Bone-Inducing Factors in Osteoinductive Implants

  • Kunio Takaoka
  • Hideki Yoshikawa
  • Shimpei Miyamoto
  • Jun Hashimoto
  • Masashi Matsui
  • Keiro Ono


Over the last decade, considerable attention has been focused on the cellular and molecular aspects of bone cell biology. In spite of advances in this area and in biomaterials science, autogeneic bone grafting still is considered to be the most effective method for augmenting bone regeneration following orthopedic surgery. The biologic potential of autogeneic cancellous bone graft material may be attributed to resident osteogenic cells that survive, proliferate, and ultimately produce new bone at the transplanted site (1,2).However, the disadvantages of autogenous bone grafting include the fact that:
  1. 1.

    A second operation is required to obtain the graft, resulting in functional and cosmetic defects as well as pain at the donor site;

  2. 2.

    The supply of autogenous bone for grafting is limited; and

  3. 3.

    Cancellous bone with high osteogenic potential does not confer significant mechanical strength to the donor site.



Bone Formation Bone Morphogenetic Protein Bone Graft Substitute Bone Induction Bone Matrix Gelatin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Burwell RG. Studies in the transplantation of bone. VII. The fresh composite homograft-autograft of cancellous bone. An analysis of factors leading to osteogenesis in marrow transplants and in marrow-containing bone grafts. J Bone Joint Surg 1965; 46-B(1): 110–140.Google Scholar
  2. 2.
    Connolly J, Guse R, Lippiello L, and Dehne R. Development of an osteogenic bone-marrow preparation. J Bone Joint Surg 1989; 71-A: 684–691.Google Scholar
  3. 3.
    Malinin TI, Martinez OV, and Brown MD. Banking of massive osteoarticular and intercalary bone allografts-12 year’s experience. Clin Orthop 1985; 197: 44.Google Scholar
  4. 4.
    Salzman NP, Psallidopoulos M, Prewett AB, and O’Leary R. Detection of HIV in bone allografts prepared from AIDS autopsy tissue. Clin Orthop 1993; 292: 384–390.Google Scholar
  5. 5.
    Friedlaender GE and Mankin HJ. Bone banking: current methods and suggested guideline. Instruct Course Lectures 1981; 30: 36–55.Google Scholar
  6. 6.
    Doppelt SM, Tomford WW, Lucas AB, and Mankin HJ. Operational and financial aspects of a hospital bone bank. J Bone Joint Surg 1981; 63A: 1472.Google Scholar
  7. 7.
    McCutchen JW, Collier JP, and Mayor MB. Osseo-integration of titanium implants in total hip arthroplasty. Clin Orthop 1990; 261: 114–125.Google Scholar
  8. 8.
    Canalis E, McCarthy TL, and Centrella M. Growth factors and the skeletal system. J Endocrinol Invest 1989; 12: 577–584.Google Scholar
  9. 9.
    Wozney JM, Rosen V, Byrne M, Moutsatsos I, and Wang EA. Growth factors influencing bone development. J Cell Sci Supp11990; 13: 149–156.Google Scholar
  10. 10.
    Marden LJ, Reddi AH, and Hollinger JO. Growth and differentiation factors: role in bone induction and potential application in craniofacial surgery. J Craniofacial Surg 1990; 1: 154–161.CrossRefGoogle Scholar
  11. 11.
    Urist MR, Nilsson O, Rusmussen J, Hirota W, Lovell T, Schmalzreid T, et al. Bone regeneration under the influence of a bone morphogenetic protein (BMP) beta tricalcium phosphate (TCP) composite in skull trephine defects in dogs. Clin Orthop Relat Res 1987; 214: 295–304.Google Scholar
  12. 12.
    Ferguson D, Davis WL, Urist MR, Hurt WC, and Allen PA. Bovine bone morphogenetic protein (bBMP) fraction-induced repair of craniotomy defects in the rhesus monkey (Macaca speciosa). Clin Orthop Relat Res 1987; 219: 251–258.Google Scholar
  13. 13.
    Johnson EE, Urist MR, and Finerman GAM. Bone morphogenetic protein augmentation grafting of resistant femoral nonunion. Clin Orthop Relat Res 1988; 230: 257–265.Google Scholar
  14. 14.
    Lovell TP, Dawson EG, Nilsson, OS, and Urist MR. Augmentation of spinal fusion with bone morphogenetic protein in dogs. Clin Orthop Relat Res 1989; 243: 266–274.Google Scholar
  15. 15.
    Doll BA, Towle HJ, Hollinger JO, Reddi AH, and Mellonig JT. The osteogenic potential of two composite graft systems using osteogenin. J Periodontol 1990; 61: 745–750.CrossRefGoogle Scholar
  16. 16.
    Toriumi DM, Kotler HS, Luxenberg DP, Haltrop ME, and Wang EA. Mandibular reconstruction with a recombinant bone-inducing factor. Arch Otolaryngol Neck Surg 1991; 117: 1101–1112.CrossRefGoogle Scholar
  17. 17.
    Heckman JD, Boyan BD, Aufdeforme TB, and Abbot JT. The use of bone morphogenetic protein in the treatment of non-union in a canine model. J Bone Joint Surg 1991; 73-A: 750–764.Google Scholar
  18. 18.
    Ripamonti U, Ma SS, van den Heever B, and Reddi AH. Osteogenin, a bone morphogenetic protein, adsorbed on hydroxyapatite substrata, induces rapid bone differentiation in calvarial defects of adult primates. Plast Reconst Surg 1992; 90: 382–393.CrossRefGoogle Scholar
  19. 19.
    Wozney JM. Bone morphogenetic proteins. Progr Growth Factor Res 1989; 1: 267–280.CrossRefGoogle Scholar
  20. 20.
    Urist MR. Bone; formation by autoinduction. Science 1965; 150: 893.CrossRefGoogle Scholar
  21. 21.
    Urist MR and Iwata H. Presrvation and biodegradation of the morphogenetic property of bone matrix. J Theor Biol 1973; 38: 155.CrossRefGoogle Scholar
  22. 22.
    Urist MR, Mikulski A, and Boyd SD. A chemosterilized antigen-extracted autodigested alloimplant for bone bank. Arch Surg 1975; 110: 416–428.CrossRefGoogle Scholar
  23. 23.
    Glowacki J and Mulliken JB. Demineralized bone implants. Clin Plast Surg 1985; 12: 233–241.Google Scholar
  24. 24.
    Kakiuchi M, Hosoya T, Takaoka K, Amitani, K, and Ono K. Human bone matrix gelatin as a clinical allo-implant. Int Orthopaedica (SICOT) 1985; 9: 181–188.CrossRefGoogle Scholar
  25. 25.
    Wozney JM, Rosen V, Celeste AJ, Mistock LM, Whitters MJ, Hewick RM, et al. Novel regulators of bone formation: molecular clones and activities. Science 1988; 242: 1528–1534.CrossRefGoogle Scholar
  26. 26.
    Luyten FP, Cunningham NS, Ma S, Muthukumdram N, Hammonds RG, Nevins WB, et al. Purification and partial amino acid sequence of osteogenin, a protein initiating bone differentiation. JBiol Chem 1989; 264: 13, 377.Google Scholar
  27. 27.
    Wang EA, Rosen V, Cordes P, Hewick RM, Kriz MJ, Luxenberg DP, et al. Purification and characterization of other distinct bone-inducing factors. Proc Natl Acad Sci USA 1988; 85: 9484.CrossRefGoogle Scholar
  28. 28.
    Bentz H, Chang R, Thompson AY, Glaser CB, and Rosen DM. Purification and characterization of a unique osteoinductive factor from bovine bone. J Biol Chem 1990; 265: 5024.Google Scholar
  29. 29.
    Takaoka K, Yoshikawa H, Hashimoto J, Miyamoto S, Masuhara K, Nakahara H, Matsui M, et al. Purification and characterization of a bone-inducing protein from a murine osteosarcoma (Dunn osteosarcoma). Clin Orthop 1993; 292: 329–336.Google Scholar
  30. 30.
    Takaoka K, Yoshikawa H, Hashimoto J, Masuhara K, Miyamoto S, Suzuki S, et al. Gene cloning and expression ofa bone morphogenetic protein derived from a murine osteosarcoma (Dunn). Clin Orthop 1993; 294: 344–352.Google Scholar
  31. 31.
    Wang EA, Rosen V, D’Alessandro JS, Bauduy M, Cordes P, Harada T, et al. Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci USA 1990; 87: 2220.Google Scholar
  32. 32.
    Nakahara H, Takaoka K, Masuhara K, Sugamoto K, Tsuda T, and Ono K. Periosteal bone formation elicited by partially purified bone morphogenetic protein. Clin Orthop 1989; 239: 299–305.Google Scholar
  33. 33.
    Wozney JM. Bone morphogenetic protein and their gene expression, in Cellular and Molecular Biology of Bone 1993; (Noda M, ed), Academic, San Diego, CA, pp 131–167.Google Scholar
  34. 34.
    Nakase T, Nomura S, Yoshikawa H, Oikawa S, Ono K, and Takaoka K. Transient and localized expression of bone morphogenetic protein-4 messenger RNA during fracture healing. J Bone Mineral Res 1994; 9: 651–659.CrossRefGoogle Scholar
  35. 35.
    Hammonds RG, Schwall R Jr, Dudley A, Berkmeier L, Lai C, Lee J., et al. Bone-inducing activity of mature BMP-2b produced from a hybrid BMP2a/2b precursor. Mol Endocrinol 1991; 150: 149–155.CrossRefGoogle Scholar
  36. 36.
    Sampath TK, Maliakal JC, and Hauschka PV. Recombinant human osteogenic protein-1 (HOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulate osteoblast proliferation and differentiation in vitro. J Biol Chem 1992; 267: 20, 353–20, 362.Google Scholar
  37. 37.
    Reddi AH. Extracellular matrix and development, in ExtracellularMatrixBiochemistry 1984; (Piez KA and Reddi AH, eds), Elsevier, New York, pp 375–412.Google Scholar
  38. 38.
    Takaoka K, Koezuka M, and Nakahara H. Telo peptide-deleted bovine skin collagen as a carrier for bone morphogenetic protein. J Orthop Res 1991; 9: 902–907.CrossRefGoogle Scholar
  39. 39.
    Takaoka K, Nakahara H, Yoshikawa H, Masuhara K, Tsuda T, and Ono K. Ectopic bone induction on and in porous hydroxyapatite combined with col lagen and bone morphogenetic protein. Clin Orthop 1988; 234: 250–254.Google Scholar
  40. 40.
    Doll BA, Towle HJ, Hollinger JO, Reddi AH, and Mellonig JT. The osteogenic potential of two comgraft systems using osteogenin. JPeriodontol 1990; 61: 745–750.CrossRefGoogle Scholar
  41. 41.
    Sela J, Applebaum J, and Uretzky G. Osteogenesis induced by bone matrix is inhibited by inflamma tion. Biomat Med Dev Art Org 1986; 14: 227–237.Google Scholar
  42. 42.
    Miyamoto S, Takaoka K, Okada T, Yoshikawa H, Hashimoto J, Suzuki S, et al. Evaluation ofpolylactic acid homopolymers as carriers for bone morpho- genetic protein. Clin Orthop 1992; 278: 274–285.Google Scholar
  43. 43.
    Miyamoto S, Takaoka K, Okada T, Yoshikawa H, Hashimoto J, Suzuki S, et al. A new biodegradable synthetic carrier for bone morphogenetic protein: polylactic acid-polyethylene glycol block copoly mer. Clin Orthop 1993; 294: 333–343.Google Scholar
  44. 44.
    Kawai T, Mieki A, Ohno Y, Umemura M, Kataoka H, Kurita S, et al. Osteoinductive activity of com posites of bone morphogenetic protein and pure titanium. Clin Orthop 1993; 290: 296–305.Google Scholar
  45. 45.
    Yasko AW, Lane JM, Fellinger EJ, Rosen V, Wozney JM, and Wang E. The healing of segmental defects, induced by recombinant human bone morphogenetic protein (rh BMP-2). J Bone Joint Surg 1992; 74-A: 659–670.Google Scholar
  46. 46.
    Gerhart TN, Kirker-Head CA, Vet MA, Kriz MJ, Holtrop ME, Herring, GE, et al. Healing segmental femoral defects in sheep using recombinant human bone morphogenetic protein. Clin Orthop 1993; 293: 317–326.Google Scholar
  47. 47.
    Hosny M and Sharawy M. Osteoinduction in rhesus monkeys using demineralized bone powder allo grafts. J Oral Maxillofac Surg 1985; 43: 837–844.CrossRefGoogle Scholar
  48. 48.
    Aspenberg P, Lohmander LS, and Thorngren K-G. Failure of bone induction by bone matrix in adult monkeys. JBone Joint Surg 1992; 70-B: 625–627.Google Scholar
  49. 49.
    Aspenberg P and Andolf E. Bone induction by fetal and adult human bone matrix in athymic rats. Acta Orthop Scand 1989; 60 (2): 195–199.CrossRefGoogle Scholar
  50. 50.
    Ripamonti U. Bone induction in nonhuman primates: an experimental study on the baboon. Clin Orthop 1991; 269: 284–294.Google Scholar
  51. 51.
    Ripamonti U, Magan A, Ma S, Vandenheever B, Moehl T, and Reddi AH. Xenogeneic osteogenin, a bone morphogenetic protein, and demineralized bone matrices, including human, induce bone differentiation in athymic rats and baboons. Matrix 1991; 11: 404–411.CrossRefGoogle Scholar
  52. 52.
    Ripamonti U. Bone induction in nonhuman primates. Clin Orthop 1991; 269: 284–294.Google Scholar
  53. 53.
    Ripamonti U, Ma S, Cunningham NS, Yeates L, and Reddi AH. Initiation of bone regeneration in adult baboons by osteogenin, a bone morphogenetic protein. Matrix 1992; 12: 369–380.CrossRefGoogle Scholar
  54. 54.
    Urist MR, Kovacs S, and Yates KA. Regeneration of an enchondroma defect under the influence of an implant of human bone morphogenetic protein. J Hand Surg 1986; 11A: 417–419.Google Scholar
  55. 55.
    Ferguson D, Davis WL, Urist MR, Hurt WC, and Allen EP. Bovine bone morphogenetic protein (bBMP) fraction-induced repair of craniotomy defects in the rhesus monkey (Macaca speciosa). Clin Orthop 1987; 219: 251–258.Google Scholar
  56. 56.
    Ripamonti U and Dent D. The induction of bone in osteogenic composites of bone matrix and porous hydroxyapatite replicas: an experimental study on the baboon (Papio ursinus). JOral Maxillofac Surg 1991; 49: 817–830.CrossRefGoogle Scholar
  57. 57.
    Ripamonti U, Ma S, and Reddi AH. The critical role of geometry of porous hydroxyapatite delivery system in induction of bone by osteogenin, a bone morphogenetic protein. Matrix 1992; 12: 202–212.CrossRefGoogle Scholar
  58. 58.
    Ripamonti U, Ma S, and Reddi AH. Induction of bone in composites of osteogenin and porous hydroxyapatite in baboons. Plast Reconst Surg 1992; 89: 731–739.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Kunio Takaoka
  • Hideki Yoshikawa
  • Shimpei Miyamoto
  • Jun Hashimoto
  • Masashi Matsui
  • Keiro Ono

There are no affiliations available

Personalised recommendations