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Erschienen in: Clinical Orthopaedics and Related Research® 11/2011

01.11.2011 | Symposium: Bone Repair and Regeneration

Functional Restoration of Critically Sized Segmental Defects With Bone Morphogenetic Protein-2 and Heparin Treatment

verfasst von: Mela R. Johnson, PhD, Joel D. Boerckel, MS, Kenneth M. Dupont, PhD, Robert E. Guldberg, PhD

Erschienen in: Clinical Orthopaedics and Related Research® | Ausgabe 11/2011

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Abstract

Background

Bone defects and fracture nonunions remain a substantial challenge for clinicians. Grafting procedures are limited by insufficient volume and donor site morbidity. As an alternative, biomaterial scaffolds functionalized through incorporation of growth factors such as bone morphogenetic proteins (BMPs) have been developed and appear to regenerate the structure and function of damaged or degenerated skeletal tissue.

Objectives/purposes

Our objectives were therefore to determine whether: (1) the addition of heparin alone to collagen scaffolds sufficed to promote bone formation in vivo; (2) collagen-heparin scaffold improved BMP-mediated bone regeneration; and (3) precomplexed heparin and BMP-2 delivered on collagen scaffold could restore long bone biomechanical strength.

Methods

We created bilateral surgical defects in the femora of 20 rats and filled the defects with PCL scaffolds with one of five treatments: collagen matrix (n = 5), collagen/heparin matrix (n = 7), collagen matrix + BMP-2 (n = 9), collagen/heparin matrix + BMP-2 (n = 9), or collagen matrix + BMP-2/heparin complex (n = 9). Bone formation was observed with radiographs and micro-CT analysis and biomechanical testing was used to assess strength.

Results

The addition of heparin alone to collagen did not promote bone ingrowth and the addition of heparin to collagen did not improve BMP-mediated bone regeneration. Delivery of precomplexed BMP-2 and heparin in a collagen matrix resulted in new bone formation with mechanical properties similar to those of intact bone.

Clinical Relevance

Our findings suggest delivery of precomplexed BMP-2 and heparin may be an advantageous strategy for treatment of clinically challenging bone defects.
Literatur
2.
Zurück zum Zitat Cheng H, Jiang W, Phillips FM, Haydon RC, Peng Y, Zhou L, Luu HH, An N, Breyer B, Vanichakarn P, Szatkowski JP, Park JY, He TC. Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg Am. 2003;85:1544–1552.PubMed Cheng H, Jiang W, Phillips FM, Haydon RC, Peng Y, Zhou L, Luu HH, An N, Breyer B, Vanichakarn P, Szatkowski JP, Park JY, He TC. Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg Am. 2003;85:1544–1552.PubMed
3.
Zurück zum Zitat Chu TM, Warden SJ, Turner CH, Stewart RL. Segmental bone regeneration using a load-bearing biodegradable carrier of bone morphogenetic protein-2. Biomaterials. 2007;28:459–467.PubMedCrossRef Chu TM, Warden SJ, Turner CH, Stewart RL. Segmental bone regeneration using a load-bearing biodegradable carrier of bone morphogenetic protein-2. Biomaterials. 2007;28:459–467.PubMedCrossRef
4.
Zurück zum Zitat Friess W, Uludag H, Foskett S, Biron R, Sargeant C. Characterization of absorbable collagen sponges as rhBMP-2 carriers. Int J Pharm. 1999;187:91–99.PubMedCrossRef Friess W, Uludag H, Foskett S, Biron R, Sargeant C. Characterization of absorbable collagen sponges as rhBMP-2 carriers. Int J Pharm. 1999;187:91–99.PubMedCrossRef
5.
Zurück zum Zitat Hosseinkhani H, Yamamoto M, Inatsugu Y, Hiraoka Y, Inoue S, Shimokawa H, Tabata Y. Enhanced ectopic bone formation using a combination of plasmid DNA impregnation into 3-D scaffold and bioreactor perfusion culture. Biomaterials. 2006;27:1387–1398.PubMedCrossRef Hosseinkhani H, Yamamoto M, Inatsugu Y, Hiraoka Y, Inoue S, Shimokawa H, Tabata Y. Enhanced ectopic bone formation using a combination of plasmid DNA impregnation into 3-D scaffold and bioreactor perfusion culture. Biomaterials. 2006;27:1387–1398.PubMedCrossRef
6.
Zurück zum Zitat Jeon O, Song SJ, Kang SW, Putnam AJ, Kim BS. Enhancement of ectopic bone formation by bone morphogenetic protein-2 released from a heparin-conjugated poly(L-lactic-co-glycolic acid) scaffold. Biomaterials. 2007;28:2763–2771.PubMedCrossRef Jeon O, Song SJ, Kang SW, Putnam AJ, Kim BS. Enhancement of ectopic bone formation by bone morphogenetic protein-2 released from a heparin-conjugated poly(L-lactic-co-glycolic acid) scaffold. Biomaterials. 2007;28:2763–2771.PubMedCrossRef
7.
Zurück zum Zitat Jeon O, Song SJ, Yang HS, Bhang SH, Kang SW, Sung MA, Lee JH, Kim BS. Long-term delivery enhances in vivo osteogenic efficacy of bone morphogenetic protein-2 compared to short-term delivery. Biochem Biophys Res Commun. 2008;369:774–780.PubMedCrossRef Jeon O, Song SJ, Yang HS, Bhang SH, Kang SW, Sung MA, Lee JH, Kim BS. Long-term delivery enhances in vivo osteogenic efficacy of bone morphogenetic protein-2 compared to short-term delivery. Biochem Biophys Res Commun. 2008;369:774–780.PubMedCrossRef
8.
Zurück zum Zitat Kim SE, Jeon O, Lee JB, Bae MS, Chun H-J, Moon S-H, Kwon IK. Enhancement of ectopic bone formation by bone morphogenetic protein-2 delivery using heparin-conjugated PLGA nanoparticles with transplantation of bone marrow-derived mesenchymal stem cells. J Biomed Sci. 2008;15:771–777.PubMedCrossRef Kim SE, Jeon O, Lee JB, Bae MS, Chun H-J, Moon S-H, Kwon IK. Enhancement of ectopic bone formation by bone morphogenetic protein-2 delivery using heparin-conjugated PLGA nanoparticles with transplantation of bone marrow-derived mesenchymal stem cells. J Biomed Sci. 2008;15:771–777.PubMedCrossRef
9.
Zurück zum Zitat Lee SJ. Cytokine delivery and tissue engineering. Yonsei Med J. 2000;41:704–719.PubMed Lee SJ. Cytokine delivery and tissue engineering. Yonsei Med J. 2000;41:704–719.PubMed
10.
Zurück zum Zitat Lieberman JR, Daluiski A, Einhorn TA. The role of growth factors in the repair of bone. Biology and clinical applications. J Bone Joint Surg Am. 2002;84:1032–1044.PubMed Lieberman JR, Daluiski A, Einhorn TA. The role of growth factors in the repair of bone. Biology and clinical applications. J Bone Joint Surg Am. 2002;84:1032–1044.PubMed
11.
Zurück zum Zitat Lin H, Zhao Y, Sun W, Chen B, Zhang J, Zhao W, Xiao Z, Dai J. The effect of crosslinking heparin to demineralized bone matrix on mechanical strength and specific binding to human bone morphogenetic protein-2. Biomaterials. 2008;29:1189–1197.PubMedCrossRef Lin H, Zhao Y, Sun W, Chen B, Zhang J, Zhao W, Xiao Z, Dai J. The effect of crosslinking heparin to demineralized bone matrix on mechanical strength and specific binding to human bone morphogenetic protein-2. Biomaterials. 2008;29:1189–1197.PubMedCrossRef
12.
Zurück zum Zitat Oest ME, Dupont KM, Kong HJ, Mooney DJ, Guldberg RE. Quantitative assessment of scaffold and growth factor-mediated repair of critically sized bone defects. J Orthop Res. 2007;25:941–950.PubMedCrossRef Oest ME, Dupont KM, Kong HJ, Mooney DJ, Guldberg RE. Quantitative assessment of scaffold and growth factor-mediated repair of critically sized bone defects. J Orthop Res. 2007;25:941–950.PubMedCrossRef
13.
Zurück zum Zitat Peister A, Deutsch ER, Kolambkar Y, Hutmacher DW, Guldberg RE. Amniotic fluid stem cells produce robust mineral deposits on biodegradable scaffolds. Tissue Eng A. 2009;15:3129–3138.CrossRef Peister A, Deutsch ER, Kolambkar Y, Hutmacher DW, Guldberg RE. Amniotic fluid stem cells produce robust mineral deposits on biodegradable scaffolds. Tissue Eng A. 2009;15:3129–3138.CrossRef
14.
Zurück zum Zitat Porter BD, Lin AS, Peister A, Hutmacher D, Guldberg RE. Noninvasive image analysis of 3D construct mineralization in a perfusion bioreactor. Biomaterials. 2007;28:2525–2533.PubMedCrossRef Porter BD, Lin AS, Peister A, Hutmacher D, Guldberg RE. Noninvasive image analysis of 3D construct mineralization in a perfusion bioreactor. Biomaterials. 2007;28:2525–2533.PubMedCrossRef
15.
Zurück zum Zitat Rai B, Oest ME, Dupont KM, Ho KH, Teoh SH, Guldberg RE. Combination of platelet-rich plasma with polycaprolactone-tricalcium phosphate scaffolds for segmental bone defect repair. J Biomed Mater Res A. 2007;81:888–899.PubMed Rai B, Oest ME, Dupont KM, Ho KH, Teoh SH, Guldberg RE. Combination of platelet-rich plasma with polycaprolactone-tricalcium phosphate scaffolds for segmental bone defect repair. J Biomed Mater Res A. 2007;81:888–899.PubMed
16.
Zurück zum Zitat Riley EH, Lane JM, Urist MR, Lyons KM. Bone morphogenetic protein-2: biology and applications. Clin Orthop Relat Res. 1996;324:39–46.PubMedCrossRef Riley EH, Lane JM, Urist MR, Lyons KM. Bone morphogenetic protein-2: biology and applications. Clin Orthop Relat Res. 1996;324:39–46.PubMedCrossRef
17.
Zurück zum Zitat Sampath TK, Muthukumaran N, Reddi AH. Isolation of osteogenin, an extracellular matrix-associated, bone-inductive protein, by heparin affinity chromatography. Proc Natl Acad Sci USA. 1987;84:7109–7113.PubMedCrossRef Sampath TK, Muthukumaran N, Reddi AH. Isolation of osteogenin, an extracellular matrix-associated, bone-inductive protein, by heparin affinity chromatography. Proc Natl Acad Sci USA. 1987;84:7109–7113.PubMedCrossRef
18.
Zurück zum Zitat Sciadini MF, Johnson KD. Evaluation of recombinant human bone morphogenetic protein-2 as a bone-graft substitute in a canine segmental defect model. J Orthop Res. 2000;18:289–302.PubMedCrossRef Sciadini MF, Johnson KD. Evaluation of recombinant human bone morphogenetic protein-2 as a bone-graft substitute in a canine segmental defect model. J Orthop Res. 2000;18:289–302.PubMedCrossRef
19.
Zurück zum Zitat Takada T, Katagiri T, Ifuku M, Morimura N, Kobayashi M, Hasegawa K, Ogamo A, Kamijo R. Sulfated polysaccharides enhance the biological activities of bone morphogenetic proteins. J Biol Chem. 2003;278:43229–43235.PubMedCrossRef Takada T, Katagiri T, Ifuku M, Morimura N, Kobayashi M, Hasegawa K, Ogamo A, Kamijo R. Sulfated polysaccharides enhance the biological activities of bone morphogenetic proteins. J Biol Chem. 2003;278:43229–43235.PubMedCrossRef
20.
Zurück zum Zitat Uludag H, D’Augusta D, Golden J, Li J, Timony G, Riedel R, Wozney JM. Implantation of recombinant human bone morphogenetic proteins with biomaterial carriers: a correlation between protein pharmacokinetics and osteoinduction in the rat ectopic model. J Biomed Mater Res. 2000;50:227–238.PubMedCrossRef Uludag H, D’Augusta D, Golden J, Li J, Timony G, Riedel R, Wozney JM. Implantation of recombinant human bone morphogenetic proteins with biomaterial carriers: a correlation between protein pharmacokinetics and osteoinduction in the rat ectopic model. J Biomed Mater Res. 2000;50:227–238.PubMedCrossRef
21.
Zurück zum Zitat Uludag H, Gao T, Porter TJ, Friess W, Wozney JM. Delivery systems for BMPs: factors contributing to protein retention at an application site. J Bone Joint Surg Am. 2001;83(Suppl 1):S128–S135.PubMed Uludag H, Gao T, Porter TJ, Friess W, Wozney JM. Delivery systems for BMPs: factors contributing to protein retention at an application site. J Bone Joint Surg Am. 2001;83(Suppl 1):S128–S135.PubMed
22.
Zurück zum Zitat Von Walter M, Herren C, Gensior TJ, Steffens GC, Hermanns-Sachweh B, Jahnen-Dechent W, Rüger M, Erli HJ. Biomimetic modification of the TiO(2)/glass composite Ecopore with heparinized collagen and the osteoinductive factor BMP-2. Acta Biomater. 2008;4:997–1004.CrossRef Von Walter M, Herren C, Gensior TJ, Steffens GC, Hermanns-Sachweh B, Jahnen-Dechent W, Rüger M, Erli HJ. Biomimetic modification of the TiO(2)/glass composite Ecopore with heparinized collagen and the osteoinductive factor BMP-2. Acta Biomater. 2008;4:997–1004.CrossRef
23.
Zurück zum Zitat Wong DA, Kumar A, Jatana S, Ghiselli G, Wong K. Neurologic impairment from ectopic bone in the lumbar canal: a potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2). Spine. 2008;8:1011–1018.CrossRef Wong DA, Kumar A, Jatana S, Ghiselli G, Wong K. Neurologic impairment from ectopic bone in the lumbar canal: a potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2). Spine. 2008;8:1011–1018.CrossRef
24.
25.
Zurück zum Zitat Xie C, Reynolds D, Awad H, Rubery PT, Pelled G, Gazit D, Guldberg RE, Schwarz EM, O’Keefe RJ, Zhang X. Structural bone allograft combined with genetically engineered mesenchymal stem cells as a novel platform for bone tissue engineering. Tissue Eng. 2007;13:435–445.PubMedCrossRef Xie C, Reynolds D, Awad H, Rubery PT, Pelled G, Gazit D, Guldberg RE, Schwarz EM, O’Keefe RJ, Zhang X. Structural bone allograft combined with genetically engineered mesenchymal stem cells as a novel platform for bone tissue engineering. Tissue Eng. 2007;13:435–445.PubMedCrossRef
26.
Zurück zum Zitat Zhao B, Katagiri T, Toyoda H, Takada T, Yanai T, Fukuda T, Chung UI, Koike T, Takaoka K, Kamijo R. Heparin potentiates the in vivo ectopic bone formation induced by bone morphogenetic protein-2. J Biol Chem. 2006;281:23246–23253.PubMedCrossRef Zhao B, Katagiri T, Toyoda H, Takada T, Yanai T, Fukuda T, Chung UI, Koike T, Takaoka K, Kamijo R. Heparin potentiates the in vivo ectopic bone formation induced by bone morphogenetic protein-2. J Biol Chem. 2006;281:23246–23253.PubMedCrossRef
Metadaten
Titel
Functional Restoration of Critically Sized Segmental Defects With Bone Morphogenetic Protein-2 and Heparin Treatment
verfasst von
Mela R. Johnson, PhD
Joel D. Boerckel, MS
Kenneth M. Dupont, PhD
Robert E. Guldberg, PhD
Publikationsdatum
01.11.2011
Verlag
Springer-Verlag
Erschienen in
Clinical Orthopaedics and Related Research® / Ausgabe 11/2011
Print ISSN: 0009-921X
Elektronische ISSN: 1528-1132
DOI
https://doi.org/10.1007/s11999-011-2012-x

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