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Published in: Knee Surgery, Sports Traumatology, Arthroscopy 7/2012

01-07-2012 | Experimental Study

Potential of healing a transected anterior cruciate ligament with genetically modified extracellular matrix bioscaffolds in a goat model

Authors: Matthew B. Fisher, Rui Liang, Ho-Joong Jung, Kwang E. Kim, Giovanni Zamarra, Alejandro J. Almarza, Patrick J. McMahon, Savio L-Y. Woo

Published in: Knee Surgery, Sports Traumatology, Arthroscopy | Issue 7/2012

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Abstract

Purpose

Biological augmentation to heal a torn anterior cruciate ligament (ACL) has gained significant interest. This study examined the potential advantages of using extracellular matrix (ECM) bioscaffolds from galactosyl-α(1,3)galactose deficient pigs to heal the transected ACL.

Methods

In 16 skeletally mature goats, the ACL in the right hindlimb was transected and repaired. In 9 of these animals, an ECM sheet was wrapped around the injury site and with an ECM hydrogel injected into the transected site. The remaining 7 animals were treated with suture repair only. The left hindlimb served as a sham-operated control.

Results

After 12 weeks, the healing ACL in the ECM-treated group showed an abundance of continuous neo-tissue formation, while only limited tissue growth was found after suture repair only. The cross-sectional area of the ACL from the ECM-treated group was similar to sham-operated controls (n.s.) and was 4.5 times those of the suture repair group (P < 0.05). The stiffness of the femur-ACL-tibia complexes from the ECM-treated group was 2.4 times those of the suture repair group (P < 0.05). Furthermore, these values reached 48% of the sham-operated controls (53 ± 19 N/mm and 112 ± 21 N/mm, respectively, P < 0.05).

Conclusions

The application of an ECM bioscaffold and hydrogel was found to accelerate the healing of a transected ACL following suture repair in the goat model with limited tissue hypertrophy and improvement in some of its biomechanical properties. Although more work is necessary to fully restore the function of the normal ACL, these early results offer a potential new approach to aid ACL healing.
Literature
1.
go back to reference Abramowitch SD, Papageorgiou CD, Withrow JD, Gilbert TW, Woo SL-Y (2003) The effect of initial graft tension on the biomechanical properties of a healing ACL replacement graft: a study in goats. J Orthop Res 21(4):708–715PubMedCrossRef Abramowitch SD, Papageorgiou CD, Withrow JD, Gilbert TW, Woo SL-Y (2003) The effect of initial graft tension on the biomechanical properties of a healing ACL replacement graft: a study in goats. J Orthop Res 21(4):708–715PubMedCrossRef
2.
go back to reference Agung M, Ochi M, Yanada S et al (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(12):1307–1314PubMedCrossRef Agung M, Ochi M, Yanada S et al (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(12):1307–1314PubMedCrossRef
3.
go back to reference Anderson AF, Snyder RB, Lipscomb AB Jr (2001) Anterior cruciate ligament reconstruction. A prospective randomized study of three surgical methods. Am J Sports Med 29(3):272–279PubMed Anderson AF, Snyder RB, Lipscomb AB Jr (2001) Anterior cruciate ligament reconstruction. A prospective randomized study of three surgical methods. Am J Sports Med 29(3):272–279PubMed
4.
go back to reference Anitua E, Sanchez M, Orive G, Andia I (2007) The potential impact of the preparation rich in growth factors (PRGF) in different medical fields. Biomaterials 28(31):4551–4560PubMedCrossRef Anitua E, Sanchez M, Orive G, Andia I (2007) The potential impact of the preparation rich in growth factors (PRGF) in different medical fields. Biomaterials 28(31):4551–4560PubMedCrossRef
5.
go back to reference Badylak SF (2007) The extracellular matrix as a biologic scaffold material. Biomaterials 28(25):3587–3593PubMedCrossRef Badylak SF (2007) The extracellular matrix as a biologic scaffold material. Biomaterials 28(25):3587–3593PubMedCrossRef
6.
go back to reference Chen G, Qian H, Starzl T et al (2005) Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys. Nat Med 11(12):1295–1298PubMedCrossRef Chen G, Qian H, Starzl T et al (2005) Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys. Nat Med 11(12):1295–1298PubMedCrossRef
7.
go back to reference Cummings JF, Grood ES (2002) The progression of anterior translation after anterior cruciate ligament reconstruction in a caprine model. J Orthop Res 20(5):1003–1008PubMedCrossRef Cummings JF, Grood ES (2002) The progression of anterior translation after anterior cruciate ligament reconstruction in a caprine model. J Orthop Res 20(5):1003–1008PubMedCrossRef
8.
go back to reference Dai Y, Vaught TD, Boone J et al (2002) Targeted disruption of the alpha1,3-galactosyltransferase gene in cloned pigs. Nat Biotechnol 20(3):251–255PubMedCrossRef Dai Y, Vaught TD, Boone J et al (2002) Targeted disruption of the alpha1,3-galactosyltransferase gene in cloned pigs. Nat Biotechnol 20(3):251–255PubMedCrossRef
9.
go back to reference Drogset JO, Grontvedt T, Robak OR et al (2006) A 16-year follow-up of three operative techniques for the treatment of acute ruptures of the anterior cruciate ligament. J Bone Jt Surg Am 88(5):944–952CrossRef Drogset JO, Grontvedt T, Robak OR et al (2006) A 16-year follow-up of three operative techniques for the treatment of acute ruptures of the anterior cruciate ligament. J Bone Jt Surg Am 88(5):944–952CrossRef
10.
go back to reference Feagin JA Jr, Curl WW (1976) Isolated tear of the anterior cruciate ligament: 5-year follow-up study. Am J Sports Med 4(3):95–100PubMedCrossRef Feagin JA Jr, Curl WW (1976) Isolated tear of the anterior cruciate ligament: 5-year follow-up study. Am J Sports Med 4(3):95–100PubMedCrossRef
11.
go back to reference Fisher MB, Jung HJ, McMahon PJ, Woo SL-Y (2010) 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 28(10):1373–1379PubMedCrossRef Fisher MB, Jung HJ, McMahon PJ, Woo SL-Y (2010) 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 28(10):1373–1379PubMedCrossRef
12.
go back to reference Freytes DO, Martin J, Velankar SS, Lee AS, Badylak SF (2008) Preparation and rheological characterization of a gel form of the porcine urinary bladder matrix. Biomaterials 29(11):1630–1637PubMedCrossRef Freytes DO, Martin J, Velankar SS, Lee AS, Badylak SF (2008) Preparation and rheological characterization of a gel form of the porcine urinary bladder matrix. Biomaterials 29(11):1630–1637PubMedCrossRef
13.
go back to reference Gilbert TW, Stolz DB, Biancaniello F, Simmons-Byrd A, Badylak SF (2005) Production and characterization of ECM powder: implications for tissue engineering applications. Biomaterials 26(12):1431–1435PubMedCrossRef Gilbert TW, Stolz DB, Biancaniello F, Simmons-Byrd A, Badylak SF (2005) Production and characterization of ECM powder: implications for tissue engineering applications. Biomaterials 26(12):1431–1435PubMedCrossRef
14.
go back to reference Gobbi A, Bathan L, Boldrini L (2009) Primary repair combined with bone marrow stimulation in acute anterior cruciate ligament lesions: results in a group of athletes. Am J Sports Med 37(3):571–578PubMedCrossRef Gobbi A, Bathan L, Boldrini L (2009) Primary repair combined with bone marrow stimulation in acute anterior cruciate ligament lesions: results in a group of athletes. Am J Sports Med 37(3):571–578PubMedCrossRef
15.
go back to reference Iannotti JP, Codsi MJ, Kwon YW et al (2006) Porcine small intestine submucosa augmentation of surgical repair of chronic two-tendon rotator cuff tears. A randomized, controlled trial. J Bone Jt Surg Am 88(6):1238–1244CrossRef Iannotti JP, Codsi MJ, Kwon YW et al (2006) Porcine small intestine submucosa augmentation of surgical repair of chronic two-tendon rotator cuff tears. A randomized, controlled trial. J Bone Jt Surg Am 88(6):1238–1244CrossRef
16.
go back to reference Jomha NM, Borton DC, Clingeleffer AJ, Pinczewski LA (1999) Long-term osteoarthritic changes in anterior cruciate ligament reconstructed knees. Clin Orthop Relat Res 358:188–193PubMedCrossRef Jomha NM, Borton DC, Clingeleffer AJ, Pinczewski LA (1999) Long-term osteoarthritic changes in anterior cruciate ligament reconstructed knees. Clin Orthop Relat Res 358:188–193PubMedCrossRef
17.
go back to reference Joshi SM, Mastrangelo AN, Magarian EM, Fleming BC, Murray MM (2009) Collagen-platelet composite enhances biomechanical and histologic healing of the porcine anterior cruciate ligament. Am J Sports Med 37(12):2401–2410PubMedCrossRef Joshi SM, Mastrangelo AN, Magarian EM, Fleming BC, Murray MM (2009) Collagen-platelet composite enhances biomechanical and histologic healing of the porcine anterior cruciate ligament. Am J Sports Med 37(12):2401–2410PubMedCrossRef
18.
go back to reference Kaplan N, Wickiewicz TL, Warren RF (1990) Primary surgical treatment of anterior cruciate ligament ruptures. A long-term follow-up study. Am J Sports Med 18(4):354–358PubMedCrossRef Kaplan N, Wickiewicz TL, Warren RF (1990) Primary surgical treatment of anterior cruciate ligament ruptures. A long-term follow-up study. Am J Sports Med 18(4):354–358PubMedCrossRef
19.
go back to reference Karaoglu S, Fisher MB, Woo SL-Y et al (2008) 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 26(2):255–263PubMedCrossRef Karaoglu S, Fisher MB, Woo SL-Y et al (2008) 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 26(2):255–263PubMedCrossRef
20.
go back to reference Kuwaki K, Tseng YL, Dor FJ et al (2005) Heart transplantation in baboons using alpha1,3-galactosyltransferase gene-knockout pigs as donors: initial experience. Nat Med 11(1):29–31PubMedCrossRef Kuwaki K, Tseng YL, Dor FJ et al (2005) Heart transplantation in baboons using alpha1,3-galactosyltransferase gene-knockout pigs as donors: initial experience. Nat Med 11(1):29–31PubMedCrossRef
21.
go back to reference Lee TQ, Woo SL-Y (1988) A new method for determining cross-sectional shape and area of soft tissues. J Biomech Eng 110(2):110–114PubMedCrossRef Lee TQ, Woo SL-Y (1988) A new method for determining cross-sectional shape and area of soft tissues. J Biomech Eng 110(2):110–114PubMedCrossRef
22.
go back to reference Li G, Van de Velde SK, Bingham JT (2008) Validation of a non-invasive fluoroscopic imaging technique for the measurement of dynamic knee joint motion. J Biomech 41(7):1616–1622PubMedCrossRef Li G, Van de Velde SK, Bingham JT (2008) Validation of a non-invasive fluoroscopic imaging technique for the measurement of dynamic knee joint motion. J Biomech 41(7):1616–1622PubMedCrossRef
23.
go back to reference Liang R, Fisher M, Yang G, Hall C, Woo SL-Y (2011) Alpha1,3-galactosyltransferase knockout does not alter the properties of porcine extracellular matrix bioscaffolds. Acta Biomater 7(4):1719–1727PubMedCrossRef Liang R, Fisher M, Yang G, Hall C, Woo SL-Y (2011) Alpha1,3-galactosyltransferase knockout does not alter the properties of porcine extracellular matrix bioscaffolds. Acta Biomater 7(4):1719–1727PubMedCrossRef
24.
go back to reference Liang R, Woo SL-Y, Takakura Y et al (2006) Long-term effects of porcine small intestine submucosa on the healing of medial collateral ligament: a functional tissue engineering study. J Orthop Res 24(4):811–819PubMedCrossRef Liang R, Woo SL-Y, Takakura Y et al (2006) Long-term effects of porcine small intestine submucosa on the healing of medial collateral ligament: a functional tissue engineering study. J Orthop Res 24(4):811–819PubMedCrossRef
25.
go back to reference Livesay GA, Fujie H, Kashiwaguchi S et al (1995) Determination of the in situ forces and force distribution within the human anterior cruciate ligament. Ann Biomed Eng 23(4):467–474PubMedCrossRef Livesay GA, Fujie H, Kashiwaguchi S et al (1995) Determination of the in situ forces and force distribution within the human anterior cruciate ligament. Ann Biomed Eng 23(4):467–474PubMedCrossRef
26.
go back to reference Ma CB, Papageogiou CD, Debski RE, Woo SL-Y (2000) Interaction between the ACL graft and MCL in a combined ACL + MCL knee injury using a goat model. Acta Orthop Scand 71(4):387–393PubMedCrossRef Ma CB, Papageogiou CD, Debski RE, Woo SL-Y (2000) Interaction between the ACL graft and MCL in a combined ACL + MCL knee injury using a goat model. Acta Orthop Scand 71(4):387–393PubMedCrossRef
27.
go back to reference Malcarney HL, Bonar F, Murrell GA (2005) Early inflammatory reaction after rotator cuff repair with a porcine small intestine submucosal implant: a report of 4 cases. Am J Sports Med 33(6):907–911PubMedCrossRef Malcarney HL, Bonar F, Murrell GA (2005) Early inflammatory reaction after rotator cuff repair with a porcine small intestine submucosal implant: a report of 4 cases. Am J Sports Med 33(6):907–911PubMedCrossRef
28.
go back to reference Ng GY, Oakes BW, Deacon OW, McLean ID, Lampard D (1995) Biomechanics of patellar tendon autograft for reconstruction of the anterior cruciate ligament in the goat: 3-year study. J Orthop Res 13(4):602–608PubMedCrossRef Ng GY, Oakes BW, Deacon OW, McLean ID, Lampard D (1995) Biomechanics of patellar tendon autograft for reconstruction of the anterior cruciate ligament in the goat: 3-year study. J Orthop Res 13(4):602–608PubMedCrossRef
29.
go back to reference Papageorgiou CD, Gil JE, Kanamori A et al (2001) The biomechanical interdependence between the anterior cruciate ligament replacement graft and the medial meniscus. Am J Sports Med 29(2):226–231PubMed Papageorgiou CD, Gil JE, Kanamori A et al (2001) The biomechanical interdependence between the anterior cruciate ligament replacement graft and the medial meniscus. Am J Sports Med 29(2):226–231PubMed
30.
go back to reference Phelps CJ, Koike C, Vaught TD et al (2003) Production of alpha 1,3-galactosyltransferase-deficient pigs. Science 299(5605):411–414PubMedCrossRef Phelps CJ, Koike C, Vaught TD et al (2003) Production of alpha 1,3-galactosyltransferase-deficient pigs. Science 299(5605):411–414PubMedCrossRef
32.
go back to reference Sakane M, Livesay GA, Fox RJ et al (1999) Relative contribution of the ACL, MCL, and bony contact to the anterior stability of the knee. Knee Surg Sports Traumatol Arthrosc 7(2):93–97PubMedCrossRef Sakane M, Livesay GA, Fox RJ et al (1999) Relative contribution of the ACL, MCL, and bony contact to the anterior stability of the knee. Knee Surg Sports Traumatol Arthrosc 7(2):93–97PubMedCrossRef
33.
go back to reference Scherping SC Jr, Schmidt CC, Georgescu HI et al (1997) Effect of growth factors on the proliferation of ligament fibroblasts from skeletally mature rabbits. Connect Tiss Res 36(1):1–8CrossRef Scherping SC Jr, Schmidt CC, Georgescu HI et al (1997) Effect of growth factors on the proliferation of ligament fibroblasts from skeletally mature rabbits. Connect Tiss Res 36(1):1–8CrossRef
34.
go back to reference Spindler KP, Kuhn JE, Freedman KB et al (2004) Anterior cruciate ligament reconstruction autograft choice: bone-tendon-bone versus hamstring: does it really matter? A systematic review. Am J Sports Med 32(8):1986–1995PubMedCrossRef Spindler KP, Kuhn JE, Freedman KB et al (2004) Anterior cruciate ligament reconstruction autograft choice: bone-tendon-bone versus hamstring: does it really matter? A systematic review. Am J Sports Med 32(8):1986–1995PubMedCrossRef
35.
go back to reference 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):8–13PubMed 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):8–13PubMed
36.
go back to reference Torry MR, Shelburne KB, Peterson DS et al (2011) Knee kinematic profiles during drop landings: a biplane fluoroscopy study. Med Sci Sports Exerc 43(3):533–541PubMedCrossRef Torry MR, Shelburne KB, Peterson DS et al (2011) Knee kinematic profiles during drop landings: a biplane fluoroscopy study. Med Sci Sports Exerc 43(3):533–541PubMedCrossRef
37.
go back to reference Vorotnikova E, McIntosh D, Dewilde A et al (2010) Extracellular matrix-derived products modulate endothelial and progenitor cell migration and proliferation in vitro and stimulate regenerative healing in vivo. Matrix Biol 29(8):690–700PubMedCrossRef Vorotnikova E, McIntosh D, Dewilde A et al (2010) Extracellular matrix-derived products modulate endothelial and progenitor cell migration and proliferation in vitro and stimulate regenerative healing in vivo. Matrix Biol 29(8):690–700PubMedCrossRef
38.
go back to reference Warren RF (1983) Primary repair of the anterior cruciate ligament. Clin Orthop Relat Res 172:65–70PubMed Warren RF (1983) Primary repair of the anterior cruciate ligament. Clin Orthop Relat Res 172:65–70PubMed
39.
go back to reference Wiig ME, Amiel D, VandeBerg J et al (1990) The early effect of high molecular weight hyaluronan (hyaluronic acid) on anterior cruciate ligament healing: an experimental study in rabbits. J Orthop Res 8(3):425–434PubMedCrossRef Wiig ME, Amiel D, VandeBerg J et al (1990) The early effect of high molecular weight hyaluronan (hyaluronic acid) on anterior cruciate ligament healing: an experimental study in rabbits. J Orthop Res 8(3):425–434PubMedCrossRef
40.
go back to reference Woo SL-Y, Abramowitch SD, Kilger R, Liang R (2006) Biomechanics of knee ligaments: injury, healing, and repair. J Biomech 39(1):1–20PubMedCrossRef Woo SL-Y, Abramowitch SD, Kilger R, Liang R (2006) Biomechanics of knee ligaments: injury, healing, and repair. J Biomech 39(1):1–20PubMedCrossRef
41.
go back to reference Woo SL-Y, Danto MI, Ohland KJ, Lee TQ, Newton PO (1990) The use of a laser micrometer system to determine the cross-sectional shape and area of ligaments: a comparative study with two existing methods. J Biomech Eng 112(4):426–431PubMedCrossRef Woo SL-Y, Danto MI, Ohland KJ, Lee TQ, Newton PO (1990) The use of a laser micrometer system to determine the cross-sectional shape and area of ligaments: a comparative study with two existing methods. J Biomech Eng 112(4):426–431PubMedCrossRef
42.
go back to reference Woo SL-Y, Hollis JM, Adams DJ, Lyon RM, Takai S (1991) Tensile properties of the human femur-anterior cruciate ligament-tibia complex: the effects of specimen age and orientation. Am J Sports Med 19(3):217–225PubMedCrossRef Woo SL-Y, Hollis JM, Adams DJ, Lyon RM, Takai S (1991) Tensile properties of the human femur-anterior cruciate ligament-tibia complex: the effects of specimen age and orientation. Am J Sports Med 19(3):217–225PubMedCrossRef
43.
go back to reference Woo SL-Y, Peterson RH, Ohland KJ, Sites TJ, Danto MI (1990) 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 8(5):712–721PubMedCrossRef Woo SL-Y, Peterson RH, Ohland KJ, Sites TJ, Danto MI (1990) 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 8(5):712–721PubMedCrossRef
44.
go back to reference Woo SL-Y, Takakura Y, Liang R, Jia F, Moon DK (2006) Treatment with bioscaffold enhances the fibril morphology and the collagen composition of healing medial collateral ligament in rabbits. Tiss Eng 12(1):159–166CrossRef Woo SL-Y, Takakura Y, Liang R, Jia F, Moon DK (2006) Treatment with bioscaffold enhances the fibril morphology and the collagen composition of healing medial collateral ligament in rabbits. Tiss Eng 12(1):159–166CrossRef
45.
go back to reference Yamada K, Yazawa K, Shimizu A et al (2005) Marked prolongation of porcine renal xenograft survival in baboons through the use of alpha1,3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue. Nat Med 11(1):32–34PubMedCrossRef Yamada K, Yazawa K, Shimizu A et al (2005) Marked prolongation of porcine renal xenograft survival in baboons through the use of alpha1,3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue. Nat Med 11(1):32–34PubMedCrossRef
Metadata
Title
Potential of healing a transected anterior cruciate ligament with genetically modified extracellular matrix bioscaffolds in a goat model
Authors
Matthew B. Fisher
Rui Liang
Ho-Joong Jung
Kwang E. Kim
Giovanni Zamarra
Alejandro J. Almarza
Patrick J. McMahon
Savio L-Y. Woo
Publication date
01-07-2012
Publisher
Springer-Verlag
Published in
Knee Surgery, Sports Traumatology, Arthroscopy / Issue 7/2012
Print ISSN: 0942-2056
Electronic ISSN: 1433-7347
DOI
https://doi.org/10.1007/s00167-011-1800-x

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