Complete subchondral bone defect regeneration with a tricalcium phosphate collagen implant and osteoinductive growth factors: A randomized controlled study in Göttingen minipigs
Tobias Gotterbarm
Clinic of Orthopaedic and Trauma Surgery, Heidelberg University Hospital, Heidelberg, Germany
Search for more papers by this authorSteffen J. Breusch
Department of Orthopaedics, New Royal Infirmary, Little France, University of Edinburgh, Edinburgh, EH16 4SU, Scotland, UK
Search for more papers by this authorNikolaus Streich
Clinic of Orthopaedic and Trauma Surgery, Heidelberg University Hospital, Heidelberg, Germany
Search for more papers by this authorJörg Wiltfang
Department of Oral and Maxillofacial Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Haus 26, 24105 Kiel, Germany
Search for more papers by this authorSimona Berardi Vilei
Centerpulse Biologics, Inc., Winterthur, Switzerland
Search for more papers by this authorWiltrud Richter
Research Centre for Experimental Orthopaedics, Heidelberg University Hospital, Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Tobias Nitsche
Department of Oral and Maxillofacial Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Haus 26, 24105 Kiel, Germany
Correspondence to: T. Nitsche (e-mail: [email protected])Search for more papers by this authorTobias Gotterbarm
Clinic of Orthopaedic and Trauma Surgery, Heidelberg University Hospital, Heidelberg, Germany
Search for more papers by this authorSteffen J. Breusch
Department of Orthopaedics, New Royal Infirmary, Little France, University of Edinburgh, Edinburgh, EH16 4SU, Scotland, UK
Search for more papers by this authorNikolaus Streich
Clinic of Orthopaedic and Trauma Surgery, Heidelberg University Hospital, Heidelberg, Germany
Search for more papers by this authorJörg Wiltfang
Department of Oral and Maxillofacial Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Haus 26, 24105 Kiel, Germany
Search for more papers by this authorSimona Berardi Vilei
Centerpulse Biologics, Inc., Winterthur, Switzerland
Search for more papers by this authorWiltrud Richter
Research Centre for Experimental Orthopaedics, Heidelberg University Hospital, Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Tobias Nitsche
Department of Oral and Maxillofacial Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Haus 26, 24105 Kiel, Germany
Correspondence to: T. Nitsche (e-mail: [email protected])Search for more papers by this authorBoth authors contributed equally to this work
Disclosure: The authors confirm that there are no other known conflicts of interest associated with this publication. The financial support for this work has not influenced its outcome.
Abstract
The restoration and reconstruction of osseous defects close to the joint, constitutes a challenging field for reconstructive surgery. A dual-layer implant of β-tricalcium phosphate (TCP) and a collagens I/III scaffold was evaluated in a prospective, randomized comparison in a larger animal model. For this purpose, a standardized osteochondral defect was created in the medial facet of the patellar groove in both stifle joints of Göttingen minipigs. Critical-size osseous defects were either left empty (spontaneous healing; group 1; n = 12) or treated with the two-layer TCP collagen implant (group 2; n = 12). In group 3 (n = 12), additional growth factor mixture (GFM) was supplemented (bone morphogenetic proteins 2, 3, 4, 6, 7, and TGF-β1, 2, 3). Osseous defect regeneration was assessed at 6, 12, and 52 weeks postoperatively (n = 4). Qualitative and quantitative histomorphometric assessment of defect regeneration and bone substitute resorption was conducted by means of light microscopy, fluorescence microscopy, and microradiography. Critical-size defects did not heal spontaneously throughout follow-up (group 1: max. 21.84 ± 2.81% defect area at 52 weeks). The TCP layer of the implant significantly increased the amount of new bone formation with 29.8 ± 9.68% at 6 weeks and 40.09 ± 4.76% at 12 weeks when compared with controls. After 52 weeks, the TCP was almost fully degraded (4.35 ± 3.70%) and the defect was restored with lamellar trabecular bone (31.28 ± 5.02%). Growth factor supplementation resulted in earlier resorption of the TCP implant and faster defect regeneration. The dual-layer TCP collagen implant is suitable to restore subchondral osseous defects. Additional use of GFM increased the resorption of the TCP layer, but did not foster new bone formation. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 102B: 933–942, 2014.
REFERENCES
- 1Badekas T, Takvorian M, Souras N. Treatment principles for osteochondral lesions in foot and ankle. Int Orthop 2013; 37: 1697–1706.
- 2Gotterbarm T, Breusch SJ, Vilei SB, Mainil-Varlet P, Richter W, Jung M. No effect of subperiosteal growth factor application on periosteal neo-chondrogenesis in osteoperiosteal bone grafts for osteochondral defect repair. Int Orthop 2013; 37: 1171–1178.
- 3Chahal J, Gross AE, Gross C, Mall N, Dwyer T, Chahal A, Whelan DB, Cole BJ. Outcomes of osteochondral allograft transplantation in the knee. Arthroscopy 2013; 29: 575–588.
- 4St John TA, Vaccaro AR, Sah AP, Schaefer M, Berta SC, Albert T, Hilibrand A. Physical and monetary costs associated with autogenous bone graft harvesting. Am J Orthop (Belle Mead, NJ) 2003; 32: 18–23.
- 5Johansson B, Grepe A, Wannfors K, Hirsch JM. A clinical study of changes in the volume of bone grafts in the atrophic maxilla. Dento Maxillofac Radiol 2001; 30: 157–161.
- 6Wiltfang J, Schultze-Mosgau S, Nkenke E, Thorwarth M, Neukam FW, Schlegel KA. Onlay augmentation versus sinuslift procedure in the treatment of the severely resorbed maxilla: a 5-year comparative longitudinal study. Int J Oral Maxillofac Surg 2005; 34: 885–889.
- 7Draenert K, Draenert Y. A new procedure for bone biopsies and cartilage and bone transplantation. Sandorama 1988; III–IV: 33–40.
- 8Hangody L, Dobos J, Balo E, Panics G, Hangody LR, Berkes I. Clinical experiences with autologous osteochondral mosaicplasty in an athletic population: a 17-year prospective multicenter study. Am J Sports Med 2010; 38: 1125–1133.
- 9Hangody L, Vasarhelyi G, Hangody LR, Sukosd Z, Tibay G, Bartha L, Bodo G. Autologous osteochondral grafting--technique and long-term results. Injury 2008; 39(Suppl 1): S32–S329.
- 10Jakob RP, Franz T, Gautier E, Mainil-Varlet P. Autologous osteochondral grafting in the knee: indication, results, and reflections. Clin Orthop 2002; 401: 170–184.
- 11Hangody L, Rathonyi GK, Duska Z, Vasarhelyi G, Fules P, Modis L. Autologous osteochondral mosaicplasty. Surgical technique. J Bone Joint Surg Am 2004; 86-A(Suppl 1): 65–72.
10.2106/00004623-200403001-00009 Google Scholar
- 12Bedi A, Feeley BT, Williams RJ 3rd. Management of articular cartilage defects of the knee. J Bone Joint Surg Am 2010; 92: 994–1009.
- 13Bentley G, Biant LC, Carrington RW, Akmal M, Goldberg A, Williams AM, Skinner JA, Pringle J. A prospective, randomised comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee. J Bone Joint Surg Br 2003; 85: 223–230.
- 14Jackson DW, Lalor PA, Aberman HM, Simon TM. Spontaneous repair of full-thickness defects of articular cartilage in a goat model. A preliminary study. J Bone Joint Surg Am 2001; 83-A: 53–64.
- 15Convery FR, Akeson WH, Keown GH. The repair of large osteochondral defects. An experimental study in horses. Clin Orthop 1972; 82: 253–262.
- 16Gotterbarm T, Reitzel T, Schneider U, Voss HJ, Stofft E, Breusch SJ. Integration of periosteum covered autogenous bone grafts with and without autologous chondrocytes. An animal experiment using the Gottinger minipig. Orthopäde 2003; 32: 65–73.
- 17van Susante JL, Wymenga AB, Buma P. Potential healing benefit of an osteoperiosteal bone plug from the proximal tibia on a mosaicplasty donor-site defect in the knee. An experimental study in the goat. Arch Orthop Trauma Surg 2003; 123: 466–470.
- 18Lane JG, Massie JB, Ball ST, Amiel ME, Chen AC, Bae WC, Sah RL, Amiel D. Follow-up of osteochondral plug transfers in a goat model: a 6-month study. Am J Sports Med 2004; 32: 1440–1450.
- 19Attmanspacher W, Dittrich V, Stedtfeld HW. Experiences with arthroscopic therapy of chondral and osteochondral defects of the knee joint with OATS (Osteochondral Autograft Transfer System). Zentralbl Chir 2000; 125: 494–499.
- 20Bobic V. Autologous osteo-chondral grafts in the management of articular cartilage lesions. Orthopäde 1999; 28: 19–25.
- 21Horas U, Pelinkovic D, Herr G, Aigner T, Schnettler R. Autologous chondrocyte implantation and osteochondral cylinder transplantation in cartilage repair of the knee joint: a prospective, comparative trial. J Bone Joint Surg Am 2003; 85-A: 185–192.
- 22Outerbridge HK, Outerbridge RE, Smith DE. Osteochondral defects in the knee. A treatment using lateral patella autografts. Clin Orthop 2000; 377: 145–151.
10.1097/00003086-200008000-00020 Google Scholar
- 23Getgood AM, Kew SJ, Brooks R, Aberman H, Simon T, Lynn AK, Rushton N. Evaluation of early-stage osteochondral defect repair using a biphasic scaffold based on a collagen-glycosaminoglycan biopolymer in a caprine model. Knee 2012; 19: 422–430.
- 24Carmont MR, Carey-Smith R, Saithna A, Dhillon M, Thompson P, Spalding T. Delayed incorporation of a TruFit plug: perseverance is recommended. Arthroscopy 2009; 25: 810–814.
- 25Dhollander AA, Liekens K, Almqvist KF, Verdonk R, Lambrecht S, Elewaut D, Verbruggen G, Verdonk PC. A pilot study of the use of an osteochondral scaffold plug for cartilage repair in the knee and how to deal with early clinical failures. Arthroscopy 2012; 28: 225–233.
- 26Joshi N, Reverte-Vinaixa M, Diaz-Ferreiro EW, Dominguez-Oronoz R. Synthetic resorbable scaffolds for the treatment of isolated patellofemoral cartilage defects in young patients: magnetic resonance imaging and clinical evaluation. Am J Sports Med 2012; 40: 1289–1295.
- 27Cook SD, Patron LP, Salkeld SL, Rueger DC. Repair of articular cartilage defects with osteogenic protein-1 (BMP-7) in dogs. J Bone Joint Surg Am 2003; 85-A(Suppl 3): 116–123.
- 28Jung M, Tuischer JS, Sergi C, Gotterbarm T, Pohl J, Richter W, Simank HG. Local application of a collagen type I/hyaluronate matrix and growth and differentiation factor 5 influences the closure of osteochondral defects in a minipig model by enchondral ossification. Growth Factors 2006; 24: 225–232.
- 29Gotterbarm T, Richter W, Jung M, Berardi Vilei S, Mainil-Varlet P, Yamashita T, Breusch SJ. An in vivo study of a growth-factor enhanced, #cell │free, two-layered collagen-tricalcium phosphate in deep osteochondral defects. Biomaterials 2006; 27: 3387–3395.
- 30Gotterbarm T, Breusch SJ, Schneider U, Jung M. The minipig model for experimental chondral and osteochondral defect repair in tissue engineering: retrospective analysis of 180 defects. Lab Anim 2008; 42: 71–82.
- 31Boden SD, Grob D, Damien C. Ne-Osteo bone growth factor for posterolateral lumbar spine fusion: results from a nonhuman primate study and a prospective human clinical pilot study. Spine 2004; 29: 504–514.
- 32Damien CJ, Grob D, Boden SD, Benedict JJ. Purified bovine BMP extract and collagen for spine arthrodesis: preclinical safety and efficacy. Spine 2002; 27: S50–S58.
- 33Atkinson BL, Fantle KS, Benedict JJ, Huffer WE, Gutierrez-Hartmann A. Combination of osteoinductive bone proteins differentiates mesenchymal C3H/10T1/2 cells specifically to the cartilage lineage. J Cell Biochem 1997; 65: 325–339.
10.1002/(SICI)1097-4644(19970601)65:3<325::AID-JCB3>3.0.CO;2-U CAS PubMed Web of Science® Google Scholar
- 34Jung M, Gotterbarm T, Gruettgen A, Vilei SB, Breusch S, Richter W. Molecular characterization of spontaneous and growth-factor-augmented chondrogenesis in periosteum-bone tissue transferred into a joint. Histochem Cell Biol 2005; 123: 447–456.
- 35Rahn BA, Perren SM. Xylenol orange, a fluorochrome useful in polychrome sequential labeling of calcifying tissues. Stain Technol 1971; 46: 125–129.
- 36Jung M, Breusch S, Daecke W, Gotterbarm T. The effect of defect localization on spontaneous repair of osteochondral defects in a Gottingen minipig model: a retrospective analysis of the medial patellar groove versus the medial femoral condyle. Lab Anim 2009; 43: 191–197.
- 37Donath K, Breuner G. A method for the study of undecalcified bones and teeth with attached soft tissues. The Sage–Schliff (sawing and grinding) technique. J. Oral Pathol. 1982; 11: 318–326.
- 38Abramoff MD, Magelhaes PJ, Ram SJ. Image processing with ImageJ. Biophoton Int 2004; 11: 36–42.
- 39Mastrogiacomo M, Muraglia A, Komlev V, Peyrin F, Rustichelli F, Crovace A, Cancedda R. Tissue engineering of bone: search for a better scaffold. Orthod Craniofac Res 2005; 8: 277–284.
- 40Niederauer GG, Slivka MA, Leatherbury NC, Korvick DL, Harroff HH, Ehler WC, Dunn CJ, Kieswetter K. Evaluation of multiphase implants for repair of focal osteochondral defects in goats. Biomaterials 2000; 21: 2561–2574.
- 41Barber FA, Dockery WD. A computed tomography scan assessment of synthetic multiphase polymer scaffolds used for osteochondral defect repair. Arthroscopy 2011; 27: 60–64.
- 42Merten HA, Wiltfang J, Grohmann U, Hoenig JF. Intraindividual comparative animal study of alpha- and beta-tricalcium phosphate degradation in conjunction with simultaneous insertion of dental implants. J Craniofac Surg 2001; 12: 59–68.
- 43Mayr HO, Klehm J, Schwan S, Hube R, Sudkamp NP, Niemeyer P, Salzmann G, von Eisenhardt-Rothe R, Heilmann A, Bohner M, Bernstein A. Microporous calcium phosphate ceramics as tissue engineering scaffolds for the repair of osteochondral defects: biomechanical results. Acta Biomater 2013; 9: 4845–4855.
- 44Marquass B, Somerson JS, Hepp P, Aigner T, Schwan S, Bader A, Josten C, Zscharnack M, Schulz RM. A novel MSC-seeded triphasic construct for the repair of osteochondral defects. J Orthop Res 2010; 28: 1586–1599.
- 45Walsh WR, Vizesi F, Michael D, Auld J, Langdown A, Oliver R, Yu Y, Irie H, Bruce W. Beta-TCP bone graft substitutes in a bilateral rabbit tibial defect model. Biomaterials 2008; 29: 266–271.
- 46Gaasbeek RD, Toonen HG, van Heerwaarden RJ, Buma P. Mechanism of bone incorporation of beta-TCP bone substitute in open wedge tibial osteotomy in patients. Biomaterials 2005; 26: 6713–6719.
- 47Okubo Y, Bessho K, Fujimura K, Konishi Y, Kusumoto K, Ogawa Y, Iizuka T. Osteoinduction by recombinant human bone morphogenetic protein-2 at intramuscular, intermuscular, subcutaneous and intrafatty sites. Int J Oral Maxillofac Surg 2000; 29: 62–66.
- 48LeGeros RZ. Properties of osteoconductive biomaterials: calcium phosphates. Clin Orthop Relat Res 2002: 81–98.
- 49Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors 2004; 22: 233–241.
- 50Azari K, Doll BA, Sfeir C, Mu Y, Hollinger JO. Therapeutic potential of bone morphogenetic proteins. Expert Opin Investig Drugs 2001; 10: 1677–1686.
- 51Pecina M, Giltaij LR, Vukicevic S. Orthopaedic applications of osteogenic protein-1 (BMP-7). Int Orthop 2001; 25: 203–208.
- 52Chubinskaya S, Kuettner KE. Regulation of osteogenic proteins by chondrocytes. Int J Biochem Cell Biol 2003; 35: 1323–1340.
- 53Kaps C, Bramlage C, Smolian H, Haisch A, Ungethum U, Burmester GR, Sittinger M, Gross G, Haupl T. Bone morphogenetic proteins promote cartilage differentiation and protect engineered artificial cartilage from fibroblast invasion and destruction. Arthritis Rheum 2002; 46: 149–162.
10.1002/1529-0131(200201)46:1<149::AID-ART10058>3.0.CO;2-W CAS PubMed Web of Science® Google Scholar
- 54Bramlage CP, Haupl T, Kaps C, Bramlage P, Muller GA, Strutz F. Bone morphogenetic proteins in the skeletal system. Z Rheumatol 2005; 64: 416–422.
- 55Siebert CH, Miltner O, Schneider U, Weber M, Wahner T, Niedhart C. Filling of osteochondral donor site defects. Experimental study with tricalcium phosphate cement and BMP-2. Z Orthop Ihre Grenzgeb 2003; 141: 227–232.
- 56Urist MR, Nilsson O, Rasmussen J, Hirota W, Lovell T, Schmalzreid T, Finerman GA. Bone regeneration under the influence of a bone morphogenetic protein (BMP) beta tricalcium phosphate (TCP) composite in skull trephine defects in dogs. Clin Orthop Relat Res 1987; 214: 295–304.
- 57Warnke PH, Bolte H, Schunemann K, Nitsche T, Sivananthan S, Sherry E, Douglas T, Wiltfang J, Becker ST. Endocultivation: does delayed application of BMP improve intramuscular heterotopic bone formation? J Craniomaxillofac Surg 2010; 38: 54–59.
- 58Jung MR, Shim IK, Chung HJ, Lee HR, Park YJ, Lee MC, Yang YI, Do SH, Lee SJ. Local BMP-7 release from a PLGA scaffolding-matrix for the repair of osteochondral defects in rabbits. J Control Release 2012; 162: 485–491.
- 59Re'em T, Witte F, Willbold E, Ruvinov E, Cohen S. Simultaneous regeneration of articular cartilage and subchondral bone induced by spatially presented TGF-beta and BMP-4 in a bilayer affinity binding system. Acta Biomater 2012; 8: 3283–3293.
- 60Reyes R, Delgado A, Sanchez E, Fernandez A, Hernandez A, Evora C. Repair of an osteochondral defect by sustained delivery of BMP-2 or TGFbeta1 from a bilayered alginate-PLGA scaffold. J Tissue Eng Regen Med 2012; doi: 10.1002/term.1549.
- 61Chen J, Chen H, Li P, Diao H, Zhu S, Dong L, Wang R, Guo T, Zhao J, Zhang J. Simultaneous regeneration of articular cartilage and subchondral bone in vivo using MSCs induced by a spatially controlled gene delivery system in bilayered integrated scaffolds. Biomaterials 2011; 32: 4793–4805.