Skip to main content
SpringerLink
Log in

Biotechnology and Bone Graft Substitutes

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Trauma, disease, developmental deformities, and tumor resection frequently cause bone defects that seriously challenge the skills of orthopedic and maxillofacial surgeons. Currently, repairing osseous deficiencies involves various medical surgical techniques, including autogenous grafts, allografts, internal and external fixation devices, electrical stimulation, and alloplastic implants. The existing technology, though effective in many cases, still is beset with numerous difficulties and disadvantages. A critical need for improved treatment methods exists today. Biotechnology now provides access to new bone repair concepts via administration of protein growth and morphogenic factors. Implantable device and drug delivery system technologies also have advanced. The converging biopharmaceutical, device, and delivery technologies represent an opportunity to improve the quality of health care for individuals with orthopedic and maxillofacial deficiencies. This report reviews current concepts in fracture healing and bone repair and examines existing treatment modalities. It also addresses novel protein drugs that stimulate osseous regeneration and delivery systems for these drugs.

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

Similar content being viewed by others

REFERENCES

  1. G. F. Muschler and J. M. Lane. Orthopedic surgery. In M. B. Habal and A. H. Reddi (eds.), Bone Grafts and Bone Substitutes, W. B. Saunders, New York, 1992, 375–407.

    Google Scholar 

  2. K. L. Grazier, T. L. Holbrook, J. L. Kelsey, and R. N. Stauffer. Muscoloskeletal injuries: Frequency of occurrence. In The Frequency of Occurrence, Impact, and Cost of Musculoskeletal Conditions in the United States, Am. Acad. Orthoped. Surg., Chicago, 1984, pp. 73–135.

    Google Scholar 

  3. Anonymous. Osteotech. Making the shift in orthopedics from service to product and from mechanical to biological. In Vivo 10:1–6 (1992).

  4. D. J. Simmons. Fracture healing perspectives. Clin. Orthop. 200:100–113 (1985).

    Google Scholar 

  5. M. E. Joyce and M. E. Bolander. Role of transforming growth factor-β. In M. B. Habal and A. H. Reddi (eds.), Bone Grafts and Bone Substitutes, W. B. Saunders, New York, 1992, pp. 99–111.

    Google Scholar 

  6. C. N. Cornell and J. M. Lane. Newest factors in fracture healing. Clin. Orthoped. Rel. Res. 277:297–311 (1992).

    Google Scholar 

  7. L. S. Beck, L. Deguzman, W. P. Lee, Y. Xu, L. A. McFatridge, N. A. Gilett, and E. P. Amento. TGF-β1 induces bone closure of skull defects. J. Bone Min. Res. 6:1257–1265 (1991).

    Google Scholar 

  8. M. Noda and J. J. Camiliere. In vivo stimulation of bone formation by TGF-β. Endocrinology 124:2991–2994 (1989).

    Google Scholar 

  9. S. C. Marks, L. K. Osier, and S. C. Miller. The role of prostaglandins in bone formation. In M. B. Habal and A. H. Reddi (eds.), Bone Grafts and Bone Substitutes, W. B. Saunders, New York, 1992, pp. 226–234.

    Google Scholar 

  10. D. G. Mohler, D. Fehnel, A. Juhn, J. M. Lane, and J. H. Healy. Stable PGE2 analog with angiogenic properties in vivo. Trans. Orthop. Res. Soc. 15:353 (1990).

    Google Scholar 

  11. D. G. Mohler, A. M. Cohen, D. Fehnel, J. M. Lane, and A. Tomin. Effect of basic fibroblast growth factor on angiogenesis and calcification of rat femoral defect. Trans. Orthop. Res. Soc. 15:380 (1990).

    Google Scholar 

  12. A. H. Reddi. Cell biology and biochemistry of endochrondral bone development. Collagen Rel. Res. 1:209–226 (1981).

    Google Scholar 

  13. A. H. Reddi and C. Huggins. Biochemical sequences in the transformation of normal fibroblasts in adolescent rats. Proc. Natl. Acad. Sci. USA 69:1601–1605 (1972).

    Google Scholar 

  14. A. H. Reddi and C. Huggins. Formation of bone marrow in fibroblast-transformation ossicles. Proc. Natl. Acad. Sci. USA 72:2212–2216 (1975).

    Google Scholar 

  15. M. Kawamura and M. R. Urist. Growth factors, mitogens, cytokines, and bone morphogenetic protein in induced chondrogenesis in tissue culture. Dev. Biol. 130:435–442 (1988).

    Google Scholar 

  16. J. Glowacki. Tissue response to bone-derived implants. In M. B. Habal and A. H. Reddi (eds.), Bone Grafts and Bone Substitutes, W. B. Saunders, New York, 1992, pp. 84–92.

    Google Scholar 

  17. M. Urist. Bone morphogenetic protein. In M. B. Habal, and A. H. Reddi (eds.), Bone Grafts and Bone Substitutes, W. B. Saunders, New York, 1992, pp. 70–83.

    Google Scholar 

  18. J. F. Connolly, L. Lippiello, and B. S. Strates. The role of bone marrow in osteogenesis. In M. B. Habal and A. H. Reddi (eds.), Bone Grafts and Bone Substitutes, W. B. Saunders, New York, 1992, pp. 121–132.

    Google Scholar 

  19. J. Hollinger, D. E. Mark, D. E. Bach, A. H. Reddi, and A. E. Seyfer. Calvarial bone regeneration using osteogenin. J. Oral Maxillofac. Surg. 47:1182–1186 (1989).

    Google Scholar 

  20. J. J. Tiedeman, J. F. Connolly, B. S. Strates, and L. Lippiello. Treatment of nonunion by percutaneous injection of bone marrow and demineralized bone matrix. Clin. Orthop. Rel. Res. 268:294–302 (1991).

    Google Scholar 

  21. J. Glowacki, L. B. Kaban, J. E. Murray, J. Folkman, and J. B. Mulliken. Application of the principle of induced osteogenesis for craniofacial defects. Lancet 8227:959–963 (1981).

    Google Scholar 

  22. M. Jarcho. Calcium phosphate ceramics as hard tissue prosthetics. Clin. Orthop. 157:259–278 (1981).

    Google Scholar 

  23. T. A. Miller, K. Ishida, M. Kobayashi, J. S. Wollman, A. E. Turk, and R. E. Holmes. The induction of bone by an osteogenic protein and the conduction of bone by porous hydroxyapatite: A laboratory study in the rabbit. Plast. Reconstr. Surg. 87:87–95 (1991).

    Google Scholar 

  24. H. Ohgushi, M. Okumura, S. Tamai, E. C. Shores, and A. I. Caplan. Marrow cell induced osteogenesis in porous hydroxyapatite and tricalcium phosphate: A comparative histomorphometric study of ectopic bone formation. J. Biomed. Mat. Res. 24:1563–1570 (1990).

    Google Scholar 

  25. H. Ohgushi, V. M. Goldberg, and A. I. Caplan. Heterotopic osteogenesis in porous ceramics induced by marrow cells. J. Orthop. Res. 7:568–578 (1989).

    Google Scholar 

  26. H. Ohgushi and M. Okumura. Osteogenic capacity of rat and human marrow cells in porous ceramics. Acta Orthop. Scand. 61:431–434 (1990).

    Google Scholar 

  27. R. Holmes, V. Mooney, R. Bucholz, and A. Tencer. A coralline hydroxyapatite bone graft substitute. Clin. Orthop. 188:252–262 (1984).

    Google Scholar 

  28. D. J. Sartoris, R. E. Holmes, A. F. Tencer, V. Mooney, and D. Resnick. Coralline hydroxyapatite bone graft substitutes in a canine metaphyseal defect model. Skel. Radiol. 15:635–641 (1986).

    Google Scholar 

  29. S. Werntz, J. M. Lane, K. Piez, S. Seyedin, A. Burstein, and M. Gebhart. Zyderm plus marrow for grafting in a rat nonunion model. Orthop. Trans. 10:200 (1986).

    Google Scholar 

  30. C. N. Cornell, J. M. Lane, M. Chapman, R. Merkow, D. Seligson, S. Henry, R. Gustilo, and K. Vincent. Multicenter trial of collagraft as bone graft substitute. J. Orthop. Trauma 5:1–8 (1991).

    Google Scholar 

  31. L. Newman. Graft substitutes near clinical and commercial viability. Orthop. Today 11:9 (1991).

    Google Scholar 

  32. J. O. Hollinger, J. P. Schmitz, J. W. Mizgala, and C. Hassler. An evaluation of two configurations of tricalcium phosphate for treating craniotomies. J. Biomed. Mater. Res. 23:17–29 (1989).

    Google Scholar 

  33. S. Ma, G. Chen, and H. Reddi. Collaboration between collagenous matrix and osteogenin is required for bone induction. Ann. N.Y. Acad. Sci. 580:524–525 (1990).

    Google Scholar 

  34. K. Takaoka, M. Koezuka, and H. Nakahara. Telopeptide-depleted bovine skin collagen as a carrier for bone morphogenetic protein. J. Orthop. Res. 9:902–907 (1991).

    Google Scholar 

  35. J. R. Deatherage and E. J. Miller. Packaging and delivery of bone induction factors in a collagenous implant. Collagen Rel. Res. 7:225–231 (1987).

    Google Scholar 

  36. M. D. Finn, S. R. Schow, and E. D. Schneiderman. Osseous regeneration in the presence of four common hemostatic agents. J. Oral Maxillofac. Surg. 50:608–612 (1992).

    Google Scholar 

  37. J. Upton, M. Boyajian, J. B. Mulliken, and J. Glowacki. The use of demineralized xenogeneic bone implants to correct phalangeal defects. J. Hand. Surg. 9A:388–391 (1984).

    Google Scholar 

  38. R. Salama. Xenogeneic bone grafting in humans. Clin. Orthop. 174:113–121 (1983).

    Google Scholar 

  39. J. D. Heckman, B. D. Boyan, T. B. Aufdemorte, and J. T. Abbott. The use of bone morphogenetic protein in the treatment of non-union in a canine model. J. Bone Joint Surg. 73-A:750–764 (1991).

    Google Scholar 

  40. D. Ferguson, W. L. Davis, M. R. Urist, W. C. Hurt, and E. P. Allen. Bovine bone morphogenetic protein fraction-induced repair of craniotomy defects in the rhesus monkey. Clin. Orthop. Rel. Res. 219:251–258 (1987).

    Google Scholar 

  41. S. Miyamoto, K. Takaoka, T. Okada, H. Yoshikawa, J. Hashimoto, S. Suzuki, and K. Ono. Evaluation of polylactic acid homopolymers as carriers for bone morphogenetic protein. Clin. Orthop. Rel. Res. 278:274–285 (1992).

    Google Scholar 

  42. J. O. Hollinger and G. C. Battistone. Biodegradable bone repair materials. Synthetic polymers and ceramics. Clin. Orthop. 207:207–209 (1986).

    Google Scholar 

  43. T. P. Lovell, E. G. Dawson, W. S. Nilsson, and M. R. Urist. Augmentation of spinal fusion with bone morphogenetic protein in dogs. Clin. Orthop. Rel. Res. 243:266–274 (1989).

    Google Scholar 

  44. J. O. Hollinger, J. P. Schmitz, D. E. Mark, and A. E. Seyfer. Osseous wound healing with xenogeneic bone implants with a biodegradable carrier. Surgery 107:50–54 (1990).

    Google Scholar 

  45. J. P. Schmitz and J. O. Hollinger. A preliminary study of the osteogenic potential of a biodegradable alloplastic-osteoinductive alloimplant. Clin. Orthop. Rel. Res. 237:245–255 (1988).

    Google Scholar 

  46. M. Kawamura and M. R. Urist. Human fibrin is a physiological delivery system for bone morphogenetic protein. Clin. Orthop. Rel. Res. 235:302–310 (1988).

    Google Scholar 

  47. K. Ono, J. Shikata, K. Shimizu, and T. Yamamuro. Bone-fibrin mixture in spinal surgery. Clin. Orthop. Rel. Res. 275:133–139.

  48. N. Schwarz, H. Redl, G. Schlag, A. Schiesser, F. Lintner, H. P. Dinges, and M. Thurnher. The influence of fibrin sealant on demineralized bone matrix-dependent osteoinduction. Clin. Orthop. Rel. Res. 238:282–287 (1989).

    Google Scholar 

  49. L. F. Peltier and D. P. Speer. Calcium sulfate. In M. B. Habal and A. H. Reddi (eds.), Bone Grafts and Bone Substitutes, W. B. Saunders, New York, 1992, pp. 243–246.

    Google Scholar 

  50. L. F. Peltier. The use of plaster of Paris to fill large defects in bone. Am. J. Surg. 97:311–315 (1959).

    Google Scholar 

  51. L. F. Peltier. The use of plaster of Paris to fill defects in bone. Clin. Orthop. 21:1–31 (1961).

    Google Scholar 

  52. M. R. Urist. Bone morphogenetic protein in bone generation and regeneration. J. Jap. Orthop. Assoc. 65:S257–258 (1991).

    Google Scholar 

  53. E. E. Johnson, M. R. Urist, and G. A. M. Finerman. Resistant nonunions and partial or complete segmental defects of long bones. Clin. Orthop. Rel. Res. 277:229–237 (1992).

    Google Scholar 

  54. E. E. Johnson, M. R. Urist, and G. A. M. Finerman. Repair of segmental defects of the tibia with cancellous bone grafts augments with human bone morphogenetic protein. Clin. Orthop. Rel. Res. 230:249–256 (1988).

    Google Scholar 

  55. E. E. Johnson, M. R. Urist, and G. A. Finerman. Bone morphogenetic protein augmentation grafting of resistant femoral nonunion. Clin. Orthop. Rel. Res. 230:257–265 (1988).

    Google Scholar 

  56. E. E. Johnson, M. R. Urist, and G. A. M. Finerman. Distal metaphyseal tibial nonunion: Deformity and bone loss treated by open reduction, internal fixation, and human bone morphogenetic protein. Clin. Orthop. Rel. Res. 250:234–240 (1990).

    Google Scholar 

  57. M. R. Urist, O. Nilsson, J. Rasmussen, W. Hirota, T. Lovell, T. Schmalzreid, and G. A. M. Finerman. Bone regeneration under the influence of a bone morphogenetic protein beta tricalcium phosphate composite in skull trephine defects in dogs. Clin. Orthop. 214:295–304 (1987).

    Google Scholar 

  58. N. Senn. On the healing of aseptic bone cavities by implantation of antiseptic decalcified bone. Am. J. Med. Sci. 98:219–243 (1889).

    Google Scholar 

  59. C. B. Huggins. The formation of bone under the influence of epithelium of the urinary tract. Arch. Surg. 22:377–408 (1931).

    Google Scholar 

  60. M. R. Urist. Bone formation by autoinduction. Science 6:150 (1965).

    Google Scholar 

  61. M. R. Urist, H. Iwata, P. L. Ceccotti, R. L. Dorfman, S. D. Boyd, and C. Chien. Bone morphogenesis in implants of insoluble bone gelatin. Proc. Natl. Acad. Sci. USA 70:3511–3515 (1973).

    Google Scholar 

  62. M. R. Urist, A. Mikulski, and A. Lietze. Solubilized and insolubilized bone morphogenetic protein. Proc. Natl. Acad. Sci. USA 76:1828–1832 (1979).

    Google Scholar 

  63. E. A. Wang, V. Rosen, P. Cordes, R. M. Hewick, M. J. Kriz, D. P. Luxemberg, B. S. Sibley, and J. M. Wozney. Purification and characterization of other distinct bone-inducing factors. Proc. Natl. Acad. Sci. USA 85:9484–9488 (1988).

    Google Scholar 

  64. J. M. Wozney, V. Rosen, A. J. Celeste, L. M. Mitsock, M. J. Whitters, R. W. Kriz, R. M. Hewick, and E. A. Wang. Novel regulators of bone formation; Molecular clones and activities. Science 242:1528–1534 (1988).

    Google Scholar 

  65. A. J. Celeste, J. A. Iannazzi, R. C. Taylor, R. M. Hewick, V. Rosen, E. A. Wang, and J. M. Wozney. Identification of transforming growth factor-β family members present in bone-inductive protein from bovine bone. Proc. Natl. Acad. Sci. USA 87:9843–9847.

  66. J. M. Wozney, Bone morphogenetic proteins. Prog. Growth Factor Res. 1:267–280 (1989).

    Google Scholar 

  67. F. P. Luyten, N. S. Cunningham, S. Ma, N. Muthukumaran, R. G. Hammonds, W. B. Nevins, W. I. Wood, and A. H. Reddi. Purification and partial amino acid sequence of osteogenin, a protein initiating bone differenation. J. Biol. Chem. 264:13377–13380 (1989).

    Google Scholar 

  68. E. Ozkaynak, D. C. Rueger, E. A. Drier, C. Corbett, R. J. Ridge, T. K. Sampath, and H. Oppermann. OP-1 cDNA encodes an osteogenic protein in the TFG-β family. EMBO 9:2085–2093 (1990).

    Google Scholar 

  69. T. K. Sampath, J. E. Coughlin, R. M. Whetstone, D. Banach, C. Corbett, R. J. Ridge, E. Ozkayanak, H. Oppermann, and D. C. Rueger. Bovine osteogenic protein is composed of dimers of OP-1 and BMP-2A, two members of the TGF-β superfamily. J. Biol. Chem. 265:13198–13205 (1990).

    Google Scholar 

  70. E. A. Wang, V. Rosen, J. S. D'Alesandro, M. Bauduy, P. Cordes, T. Harada, D. I. Isreal, R. M. Hewick, K. M. Kerns, P. LaPan, D. P. Luxenberg, D. McQuaid, I. K. Matsoutsos, J. Nove, and J. M. Wozney. Recombinant human bone morphogenetic protein induces bone formation. Proc. Natl. Acad. Sci. USA 87:2220–2224 (1990).

    Google Scholar 

  71. M. D. Bond, M. A. Jankowski, S. A. Martin, and H. A. Scoble. Structural characterization of CHO rhBMP-2. Sixth International Symposium of the Protein Society, San Diego, CA, 1992 (abstr.).

  72. A. W. Yasko, J. M. Lane, E. J. Fellinger, V. Rosen, J. M. Wozney, and E. A. Wang. The healing of segmental defects, induced by recombinant human bone morphogenetic protein-2. J. Bone Joint Surg. 74-A:659–671 (1992).

    Google Scholar 

  73. J. O. Hollinger and A. O. Kleinschmidt. Animal models in bone research. In M. B. Habal and A. H. Reddi (eds.), Bone Grafts and Bone Substitutes, W. B. Saunders, New York, 1992, pp. 133–146.

    Google Scholar 

  74. D. M. Toriumi, H. S. Kotler, D. P. Luxenberg, M. E. Holtrop, and E. A. Wang. Mandibular reconstruction with a recombinant bone-inducing factor. Arch. Otolaryngol. Neck Surg. 117:1101–1112 (1991).

    Google Scholar 

  75. E. Ron, R. G. Schaub, and T. J. Turek. Formulations of bloodclot polymer matrix for delivery of osteogenic proteins. U.S. Patent 5,171,579 (1992).

Download references

Author information

Authors and Affiliations

  1. Genetics Institute, 1 Burtt Road, Andover, Massachusetts, 01810

    Richard A. Kenley, Kalvin Yim, Joan Abrams & Tom Turek

  2. Focal Interventional Therapies, Inc., One Kendall Square, Building 600, Cambridge, Massachusetts, 02139

    Eyal Ron

  3. U.S. Army Institute of Dental Research, Walter Reed Army Medical Center, Building 40, Washington, D.C, 20307

    Leslie J. Marden & Jeffrey O. Hollinger

Authors
  1. Richard A. Kenley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kalvin Yim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joan Abrams
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eyal Ron
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tom Turek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leslie J. Marden
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jeffrey O. Hollinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kenley, R.A., Yim, K., Abrams, J. et al. Biotechnology and Bone Graft Substitutes. Pharm Res 10, 1393–1401 (1993). https://doi.org/10.1023/A:1018902720816

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018902720816

Search

Navigation