• 1.

    Giannoudis PV, Dinopoulos H, Tsiridis E. Bone substitutes: an update. Injury 2005;36(suppl 3):S20S27.

  • 2.

    Einhorn TA. Clinical applications of recombinant human BMPs: early experience and future development. J Bone Joint Surg Am 2003;85-A(suppl 3):8288.

    • Search Google Scholar
    • Export Citation
  • 3.

    Reddi AH, Marshall R. Urist: a renaissance scientist and orthopaedic surgeon. J Bone Joint Surg Am 2003;85-A:37.

  • 4.

    Sampath T, Reddi H. Bone morphogenetic protein (BMP) implants as bone graft substitutes—promises and challenges. In: Laurencin CT, ed. Bone graft substitutes. West Conshohocken, Pa: ASTM International & American Academy of Orthopaedic Surgeons, 2003;194213.

    • Search Google Scholar
    • Export Citation
  • 5.

    Urist MR, Strates BS. Bone morphogenetic protein. J Dent Res 1971;50:13921406.

  • 6.

    Kirker-Head CA. Potential applications and delivery strategies for bone morphogenetic proteins. Adv Drug Deliv Rev 2000;43:6592.

  • 7.

    Johnson EE, Marshall R, Urist MR. Resistant nonunions and partial or complete segmental defects of long bones. Treatment with implants of a compostie of human bone morphogenetic protein (BMP) and autolyzed, antigenextracted, allogeneic (AAA) bone. Clin Orthop Relat Res 1992;277:229237.

    • Search Google Scholar
    • Export Citation
  • 8.

    Johnson EE, Urist MR, Finerman GA. Bone morphogenetic protein augmentation grafting of resistant femoral nonunions. A preliminary report. Clin Orthop Relat Res 1988;230:257265.

    • Search Google Scholar
    • Export Citation
  • 9.

    Johnson EE, Urist MR, Finerman GA. Repair of segmental defects of the tibia with cancellous bone grafts augmented with human bone morphogenetic protein. A preliminary report. Clin Orthop Relat Res 1988;236:249257.

    • Search Google Scholar
    • Export Citation
  • 10.

    Kujala S, Raatikainen T, Ryhanen J, et al. Composite implant of native bovine bone morphogenetic protein (BMP), collagen carrier and biocoral in the treatment of resistant ulnar nonunions: report of five preliminary cases. Arch Orthop Trauma Surg 2004;124:2630.

    • Search Google Scholar
    • Export Citation
  • 11.

    Vallejo LF, Brokelmann M, Marten S, et al. Renaturation and purification of bone morphogenetic protein-2 produced as inclusion bodies in high-cell-density cultures of recombinant Escherichia coli. J Biotechnol 2002;94:185194.

    • Search Google Scholar
    • Export Citation
  • 12.

    Southwood LL, Frisbie DD, Kawcak CE, et al. Delivery of growth factors using gene therapy to enhance bone healing. Vet Surg 2004;33:565578.

    • Search Google Scholar
    • Export Citation
  • 13.

    European Agency for the Evaluation of Medicinal Products. Dibotermin alfa. Scientific discussion. European Public Assessment Record. Available at: www.emea.europa.eu/humandocs/pdfs/EPAR/inductos/318802en6.pdf. Accessed Sep 10, 2007.

    • Search Google Scholar
    • Export Citation
  • 14.

    Samartzis D, Khanna N, Shen FH, et al. Update on bone morphogenetic proteins and their application in spine surgery. J Am Coll Surg 2005;200:236248.

    • Search Google Scholar
    • Export Citation
  • 15.

    Lianjia Y, Yan J. Immunohistochemical observations on bone morphogenetic protein in normal and abnormal conditions. Clin Orthop Relat Res 1990;257:249256.

    • Search Google Scholar
    • Export Citation
  • 16.

    Sakou T. Bone morphogenetic proteins: from basic studies to clinical approaches. Bone 1998;22:591603.

  • 17.

    Bostrom MP. Expression of bone morphogenetic proteins in fracture healing. Clin Orthop Relat Res 1998;(suppl 355):S116S123.

  • 18.

    Cheng H, Jiang W, Phillips FM, et al. Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg Am 2003;85-A:15441552.

    • Search Google Scholar
    • Export Citation
  • 19.

    Ferguson CM, Miclau T, Hu D, et al. Common molecular pathways in skeletal morphogenesis and repair. Ann N Y Acad Sci 1998;857:3342.

  • 20.

    Karsenty G. Genetics of skeletogenesis. Dev Genet 1998;22:301313.

  • 21.

    Reddi AH. Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat Biotechnol 1998;16:247252.

  • 22.

    Irie K, Alpaslan C, Takahashi K, et al. Osteoclast differentiation in ectopic bone formation induced by recombinant human bone morphogenetic protein 2 (rhBMP-2). J Bone Miner Metab 2003;21:363369.

    • Search Google Scholar
    • Export Citation
  • 23.

    Ganan Y, Macias D, Duterque-Coquillaud M, et al. Role of TGF beta s and BMPs as signals controlling the position of the digits and the areas of interdigital cell death in the developing chick limb autopod. Development 1996;122:23492357.

    • Search Google Scholar
    • Export Citation
  • 24.

    Zou H, Niswander L. Requirement for BMP signaling in interdigital apoptosis and scale formation. Science 1996;272:738741.

  • 25.

    Barth KA, Kishimoto Y, Rohr KB, et al. BMP activity establishes a gradient of positional information throughout the entire neural plate. Development 1999;126:49774987.

    • Search Google Scholar
    • Export Citation
  • 26.

    Farkas LM, Jaszai J, Unsicker K, et al. Characterization of bone morphogenetic protein family members as neurotrophic factors for cultured sensory neurons. Neuroscience 1999;92:227235.

    • Search Google Scholar
    • Export Citation
  • 27.

    Mabie PC, Mehler MF, Kessler JA. Multiple roles of bonemorphogenetic protein signaling in the regulation of cortical cell number and phenotype. J Neurosci 1999;19:70777088.

    • Search Google Scholar
    • Export Citation
  • 28.

    Mehler MF, Mabie PC, Zhang D, et al. Bone morphogenetic proteins in the nervous system. Trends Neurosci 1997;20:309317.

  • 29.

    Keshishian H, Kim YS. Orchestrating development and function: retrograde BMP signaling in the Drosophila nervous system. Trends Neurosci 2004;27:143147.

    • Search Google Scholar
    • Export Citation
  • 30.

    Mohan RR, Kim WJ, Mohan RR, et al. Bone morphogenic proteins 2 and 4 and their receptors in the adult human cornea. Invest Ophthalmol Vis Sci 1998;39:26262636.

    • Search Google Scholar
    • Export Citation
  • 31.

    You L, Kruse FE, Pohl J, et al. Bone morphogenetic proteins and growth and differentiation factors in the human cornea. Invest Ophthalmol Vis Sci 1999;40:296311.

    • Search Google Scholar
    • Export Citation
  • 32.

    Peters H, Balling R. Teeth. Where and how to make them. Trends Genet 1999;15:5965.

  • 33.

    Harris SE, Harris MA, Mahy P, et al. Expression of bone morphogenetic protein messenger RNAs by normal rat and human prostate and prostate cancer cells. Prostate 1994;24:204211.

    • Search Google Scholar
    • Export Citation
  • 34.

    Shimasaki S, Zachow RJ, Li D, et al. A functional bone morphogenetic protein system in the ovary. Proc Natl Acad Sci U S A 1999;96:72827287.

    • Search Google Scholar
    • Export Citation
  • 35.

    Weaver M, Yingling JM, Dunn NR, et al. Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development. Development 1999;126:40054015.

    • Search Google Scholar
    • Export Citation
  • 36.

    Ozkaynak E, Schnegelsberg PN, Oppermann H. Murine osteogenic protein (OP-1): high levels of mRNA in kidney. Biochem Biophys Res Commun 1991;179:116123.

    • Search Google Scholar
    • Export Citation
  • 37.

    Croteau S, Rauch F, Silvestri A, et al. Bone morphogenetic proteins in orthopedics: from basic science to clinical practice. Orthopedics 1999;22:686695.

    • Search Google Scholar
    • Export Citation
  • 38.

    Sampath TK, Rashka KE, Doctor JS, et al. Drosophila transforming growth factor beta superfamily proteins induce endochondral bone formation in mammals. Proc Natl Acad Sci U S A 1993;90:60046008.

    • Search Google Scholar
    • Export Citation
  • 39.

    Hayward DC, Samuel G, Pontynen PC, et al. Localized expression of a dpp/BMP2/4 ortholog in a coral embryo. Proc Natl Acad Sci U S A 2002;99:81068111.

    • Search Google Scholar
    • Export Citation
  • 40.

    Wozney JM, Rosen V. Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair. Clin Orthop Relat Res 1998;346:2637.

    • Search Google Scholar
    • Export Citation
  • 41.

    Sampath TK, Coughlin JE, Whetstone RM, et al. Bovine osteogenic protein is composed of dimers of OP-1 and BMP-2A, two members of the transforming growth factor-beta superfamily. J Biol Chem 1990;265:1319813205.

    • Search Google Scholar
    • Export Citation
  • 42.

    Cheung E, Katti D, Rosier R, et al. Review of state of the art: growth factor based systems for use as bone graft substitutes. In: Laurencin C, ed. Bone graft substitutes. West Conshohocken, Pa: ASTM International & the American Academy of Orthopaedic Surgeons, 2003;174193.

    • Search Google Scholar
    • Export Citation
  • 43.

    Arteaga-Solis E, Gayraud B, Lee SY, et al. Regulation of limb patterning by extracellular microfibrils. J Cell Biol 2001;154:275281.

  • 44.

    Larrain J, Oelgeschlager M, Ketpura NI, et al. Proteolytic cleavage of Chordin as a switch for the dual activities of Twisted gastrulation in BMP signaling. Development 2001;128:44394447.

    • Search Google Scholar
    • Export Citation
  • 45.

    Ohkawara B, Iemura S, ten Dijke P, et al. Action range of BMP is defined by its N-terminal basic amino acid core. Curr Biol 2002;12:205209.

    • Search Google Scholar
    • Export Citation
  • 46.

    Rosen V. BMP and BMP inhibitors in bone. Ann N Y Acad Sci 2006;1068:1925.

  • 47.

    Wan M, Cao X. BMP signaling in skeletal development. Biochem Biophys Res Commun 2005;328:651657.

  • 48.

    Tsuji K, Bandyopadhyay A, Harfe BD, et al. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet 2006;38:14241429.

    • Search Google Scholar
    • Export Citation
  • 49.

    Bandyopadhyay A, Tsuji K, Cox K, et al. Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet 2006;2:e216.

    • Search Google Scholar
    • Export Citation
  • 50.

    Nilsson O, Parker EA, Hegde A, et al. Gradients in bone morphogenetic protein-related gene expression across the growth plate. J Endocrinol 2007;193:7584.

    • Search Google Scholar
    • Export Citation
  • 51.

    Minina E, Schneider S, Rosowski M, et al. Expression of Fgf and Tgfbeta signaling related genes during embryonic endochondral ossification. Gene Expr Patterns 2005;6:102109.

    • Search Google Scholar
    • Export Citation
  • 52.

    Kobayashi T, Lyons KM, McMahon AP, et al. BMP signaling stimulates cellular differentiation at multiple steps during cartilage development. Proc Natl Acad Sci U S A 2005;102:1802318027.

    • Search Google Scholar
    • Export Citation
  • 53.

    Urist MR, Hudak RT. Radioimmunoassay of bone morphogenetic protein in serum: a tissue-specific parameter of bone metabolism. Proc Soc Exp Biol Med 1984;176:472475.

    • Search Google Scholar
    • Export Citation
  • 54.

    Einhorn TA. Clinical applications of recombinant gene technology: bone and cartilage repair. Cells Mater 1992;2:111.

  • 55.

    Turgeman G, Zilberman Y, Zhou S, et al. Systemically administered rhBMP-2 promotes MSC activity and reverses bone and cartilage loss in osteopenic mice. J Cell Biochem 2002;86:461474.

    • Search Google Scholar
    • Export Citation
  • 56.

    Maric I, Poljak L, Zoricic S, et al. Bone morphogenetic protein7 reduces the severity of colon tissue damage and accelerates the healing of inflammatory bowel disease in rats. J Cell Physiol 2003;196:258264.

    • Search Google Scholar
    • Export Citation
  • 57.

    Lefer AM, Tsao PS, Ma XL, et al. Anti-ischaemic and endothelial protective actions of recombinant human osteogenic protein (hOP-1). J Mol Cell Cardiol 1992;24:585593.

    • Search Google Scholar
    • Export Citation
  • 58.

    Chang CF, Lin SZ, Chiang YH, et al. Intravenous administration of bone morphogenetic protein-7 after ischemia improves motor function in stroke rats. Stroke 2003;34:558564.

    • Search Google Scholar
    • Export Citation
  • 59.

    Niksic L, Martin PY. BMP-7 (Bone morphogenetic protein-7): a future treatment for chronic renal failure? [in French]. Rev Med Suisse 2005;1:568570, 572573.

    • Search Google Scholar
    • Export Citation
  • 60.

    Alden TD, Varady P, Kallmes DF, et al. Bone morphogenetic protein gene therapy. Spine 2002;27:S87S93.

  • 61.

    Niyibizi C, Baltzer A, Lattermann C, et al. Potential role for gene therapy in the enhancement of fracture healing. Clin Orthop Relat Res 1998;(suppl 355):S148S153.

    • Search Google Scholar
    • Export Citation
  • 62.

    Chen Y. Orthopedic applications of gene therapy. J Orthop Sci 2001;6:199207.

  • 63.

    Goldstein SA, Bonadio J. Potential role for direct gene transfer in the enhancement of fracture healing. Clin Orthop Relat Res 1998;(suppl 355):S154S162.

    • Search Google Scholar
    • Export Citation
  • 64.

    Fang J, Zhu YY, Smiley E, et al. Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci U S A 1996;93:57535758.

    • Search Google Scholar
    • Export Citation
  • 65.

    Zhang YP, Sekirov L, Saravolac EG, et al. Stabilized plasmidlipid particles for regional gene therapy: formulation and transfection properties. Gene Ther 1999;6:14381447.

    • Search Google Scholar
    • Export Citation
  • 66.

    Musgrave DS, Bosch P, Lee JY, et al. Ex vivo gene therapy to produce bone using different cell types. Clin Orthop Relat Res 2000;378:290305.

    • Search Google Scholar
    • Export Citation
  • 67.

    Lieberman JR, Le LQ, Wu L, et al. Regional gene therapy with a BMP-2-producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents. J Orthop Res 1998;16:330339.

    • Search Google Scholar
    • Export Citation
  • 68.

    Lou J, Xu F, Merkel K, et al. Gene therapy: adenovirus-mediated human bone morphogenetic protein-2 gene transfer induces mesenchymal progenitor cell proliferation and differentiation in vitro and bone formation in vivo. J Orthop Res 1999;17:4350.

    • Search Google Scholar
    • Export Citation
  • 69.

    Gazit D, Turgeman G, Kelley P, et al. Engineered pluripotent mesenchymal cells integrate and differentiate in regenerating bone: a novel cell-mediated gene therapy. J Gene Med 1999;1:121133.

    • Search Google Scholar
    • Export Citation
  • 70.

    Wright V, Peng H, Usas A, et al. BMP4-expressing musclederived stem cells differentiate into osteogenic lineage and improve bone healing in immunocompetent mice. Mol Ther 2002;6:169178.

    • Search Google Scholar
    • Export Citation
  • 71.

    Bertone AL, Pittman DD, Bouxsein ML, et al. Adenoviral-mediated transfer of human BMP-6 gene accelerates healing in a rabbit ulnar osteotomy model. J Orthop Res 2004;22:12611270.

    • Search Google Scholar
    • Export Citation
  • 72.

    Lieberman JR, Daluiski A, Stevenson S, et al. The effect of regional gene therapy with bone morphogenetic protein-2-producing bone-marrow cells on the repair of segmental femoral defects in rats. J Bone Joint Surg Am 1999;81:905917.

    • Search Google Scholar
    • Export Citation
  • 73.

    Baltzer AW, Lattermann C, Whalen JD, et al. Genetic enhancement of fracture repair: healing of an experimental segmental defect by adenoviral transfer of the BMP-2 gene. Gene Ther 2000;7:734739.

    • Search Google Scholar
    • Export Citation
  • 74.

    Einhorn TA, Majeska RJ, Mohaideen A, et al. A single percutaneous injection of recombinant human bone morphogenetic protein-2 accelerates fracture repair. J Bone Joint Surg Am 2003;85A:14251435.

    • Search Google Scholar
    • Export Citation
  • 75.

    Winn SR, Uludag H, Hollinger JO. Carrier systems for bone morphogenetic proteins. Clin Orthop Relat Res 1999;(suppl 367):S95S106.

  • 76.

    Cook SD, Baffes GC, Wolfe MW, et al. Recombinant human bone morphogenetic protein-7 induces healing in a canine long-bone segmental defect model. Clin Orthop Relat Res 1994;301:302312.

    • Search Google Scholar
    • Export Citation
  • 77.

    Welch RD, Jones AL, Bucholz RW, et al. Effect of recombinant human bone morphogenetic protein-2 on fracture healing in a goat tibial fracture model. J Bone Miner Res 1998;13:14831490.

    • Search Google Scholar
    • Export Citation
  • 78.

    De Groot J. Carriers that concentrate native bone morphogenetic protein in vivo. Tissue Eng 1998;4:337341.

  • 79.

    Seeherman H, Li R, Wozney J. A review of preclinical program development for evaluating injectable carriers for osteogenic factors. J Bone Joint Surg Am 2003;85-A(suppl 3):96108.

    • Search Google Scholar
    • Export Citation
  • 80.

    Gerhart TN, Kirker-Head CA, Kriz MJ, et al. Healing segmental femoral defects in sheep using recombinant human bone morphogenetic protein. Clin Orthop Relat Res 1993;293:317326.

    • Search Google Scholar
    • Export Citation
  • 81.

    Kirker-Head CA, Gerhart TN, Schelling SH, et al. Long-term healing of bone using recombinant human bone morphogenetic protein 2. Clin Orthop Relat Res 1995;318:222230.

    • Search Google Scholar
    • Export Citation
  • 82.

    Vail TB, Trotter GW, Powers BE. Equine demineralized bone matrix: relationship between particle size and osteoinduction. Vet Surg 1994;23:386395.

    • Search Google Scholar
    • Export Citation
  • 83.

    Takaoka K, Koezuka M, Nakahara H. Telopeptide-depleted bovine skin collagen as a carrier for bone morphogenetic protein. J Orthop Res 1991;9:902907.

    • Search Google Scholar
    • Export Citation
  • 84.

    Strong MD, Sayers MH, Conrad EU. Screening tissue donors for infectious markers. In: Friedlaender GE, Goldberg VM, eds. Bone and cartilage allografts. Park Ridge, Ill: American Academy of Orthopedic Surgeons, 1989;193211.

    • Search Google Scholar
    • Export Citation
  • 85.

    Geiger M, Li RH, Friess W. Collagen sponges for bone regeneration with rhBMP-2. Adv Drug Deliv Rev 2003;55:16131629.

  • 86.

    Friess W, Uludag H, Foskett S, et al. Characterization of absorbable collagen sponges as recombinant human bone morphogenetic protein-2 carriers. Int J Pharm 1999;185:5160.

    • Search Google Scholar
    • Export Citation
  • 87.

    Seeherman H, Wozney JM. Delivery of bone morphogenetic proteins for orthopedic tissue regeneration. Cytokine Growth Factor Rev 2005;16:329345.

    • Search Google Scholar
    • Export Citation
  • 88.

    Yang C, Hillas PJ, Baez JA, et al. The application of recombinant human collagen in tissue engineering. BioDrugs 2004;18:103119.

  • 89.

    Sofia S, McCarthy MB, Gronowicz G, et al. Functionalized silk-based biomaterials for bone formation. J Biomed Mater Res 2000;54:139148.

    • Search Google Scholar
    • Export Citation
  • 90.

    Meinel L, Hofmann S, Karageorgiou V, et al. The inflammatory responses to silk films in vitro and in vivo. Biomaterials 2005;26:147155.

    • Search Google Scholar
    • Export Citation
  • 91.

    Meinel L, Betz O, Fajardo R, et al. Silk based biomaterials to heal critical sized femur defects. Bone 2006;39:922931.

  • 92.

    Kirker-Head C, Karageorgian V, Hofmann S, et al. BMP-silk composite matrices heal critically sized femoral defects. Bone 2007;41:247255.

    • Search Google Scholar
    • Export Citation
  • 93.

    Kirker-Head CA, Gerhart TN, Armstrong R, et al. Healing bone using recombinant human bone morphogenetic protein 2 and copolymer. Clin Orthop Relat Res 1998;349:205217.

    • Search Google Scholar
    • Export Citation
  • 94.

    Wang Y, Kim YM, Langer R. In vivo degradation characteristics of poly(glycerol sebacate). J Biomed Mater Res A 2003;66:192197.

  • 95.

    Saito N, Okada T, Horiuchi H, et al. Local bone formation by injection of recombinant human bone morphogenetic protein-2 contained in polymer carriers. Bone 2003;32:381386.

    • Search Google Scholar
    • Export Citation
  • 96.

    Bulpitt P, Aeschlimann D. New strategy for chemical modification of hyaluronic acid: preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels. J Biomed Mater Res 1999;47:152169.

    • Search Google Scholar
    • Export Citation
  • 97.

    Hong L, Tabata Y, Yamamoto M, et al. Comparison of bone regeneration in a rabbit skull defect by recombinant human BMP-2 incorporated in biodegradable hydrogel and in solution. J Biomater Sci Polym Ed 1998;9:10011014.

    • Search Google Scholar
    • Export Citation
  • 98.

    Yamamoto M, Tabata Y, Ikada Y. Ectopic bone formation induced by biodegradable hydrogels incorporating bone morphogenetic protein. J Biomater Sci Polym Ed 1998;9:439458.

    • Search Google Scholar
    • Export Citation
  • 99.

    Yamamoto M, Takahashi Y, Tabata Y. Enhanced bone regeneration at a segmental bone defect by controlled release of bone morphogenetic protein-2 from a biodegradable hydrogel. Tissue Eng 2006;12:13051311.

    • Search Google Scholar
    • Export Citation
  • 100.

    Lutolf MP, Hubbell JA. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat Biotechnol 2005;23:4755.

    • Search Google Scholar
    • Export Citation
  • 101.

    Lutolf MP, Weber FE, Schmoekel HG, et al. Repair of bone defects using synthetic mimetics of collagenous extracellular matrices. Nat Biotechnol 2003;21:513518.

    • Search Google Scholar
    • Export Citation
  • 102.

    Wozney JM, Li RH. Engineering what comes naturally. Nat Biotechnol 2003;21:506508.

  • 103.

    Lindholm TS, Gao TJ. Functional carriers for bone morphogenetic proteins. Ann Chir Gynaecol Suppl 1993;207:312.

  • 104.

    Edwards RB 3rd, Seeherman HJ, Bogdanske JJ, et al. Percutaneous injection of recombinant human bone morphogenetic protein-2 in a calcium phosphate paste accelerates healing of a canine tibial osteotomy. J Bone Joint Surg Am 2004;86-A:14251438.

    • Search Google Scholar
    • Export Citation
  • 105.

    Akamaru T, Suh D, Boden SD, et al. Simple carrier matrix modifications can enhance delivery of recombinant human bone morphogenetic protein-2 for posterolateral spine fusion. Spine 2003;28:429434.

    • Search Google Scholar
    • Export Citation
  • 106.

    Spiro RC, Liu L, Heidaran MA, et al. Inductive activity of recombinant human growth and differentiation factor-5. Biochem Soc Trans 2000;28:362368.

    • Search Google Scholar
    • Export Citation
  • 107.

    Jahng TA, Fu TS, Cunningham BW, et al. Endoscopic instrumented posterolateral lumbar fusion with Healos and recombinant human growth/differentiation factor-5. Neurosurgery 2004;54:171180.

    • Search Google Scholar
    • Export Citation
  • 108.

    Govender S, Csimma C, Genant HK, et al. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 2002;84-A:21232134.

    • Search Google Scholar
    • Export Citation
  • 109.

    Friedlaender GE, Perry CR, Cole JD, et al. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 2001;83-A(suppl 1):S151S158.

    • Search Google Scholar
    • Export Citation
  • 110.

    den Boer FC, Bramer JA, Blokhuis TJ, et al. Effect of recombinant human osteogenic protein-1 on the healing of a freshly closed diaphyseal fracture. Bone 2002;31:158164.

    • Search Google Scholar
    • Export Citation
  • 111.

    Bouxsein ML, Turek TJ, Blake CA, et al. Recombinant human bone morphogenetic protein-2 accelerates healing in a rabbit ulnar osteotomy model. J Bone Joint Surg Am 2001;83-A:12191230.

    • Search Google Scholar
    • Export Citation
  • 112.

    Faria ML, Lu Y, Heaney K, et al. Recombinant human bone morphogenetic protein-2 in absorbable collagen sponge enhances bone healing of tibial osteotomies in dogs. Vet Surg 2007;36:122131.

    • Search Google Scholar
    • Export Citation
  • 113.

    Paatsama S, Lindholm S, Oksanen J, et al. The use of bone morphogenetic proteins in delayed fracture healing, pseudoarthrosis and in ulna osteotomy carried out because of elbow joint diseases [in German]. Tierarztl Prax 1996;24:164168.

    • Search Google Scholar
    • Export Citation
  • 114.

    Itoh T, Mochizuki M, Fuda K, et al. Femoral nonunion fracture treated with recombinant human bone morphogenetic protein-2 in a dog. J Vet Med Sci 1998;60:535538.

    • Search Google Scholar
    • Export Citation
  • 115.

    Hong H. Ulnar radial nonunion fracture treated with recombinant human bone morphogenetic protein-2 in a dog. J Vet Clin (Seoul) 2001;18:156159.

    • Search Google Scholar
    • Export Citation
  • 116.

    Schmokel HG, Weber FE, Seiler G, et al. Treatment of nonunions with nonglycosylated recombinant human bone morphogenetic protein-2 delivered from a fibrin matrix. Vet Surg 2004;33:112118.

    • Search Google Scholar
    • Export Citation
  • 117.

    Milovancev M, Muir P, Manley PA, et al. Clinical application of recombinant human bone morphogenetic protein-2 in 4 dogs. Vet Surg 2007;36:132140.

    • Search Google Scholar
    • Export Citation
  • 118.

    Shen HC, Peng H, Usas A, et al. Structural and functional healing of critical-size segmental bone defects by transduced muscle-derived cells expressing BMP4. J Gene Med 2004;6:984991.

    • Search Google Scholar
    • Export Citation
  • 119.

    Dzugan S, Galjour C, Conflitti J, et al. Sustained release of OP-1 and antibiotics in treatment of femoral defects in male rats. Biomed Sci Instrum 2005;41:8085.

    • Search Google Scholar
    • Export Citation
  • 120.

    Hu YY, Zhang C, Lu R, et al. Repair of radius defect with bonemorphogenetic-protein loaded hydroxyapatite/collagen-poly (L-lactic acid) composite. Chin J Traumatol 2003;6:6774.

    • Search Google Scholar
    • Export Citation
  • 121.

    Dai KR, Xu XL, Tang TT, et al. BMP-2 gene modified tissue-engineered bone repairing segmental tibial bone defects in goats [in Chinese]. Zhonghua Yi Xue Za Zhi 2003;83:13451349.

    • Search Google Scholar
    • Export Citation
  • 122.

    Kokubo S, Fujimoto R, Yokota S, et al. Bone regeneration by recombinant human bone morphogenetic protein-2 and a novel biodegradable carrier in a rabbit ulnar defect model. Biomaterials 2003;24:16431651.

    • Search Google Scholar
    • Export Citation
  • 123.

    Geesink RG, Hoefnagels NH, Bulstra SK. Osteogenic activity of OP-1 bone morphogenetic protein (BMP-7) in a human fibular defect. J Bone Joint Surg Br 1999;81:710718.

    • Search Google Scholar
    • Export Citation
  • 124.

    Riew KD, Lou J, Wright NM, et al. Thoracoscopic intradiscal spine fusion using a minimally invasive gene-therapy technique. J Bone Joint Surg Am 2003;85-A:866871.

    • Search Google Scholar
    • Export Citation
  • 125.

    Campisi P, Hamdy RC, Lauzier D, et al. Expression of bone morphogenetic proteins during mandibular distraction osteogenesis. Plast Reconstr Surg 2003;111:201208, discussion 209210.

    • Search Google Scholar
    • Export Citation
  • 126.

    Kraiwattanapong C, Boden SD, Louis-Ugbo J, et al. Comparison of Healos/bone marrow to INFUSE(rhBMP-2/ACS) with a collagen-ceramic sponge bulking agent as graft substitutes for lumbar spine fusion. Spine 2005;30:10011007.

    • Search Google Scholar
    • Export Citation
  • 127.

    Arosarena OA, Falk A, Malmgren L, et al. Defect repair in the rat mandible with bone morphogenic proteins and marrow cells. Arch Facial Plast Surg 2003;5:103108.

    • Search Google Scholar
    • Export Citation
  • 128.

    Park J, Ries J, Gelse K, et al. Bone regeneration in critical size defects by cell-mediated BMP-2 gene transfer: a comparison of adenoviral vectors and liposomes. Gene Ther 2003;10:10891098.

    • Search Google Scholar
    • Export Citation
  • 129.

    Sun Y, Ma G, Li D. Repair of large cranial defect using allogeneic cranial bone and bone morphogenetic protein [in Chinese]. Zhonghua Zheng Xing Shao Shang Wai Ke Za Zhi 1995;11:89.

    • Search Google Scholar
    • Export Citation
  • 130.

    Ma G, Zhu XZ. Clinical observation on repair of bone defects in maxillofacial region by grafting hydroxylapatite combined with porcine bone morphogenetic protein [in Chinese]. Zhonghua Kou Qiang Yi Xue Za Zhi 1994;29:223225.

    • Search Google Scholar
    • Export Citation
  • 131.

    Sailer HF, Kolb E. Application of purified bone morphogenetic protein (BMP) in cranio-maxillo-facial surgery. BMP in compromised surgical reconstructions using titanium implants. J Craniofac Surg 1994;22:211.

    • Search Google Scholar
    • Export Citation
  • 132.

    Moghadam HG, Urist MR, Sandor GK, et al. Successful mandibular reconstruction using a BMP bioimplant. J Craniofac Surg 2001;12:119127.

    • Search Google Scholar
    • Export Citation
  • 133.

    Boudrieau RJ, Mitchell SL, Seeherman H. Mandibular reconstruction of a partial hemimandibulectomy in a dog with severe malocclusion. Vet Surg 2004;33:119130.

    • Search Google Scholar
    • Export Citation
  • 134.

    Kawamoto T, Motohashi N, Kitamura A, et al. Experimental tooth movement into bone induced by recombinant human bone morphogenetic protein-2. Cleft Palate Craniofac J 2003;40:538543.

    • Search Google Scholar
    • Export Citation
  • 135.

    Jin QM, Anusaksathien O, Webb SA, et al. Gene therapy of bone morphogenetic protein for periodontal tissue engineering. J Periodontol 2003;74:202213.

    • Search Google Scholar
    • Export Citation
  • 136.

    Takahashi D, Odajima T, Morita M, et al. Formation and resolution of ankylosis under application of recombinant human bone morphogenetic protein-2 (rhBMP-2) to class III furcation defects in cats. J Periodontal Res 2005;40:299305.

    • Search Google Scholar
    • Export Citation
  • 137.

    Wikesjo UM, Xiropaidis AV, Thomson RC, et al. Periodontal repair in dogs: rhBMP-2 significantly enhances bone formation under provisions for guided tissue regeneration. J Clin Periodontol 2003;30:705714.

    • Search Google Scholar
    • Export Citation
  • 138.

    Wikesjo UM, Qahash M, Thomson RC, et al. rhBMP-2 significantly enhances guided bone regeneration. Clin Oral Implants Res 2004;15:194204.

    • Search Google Scholar
    • Export Citation
  • 139.

    Jovanovic SA, Hunt DR, Bernard GW, et al. Long-term functional loading of dental implants in rhBMP-2 induced bone. A histologic study in the canine ridge augmentation model. Clin Oral Implants Res 2003;14:793803.

    • Search Google Scholar
    • Export Citation
  • 140.

    Wikesjo UM, Sorensen RG, Kinoshita A, et al. Periodontal repair in dogs: effect of recombinant human bone morphogenetic protein-12 (rhBMP-12) on regeneration of alveolar bone and periodontal attachment. J Clin Periodontol 2004;31:662670.

    • Search Google Scholar
    • Export Citation
  • 141.

    Sorensen RG, Polimeni G, Kinoshita A, et al. Effect of recombinant human bone morphogenetic protein-12 (rhBMP-12) on regeneration of periodontal attachment following tooth replantation in dogs. J Clin Periodontol 2004;31:654661.

    • Search Google Scholar
    • Export Citation
  • 142.

    Saito E, Saito A, Kawanami M. Favorable healing following space creation in rhBMP-2-induced periodontal regeneration of horizontal circumferential defects in dogs with experimental periodontitis. J Periodontol 2003;74:18081815.

    • Search Google Scholar
    • Export Citation
  • 143.

    Kirker-Head CA, Nevins M, Palmer R, et al. A new animal model for maxillary sinus floor augmentation: evaluation parameters. Int J Oral Maxillofac Implants 1997;12:403411.

    • Search Google Scholar
    • Export Citation
  • 144.

    Jung RE, Glauser R, Scharer P, et al. Effect of rhBMP-2 on guided bone regeneration in humans. Clin Oral Implants Res 2003;14:556568.

    • Search Google Scholar
    • Export Citation
  • 145.

    Bragdon CR, Doherty AM, Rubash HE, et al. The efficacy of BMP-2 to induce bone ingrowth in a total hip replacement model. Clin Orthop Relat Res 2003;417:5061.

    • Search Google Scholar
    • Export Citation
  • 146.

    Barrack RL, Cook SD, Patron LP, et al. Induction of bone ingrowth from acetabular defects to a porous surface with OP-1. Clin Orthop Relat Res 2003;417:4149.

    • Search Google Scholar
    • Export Citation
  • 147.

    Soballe K, Jensen TB, Mouzin O, et al. Differential effect of a bone morphogenetic protein-7 (OP-1) on primary and revision loaded, stable implants with allograft. J Biomed Mater Res A 2004;71:569576.

    • Search Google Scholar
    • Export Citation
  • 148.

    Yazawa M, Kishi K, Nakajima H, et al. Expression of bone morphogenetic proteins during mandibular distraction osteogenesis in rabbits. J Oral Maxillofac Surg 2003;61:587592.

    • Search Google Scholar
    • Export Citation
  • 149.

    Farhadieh RD, Gianoutsos MP, Yu Y, et al. The role of bone morphogenetic proteins BMP-2 and BMP-4 and their related postreceptor signaling system (Smads) in distraction osteogenesis of the mandible. J Craniofac Surg 2004;15:714718.

    • Search Google Scholar
    • Export Citation
  • 150.

    Mizumoto Y, Moseley T, Drews M, et al. Acceleration of regenerate ossification during distraction osteogenesis with recombinant human bone morphogenetic protein-7. J Bone Joint Surg Am 2003;85-A(suppl 3):124130.

    • Search Google Scholar
    • Export Citation
  • 151.

    Friedlaender G. Clinical experience of osteogenic protein-1 (OP-1) in the repair of bone defects and fractures of long bones. In: Vukicevik S, Sampath KT, eds. Bone morphogenetic proteins: regeneration of bone and beyond. Basel, Switzerland: Birkhauser Verlag, 2004;157163.

    • Search Google Scholar
    • Export Citation
  • 152.

    Poynton AR, Lane JM. Safety profile for the clinical use of bone morphogenetic proteins in the spine. Spine 2002;27:S40S48.

  • 153.

    European Agency for the Evaluation of Medicinal Products. Eptotermin alfa. Scientific discussion. European Public Assessment Record. 2002. Available at: www.emea.europa.eu/humandocs/pdfs/EPAR/Osigraft/039301en6.pdf. Accessed Sep 10, 2007.

    • Search Google Scholar
    • Export Citation
  • 154.

    Kirker-Head C. Development and application of bone morphogenetic proteins for the enhancement of bone healing. J Orthop Traumatol 2005;6:19.

    • Search Google Scholar
    • Export Citation

Advertisement

Use of bone morphogenetic proteins for augmentation of bone regeneration

Carl A. Kirker-Head MA, Vet MB, DACVS, DECVS1, Randy J. Boudrieau DVM, DACVS, DECVS2, and Karl H. Kraus MSc, DVM, DACVS, DABVP3
View More View Less
  • 1 Orthopaedic Research Laboratory, Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536.
  • | 2 Orthopaedic Research Laboratory, Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536.
  • | 3 Orthopaedic Research Laboratory, Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536.

Refinements in anesthetic and surgical techniques, implant design and application, and perioperative management have helped substantially improve treatment of complex fractures and other skeletal defects caused by trauma, disease, developmental deformity, and tumor resection. Nonetheless, an unfavorable wound environment caused by adverse tissue conditions, suboptimal surgical technique, or large body mass relative to fixation strength can lead to delayed healing or nonunion. Under these circumstances, some means of augmenting or accelerating bone regeneration would be desirable. A number of techniques have been used in attempts to achieve this goal, including various organic and inorganic osteoconductive and osteopromotive implants, biomechanical stimuli,

Contributor Notes

Dr. Kraus' present address is the Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.

Address correspondence to Dr. Kirker-Head.