Outcome Assessment for ACL Tissue Engineering

  • Patrick Vavken
  • Martha M. Murray
  • Braden C. Fleming


Outcome assessment measures, directly or indirectly, how well a medical treatment functions. For clinical treatments this is measured by measuring safety (i.e., the rate of complications) and effectiveness (i.e., resolution of pain or improvement in function). For basic science, outcome assessment often means objectively quantifying cellular behavior and characteristics and other laboratory measurements. When developing tissue engineering treatments for improving outcomes following ACL injury, evaluation of the tissue-engineered structure is necessary to optimize the treatment, too. These evaluations prove that the method will be safe and efficacious and demonstrate that the alternative treatment is better than the gold standard, in our case, ACL reconstruction with an autograft. When translating any new technology from benchtop (lab) to the bedside (clinic), in vitro (petri dish) studies and preclinical models are first required to validate the concept and to prove that it is likely to be efficacious, prior to initiating a clinical trial in humans. This chapter briefly highlights some of the outcome measures that are important at all three levels: in vitro, preclinical, and clinical studies.


Failure Load Preclinical Model Gait Analysis Pivot Shift Knee Laxity 
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-AR047910, 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.
    Nightingale F. Notes on nursing: what nursing is, what nursing is not. London: Harrison & Sons; 1859.Google Scholar
  2. 2.
    Nightingale F. Report on Medical Care. British National Archives (WO 33/1 ff. 119, 124, 146-147. Dated 1855-02-23.Google Scholar
  3. 3.
    Codman E. A study in hospital efficiency. Boston: Privately Printed; 1916.Google Scholar
  4. 4.
    Ellwood PM. Shattuck lecture – outcomes management. A technology of patient experience. N Engl J Med. 1988;318(23):1549–56.PubMedCrossRefGoogle Scholar
  5. 5.
    Montero C. The antigen-antibody reaction in immunohistochemistry. J Histochem Cytochem. 2003;51(1):1–4.PubMedCrossRefGoogle Scholar
  6. 6.
    Pettigrew NM. Techniques in immunocytochemistry. Application to diagnostic pathology. Arch Pathol Lab Med. 1989;113(6):641–4.PubMedGoogle Scholar
  7. 7.
    Swanson PE. Foundations of immunohistochemistry. A practical review. Am J Clin Pathol. 1988;90(3):333–9.PubMedGoogle Scholar
  8. 8.
    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.PubMedCrossRefGoogle Scholar
  9. 9.
    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(12):2401–10.PubMedCrossRefGoogle Scholar
  10. 10.
    Mullaji AB, Marawar SV, Luthra M. Tibial articular cartilage wear in varus osteoarthritic knees: correlation with anterior cruciate ligament integrity and severity of deformity. J Arthroplasty. 2008;23(1):128–35.PubMedCrossRefGoogle Scholar
  11. 11.
    Bej AK, Mahbubani MH, Atlas RM. Amplification of nucleic acids by polymerase chain reaction (PCR) and other methods and their applications. Crit Rev Biochem Mol Biol. 1991;26(3–4):301–34.PubMedCrossRefGoogle Scholar
  12. 12.
    Gyllensten UB. PCR and DNA sequencing. Biotechniques. 1989;7(7):700–8.PubMedGoogle Scholar
  13. 13.
    Kroczek RA. Southern and northern analysis. J Chromatogr. 1993;618(1–2):133–45.PubMedGoogle Scholar
  14. 14.
    Wirth PJ, Romano A. Staining methods in gel electrophoresis, including the use of multiple detection methods. J Chromatogr A. 1995;698(1–2):123–43.PubMedGoogle Scholar
  15. 15.
    Zewert TE, Harrington MG. Protein electrophoresis. Curr Opin Biotechnol. 1993;4(1):3–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Kramer DB, Xu S, Kesselheim AS. Regulation of medical devices in the United States and European Union. N Engl J Med. 2012;366(9):848–55.PubMedCrossRefGoogle Scholar
  17. 17.
    Zywiel MG, Mont MA. Orthopedic implant approval: achieving the right balance. Expert Rev Med Devices. 2011;8(4):405–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Butler DL, Lewis JL, Frank CB, et al. Evaluation criteria for musculoskeletal and craniofacial tissue engineering constructs: a conference report. Tissue Eng Part A. 2008; 14(12):2089–104.CrossRefGoogle Scholar
  19. 19.
    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(8):1554–63.PubMedCrossRefGoogle Scholar
  20. 20.
    Fleming BC, Magarian EM, Harrison SL, Paller DJ, Murray MM. Collagen scaffold supplementation does not improve the functional properties of the repaired anterior cruciate ligament. J Orthop Res. 2010;28(5):703–9.PubMedGoogle Scholar
  21. 21.
    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(3):217–25.PubMedCrossRefGoogle Scholar
  22. 22.
    Butler DL, Dressler MR, Awad H. Functional tissue engineering: assessment of function in tendon and ligament repair. In: Guilak F, Butler DL, Goldstein SA, Mooney DJ, editors. Functional tissue engineering. New York: Springer; 2003. p. 213–26.CrossRefGoogle Scholar
  23. 23.
    Hashemi J, Mansouri H, Chandrashekar N, Slauterbeck JR, Hardy DM, Beynnon BD. Age, sex, body anthropometry, and ACL size predict the structural properties of the human anterior cruciate ligament. J Orthop Res. 2011;29(7):993–1001.PubMedCrossRefGoogle Scholar
  24. 24.
    Fleming BC, Vajapeyam S, Connolly SA, Magarian EM, Murray MM. The use of magnetic resonance imaging to predict ACL graft structural properties. J Biomech. 2011;44(16): 2843–6.PubMedCrossRefGoogle Scholar
  25. 25.
    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(6):751–61.PubMedGoogle Scholar
  26. 26.
    Saupe N, White LM, Chiavaras MM, et al. Anterior cruciate ligament reconstruction grafts: MR imaging features at long-term follow-up – correlation with functional and clinical evaluation. Radiology. 2008;249(2):581–90.PubMedCrossRefGoogle Scholar
  27. 27.
    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(10):1318–25.PubMedCrossRefGoogle Scholar
  28. 28.
    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(1):50–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Howell SM, Clark JA, Blasier RD. Serial magnetic resonance imaging of hamstring anterior cruciate ligament autografts during the first year of implantation. A preliminary study. Am J Sports Med. 1991;19(1):42–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Daniel DM, Malcom LL, Losse GM, Stone ML, Sachs R, Burks RT. Instrumented measurement of anterior laxity of the knee. J Bone Joint Surg Am. 1985;67(5):720–6.PubMedGoogle Scholar
  31. 31.
    Almekinders LC, Pandarinath R, Rahusen FT. Knee stability following anterior cruciate ligament rupture and surgery. The contribution of irreducible tibial subluxation. J Bone Joint Surg Am. 2004;86(5):983–7.PubMedGoogle Scholar
  32. 32.
    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(6):878–85.PubMedCrossRefGoogle Scholar
  33. 33.
    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(6):812–20.PubMedCrossRefGoogle Scholar
  34. 34.
    Murray MM et al. 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.CrossRefGoogle Scholar
  35. 35.
    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;26:1500–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Cummings JF, Grood ES. The progression of anterior translation after anterior cruciate ligament reconstruction in a caprine model. J Orthop Res. 2002;20(5):1003–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Tapper JE, Fukushima S, Azuma H, et al. Dynamic in vivo three-dimensional (3D) kinematics of the anterior cruciate ligament/medial collateral ligament transected ovine stifle joint. J Orthop Res. 2008;26:660–72.PubMedCrossRefGoogle Scholar
  38. 38.
    Tashman S, Anderst W, Kolowich P, Havstad S, Arnoczky S. Kinematics of the ACL-deficient canine knee during gait: serial changes over two years. J Orthop Res. 2004;22(5):931–41.PubMedCrossRefGoogle Scholar
  39. 39.
    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
  40. 40.
    Frank CB, Beveridge JE, Huebner KD, et al. Complete ACL/MCL deficiency induces variable degrees of instability in sheep with specific kinematic abnormalities correlating with degrees of early osteoarthritis. J Orthop Res. 2012;30(3):384–92.PubMedCrossRefGoogle Scholar
  41. 41.
    Ware JE, Gandek B. Overview of the SF-36 health survey and the international quality of life assessment (IQOLA) project. J Clin Epidemiol. 1998;51(11):903–12.PubMedCrossRefGoogle Scholar
  42. 42.
    Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Medical Care. 1992;30(6):473–83.PubMedCrossRefGoogle Scholar
  43. 43.
    Mohan H, Ryan J, Whelan B, Wakai A. The end of the line? The Visual Analogue Scale and Verbal Numerical Rating Scale as pain assessment tools in the emergency department. Emerg Med J. 2010;27(5):372–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Scrimshaw SV, Maher C. Responsiveness of visual analogue and McGill pain scale measures. J Manipulative Physiol Ther. 2001;24(8):501–4.PubMedCrossRefGoogle Scholar
  45. 45.
    Katz JW, Fingeroth RJ. The diagnostic accuracy of ruptures of the anterior cruciate ligament comparing the Lachman test, the anterior drawer sign, and the pivot shift test in acute and chronic knee injuries. Am J Sports Med. 1986;14(1):88–91.PubMedCrossRefGoogle Scholar
  46. 46.
    Muellner T, Bugge W, Johansen S, Holtan C, Engebretsen L. Inter- and intratester comparison of the Rolimeter knee tester: effect of tester’s experience and the examination technique. Knee. 2001;9(5):302–6.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Patrick Vavken
    • 1
  • Martha M. Murray
    • 2
  • Braden C. Fleming
    • 3
  1. 1.Department of Orthopedic SurgeryBoston Children’s Hospital, Harvard Medical SchoolBostonUSA
  2. 2.Department of Orthopedic Surgery, Division of Sports MedicineBoston Children’s Hospital, Harvard Medical SchoolBostonUSA
  3. 3.Department of OrthopedicsWarren Alpert Medical School of Brown University/Rhode Island HospitalProvidenceUSA

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