Skip to main content
SpringerLink
Log in

New bone formation in a true bone ceramic scaffold loaded with desferrioxamine in the treatment of segmental bone defect: a preliminary study

  • Original Article
  • Published:
Journal of Orthopaedic Science

Abstract

Background

Desferrioxamine (DFO), an iron chelator, can stimulate osteogenesis and angiogenesis by stabilizing hypoxia-inducible factor 1α. We postulate that a bone graft substitute combined with DFO is beneficial to the reconstruction of bone defects.

Methods

We implanted pure true bone ceramic (TBC) and DFO-loaded TBC (DFO/TBC) scaffolds into 15-mm rabbit radial defects for 8 weeks. The bone segments were examined with X-ray, micro-CT and histology.

Results

Radiographs showed that the DFO/TBC scaffold became radiopaque, and the gaps between the scaffold and radial cut ends were often invisible. Variables from micro-CT, including the bone volume fraction (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N), were significantly increased in pure TBC and DFO/TBC scaffolds that had been implanted for 8 weeks compared to unimplanted TBC scaffolds (p values <0.05–0.001). Between the former two groups, BV/TV and Tb.Th were significantly increased in DFO/TBC scaffolds (p < 0.001), but Tb.N did not show significant differences. Histological examinations showed considerably increased new bone and decreased TBC trabecular remnants in DFO/TBC scaffolds compared to pure TBC scaffolds. Many cavities in the new bone area in DFO/TBC scaffolds were occupied by bone marrow elements and blood vessels. Percent of new bone with tetracycline labeling was significantly greater in DFO/TBC scaffolds than in pure TBC scaffolds (p < 0.001).

Conclusion

This preliminary study reveals that DFO can effectively induce new bone growing into TBC scaffolds, suggesting that the DFO/TBC composite is a promising bone graft substitute for the treatment of 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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Yazar S, Lin CH, Wei FC. One-stage reconstruction of composite bone and soft-tissue defects in traumatic lower extremities. Plast Reconstr Surg. 2004;114(6):1457–66.

    Article  PubMed  Google Scholar 

  2. El-Gammal TA, El-Sayed A, Kotb MM. Microsurgical reconstruction of lower limb bone defects following tumor resection using vascularized fibula osteoseptocutaneous flap. Microsurgery. 2002;22(5):193–8.

    Article  PubMed  Google Scholar 

  3. Rozbruch SR, Pugsley JS, Fragomen AT, Ilizarov S. Repair of tibial nonunions and bone defects with the Taylor spatial frame. J Orthop Trauma. 2008;22(2):88–95.

    Article  PubMed  Google Scholar 

  4. Cowan CM, Shi YY, Aalami OO, Chou YF, Mari C, Thomas R, Quarto N, Contag CH, Wu B, Longaker MT. Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol. 2004;22(5):560–7.

    Article  PubMed  CAS  Google Scholar 

  5. Kasten P, Vogel J, Geiger F, Niemeyer P, Luginbuhl R, Szalay K. The effect of platelet-rich plasma on healing in critical-size long-bone defects. Biomaterials. 2008;29(29):3983–92.

    Article  PubMed  CAS  Google Scholar 

  6. Jupiter JB, Leffert RD. Non-union of the clavicle. Associated complications and surgical management. J Bone Joint Surg Am. 1987;69(5):753–60.

    PubMed  CAS  Google Scholar 

  7. Johnson EE, Urist MR, Finerman GA. Distal metaphyseal tibial nonunion. Deformity and bone loss treated by open reduction, internal fixation, and human bone morphogenetic protein (hBMP). Clin Orthop Relat Res. 1990;250:234–40.

    PubMed  Google Scholar 

  8. Finkemeier CG. Bone-grafting and bone-graft substitutes. J Bone Joint Surg Am. 2002;84-A(3):454–64.

    Google Scholar 

  9. Arrington ED, Smith WJ, Chambers HG, Bucknell AL, Davino NA. Complications of iliac crest bone graft harvesting. Clin Orthop Relat Res. 1996;329:300–9.

    Article  PubMed  Google Scholar 

  10. Gazdag AR, Lane JM, Glaser D, Forster RA. Alternatives to autogenous bone graft: efficacy and indications. J Am Acad Orthop Surg. 1995;3(1):1–8.

    PubMed  Google Scholar 

  11. Bucholz RW. Nonallograft osteoconductive bone graft substitutes. Clin Orthop Relat Res. 2002;395:44–52.

    Article  PubMed  Google Scholar 

  12. Hak DJ. The use of osteoconductive bone graft substitutes in orthopaedic trauma. J Am Acad Orthop Surg. 2007;15(9):525–36.

    PubMed  Google Scholar 

  13. Khan Y, Yaszemski MJ, Mikos AG, Laurencin CT. Tissue engineering of bone: material and matrix considerations. J Bone Joint Surg Am. 2008;90(Suppl 1):36–42.

    Article  PubMed  Google Scholar 

  14. 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(7):941–50.

    Article  PubMed  CAS  Google Scholar 

  15. Drosse I, Volkmer E, Capanna R, De Biase P, Mutschler W, Schieker M. Tissue engineering for bone defect healing: an update on a multi-component approach. Injury. 2008;39(Suppl 2):S9–20.

    Article  PubMed  Google Scholar 

  16. Liu Y, Lu Y, Tian X, Cui G, Zhao Y, Yang Q, Yu S, Xing G, Zhang B. Segmental bone regeneration using an rhBMP-2-loaded gelatin/nanohydroxyapatite/fibrin scaffold in a rabbit model. Biomaterials. 2009;30(31):6276–85.

    Article  PubMed  CAS  Google Scholar 

  17. Saito A, Suzuki Y, Kitamura M, Ogata S, Yoshihara Y, Masuda S, Ohtsuki C, Tanihara M. Repair of 20-mm long rabbit radial bone defects using bmp-derived peptide combined with an alpha-tricalcium phosphate scaffold. J Biomed Mater Res A. 2006;77(4):700–6.

    PubMed  Google Scholar 

  18. Genetos DC, Toupadakis CA, Raheja LF, Wong A, Papanicolaou SE, Fyhrie DP, Loots GG, Yellowley CE. Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts. J Cell Biochem. 2010;110(2):457–67.

    PubMed  CAS  Google Scholar 

  19. Shen X, Wan C, Ramaswamy G, Mavalli M, Wang Y, Duvall CL, Deng LF, Guldberg RE, Eberhart A, Clemens TL, Gilbert SR. Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice. J Orthop Res. 2009;27(10):1298–305.

    Article  PubMed  CAS  Google Scholar 

  20. Wan C, Gilbert SR, Wang Y, Cao X, Shen X, Ramaswamy G, Jacobsen KA, Alaql ZS, Eberhardt AW, Gerstenfeld LC, Einhorn TA, Deng L, Clemens TL. Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration. Proc Natl Acad Sci USA. 2008;105(2):686–91.

    Article  PubMed  CAS  Google Scholar 

  21. Blancher C, Moore JW, Talks KL, Houlbrook S, Harris AL. Relationship of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines. Cancer Res. 2000;60(24):7106–13.

    PubMed  CAS  Google Scholar 

  22. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von hippel-lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468–72.

    Article  PubMed  CAS  Google Scholar 

  23. Wang AY, Bobryshev YV, Liang H, Cherian SM, Inder SJ, Ashwell KW, Farnsworth AE, Lord RS. Electron-microscopic detection of apoptotic and necrotic cell death in non-atherosclerotic areas of stenotic aortocoronary saphenous vein bypass grafts. J Submicrosc Cytol Pathol. 2000;32(2):209–19.

    PubMed  CAS  Google Scholar 

  24. Wan C, Shao J, Gilbert SR, Riddle RC, Long F, Johnson RS, Schipani E, Clemens TL. Role of HIF-1alpha in skeletal development. Ann N Y Acad Sci. 2010;1192(1):322–6.

    Article  PubMed  CAS  Google Scholar 

  25. Schipani E, Maes C, Carmeliet G, Semenza GL. Regulation of osteogenesis–angiogenesis coupling by HIFs and VEGF. J Bone Miner Res. 2009;24(8):1347–53.

    Article  PubMed  CAS  Google Scholar 

  26. Matsumoto T, Kawakami M, Kuribayashi K, Takenaka T, Minamide A, Tamaki T. Effects of sintered bovine bone on cell proliferation, collagen synthesis, and osteoblastic expression in mc3t3-e1 osteoblast-like cells. J Orthop Res. 1999;17(4):586–92.

    Article  PubMed  CAS  Google Scholar 

  27. Minamide A, Kawakami M, Hashizume H, Sakata R, Yoshida M, Tamaki T. Experimental study of carriers of bone morphogenetic protein used for spinal fusion. J Orthop Sci. 2004;9(2):142–51.

    Article  PubMed  CAS  Google Scholar 

  28. Patel ZS, Young S, Tabata Y, Jansen JA, Wong ME, Mikos AG. Dual delivery of an angiogenic and an osteogenic growth factor for bone regeneration in a critical size defect model. Bone. 2008;43(5):931–40.

    Article  PubMed  CAS  Google Scholar 

  29. Wang Y, Wan C, Deng L, Liu X, Cao X, Gilbert SR, Bouxsein ML, Faugere MC, Guldberg RE, Gerstenfeld LC, Haase VH, Johnson RS, Schipani E, Clemens TL. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest. 2007;117(6):1616–26.

    Article  PubMed  CAS  Google Scholar 

  30. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294(5545):1337–40.

    Article  PubMed  CAS  Google Scholar 

  31. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464–8.

    Article  PubMed  CAS  Google Scholar 

  32. Min JH, Yang H, Ivan M, Gertler F, Kaelin WG Jr, Pavletich NP. Structure of an HIF-1alpha–pVHL complex: hydroxyproline recognition in signaling. Science. 2002;296(5574):1886–9.

    Article  PubMed  CAS  Google Scholar 

  33. Hanson ES, Rawlins ML, Leibold EA. Oxygen and iron regulation of iron regulatory protein 2. J Biol Chem. 2003;278(41):40337–42.

    Article  PubMed  CAS  Google Scholar 

  34. Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. 1999;5(6):623–8.

    Article  PubMed  CAS  Google Scholar 

  35. Street J, Bao M, deGuzman L, Bunting S, Peale FV Jr, Ferrara N, Steinmetz H, Hoeffel J, Cleland JL, Daugherty A, van Bruggen N, Redmond HP, Carano RA, Filvaroff EH. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci USA. 2002;99(15):9656–61.

    Article  PubMed  CAS  Google Scholar 

  36. Mayr-Wohlfart U, Waltenberger J, Hausser H, Kessler S, Gunther KP, Dehio C, Puhl W, Brenner RE. Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts. Bone. 2002;30(3):472–7.

    Article  PubMed  CAS  Google Scholar 

  37. Zelzer E, McLean W, Ng YS, Fukai N, Reginato AM, Lovejoy S, D’Amore PA, Olsen BR. Skeletal defects in VEGF (120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development. 2002;129(8):1893–904.

    PubMed  CAS  Google Scholar 

  38. Kaigler D, Krebsbach PH, Polverini PJ, Mooney DJ. Role of vascular endothelial growth factor in bone marrow stromal cell modulation of endothelial cells. Tissue Eng. 2003;9(1):95–103.

    Article  PubMed  CAS  Google Scholar 

  39. Bouletreau PJ, Warren SM, Spector JA, Peled ZM, Gerrets RP, Greenwald JA, Longaker MT. Hypoxia and VEGF up-regulate bmp-2 mRNA and protein expression in microvascular endothelial cells: implications for fracture healing. Plast Reconstr Surg. 2002;109(7):2384–97.

    Article  PubMed  Google Scholar 

  40. Case N, Rubin J. Beta-catenin: a supporting role in the skeleton. J Cell Biochem. 2010;110(3):545–53.

    Article  PubMed  CAS  Google Scholar 

  41. Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell. 2005;8(5):727–38.

    Article  PubMed  CAS  Google Scholar 

  42. Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell. 2005;8(5):739–50.

    Article  PubMed  CAS  Google Scholar 

  43. Qu ZH, Zhang XL, Tang TT, Dai KR. Promotion of osteogenesis through beta-catenin signaling by desferrioxamine. Biochem Biophys Res Commun. 2008;370(2):332–7.

    Article  PubMed  CAS  Google Scholar 

  44. Minamide A, Tamaki T, Kawakami M, Hashizume H, Yoshida M, Sakata R. Experimental spinal fusion using sintered bovine bone coated with type I collagen and recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976). 1999;24(18):1863–70. discussion 1871-2.

    Article  CAS  Google Scholar 

  45. Hashizume H, Tamaki T, Oura H, Minamide A. Changes in the extracellular matrix on the surface of sintered bovine bone implanted in the femur of a rabbit: an immunohistochemical study. J Orthop Sci. 1998;3(1):42–53.

    Article  PubMed  CAS  Google Scholar 

  46. Katoh T, Sato K, Kawamura M, Iwata H, Miura T. Osteogenesis in sintered bone combined with bovine bone morphogenetic protein. Clin Orthop Relat Res. 1993;287:266–75.

    PubMed  Google Scholar 

  47. Ruhe PQ, Boerman OC, Russel FG, Mikos AG, Spauwen PH, Jansen JA. In vivo release of rhBMP-2 loaded porous calcium phosphate cement pretreated with albumin. J Mater Sci Mater Med. 2006;17(10):919–27.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by funds from the National Natural Science Foundation of China (no. 30872641) and Foundation of Science and Technology Commission of Shanghai Municipality (no. 10410702000, No. 09DZ2200500).

Conflict of interest

The authors have no conflict of interests.

Author information

Authors and Affiliations

  1. Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, People’s Republic of China

    Weibin Zhang, Guosong Li, Lianfu Deng & Shijing Qiu

  2. Department of Biomedical Engineering, School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China

    Ruoxian Deng

  3. Bone and Mineral Research Laboratory, Henry Ford Hospital, Detroit, MI, USA

    Shijing Qiu

Authors
  1. Weibin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guosong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruoxian Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lianfu Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shijing Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lianfu Deng.

Additional information

W. Zhang and G. Li contributed equally.

Appendix

Appendix

See Figs. 9, 10.

Fig. 9
figure 9

X-ray examination. Left column is TBC implantation for 8 weeks. Right column is DFO/TBC implantation for 8 weeks

Full size image
Fig. 10
figure 10

Micro-CT examination. Left column is TBC implantation for 8 weeks. Right column is DFO/TBC implantation for 8 weeks

Full size image

About this article

Cite this article

Zhang, W., Li, G., Deng, R. et al. New bone formation in a true bone ceramic scaffold loaded with desferrioxamine in the treatment of segmental bone defect: a preliminary study. J Orthop Sci 17, 289–298 (2012). https://doi.org/10.1007/s00776-012-0206-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00776-012-0206-z

Keywords

Search

Navigation