Alzoobaee S, Gao Y, Rodeo SA. The effect of platelet-rich plasma on muscle contusion healing in a rat model. Am J Sports Med. 2014;42(9):2067–74.CrossRefGoogle Scholar
  19. 19.
    MS AH, 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):2410–8.CrossRefGoogle Scholar
  20. 20.
    Martinez-Zapata MJ, Orozco L, Balius R, Soler R, Bosch A, Rodas G, et al. 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):245–54.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Grassi A, Napoli F, Romandini I, Samuelsson K, Zaffagnini S, Candrian C, et al. Is platelet-rich plasma (PRP) effective in the treatment of acute muscle injuries? A systematic review and meta-analysis. Sports Med. 2018;48(4):971–89.CrossRefGoogle Scholar
  22. 22.
    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.CrossRefGoogle Scholar
  23. 23.
    Noonan TJ, Garrett WE Jr. Muscle strain injury: diagnosis and treatment. J Am Acad Orthop Surg. 1999;7(4):262–9.CrossRefGoogle Scholar
  24. 24.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.CrossRefGoogle Scholar
  25. 25.
    Iyer SS, Rojas M. Anti-inflammatory effects of mesenchymal stem cells: novel concept for future therapies. Expert Opin Biol Ther. 2008;8(5):569–81.CrossRefGoogle Scholar
  26. 26.
    Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8(9):726–36.CrossRefGoogle Scholar
  27. 27.
    Mori R, Kamei N, Okawa S, Nakabayashi A, Yokota K, Higashi Y, et al. Promotion of skeletal muscle repair in a rat skeletal muscle injury model by local injection of human adipose tissue-derived regenerative cells. J Tissue Eng Regen Med. 2015;9(10):1150–60.CrossRefGoogle Scholar
  28. 28.
    Lim DS, Lutucuta S, Bachireddy P, Youker K, Evans A, Entman M, et al. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation. 2001;103(6):789–91.CrossRefGoogle Scholar
  29. 29.
    Paizis G, Gilbert RE, Cooper ME, Murthi P, Schembri JM, Wu LL, et al. Effect of angiotensin II type 1 receptor blockade on experimental hepatic fibrogenesis. J Hepatol. 2001;35(3):376–85.CrossRefGoogle Scholar
  30. 30.
    Suga S, Mazzali M, Ray PE, Kang DH, Johnson RJ. Angiotensin II type 1 receptor blockade ameliorates tubulointerstitial injury induced by chronic potassium deficiency. Kidney Int. 2002;61(3):951–8.CrossRefGoogle Scholar
  31. 31.
    Bedair HS, Karthikeyan T, Quintero A, Li Y, Huard J. Angiotensin II receptor blockade administered after injury improves muscle regeneration and decreases fibrosis in normal skeletal muscle. Am J Sports Med. 2008;36(8):1548–54.CrossRefGoogle Scholar
  32. 32.
    Kobayashi T, Uehara K, Ota S, Tobita K, Ambrosio F, Cummins JH, et al. The timing of administration of a clinically relevant dose of losartan influences the healing process after contusion induced muscle injury. J Appl Physiol (1985). 2013;114(2):262–73.CrossRefGoogle Scholar
  33. 33.
    Terada S, Ota S, Kobayashi M, Kobayashi T, Mifune Y, Takayama K, et al. 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):980–8.CrossRefGoogle Scholar
  34. 34.
    Kobayashi M, Ota S, Terada S, Kawakami Y, Otsuka T, Fu FH, et al. The combined use of losartan and muscle-derived stem cells significantly improves the functional recovery of muscle in a young mouse model of contusion injuries. Am J Sports Med. 2016;44(12):3252–61.CrossRefGoogle Scholar
  35. 35.
    Evans C. Using genes to facilitate the endogenous repair and regeneration of orthopaedic tissues. Int Orthop. 2014;38(9):1761–9.CrossRefGoogle Scholar
  36. 36.
    Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J. Gene therapy clinical trials worldwide to 2012—an update. J Gene Med. 2013;15(2):65–77.CrossRefGoogle Scholar
  37. 37.
    Schertzer JD, Lynch GS. Comparative evaluation of IGF-I gene transfer and IGF-I protein administration for enhancing skeletal muscle regeneration after injury. Gene Ther. 2006;13(23):1657–64.CrossRefGoogle Scholar
  38. 38.
    Li Y, Li J, Zhu J, Sun B, Branca M, Tang Y, et al. Decorin gene transfer promotes muscle cell differentiation and muscle regeneration. Mol Ther. 2007;15(9):1616–22.CrossRefGoogle Scholar
  39. 39.
    Evans CH, Huard J. Gene therapy approaches to regenerating the musculoskeletal system. Nat Rev Rheumatol. 2015;11(4):234–42.CrossRefGoogle Scholar
  40. 40.
    Zhou Y, Zhang J, Wu H, Hogan MV, Wang JH-C. The differential effects os leukocyte-containing and pure platelet-rich plasma (PRP) on tendon stem/progenitor cells—implication of PRP application for the clinical treatment of tendon injuries. Stem Cell Res Ther. 2015;6:173.CrossRefGoogle Scholar
  41. 41.
    Kannus P, Natri A. Etiology and patophysiology of tendon ruptures in sports. Scand J Med Sci Sports. 1997;7:107–12.CrossRefGoogle Scholar
  42. 42.
    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;45(1):226–33.CrossRefGoogle Scholar
  43. 43.
    Docheva D, Müller SA, Majewski M, et al. Biologics for tendon repair. Adv Drug Deliv Rev. 2015;84:222–39.CrossRefGoogle Scholar
  44. 44.
    Ambrosio F, Wolf SL, Delitto A, et al. The emerging relationship between regenerative medicine and physical therapeutics. Phys Ther. 2010;90(12):1807–14.CrossRefGoogle Scholar
  45. 45.
    Andia I, Martin JI, Maffulli N. Advances with platelet rich plasma therapies for tendon regeneration. Expert Opin Biol Ther. 2018;18(4):389–98.CrossRefGoogle Scholar
  46. 46.
    Ahmad Z, Brooks R, Kang SN, et al. The effect of platelet-rich plasma on clinical outcomes in lateral epicondylitis. Arthroscopy. 2013;29(11):1851–62.CrossRefGoogle Scholar
  47. 47.
    Baksh N, Hannon CP, Murawski CD, Smyth NA, Kennedy JG. Platelet-rich plasma in tendon models: a systematic review of basic science literature. Arthroscopy. 2013;29(3):596–607.CrossRefGoogle Scholar
  48. 48.
    de Vos RJ, van Veldhoven PL, Moen MH, Weir A, Tol JL, Maffulli N. Autologous growth factor injections in chronic tendinopathy: a systematic review. Br Med Bull. 2010;95:63–77.CrossRefGoogle Scholar
  49. 49.
    de Vos RJ, Windt J, Weir A. Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review. Br J Sports Med. 2014;48(12):952–6.CrossRefGoogle Scholar
  50. 50.
    Krogh TP, Bartels EM, Ellingsen T, et al. Comparative effectiveness of injection therapies in lateral epicondylitis: a systematic review and network meta-analysis of randomized controlled trials. Am J Sports Med. 2013;41(6):1435–46.CrossRefGoogle Scholar
  51. 51.
    Moraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JC. Platelet- rich therapies for musculoskeletal soft tissue injuries. Cochrane Database Syst Rev. 2014;4:CD010071.Google Scholar
  52. 52.
    Giai Via A, McCarthy MB, de Girolamo L, Ragni E, Oliva F, Maffulli N. Making them commit: strategies to influence phenotypic differentiation in mesenchymal stem cells. Sports Med Arthrosc Rev. 2018;26(2):64–9.CrossRefGoogle Scholar
  53. 53.
    Leo AJ, Grande DA. Mesenchymal stem cells in tissue engineering. Cells Tissues Organs. 2006;183:112–22.CrossRefGoogle Scholar
  54. 54.
    Rosenbaum AJ, Grande DA, Dines JS. The use of mesenchymal stem cells in tissue engineering: a global assessment. Organogenesis. 2008;4:23–7.CrossRefGoogle Scholar
  55. 55.
    Chaudhury S. Mesenchymal stem cell applications to tendon healing. Muscles Ligaments Tendons J. 2012;2(3):222–9.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Liu L, Hindieh J, Leong DJ, Sun HB. Advances of stem cell based-therapeutic approaches for tendon repair. J Orthop Translat. 2017;9:69–75.CrossRefGoogle Scholar
  57. 57.
    Lee SY, Kim W, Lim C, et al. Treatment of lateral epicondylosis by using allogeneic adipose-derived mesenchymal stem cells: a pilot study. Stem Cells. 2015;33:2995–3005.CrossRefGoogle Scholar
  58. 58.
    Connell D, Datir A, Alyas F, et al. Treatment of lateral epicondylitis using skin-derived tenocyte-like cells. Br J Sports Med. 2009;43:293–8.CrossRefGoogle Scholar
  59. 59.
    Clarke AW, Alyas F, Morris T, et al. Skin-derived tenocyte-like cells for the treatment of patellar tendinopathy. Am J Sports Med. 2011;39:614–23.CrossRefGoogle Scholar
  60. 60.
    Lin J, Zhou W, Han S, Bunpetch V, Zhao K, Yin Z, Ouyang H. Cell-materail interactions in tendon tissue engineering. Acta Biomater. 2018;70:1–11.CrossRefGoogle Scholar
  61. 61.
    Majewski M, Heisterbach P, Jaquiéry C, et al. Improved tendon healing using bFGF, BMP-12 and TGFβ1 in a rat model. Eur Cell Mater. 2018;35:318–34.CrossRefGoogle Scholar
  62. 62.
    Rabago D, Slattengren A, Zgierska A. Prolotherapy in primary care practice. Prim Care. 2010;37:65–80.CrossRefGoogle Scholar
  63. 63.
    Freeman J, Empson Y, Ekwueme E, Paynter D, Bsolinson P. Effect of prolotherapy on cellular proliferation and collagen deposition in MC3T3-E1 and patellar tendon fibroblast populations. Transl Res. 2011;158:132–9.CrossRefGoogle Scholar
  64. 64.
    Rabago D, Best T, Beamsley M, Patterson J. A systematic review of prolotherapy for chronic musculoskeletal pain. Clin Sports Med. 2005;15(5):376–80.CrossRefGoogle Scholar
  65. 65.
    Yelland M, Sweeting K, Lyftogt J, Ng SK, Scuffham P, Evans K. Prolotherapy injections and eccentric loading exercises for painful Achilles tendinosis: a randomized trial. Br J Sports Med. 2011;45:421–8.CrossRefGoogle Scholar
  66. 66.
    Kim E, Lee J. Autologous platelet rich plasma versus dextrose prolotherapy for the treatment of chronic recalcitrant plantar fasciitis. Phys Med Rehabil Int. 2014;6:152–8.Google Scholar
  67. 67.
    Ryan M, Wong A, Gillies J, Wong J, Taunton J. Sonographically guided intratendinous injections of hyperosmolar dextrose/lidocaine: a pilot study for the treatment of chronic plantar fasciitis. Br J Sports Med. 2009;43:303–68.CrossRefGoogle Scholar
  68. 68.
    Scarpone M, Rabago DP, Zgierska A, Arbogast G, Snell E. The efficacy of prolotherapy for lateral epicondylosis: a pilot study. Clin Sports Med. 2008;18(3):248–54.CrossRefGoogle Scholar
  69. 69.
    Bertrand H, Reeves KD, Bennett CJ, et al. Dextrose prolotherapy versus control injections in painful rotator cuff tendinopathy. Arch Phys Med Rehabil. 2016;97:17–25.CrossRefGoogle Scholar

Copyright information

© ISAKOS 2019

Authors and Affiliations

  • Moises Cohen
    • 1
  • Gustavo Gonçalves Arliani
    • 1
  • Camila Cohen Kaleka
    • 2
    • 3
  1. 1.Department of Orthopedics and TraumatologyUNIFESPSão PauloBrazil
  2. 2.Cohen InstituteSão PauloBrazil
  3. 3.Hospital Israelista Albert EinsteinSão PauloBrazil

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