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The Use of a Large Animal Model and Robotic Technology to Validate New Biotherapies for ACL Healing

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Bio-orthopaedics

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Abstract

The anterior cruciate ligament (ACL) is the most frequently injured ligament of the knee. Its surgical management has been using a soft tissue graft as a replacement. The results of ACL reconstruction have been successful for many patients as it can restore joint stability and relieve pain. However, longer term follow up studies have shown unsatisfactory outcomes with as many as 25% of patients having complications that include prevalence of osteoarthritis. With the advances in tissue engineering and regeneration, there is a renewed interest in healing an injured ACL in order to preserve its complex anatomy and proprioceptive responses of the native ACL. Biotherapies including microfracture have been used clinically for healing of an injured ACL. In animal studies, the use of hyaluronic acid, mesenchymal stem cells, platelet-rich plasma, and extracellular matrix bioscaffolds have also resulted in neo-tissue formation to a varying degree. In general, the ACL heal rate is slow and the lack of loading to the healing ACL has deleterious effects on its attachments to bone. Thus, in our research center, mechanical augmentation that could maintain joint stability while simultaneously loading the healing ACL has been used in combination with biological augmentation to incite more robust tissue healing. Using a goat model, the ACL was found to be well healed at 12 weeks. Robotic measurements revealed good stifle joint stability while the tensile strength of the healing ACL was 3 times greater than suture repair and 1.8 times greater than ACL reconstruction. For the future, novel biotherapies, together with precision medicine that is “big data” based, in combination with mechanical augmentation will be explored for human application. In the end, surgeons will be able to tailor biotherapies to heal the ACL on selected patients for more positive outcomes in the long term.

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References

  1. Beynnon BD, Johnson RJ, Abate JA, Fleming BC, Nichols CE. Treatment of anterior cruciate ligament injuries, part I. Am J Sports Med. 2005;33(10):1579–602.

    Article  PubMed  Google Scholar 

  2. Feagin JA, Pierce CM, Geyer MR. ACL primary repair: what we did, the results, and how it helps today to tailor treatments to the patient and the pathology. In: Sanchis-Alfonso V, Monllau JC, editors. The ACL-deficient knee. London: Springer; 2013. p. 97–104.

    Chapter  Google Scholar 

  3. Sandberg R, Balkfors B, Nilsson B, Westlin N. Operative versus nonoperative treatment of recent injuries to the ligaments of the knee—a prospective randomized study. J Bone Joint Surg Am. 1987;69A(8):1120–6.

    Article  Google Scholar 

  4. Taylor DC, Posner M, Curl WW, Feagin JA. Isolated tears of the anterior cruciate ligament over 30-year follow-up of patients treated with arthrotomy and primary repair. Am J Sports Med. 2009;37(1):65–71.

    Article  PubMed  Google Scholar 

  5. Engebretsen L, Benum P, Fasting O, Mølster A, Strand T. A prospective, randomized study of three surgical techniques for treatment of acute ruptures of the anterior cruciate ligament. Am J Sports Med. 1990;18(6):585–90.

    Article  CAS  PubMed  Google Scholar 

  6. Pinczewski LA, Lyman J, Salmon LJ, Russell VJ, Roe J, Linklater J. A 10-year comparison of anterior cruciate ligament reconstructions with hamstring tendon and patellar tendon autograft—a controlled, prospective trial. Am J Sports Med. 2007;35(4):564–74.

    Article  PubMed  Google Scholar 

  7. Salmon LJ, Russell VJ, Refshauge K, Kader D, Connolly C, Linklater J, Pinczewski LA. Long-term outcome of endoscopic anterior cruciate ligament reconstruction with patellar tendon autograft—minimum 13-year review. Am J Sports Med. 2006;34(5):721–32.

    Article  PubMed  Google Scholar 

  8. 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(3):269–73.

    Article  Google Scholar 

  9. Steadman JR, Matheny LM, Briggs KK, Rodkey WG, Carreira DS. Outcomes following healing response in older, active patients: a primary anterior cruciate ligament repair technique. J Knee Surg. 2012;25(03):255–60.

    Article  PubMed  Google Scholar 

  10. Fisher MB, Liang R, Jung H-J, Kim KE, Zamarra G, Almarza AJ, McMahon PJ, Woo SL. Potential of healing a transected anterior cruciate ligament with genetically modified extracellular matrix bioscaffolds in a goat model. Knee Surg Sports Traumatol Arthrosc. 2012;20(7):1357–65.

    Article  PubMed  Google Scholar 

  11. Kanaya A, Deie M, Adachi N, Nishimori M, Yanada S, Ochi M. Intra-articular injection of mesenchymal stromal cells in partially torn anterior cruciate ligaments in a rat model. Arthroscopy. 2007;23(6):610–7.

    Article  PubMed  Google Scholar 

  12. Kimura Y, Hokugo A, Takamoto T, Tabata Y, Kurosawa H. Regeneration of anterior cruciate ligament by biodegradable scaffold combined with local controlled release of basic fibroblast growth factor and collagen wrapping. Tissue Eng Pt C Methods. 2008;14(1):47–57.

    Article  CAS  Google Scholar 

  13. Kobayashi D, Kurosaka M, Yoshiya S, Mizuno K. Effect of basic fibroblast growth factor on the healing of defects in the canine anterior cruciate ligament. Knee Surg Sports Traumatol Arthrosc. 1997;5(3):189–94.

    Article  CAS  PubMed  Google Scholar 

  14. 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(8):1007–17.

    Article  CAS  PubMed  Google Scholar 

  15. Wiig ME, Amiel D, Vandeberg J, Kitabayashi L, Harwood FL, Arfors KE. The early effect of high molecular weight hyaluronan (hyaluronic acid) on anterior cruciate ligament healing: an experimental study in rabbits. J Orthop Res. 1990;8(3):425–34.

    Article  CAS  PubMed  Google Scholar 

  16. Gobbi A, Bathan L, Boldrini L. Primary repair combined with bone marrow stimulation in acute anterior cruciate ligament lesions results in a group of athletes. Am J Sports Med. 2009;37(3):571–8.

    Article  PubMed  Google Scholar 

  17. Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials. 2003;24(24):4337–51.

    Article  CAS  PubMed  Google Scholar 

  18. Badylak SF, Freytes DO, Gilbert TW. Extracellular matrix as a biological scaffold material: structure and function. Acta Biomater. 2009;5(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  19. Nair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog Polym Sci. 2007;32(8–9):762–98.

    Article  CAS  Google Scholar 

  20. Lazarus HM, Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant. 1995;16(4):557–64.

    CAS  PubMed  Google Scholar 

  21. Watanabe N, Woo SL, Papageorgiou C, Celechovsky C, Takai S. Fate of donor bone marrow cells in medial collateral ligament after simulated autologous transplantation. Microsc Res Tech. 2002;58(1):39–44.

    Article  PubMed  Google Scholar 

  22. Hildebrand KA, Woo SL, Smith DW, Allen CR, Deie M, Taylor BJ, Schmidt CC. The effects of platelet-derived growth factor-BB on healing of the rabbit medial collateral ligament an in vivo study. Am J Sports Med. 1998;26(4):549–54.

    Google Scholar 

  23. Marui T, Niyibizi C, Georgescu HI, Cao M, Kavalkovich KW, Levine RE, Woo SLY. Effect of growth factors on matrix synthesis by ligament fibroblasts. J Orthop Res. 1997;15(1):18–23.

    Article  CAS  PubMed  Google Scholar 

  24. Woo SLY, Smith DW, Hildebrand KA, Zeminski JA, Johnson LA. Engineering the healing of the rabbit medial collateral ligament. Med Biol Eng Comput. 1998;36(3):359–64.

    Article  CAS  PubMed  Google Scholar 

  25. Musahl V, Abramowitch SD, Gilbert TW, Tsuda E, Wang JHC, Badylak SF, Woo SLY. The use of porcine small intestinal submucosa to enhance the healing of the medial collateral ligament—a functional tissue engineering study in rabbits. J Orthop Res. 2004;22(1):214–20.

    Article  PubMed  Google Scholar 

  26. Liang R, Woo SL, Takakura Y, Moon DK, Jia F, Abramowitch SD. Long-term effects of porcine small intestine submucosa on the healing of medial collateral ligament: a functional tissue engineering study. J Orthop Res. 2006;24(4):811–9.

    Article  PubMed  Google Scholar 

  27. Liang R, Woo SL, Nguyen TD, Liu PC, Almarza A. Effects of a bioscaffold on collagen fibrillogenesis in healing medial collateral ligament in rabbits. J Orthop Res. 2008;26(8):1098–104.

    Article  CAS  PubMed  Google Scholar 

  28. Karaoglu S, B Fisher M, Woo SL, Fu YC, Liang R, Abramowitch SD. Use of a bioscaffold to improve healing of a patellar tendon defect after graft harvest for ACL reconstruction: a study in rabbits. J Orthop Res. 2008;26(2):255–63.

    Article  PubMed  Google Scholar 

  29. Woo SL, Fox RJ, Sakane M, Livesay GA, Rudy TW, Fu FH. Biomechanics of the ACL: measurements of in situ force in the ACL and knee kinematics. Knee. 1998;5(4):267–88.

    Article  Google Scholar 

  30. Hollis JM, Takai S, Adams DJ, Horibe S, Woo SLY. The effects of knee motion and external loading on the length of the anterior cruciate ligament (Acl)—a kinematic study. J Biomech Eng. 1991;113(2):208–14.

    Article  CAS  PubMed  Google Scholar 

  31. Inoue M, McGurk-Burleson E, Hollis JM, Woo SL-Y. Treatment of the medial collateral ligament injury I: the importance of anterior cruciate ligament on the varus-valgus knee laxity. Am J Sports Med. 1987;15(1):15–21.

    Article  CAS  PubMed  Google Scholar 

  32. Rudy TW, Livesay GA, Woo SL-Y, Fu FH. A combined robotic/universal force sensor approach to determine in situ forces of knee ligaments. J Biomech. 1996;29(10):1357–60.

    Article  CAS  PubMed  Google Scholar 

  33. Livesay GA, Fujie H, Kashiwaguchi S, Morrow DA, Fu FH, Woo SL-Y. Determination of the in-situ forces and force distribution within the human anterior cruciate ligament. Ann Biomed Eng. 1995;23(4):467–74.

    Article  CAS  PubMed  Google Scholar 

  34. Woo SLY, Kanamori A, Zeminski J, Yagi M, Papageorgiou C, Fu FH. The effectiveness of reconstruction of the anterior cruciate ligament with hamstrings and patellar tendon—a cadaveric study comparing anterior tibial and rotational loads. J Bone Joint Surg Am. 2002;84A(6):907–14.

    Article  Google Scholar 

  35. Sasaki N, Farraro KF, Kim KE, Woo SL. Biomechanical evaluation of the quadriceps tendon autograft for anterior cruciate ligament reconstruction: a cadaveric study. Am J Sports Med. 2014;42(3):723–30.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Livesay GA, Rudy TW, Woo SLY, Runco TJ, Sakane M, Li G, Fu FH. Evaluation of the effect of joint constraints on the in situ force distribution in the anterior cruciate ligament. J Orthop Res. 1997;15(2):278–84.

    Article  CAS  PubMed  Google Scholar 

  37. Allen CR, Wong EK, Livesay GA, Sakane M, Fu FH, Woo SLY. Importance of the medial meniscus in the anterior cruciate ligament-deficient knee. J Orthop Res. 2000;18(1):109–15.

    Article  CAS  PubMed  Google Scholar 

  38. Papageorgiou CD, Gil JE, Kanamori A, Fenwick JA, Woo SL-Y, Fu FH. The biomechanical interdependence between the anterior cruciate ligament replacement graft and the medial meniscus. Am J Sports Med. 2001;29(2):226–31.

    CAS  PubMed  Google Scholar 

  39. Murray MM, Spindler KP, Abreu E, Muller JA, Nedder A, Kelly M, Frino J, Zurakowski D, Valenza M, Snyder BD. Collagen-platelet rich plasma hydrogel enhances primary repair of the porcine anterior cruciate ligament. J Orthop Res. 2007;25(1):81–91.

    Article  PubMed  Google Scholar 

  40. Joshi SM, Mastrangelo AN, Magarian EM, Fleming BC, Murray MM. Collagen-platelet composite enhances biomechanical and histologic healing of the porcine anterior cruciate ligament. Am J Sports Med. 2009;37(12):2401–10.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Abramowitch SD, Papageorgiou CD, Withrow JD, Gilbert TW, Woo SLY. The effect of initial graft tension on the biomechanical properties of a healing ACL replacement graft: a study in goats. J Orthop Res. 2003;21(4):708–15.

    Article  PubMed  Google Scholar 

  42. Ng GY, Oakes BW, Deacon OW, McLean ID, Lampard D. Biomechanics of patellar tendon autograft for reconstruction of the anterior cruciate ligament in the goat: three-year study. J Orthop Res. 1995;13(4):602–8.

    Article  CAS  PubMed  Google Scholar 

  43. Papageorgiou CD, Ma CB, Abramowitch SD, Clineff TD, Woo SL. A multidisciplinary study of the healing of an intraarticular anterior cruciate ligament graft in a goat model. Am J Sports Med. 2001;29(5):620–6.

    CAS  PubMed  Google Scholar 

  44. Musahl V, Abramowitch SD, Gabriel MT, Debski RE, Hertel P, Fu FH, Woo SL. Tensile properties of an anterior cruciate ligament graft after bone-patellar tendon-bone press-fit fixation. Knee Surg Sports Traumatol Arthrosc. 2003;11(2):68–74.

    Article  PubMed  Google Scholar 

  45. Nguyen DT, Dellbrügge S, Tak PP, Woo SL, Blankevoort L, van Dijk NC. Histological characteristics of ligament healing after bio-enhanced repair of the transected goat ACL. J Exp Orthop. 2015;2(1):1.

    Article  CAS  Google Scholar 

  46. Nguyen DT, Geel J, Schulze M, Raschke MJ, Woo SL, van Dijk CN, Blankevoort L. Healing of the goat anterior cruciate ligament after a new suture repair technique and bioscaffold treatment. Tissue Eng Part A. 2013;19(19–20):2292–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fleming BC, Carey JL, Spindler KP, Murray MM. Can suture repair of ACL transection restore normal anteroposterior laxity of the knee? An ex vivo study. J Orthop Res. 2008;26(11):1500–5.

    Google Scholar 

  48. Fisher MB, Jung HJ, McMahon PJ, Woo SL-Y. Evaluation of bone tunnel placement for suture augmentation of an injured anterior cruciate ligament: effects on joint stability in a goat model. J Orthop Res. 2010;28(10):1373–9.

    Article  PubMed  Google Scholar 

  49. Fisher MB, Jung HJ, McMahon PJ, Woo SL-Y. Suture augmentation following ACL injury to restore the function of the ACL, MCL, and medial meniscus in the goat stifle joint. J Biomech. 2011;44(8):1530–5.

    Article  PubMed  Google Scholar 

  50. Fisher MB, Kim KE, Jung H-J, McMahon PJ, Woo SL-Y. Mechanical augmentation using sutures to stimulate healing of the ACL in the goat model. International Symposium on Ligaments and Tendons—XI:42; 2011.

    Google Scholar 

  51. Farraro KF, Sasaki N, Woo SLY, Kim KE, Tei MM, Speziali A, McMahon PJ. Magnesium ring device to restore function of a transected anterior cruciate ligament in the goat stifle joint. J Orthop Res. 2016;34(11):2001–8.

    Article  CAS  PubMed  Google Scholar 

  52. Kathryn F. Farraro AP, JR Mau, SL-Y Woo (2016) A novel magnesium ring device can enhance anterior cruciate ligament healing. Paper presented at the Orthopaedic Reseach Society Annual Meeting, Orlando, Florida.

    Google Scholar 

  53. Farraro KF, Kim KE, Woo SL, Flowers JR, McCullough MB. Revolutionizing orthopaedic biomaterials: the potential of biodegradable and bioresorbable magnesium-based materials for functional tissue engineering. J Biomech. 2014;47(9):1979–86.

    Article  PubMed  Google Scholar 

  54. Song Y, Debski RE, Musahl V, Thomas M, Woo SLY. A three-dimensional finite element model of the human anterior cruciate ligament: a computational analysis with experimental validation. J Biomech. 2004;37(3):383–90.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Musculoskeletal Research Center, Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, 405 Center for Bioengineering, 300 Technology Drive, Pittsburgh, PA, 15219, USA

    Jonquil R. Mau, Huizhi Wang & Savio L-Y. Woo PhD, DSc (Hon), D. Eng (Hon)

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  1. Jonquil R. Mau
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  2. Huizhi Wang
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  3. Savio L-Y. Woo PhD, DSc (Hon), D. Eng (Hon)
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Correspondence to Savio L-Y. Woo PhD, DSc (Hon), D. Eng (Hon) .

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Editors and Affiliations

  1. O.A.S.I. Bioresearch Foundation NPO, Milan, Italy

    Alberto Gobbi

  2. Clínica do Dragão, Espregueira-Mendes Sports Centre – FIFA Medical Centre of Excellence, Porto, Portugal

    João Espregueira-Mendes

  3. Musculoskeletal and Joint Research Foundation, San Diego, California, USA

    John G. Lane

  4. Department of Orthopedics, Acibadem University, Istanbul, Turkey

    Mustafa Karahan

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Mau, J.R., Wang, H., Woo, S.LY. (2017). The Use of a Large Animal Model and Robotic Technology to Validate New Biotherapies for ACL Healing. In: Gobbi, A., Espregueira-Mendes, J., Lane, J., Karahan, M. (eds) Bio-orthopaedics. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-54181-4_15

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  • DOI: https://doi.org/10.1007/978-3-662-54181-4_15

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