Functional Tissue Engineering of the Healing Anterior Cruciate Ligament: A Combined Experimental and Computational Approach

The anterior cruciate ligament (ACL) is the most important knee stabilizer and is frequently injured during sports and work related activities. Unfortunately, midsubstance ACL ruptures have a limited healing capacity. As such, surgical reconstruction using soft tissue autografts is often performed. However, long-term follow-up studies have revealed that 20-25% of patients had a less than satisfactory outcome. These negative results have renewed clinical interests in healing of a torn ACL by means of biological stimulation. Thus, there is a need for basic science studies in order to better understand such an approach and also to logically develop an effective functional tissue engineering (FTE) treatment for an injured ACL.

The overall objective of this dissertation was to evaluate the positive impact of biological and mechanical augmentation on the healing of the ACL using a combined experimental and computational approach. The ability of an extracellular matrix (ECM) bioscaffold in combination with an ECM hydrogel to enhance ACL healing following suture repair was first demonstrated in the goat model. At 12 weeks of healing, ECM-treatment led to an increase in neo-tissue formation as well as improved biomechanical properties of the healing ACL compared to suture repair alone. Second, as the healing process of the ACL was relatively slow even with ECM treatment, mechanical augmentation to better restore initial joint stability was required. Therefore, a suture augmentation procedure was developed, and improved joint function was achieved versus suture repair alone at the time of surgery. Further, there was increased tissue formation and improved biomechanical properties of the healing ACL at 12 weeks of healing. Finally, as a step toward predicting long-term outcomes following these biological and mechanical augmentation procedures, a preliminary mathematical model was developed to describe the remodeling process of healing ligaments. The results of this work can now be used to guide future experiments using FTE treatments to enhance ACL healing. With a sound scientific basis, it is hoped that such exciting new technologies could then be translated into the clinical arena to improve patient outcome following ACL injuries.

Year	Entry
1998	Young RG, Butler DL, Weber W, Caplan AI, Gordon SL, Fink DJ. Use of mesenchymal stem cells in a collagen matrix for achilles tendon repair. J Orthop Res. July 1998;16(4):406-413.
1996	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. October 1996;29(10):1357-1360.
1983	Lanir Y. Constitutive equations for fibrous connective tissues. J Biomech. 1983;16(1):1-12.
1986	Woo SL-Y, Orlando CA, Camp JF, Akeson WH. Effects of postmortem storage by freezing on ligament tensile behavior. J Biomech. 1986;19(5):399-404.
2003	Elliott DM, Robinson PS, Gimbel JA, Sarver JJ, Abboud JA, Iozzo RV, Soslowsky LJ. Effect of altered matrix proteins on quasilinear viscoelastic properties in transgenic mouse tail tendons. Ann Biomed Eng. May 2003;31(5):599-605.
1987	Woo SL-Y, Inoue M, McGurk-Burleson E, Gomez MA. Treatment of the medial collateral ligament injury, II: structure and function of canine knees in response to differing treatment regimens. Am J Sports Med. January–February 1987;15(1):22-29.
1994	Holden JP, Grood ES, Korvick DL, Cummings JF, Butler DL, Bylski-Austrow DI. In vivo forces in the anterior cruciate ligament: direct measurements during walking and trotting in a quadruped. J Biomech. May 1994;27(5):517-526.
1981	Woo SL-Y, Gomez MA, Amiel D, Ritter MA, Gelberman RH, Akeson WH. The effects of exercise on the biomechanical and biochemical properties of swine digital flexor tendons. J Biomech Eng. February 1981;103(1):51-56.
2007	Faul F, Erdfelder E, Lang A-G, Buchner A. GPower 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods*. May 2007;39(2):175-191.
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1983	Frank C, Woo SL-Y, Amiel D, Harwood F, Gomez M, Akeson W. Medial collateral ligament healing: a multidisciplinary assessment in rabbits. Am J Sports Med. 1983;11(6):379-389.
1991	Weiss JA, Woo SL-Y, Ohland KJ, Horibe S, Newton PO. Evaluation of a new injury model to study medial collateral ligament healing: primary repair versus nonoperative treatment. J Orthop Res. July 1991;9(4):516-528.
1997	Hurschler C, Loitz-Ramage B, Vanderby R Jr. A structurally based stress-stretch relationship for tendon and ligament. J Biomech Eng. November 1997;119(4):392-399.
1994	Daniel DM, Stone ML, Dobson BE, Fithian DC, Rossman DJ, Kaufman KR. Fate of the ACL-injured patient: a prospective outcome study. Am J Sports Med. September–October 1994;22(5):632-644.
1993	Fung YC. Biomechanics: Mechanical Properties of Living Tissues. 2nd ed. New York, NY: Springer-Verlag; 1993.
2004	Song Y, Debski RE, Musahl V, Thomas M, Woo SL-Y. A three-dimensional finite element model of the human anterior cruciate ligament: a computational analysis with experimental validation. J Biomech. March 2004;37(3):383-390.
1988	Lee TQ, Woo SL-Y. A new method for determining cross-sectional shape and area of soft tissues. J Biomech Eng. May 1988;110(2):110-114.
2004	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. March 2004;63(3):269-273.
1982	Woo SL-Y, Gomez MA, Woo Y-K, Akeson WH. Mechanical properties of tendons and ligaments, II: the relationships of immobilization and exercise on tissue remodeling. Biorheology. 1982;19(3):397-408.
1990	Woo SL-Y, Peterson RH, Ohland KJ, Sites TJ, Danto MI. The effects of strain rate on the properties of the medial collateral ligament in skeletally immature and mature rabbits: a biomechanical and histological study. J Orthop Res. September 1990;8(5):712-721.
1997	Frank C, McDonald D, Shrive N. Collagen fibril diameters in the rabbit medial collateral ligament scar: a longer term assessment. Connect Tissue Res. 1997;36(3):261-269.

Year

Entry

1998

Young RG, Butler DL, Weber W, Caplan AI, Gordon SL, Fink DJ. Use of mesenchymal stem cells in a collagen matrix for achilles tendon repair. J Orthop Res. July 1998;16(4):406-413.

1996

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. October 1996;29(10):1357-1360.

1983

Lanir Y. Constitutive equations for fibrous connective tissues. J Biomech. 1983;16(1):1-12.

1986

Woo SL-Y, Orlando CA, Camp JF, Akeson WH. Effects of postmortem storage by freezing on ligament tensile behavior. J Biomech. 1986;19(5):399-404.

2003

Elliott DM, Robinson PS, Gimbel JA, Sarver JJ, Abboud JA, Iozzo RV, Soslowsky LJ. Effect of altered matrix proteins on quasilinear viscoelastic properties in transgenic mouse tail tendons. Ann Biomed Eng. May 2003;31(5):599-605.