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BASIC AND CLINICAL RESEARCH

Demonstration of the Osseoinductive Effect of Bone Morphogenetic Protein Within Endosseous Dental Implants

Boyne, Phillip DMD, MS, DSc*; Jones, Shedrick D. DDS*†

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doi: 10.1097/01.ID.0000127520.06443.42
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Abstract

Clinical experience during the past 30 years has demonstrated that endosseous implants can successfully replace missing teeth. In the 1960s and 1970s, early forms of these implants tended to be encapsulated with fibrous connective tissue or a combination of fibrous connective tissue and bone. The work of Branemark et al. demonstrated that a direct bone-to-implant contact could be achieved. 1 This type of bone contact, called osseointegration, is considered to be the ideal bone–implant interface. 2

Over 35 years ago, Urist demonstrated that protein extracts from bone could induce the local formation of new cartilage and bone when implanted in ectopic sites. Urist called this protein extract “bone morphogenetic protein (BMP).” 3 One of the main problems encountered by Urist was the limited amount of human bone available for processing to obtain BMP. The advancement of molecular biologic techniques, in particular the use of recombinant DNA, has permitted the production and the characterization of at least 14 BMPs. 4–7 One of these BMPs (rhBMP-2) has been assayed extensively and has been shown to have a very high osteogenic activity. 8,12,13 Thorarinn and coworkers 14 successfully induced peri-implant bone regeneration and osseointegration. Nevins and associates 4 were successful in inducing bone in the goat maxillary sinus using collagen sponges impregnated with rhBMP-2. Howell and coworkers 5 demonstrated radiographic evidence of bone growth in tooth extraction sockets. Boyne and associates 6 were able to induce bone formation in sinus augmentation grafts in humans as demonstrated by means of clinical, radiographic, and histologic methods.

Transforming growth factors (TGFs), despite their molecular similarities to BMPs, have not been demonstrated to be effective in inducing bone formation. 7 TGF-beta does play a positive role in skin and connective tissue healing. 15–17 It has been shown that TGF-B2 in combination with BMP induces osteogenic activity. 18

Autogenous particulate marrow (APM) and cancellous bone (CB) have been considered to be the gold standard for comparing the effectiveness of all osteogenic materials. 19,20 The future use of a dental implant as a carrier of BMP, TFG-B, or autogenous bone is clearly possible. This demonstration case report was undertaken to demonstrate that an optional degree of osseointegration can be achieved in approximately 6 weeks when using BMP and the subject implant.

Materials and Methods

A Macaca fascicularis monkey involved in another study required the extraction of the maxillary premolar teeth. The animal’s chronologic age (12 years) would be comparable to that of a middle-aged human. The subject implant system involves a coring devise using a special trephine that prepares the osteotomy and collects the autogenous bone. The collected bone can be placed back into the horizontal portals of the implant. The implant is a cylinder design appliance with a series of horizontal portals and one apical opening. The proposed advantages of this design are: 1) the horizontal portals could carry BMP, PRP, or autogenous bone, and 2) the horizontal portals could allow an additional 12 to 15 mm of internal surface area for bony growth.

The BMP was placed in the implant on a collagen sponge carrier in the apex and in the horizontal portals of one implant (Fig. 1). In the control implant, autogenous bone removed in preparation of the osteotomy was placed in the apex, and in horizontal portals (Fig. 2), tooth extraction sockets were prepared in maxillary right and left premolar areas using the specially designed coring system (Figs. 3, 4, and 5). Two implants were placed on the left side 6 weeks before sacrifice and on the right side 1 week before sacrifice (Fig. 6). The animal was given tetracycline 8 days before sacrifice. Specimens representing 1 week and 6 weeks of healing (Fig. 6) were obtained. The biopsied materials were processed as nondecalcified specimens and evaluated histologically with incandescent and fluorescent microscopy to determine the quality of bone regeneration around the dental implant fixtures.

Fig. 1.
Fig. 1.:
An implant filled with absorbable collagen sponge saturated with bone morphogenetic protein.
Fig. 2.
Fig. 2.:
The subject implant showing the horizontal portals filled with autogenous bone.
Fig. 3.
Fig. 3.:
The new micro-osseous core drill system used.
Fig. 4.
Fig. 4.:
The implant showing the horizontal portals designed to allow bone ingrowth.
Fig. 5.
Fig. 5.:
A dappen dish with the bone coagulum mass after removal from the core drill. The coagulum mass is packed in the horizontal portals of the implant.
Fig. 6.
Fig. 6.:
After extraction of upper premolars, subject implants were surgically placed.

Results

At 1 week, the specimens showed tetracycline-induced fluorescence in the soft tissue at the apex of the implant, indicating that tetracycline was being taken up by mineral elements in the soft tissue (Fig. 7). At 6 weeks, a marked increase in bone formation was evident around the apex and the peri-implant space with bone growth visible through the open portals of the implant fixture itself (Fig. 8).

Fig. 7.
Fig. 7.:
Histologic at 1 week postoperatively section of bone morphogenetic protein-containing implant shows tetracycline uptake by mineral elements in the soft tissue surrounding the apex of the implant fixture.
Fig. 8.
Fig. 8.:
A histologic section under incandescent light of the implant at the sixth postoperative week showing marked new bone at the apex in the peri-implant space. New bone is also seen in the open portals of the implant.

Discussion

To date, little information is available concerning the role of BMP within implants in human subjects. Therefore, the present demonstration was made to evaluate the feasibility of BMP and a new dental implant in a nonhuman animal primate model.

In this preliminary demonstration, the goal was to observe the level of osseointegration at a time at which a new osseous matrix is usually seen. The typical objective after a demonstration such as this is to proceed to a full-scale study that is designed to test the hypothesis that internally delivered BMP in an implant can possibly affect osseointegration. 21

Conclusions

The test dental implant appears to offer a bone-induction delivery capability, allowing the alveolus adequate exposure to the inductor material. If healing continues at the same rate and osseointegration is achieved, the osseous healing time of the implant could be decreased, possibly allowing the implant to be loaded immediately in selected cases.

Disclosure

One of the authors, Shedrick Jones, has a financial interest in Senoj Biocare, Inc., whose products, Senoj dental implant and trephine, are mentioned in this article. The other author has no financial interest in the company or product mentioned in this article.

References

1. Branemark PI, Breine U, Lindstrom J, et al. Intra-osseous anchorage of dental prostheses, I. Experimental studies. Scand J Plast Reconstr Surg. 1969;3:81–100.
2. Branemark PI, Zarb GA, Albrektsson T. Tissue-Integrated Prostheses: Osseointegration in Clinical Dentistry. Chicago: Quintessence Publishing Col 1985.
3. Urist MR. Bone formation by antoinduction. Science. 1965;150:893–899.
4. Nevins M, Kirker-Head C, Nevins M, et al. Bone formation in the goat maxillary sinus induced by absorbable collagen sponge implants impregnated with bone morphogenetic protein-2. Int J Periodontics Restorative Dent. 1996;16:9–19.
5. Howell TH, Fiorellini J, Jones A, et al. A feasibility study evaluating rhBMP-2/absorbable collagen sponge device for local alveolar ridge preservation or augmentation. Int J Periodont Rest Dent. 1997;17:125–139.
6. Boyne PJ, Marx RE, Nevins M, et al. A feasibility study evaluating rhBMP-2/absorbable collagen sponge for maxillary sinus floor augmentation. Int J Periodontics Restorative Dent. 1997;17:11–25.
7. Takatis DN, Wikesjo UM, Razi SS, et al. Periodontal repair in dogs: effect of transforming growth factor-beta 1 on alveolar bone and cementum regeneration. J Clin Periodontol. 200x;27:698–704.
8. Wang EA, Rosen V, D’Alessandro JS, et al. Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci U S A. 1990;87:2220–2224.
9. Wozney JM. The bone morphogenetic protein family and osteogenesis. Mol Reprod Dev. 1992;32:160–167.
10. Celeste AJ, Taylor R, Yamaji N. Molecular cloning of BMP-8: a protein present in bovine bone which is highly related to the BMP-5/6/7 sub-family of osteoinductive molecules. J Cell Biochem. 1992;16F(suppl):100.
    11. Celeste AJ, Song JJ, Cox K, et al. Bone morphogenetic protein-9, a new member of the TGF-β superfamily. J Bone Miner Res. 1994;9(suppl 1):S136.
      12. Boyne PJ. Reconstruction of discontinuity mandibular defects in rhesus monkeys using rhBMP-2. J Oral Maxillofac Surg. 1995;53(suppl 4):92.
      13. Toriumi DM, Kotler HS, Luxenberg DP, et al. Mandibular reconstruction with a recombinant bone-inducing factor. Functional, histologic and biomechanical evaluation. Arch Otolaryngol Head Neck Surg. 1991;117:1101–1112.
      14. Thorarinn, Sigurdsson J. Bone morphogenetic protein-2 for peri-implant bone regeneration in osseointegration. Clin Oral Implants Res. 1997;8:367–374.
      15. Lynch SE, Covin RB, Antoiades HN. Growth factors in wound healing. Single and synergistic effects on partial thickness porcine skin wounds. J Clin Invest. 1989;84:640–646.
      16. Sprugel KH, McPherson JM, Clowes AW, et al. Effect of growth factors in vivo. I. Cell ingrowth into porous subcutaneous chambers. Am J Pathol. 1987;129:601–613.
      17. Sporn MB, Roberts AB, Shull JH, et al. Polypeptide transforming growth factors isolated from bovine sources and used for wound healing in vivo. Science. 1983;219:1329–1331.
      18. Bentz H, Thompson AY, Armstrong R, et al. Transforming growth factor-beta 2 enhances the osteoinductive activity of a bovine-bone-derived fraction containing bone morphogenetic protein-2 and 3. Matrix. 1991;11:269–275.
      19. Burchardt H. Biology of bone transplantation. Orthop Clin North Am. 1987;18:187–195.
      20. Friedlander G. Current concepts review. Bone grafts: the basic science rationale for clinical applications. J Bone Joint Surg. 1987;69:786.
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      Abstract Translations [German, Spanish, Portugese, Japanese]

      AUTOR(EN): Philip Boyne, D.M.D.. M.S., DSc*, Shedrick D. Jones, D.D.S.**. * Professor Emeritus, Abteilung für Weiterbildung, Kiefer- und Gesichtschirurgie, zahnmedizinische Fakultät, Loma Lina Universität, Loma Linda, Kalifornien 92350. ** Klinischer Professor, ehemals in der Abteilung für Weiterbildung - Spezialgebiet Prothetik, ehemals Leiter Zahnimplantatheilkunde, Universität von Südkalifornien, zahnmedizinische Fakultät, Los Angeles, Kalifornien 90089-0641. Schriftverkehr: Shedrick Jones, DDS, 2021 Santa Monica Blvd., Suite 408 East Tower, Santa Monica, Kalifornien 90404. Fax: (310) 829 - 5587

      Einwirkung von osteomorphogenetischem Protein auf die Knochengewebsbildung: Nachweis bei direkt ins Knochengewebe eingelagerten Zahnimplantaten

      ZUSAMMENFASSUNG: Ziel vorliegender Fallstudie war es, die Reaktion des Wirtsknochens im Oberkiefer nach Platzierung von osteomorphogenetischen Protein (BMP - bone morphogenetic protein) innerhalb eines speziell für diese Zwecke geeigneten Implantats nachzuweisen.

      Normalerweise muss man vier bis sechs Monate, in manchen Fällen sogar noch länger, auf eine Knochengewebsintegration warten. Unsere Untersuchungen zielten darauf ab, die Fähigkeit des osteomorphogenetischen Proteins zur Knochenbildung zu bewerten. Zum Versuch wurde ein faszikulärer Makake herangezogen, dem das Protein auf einem resorbierbaren Kollagenschwamm in die horizontalen Portale des betreffenden Implantats eingesetzt wurde. Ein Kontrollimplantat wurde innen mit autogenem Knochengewebe ausgestattet. Dieses Knochengewebe war zuvor bei der Vorbereitung der Osteotomie gewonnen worden.

      Bei der Verwendung des osteomorphogenetischen Proteins (BMP) in der oben angegebenen Weise konnte gemäß den Untersuchungsergebnissen eine Knochengewebsheilung im das Implantat umlagernden Knochengewebe festgestellt werden.

      SCHLÜSSELWÖRTER: interne Zahnimplantierung, BMP (osteomorphogenetisches Protein), Knochengewebsintegration

      AUTOR(ES): Philip Boyne, D.M.D., M.S., DSc*, Shedrick D. Jones, D.D.S. ** *Profesor Emeritus, Departamento de Educación Avanzada, Cirugía Oral y Maxilofacial, Facultad de Odontología, Loma Linda University, Loma Linda, California 92350. **Profesor Clínico, Departamento de Educación Avanzada en Prostodóntica (antiguamente), Director de Odontología de Implantes (antiguamente), Universidad del Sur de California, Facultad de Odontología, Los Ángeles, California 90089-0641. Correspondencia a: Shedrick Jones, DDS, 2021 Santa Monica Blvd., Suite 408 East Tower, Santa Monica, California 90404. Fax: (310) 829-5587

      Demostración del efecto oseoinductivo de una proteína morfogenética de hueso (BMP) dentro de implantes dentales endoóseos

      ABSTRACTO: El propósito de este informe de caso fue demostrar la respuesta ósea del paciente en el maxilar después de colocar una proteína morfogenética de hueso (BMP por sus siglas en inglés), dentro de un implante especialmente diseñado.

      En circunstancias normales, es generalmente necesario esperar de cuatro a seis meses o incluso más tiempo en algunos casos, para lograr la integración ósea. Nuestro objetivo fue evaluar la capacidad de la proteína morfogenética de hueso (BMP), que fue transportada en una esponja absorbible de colágeno en portales horizontales del implante del sujeto, de afectar la formación de hueso en un mono Macaca fascicularis. Un implante de control se colocó internamente con hueso autógeno recuperado de la preparación de la osteotomía.

      Los resultados demostraron que la curación ósea periimplante ocurre usando la proteína morfogenética de hueso en este formato.

      PALABRAS CLAVES: colocación de un implante dental interno, proteína morfogenética de hueso (BMP), integración ósea

      AUTOR(ES): Phillip Boyne, Doutor em Medicina Dentária, Mestre em Ciências, Doutor em Ciências, Shedrick D. Jones, Doutor em Ciência Dentária. *Professor Emérito, Departamento de Educação Avançada, Cirurgia Oral e Maxilofacial, Escola de Odontologia, Loma Linda University, Loma Linda, California 92350. **Professor Clínico, Departamento de Educação Avançada em Prostodontia (Antigamente), Diretor de Odontologia de Implantes (Antigamente), University of South California, Escola de Odontologia, Los Angeles, California 90089-0641. Correspondência para: Shedrick Jones, DDS, 2021 Santa Monica Blvd., Suite 408 East Tower, Santa Monica, California 90404. FAX (310) 829-5587

      Demonstração do Efeito Ósseo-Indutivo do BMP dentro de Implantes Dentários Endósseos

      RESUMO: O propóstio deste relato de caso era demonstrar a resposta óssea do receptor na maxila após a colocação do BMP dentro de um implantes especialmente projetado.

      Sob circunstâncias normais, normalmente é necessário esperar de quatro a seis meses, ou mesmo mais em alguns casos, para a integração óssea. Nosso objetivo era avaliar a capacidade de proteína morfogenática do osso (BMP), o que foi realizado numa esponja de colágeno absorvível em portais horizontais do implante do paciente, para afetar a formação de osso num macaco Macaca fascicularis. Um implante de controle foi carregado internamente com osso autógeno recuperado da preparação da osteotomia.

      Os resultados demonstraram que a cura do peri-implante ósseo ocorre usando BMP neste formato.

      PALAVRAS-CHAVE: remissão do implante dentário interno, BMP, ósseo-integração.

      FIGURE

      FIGURE
      FIGURE
      Keywords:

      internal dental implant delivery; BMP; osseointegration

      © 2004 Lippincott Williams & Wilkins, Inc.