Search

The objective of the following case reports was to assess whether mineralized bone replacement grafts (eg, xenografts and allografts) could be added to recombinant human bone morphogenetic protein-2/acellular collagen sponge (rhBMP-2/ACS) in an effective manner that would: (1) reduce the graft shrinkage observed when using rhBMP-2/ACS alone, (2) reduce the volume and dose of rhBMP-2 required, and (3) preserve the osteoinductivity that rhBMP-2/ACS has shown when used alone. The primary outcome measures were histomorphometric analysis of vital bone production and analysis of serial computed tomographic scans to determine changes in bone graft density and stability. Over the 6-month course of this investigation, bone graft densities tended to increase (moreso with the xenograft than the allograft). The increased density in allograft cases was likely the result of both compression of the mineralized bone replacement graft and vital bone formation, seen histologically. Loss of volume was greater with the four-sponge dose than the two-sponge dose because of compression and resorption of the sponges. Vital bone formation in the allograft cases ranged from 36% to 53% but, because of the small sample size, it was not possible to determine any significant difference between the 5.6 mL (four-sponge) dose and the 2.8 mL (two-sponge) dose. Histology revealed robust new woven bone formation with only minimal traces of residual allograft, which appeared to have undergone accelerated remodeling or rhBMP-2-mediated resorption.

The uncoupling of osteoblastic and osteoclastic activity is central to disorders such as osteoporosis, osteolytic malignancies, and periodontitis. Numerous studies have shown explicit functions for bone morphogenetic proteins (BMPs) in skeletogenesis. Their signaling activity has been shown in various contexts to be regulated by extracellular proteins, including Twisted gastrulation (TWSG1). However, experimental paradigms determining the effects of BMP regulators on bone remodeling are limited. In this study, we assessed the role of TWSG1 in postnatal bone homeostasis. Twsg1-deficient (Twsg1(-/-)) mice developed osteopenia that could not be explained by defective osteoblast function, because mineral apposition rate and differentiation markers were not significantly different compared with wildtype (WT) mice. Instead, we discovered a striking enhancement of osteoclastogenesis in Twsg1(-/-) mice, leading to increased bone resorption with resultant osteopenia. Enhanced osteoclastogenesis in Twsg1(-/-) mice was caused by increased cell fusion, differentiation, and function of osteoclasts. Furthermore, RANKL-mediated osteoclastogenesis and phosphorylated Smad1/5/8 levels were enhanced when WT osteoclasts were treated with recombinant BMP2, suggesting direct regulation of osteoclast differentiation by BMPs. Increase in detectable levels of phosphorylated Smad 1/5/8 was noted in osteoclasts from Twsg1(-/-) mice compared with WT mice. Furthermore, the enhanced osteoclastogenesis in Twsg1(-/-) mice was reversed in vitro in a dose-dependent manner with exposure to Noggin, a BMP antagonist, strongly suggesting that the enhanced osteoclastogenesis in Twsg1 mutants is attributable to increased BMP signaling. Thus, we present a novel and previously uncharacterized role for TWSG1 in inhibiting osteoclastogenesis through regulation of BMP activity.

Abstract: Background: Recombinant human bone morphogenetic protein‐2 in an absorbable collagen sponge carrier (rhBMP‐2/ACS) has been shown to support significant bone formation when used to augment the maxillary sinus for implant dentistry. Nevertheless, bone biomaterials have been suggested to extend rhBMP‐2/ACS with limited support of the merits of such approaches. Objectives: To evaluate local bone formation/dental implant osseointegration following implantation of rhBMP‐2/ACS combined with a ceramic bone biomaterial using a mini‐pig sinus augmentation model. Methods: Twelve adult Göttingen mini‐pigs received rhBMP‐2/ACS (rhBMP‐2 adjusted to 0.43 mg/cc) alone or combined with an off‐the‐shelf biphasic ceramic (15%/85% HA/ß‐TCP) biomaterial at 3:1, 1:1 and 1:3 ratios randomized to contra‐lateral maxillary sinus sites yielding rhBMP‐2/ACS fractions of 100%, 75%, 50% and 25%, respectively. A 4‐cc implant volume was used for all sites. Two threaded dental implants (ø4.0 × 11.5 mm) were placed at each site. The animals were euthanized at 8 weeks for histologic analysis. Results: Surgical execution and healing were generally uneventful, infraorbital local swelling was observed in all animals until suture removal. rhBMP‐2/ACS combined with the ceramic biomaterial did not significantly enhance local bone formation (range 9.0 ± 1.5 to 9.7 ± 2.1 mm) compared with rhBMP‐2/ACS alone (8.6 ± 1.1 mm; p > 0.05). Variations in rhBMP‐2/ACS to ceramic matrix ratios yielding rhBMP‐2 doses approximating 0.4, 0.9, 1.3 and 1.7 mg/sinus did not appreciably influence bone formation/osseointegration. Conclusions: Whereas rhBMP‐2/ACS supports significant bone formation/osseointegration in the mini‐pig sinus augmentation model and thus appears an effective alternative for sinus augmentation procedures, adding a ceramic biomaterial to rhBMP‐2/ACS does not produce meaningful biological advantages. [ABSTRACT FROM AUTHOR]

Background Present clinical practice broadly relies on off-the-shelf allogeneic, xenogeneic or synthetic bone biomaterials in support of sinus augmentation. Also, recombinant human bone morphogenetic protein-2 in an absorbable collagen sponge carrier (rhBMP-2/ACS) has been shown to support clinically relevant bone formation when used to augment the maxillary sinus. Objectives To evaluate local bone formation/dental implant osseointegration following implantation of two particulate bone biomaterials using the mini-pig sinus augmentation model. Methods Nine adult Göttingen mini-pigs were used for evaluation of a biphasic ceramic (15%/85% HA/ß-TCP) and an allogeneic mineralized bone biomaterial. Treatments randomized to contralateral sinus sites included sham-surgery (control) and biomaterials. Two threaded dental implants (ø4.0 × 11.5 mm) were placed at each sinus site. The animals were euthanized at 8 weeks for histologic analysis. Results Execution of the surgical protocol and healing was unremarkable. Limited infraorbital swelling was observed until suture removal. The biphasic ceramic and allogeneic bone biomaterials produced significantly increased bone formation (5.2 ± 1.9 mm and 4.9 ± 1.6 mm vs. 2.6 ± 0.5 mm, p < 0.05) and osseointegration (18.0 ± 6.0% and 25.1 ± 18.2% vs. 10.1 ± 8.0%, p < 0.05) over the sham-surgery control. No significant differences were observed between biomaterials. Conclusions Implantation of biphasic ceramic or allogeneic bone biomaterials enhances bone formation in the mini-pig maxillary sinus, however, dental implant bone support is incomplete resulting in overall limited osseointegration. [ABSTRACT FROM AUTHOR]

Background Implant dentistry in the posterior maxilla often requires bone augmentation. The gold standard, autogenous bone graft, requires additional surgery with associated morbidity, while bone biomaterials may not support relevant bone formation. Recombinant human bone morphogenetic protein-2 ( rhBMP-2) in an absorbable collagen sponge ( ACS), however, induces significant, clinically relevant bone formation in several settings including the maxillary sinus floor. Objective The objective of this study was to compare local bone formation and osseointegration following maxillary sinus augmentation using rhBMP-2/ ACS or a particulate autogenous cancellous bone graft obtained from the iliac crest in conjunction with immediate placement of dental implants. Materials and methods Bilateral sinus augmentation using an extraoral approach including rhBMP-2 (0.43 mg/ml)/ACS or the autogenous bone graft, alternated between left and right sinus cavities in five adult male Yucatan mini-pigs, was performed. Two 12-mm dental implants were inserted into the sinus wall protruding approximately 8 mm into the sinus cavity. Surgical sites were closed and sutured in layers; block biopsies collected for histometric analysis at 8 weeks. Results rhBMP-2/ ACS induced bone of significantly greater and consistent quality compared with the iliac crest autogenous bone graft; bone density averaging 51.9 ± 3.0% vs. 32.9 ± 2.5% ( P = 0.01). However, there were only numerical differences in augmented bone height (9.3 ± 0.5 vs. 8.6 ± 0.7 mm) and bone-implant contact (37.4 ± 3.0% vs. 30.7 ± 5.9%) between treatments. Conclusion rhBMP-2/ ACS induces bone of superior quality compared with an iliac crest particulate autogenous cancellous bone graft when used for maxillary sinus augmentation, and should perhaps be considered the new standard for this indication. [ABSTRACT FROM AUTHOR]

Background: Chinese hamster ovary (CHO) ceil-derived recombinant human bone morphogenetic protein-2 (rhBMP-2) has been introduced for spine, long bone, and craniofacial indications. Escherichia coli- (E. coli) derived rhBMP-2 displays comparable efficacy to CHO cell-derived rhBMP-2 in vitro and in small-animal models. The objective of this study is to evaluate the efficacy of E. coli-derived rhBMP-2 compared to the benchmark CHO cell-derived rhBMP-2 using an established large-animal model. Methods: Contralateral, critical-size supraalveolar peri-implant defects in six adult male Hound Labrador mongrel dogs received CHO cell- or E. coli-derived rhBMP-2 (0.2 mg/mL) in an absorbable collagen sponge (ACS) carrier. In each quadrant, three dental implants were placed. A titanium mesh device was used to support space provision. The animals received fluorescent bone markers for qualitative evaluations. Animals were euthanized at 8 weeks for histopathologic and histometric evaluation. Results: Clinical healing included significant swelling, but none of the animals experienced wound dehiscences. CHO cell- and E. coli-derived rhBMP-2 supported comparable bone formation (new bone area, 35.8 ± 3.6 versus 30.1 ± 2.2 mm²; bone density, 31.8% ± 1.6% versus 35.6% ± 2.5%; and osseointegration, 32.9% ± 7.4% versus 33.7% ± 8.1%) without statistically significant differences between treatments. Newly formed immature delicate trabecular bone in fibrovascular marrow filled the space underneath the titanium mesh and extended coronally above the mesh. Seroma formation was frequently observed. There were no discernable qualitative histologic differences between treatments. Conclusion: CHO cell- and E. coli-derived rhBMP-2 in an ACS carrier appear equally effective at inducing local bone formation in support of dental implant osseointegration. [ABSTRACT FROM AUTHOR]

Background: Studies using ectopic rodent and orthotopic canine models (Type II bone) have shown that titanium porous oxide (TPO) surface implants adsorbed with recombinant human bone morphogenetic protein-2 (rhBMP-2) induce local bone formation including osseointegration. The objective of this study was to evaluate local bone formation and osseointegration at such implants placed into Type IV bone. Material and Methods: rhBMP-2-coated implants were installed into the edentulated posterior maxilla in eight young adult Cynomolgus monkeys: four animals each received three TPO implants adsorbed with rhBMP-2 (2.0 mg/ml) and four animals each received three TPO implants adsorbed with rhBMP-2 (0.2 mg/ml). Contra-lateral jaw quadrants received three TPO implants without rhBMP-2 (control). Treatments were alternated between left and right jaw quadrants. Mucosal flaps were advanced and sutured to submerge the implants. The animals received fluorescent bone markers at weeks 2, 3, 4, and at week 16 when they were euthanized for histologic analysis. Results: Clinical healing was uneventful. Extensive local bone formation was observed in animals receiving implants adsorbed with rhBMP-2 (2.0 mg/ml). The newly formed bone exhibited a specific pinpoint bone–implant contact pattern regardless of rhBMP-2 concentration resulting in significant osseointegration; rhBMP-2 (2.0 mg/ml): 43% and rhBMP-2 (0.2 mg/ml): 37%. Control implants exhibited a thin layer of bone covering a relatively larger portion of the implant threads. Thus, TPO control implants bone exhibited significantly greater bone–implant contact (∼75%; p<0.05). There were no statistically significant differences between rhBMP-2-coated and control implants relative to any other parameter including peri-implant and intra-thread bone density. Conclusion: rhBMP-2-coated TPO implants enhanced/accelerated local bone formation in Type IV bone in a dose-dependent fashion in non-human primates resulting in significant osseointegration. rhBMP-2-induced de novo bone formation did not reach the level of osseointegration observed in native resident bone within the 16-week interval. [ABSTRACT FROM AUTHOR]

Objective: Novel implant technologies and reconstructive therapies for alveolar augmentation require pre-clinical evaluation to estimate their biologic potential, efficacy, and safety before clinical application. The objective of this report is to present characteristics and use of the critical-size, supraalveolar, peri-implant defect model. Methods: Bilateral extraction of the mandibular premolars was performed in 12 Hound Labrador mongrel dogs following horizontal surgical cut-down of the alveolar ridge approximating 6 mm. Each jaw quadrant received three custom-produced TiUnite™, ∅4.0 × 10 mm threaded implants placed into osteotomies prepared into the extraction sites of the third and fourth premolars. The implants exhibited a reference notch 5 mm from the implant platform to facilitate surgical placement leaving 5 mm of the implant in a supraalveolar position, and to serve as a reference point in the radiographic, histologic and histometric analysis. The implants were submerged under the mucoperiosteal flaps for primary intention healing. Fluorescent bone markers were administered at weeks 3 and 4 post-surgery, and pre-euthanasia. The animals were euthanized following an 8-week healing interval when block biopsies were collected for analysis. Results: Healing was generally uneventful. The radiographic and histometric evaluations demonstrate the limited osteogenic potential of this defect model. Whereas lingual peri-implant sites exhibited a mean (±SE) bone gain of 0.4±0.1 mm, resorption of the buccal crestal plate resulted in a mean bone loss of 0.4±0.2 mm for an overall osteogenic potential following sham-surgery averaging 0.0±0.1 mm. Overall bone density and bone–implant contact in the contiguous resident bone averaged 79.1±1.1% and 76.9±2.3%, respectively. Conclusion: The results suggest that the critical-size, supraalveolar, peri-implant defect model appears a rigorous tool in the evaluation of candidate technologies for alveolar reconstruction and osseointegration of endosseous oral implants. Limited innate osteogenic potential allows critical evaluation of osteogenic, osteoconductive, or osteoinductive technologies in a challenging clinical setting. [ABSTRACT FROM AUTHOR]