JBJS | Application of Bone Morphogenetic Proteins in the Treatment of Clinical Oral and Maxillofacial Osseous Defects

The Journal of Bone & Joint Surgery, Volume 83, Issue 1 suppl 2

Clinical Applications of BMPs in Oral and Maxillofacial Surgery | April 01, 2001

Application of Bone Morphogenetic Proteins in the Treatment of Clinical Oral and Maxillofacial Osseous Defects

Philip J. Boyne, DMD, MS, DSc

Investigation performed at Oral and Maxillofacial Surgery Service, Loma Linda University Medical Center, Loma Linda, California
Philip J. Boyne, DMD, MS, DSc
Oral and Maxillofacial Surgery Service, Loma Linda University Medical Center, Loma Linda, California 92350

In support of his research or preparation of this manuscript, the author received grants or outside funding from Genetics Institute Inc. The author did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author is affiliated or associated.

The Journal of Bone & Joint Surgery. 2001; 83:S146-S150

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Abstract

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 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 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.

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Introduction

The complete osseous regeneration of traumatic defects in membranous bone of the face has been a matter of considerable clinical and surgical concern for many years. The development of different techniques for autogenous grafting including free flaps with microvascular anastomosis has been pursued during the past two decades. The multiplicity of techniques is an indication of the problem of regeneration of large maxillofacial traumatic defects as well as those of developmental or congenital origin. The optimal maxillofacial bone grafting technique has not yet been developed. The development of effective reconstruction procedures using osteoindicative factors without the need for conventional bone grafting would have a tremendous impact on reconstructive surgery of the head and neck area¹.

The purpose of this paper is to report the results of the repair of a series of surgically produced maxillofacial defects utilizing bone osteoindicative cytokines², particularly recombinant human bone morphogenetic protein-2 (rhBMP-2). This information should be relevant in determining the efficacy of using BMP inductors without bone grafts in repairing large critical-sized defects of the maxillofacial area.

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Fig. 1-A:: Figure 1 The effect of recombinant human bone morphogenetic protein (rhBMP-2)/collagen implants on bone regeneration in critical-sized hemi-mandibulectomy bone defects. A: A dry specimen indicating the extent of the mandibular body resection utilized for evaluation of rhBMP-2. The entire mass of the mandible was removed, and the resulting critical-sized defect space was maintained with a titanium mesh orthopaedic plate. B: A view of the critical-sized defect created surgically and maintained with orthopaedic mesh in a group of six male Macaca fascicularis animals, 6-9 years of age. The defect contains a collagen sponge saturated with rhBMP-2. The tissues were closed in layers from the submandibular approach. The animal was allowed to function for 6 months. C: A view of the intraoral surgical site at the fourth postoperative month, showing excellent restoration of the alveolar ridge portion of the defect. At the end of 5 months, a mucoperiosteal flap was raised, which showed the underlying regenerated mandible with excellent remodeling of the newly formed bone to form an outer cortex. D: A microscopic view of a specimen of the regenerated bone at the end of 6 months. The animal had been given tetracycline at the fourth and fifth postoperative months. The yellow fluorescence indicates new bone formation. There is excellent formation of cortex at the crest of the ridge and good trabecular bone formation; however, there are some large marrow vascular spaces in the center portion of the regenerated bone.

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Fig. 1-B:: Figure 1 The effect of recombinant human bone morphogenetic protein (rhBMP-2)/collagen implants on bone regeneration in critical-sized hemi-mandibulectomy bone defects. A: A dry specimen indicating the extent of the mandibular body resection utilized for evaluation of rhBMP-2. The entire mass of the mandible was removed, and the resulting critical-sized defect space was maintained with a titanium mesh orthopaedic plate. B: A view of the critical-sized defect created surgically and maintained with orthopaedic mesh in a group of six male Macaca fascicularis animals, 6-9 years of age. The defect contains a collagen sponge saturated with rhBMP-2. The tissues were closed in layers from the submandibular approach. The animal was allowed to function for 6 months. C: A view of the intraoral surgical site at the fourth postoperative month, showing excellent restoration of the alveolar ridge portion of the defect. At the end of 5 months, a mucoperiosteal flap was raised, which showed the underlying regenerated mandible with excellent remodeling of the newly formed bone to form an outer cortex. D: A microscopic view of a specimen of the regenerated bone at the end of 6 months. The animal had been given tetracycline at the fourth and fifth postoperative months. The yellow fluorescence indicates new bone formation. There is excellent formation of cortex at the crest of the ridge and good trabecular bone formation; however, there are some large marrow vascular spaces in the center portion of the regenerated bone.

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Fig. 1-C:: Figure 1 The effect of recombinant human bone morphogenetic protein (rhBMP-2)/collagen implants on bone regeneration in critical-sized hemi-mandibulectomy bone defects. A: A dry specimen indicating the extent of the mandibular body resection utilized for evaluation of rhBMP-2. The entire mass of the mandible was removed, and the resulting critical-sized defect space was maintained with a titanium mesh orthopaedic plate. B: A view of the critical-sized defect created surgically and maintained with orthopaedic mesh in a group of six male Macaca fascicularis animals, 6-9 years of age. The defect contains a collagen sponge saturated with rhBMP-2. The tissues were closed in layers from the submandibular approach. The animal was allowed to function for 6 months. C: A view of the intraoral surgical site at the fourth postoperative month, showing excellent restoration of the alveolar ridge portion of the defect. At the end of 5 months, a mucoperiosteal flap was raised, which showed the underlying regenerated mandible with excellent remodeling of the newly formed bone to form an outer cortex. D: A microscopic view of a specimen of the regenerated bone at the end of 6 months. The animal had been given tetracycline at the fourth and fifth postoperative months. The yellow fluorescence indicates new bone formation. There is excellent formation of cortex at the crest of the ridge and good trabecular bone formation; however, there are some large marrow vascular spaces in the center portion of the regenerated bone.

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Fig. 1-D:: Figure 1 The effect of recombinant human bone morphogenetic protein (rhBMP-2)/collagen implants on bone regeneration in critical-sized hemi-mandibulectomy bone defects. A: A dry specimen indicating the extent of the mandibular body resection utilized for evaluation of rhBMP-2. The entire mass of the mandible was removed, and the resulting critical-sized defect space was maintained with a titanium mesh orthopaedic plate. B: A view of the critical-sized defect created surgically and maintained with orthopaedic mesh in a group of six male Macaca fascicularis animals, 6-9 years of age. The defect contains a collagen sponge saturated with rhBMP-2. The tissues were closed in layers from the submandibular approach. The animal was allowed to function for 6 months. C: A view of the intraoral surgical site at the fourth postoperative month, showing excellent restoration of the alveolar ridge portion of the defect. At the end of 5 months, a mucoperiosteal flap was raised, which showed the underlying regenerated mandible with excellent remodeling of the newly formed bone to form an outer cortex. D: A microscopic view of a specimen of the regenerated bone at the end of 6 months. The animal had been given tetracycline at the fourth and fifth postoperative months. The yellow fluorescence indicates new bone formation. There is excellent formation of cortex at the crest of the ridge and good trabecular bone formation; however, there are some large marrow vascular spaces in the center portion of the regenerated bone.

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Fig. 2-A:: Figure 2 Effect of occlusal forces on the regenerated bone formed with use of implants of recombinant human bone morphogenetic protein-2 in a collagen carrier. A: In a second group of animals, titanium implants were implanted into the regenerated bone at 6 months postoperatively and were attached to a prosthesis. The effect of occlusive forces on the regenerated bone for 8 months was then evaluated. B: Photomicrograph of the specimen after 8 months of function on the titanium implants, prosthesis, and regenerated bone. Compared with the first group of animals, bone density is substantially increased. C: Histomorphometric analysis of the regenerated bone around the implants showed an increase in the density of the bone compared with the first group of animals in whom the regenerated bone had not been subjected to occlusive forces.

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Fig. 2-B:: Figure 2 Effect of occlusal forces on the regenerated bone formed with use of implants of recombinant human bone morphogenetic protein-2 in a collagen carrier. A: In a second group of animals, titanium implants were implanted into the regenerated bone at 6 months postoperatively and were attached to a prosthesis. The effect of occlusive forces on the regenerated bone for 8 months was then evaluated. B: Photomicrograph of the specimen after 8 months of function on the titanium implants, prosthesis, and regenerated bone. Compared with the first group of animals, bone density is substantially increased. C: Histomorphometric analysis of the regenerated bone around the implants showed an increase in the density of the bone compared with the first group of animals in whom the regenerated bone had not been subjected to occlusive forces.

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Fig. 2-C:: Figure 2 Effect of occlusal forces on the regenerated bone formed with use of implants of recombinant human bone morphogenetic protein-2 in a collagen carrier. A: In a second group of animals, titanium implants were implanted into the regenerated bone at 6 months postoperatively and were attached to a prosthesis. The effect of occlusive forces on the regenerated bone for 8 months was then evaluated. B: Photomicrograph of the specimen after 8 months of function on the titanium implants, prosthesis, and regenerated bone. Compared with the first group of animals, bone density is substantially increased. C: Histomorphometric analysis of the regenerated bone around the implants showed an increase in the density of the bone compared with the first group of animals in whom the regenerated bone had not been subjected to occlusive forces.

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Fig. 3-A:: Figure 3 Creation of osseous maxillary defects resembling bilateral cleft palate in a child. A: A dry specimen of a Macaca mulatta maxilla with the area of the ostectomy indicated by orange marking tape. B: Intraoperative view of the ostectomy along the lateral surface of the maxilla from the crest of the ridge to the periform aperture of the nose simulating a cleft maxillary palatal defect. A similar ostectomy was performed across the palate on the contralateral side. The oral mucosa was then closed to the nasal mucosa to deliberately produce bilateral fistulas as shown in Fig. 3-C. C: After 3 months of healing, there are bilateral fistulas and osseous defects resembling a bilateral cleft in a 5-year-old child. This 1-year-old Macaca mulatta monkey is chronologically similar to a 5 to 6-year-old child. D: A 5-year-old child presenting with a bilateral cleft with patent oral nasal fistulas remarkably similar to that of the simulated clefts in a Macaca mulatta monkey (Fig. 3-C). (Reprinted, with permission, from: 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.)

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Fig. 3-B:: Figure 3 Creation of osseous maxillary defects resembling bilateral cleft palate in a child. A: A dry specimen of a Macaca mulatta maxilla with the area of the ostectomy indicated by orange marking tape. B: Intraoperative view of the ostectomy along the lateral surface of the maxilla from the crest of the ridge to the periform aperture of the nose simulating a cleft maxillary palatal defect. A similar ostectomy was performed across the palate on the contralateral side. The oral mucosa was then closed to the nasal mucosa to deliberately produce bilateral fistulas as shown in Fig. 3-C. C: After 3 months of healing, there are bilateral fistulas and osseous defects resembling a bilateral cleft in a 5-year-old child. This 1-year-old Macaca mulatta monkey is chronologically similar to a 5 to 6-year-old child. D: A 5-year-old child presenting with a bilateral cleft with patent oral nasal fistulas remarkably similar to that of the simulated clefts in a Macaca mulatta monkey (Fig. 3-C). (Reprinted, with permission, from: 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.)

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Fig. 3-C:: Figure 3 Creation of osseous maxillary defects resembling bilateral cleft palate in a child. A: A dry specimen of a Macaca mulatta maxilla with the area of the ostectomy indicated by orange marking tape. B: Intraoperative view of the ostectomy along the lateral surface of the maxilla from the crest of the ridge to the periform aperture of the nose simulating a cleft maxillary palatal defect. A similar ostectomy was performed across the palate on the contralateral side. The oral mucosa was then closed to the nasal mucosa to deliberately produce bilateral fistulas as shown in Fig. 3-C. C: After 3 months of healing, there are bilateral fistulas and osseous defects resembling a bilateral cleft in a 5-year-old child. This 1-year-old Macaca mulatta monkey is chronologically similar to a 5 to 6-year-old child. D: A 5-year-old child presenting with a bilateral cleft with patent oral nasal fistulas remarkably similar to that of the simulated clefts in a Macaca mulatta monkey (Fig. 3-C). (Reprinted, with permission, from: 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.)

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Fig. 3-D:: Figure 3 Creation of osseous maxillary defects resembling bilateral cleft palate in a child. A: A dry specimen of a Macaca mulatta maxilla with the area of the ostectomy indicated by orange marking tape. B: Intraoperative view of the ostectomy along the lateral surface of the maxilla from the crest of the ridge to the periform aperture of the nose simulating a cleft maxillary palatal defect. A similar ostectomy was performed across the palate on the contralateral side. The oral mucosa was then closed to the nasal mucosa to deliberately produce bilateral fistulas as shown in Fig. 3-C. C: After 3 months of healing, there are bilateral fistulas and osseous defects resembling a bilateral cleft in a 5-year-old child. This 1-year-old Macaca mulatta monkey is chronologically similar to a 5 to 6-year-old child. D: A 5-year-old child presenting with a bilateral cleft with patent oral nasal fistulas remarkably similar to that of the simulated clefts in a Macaca mulatta monkey (Fig. 3-C). (Reprinted, with permission, from: 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.)

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Fig. 4-A:: Figure 4 The effect of recombinant human bone morphogenetic protein (rhBMP-2) collagen implants on bone regeneration in the maxillary clefts. A: Three months after surgery, the oral mucoperiosteal flaps were raised again to expose the defect. There was no appreciable osseous healing of the ostectomy defect. The 8-mm-wide ostectomy remained the same. On the right side of the cleft, rhBMP-2 (1.5 mg/ml in a collagen carrier) was inserted. On the contralateral side, autogenous iliac crest cancellous bone was utilized as a positive control. The nasal mucosal floor was closed carefully prior to placement of the autogenous graft, and the oral mucosa was closed over the BMP/collagen implant material and the autogenous grafts. The animals were allowed to function for an additional 3 months. B: An axial view of a specimen showing the pyriform aperture of the cleft palate defect after a 3-month healing period. The right side of the slide shows the defect that received rhBMP-2 (arrow); it is completely healed with a normal cortex. The side that received a particulate cancellous bone has not completely remodeled although the area is undergoing regeneration. At this point (3 months postoperatively), the BMP side has more accelerated bone regeneration than the contralateral side, which had received the standard bone graft material for cleft palate defects (i.e., particulate cancellous bone). C: A coronally sectioned specimen out through the palatal ostectomy site showing a completely regenerated palatal site on the right (rh-BMP-2) (arrow) and incomplete regeneration on the left. (Reprinted, with permission, from: 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.)

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Fig. 4-B:: Figure 4 The effect of recombinant human bone morphogenetic protein (rhBMP-2) collagen implants on bone regeneration in the maxillary clefts. A: Three months after surgery, the oral mucoperiosteal flaps were raised again to expose the defect. There was no appreciable osseous healing of the ostectomy defect. The 8-mm-wide ostectomy remained the same. On the right side of the cleft, rhBMP-2 (1.5 mg/ml in a collagen carrier) was inserted. On the contralateral side, autogenous iliac crest cancellous bone was utilized as a positive control. The nasal mucosal floor was closed carefully prior to placement of the autogenous graft, and the oral mucosa was closed over the BMP/collagen implant material and the autogenous grafts. The animals were allowed to function for an additional 3 months. B: An axial view of a specimen showing the pyriform aperture of the cleft palate defect after a 3-month healing period. The right side of the slide shows the defect that received rhBMP-2 (arrow); it is completely healed with a normal cortex. The side that received a particulate cancellous bone has not completely remodeled although the area is undergoing regeneration. At this point (3 months postoperatively), the BMP side has more accelerated bone regeneration than the contralateral side, which had received the standard bone graft material for cleft palate defects (i.e., particulate cancellous bone). C: A coronally sectioned specimen out through the palatal ostectomy site showing a completely regenerated palatal site on the right (rh-BMP-2) (arrow) and incomplete regeneration on the left. (Reprinted, with permission, from: 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.)

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Fig. 4-C:: Figure 4 The effect of recombinant human bone morphogenetic protein (rhBMP-2) collagen implants on bone regeneration in the maxillary clefts. A: Three months after surgery, the oral mucoperiosteal flaps were raised again to expose the defect. There was no appreciable osseous healing of the ostectomy defect. The 8-mm-wide ostectomy remained the same. On the right side of the cleft, rhBMP-2 (1.5 mg/ml in a collagen carrier) was inserted. On the contralateral side, autogenous iliac crest cancellous bone was utilized as a positive control. The nasal mucosal floor was closed carefully prior to placement of the autogenous graft, and the oral mucosa was closed over the BMP/collagen implant material and the autogenous grafts. The animals were allowed to function for an additional 3 months. B: An axial view of a specimen showing the pyriform aperture of the cleft palate defect after a 3-month healing period. The right side of the slide shows the defect that received rhBMP-2 (arrow); it is completely healed with a normal cortex. The side that received a particulate cancellous bone has not completely remodeled although the area is undergoing regeneration. At this point (3 months postoperatively), the BMP side has more accelerated bone regeneration than the contralateral side, which had received the standard bone graft material for cleft palate defects (i.e., particulate cancellous bone). C: A coronally sectioned specimen out through the palatal ostectomy site showing a completely regenerated palatal site on the right (rh-BMP-2) (arrow) and incomplete regeneration on the left. (Reprinted, with permission, from: 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.)

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Fig. 5-A:: Figure 5 Histomorphometric analysis of the amount of regenerated bone (calcified matrix) and marrow-vascular space (MV Space) formed in the maxillary clefts of animals treated with autogenous cancellous bone (A) or with rhBMP-2/collagen implants (B). The amount of regenerated bone formed on the side treated with the BMP/collagen implant is not significantly different from the autogenous cancellous bone.

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Fig. 5-B:: Figure 5 Histomorphometric analysis of the amount of regenerated bone (calcified matrix) and marrow-vascular space (MV Space) formed in the maxillary clefts of animals treated with autogenous cancellous bone (A) or with rhBMP-2/collagen implants (B). The amount of regenerated bone formed on the side treated with the BMP/collagen implant is not significantly different from the autogenous cancellous bone.

Hemi-Mandibulectomy Defects

Methods

A model involving a hemi-mandibulectomy type of defect in subhuman primates has been most effective in evaluating bone grafting systems, particularly autogenous particulate grafts and various other types of bone reconstructive procedures, both osteoinductive and osteoconductive. This model and surgical procedure were utilized to evaluate the clinical effectiveness of one particular BMP-2 in regeneration of critical-sized hemi-mandibulectomy type defects (Figs. 1-A, 1-B, 1-C, and 1-D). The procedure was used in eight fully mature adult male Macaca fascicularis animals.

Results

The rhBMP-2 was very effective in establishing complete bone regeneration in the defect at 4 and 6 months, as assessed by intraoperative observations and histologic studies (Figs. 1-C and 1-D)³. Histologic examination showed excellent bone regeneration of the defects with good bone remodeling and thick outer cortex formation (Fig. 1-D).

Effect of Occlusal Forces on the Regenerated Bone

Methods

The long-term maintenance of the bone repair, stability of bone, and response of the regenerated bone to function was assessed by utilizing the same mandibular model and subjecting the regenerated bone to function through the use of intraosseous titanium implant devices, which were attached to a functional prostheses (Figs. 2-A, 2-B, and 2-C). Specifically, in a second group of Macaca fascicularis animals of the same age group (6-9 years), the hemi-mandiblectomy defect was implanted with rhBMP-2 with use of the same procedure as shown in Fig. 1. At the end of 6 months, the regenerated bone was stimulated by the placement of root form titanium implants (Fig. 2-A). These implants were later brought into function, and the animal was allowed to function with the implants for an additional 8 months to determine the effect of directly transmitted occlusal forces on the regenerated bone.

Results

Photomicrographs of the specimens (Fig. 2-B) and histomorphometric analysis (Fig. 2-C) showed an increase in the density of the bone surrounding the implants compared with the density of the regenerated bone in the first group of animals without titanium implants. No large marrow spaces of the kind seen in animals without implants were seen in the regenerated bone (Fig. 1-D). The effect of function was to increase bone density. There was no indication of bone resorption on the regenerated bone subjected to occlusal forces.

Effect of rhBMP-2 on Bone Regeneration in Aging Animals

It has been reported that stem cell populations in aging animals decrease as a function of age and that this decrease in numbers of stem cells can diminish the osteoinductive effect of the BMPs⁵. This decreased cell population therefore could be expected to militate against good regeneration of bone. It was necessary to determine if this concept would hold in subhuman primates, since earlier work in rodents as well as in vitro studies in tissue culture have suggested that the BMPs might not be as effective in aging cell lines and older animals.

Methods

The same model previously established in mature subhuman primates was used again in six aging animals (in excess of 20 years, comparable with 75 to 80-year-old men) with the same dose of rhBMP-2.

Results

Six months after implantation of rhBMP-2 in the aging primates, there was no gross or microscopically discernible difference in the amount or quality of bone formation in the younger or older animals. Indeed, in many cases, more bone had formed in the older animals. In this study, aging appeared to have no effect on the osteoinductive effect of rhBMP-2.

The Use of BMP in Younger Animals with Maxillary Clefts Analagous to Cleft Palate

Methods

To determine if rhBMP-2 would be effective in the treatment of younger individuals with maxillary clefts, a series of six young Macaca mulatta animals 1 years of age was operated on, producing by ostectomy a simulated bilateral cleft (Figs. 3-A, 3-B, 3-C, and 3-D). In producing this ostectomy, the soft-tissue oral flaps were deliberately sutured to the nasal mucosa to produce bilateral fistulas so that the resulting effect after 3 months of healing was similar to that of the 5-year-old human child with a bilateral cleft as shown in Fig. 3-D. The area was operated on again at 3 months by elevating the oral mucoperiosteal flaps to the nasal mucosa in a procedure similar to that used for bone grafting in children with bilateral cleft palate. The previously created defect in the primates had not repaired with new bone. The oral nasal mucosa was then closed carefully. RhBMP-2 in a collagen sponge was placed in the defect on one side, and autogenous particulate cancellous bone and marrow was placed on the contralateral side, since, as indicated previously, autogenous particulate marrow appears to be the present treatment of choice for children of this age presenting for bone grafting of clefts.

Results

At the end of 3 months, the side implanted with rhBMP-2 had excellent healing. The contralateral side with autogenous particulate marrow cancellous bone had not yet completely remodeled to form a normal cortex (Figs. 4-A, 4-B, and 4-C). The thickness of the cortical bone surface in the regenerated cleft defect was bilaterally similar to that in the control side that had received the autogenous particulate marrow cancellous bone, with incomplete repair of the cortex. Histomorphometric analysis indicated no significant difference in the amount of new bone formed on the sides treated with BMP compared with autograft (Figs. 5-A and 5-B). Therefore, rhBMP-2 in an appropriate carrier may offer an alternative to autogenous grafting in the child with cleft palate.

Clinical Studies

Additional clinical studies in a multicentered investigation by the Genetics Institute have indicated that in atrophic maxillary antral floor defects, rhBMP-2 is effective in restoration of bone in the maxillary antrum and produces sufficient bone height for the reception of root form titanium implants for dental prosthetic function⁸. This large clinical study has not been completed, but the initial clinically reported results indicated that bone formation of the floor of the antrum would be receptive to bone and prosthetic restoration⁸. Thus, as in the animal studies, the initial clinical results are encouraging.

References

WozneyJM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM,Wang EA. Novel regulators of bone formation: molecular clones and activities. Science,1988;242: 1528-34. 2421528 1988 [PubMed]

UristMR,Strates BS. Bone morphogenetic protein. J Dent Res.,1971;50: 1392-406. 501392 1971 [PubMed]

BoynePJ. Animal studies of the application of rhBMP-2 in maxillofacial reconstruction. Bone.,1996;19(1 Suppl):1: 83S-92S. 19(1 Suppl):183 1996

BoynePJ, Nakamura A,Shabahang S. Evaluation of the long-term effect of function on rhBMP-2 regenerated hemimandibulectomy defects. Br J Oral Maxillofac Surg,1999;37: 344-352. 37344 1999 [PubMed]

BesshoK,Iizuka T. Changes in bone inducing activity of bone morphogenetic protein with aging. Ann Chir Gynaecol,1993;Suppl 207: 49-53. Suppl 20749 1993

Salina S, Boyne PJ, Nakamura A, Maiorana C, Audia F. Quality of bone regenerated by rhBMP-2 induction in hemi-mandibulectomy defects of elderly monkeys. Abstract presented at the 19th Annual Conference of the American College of Oral and Maxillofacial Surgeons, April 30-May 3, 1998, Cleveland, OH

BoynePJ, 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. 3684 1998 [PubMed]

BoynePJ, Marx RE, Nevins M, Triplett G, Lazaro E, Lilly LC, Alder M,Nummikoski P. A feasibility study evaluating rhBMP-2/absorbable collagen sponge for maxillary sinus floor augmentation. Int J Periodont Rest Dent,1997;17: 11-25. 1711 1997

Topics

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UristMR,Strates BS. Bone morphogenetic protein. J Dent Res.,1971;50: 1392-406. 501392 1971 [PubMed]

BoynePJ. Animal studies of the application of rhBMP-2 in maxillofacial reconstruction. Bone.,1996;19(1 Suppl):1: 83S-92S. 19(1 Suppl):183 1996

BoynePJ, Nakamura A,Shabahang S. Evaluation of the long-term effect of function on rhBMP-2 regenerated hemimandibulectomy defects. Br J Oral Maxillofac Surg,1999;37: 344-352. 37344 1999 [PubMed]

BesshoK,Iizuka T. Changes in bone inducing activity of bone morphogenetic protein with aging. Ann Chir Gynaecol,1993;Suppl 207: 49-53. Suppl 20749 1993

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Philip J. Boyne; Application of Bone Morphogenetic Proteins in the Treatment of Clinical Oral and Maxillofacial Osseous Defects. The Journal of Bone & Joint Surgery. 2001 Apr;83(1_suppl_2):S146-S150.

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