Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Tissue-engineered bone regeneration


Bone lesions above a critical size become scarred rather than regenerated, leading to nonunion. We have attempted to obtain a greater degree of regeneration by using a resorbable scaffold with regeneration-competent cells to recreate an embryonic environment in injured adult tissues, and thus improve clinical outcome. We have used a combination of a coral scaffold with in vitro-expanded marrow stromal cells (MSC) to increase osteogenesis more than that obtained with the scaffold alone or the scaffold plus fresh bone marrow. The efficiency of the various combinations was assessed in a large segmental defect model in sheep. The tissue-engineered artificial bone underwent morphogenesis leading to complete recorticalization and the formation of a medullary canal with mature lamellar cortical bone in the most favorable cases. Clinical union never occurred when the defects were left empty or filled with the scaffold alone. In contrast, clinical union was obtained in three out of seven operated limbs when the defects were filled with the tissue-engineered bone.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Radiographic follow-ups.
Figure 2: Radiographic follow-ups.
Figure 3: Micro-X-rays and photomicrographs at 16 weeks.


  1. 1

    Damien, C. & Parsons, R. Bone graft and bone graft substitutes: a review of current technology and applications. J. Appl. Biomat. 2, 187–208 (1991).

    CAS  Article  Google Scholar 

  2. 2

    Langer, R. & Vacanti, J.P. Tissue engineering. Science 260, 920–926 (1993).

    CAS  Article  Google Scholar 

  3. 3

    Caplan, A.I. Mesenchymal stem cells. J. Orthop. Res. 9, 641–650 (1991).

    CAS  Article  Google Scholar 

  4. 4

    Caplan, A.I. & Bruder, S.P. Cell and molecular engineering of bone regeneration. In Principles of tissue engineering. (eds Lanza, R.P., Langer, R. & Chick, W.L.) 603–619 (Landes, Georgetown, TX; 1997).

    Google Scholar 

  5. 5

    Prockop, D.J. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276, 71–74 (1997).

    CAS  Article  Google Scholar 

  6. 6

    Triffitt, J.T. The stem cell of the osteoblast. In Principles of bone biology. (eds Bilezikian, J.P. & Raisz, L.G.) 39–50 (Academic, San Diego, CA; 1996).

    Google Scholar 

  7. 7

    Ohgushi, H., Goldberg, V.M. & Caplan, A.I. Repair of bone defects with marrow cells and porous ceramic. Experiments in rats. Acta Orthop. Scand. 60, 334–339 (1989).

    CAS  Article  Google Scholar 

  8. 8

    Bruder, S.P et al. Bone regeneration by implantation of purified, culture-expanded human mesenchymal stem cells. J. Orthop. Res. 16, 155–162 (1998).

    CAS  Article  Google Scholar 

  9. 9

    Bruder, S.P., Kraus, K.H., Goldberg, V.M. & Kadiyala, S. The effect of implants loaded with autologous mesenchymal stem cells on the healing of canine segmental bone defects. J. Bone Joint Surg. Am. 80, 985–996 (1998).

    CAS  Article  Google Scholar 

  10. 10

    Moore, D.C., Chapman, M.W. & Manske, D. The evaluation of a biphasic calcium phosphate ceramic for use in grafting long-bone diaphyseal defects. J. Orthop. Res. 5, 356–365 (1987).

    CAS  Article  Google Scholar 

  11. 11

    Grundel, R.E., Chapman, M.W., Yee, T., and Moore, D.C. Autogeneic bone marrow and porous biphasic calcium phosphate ceramic for segmental bone defects in the canine ulna. Clin. Orthop. 266, 244–258 (1991).

    Google Scholar 

  12. 12

    Guillemin, G., Patat, J.L. & Meunier, A. Natural corals used as bone graft substitutes. Bulletin de l'institut océanographique Monaco 14, 67–77 (1995).

    Google Scholar 

  13. 13

    Piecuch, J.F., Goldberg, A.J., Shastry, C.V. & Chrzanowski, R.B. Compressive strength of implanted porous replamineform hydroxyapatite. J. Biomed. Mater. Res. 18, 39–45 (1984).

    CAS  Article  Google Scholar 

  14. 14

    Guillemin, G., Patat, J.L., Fournié, J. & Chétail M. The use of coral as a bone graft substitute. J. Biomed. Mater. Res. 21, 557–567 (1987).

    CAS  Article  Google Scholar 

  15. 15

    Yukna, R.A., & Yukna C.N. A 5-year follow-up of 16 patients treated with coralline calcium carbonate (Biocoral) bone replacement grafts in infrabony defects. J. Clin. Periodontol. 25, 1036–1040 (1998).

    CAS  Article  Google Scholar 

  16. 16

    Yukna, R.A. Clinical evaluation of coralline calcium carbonate as a bone replacement graft material in human periodontal osseous defects. J. Periodontol. 65, 177–185 (1994).

    CAS  Article  Google Scholar 

  17. 17

    Roux, F.X., Brasnu, D., Loty, B., Georges, B. & Guillemin, G. Madreporic coral: a new bone graft substitute for cranial surgery. J. Neuro. Surg. 69, 510–513 (1988).

    CAS  Google Scholar 

  18. 18

    Pouliquen, J.C., Noat, M., Verneret, C., Guillemin, G. & Patat J.L. Coral as a substitute for bone graft in posterior spine fusion in childhood. Fr. J. Orthop. Surg. 3, 272–280 (1989).

    Google Scholar 

  19. 19

    Kadiyala, S., Jaiswal, N. & Bruder, S. Culture-expanded bone marrow-derived mesenchymal stem cells can regenerate a critical-sized segmental bone defect. Tissue Engineering 3, 173–185 (1997).

    Article  Google Scholar 

  20. 20

    Gross, U., Müller-Mai, C. and Voigt, C. Comparative morphology of the bone interface with glass ceramics, hydroxyapatite and natural coral. In The bone–biomaterial interface. (ed. Davies, J.E.). 308–320 (University of Toronto Press, Toronto, ON; 1991).

    Google Scholar 

  21. 21

    Goshima, J., Goldberg, V.M. & Caplan, A.I. Osteogenic potential of culture-expanded rat marrow cells as assayed in vivo with porous calcium phosphate ceramic. Biomaterials 12, 253–258 (1991).

    CAS  Article  Google Scholar 

  22. 22

    Ostrum, R.F. et al. Bone injury, regeneration and repair. In Orthopaedic basic science. (ed. Simon, S.R.) 277–323 (American Academy of Orthopaedic Surgeons, Rosemont, IL; 1994).

    Google Scholar 

  23. 23

    Marks, S.C., & Hermey, D.C. The structure and development of bone. In Principles of bone biology. (eds Bilezikian, J.P. & Raisz, L.G.) 3–14 (Academic Press, San Diego, CA; 1996).

    Google Scholar 

  24. 24

    Hulbert, S.F et al. Potential of ceramic materials as permanently implantable skeletal prostheses. J. Biomed. Mater. Res. 4, 433–456 (1970).

    CAS  Article  Google Scholar 

  25. 25

    Guillemin, G. et al. Comparison of coral resorption and bone apposition with two natural corals of different porosities. J. Biomed. Mater. Res. 23, 765–779 (1989).

    CAS  Article  Google Scholar 

  26. 26

    Gay, C.V. & Mueller, W.J. Carbonic anhydrase and osteoclasts: localization by labeled inhibitor autoradiography. Science 183, 432–434 (1974).

    CAS  Article  Google Scholar 

  27. 27

    Guillemin, G., Hunter, S.J. & Gay, C.V. Resorption of natural calcium carbonate by avian osteoclasts in vitro. Cells and Material s5, 157–165 (1995).

    Google Scholar 

  28. 28

    Shors, E.C. Coralline bone graft substitutes. Orthop. Clin. North Am. 30, 599–613 (1999).

    CAS  Article  Google Scholar 

  29. 29

    Daculsi, G., Bouler, J.M. & LeGeros, R.Z. Adaptative crystal formation in normal and pathological calcifications in synthetic calcium phosphate and related biomaterials. Int. Rev. Cytol. 172, 129–191 (1997).

    CAS  Article  Google Scholar 

  30. 30

    Pachence, J.M. & Kohn, J. Biodegradable polymers for tissue engineering. In Principles of tissue engineering. (eds Lanza, R.P., Langer, R. & Chick, W.L.) 274–193 (R.G. Landes, Georgetown, TX 1997).

    Google Scholar 

  31. 31

    Zawicki, D.F., Jain, R.K., Schmid-Schoenbein, G.W. & Chien, S. Dynamics of neovascularization in normal tissue. Microvasc. Res. 21, 27–47 (1981).

    CAS  Article  Google Scholar 

  32. 32

    Irigaray, J.L. et al. Effet de la température sur la structure cristalline d'un Biocoral. J. Thermal Analysis 39, 3–14 (1993).

    CAS  Article  Google Scholar 

  33. 33

    Petite, H., Kacem, K. & Triffitt, J.T. Adhesion, growth and differentiation of human bone marrow cells on non porous calcium carbonate and pastic substrata: effects of dexamethasone and 1,25 dihydroxyvitamin d3. Mater. Med. 7, 665–671 (1996).

    CAS  Article  Google Scholar 

  34. 34

    Herbertson, A. & Aubin, J.E. Dexamethasone alters the subpopulation make-up of rat bone marrow stromal cell cultures. J. Bone Miner. Res. 10, 285–294 (1995).

    CAS  Article  Google Scholar 

  35. 35

    Gamou, S., Shimizy, Y. & Shimizu, N. In Animal cell culture. (ed. Pollard, J. & Walker, J.) 197–207 (Humana, Clifton, NJ; 1990).

    Book  Google Scholar 

  36. 36

    Louisia, S., Stromboni, M., Meunier, A., Sedel, L. & Petite, H. Coral grafting supplemented with bone marrow. J. Bone Joint Surg. Br. 81, 719–724 (1999).

    CAS  Article  Google Scholar 

Download references


We thank Inoteb (France) for donating the coral implants (Biocoral), Mrs M. Vallot for animal care and the Fondation pour l'Avenir ET8-263, Assistance Publique des Hopitaux de Paris AP-HP 97-002, CNRS and INSERM for financial support.

Author information



Corresponding author

Correspondence to Herve Petite.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Petite, H., Viateau, V., Bensaïd, W. et al. Tissue-engineered bone regeneration. Nat Biotechnol 18, 959–963 (2000).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing