Use of stem cells and growth factors in rotator cuff tendon repair

  • Dimitrios Tsekes
  • Georgios KonstantopoulosEmail author
  • Wasim S. Khan
  • Daniel Rossouw
  • Mike Elvey
  • Jagwant Singh


The management of rotator cuff tears continues to prove challenging for orthopaedic surgeons. Such tears affect most age groups and can lead to significant morbidity in patients. The aetiology of these tears is likely to be multifactorial; however, an understanding of the mechanisms involved is still under review. Despite advancements in surgical operative techniques and the materials used, post-operative recurrence rates after surgical repair remain high. A growing area of research surrounds biological adjuncts used to improve the healing potential of the repaired tissues. This review of recent publications focuses on the strengths and limitations of using stem cells and growth factors in rotator cuff repair.


Rotator cuff tears Mesenchymal stem cells Growth factors 



The authors confirm that no funds were received in support of this study and no benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Gomoll AH, Katz JN, Warner JJP, Millett PJ (2004) Rotator cuff disorders: recognition and management among patients with shoulder pain. Arthritis Rheum 50(12):3751–3761Google Scholar
  2. 2.
    Meislin RJ, Sperling JW, Stitik TP (2005) Persistent shoulder pain: epidemiology, pathophysiology, and diagnosis. Am J Orthop 34(12 Suppl):5–9Google Scholar
  3. 3.
    Klatte Schulz F, Pauly S, Scheibel M, Greiner S, Gerhardt C, Hartwig J et al (2013) Characteristics and stimulation potential with BMP-2 and BMP-7 of tenocyte-like cells isolated from the rotator cuff of female donors. PLoS ONE 8(6):e67209Google Scholar
  4. 4.
    Baumgarten KM, Gerlach D, Galatz LM, Teefey SA, Middleton WD, Ditsios K et al (2010) Cigarette smoking increases the risk for rotator cuff tears. Clin Orthop Relat Res 468(6):1534–1541Google Scholar
  5. 5.
    Cross JA, Cole BJ, Spatny KP, Sundman E, Romeo AA, Nicholson GP et al (2015) Leukocyte-reduced platelet-rich plasma normalizes matrix metabolism in torn human rotator cuff tendons. Am J Sports Med 43(12):2898–2906Google Scholar
  6. 6.
    Hoppe S, Alini M, Benneker LM, Milz S, Boileau P, Zumstein MA (2013) Tenocytes of chronic rotator cuff tendon tears can be stimulated by platelet-released growth factors. J Shoulder Elb Surg 22(3):340–349Google Scholar
  7. 7.
    Jo CH, Shin JS, Park IW, Kim H, Lee SY (2013) Multiple channeling improves the structural integrity of rotator cuff repair. Am J Sports Med 41(11):2650–2657Google Scholar
  8. 8.
    Beck J, Evans D, Tonino PM, Yong S, Callaci JJ (2012) The biomechanical and histologic effects of platelet-rich plasma on rat rotator cuff repairs. Am J Sports Med 40(9):2037–2044Google Scholar
  9. 9.
    Dolkart O, Chechik O, Zarfati Y, Brosh T, Alhajajra F, Maman E (2014) A single dose of platelet-rich plasma improves the organization and strength of a surgically repaired rotator cuff tendon in rats. Arch Orthop Trauma Surg 134(9):1271–1277Google Scholar
  10. 10.
    Ersen A, Demirhan M, Atalar AC, Kapicioğlu M, Baysal G (2014) Platelet-rich plasma for enhancing surgical rotator cuff repair: evaluation and comparison of two application methods in a rat model. Arch Orthop Trauma Surg 134(3):405–411Google Scholar
  11. 11.
    Wu Y, Dong Y, Chen S, Li Y (2014) Effect of platelet-rich plasma and bioactive glass powder for the improvement of rotator cuff tendon-to-bone healing in a rabbit model. Int J Mol Sci 15:21980–21991Google Scholar
  12. 12.
    Chung SW, Song BW, Kim YH, Park KU, Oh JH (2013) Effect of platelet-rich plasma and porcine dermal collagen graft augmentation for rotator cuff healing in a rabbit model. Am J Sports Med 41(12):2909–2918Google Scholar
  13. 13.
    Bergeson AG, Tashjian RZ, Greis PE, Crim J, Stoddard GJ, Burks RT (2012) Effects of platelet-rich fibrin matrix on repair integrity of at-risk rotator cuff tears. Am J Sports Med 40(2):286–293Google Scholar
  14. 14.
    Castricini R, Longo UG, De Benedetto M, Panfoli N, Pirani P, Zini R, Maffulli N, Denaro V (2011) Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial. Am J Sports Med 39(2):258–265Google Scholar
  15. 15.
    Zumstein MA, Rumian A, Thélu CÉ, Lesbats V, O’Shea K, Schaer M et al (2016) 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 Elb Surg 25(1):2–11Google Scholar
  16. 16.
    Hurley ET, Daren LF, Moran CJ, Mullett H (2018) The efficacy of platelet-rich plasma and platelet-rich fibrin in arthroscopic rotator cuff repair: a meta-analysis of randomized controlled trials. Am J Sports Med. p 363546517751397.
  17. 17.
    Lipner J, Shen H, Cavinatto L, Liu W, Havlioglu N, Xia Y et al (2015) In vivo evaluation of adipose-derived stromal cells delivered with a nanofiber scaffold for tendon-to-bone repair. Tissue Eng Part A 21(21–22):2766–2774Google Scholar
  18. 18.
    Pauly S, Klatte F, Strobel C, Schmidmaier G, Greiner S, Scheibel M et al (2012) BMP-2 and BMP-7 affect human rotator cuff tendon cells in vitro. J Shoulder Elb Surg 21(4):464–473Google Scholar
  19. 19.
    Morihara T, Kabuto Y, Sukenari T, Kida Y, Oda R, Arai Y et al (2015) Stimulation of rotator cuff repair by sustained release of bone morphogenetic protein-7 using a gelatin hydrogel sheet. Tissue Eng Part A 21(13–14):2025–2033Google Scholar
  20. 20.
    Kim HM, Galatz LM, Das R, Havlioglu N, Rothermich SY, Thomopoulos S (2011) The role of transforming growth factor beta isoforms in tendon-to-bone healing. Connect Tissue Res 52(2):87–98Google Scholar
  21. 21.
    Kovacevic D, Fox AJ, Bedi A, Ying L, Deng XH, Warren RF et al (2011) Calcium-phosphate matrix with or without TGF-β3 improves tendon-bone healing after rotator cuff repair. Am J Sports Med 39(4):811–819Google Scholar
  22. 22.
    Manning CN, Kim HM, Sakiyama-Elbert S, Galatz LM, Havlioglu N, Thomopoulos S (2011) Sustained delivery of transforming growth factor beta three enhances tendon-to-bone healing in a rat model. J Orthop Res 29(7):1099–1105Google Scholar
  23. 23.
    Hee CK, Dines JS, Dines DM, Roden CM, Wisner-Lynch LA, Turner AS et al (2011) Augmentation of a rotator cuff suture repair using rhPDGF-BB and a type I bovine collagen matrix in an ovine model. Am J Sports Med 39(8):1630–1639Google Scholar
  24. 24.
    Uggen C, Dines J, McGarry M, Grande D, Lee T, Limpisvasti O (2010) The effect of recombinant human platelet-derived growth factor BB-coated sutures on rotator cuff healing in a sheep model. Arthroscopy 26(11):1456–1462Google Scholar
  25. 25.
    Ide J, Kikukawa K, Hirose J, Iyama K-I, Sakamoto H, Mizuta H (2009) The effects of fibroblast growth factor-2 on rotator cuff reconstruction with acellular dermal matrix grafts. Arthroscopy: J Arthrosc Relat Surg 25(6):608–616Google Scholar
  26. 26.
    Peterson DR, Ohashi KL, Aberman HM, Piza PA, Crockett HC, Fernandez JI et al (2015) Evaluation of a collagen-coated, resorbable fiber scaffold loaded with a peptide basic fibroblast growth factor mimetic in a sheep model of rotator cuff repair. J Shoulder Elb Surg 24(11):1764–1773Google Scholar
  27. 27.
    Zhao S, Zhao J, Dong S, Huangfu X, Li Bin, Yang H et al (2014) Biological augmentation of rotator cuff repair using bFGF-loaded electrospun poly(lactide-co-glycolide) fibrous membranes. Int J Nanomed 9:2373–2385Google Scholar
  28. 28.
    Ross D, Maerz T, Kurdziel M, Hein J, Doshi S, Bedi A et al (2015) The effect of granulocyte-colony stimulating factor on rotator cuff healing after injury and repair. Clin Orthop Relat Res 473(5):1655–1664Google Scholar
  29. 29.
    Buchmann S, Sandmann GH, Walz L, Hoppe H, Beitzel K, Wexel G et al (2013) Refixation of the supraspinatus tendon in a rat model—influence of continuous growth factor application on tendon structure. J Orthop Res 31(2):300–305Google Scholar
  30. 30.
    Tao X, Liu J, Chen L, Zhou Y, Tang K (2015) EGR1 induces tenogenic differentiation of tendon stem cells and promotes rabbit rotator cuff repair. Cell Physiol Biochem 35(2):699–709Google Scholar
  31. 31.
    Murray DH, Kubiak EN, Jazrawi LM, Araghi A, Kummer F, Loebenberg MI et al (2007) The effect of cartilage-derived morphogenetic protein 2 on initial healing of a rotator cuff defect in a rat model. J Shoulder Elb Surg 16(2):251–254Google Scholar
  32. 32.
    Gulotta LV, Kovacevic D, Cordasco F, Rodeo SA (2011) Evaluation of tumor necrosis factor α blockade on early tendon-to-bone healing in a rat rotator cuff repair model. Arthroscopy: J Arthrosc Relat Surg 27(10):1351–1357Google Scholar
  33. 33.
    Cheng B, Ge H, Zhou J, Zhang Q (2014) TSG-6 mediates the effect of tendon derived stem cells for rotator cuff healing. Eur Rev Med Pharmacol Sci 18:247–251Google Scholar
  34. 34.
    MacLean S, Khan WS, Malik AA, Snow M, Anand S (2011) Tendon regeneration and repair with stem cells. Stem Cells Int 2012(4):1–6Google Scholar
  35. 35.
    Pelinkovic D, Lee JY, Engelhardt M, Rodosky M, Cummins J, Fu FH et al (2004) Muscle cell-mediated gene delivery to the rotator cuff. Tissue Eng 9(1):143–151Google Scholar
  36. 36.
    Meyer GA, Gibbons MC, Sato E, Lane JG, Ward SR, Engler AJ (2015) Epimuscular fat in the human rotator cuff is a novel beige depot. Stem Cells Transl Med 4(7):764–774Google Scholar
  37. 37.
    Meyer GA, Farris AL, Sato E, Gibbons M, Lane JG, Ward SR et al (2015) Muscle progenitor cell regenerative capacity in the torn rotator cuff. J Orthop Res 33(3):421–429Google Scholar
  38. 38.
    Chen H-S, Su Y-T, Chan T-M, Su Y-J, Syu W-S, Harn H-J et al (2015) Human adipose-derived stem cells accelerate the restoration of tensile strength of tendon and alleviate the progression of rotator cuff injury in a rat model. Cell Transpl 24(3):509–520Google Scholar
  39. 39.
    Mora MV, Antuña SA, Arranz MG, Carrascal MT, Barco R (2014) Application of adipose tissue-derived stem cells in a rat rotator cuff repair model. Injury 45:S22–S27Google Scholar
  40. 40.
    Kim SH, Chung SW, Oh JH (2014) Expression of insulin-like growth factor type 1 receptor and myosin heavy chain in rabbit’s rotator cuff muscle after injection of adipose-derived stem cell. Knee Surg Sports Traumatol Arthrosc 22(11):2867–2873Google Scholar
  41. 41.
    Park GY, Kwon DR, Lee SC (2015) Regeneration of Full-Thickness Rotator Cuff Tendon Tear After Ultrasound-Guided Injection With Umbilical Cord Blood-Derived Mesenchymal Stem Cells in a rabbit model. Stem Cells Transl Med 4:1344–1351Google Scholar
  42. 42.
    Gumucio JP, Flood MD, Roche SM, Sugg KB, Momoh AO, Kosnik PE et al (2015) Stromal vascular stem cell treatment decreases muscle fibrosis following chronic rotator cuff tear. Int Orthop 40(4):759–764Google Scholar
  43. 43.
    Funakoshi T, Spector M (2010) Chondrogenic differentiation and lubricin expression of caprine infraspinatus tendon cells. J Orthop Res 28(6):716–725Google Scholar
  44. 44.
    Song N, Armstrong D, Li F, Ouyang H, Niyibizi C (2013) Multipotent mesenchymal stem cells from human subacromial bursa: potential for cell based tendon tissue engineering. Tissue Eng Part A 20(1–2):239–249Google Scholar
  45. 45.
    Steinert AF, Kunz M, Prager P, Göbel S, Klein-Hitpass L, Ebert R et al (2015) Characterization of bursa subacromialis-derived mesenchymal stem cells. Stem Cell Res Ther 6(1):1–14Google Scholar
  46. 46.
    Utsunomiya H, Uchida S, Sekiya I, Sakai A, Moridera K, Nakamura T (2013) Isolation and characterization of human mesenchymal stem cells derived from shoulder tissues involved in rotator cuff tears. Am J Sports Med 41(3):0363546512473269–0363546512473668Google Scholar
  47. 47.
    Randelli P, Conforti E, Piccoli M, Ragone V, Creo P, Cirillo F et al (2013) Isolation and characterization of 2 new human rotator cuff and long head of biceps tendon cells possessing stem cell-like self-renewal and multipotential differentiation capacity. Am J Sports Med 41(7):1653–1664Google Scholar
  48. 48.
    Tsai C-C, Huang T-F, Ma H-L, Chiang E-R, Hung S-C (2013) Isolation of mesenchymal stem cells from shoulder rotator cuff: a potential source for muscle and tendon repair. Cell Transpl 22(3):413–422Google Scholar
  49. 49.
    Sundar S, Pendegrass CJ, Blunn GW (2009) Tendon bone healing can be enhanced by demineralized bone matrix: a functional and histological study. J Biomed Mater Res B Appl Biomater 88B(1):115–122Google Scholar
  50. 50.
    Chang C-H, Chen C-H, Su C-Y, Liu H-T, Yu C-M (2009) Rotator cuff repair with periosteum for enhancing tendon-bone healing: a biomechanical and histological study in rabbits. Knee Surg Sports Traumatol Arthrosc 17(12):1447–1453Google Scholar
  51. 51.
    Durant TJS, Dyment N, McCarthy MBR, Cote MP, Arciero RA, Mazzocca AD et al (2014) Mesenchymal stem cell response to growth factor treatment and low oxygen tension in 3-dimensional construct environment. Muscles Ligaments Tendons J 4(1):46–51Google Scholar
  52. 52.
    Hernigou P, Merouse G, Duffiet P, Chevalier N, Rouard H (2015) Reduced levels of mesenchymal stem cells at the tendon-bone interface tuberosity in patients with symptomatic rotator cuff tear. Int Orthop 39(6):1219–1225Google Scholar
  53. 53.
    Mazzocca AD, McCarthy MBR, Chowaniec DM, Cote MP, Arciero RA, Drissi H (2010) Rapid isolation of human stem cells (connective tissue progenitor cells) from the proximal humerus during arthroscopic rotator cuff surgery. Am J Sports Med 38(7):1438–1447Google Scholar
  54. 54.
    Kida Y, Morihara T, Matsuda K-I, Kajikawa Y, Tachiiri H, Iwata Y et al (2013) Bone marrow-derived cells from the footprint infiltrate into the repaired rotator cuff. J Shoulder Elb Surg 22(2):197–205Google Scholar
  55. 55.
    Levy DM, Saifi C, Perri JL, Zhang R, Gardner TR, Ahmad CS (2013) Rotator cuff repair augmentation with local autogenous bone marrow via humeral cannulation in a rat model. J Shoulder Elb Surg 22(9):1256–1264Google Scholar
  56. 56.
    Gulotta LV, Kovacevic D, Montgomery S, Ehteshami JR, Packer JD, Rodeo SA (2010) Stem cells genetically modified with the developmental gene MT1-MMP improve regeneration of the supraspinatus tendon-to-bone insertion site. Am J Sports Med 38(7):1429–1437Google Scholar
  57. 57.
    Gulotta LV, Kovacevic D, Packer JD, Deng XH, Rodeo SA (2011) Bone marrow-derived mesenchymal stem cells transduced with scleraxis improve rotator cuff healing in a rat model. Am J Sports Med 39(6):1282–1289Google Scholar
  58. 58.
    Loeffler BJ, Scannell BP, Peindl RD, Connor P, Davis DE, Hoelscher GL et al (2013) Cell-based tissue engineering augments tendon-to-bone healing in a rat supraspinatus model. J Orthop Res 31(3):407–412Google Scholar
  59. 59.
    Tornero-Esteban P, Hoyas JA, Villafuertes E, Rodríguez-Bobada C, López-Gordillo Y, Rojo FJ et al (2015) Efficacy of supraspinatus tendon repair using mesenchymal stem cells along with a collagen I scaffold. J Orthop Surg Res 10(1):1Google Scholar
  60. 60.
    Omi R, Gingery A, Steinmann SP, Amadio PC, An K-N, Zhao C (2016) Rotator cuff repair augmentation in a rat model that combines a multilayer xenograft tendon scaffold with bone marrow stromal cells. J Shoulder Elb Surg 25(3):469–477Google Scholar
  61. 61.
    Kim Y-S, Lee H-J, Ok J-H, Park J-S, Kim D-W (2013) Survivorship of implanted bone marrow-derived mesenchymal stem cells in acute rotator cuff tear. J Shoulder Elb Surg 22(8):1037–1045Google Scholar
  62. 62.
    Gomes JLE, da Silva RC, Silla LMR, Abreu MR, Pellanda R (2012) Conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells. Knee Surg Sports Traumatol Arthrosc 20(2):373–377Google Scholar
  63. 63.
    Hernigou P, Lachaniette CHF, Delambre J, Zilber S, Duffiet P, Chevallier N et al (2014) Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study. Int Orthop 38(9):1811–1818Google Scholar
  64. 64.
    Taniguchi N, Suenaga N, Oizumi N, Miyoshi N, Yamaguchi H, Inoue K et al (2015) Bone marrow stimulation at the footprint of arthroscopic surface-holding repair advances cuff repair integrity. J Shoulder Elb Surg 24(6):860–866Google Scholar
  65. 65.
    Grambart ST (2015) Sports medicine and platelet-rich plasma. Clin Podiatr Med Surg 32(1):99–107Google Scholar
  66. 66.
    Moraes VY, Lenza M, Tamaoki MJ (2014) Platelet-rich therapies for musculoskeletal soft tissue injuries. Database Syst Rev 12:CD010071Google Scholar
  67. 67.
    Cai Y-Z, Zhang C, Lin X-J (2015) Efficacy of platelet-rich plasma in arthroscopic repair of full-thickness rotator cuff tears: a meta-analysis. J Shoulder Elb Surg 24(12):1852–1859Google Scholar
  68. 68.
    Ahmad Z, Wardale J, Brooks R, Henson F, Noorani A, Rushton N (2012) Exploring the application of stem cells in tendon repair and regeneration. Arthroscopy: J Arthrosc Relat Surg 28(7):1018–1029Google Scholar

Copyright information

© Springer-Verlag France SAS, part of Springer Nature 2019

Authors and Affiliations

  • Dimitrios Tsekes
    • 1
  • Georgios Konstantopoulos
    • 2
    Email author
  • Wasim S. Khan
    • 1
  • Daniel Rossouw
    • 3
  • Mike Elvey
    • 4
  • Jagwant Singh
    • 1
  1. 1.Barnet General Hospital, Royal Free NHS Foundation TrustLondonUK
  2. 2.Royal Derby Hospital, Derby Teaching HospitalsDerbyUK
  3. 3.Shoulder UnitBarnet General Hospital, Royal Free NHS Foundation TrustLondonUK
  4. 4.Writtington HospitalWrittingtonUK

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