Archives of Orthopaedic and Trauma Surgery

, Volume 134, Issue 11, pp 1573–1578 | Cite as

ACL injuries and stem cell therapy

  • Corinna Hirzinger
  • Mark Tauber
  • Stefanie Korntner
  • Michael Quirchmayr
  • Hans-Christian Bauer
  • Andreas Traweger
  • Herbert Tempfer
Arthroscopy and Sports Medicine


Tears of the anterior cruciate ligament (ACL) are very frequent injuries, particularly in young and active people. Arthroscopic reconstruction using tendon auto- or allograft represents the gold-standard for the management of ACL tears. Interestingly, the ACL has the potential to heal upon intensive non-surgical rehabilitation procedures. Several biological factors influence this healing process as local intraligamentous cytokines and mainly cell repair mechanisms controlled by stem cells or progenitor cells. Understanding the mechanisms of this regeneration process and the cells involved may pave the way for novel, less invasive and biology-based strategies for ACL repair. This review aims to focus on the current knowledge on the mechanisms of ACL healing, the nature and potential of ligament derived stem/progenitor cells as well as on the potential and the limitations of using mesenchymal stem cells (MSCs) for treating injured ACL.


ACL regeneration Stem/progenitor cells Mesenchymal stem cells 



This work was supported by the Hermann and Marianne Straniak Foundation (Sarnen, Switzerland) and by grants Nr. E09/09/051-BAH and R-13/02/047-TEM, Nr. E09/09/051-BAH and R-13/02/047-TEM from the Paracelsus Medical University Research Fund (Salzburg, Austria). The Institute for Tendon and Bone Regeneration is part of the Austrian Cluster for Tissue Regeneration.

Conflict of interest



  1. 1.
    Clayton R, Court-Brown CM (2008) The epidemiology of musculoskeletal tendinous and ligamentous injuries. Inj Int J Care Inj 39:1338–1344. doi: 10.1016/j.injury.2008.06.021 CrossRefGoogle Scholar
  2. 2.
    Prodromos CC, Han Y, Rogowski J, Joyce B, Shi K (2007) A meta-analysis of the incidence of anterior cruciate ligament tears as a function of gender, sport, and a knee injury-reduction regimen. Arthroscopy 23:1320–1325PubMedCrossRefGoogle Scholar
  3. 3.
    Lipps DB, Oh YK, Ashton-Miller JA, Wojtys EM (2012) Morphologic characteristics help explain the gender difference in peak anterior cruciate ligament strain during a simulated pivot landing. Am J Sports Med 40:32–40. doi: 10.1177/0363546511422325 PubMedCrossRefGoogle Scholar
  4. 4.
    Frobell RB, Roos HP, Roos EM, Roemer FW, Ranstam J, Lohmander LS (2013) Treatment for acute anterior cruciate ligament tear: five year outcome of randomised trial. BMJ 346:232–244CrossRefGoogle Scholar
  5. 5.
    Costa-Paz M, Ayerza MA, Tanoira I, Astoul J, Muscolo DL (2012) Spontaneous healing in complete ACL ruptures: a clinical and MRI study. Clin Orthop Relat Res 470(4):979–985. doi: 10.1007/s11999-011-1933-8 PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Lohmander LS, Ostenberg A, Englund M, Roos H (2004) High prevalence of knee osteoarthritis, pain, and functional limitations in female soccer players twelve years after anterior cruciate ligament injury. Arthritis Rheum 50:3145–3152PubMedCrossRefGoogle Scholar
  7. 7.
    Hoffelner T, Resch H, Forstner Michael M, Minnich B, Tauber M (2011) Arthroscopic all-inside meniscal repair—does the meniscus heal? A clinical and radiological follow-up examination to verify meniscal healing using a 3-T MRI. Skeletal Radiol 40(2):181–187PubMedCrossRefGoogle Scholar
  8. 8.
    Feagin JA Jr, Curl WW (1976) Isolated tear of the anterior cruciate ligament: 5-year follow-up study. Am J Sports Med 3:95–100CrossRefGoogle Scholar
  9. 9.
    Lidén M, Ejerhed L, Sernert N, Laxdal G, Kartus J (2007) Patellar tendon or semitendinosus tendon autografts for anterior cruciate ligament reconstruction: a prospective, randomized study with a 7-year follow-up. Am J Sports Med 35:740–748PubMedCrossRefGoogle Scholar
  10. 10.
    Steadman JR, Cameron-Donaldson ML, Briggs KK, Rodkey WG (2006) A minimally invasive technique (“healing response”) to treat proximal ACL injuries in skeletally immature athletes. J Knee Surg 19(1):8–13PubMedGoogle Scholar
  11. 11.
    Steadman JR, Matheny LM, Briggs KK, Rodkey WG, Carreira DS (2012) Outcomes following healing response in older, active patients: a primary anterior cruciate ligament repair technique. J Knee Surg 25(3):255–260PubMedCrossRefGoogle Scholar
  12. 12.
    Wasmaier J, Kubik-Huch R, Pfirrmann C, Grehn H, Bieg C, Eid K (2013) Proximal anterior cruciate ligament tears: the healing response technique versus conservative treatment. J Knee Surg 26(4):263–271PubMedGoogle Scholar
  13. 13.
    Peacock E et al (1965) Physiology of tendon repair. Am J Surg 109:283–286PubMedCrossRefGoogle Scholar
  14. 14.
    Sharma P, Maffulli N (2005) Basic biology of tendon injury and healing. Surgeon 3:309–316PubMedCrossRefGoogle Scholar
  15. 15.
    Murray MM, Spindler KP, Ballard P, Welch TP, Zurakowski D, Nanney LB (2007) Enhanced histologic repair in a central wound in the anterior cruciate ligament with a collagen-platelet-rich plasma scaffold. J Orthop Res 25:1007–1017PubMedCrossRefGoogle Scholar
  16. 16.
    Higuchi H, Shirakura K, Kimura M, Terauchi M, Shinozaki T, Watanabe H, Takagishi K (2006) Changes in biochemical parameters after anterior cruciate ligament injury. Int Orthop 1:43–47CrossRefGoogle Scholar
  17. 17.
    Lohmander LS, Hoerrner LA, Lark MW (1993) Metalloproteinases, tissue inhibitor, and proteoglycan fragments in knee synovial fluid in human osteoarthritis. Arthritis Rheum 36:181–189PubMedCrossRefGoogle Scholar
  18. 18.
    Tang Z, Yang L, Wang Y, Xue R, Zhang J, Huang W, Chen PC, Sung KL (2009) Contributions of different intraarticular tissues to the acute phase elevation of synovial fluid MMP-2 following rat ACL rupture. J Orthop Res 2:243–248. doi: 10.1002/jor.20763 CrossRefGoogle Scholar
  19. 19.
    Burdon T, Smith A, Savatier P (2002) Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol 12:432–438PubMedCrossRefGoogle Scholar
  20. 20.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 5391:1145–1147CrossRefGoogle Scholar
  21. 21.
    Watts AE, Yeager AE, Kopyov OV, Nixon AJ (2011) Fetal derived embryonic-like stem cells improve healing in a large animal flexor tendonitis model. Stem Cell Res Ther 2(1):4. doi: 10.1186/scrt45 PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Lodi D, Iannitti T, Palmieri B (2011) Stem cells in clinical practice: applications and warnings. J Exp Clin Cancer Res 17(30):9CrossRefGoogle Scholar
  23. 23.
    Caplan AI (2008) All MSCs are pericytes? Cell Stem Cell 3:229–230PubMedCrossRefGoogle Scholar
  24. 24.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Dj Prockop, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 4:315–317CrossRefGoogle Scholar
  25. 25.
    Salingcarnboriboon R, Yoshitake H, Tsuji K, Obinata M, Amagasa T, Nifuji A, Noda M (2003) Establishment of tendon-derived cell lines exhibiting pluripotent mesenchymal stem cell-like property. Exp Cell Res 287:289–300PubMedCrossRefGoogle Scholar
  26. 26.
    Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, Li L, Leet AI, Seo BM, Zhang L, Shi S, Young MF (2007) Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med 10:1219–1227CrossRefGoogle Scholar
  27. 27.
    Cheng MT, Liu CL, Chen TH, Lee OK (2010) Comparison of potentials between stem cells isolated from human anterior cruciate ligament and bone marrow for ligament tissue engineering. Tissue Eng Part A 16(7):2237–2253PubMedCrossRefGoogle Scholar
  28. 28.
    Matsumoto T, Ingham SM, Mifune Y, Osawa A, Logar A, Usas A, Kuroda R, Kurosaka M, Fu FH, Huard J (2012) Isolation and characterization of human anterior cruciate ligament-derived vascular stem cells. Stem Cells Develop 6:859–872. doi: 10.1089/scd.2010.0528 CrossRefGoogle Scholar
  29. 29.
    Tempfer H, Wagner A, Gehwolf R, Lehner C, Tauber M, Resch H, Bauer HC (2009) Perivascular cells of the supraspinatus tendon express both tendon- and stem cell related markers. Histochem Cell Biol 131:733–741. doi: 10.1007/s00418-009-0581-5 PubMedCrossRefGoogle Scholar
  30. 30.
    Steinert AF, Kunz M, Prager P, Barthel T, Jakob F, Nöth U, Murray MM, Evans CH, Porter RM (2011) Mesenchymal stem cell characteristics of human anterior cruciate ligament outgrowth cells. Tissue Eng Part A 17:1375–1388. doi: 10.1089/ten.TEA.2010.0413 PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Lui PP, Wong OT, Lee YW (2014) Application of tendon-derived stem cell sheet for the promotion of graft healing in anterior Cruciate ligament reconstruction. Am J Sports Med [Epub ahead of print]Google Scholar
  32. 32.
    Amiel D, Frank C, Harwood F, Fronek J, Akeson W (1984) Tendons and ligaments: a morphological and biochemical comparison. J Orthop Res 1(3):257–265PubMedCrossRefGoogle Scholar
  33. 33.
    Rumian AP, Wallace AL, Birch HL (2007) Tendons and ligaments are anatomically distinct but overlap in molecular and morphological features—a comparative study in an ovine mode journal of orthopaedic research. J Orthop Res 25(4):458–464PubMedCrossRefGoogle Scholar
  34. 34.
    Hadjicostas PT, Soucacos PN, Koleganova N, Krohmer G, Berger I (2008) Comparative and morphological analysis of commonly used autografts for anterior cruciate ligament reconstruction with the native ACL: an electron, microscopic and morphologic study. Knee Surg Sports Traumatol Arthrosc 16:1099–1107. doi: 10.1007/s00167-008-0603-1 PubMedCrossRefGoogle Scholar
  35. 35.
    Becerra P, Valdés Vázquez MA, Dudhia J, Fiske-Jackson AR, Neves F, Hartman NG, Smith RK (2013) Distribution of injected technetium(99m)-labeled mesenchymal stem cells in horses with naturally occurring tendinopathy. J Orthop Res 31(7):1096–1102. doi: 10.1002/jor.22338 PubMedCrossRefGoogle Scholar
  36. 36.
    Agung M, Ochi M, Yanada S, Adachi N, Izuta Y, Yamasaki T, Toda K (2006) Mobilization of bone marrow-derived mesenchymal stem cells into the injured tissues after intraarticular injection and their contribution to tissue regeneration. Knee Surg Sports Traumatol Arthrosc 14:1307–1314PubMedCrossRefGoogle Scholar
  37. 37.
    Murphy JM, Fink DJ, Hunziker EB, Barry FP (2003) Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum 48:3464–3474PubMedCrossRefGoogle Scholar
  38. 38.
    Kanaya A, Deie M, Adachi N, Nishimori M, Yanada S, Ochi M (2007) Intra-articular injection of mesenchymal stromal cells in partially torn anterior cruciate ligaments in a rat model. Arthroscopy 23:610–617PubMedCrossRefGoogle Scholar
  39. 39.
    Kasper G, Glaeser JD, Geissler S, Ode A, Tuischer J, Matziolis G, Perka C, Duda GN (2007) Matrix metalloprotease activity is an essential link between mechanical stimulus and mesenchymal stem cell behavior. Stem Cells 25(8):1985–1994PubMedCrossRefGoogle Scholar
  40. 40.
    Xie J, Wang C, Huang DY, Zhang Y, Xu J, Kolesnikov SS, Sung KL, Zhao H (2013) TGF-beta1 induces the different expressions of lysyl oxidases and matrix metalloproteinases in anterior cruciate ligament and medial collateral ligament fibroblasts after mechanical injury. J Biomech 46:890–898. doi: 10.1016/j.jbiomech.2012.12.019 PubMedCrossRefGoogle Scholar
  41. 41.
    Smith-Mungo LI, Kagan HM (1998) Lysyl oxidase: properties, regulation and multiple functions in biology. Matrix Biol 16(7):387–398PubMedCrossRefGoogle Scholar
  42. 42.
    Figueroa D, Espinosa M, Calvo R, Scheu M, Vaisman A, Gallegos M, Conget P (2013) Anterior cruciate ligament regeneration using mesenchymal stem cells and collagen type I scaffold in a rabbit model. Knee Surg Sports Traumatol Arthrosc [Epub ahead of print]Google Scholar
  43. 43.
    Silva A, Sampaio R, Fernandes R, Pinto E (2012) Is there a role for adult non-cultivated bone marrow stem cells in ACL reconstruction? Knee Surg Sports Traumatol Arthrosc [Epub ahead of print]Google Scholar
  44. 44.
    Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, Sentís J, Sánchez A, García-Sancho J (2013) Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation 12:1535–1541. doi: 10.1097/TP.0b013e318291a2da CrossRefGoogle Scholar
  45. 45.
    Davatchi F, Abdollahi BS, Mohyeddin M, Shahram F, Nikbin B (2011) Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis 14:211–215. doi: 10.1111/j.1756-185X.2011.01599.x PubMedCrossRefGoogle Scholar
  46. 46.
    Centeno CJ, Schultz JR, Cheever M, Freeman M, Faulkner S, Robinson B, Hanson R (2011) Safety and complications reporting update on the re-implantation of cultured-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther 6:368–378PubMedCrossRefGoogle Scholar
  47. 47.
    Mayr HO, Weig TG, Plitz W (2004) Arthrofibrosis following ACL reconstruction: reasons and outcomes. Arch Orthop Trauma Surg 124:518–522PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Corinna Hirzinger
    • 1
    • 2
  • Mark Tauber
    • 3
    • 4
  • Stefanie Korntner
    • 2
  • Michael Quirchmayr
    • 1
  • Hans-Christian Bauer
    • 2
  • Andreas Traweger
    • 2
  • Herbert Tempfer
    • 2
  1. 1.Department of Trauma Surgery and Sports InjuriesUniversity Hospital of SalzburgSalzburgAustria
  2. 2.Institute of Tendon and Bone Regeneration, Spinal Cord Injury and Tissue Regeneration Center SalzburgParacelsus Medical UniversitySalzburgAustria
  3. 3.ATOS Clinic MunichMunichGermany
  4. 4.Paracelsus Medical University SalzburgSalzburgAustria

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