Skip to main content
SpringerLink
Log in

Repairing of goat Tibial Bone Defects with BMP-2 Gene–Modified Tissue-Engineered Bone

  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Bone defects larger than a critical size are major challenges in orthopedic medicine. We combined tissue-engineered bone and gene therapy to provide osteoprogenitor cells, osteoinductive factors, and osteoconductive carrier for ideal bone regeneration in critical-sized bone defects. Goat diaphyseal bone defects were repaired with tissue and genetically engineered bone implants, composed of biphasic calcined bone (BCB) and autologous bone marrow derived mesenchymal stem cells (BMSC) transduced with human bone morphogenetic protein-2 (hBMP-2). Twenty six goats with tibial bone defects were divided into groups receiving implants by using a combination of BCB and BMSCs with or without the hBMP-2 gene. In eight goats that were treated with BCB that contained hBMP-2 transduced BMSC, five had complete healing and three showed partial healing. Goats in other experimental groups had only slight or no healing. Furthermore, the area and biochemical strength of the callus in the bone defects were significantly better in animals treated with genetically engineered implants. We concluded that the combination of genetic and tissue engineering provides an innovative way for treating critical-sized bone defects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. TJ Gao TS Lindholm B Kommonen P Ragni A Paronzini TC Lindholm P Jalovaara MR Urist (1997) ArticleTitleThe use of a coral composite implant containing bone morphogenetic protein to repair a segmental tibial defect in sheep Int Orthop 21 194–200 Occurrence Handle10.1007/s002640050149 Occurrence Handle9266302

    Article  PubMed  Google Scholar 

  2. XL Xu KW Wang ZH Yang (2001) ArticleTitleA biomechanical study of bBMP-collagen-coral composite bone substitute in the repair of bone defects of femoral heads China J Orthop ‘Trauma 14 17–19

    Google Scholar 

  3. CA Kirker-Head TN Gerhart R Armstrong SH Schelling LA Carmel (1998) ArticleTitleHealing bone using recombinant human bone morphogenetic protein 2 and copolymer Clin Orthop 349 205–217 Occurrence Handle9584385

    PubMed  Google Scholar 

  4. JM Wozney V Rosen (1998) ArticleTitleBone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair Clin Orthop 346 26–37 Occurrence Handle9577407

    PubMed  Google Scholar 

  5. GE Friedlaender CR Perry JD Cole SD Cook G Cierny GF Muschler GA Zych JH Calhoun AJ LaForte S Yin (2001) ArticleTitleOsteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions J Bone Joint Surg Ann 83 IssueIDSuppl 1 151–158

    Google Scholar 

  6. EE Johnson MR Urist (1998) ArticleTitleOne-stage lengthening of femoral nonunion augmented with human bone morphogenetic protein Clin Orthop 347 105–116 Occurrence Handle9520880

    PubMed  Google Scholar 

  7. H Schilephake (2002) ArticleTitleBone growth factors in maxillofacial skeletal reconstruction Int J Oral Maxillofac Surg 31 469–484 Occurrence Handle10.1054/ijom.2002.0244 Occurrence Handle12418561

    Article  PubMed  Google Scholar 

  8. J Lou F Xu K Merkel P Manske (1999) ArticleTitleGene 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 17 43–50 Occurrence Handle10.1002/jor.1100170108 Occurrence Handle10073646

    Article  PubMed  Google Scholar 

  9. Y Okubo K Bessho K Fujimura T lizuka SI Miyatake (2001) ArticleTitleIn vitro and in vivo studies of a bone morphogenetic protein-2 expressing adenoviral vector J Bone Joint Surg Am 83 IssueIDSuppl 1 99–104 Occurrence Handle10.1302/0301-620X.83B1.10699

    Article  Google Scholar 

  10. DS Musgrave P Bosch JY Lee D Pelinkovic SC Ghivizzani J Whalen C Niyibizi J Huard (2000) ArticleTitleEx vivo gene therapy to produce bone using different cell types Clin Orthop 378 290–305 Occurrence Handle10.1097/00003086-200009000-00040 Occurrence Handle10987005

    Article  PubMed  Google Scholar 

  11. PH Krebsbach K Gu RT Franceschi RB Rutherford (2000) ArticleTitleGene therapy-directed osteogenesis: BMP-7-transduced human fibroblasts form bone in vivo Hum Gene Ther 11 1201–l210 Occurrence Handle10.1089/10430340050015248 Occurrence Handle10834621

    Article  PubMed  Google Scholar 

  12. LL Zhu KR Dai TT Tang (2003) ArticleTitleBMP-2 gene transfected human bone marrow mesenchymal stem cells inducing in vivo ectopic osteogenesis of nude mice Chinese J Reparative Reconstructive Surgery 17(2) 131–135

    Google Scholar 

  13. Y Chen KM Cheung HF Kung JC Leong WW Lu KD Luk (2002) ArticleTitleIn vivo new bone formation by direct transfer of adenoviral-mediated bone morphogenetic protein-4 gene Biochem Biophys Res Commun 298 121–127 Occurrence Handle10.1016/S0006-291X(02)02394-X Occurrence Handle12379229

    Article  PubMed  Google Scholar 

  14. JR Lieberman A Daluiski S Stevenson L Wu P McAllister YP Lee JM Kabo GA Finerman AJ Berk ON Witte (1999) ArticleTitleThe 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 81 905–917 Occurrence Handle10428121

    PubMed  Google Scholar 

  15. JY Lee D Musgrave D Pelinkovic K Fukushima J Cummins A Usas P Robbins FH Fu J Huard (2001) ArticleTitleEffect of bone morphogenetic protein-2-expressing muscle-derived cells on healing of critical-sized bone defects in mice J Bone Joint Surg Am 83 1032–1039 Occurrence Handle11451972

    PubMed  Google Scholar 

  16. H Tsuchida J Hashimoto E Crawford P Manske J Lou (2003) ArticleTitleEngineered allogeneic mesenchymal stem cells repair femoral segmental defect in rats J Orthop Res 21 44–53 Occurrence Handle10.1016/S0736-0266(02)00108-0 Occurrence Handle12507579

    Article  PubMed  Google Scholar 

  17. AW Baltzer C Lattermann JD Whalen S Ghivizzani P Wooley R Krauspe PD Robbins CH Evans (2000) ArticleTitlePotential role of direct adenoviral gene transfer in enhancing fracture repair Clin Orthop 379 IssueIDSuppl 120–125

    Google Scholar 

  18. XL Xu KR Dai TT Tang (2002) ArticleTitleRepair of radial bone defects of rabbits by adenovirus mediated human BMP-2 gene Chin J Traumatol 18 677–680

    Google Scholar 

  19. R Gysin JE Wergedal MH Sheng Y Kasukawa N Miyakoshi ST Chen H Peng KH Lau S Mohan DJ Baylink (2002) ArticleTitleEx vivo gene therapy with stromal cells transduced with a retroviral vector containing the BMP4 gene completely heals critical size calvarial defect in rats Gene Ther 9 991–999 Occurrence Handle10.1038/sj.gt.3301772 Occurrence Handle12101429

    Article  PubMed  Google Scholar 

  20. RJ Dumont H Dayoub JZ Li AS Dumont DF Kallmes GR Hankins GA Helm (2002) ArticleTitleEx vivo bone morphogenetic protein-9 gene therapy using human mesenchymal stem cells induces spinal fusion in rodents Neurosurgery 51 1239–1245 Occurrence Handle10.1097/00006123-200211000-00020 Occurrence Handle12383369

    Article  PubMed  Google Scholar 

  21. KD Riew NM Wright S Cheng LV Avioli J Lou (1998) ArticleTitleInduction of bone formation using a recombinant adenoviral vecter carrying the human BMP-2 gene in a rabbit spinal fusion model Calcif Tissue Int 63 357–360 Occurrence Handle10.1007/s002239900540 Occurrence Handle9744997

    Article  PubMed  Google Scholar 

  22. V Martinek C Latterman A Usas S Abramowitch SL Woo FH Fu J Huard (2002) ArticleTitleEnhancement of tendon-bone integration of anterior cruciate ligament grafts with bone morphogenetic protein-2 gene transfer: a histological and biomechanical study J Bone Joint Surg Am 84 1123–1131 Occurrence Handle12107310

    PubMed  Google Scholar 

  23. FH Lin CJ Liao KS Chen JS Sun CY Lin (2000) ArticleTitlePreparation of betaTCP/HAP biphasic ceramics with natural bone structure by heating bovine cancellous bone with the addition of (NH(4))(2)HPO(4) J Biomed Mater Res 51 157–163 Occurrence Handle10.1002/(SICI)1097-4636(200008)51:2<157::AID-JBM3>3.0.CO;2-R Occurrence Handle10825214

    Article  PubMed  Google Scholar 

  24. JM Lane E Tomin MP Bostrom (1999) ArticleTitleBiosynthetic bone grafting Clin Orthop 367 IssueIDSuppl S107–117 Occurrence Handle10.1097/00003086-199910001-00011 Occurrence Handle10546640

    Article  PubMed  Google Scholar 

  25. EH Riley JM Lane MR Urist KM Lyons JR Lieberman (1996) ArticleTitleBone morphogenetic protein-2: biology and applications Clin Orthop 324 39–46 Occurrence Handle10.1097/00003086-199603000-00006 Occurrence Handle8595775

    Article  PubMed  Google Scholar 

  26. AH Reddi (2001) ArticleTitleBone morphogenetic proteins: from basic science to clinical applications J Bone Joint Surg Am 83 IssueIDSuppl l l–6

    Google Scholar 

  27. E Marshall (2003) ArticleTitleGene therapy. Second child in French trial is found to have leukemia Science 299 320 Occurrence Handle10.1126/science.299.5605.320 Occurrence Handle12531981

    Article  PubMed  Google Scholar 

  28. JE Fleming SuffixJr CN Cornell GF Muschler (2000) ArticleTitleBone cells and matrices in orthopedic tissue engineering Orthop Clin North Am 31 357–374 Occurrence Handle10.1016/S0030-5898(05)70156-5 Occurrence Handle10882463

    Article  PubMed  Google Scholar 

  29. J Lou (2000) ArticleTitleIn vivo gene transfer into tendon by recombinant adenovirus Clin Orthop 379 IssueIDSuppl S252–255 Occurrence Handle11039777

    PubMed  Google Scholar 

  30. H Petite V Viateau W Bensaid A Meunier C Pollak Particlede M Bourguignon K Oudina L Sedel G Guillemin (2000) ArticleTitleTissue-engineered bone regeneration Nat Biotechnol 18 959–963 Occurrence Handle10.1038/79449 Occurrence Handle10973216

    Article  PubMed  Google Scholar 

  31. E Kon A Muraglia A Corsi P Bianco M Marcacci I Martin A Boyde I Ruspantini P Chistolini M Rocca R Giardino R Cancedda R Quarto (2000) ArticleTitleAutologous bone marrow stromal cells loaded onto porous hydroxyapatite ceramic accelerate bone repair in critical-size defects of sheep long bones J Biomed Mater Res 49 328–337 Occurrence Handle10.1002/(SICI)1097-4636(20000305)49:3<328::AID-JBM5>3.0.CO;2-Q Occurrence Handle10602065

    Article  PubMed  Google Scholar 

  32. SP Bruder KH Kraus VM Goldberg S Kadiyala (1998) ArticleTitleThe effect of implants loaded with autologous mesenchymal stem cells on the healing of canine segmental bone defects J Bone Joint Surg Am 80 985–96 Occurrence Handle9698003

    PubMed  Google Scholar 

  33. TL Arinzeh SJ Peter MP Archambault C Bos Particlevan den S Gordon K Kraus A Smith S Kadiyala (2003) ArticleTitleAllogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect J Bone Joint Surg Am 85 1927–1935 Occurrence Handle14563800

    PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by grants from Shanghai Science and Technology Development Foundation (No. 01JC14028) and Shanghai International Cooperation Foundation (No. 014307021).

Author information

Authors and Affiliations

  1. Department of Orthopaedics, Ninth People’s Hospital, Shanghai Second Medical University, 639 Zhizaoju Road, Shanghai, 200011, P.R.China

    K. R. Dai, X. L. Xu, T. T. Tang, Z. A .Zhu & C. F. Yu

  2. Health Science Center, SIBS CAS and SSMU, 225 South Chongqing Road, Shanghai, 200025, P.R. China

    K. R. Dai & X. L. Zhang

  3. Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA

    J. R. Lou

Authors
  1. K. R. Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X. L. Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. T. Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Z. A .Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. F. Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. R. Lou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. X. L. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. R. Dai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dai, K., Xu, X.L., Tang, T.T. et al. Repairing of goat Tibial Bone Defects with BMP-2 Gene–Modified Tissue-Engineered Bone. Calcif Tissue Int 77, 55–61 (2005). https://doi.org/10.1007/s00223-004-0095-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-004-0095-z

Keywords

Search

Navigation