DISCUSIÓN

Base Theories and the clinical application of bone morphogenetic proteins in maxillofacial surgery

Bases teóricas y aplicación clínica de las proteínas morfogenéticas óseas en cirugía maxilofacial

Luis Manuel Junquera Gutiérrez Lorena Gallego López

Servicio de Cirugía Oral y Maxilofacial. Hospital Universitario Central de Asturias, Oviedo.

The Group of bone inductive proteins that we call Bone Morphogenetic Proteins is obtained using the non mineralized bone matrix. These proteins are able to initiate and stimulate differentiation of pluripotent mesenchymal cells into progenitor bone cells. These proteins are of great interest because of their potential ability to form bone and cartilage de novo.¹ In the work that precedes this discussion the authors update our knowledge about the BMPs and also present the great clinical possibilities that can be achieved in the context of our specialty. Because of the interest entailed in its application similar studies can be found in published in other special interest magazines.²

As busy as we are day by day in our clinic, its no surprise that upon hearing or reading about the BMPs our faces darken when we do not have clear answers about the key issues. Where and how are BMPs obtained? How can we make clinical use of them?

In 1893 Virchow was the first person to describe the non mineralized organic bone matrix made up mainly of collagen (90%). In 1889 some surgeous as Senn reported the use of xerogenic demineralized gone as osseous graft in cranial defects in dogs. Though the true properties of these grafts could be provided, they went unnoticed. This happened because of the fact that these first investigators used EDTA as a means for bone mineralization which irreversibly de activated the matrix proteins. It was not until 1965 when Urst⁴ after replacing EDTA with hydrochloric acid found that ectopic bone formation following implantation of part of the demineralized bone matrix between soft tissues in rats. He published his work in the magazine Science and from there the concept of auto bone induction was created, but he did not correctly identify the BMPs. What he had discovered was the unanticipated behavior of the graft host neighbors that ended in their progenitor bone differentiation. It was not until 1980 when Urist disclosed that he had identified a light weight insoluble protein in the organic matrix. Shortly after this other authors would isolate different polypeptides, from 16-18 and 30 KDA, from the bovine bone that went on to dominate the BMP 1-3.⁶

At the beginning one of the biggest problems with these methods of isolations was the fact that in order to obtain 1 mg of pure BMP more that 1 Kg of bovine bone was needed. On the other hand the scaffold or ideal support matrix for the BMP was sought and controversial. All of this created a barrier to the experimental and clinical use of the BMPs. An important event at this stage was the identification of the gene that corresponds to the BMP-2. This allowed for intervention techniques in molecular biology and tissue engineering, the acquirement of cells capable of synthesizing large quantities of recombinant human BMP-2 with the same natural bone inductive ability as the natural process.

The volume of generated bone is determined by the quantity of rhBMP-2 used. At the moment at least two types of BMPs are commercialized, although at a higher price because of the current situation: rhBMP-2 (INFUSE, Medtronics, Sofamor Danek) and the rhBMP-7 (OP-1 Putty, Stryker Biotech). Since then, during the first few years of 2000 the FDA approved clinical use of rhBMP-2 and rhBMP-7 in patients with diverse spinal column pathologies and long bone pseudoarthrosis.⁷

Philip J. Boyne is an important figure in BMP experimentation that first took place in animals and later in humans. Since 1996 this author and his collaborators have demonstrated rhBMP-2's ability to repair mandible continuity and palatine cracks in different types of monkeys. (Macaque fascicularis, mulatta).^8,9 In 1997 he proved its successful application in sinus elevation surgery. In 1999 he showed that neoformed bone when exclusively used with rhBMP-2 in collagen sponges showed favorable bone integration behavior with conventional implants and titanium mesh grafts. In 2005 an excellent study compared two types of rhBMP-2 concentrations for maxillary sinus elevation. It also gave details about the amount of protein used in this increasingly frequent surgery of our specialty. But perhaps one of the most stimulating projects is the attached article published by Alan Herford in 2008 and in J Oral Maxillofacial Surg.¹³ It documents 14 patients (from a series of 36) who had excellent bone reconstruction of defects extremely critical to maxillaries. They were performed exclusively of kits of great size (defects larger than 3.5 cm) of rh-BMP-2 (INFUSE, Medtronics, Nashville, TN) in reabsorb able collagen sponges.

44 years have passed since the first Pioneer work of Urist and 13 years have past since Boyne's animal experimentation. In the end the BMPs and their implementation are a reality and their future can only get better. Alone related to cultivated cells with collagen and other more resistant scaffolds many things will change in our specialty and the lives of our patients.

Works like the ones mentioned by our colleagues update us on this very important topic.

References

1. Urist MR, DeLange RJ, Finerman GAM. Bone cell differentiation and growth factors. Science 1983;220:680-6.        [ Links ]

2. Jeong GK, Sandhu H, Farmer J. Bone Morphogenic Proteins: Applications in Spinal Surgery. HSSJ 2005;1:110-7.        [ Links ]

3. Senn N. On the healing of aseptic bone cavities by implantation of antiseptic decalcified bone. Am J Med Sci 1889;98:219-43.        [ Links ]

4. Urist MR. Bone: Formation by autoinduction. Science 1965;150:893-9.        [ Links ]

5. Urist MR, Chang JJ, Lietze A y cols. Preparation and bioassay of bone morphogenetic protein and polypeptides fragments. Methods in Enzymol 1987;146:294-312.        [ Links ]

6. Wang EA, Rosen V, Cordes P y cols. Purification and characterization of other distinct boneinducing factors. Proc Natl Acad Sci 1988;85:9484- 98.        [ Links ]

7. Food and Drug Administration (2002) Document P000058-InFUSE Bone Graft /LT-CAGE lumbar tapered fusion device. http://www.fda.gov/cdrh/PDF/p000054a.pdf

8. Boyne PJ. Animal studies of the application of rhBMP-2 in maxillofacial reconstruction. Bone 1996;19(Suppl):83S-92S.        [ Links ]

9. Boyne PJ, Nath R, Nakamura A. Human recombinant BMP-2 in osseous reconstruction of simulated cleft palate defects. Br J Oral Maxillofac Surg 1998;36:84-90.        [ Links ]

10. Boyne PJ, Nakamura A, Shabahang S. Evaluation o f the long-term effect of function on rhBMP-2 regenerated hemimandibulectomy defects. Br J Oral and Maxillofac Surg 1999;37:344-52.        [ Links ]

11. Boyne PJ, Marx RE, Nevins M, y cols. A feasibility study evaluating rhBMP-2/absorbable collagen sponge for maxillary sinus floor augmentation. Int J Periodont Rest Dent 1997;17:11-25.        [ Links ]

12. Boyne PJ, Lilly LC, Marx RE, Moy PK, Nevins M, Spagnoli DB, Triplett RG. De Novo Bone Induction by Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) in Maxillary Sinus Floor Augmentation. J Oral Maxillofac Surg 2005; 63:1693-707.        [ Links ]

13. Herford AS, Boyne PJ. Reconstruction of Mandibular Continuity Defects With Bone Morphogenetic Protein-2 (rhBMP-2). J Oral Maxillofac Surg 2008;66:616-24.        [ Links ]