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Published in: Archives of Orthopaedic and Trauma Surgery 9/2012

01-09-2012 | Basic Science

The optimal carrier for BMP-2: a comparison of collagen versus fibrin matrix

Authors: Sebastian Schützenberger, Arthur Schultz, Thomas Hausner, Rudolf Hopf, Gerald Zanoni, Tatjana Morton, Karl Kropik, Martijn van Griensven, Heinz Redl

Published in: Archives of Orthopaedic and Trauma Surgery | Issue 9/2012

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Abstract

Introduction

The aim of our study was to investigate in vitro and in a new in vivo rat model for impaired bone healing whether a low dose BMP-2 preparation in fibrin would be equivalent or better than the combination of collagen and a high dose of BMP-2 which is currently in clinical use.

Materials and methods

In a 14 day period we compared the in vitro release kinetics of an absorbable collagen sponge (ACS) with 72 μg rhBMP-2 in the BMPC group and fibrin matrix with 10 μg rhBMP-2 in the BMPF group. In our in vivo experiment a critical sized osteotomy was performed in the rat femur, which was filled with a spacer, inhibiting bone formation for a period of 4 weeks. In a second operation this spacer was removed and the test item was applied into the defect. We compared the BMPF and BMPC groups with the ACS alone, FIBRIN alone and the EMPTY (4w/8w) control groups. 4 and 8 weeks after the second operation, specimens were analysed by X-ray and μCT imaging. Mechanically stable femurs were biomechanically evaluated.

Results

Cumulative BMP-2 release was five times higher in the BMPF group than in the BMPC group during the observation period. μCT analysis revealed that both the extent of bone union and the bone volume were significantly higher in the group with a lower dose of BMP-2 in fibrin matrix than in the groups without BMP-2 treatment. However there was no statistically significant difference between the BMPF and BMPC groups.

Conclusion

We conclude that fibrin matrix is an excellent carrier for BMP-2 and that it provides equivalent results with a sevenfold lower dose of BMP-2 compared with ACS.
Literature
2.
go back to reference Yamamoto M, Takahashi Y, Tabata Y (2003) Controlled release by biodegradable hydrogels enhances the ectopic bone formation of bone morphogenetic protein. Biomaterials 24:4375–4383PubMedCrossRef Yamamoto M, Takahashi Y, Tabata Y (2003) Controlled release by biodegradable hydrogels enhances the ectopic bone formation of bone morphogenetic protein. Biomaterials 24:4375–4383PubMedCrossRef
3.
go back to reference Schmoekel HG, Weber FE, Schense JC, Gratz KW, Schawalder P, Hubbell JA (2005) Bone repair with a form of BMP-2 engineered for incorporation into fibrin cell ingrowth matrices. Biotechnol Bioeng 89:253–262PubMedCrossRef Schmoekel HG, Weber FE, Schense JC, Gratz KW, Schawalder P, Hubbell JA (2005) Bone repair with a form of BMP-2 engineered for incorporation into fibrin cell ingrowth matrices. Biotechnol Bioeng 89:253–262PubMedCrossRef
4.
go back to reference Zabka AG, Pluhar GE, Edwards RB III, Manley PA, Hayashi K, Heiner JP et al (2001) Histomorphometric description of allograft bone remodeling and union in a canine segmental femoral defect model: a comparison of rhBMP-2, cancellous bone graft, and absorbable collagen sponge. J Orthop Res 19:318–327PubMedCrossRef Zabka AG, Pluhar GE, Edwards RB III, Manley PA, Hayashi K, Heiner JP et al (2001) Histomorphometric description of allograft bone remodeling and union in a canine segmental femoral defect model: a comparison of rhBMP-2, cancellous bone graft, and absorbable collagen sponge. J Orthop Res 19:318–327PubMedCrossRef
5.
go back to reference Kawamura M, Urist MR (1988) Human fibrin is a physiologic delivery system for bone morphogenetic protein. Clin Orthop Relat Res 302–310 Kawamura M, Urist MR (1988) Human fibrin is a physiologic delivery system for bone morphogenetic protein. Clin Orthop Relat Res 302–310
6.
go back to reference Vogelin E, Jones NF, Huang JI, Brekke JH, Lieberman JR (2005) Healing of a critical-sized defect in the rat femur with use of a vascularized periosteal flap, a biodegradable matrix, and bone morphogenetic protein. J Bone Joint Surg Am 87:1323–1331PubMedCrossRef Vogelin E, Jones NF, Huang JI, Brekke JH, Lieberman JR (2005) Healing of a critical-sized defect in the rat femur with use of a vascularized periosteal flap, a biodegradable matrix, and bone morphogenetic protein. J Bone Joint Surg Am 87:1323–1331PubMedCrossRef
7.
go back to reference Isobe M, Yamazaki Y, Mori M, Amagasa T (1999) Bone regeneration produced in rat femur defects by polymer capsules containing recombinant human bone morphogenetic protein-2. J Oral Maxillofac Surg 57:695–698PubMedCrossRef Isobe M, Yamazaki Y, Mori M, Amagasa T (1999) Bone regeneration produced in rat femur defects by polymer capsules containing recombinant human bone morphogenetic protein-2. J Oral Maxillofac Surg 57:695–698PubMedCrossRef
8.
go back to reference Lee SC, Shea M, Battle MA, Kozitza K, Ron E, Turek T et al (1994) Healing of large segmental defects in rat femurs is aided by RhBMP-2 in PLGA matrix. J Biomed Mater Res 28:1149–1156PubMedCrossRef Lee SC, Shea M, Battle MA, Kozitza K, Ron E, Turek T et al (1994) Healing of large segmental defects in rat femurs is aided by RhBMP-2 in PLGA matrix. J Biomed Mater Res 28:1149–1156PubMedCrossRef
9.
go back to reference Seeherman HJ, Azari K, Bidic S, Rogers L, Li XJ, Hollinger JO et al (2006) rhBMP-2 delivered in a calcium phosphate cement accelerates bridging of critical-sized defects in rabbit radii. J Bone Joint Surg Am 88:1553–1565PubMedCrossRef Seeherman HJ, Azari K, Bidic S, Rogers L, Li XJ, Hollinger JO et al (2006) rhBMP-2 delivered in a calcium phosphate cement accelerates bridging of critical-sized defects in rabbit radii. J Bone Joint Surg Am 88:1553–1565PubMedCrossRef
10.
go back to reference Pluhar GE, Manley PA, Heiner JP, Vanderby R Jr, Seeherman HJ, Markel MD (2001) The effect of recombinant human bone morphogenetic protein-2 on femoral reconstruction with an intercalary allograft in a dog model. J Orthop Res 19:308–317PubMedCrossRef Pluhar GE, Manley PA, Heiner JP, Vanderby R Jr, Seeherman HJ, Markel MD (2001) The effect of recombinant human bone morphogenetic protein-2 on femoral reconstruction with an intercalary allograft in a dog model. J Orthop Res 19:308–317PubMedCrossRef
11.
go back to reference Sciadini MF, Johnson KD (2000) Evaluation of recombinant human bone morphogenetic protein-2 as a bone-graft substitute in a canine segmental defect model. J Orthop Res 18:289–302PubMedCrossRef Sciadini MF, Johnson KD (2000) Evaluation of recombinant human bone morphogenetic protein-2 as a bone-graft substitute in a canine segmental defect model. J Orthop Res 18:289–302PubMedCrossRef
12.
go back to reference Seeherman HJ, Bouxsein M, Kim H, Li R, Li XJ, Aiolova M et al (2004) Recombinant human bone morphogenetic protein-2 delivered in an injectable calcium phosphate paste accelerates osteotomy-site healing in a nonhuman primate model. J Bone Joint Surg Am 86-A(9):1961–1972PubMed Seeherman HJ, Bouxsein M, Kim H, Li R, Li XJ, Aiolova M et al (2004) Recombinant human bone morphogenetic protein-2 delivered in an injectable calcium phosphate paste accelerates osteotomy-site healing in a nonhuman primate model. J Bone Joint Surg Am 86-A(9):1961–1972PubMed
13.
go back to reference Schmidmaier G, Schwabe P, Wildemann B, Haas NP (2007) Use of bone morphogenetic proteins for treatment of non-unions and future perspectives. Injury 38(Suppl 4):S35–S41PubMedCrossRef Schmidmaier G, Schwabe P, Wildemann B, Haas NP (2007) Use of bone morphogenetic proteins for treatment of non-unions and future perspectives. Injury 38(Suppl 4):S35–S41PubMedCrossRef
14.
go back to reference Hsu HP, Zanella JM, Peckham SM, Spector M (2006) Comparing ectopic bone growth induced by rhBMP-2 on an absorbable collagen sponge in rat and rabbit models. J Orthop Res 24:1660–1669PubMedCrossRef Hsu HP, Zanella JM, Peckham SM, Spector M (2006) Comparing ectopic bone growth induced by rhBMP-2 on an absorbable collagen sponge in rat and rabbit models. J Orthop Res 24:1660–1669PubMedCrossRef
15.
go back to reference Jones AL (2005) Recombinant human bone morphogenic protein-2 in fracture care. J Orthop Trauma 19:S23–S25PubMedCrossRef Jones AL (2005) Recombinant human bone morphogenic protein-2 in fracture care. J Orthop Trauma 19:S23–S25PubMedCrossRef
16.
go back to reference Jones AL, Bucholz RW, Bosse MJ, Mirza SK, Lyon TR, Webb LX et al (2006) Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. J Bone Joint Surg Am 88:1431–1441PubMedCrossRef Jones AL, Bucholz RW, Bosse MJ, Mirza SK, Lyon TR, Webb LX et al (2006) Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. J Bone Joint Surg Am 88:1431–1441PubMedCrossRef
17.
go back to reference Kuklo TR, Groth AT, Anderson RC, Frisch HM, Islinger RB (2008) Recombinant human bone morphogenetic protein-2 for grade III open segmental tibial fractures from combat injuries in Iraq. J Bone Joint Surg Br 90:1068–1072PubMed Kuklo TR, Groth AT, Anderson RC, Frisch HM, Islinger RB (2008) Recombinant human bone morphogenetic protein-2 for grade III open segmental tibial fractures from combat injuries in Iraq. J Bone Joint Surg Br 90:1068–1072PubMed
18.
go back to reference Han D, Liu W, Ao Q, Wang G (2008) Optimal delivery systems for bone morphogenetic proteins in orthopedic applications should model initial tissue repair structures by using a heparin-incorporated fibrin-fibronectin matrix. Med Hypotheses 71:374–378PubMedCrossRef Han D, Liu W, Ao Q, Wang G (2008) Optimal delivery systems for bone morphogenetic proteins in orthopedic applications should model initial tissue repair structures by using a heparin-incorporated fibrin-fibronectin matrix. Med Hypotheses 71:374–378PubMedCrossRef
19.
go back to reference Schlag G, Redl H (1988) Fibrin sealant in orthopedic surgery. Clin Orthop Relat Res 227:269–285PubMed Schlag G, Redl H (1988) Fibrin sealant in orthopedic surgery. Clin Orthop Relat Res 227:269–285PubMed
20.
go back to reference Schmokel HG, Weber FE, Seiler G, von Rechenberg B, Schense JC, Schawalder P et al (2004) Treatment of nonunions with nonglycosylated recombinant human bone morphogenetic protein-2 delivered from a fibrin matrix. Vet Surg 33:112–118PubMedCrossRef Schmokel HG, Weber FE, Seiler G, von Rechenberg B, Schense JC, Schawalder P et al (2004) Treatment of nonunions with nonglycosylated recombinant human bone morphogenetic protein-2 delivered from a fibrin matrix. Vet Surg 33:112–118PubMedCrossRef
21.
go back to reference Schmoekel H, Schense JC, Weber FE, Gratz KW, Gnagi D, Muller R et al (2004) Bone healing in the rat and dog with nonglycosylated BMP-2 demonstrating low solubility in fibrin matrices. J Orthop Res 22:376–381PubMedCrossRef Schmoekel H, Schense JC, Weber FE, Gratz KW, Gnagi D, Muller R et al (2004) Bone healing in the rat and dog with nonglycosylated BMP-2 demonstrating low solubility in fibrin matrices. J Orthop Res 22:376–381PubMedCrossRef
22.
go back to reference Harrison LJ, Cunningham JL, Stromberg L, Goodship AE (2003) Controlled induction of a pseudarthrosis: a study using a rodent model. J Orthop Trauma 17:11–21PubMedCrossRef Harrison LJ, Cunningham JL, Stromberg L, Goodship AE (2003) Controlled induction of a pseudarthrosis: a study using a rodent model. J Orthop Trauma 17:11–21PubMedCrossRef
23.
go back to reference Weber BG, Cech O (1976) Pseudathrosis: pathology, biomechanics, therapy, results. Hans Huber Medical Publisher, Berne Weber BG, Cech O (1976) Pseudathrosis: pathology, biomechanics, therapy, results. Hans Huber Medical Publisher, Berne
24.
go back to reference Huang Z, Nelson ER, Smith RL, Goodman SB (2007) The sequential expression profiles of growth factors from osteoprogenitors (correction of osteroprogenitors) to osteoblasts in vitro. Tissue Eng 13:2311–2320PubMedCrossRef Huang Z, Nelson ER, Smith RL, Goodman SB (2007) The sequential expression profiles of growth factors from osteoprogenitors (correction of osteroprogenitors) to osteoblasts in vitro. Tissue Eng 13:2311–2320PubMedCrossRef
25.
go back to reference Drosse I, Volkmer E, Seitz S, Seitz H, Penzkofer R, Zahn K et al (2008) Validation of a femoral critical size defect model for orthotopic evaluation of bone healing: a biomechanical, veterinary and trauma surgical perspective. Tissue Eng 14(1):79–88CrossRef Drosse I, Volkmer E, Seitz S, Seitz H, Penzkofer R, Zahn K et al (2008) Validation of a femoral critical size defect model for orthotopic evaluation of bone healing: a biomechanical, veterinary and trauma surgical perspective. Tissue Eng 14(1):79–88CrossRef
26.
go back to reference Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF et al (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 83-A(Suppl 1):S151–S158PubMed Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF et al (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 83-A(Suppl 1):S151–S158PubMed
27.
go back to reference Thomsen JS, Laib A, Koller B, Prohaska S, Mosekilde L, Gowin W (2005) Stereological measures of trabecular bone structure: comparison of 3D micro computed tomography with 2D histological sections in human proximal tibial bone biopsies. J Microsc 218(Pt 2):171–179PubMedCrossRef Thomsen JS, Laib A, Koller B, Prohaska S, Mosekilde L, Gowin W (2005) Stereological measures of trabecular bone structure: comparison of 3D micro computed tomography with 2D histological sections in human proximal tibial bone biopsies. J Microsc 218(Pt 2):171–179PubMedCrossRef
28.
go back to reference Schmidhammer R, Zandieh S, Mittermayr R, Pelinka LE, Leixnering M, Hopf R et al (2006) Assessment of bone union/nonunion in an experimental model using microcomputed technology. J Trauma 61:199–205PubMedCrossRef Schmidhammer R, Zandieh S, Mittermayr R, Pelinka LE, Leixnering M, Hopf R et al (2006) Assessment of bone union/nonunion in an experimental model using microcomputed technology. J Trauma 61:199–205PubMedCrossRef
29.
go back to reference Dickson GR, Geddis C, Fazzalari N, Marsh D, Parkinson I (2008) Microcomputed tomography imaging in a rat model of delayed union/non-union fracture. J Orthop Res 26:729–736PubMedCrossRef Dickson GR, Geddis C, Fazzalari N, Marsh D, Parkinson I (2008) Microcomputed tomography imaging in a rat model of delayed union/non-union fracture. J Orthop Res 26:729–736PubMedCrossRef
Metadata
Title
The optimal carrier for BMP-2: a comparison of collagen versus fibrin matrix
Authors
Sebastian Schützenberger
Arthur Schultz
Thomas Hausner
Rudolf Hopf
Gerald Zanoni
Tatjana Morton
Karl Kropik
Martijn van Griensven
Heinz Redl
Publication date
01-09-2012
Publisher
Springer-Verlag
Published in
Archives of Orthopaedic and Trauma Surgery / Issue 9/2012
Print ISSN: 0936-8051
Electronic ISSN: 1434-3916
DOI
https://doi.org/10.1007/s00402-012-1551-2

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