Application of bone morphogenetic proteins in the treatment of clinical oral and maxillofacial osseous defects.

BACKGROUND: Commonly occurring extensive osseous defects in the oral and maxillofacial area are seen following complete or partial resection of the mandible and other facial bones in oncologic surgery or following traumatic injury. Autogenous osseous grafts have been used to restore these defects. Additionally, bone graft substitute materials and autogenous osseous grafts are applied to congenital defects such as cleft palate, facial clefts, and facial asymmetry. We have simulated these types of defects in appropriately aged Macaca fascicularis and Macaca mulatta monkeys to study the efficacy of using bone morphogenetic protein (BMP) as an osseous inductor. The objective of these studies was to obtain information on the feasibility of employing bone inductors to regenerate large continuity critical-sized maxillofacial defects without using bone grafts.

METHODS AND RESULTS: In one study, involving eight animals, the body of the mandible was removed, simulating hemi-mandibulectomy defects following traumatic bone loss or oncologic surgery. Recombinant human (rh) BMP-2 (Genetics Institute, Cambridge, Massachusetts) in a collagen carrier (Colla-Tec Inc., Plainsboro, New Jersey) then was placed in the hemi-mandibulectomy defect with use of titanium orthopaedic mesh fixation (Sofamor Danek-Medtronic, Memphis, Tennessee). Entire bone regeneration of the defect was observed 5 and 6 months postoperatively. In another group of subhuman primates, the restored area was functionally stimulated at the 5-month post-BMP implantation level by placement of intraoral titanium implants. The animals were allowed to function for 8 months with these titanium implants. Microscopic results showed increased density, bone volume, and thickness of the trabecular bone pattern. The bone cortex in the restored defect also increased in thickness compared with the nonsurgical areas. To evaluate the effect of rhBMP-2 in aging individuals, a group of six Macaca animals over 20 years of age received the same type of mandibular resection followed by BMP grafting with functional stimulation by mastication on root form implants placed at 5 months after BMP implantation. The entire mandible regenerated as in the younger group of animals; therefore, age did not appear to be a factor in the reparative process. Thus, the number of stem cells supposedly reduced with increasing age did not appear to affect the overall result of BMP-induced bone regeneration. Additionally, in applying the inductor material to younger monkeys (1-1 1/2 years of age), the rhBMP-2 was placed in simulated bilateral cleft palate defects. On one side, the rhBMP-2 was placed with use of the collagen sponge carrier. The autogenous graft most frequently used at present for regeneration of the osseous defects of maxillary clefts is iliac crest particulate cancellous bone. As a control graft on the contralateral side, therefore, autogenous particulate bone and marrow was placed. At the end of 3 months, the cleft side receiving the BMP-2 showed complete osseous restoration of the simulated cleft. The autogenously grafted side exhibited bone repair but incomplete regeneration of the bone defect at the early (3-months postoperative) stage of healing.

CONCLUSIONS AND CLINICAL RELEVANCE: The results of these three subhuman primate defect studies--(a) mandibular resection defects in middle-aged Macaca fascicularis animals, (b) mandibular resection defects in Macaca fascicularis animals over 20 years of age, and (c) simulated bilateral clefts in Macaca mulatta animals 1 1/2 years of age (comparable with a 5-year-old child)--were very encouraging. Histomorphometric analysis in all of these investigations indicated that the use of rhBMP-2 in bone repair without the use of bone grafting materials will offer a new method of osseous reconstruction in clinical facial bone defects.