Bio-enhancement of ACL Graft Healing

  • Braden C. Fleming


Although ACL reconstruction surgery using is commonly performed to restore function to the ACL injured knee, clinical outcomes are variable and far from perfect. It may be possible to stimulate or enhance the healing process (“bio-enhanced” ACL reconstruction) to improve these outcomes. Bio-enhancement of a graft would likely require the addition of growth factors (i.e., PDGF) or a source for growth factors (e.g., platelets, cells) to augment healing in the hostile synovial fluid environment. For many applications, the growth factors or the source of growth factors could be held in place and protected during the initial healing stage via tissue-engineered scaffolds. Preliminary results using preclinical models and early clinical studies are encouraging, and bio-enhanced ACL reconstruction may become a widely available option in the near future. This chapter reviews the current state of the art of bio-enhanced ACL reconstruction.


Vascular Endothelial Growth Factor Fibrin Sealant Healing Response Knee Laxity Concentrate Platelet 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Research reported in this chapter was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Numbers RO1-AR054099 and RO1-AR056834. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


  1. 1.
    Beynnon BD, Johnson RJ, Naud S, et al. Accelerated versus nonaccelerated rehabilitation after anterior cruciate ligament reconstruction: a prospective, randomized, double-blind investigation evaluating knee joint laxity using Roentgen Stereophotogrammetric Analysis. Am J Sports Med. 2011;39:2536–48.PubMedCrossRefGoogle Scholar
  2. 2.
    Fleming BC, Brattbakk B, Peura GD, Badger GJ, Beynnon BD. Measurement of anterior-­posterior knee laxity: a comparison of three techniques. J Orthop Res. 2002;20:421–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Tashman S, Kolowich P, Collon D, Anderson K, Anderst W. Dynamic function of the ACL-­reconstructed knee during running. Clin Orthop Relat Res. 2007;454:66–73.PubMedCrossRefGoogle Scholar
  4. 4.
    Scanlan SF, Chaudhari AM, Dyrby CO, Andriacchi TP. Differences in tibial rotation during walking in ACL reconstructed and healthy contralateral knees. J Biomech. 2010;43:1817–22.PubMedCrossRefGoogle Scholar
  5. 5.
    Von Porat A, Roos EM, Roos H. High prevalence of osteoarthritis 14 years after an anterior cruciate ligament tear in male soccer players: a study of radiographic and patient relevant outcomes. Ann Rheum Dis. 2004;63:269–73.CrossRefGoogle Scholar
  6. 6.
    Aglietti P, Giron F, Losco M, Cuomo P, Ciardullo A, Mondanelli N. Comparison between single- and double-bundle anterior cruciate ligament reconstruction: a prospective, randomized, single-blinded clinical trial. Am J Sports Med. 2010;38:25–34.PubMedCrossRefGoogle Scholar
  7. 7.
    Spindler KP, Huston LJ, Wright RW, et al. The prognosis and predictors of sports function and activity at minimum 6 years after anterior cruciate ligament reconstruction: a population cohort study. Am J Sports Med. 2010;39:348–59.PubMedCrossRefGoogle Scholar
  8. 8.
    Kaeding CC, Aros B, Pedroza A, et al. Allograft versus autograft anterior cruciate ligament reconstruction: predictors of failure from a MOON prospective longitudinal cohort. Sports Health. 2011;3:73–81.PubMedCrossRefGoogle Scholar
  9. 9.
    Jackson DW, Grood ES, Goldstein JD, et al. A comparison of patellar tendon autograft and allograft used for anterior cruciate ligament reconstruction in the goat model. Am J Sports Med. 1993;21:176–85.PubMedCrossRefGoogle Scholar
  10. 10.
    Scheffler SU, Schmidt T, Gangey I, Dustmann M, Unterhauser F, Weiler A. Fresh-frozen free-­tendon allografts versus autografts in anterior cruciate ligament reconstruction: delayed remodeling and inferior mechanical function during long-term healing in sheep. Arthroscopy. 2008;24:448–58.PubMedCrossRefGoogle Scholar
  11. 11.
    Dustmann M, Schmidt T, Gangey I, Unterhauser FN, Weiler A, Scheffler SU. The extracellular remodeling of free-soft-tissue autografts and allografts for reconstruction of the anterior cruciate ligament: a comparison study in a sheep model. Knee Surg Sports Traumatol Arthrosc. 2008;16:360–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Arnoczky SP, Warren RF, Ashlock MA. Replacement of the anterior cruciate ligament using a patellar tendon allograft. J Bone Joint Surg Am. 1986;68:376–85.PubMedGoogle Scholar
  13. 13.
    Amiel D, Kleiner JB, Akeson WH. The natural history of the anterior cruciate ligament autograft of patellar tendon origin. Am J Sports Med. 1986;14:449–62.PubMedCrossRefGoogle Scholar
  14. 14.
    Panni AS, Milano G, Lucania L, Fabbriciani C. Graft healing after anterior cruciate ligament reconstruction in rabbits. Clin Orthop Relat Res. 1997;343:203–12.PubMedCrossRefGoogle Scholar
  15. 15.
    Beynnon BD, Johnson RJ, Tohyama H, Renstrom PA, Arms SW, Fischer RA. The relationship between anterior-posterior knee laxity and the structural properties of the patellar tendon graft. A study in canines. Am J Sports Med. 1994;22:812–20.PubMedCrossRefGoogle Scholar
  16. 16.
    Grood ES, Walz-Hasselfeld KA, Holden JP, et al. The correlation between anterior-posterior translation and cross-sectional area of anterior cruciate ligament reconstructions. J Orthop Res. 1992;10:878–85.PubMedCrossRefGoogle Scholar
  17. 17.
    Wilson TW, Zafuta MP, Zobitz M. A biomechanical analysis of matched bone-patellar tendon-­bone and double-looped semitendinosus and gracilis tendon grafts. Am J Sports Med. 1999;27:202–7.PubMedGoogle Scholar
  18. 18.
    Woo SL-Y, Hollis JM, Adams DJ, Lyon RM, Takai S. Tensile properties of the human femur-­anterior cruciate ligament-tibia complex: the effect of specimen age and orientation. Am J Sports Med. 1991;19:217–25.PubMedCrossRefGoogle Scholar
  19. 19.
    Butler DL, Grood ES, Noyes FR, et al. Mechanical properties of primate vascularized vs. nonvascularized patellar tendon grafts; changes over time. J Orthop Res. 1989;7:68–79.PubMedCrossRefGoogle Scholar
  20. 20.
    Clancy WG, Narechania RG, Rosenberg TD, Gmeiner JG, Wisnefske DD, Lange TA. Anterior and posterior cruciate ligament reconstruction in Rhesus monkeys. J Bone Joint Surg Am. 1981;63:1270–84.PubMedGoogle Scholar
  21. 21.
    Hurley PB, Andrish JT, Yoshiya S, Manley MT, Kurosaka M. Tensile strength of the reconstructed canine anterior cruciate ligament: a long-term evaluation of the modified Jones technique. Am J Sports Med. 1987;15:393.Google Scholar
  22. 22.
    Ballock RT, Woo SL-Y, Lyon RM, Hollis JM, Akeson WH. Use of patellar tendon autograft for anterior cruciate ligament reconstruction in the rabbit: a long-term histologic and biomechanical study. J Orthop Res. 1989;7:474–85.PubMedCrossRefGoogle Scholar
  23. 23.
    Scheffler SU, Sudkamp NP, Gockenjan A, Hoffmann RFG, Weiler A. Biomechanical comparison of hamstring and patellar tendon graft anterior cruciate ligament reconstruction techniques: the impact of fixation level and fixation method under cyclic loading. Arthroscopy. 2002;18:304–15.PubMedCrossRefGoogle Scholar
  24. 24.
    Murray MM, Spindler KP, Ballard P, Welch TP, Zurakowski D, Nanney LB. Enhanced histologic repair in a central wound in the anterior cruciate ligament with a collagen-platelet-rich plasma scaffold. J Orthop Res. 2007;25:1007–17.PubMedCrossRefGoogle Scholar
  25. 25.
    Rosc D, Powierza W, Zastawna E, Drewniak W, Michalski A, Kotschy M. Post-traumatic plasminogenesis in intra-articular exudate in the knee joint. Med Sci Monitor. 2002; 8:CR371–8.Google Scholar
  26. 26.
    Meaney Murray M, Rice K, Wright RJ, Spector M. The effect of selected growth factors on human anterior cruciate ligament cell interactions with a three-dimensional collagen-GAG scaffold. J Orthop Res. 2003;21:238–44.PubMedCrossRefGoogle Scholar
  27. 27.
    Murray MM, Forsythe B, Chen F, et al. The effect of thrombin on ACL fibroblast interactions with collagen hydrogels. J Orthop Res. 2006;24:508–15.PubMedCrossRefGoogle Scholar
  28. 28.
    Murray MM, Spindler KP, Devin C, et al. Use of a collagen-platelet rich plasma scaffold to stimulate healing of a central defect in the canine ACL. J Orthop Res. 2006;24:820–30.PubMedCrossRefGoogle Scholar
  29. 29.
    Molloy T, Wang Y, Murrell G. The roles of growth factors in tendon and ligament healing. Sports Med. 2003;33:381–94.PubMedCrossRefGoogle Scholar
  30. 30.
    Yasuda K, Tomita F, Yamazaki S, Minami A, Tohyama H. The effect of growth factors on biomechanical properties of the bone-patellar tendon-bone graft after anterior cruciate ligament reconstruction: a canine model study. Am J Sports Med. 2004;32:870–80.PubMedCrossRefGoogle Scholar
  31. 31.
    Weiler A, Forster C, Hunt P, et al. The influence of locally applied platelet-derived growth factor-BB on free tendon graft remodeling after anterior cruciate ligament reconstruction. Am J Sports Med. 2004;32:881–91.PubMedCrossRefGoogle Scholar
  32. 32.
    Yoshikawa T, Tohyama H, Enomoto H, Matsumoto H, Toyama Y, Yasuda K. Expression of vascular endothelial growth factor and angiogenesis in patellar tendon grafts in the early phase after anterior cruciate ligament reconstruction. Knee Surg Sports Traumatol Arthrosc. 2006; 14:804–10.PubMedCrossRefGoogle Scholar
  33. 33.
    Yoshikawa T, Tohyama H, Katsura T, et al. Effects of local administration of vascular endothelial growth factor on mechanical characteristics of the semitendinosus tendon graft after anterior cruciate ligament reconstruction in sheep. Am J Sports Med. 2006;34:1918–25.PubMedCrossRefGoogle Scholar
  34. 34.
    Wei X, Mao Z, Hou Y, et al. Local administration of TGFbeta-1/VEGF165 gene-transduced bone mesenchymal stem cells for Achilles allograft replacement of the anterior cruciate ligament in rabbits. Biochem Biophys Res Commun. 2011;406:204–10.PubMedCrossRefGoogle Scholar
  35. 35.
    Boswell SG, Cole BJ, Sundman EA, Karas V, Fortier LA. Platelet-rich plasma: a milieu of bioactive factors. Arthroscopy. 2012;28:429–39.PubMedCrossRefGoogle Scholar
  36. 36.
    Jacobson M, Fufa D, Abreu EL, Kevy S, Murray MM. Platelets, but not erythrocytes significantly affect cytokine release and scaffold contraction in a provisional scaffold model. Wound Repair Regen. 2008;16:370–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Murray MM, Magarian E, Zurakowski D, Fleming BC. Bone-to-bone fixation enhances functional healing of the porcine anterior cruciate ligament using a collagen-platelet composite. Arthroscopy. 2010;29:S49–57.Google Scholar
  38. 38.
    Murray MM, Spindler KP, Abreu E, et al. Collagen-platelet rich plasma hydrogel enhances primary repair of the porcine anterior cruciate ligament. J Orthop Res. 2007;25:81–91.PubMedCrossRefGoogle Scholar
  39. 39.
    Joshi S, Mastrangelo A, Magarian E, Fleming BC, Murray MM. Collagen-platelet composite enhances biomechanical and histologic healing of the porcine ACL. Am J Sports Med. 2009;37:2401–10.PubMedCrossRefGoogle Scholar
  40. 40.
    Spindler KP, Murray MM, Carey JL, Zurakowski D, Fleming BC. The use of platelets to affect functional healing of an anterior cruciate ligament (ACL) autograft in a caprine ACL reconstruction model. J Orthop Res. 2009;27:631–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Fleming BC, Spindler KP, Palmer MP, Magarian EM, Murray MM. Collagen-platelet composites improve the biomechanical properties of healing anterior cruciate ligament grafts in a porcine model. Am J Sports Med. 2009;37:1554–63.PubMedCrossRefGoogle Scholar
  42. 42.
    Vavken P, Sadoghi P, Murray MM. The effect of platelet concentrates on graft maturation and graft-bone interface healing in anterior cruciate ligament reconstruction in human patients: a systematic review of controlled trials. Arthroscopy. 2011;27:1573–83.PubMedCrossRefGoogle Scholar
  43. 43.
    Orrego M, Larrain C, Rosales J, et al. Effects of platelet concentrate and a bone plug on the healing of hamstring tendons in a bone tunnel. Arthroscopy. 2008;24:1373–80.PubMedCrossRefGoogle Scholar
  44. 44.
    Sanchez M, Anitua E, Azofra J, Prado R, Muruzabal F, Andia I. Ligamentization of tendon grafts treated with an endogenous preparation rich in growth factors: gross morphology and histology. Arthroscopy. 2010;26:470–80.PubMedCrossRefGoogle Scholar
  45. 45.
    Radice F, Yanez R, Gutierrez V, Rosales J, Pinedo M, Coda S. Comparison of magnetic resonance imaging findings in anterior cruciate ligament grafts with and without autologous platelet-­derived growth factors. Arthroscopy. 2010;26:50–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Ventura A, Terzaghi C, Borgo E, Verdoia C, Gallazzi M, Failoni S. Use of growth factors in ACL surgery: preliminary study. J Orthop Traumatol. 2005;6:76–9.CrossRefGoogle Scholar
  47. 47.
    Weiler A, Peters G, Maurer J, Unterhauser FN, Sudkamp NP. Biomechanical properties and vascularity of an anterior cruciate ligament graft can be predicted by contrast-enhanced magnetic resonance imaging – a two-year study in sheep. Am J Sports Med. 2001;29:751–61.PubMedGoogle Scholar
  48. 48.
    Vogrin M, Rupreht M, Dinevski D, et al. Effects of a platelet gel on early graft revascularization after anterior cruciate ligament reconstruction: a prospective, randomized, double-blind, clinical trial. Eur Surg Res. 2010;45:77–85.PubMedCrossRefGoogle Scholar
  49. 49.
    Figueroa D, Melean P, Calvo R, et al. Magnetic resonance imaging evaluation of the integration and maturation of semitendinosus-gracilis graft in anterior cruciate ligament reconstruction using autologous platelet concentrate. Arthroscopy. 2010;26:1318–25.PubMedCrossRefGoogle Scholar
  50. 50.
    Nin JR, Gasque GM, Azcarate AV, Beola JD, Gonzalez MH. Has platelet-rich plasma any role in anterior cruciate ligament allograft healing? Arthroscopy. 2009;25:1206–13.PubMedCrossRefGoogle Scholar
  51. 51.
    Silva A, Sampaio R. Anatomic ACL reconstruction: does the platelet-rich plasma accelerate tendon healing? Knee Surg Sports Traumatol Arthrosc. 2009;17:676–82.PubMedCrossRefGoogle Scholar
  52. 52.
    Mazzocca AD, McCarthy MB, Chowaniec DM, et al. Platelet-rich plasma differs according to preparation method and human variability. J Bone Joint Surg Am. 2012;94:308–16.PubMedCrossRefGoogle Scholar
  53. 53.
    Sheth U, Simunovic N, Klein G, et al. Efficacy of autologous platelet-rich plasma use for orthopedic indications: a meta-analysis. J Bone Joint Surg Am. 2012;94:298–307.PubMedCrossRefGoogle Scholar
  54. 54.
    Murray MM, Palmer M, Abreu E, Spindler KP, Zurakowski D, Fleming BC. Platelet-rich plasma alone is not sufficient to enhance suture repair of the ACL in skeletally immature animals: an in vivo study. J Orthop Res. 2009;27:639–45.PubMedCrossRefGoogle Scholar
  55. 55.
    Eagan MJ, Zuk PA, Zhao KW, et al. The suitability of human adipose-derived stem cells for the engineering of ligament tissue. J Tissue Eng Regen Med. 2011. doi: 10.1002/term.474.
  56. 56.
    Matsumoto T, Ingham SM, Mifune Y, et al. Isolation and characterization of human anterior cruciate ligament-derived vascular stem cells. Stem Cells Dev. 2012;21:859–72.PubMedCrossRefGoogle Scholar
  57. 57.
    Nohmi S, Yamamoto Y, Mizukami H, et al. Post injury changes in the properties of mesenchymal stem cells derived from human anterior cruciate ligaments. Int Orthop. 2012; 36:1515–22.PubMedCrossRefGoogle Scholar
  58. 58.
    Ma J, Smietana MJ, Kostrominova TY, Wojtys EM, Larkin LM, Arruda EM. Three-dimensional engineered bone-ligament-bone constructs for anterior cruciate ligament replacement. Tissue Eng Part A. 2012;18:103–16.PubMedCrossRefGoogle Scholar
  59. 59.
    Kondo E, Yasuda K, Katsura T, Hayashi R, Azuma C, Tohyama H. Local administration of autologous synovium-derived cells improve the structural properties of anterior cruciate ligament autograft reconstruction in sheep. Am J Sports Med. 2011;39:999–1007.PubMedCrossRefGoogle Scholar
  60. 60.
    Li F, Jia H, Yu C. ACL reconstruction in a rabbit model using irradiated Achilles allograft seeded with mesenchymal stem cells or PDGF-B gene-transfected mesenchymal stem cells. Knee Surg Sports Traumatol Arthrosc. 2007;15:1219–27.PubMedCrossRefGoogle Scholar
  61. 61.
    Cheng MT, Liu CL, Chen TH, Lee OK. Comparison of potentials between stem cells isolated from human anterior cruciate ligament and bone marrow for ligament tissue engineering. Tissue Eng Part A. 2010;16:2237–53.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of OrthopedicsWarren Alpert Medical School of Brown University/Rhode Island HospitalProvidenceUSA

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