Periodontal repair in dogs: rhBMP-2 significantly enhances bone formation under provisions for guided tissue regeneration

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been shown to support the regeneration of alveolar bone and periodontal attachment in surgically created periodontal defects and in defects with a history of dental plaque and calculus exposure. Periodontal regeneration has also been shown following guided tissue regeneration using space-providing expanded polytetrafluoroethylene (ePTFE) devices. The objective of this study was to evaluate the influence of rhBMP-2 on regeneration of alveolar bone and periodontal attachment used in conjunction with a space-providing ePTFE device. METHODS: Routine, critical-size, 5-6 mm, supra-alveolar, periodontal defects were created around the third and fourth mandibular premolar teeth in four young adult Hound Labrador mongrel dogs. rhBMP-2 (0.2 mg/ml) in an absorbable collagen sponge (rhBMP-2/ACS) or buffer/ACS (control) implants were randomly assigned to be placed around the premolar teeth in the left and right jaw quadrants in subsequent animals. Space-providing ePTFE devices with 300-microm laser-drilled pores, 0.8 mm apart, were used to cover the rhBMP-2 and control implants. The gingival flaps were advanced for primary wound closure. The animals were euthanized at 8 weeks postsurgery for histologic and histometric analyses. RESULTS: Bone regeneration and ankylosis were significantly increased in jaw quadrants receiving rhBMP-2/ACS compared to control (bone height 4.8+/-0.3 versus 2.0+/-0.2 mm, p=0.001; bone area 10.9+/-1.3 versus 1.4+/-0.1 mm2; p=0.009, and ankylosis 2.2+/-0.2 versus 0.04+/-0.7 mm; p=0.01). No differences between groups were found for cementum regeneration and root resorption. CONCLUSIONS: rhBMP-2 significantly enhances regeneration of alveolar bone in conjunction with a space-providing, macroporous ePTFE device for GTR.     

Periodontal repair in dogs: evaluation of a bioabsorbable space-providing macroporous membrane with recombinant human bone morphogenetic protein-2

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) technologies have been shown to significantly support alveolar bone formation. Biomaterial limitations, however, have restricted the biologic potential for onlay indications. The objective of this study was to evaluate regeneration of alveolar bone and periodontal attachment, and biomaterials reaction following surgical implantation of a space-providing, bioabsorbable, macroporous, polyglycolic acid-trimethylene carbonate (PGA-TMC) membrane combined with a rhBMP-2 construct in a discriminating onlay defect model. METHODS: Routine supraalveolar periodontal defects were created at the mandibular premolar teeth in 9 beagle dogs. Contralateral jaw quadrants in subsequent animals were randomly assigned to receive the dome-shaped PGA-TMC (100 to 120 microm pores) membrane with rhBMP-2 (0.2 mg/mL) in a bioresorbable hyaluronan (Hy) carrier or the PGA-TMC membrane with Hy alone (control). The gingival flaps were advanced to submerge the membranes and teeth and sutured. Animals were euthanized at 8 and 24 weeks postsurgery for histologic observations. RESULTS: Jaw quadrants receiving the PGA-TMC membrane alone experienced exposures at various time points throughout the study. Jaw quadrants receiving the PGA-TMC/rhBMP-2 combination remained intact, although one site experienced a late minor exposure. Newly formed alveolar bone approached and became incorporated into the macroporous PGA-TMC membrane in sites receiving rhBMP-2. The PGA-TMC biomaterial was occasionally associated with a limited inflammatory reaction. Residual PGA-TMC could not be observed at 24 weeks postsurgery. Residual Hy could not be observed at any time interval. Regeneration of alveolar bone height (means +/- SD) was significantly increased in sites receiving the PGA-TMC/rhBMP 2 combination compared to control (3.8 +/- 1.3 versus 0.7 +/- 0.5 mm at 8 weeks and 4.6 +/- 0.8 versus 2.1 +/- 0.4 mm at 24 weeks; P < 0.05). Limited cementum regeneration was observed for PGA-TMC/rhBMP-2 and PGA-TMC control sites. Ankylosis compromised regeneration in sites receiving PGA-TMC/rhBMP-2. CONCLUSIONS: The bioabsorbable, space-providing, macroporous PGA-TMC membrane appears to be a compatible biomaterial for bone augmentation procedures. rhBMP-2 significantly enhances alveolar bone augmentation and soft tissue healing when combined with the PGA-TMC membrane.     

rhBMP-2 significantly enhances guided bone regeneration

BACKGROUND: Previous studies have shown a limited potential for bone augmentation following guided bone regeneration (GBR) in horizontal alveolar defects. Surgical implantation of recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge carrier (ACS) significantly enhances bone regeneration in such defects; however, sufficient quantities of bone for implant dentistry are not routinely obtained. The objective of this study was to evaluate the potential of rhBMP-2/ACS to enhance GBR using a space-providing, macro-porous expanded polytetrafluoroethylene (ePTFE) device. METHODS: Bilateral, critical size, supra-alveolar, peri-implant defects were surgically created in four Hound Labrador mongrel dogs. Two turned and one surface-etched 10-mm titanium dental implant were placed 5 mm into the surgically reduced alveolar ridge creating 5-mm supra-alveolar defects. rhBMP-2/ACS (rhBMP-2 at 0.2 mg/ml) or buffer/ACS was randomly assigned to left and right jaw quadrants in subsequent animals. The space-providing, macro-porous ePTFE device was placed to cover rhBMP-2/ACS and control constructs and dental implants. Gingival flaps were advanced for primary wound closure. The animals were euthanized at 8 weeks postsurgery for histologic and histometric analysis. RESULTS: Bone formation was significantly enhanced in defects receiving rhBMP-2/ACS compared to control. Vertical bone gain averaged (+/- SD) 4.7 +/- 0.3 and 4.8 +/- 0.1 mm, and new bone area 10.3 +/- 2.0 and 8.0 +/- 2.5 mm2 at turned and surface-etched dental implants, respectively. Corresponding values for the control were 1.8 +/- 2.0 and 1.3 +/- 1.3 mm, and 1.8 +/- 1.3 and 1.2 +/- 0.6 mm2. Bone-implant contact in rhBMP-2-induced bone averaged 6.4 +/- 1.4% and 9.6 +/- 7.5% for turned and surface-etched dental implants, respectively (P=0.399). Corresponding values for the control were 14.6 +/- 19.4% and 23.7 +/- 9.7% (P=0.473). Bone-implant contact in resident bone ranged between 43% and 58% without significant differences between dental implant surfaces. CONCLUSIONS: rhBMP-2/ACS significantly enhances GBR at turned and surface-etched dental implants. The dental implant surface technology does not appear to substantially influence bone formation.     

Effect of recombinant human bone morphogenetic protein-2 in an absorbable collagen sponge with space-providing biomaterials on the augmentation of chronic alveolar ridge defects

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge (ACS) carrier has been shown to support significant bone formation in the craniofacial skeleton. When used as an onlay, however, rhBMP-2/ACS may become compressed with limited resulting bone formation. The objective of this study was to evaluate the effect of two space-providing biomaterials, bioactive glass (BG) and demineralized/mineralized bone matrix (DMB), on rhBMP-2/ACS induced alveolar ridge augmentation. METHODS: Bilateral alveolar ridge defects were produced in the mandible in six mongrel dogs. rhBMP-2/ACS with biomaterials was surgically implanted into contralateral defects in four animals. Treatments were alternated between jaw quadrants in consecutive animals. Two animals received rhBMP-2/ACS or sham-surgery in contralateral defects. The animals were injected with fluorescent bone labels to monitor bone formation. Clinical evaluations were made at ridge augmentation and 12 weeks post-implantation when the animals were euthanized and block biopsies collected for histopathologic evaluation. RESULTS: Sham-surgery produced limited horizontal alveolar augmentation (0.1 +/- 0.6 mm). Implantation of rhBMP-2/ACS resulted in alveolar augmentation amounting to 2.2 +/- 1.8 mm. Alveolar augmentation in sites receiving rhBMP-2/ACS with DMB or BG was 2-fold greater compared to rhBMP-2/ACS alone averaging 4.4 +/- 1.3 and 4.6 +/- 1.5 mm, respectively. The DMB biomaterial appeared substituted by newly formed bone. The BG particles were observed imbedded in bone or encapsulated in dense connective tissue without associated bone metabolic activity. Fluorescent light microscopy suggested that the new bone was formed within 4 weeks. CONCLUSION: The bioglass and demineralized/mineralized bone matrix biomaterials utilized in this study in combination with rhBMP-2/ACS supported clinical and histological ridge augmentation.     

Space-providing expanded polytetrafluoroethylene devices define alveolar augmentation at dental implants induced by recombinant human bone morphogenetic protein 2 in an absorbable collagen sponge carrier

Background: Surgical implantation of recombinant human bone morphogenetic protein 2 (rhBMP‐2) in an absorbable collagen sponge carrier (ACS) significantly enhances bone regeneration in horizontal alveolar defects; however, sufficient quantities of bone for implant dentistry are not routinely obtained. Purpose: The objective of this proof‐of‐principle study was to evaluate the potential of a space‐providing macroporous expanded polytetrafluoroethylene (ePTFE) device to control volume and geometry of rhBMP‐2/ACS‐induced alveolar bone augmentation. Materials and Methods: Bilateral critical‐size supra‐alveolar periimplant defects were created in four Hound‐Labrador mongrel dogs. Two turned and one surface‐etched 10 mm titanium dental implants were placed 5 mm into the surgically reduced alveolar ridge creating 5 mm supra‐alveolar defects. rhBMP‐2/ACS (0.4 mg rhBMP‐2) was placed around the exposed dental implants. Additionally, one jaw quadrant in each animal was randomly assigned to receive the domeshaped macroporous ePTFE device. Mucoperiosteal flaps were advanced for primary wound closure. The animals were euthanized at 8 weeks post surgery for histometric analysis. Results: The space‐providing macroporous ePTFE device defined the volume and geometry of rhBMP‐2/ACS‐induced bone formation, whereas bone formation at sites receiving rhBMP‐2/ACS alone varied considerably. Vertical bone gain at turned dental implants averaged (SD) 4.7 ± 0.2 mm at sites receiving rhBMP‐2/ACS and the ePTFE device compared with 3.5 ± 0.9 mm at sites receiving rhBMP‐2/ACS only. The corresponding values for rhBMP‐2/ACS‐induced bone area were 9.6 ± 0.7 mm ² and 7.5 ± 6.2 mm ². There was a highly significant correlation between induced bone area and the space provided by the ePTFE device (p .001). There was no difference in induced bone density or bone‐implant contact between the two technologies. These observations were consistent with those observed at surface‐etched dental implants. Conclusions: The data from this study suggest that a space‐providing macroporous ePTFE device defines rhBMP‐2/ACS‐induced alveolar augmentation to provide adequate bone quantities for implant dentistry. The dental implant surface technology does not appear to substantially influence bone formation.     

Effect of surgical implantation of recombinant human bone morphogenetic protein-2 in a bioabsorbable collagen sponge or calcium phosphate putty carrier in intrabony periodontal defects in the baboon

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) in a proper carrier has been shown to induce clinically relevant bone formation for several oral/maxillofacial and periodontal indications and to stimulate regeneration of the periodontal attachment. The objective of this study is to evaluate regeneration of alveolar bone, cementum, periodontal ligament, and associated root resorption and ankylosis following surgical implantation of rhBMP-2 in an absorbable collagen sponge (ACS) or a calcium phosphate putty (alphaBSM) carrier in 3-wall intrabony periodontal defects in the baboon. METHODS: rhBMP-2/ACS and rhBMP-2/alphaBSM were implanted in surgically produced, maxillary and mandibular, large size, 3-wall intrabony defects in 4 baboons. Contralateral jaw quadrants were implanted with buffer/ACS, buffer/ alphaBSM, or served as sham-operated surgical controls. Treatments were allocated to left and right, maxillary and mandibular, jaw quadrants following a randomization schedule. Four months following implantation, block biopsies of defect sites were obtained, processed, and subjected to histologic and histometric analysis. RESULTS: Defect sites receiving rhBMP-2/ACS and rhBMP-2/alphaBSM demonstrated significantly greater regeneration than controls. No significant differences were observed between defect sites receiving rhBMP-2/ACS or rhBMP-2/alphaBSM regarding epithelial migration and connective tissue attachment and new bone formation. However, rhBMP-2/ACS supported significantly greater new cementum formation. Ankylosis or root resorption were not observed. CONCLUSIONS: The results of this study support the use of rhBMP-2 to enhance periodontal regeneration of intrabony periodontal defects. While this novel technology holds promise, refinement in carrier systems may provide the key to enhancement of the regenerative potential.     

Effect of human bone morphogenetic protein 2 implant on tooth eruption in an experimental design

This study evaluated the influence of recombinant human bone morphogenetic protein 2 (rhBMP-2) on the development and eruption of the secondary dentition. Primary premolar tooth extraction sockets in 12 16-week-old felines were implanted with either rhBMP-2, in collagen sponge or with buffer/absorbable collagen sponge (ACS). Unoperated jaw quadrants served as controls. Experimental conditions were randomized between jaw quadrants in all animals. Two animals receiving rhBMP-2/ACS and buffer/ACS in two quadrants per implant were sacrificed at 4 weeks postsurgery. Ten animals receiving rhBMP-2/ACS (two quadrants), buffer/ACS implants (one quadrant), and one quadrant serving as an unoperated control were evaluated at 12 weeks postsurgery. Clinical assessments included healing, eruption patterns, and crown development. Radiographic assessments included tooth development, eruption patterns, and bone formation. Histological observations were also made from the 4-week animals. The secondary dentition remained unerupted at 4 weeks postsurgery. Histological analysis showed normal alveolar bone coronal to the erupting teeth in rhBMP-2/ACS-implanted quadrants. At 12 weeks postsurgery, all teeth were erupted without differences between quadrants. Clinically, the crowns of all teeth were normal. Radiographs suggested that teeth in rhBMP-2/ACS- and buffer/ACS-implanted jaw quadrants exhibited similar tooth development and eruption patterns as the normal control. The evidence from this study suggests that surgical implantation of rh-BMP-2/ACS in the pathway of the developing and erupting secondary dentition does not interfere with the normal development and eruption patterns of the teeth.     

Periodontal repair in dogs: gingival tissue occlusion,a critical requirement for GTR?

BACKGROUND: Design criteria for guided tissue regeneration (GTR) devices include biocompatibility, cell occlusion, space maintenance, tissue integration, and ease of use. Previous studies have established the importance of wound stabilization and space provision during the early healing sequel for successful GTR outcomes as well as evaluated biocompatibility, tissue integration, and clinical manageability of various biomaterials. The importance of cell or tissue occlusion has yet to be established. The objective of this study was to evaluate the role of tissue occlusion as a critical determinant for GTR outcomes. METHODS: Routine, critical size, 5-6 mm, supra-alveolar, periodontal defects were created around the mandibular premolar teeth in six young adult Beagle dogs. Space-providing expanded polytetrafluoroethylene (ePTFE) membranes, with (macroporous) or without (occlusive) 300- microm laser-drilled pores, 0.8 mm apart, were implanted to provide for GTR. Treatments were randomly assigned to left and right jaw quadrants in subsequent animals. The gingival flaps were advanced to cover the membranes and sutured. The animals were euthanized at 8 weeks postsurgery for histologic and histometric analysis. RESULTS: Three animals experienced wound failure within 2-3 weeks postsurgery resulting in exposure and removal of the occlusive ePTFE membranes. All defect sites, irrespective of membrane configuration or history of membrane exposure and removal, exhibited substantial evidence of periodontal regeneration including a functionally oriented periodontal ligament. To evaluate the biologic potential of GTR devices, only animals without wound failure and membrane removal were included. Alveolar bone regeneration for animals receiving occlusive and macroporous ePTFE membranes averaged (+/-sd) 3.2+/-1.1 versus 2.0+/-0.4 mm (p=0.3113). Cementum regeneration was enhanced in defect sites receiving the occlusive ePTFE membrane compared to the macroporous membrane (4.7+/-0.4 versus 2.3+/-0.2 mm; p=0.0167). Ankylosis was observed in one animal. Limited root resorption was observed in a second animal. CONCLUSION: Tissue occlusion does not appear to be a critical determinant for GTR. However, tissue occlusion may be a requirement for optimal GTR. Moreover, macroporous space-providing devices may increase the predictability of clinical GTR therapy.     

Long-term functional loading of dental implants in rhBMP-2 induced bone. A histologic study in the canine ridge augmentation model

Osseointegration [direct bone-implant contact (BIC)] is a primary goal following installation of endosseous dental implants. Such bone contact provides stability for the dental implant over time. The objective of this study was to evaluate bone formation and BIC at long-term, functionally loaded, endosseous dental implants placed into bone induced by recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge (ACS) carrier. Mandibular, saddle-type, alveolar ridge defects (approximately 15 x 10 x 10 mm), two per jaw quadrant, were surgically induced in each of six young adult American fox hounds. The defects were immediately implanted with rhBMP-2/ACS. Two defects per animal additionally received a nonresorbable expanded polytetrafluoroethylene (ePTFE) membrane or a bioresorbable polyglycolide fiber membrane. Healing was allowed to progress for 3 months, when the ePTFE membrane was removed, and machined, threaded, titanium dental implants were installed into the rhBMP-2/ACS induced bone and into the adjacent resident bone. At 4 months of osseointegration, the implants were exposed to receive abutments and prosthetic treatment (two- or three-unit bridges). Some implants were removed for histologic analysis. The remainder of implants were exposed to functional loading for 12 months at which time the animals were killed for histometric analysis. One animal died prematurely due to kidney failure unrelated to the experimental protocol and was not included in the analysis. The 12-month block sections from a second animal were lost in the histological processing. Four sites receiving rhBMP-2/ACS and ePTFE or resorbable membranes experienced wound failure and membrane exposure, and subsequently exhibited limited bone formation. Defects without wound failure filled to contour with the adjacent alveolar bone. The newly formed bone exhibited features of the resident bone with a re-established cortex; however, it commonly included radiolucent areas that resolved over time. Dental implants block biopsied at 4 months exhibited limited, if any, crestal resorption, whereas those exposed to functional loading for 12 months exhibited some crestal resorption. Implants biopsied at 4 months exhibited a mean (+/- SD) BIC of 40.6 +/- 8.2% in rhBMP-2/ACS induced bone vs. 52.7 +/- 11.4% in resident bone. Dental implants exposed to 12 months of functional loading exhibited a mean BIC of 51.7 +/- 7.1% in rhBMP-2/ACS induced bone vs. 74.7 +/- 7.0% in resident bone. There were no significant differences between dental implants placed into rhBMP-2/ACS induced bone and resident bone for any parameter at any observation interval. In conclusion, rhBMP-2/ACS-induced bone allows installation, osseointegration, and long-term functional loading of machined, threaded, titanium dental implants in dogs.     

Peri-implant bone regeneration using recombinant human bone morphogenetic protein-2 in a canine model: a dose-response study

The objective of this study was to evaluate the effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) dose on alveolar ridge augmentation and dental implant osseointegration. Bilateral, 5 mm supraalveolar, peri-implant defects were surgically created in 6 beagle dogs. rhBMP-2 (0.05, 0.1 or 0.2 mg/ml) in an absorbable collagen sponge (ACS) carrier was molded around the fixtures and wounds were closed. Treatment variations were alternated between animals (incomplete block design). Animals were sacrificed at week 8 postsurgery. Nine of twelve jaw quadrants healed uneventfully. Two jaw quadrants exhibited wound failure by week 4 and one by week 8 postsurgery. Radiographic bone regeneration was observed in defects without wound failure from week 4 postsurgery. Radiolucent voids of variable size and shape were observed and regressed over time. In weeks 6 through 8, there was an apparent increase in bone density and trabecular structure, while bone height and volume decreased. Histometric analysis revealed limited differences in bone regeneration between experimental conditions. Bone regeneration area averaged (+/- SD) 1.0 +/- 0.5, 3.5 +/- 1.4 and 2.3 +/- 0.4 mm2 for the 0.05, 0.1 and 0.2 mg/ml dose, respectively. There were no significant differences in osseointegration. Osseointegration in newly formed bone averaged 19 +/- 4%, 18 +/- 10% and 21 +/- 6% for the 0.05, 0.1 and 0.2 mg/ml rhBMP-2 sites, respectively. Collectively, the data suggest that there are no dramatic differences in bone induction and osseointegration within the selected dose and observation interval.     

Periodontal repair in dogs: effect of recombinant human bone morphogenetic protein-12 (rhBMP-12) on regeneration of alveolar bone and periodontal attachment

OBJECTIVES: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been shown to stimulate alveolar bone and cementum formation in periodontal defects but not a functionally oriented periodontal ligament (PDL). Subcutaneous and intramuscular implants of BMP-12 have been shown to induce tendon formation and ligament-like tissue. The objective of this study was to evaluate rhBMP-12 for periodontal regeneration, in particular PDL formation. METHODS: Six young adult Hound Labrador mongrel dogs were used. Routine supraalveolar periodontal defects were created around the mandibular premolar teeth. Three animals received rhBMP-12(0.04 mg/ml) in an absorbable collagen sponge (ACS) carrier vs. rhBMP-12(0.2 mg/mL)/ACS in contralateral defects. Three animals received rhBMP-12(1.0 mg/ml)/ACS vs. rhBMP-2(0.2 mg/ml)/ACS (total implant volume/defect approximately 1 ml). The animals were euthanized 8 weeks postsurgery and block biopsies were processed for histometric analysis. RESULTS: Bone regeneration appeared increased in sites receiving rhBMP-2/ACS compared to sites receiving rhBMP-12/ACS. Cementum regeneration was similar comparing sites implanted with rhBMP-2/ACS to sites implanted with rhBMP-12/ACS. In contrast, sites receiving rhBMP-12/ACS exhibited a functionally oriented PDL bridging the gap between newly formed bone and cementum whereas this was a rare observation in sites receiving rhBMP-2/ACS. Ankylosis appeared increased in sites receiving rhBMP-2/ACS compared to those receiving rhBMP-12/ACS. CONCLUSIONS: The outcomes of this study suggest that rhBMP-12 may have significant effects on regeneration of the PDL. Additional preclinical evaluation is needed to confirm these initial observations prior to clinical application.     

Bone repair following recombinant human bone morphogenetic protein-2 stimulated periodontal regeneration

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable sponge (ACS) carrier is currently being evaluated as candidate therapy for periodontal regeneration. The objective of this study was to characterize, in some detail, tissue reactions following surgical implantation of rhBMP-2/ACS into periodontal defects. METHODS: Four young adult, male beagle dogs with surgically induced, bilateral, critical size, supra-alveolar, mandibular premolar defects sequentially received rhBMP-2/ACS (rhBMP-2 at 0.2 mg/ml) in right and left jaw quadrants. After 4 or 8 weeks of healing, experimental teeth with surrounding tissues were harvested and processed for light and transmission electron microscopy. RESULTS: Surgical implantation of rhBMP-2/ACS into large supra-alveolar periodontal defects resulted in a variable tissue response without marked difference between 4- and 8-week observations. New bone, exceeding the volume of the normal alveolar process, had formed within 4 weeks. The regenerated bone tissue consisted of finely trabeculated woven bone. Marrow spaces exhibited a continuous lining of osteoblasts, osteoclasts, and resting cells. The marrow spaces contained numerous large, thin-walled vessels but were almost devoid of collagen fibrils or fibroblasts. Large voids (seromas) encountered in the newly formed bone were free of structured elements except for occasional aggregates of effete erythrocytes. A variety of tissue reactions were observed along the root surface including areas of resorption, areas of hard tissue deposition, and areas without resorptive or appositional activity. Ankylosis was a frequent observation, although areas showing characteristics of a periodontal ligament with a fine layer of acellular fiber cementum and occasional inserting Sharpey's fibers were also observed. Osteoblasts facing the root surface often appeared to be in a highly active state judged by their cuboidal shape, well-developed endoplasmic reticulum and numerous mitochondria, and the presence of an adjacent layer of preosteoblasts. Conspicuous bundles of wide collagen fibrils near the dentin surface as well as within the marrow spaces were considered to represent remnants of the ACS. These fibrils were associated with areas of mineralization as verified by examination of undecalcified specimens. CONCLUSIONS: rhBMP-2/ACS elicits a rapid osteoinductive process throughout the implant as well as along and onto the instrumented adjacent root surface. Lamellated trabecular bone was the predominant regenerated tissue. A typical cementum-periodontal ligament-alveolar bone relationship was a rare observation. The great variability in histological tissue response along the instrumented root surface indicates that the stimulus to hard tissue formation resided primarily in the rhBMP-2/ACS implant rather than in the root surface.     

Effect of recombinant human bone morphogenetic protein-2/absorbable collagen sponge (rhBMP-2/ACS) on healing in 3-wall intrabony defects in dogs

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge (ACS) carrier is being evaluated as a candidate therapy for periodontal regeneration. The objective of this study was to evaluate regeneration of alveolar bone and cementum, and associated root resorption and ankylosis following surgical implantation of rhBMP-2/ACS in a canine clinical model. METHODS: Bilateral 3-wall intrabony periodontal defects were surgically induced in the premolar region in the maxilla and mandible in 8 young adult Korean mongrel dogs. The defects in each animal received rhBMP-2/ACS (rhBMP-2 at 0.2 mg/ml, total implant volume/defect approximately 0.1 ml) or buffer/ACS, or served as sham-operated controls. Surgeries were sequenced for each animal to provide postmortem observations following 8- and 24-week healing intervals. Treatment outcomes were evaluated using clinical, radiographic, and histometric parameters. RESULTS: Surgical implantation of rhBMP-2/ACS resulted in accelerated enhanced bone formation in the 3-wall intrabony periodontal defects but in no apparent enhancement of cementum regeneration. rhBMP-2/ACS did not appear to be associated with aberrant healing events such as root resorption and ankylosis under these simulated clinical conditions. CONCLUSIONS: Surgical implantation of rhBMP-2/ACS may be used safely to support regeneration of alveolar bone in intrabony periodontal defects in dogs without aberrant events such as root resorption or ankylosis complicating the regenerative procedure. rhBMP-2/ACS does not appear to have a significant effect on cementum regeneration and formation of a functional periodontal ligament in this model.     

Effect of recombinant human bone morphogenetic protein-2 in dehiscence defects with non-submerged immediate implants: an experimental study in Cynomolgus monkeys

BACKGROUND: Alveolar ridge aberrations commonly compromise optimal dental implant installation. To offset any variance between an aberrant alveolar ridge and prosthetic designs, bone augmentation procedures become necessary. The objective of this study was to evaluate bone formation and osseointegration at alveolar dehiscence defects following augmentation of the defect site with recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge carrier (ACS) at dental implant installation including transmucosal positioning of the dental implant. METHODS: Four adult male Cynomolgus monkeys received dental implants in contralateral extraction socket sites with surgically created 6 x 4 mm buccal dehiscence defects following elevation of mucoperiosteal flaps. Contralateral sites received rhBMP-2/ACS (rhBMP-2 at 1.5 mg/ml; 0.1 mg/defect) or served as sham-surgery controls. The flaps were adapted and sutured around the healing abutments leaving the implants in a transmucosal position. The animals were sacrificed at 16 weeks postsurgery and block sections of the implant sites were harvested and prepared for histometric analysis. RESULTS: One dental implant from each treatment group failed to osseointegrate. Another 3 dental implants (sham-surgery controls) failed to osseointegrate with newly-formed bone in the defect area. Thus, 7 of 8 defect sites (4/4 animals) receiving rhBMP-2/ACS compared to 4 of 8 sites (2/4 animals) receiving sham-surgery exhibited evidence of osseointegration with newly formed bone in the defect area. Mean +/- SD defect height amounted to 5.3 +/- 0.2 and 5.4 +/- 0.1 mm for the rhBMP-2/ACS and sham-surgery sites, respectively. Vertical bone gain in rhBMP-2/ACS treated defects (3.9 +/- 0.3 mm) did not differ significantly from that in the sham-surgery control (3.7 +/- 0.4 mm; P > 0.05; paired t-test, N = 4). There were also no significant differences noted for coronal bone-implant contact (3.0 +/- 0.6 versus 3.6 +/- 0.5 mm), and bone-implant contact within the defect site (28.5% +/- 15.1% versus 27.4% +/- 31.7%) and within resident bone (46.9% +/- 26.8% versus 47.8% +/- 39.4%) for the rhBMP-2/ACS and control sites, respectively. CONCLUSIONS: The observations in this study point to a substantial native osteogenic potential of the alveolar process that has previously not been explored and show that surgical reentry observations of new bone formation may not necessarily indicate that osseointegration has occurred. Bone formation in control defects was substantially greater than predicted, limiting the value of adding an osteoinductive biologic construct.     

Ridge augmentation following implantation of recombinant human bone morphogenetic protein-2 in the dog

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge (ACS) carrier induces bone for reconstruction of skeletal defects. The rhBMP-2/ACS implant is prepared by administering a rhBMP-2 solution to dry ACS. Once prepared, rhBMP-2/ACS forms a moldable, cohesive, and adhesive implant. However, rhBMP-2/ACS does not have sufficient structural strength to withstand soft tissue compression at specific anatomic sites. To more fully understand the mechanisms that affect bone induction by rhBMP-2/ACS in the presence of soft tissue compression, it would be useful to have a preclinical model that appropriately simulates such circumstances in patients. This pilot study evaluated one such potential model. METHODS: Bilateral, Class III alveolar defects were surgically produced in 4 adult mongrel dogs following extraction of the mandibular fourth premolars and reduction of the alveolar ridge. After an 8-week healing interval, mucoperiosteal flaps were elevated and rhBMP-2/ACS or rhBMP-2/ACS combined with hydroxyapatite (HA) was implanted into contralateral defects. The animals were euthanized at 12 weeks post-augmentation and block biopsies processed for histologic evaluation. RESULTS: Limited augmentation followed implantation of rhBMP-2/ACS (0.7 +/- 0.6 mm). In contrast, sites receiving rhBMP-2/ACS/HA exhibited clinically relevant ridge augmentation (5.5 +/- 1.6 mm). Defects implanted with rhBMP-2/ACS exhibited dense trabeculation within the corpus of the reduced alveolar process. The cortices appeared intact without evidence of expansion into the defect area. Three defects receiving rhBMP-2/ACS/HA exhibited sparse bone trabeculae amidst HA particles, fibrovascular tissue, and marrow. Commonly, the HA particles were encapsulated by fibrous tissue. Some particles were observed in contact with bone. CONCLUSIONS: The results suggests that rhBMP-2/ACS has limited effect alone in this augmentation model of Class III alveolar ridge defects. Inclusion of HA into the rhBMP-2 construct results in clinically relevant augmentation, however, the quality of bone is compromised.     

Bone reconstruction following implantation of rhBMP-2 and guided bone regeneration in canine alveolar ridge defects

BACKGROUND: Alveolar ridge aberrations commonly require bone augmentation procedures for optimal placement of endosseous dental implants. The objective of this study was to evaluate local bone formation following implantation of recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge (ACS) carrier with or without provisions for guided bone regeneration (GBR) as potential treatment modalities for alveolar augmentation. METHODS: Surgically induced, large, mandibular alveolar ridge saddle-type defects (2 defects/jaw quadrant) in seven young adult Hound dogs were assigned to receive rhBMP-2/ACS, rhBMP-2/ACS combined with GBR (rhBMP-2/GBR), GBR, and surgery controls. The animals were euthanized at 12 weeks post-surgery when block sections of the defect sites were collected for histologic analysis. RESULTS: Clinical complications included swelling for sites receiving rhBMP-2 and wound failure with exposure of the barrier device for sites receiving GBR (4/6) or rhBMP-2/GBR (3/7). The radiographic evaluation showed substantial bone fill for sites receiving rhBMP-2/ACS, rhBMP-2/GBR, and GBR. In particular, sites receiving rhBMP-2/GBR presented with seroma-like radiolucencies. The surgery control exhibited moderate bone fill. To evaluate the biologic potential of the specific protocols, sites exhibiting wound failure were excluded from the histometric analysis. Sites receiving rhBMP-2/ACS or rhBMP-2/GBR exhibited bone fill averaging 101%. Bone fill averaged 92% and 60%, respectively, for sites receiving GBR and surgery controls. Bone density ranged from 50% to 57% for sites receiving rhBMP-2/ACS, GBR, or surgery controls. Bone density for sites receiving rhBMP-2/GBR averaged 34% largely due to seroma formation encompassing 13% to 97% of the sites. CONCLUSION: rhBMP-2/ACS appears to be an effective alternative to GBR in the reconstruction of advanced alveolar ridge defects. Combining rhBMP-2/ACS with GBR appears to be of limited value due to the potential for wound failure or persistent seromas.     

Evaluation of recombinant human bone morphogenetic protein-2 on the repair of alveolar ridge defects in baboons

BACKGROUND: The objective of this study was to evaluate alveolar ridge augmentation following surgical implantation of recombinant human bone morphogenetic protein-2 (rhBMP-2) using two novel space-providing carrier technologies in the baboon (Papio anubis) model. METHODS: Standardized alveolar ridge defects ( approximately 15 x 8 x 5 mm) were surgically produced in maxillary and mandibular edentulous areas in four baboons. The defect sites were implanted with rhBMP-2 (0.4 mg/mL) in a tricalcium phosphate/hydroxyapatite/ absorbable collagen sponge composite (TCP/HA/ACS) or calcium phosphate cement (alpha-BSM). Control treatments were TCP/HA/ACS and ?-BSM without rhBMP-2 and sham surgery. Stainless steel pins were placed at the mid-apical and coronal level of the defect sites to provide landmarks for clinical measurements pre- and post-implantation. Impressions were obtained pre- and postimplantation to determine changes in alveolar ridge volume. Radiographic registrations were obtained pre- and post-implantation. Block sections of the defect sites were harvested at week 16 postimplantation and processed for histometric analysis including new bone area and bone density. Statistical comparisons between treatments were made using a mixed effect generalized linear model using least squares estimation. RESULTS: The carrier systems without rhBMP-2 provided a modest ridge augmentation. The addition of rhBMP-2 resulted in an almost 2-fold increase in alveolar ridge width, including a greater percentage of trabecular bone and a higher bone density compared to controls (P < or =0.05) without significant differences between the two rhBMP-2 protocols. CONCLUSIONS: TCP/HA/ACS and alphaBSM appear to be suitable carrier technologies for rhBMP-2. Alveolar augmentation procedures using either technology combined with rhBMP-2, rather than stand-alone therapies, may provide clinically relevant augmentation of alveolar ridge defects for placement of endosseous dental implants.     

Periodontal repair in dogs: a bioabsorbable calcium carbonate coral implant enhances space provision for alveolar bone regeneration in conjunction with guided tissue regeneration

BACKGROUND: Collapse or compression of a barrier device into a periodontal defect or onto the root surface compromises outcomes following guided tissue regeneration (GTR). Bone biomaterials have been suggested to support regeneration of alveolar bone and to improve space provision with GTR devices. The objective of this study was to evaluate space provision, alveolar bone, and cementum regeneration following use of a bioabsorbable, calcium carbonate biomaterial in conjunction with GTR. METHODS: Routine, critical size, 5 to 6 mm, supraalveolar, periodontal defects were created in 5 young adult beagle dogs. Alternate jaw quadrants in consecutive animals received GTR and the coral biomaterial (cGTR) or GTR alone. The animals were euthanized 4 weeks postsurgery and tissue blocks processed for histometric analysis. RESULTS: The coral implant particles were surrounded by newly-formed bone or immersed in connective tissue and appeared to resorb and be replaced by bone. There was limited, if any, appreciable cementum regeneration. Space provision was enhanced in cGTR compared to GTR sites (6.1 +/- 1.6 versus 2.4 +/- 0.8 mm2; P<0.05). Bone regeneration (height) was significantly increased in cGTR compared to GTR sites averaging 1.9 +/- 0.6 and 1.2 +/- 0.6 mm, respectively (P<0.05). Bone regeneration (area) was 2-fold greater in cGTR sites compared to the GTR control (3.3 +/- 1.8 versus 1.4 +/- 0.5 mm2), however the difference was not statistically significant (P>0.05). CONCLUSIONS: The coral implant significantly enhanced space provision for GTR while alveolar bone formation appeared to be enhanced by its use. Increased healing intervals are needed to fully understand the biologic value of the coral implant as an adjunct to GTR.     

Effect of recombinant human bone morphogenetic protein-4 dose on bone formation in a rat calvarial defect model

BACKGROUND: Bone morphogenetic proteins (BMPs) are being evaluated for periodontal and bone regenerative therapy. The objective of this study was to evaluate the effect of recombinant human bone morphogenetic protein-4 (rhBMP-4) dose on local bone formation in a rat calvaria defect model. METHODS: Calvarial, 8 mm diameter, critical-size osteotomy defects were created in 140 male Sprague-Dawley rats. Seven groups of 20 animals each received either 1) rhBMP-4 (2.5 microg) in an absorbable collagen sponge (ACS) carrier, 2) rhBMP-4 (5 microg)/ACS, 3) rhBMP-4 (2.5 microg) in a beta-tricalcium phosphate (beta-TCP) carrier, 4) rhBMP-4 (5 microg)/beta-TCP, 5) ACS or 6) beta-TCP carrier controls, or 7) a sham-surgery control, and were evaluated by histologic and histometric parameters following a 2- or 8-week healing interval (10 animals/group/healing interval). RESULTS: Surgical implantation of rhBMP-4/ACS and rhBMP-4/beta-TCP resulted in enhanced local bone formation at both 2 and 8 weeks. Within the dose range examined, rhBMP-4 did not exhibit an appreciable dose-dependent response. Defect closure was not significantly different between the rhBMP-4/ACS and rhBMP-4/beta-TCP groups. New bone area of the rhBMP-4/ beta-TCP group was significantly greater than that of the rhBMP-4/ ACS group; however, bone density in the rhBMP-4/ACS group was significantly greater than that in the rhBMP-4/beta-TCP group at 8 weeks (P < 0.05). CONCLUSIONS: rhBMP-4 combined with ACS or beta-TCP has a significant potential to induce bone formation in the rat calvaria defect model. Within the selected rhBMP-4 dose range and observation interval, there appeared to be no meaningful differences in bone formation.     

Periodontal repair in dogs: effect of rhBMP-2 concentration on regeneration of alveolar bone and periodontal attachment

The objective of this study was to evaluate the effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) concentration on regeneration of alveolar bone and cementum, and on associated root resorption and ankylosis. Contralateral, critical size, supra-alveolar, periodontal defects were surgically produced and immediately implanted with rhBMP-2 in an absorbable collagen sponge (ACS) carrier in 8, young adult, male, beagle dogs. 6 animals received rhBMP-2/ACS (rhBMP-2 at 0.05, 0.10, or 0.20 mg/mL; total construct volume/defect approximately 4.0 mL) in contralateral defects following an incomplete block design. 2 animals received rhBMP-2/ACS (rhBMP-2 at 0 and 0.10 mg/mL) in contralateral defects (controls). The animals were euthanised at 8 weeks post-surgery and block sections of the defects were collected for histologic and histometric analysis. Supra-alveolar periodontal defects receiving rhBMP-2 at 0.05, 0.10, or 0.20 mg/ml exhibited extensive alveolar regeneration comprising 86%, 96%, and 88% of the defect height, respectively. Cementum regeneration encompassed 8%, 6%, and 8% of the defect height, respectively. Root resorption was observed for all rhBMP-2 concentrations. Ankylosis was observed in almost all teeth receiving rhBMP-2. Control defects without rhBMP-2 exhibited limited, if any, evidence of alveolar bone and cementum regeneration, root resorption, or ankylosis. Within the selected rhBMP-2 concentration and observation interval, there appear to be no meaningful differences in regeneration of alveolar bone and cementum. There also appear to be no significant differences in the incidence and extent of root resorption and ankylosis, though there may be a positive correlation with rhBMP-2 concentration.