A Model for Osteonecrosis of the Jaw with Zoledronate Treatment following Repeated Major Trauma.

This study aims to develop a reproducible rat model for post-traumatic bisphosphonate-related osteonecrosis of the jaw (BRONJ). In our previous studies using dental extraction as an inducing factor, only 30%-60% of zoledronate-treated animals fulfilled the definition of clinical BRONJ. We modified the zoledronate regimen and introduced repeated surgical extraction to illicit quantifiable BRONJ in all animals. Eighty retired-breeder female Sprague-Dawley rats were divided between the treatment (i.v. zoledronate; 80 µg/kg/week for 13 weeks) and control (saline) groups. On week 13, the left mandibular first molar was surgically extracted, followed by the second molar a week later. Animals were euthanized at 1-week, 2-weeks, and 8-weeks following extraction. The occurrence and severity of BRONJ were scored in each animal based on gross and MicroCT analysis. Parameters of bone formation and osteoclast functions at the extraction site were compared between groups. All zoledronate-treated animals developed a severe case of BRONJ that fulfilled the clinical definition of the condition in humans. Osteoclast attachment continued to be defective eight weeks after stopping the treatment. There were no signs of kidney or liver toxicity. Our data confirmed that repeated surgical extraction (major trauma) by itself consistently precipitated massive bone necrosis in ZA-treated animals, eliminating the need to induce pre-existing infection or comorbidity. These results will be the basis for further studies examining the in-vivo pathogenesis and prevention of BRONJ.

Delayed versus immediate reconstruction of mandibular segmental defects using recombinant human bone morphogenetic protein 2/absorbable collagen sponge.

PURPOSE: To compare the efficiency of recombinant human bone morphogenetic protein 2 (rhBMP2)/absorbable collagen sponge (ACS) in the delayed versus immediate reconstruction of mandibular segmental defects in a canine model. METHODS: We randomized 11 dogs into 2 groups: immediate reconstruction (group 1, n = 6) and delayed reconstruction (group 2, n = 5). A 35-mm osteoperiosteal segmental defect was created on the left side of the mandible. Reconstruction with rhBMP2/ACS was carried out in the same setting in group 1 or at 4 weeks postoperatively in group 2. The contralateral side acted as an internal control. Animals were monitored both clinically and radiographically throughout the experiment. Twelve weeks after the application of rhBMP2/ACS, the quantity of bone formation was evaluated using regenerate mapping and histomorphometric analysis. Qualitative evaluation was performed based on bone mineral density and Vickers microhardness (µHV) testing. RESULTS: Postoperative seromas were observed in 83.3% of group 1 dogs only. Group 1 showed significantly larger physical dimensions than group 2 in most regenerate zones. Successful regeneration was achieved in 83.3% of group 1 dogs (discontinuity defect was seen in 1 of 6 dogs in group 1). Meanwhile, none of the 5 dogs in group 2 could be considered to have undergone successful regeneration (3 dogs had discontinuity defects, bony union occurred only in the basal third in the fourth dog, and the last dog showed union with only a shell of bone). The percent bone area and percent defect filling were significantly higher in group 1 than in group 2 (percent bone area, 52.4% ± 5.6% in group 1 and 36.6% ± 11.2% in group 2 [P = .02]; percent defect filling, 56.3% ± 5.5% in group 1 and 38.5% ± 10.8% in group 2 [P = .01]). Group 1 showed higher bone mineral density (0.7 ± 0.3 mg/cm(3) in group 1 and 0.4 ± 0.1 mg/cm(3) in group 2, P = .1). Finally, µHV was significantly higher in group 1 (20.3 ± 2.6 µHV) than in group 2 (13.2 ± 2.4 µHV) (P = .01). CONCLUSIONS: Delaying the application of rhBMP2/ACS for 4 weeks attenuated the quantity and quality of regenerated bone in mandibular segmental defects.

Alveolar ridge augmentation for implant fixation: status review.

This literature review was performed to illustrate and compare different alveolar ridge augmentation procedures before dental implant placement. The review was based on clinical and research studies listed in Pubmed. There is not enough evidence to support any single method as gold standard for any given condition, and choice seemed to be based on personal preferences. There is a lack of long-term survival data or success rates of grafting materials regarding donor and recipient sites. Although ridge splitting and distraction osteogenesis techniques eliminate donor site morbidity, circumvent the use of grafting materials, and reduce the operation time, some disadvantages and limitations should be considered. More studies are needed to compare the fate and characteristics of new bone obtained by these different procedures, as well as subsequent implant survival rates.

Bone regeneration and docking site healing after bone transport distraction osteogenesis in the canine mandible.

PURPOSE: Bone transport distraction osteogenesis provides a promising alternative to traditional grafting techniques. However, existing bone transport distraction osteogenesis devices have many limitations. The purpose of this research was to test a new device, the mandibular bone transport reconstruction plate, in an animal model with comparable mandible size to humans and to histologically and mechanically examine the regenerate bone. MATERIALS AND METHODS: Eleven adult foxhounds were divided into an unreconstructed control group of 5 animals and an experimental group of 6 animals. In each animal, a 34-mm segmental defect was created in the mandible. The defect was reconstructed with a bone transport reconstruction plate. Histologic and biomechanical characteristics of the regenerate and unrepaired defect were analyzed and compared with bone on the contralateral side of the mandible after 4 weeks of consolidation. RESULTS: The reconstructed defect was bridged with new bone, with little bone in the control defect. Regenerate density and microhardness were 22.3% and 42.6%, respectively, lower than the contralateral normal bone. Likewise, the anisotropy of the experimental group was statistically lower than in the contralateral bone. Half the experimental animals showed nonunion at the docking site. CONCLUSION: The device was very stable and easy to install and activate. After 1 month of consolidation, the defect was bridged with new bone, with evidence of active bone formation. Regenerate bone was less mature than the control bone. Studies are underway to identify when the regenerate properties compare with normal bone and to identify methods to augment bone union at the docking site.

Difference in soft tissue response between immediate and delayed delivery suggests a new mechanism for recombinant human bone morphogenetic protein 2 action in large segmental bone defects.

The ability of recombinant human bone morphogenetic protein 2 on absorbable collagen sponge (rhBMP2/ACS) to regenerate bone in segmental defect has been well characterized. However, clinical results of rhBMP2/ACS constructs in secondary reconstruction of large mandibular and craniofacial defects have not been consistent. We hypothesized that rhBMP2 delivery triggers an endogenous response in the soft tissues surrounding the defect, in the form of expression of BMP2 and vascular endothelial growth factor (VEGF). Such osteogenic response will occur only after immediate, as opposed to delayed, rhBMP2 delivery, suggesting a new explanation to the difference in bone regeneration between the two settings. A 35-mm segmental bone and periosteum defect was created on one side of the mandible in 16 dogs divided in three groups. Group 1 (Gp1, n=6) ACS was loaded with 8 mL of rhBMP2 (0.2 mg/mL). In Gp2 (n=5) the same dose of rhBMP2/ACS was delivered into the defect 4 weeks after surgery. In Gp3 (control; n=5) the defect was reconstructed using ACS loaded with 8 mL of buffer only (devoid of rhBMP2). Tissues were collected after 12 weeks of reconstruction in all groups. Direct measurement of physical dimensions of regenerates and bone morphometry was performed to evaluate bone regeneration. The mRNA expression of both BMP2 and VEGF in the soft tissue surrounding the defect was evaluated using real-time quantitative PCR. Both BMP2 and VEGF proteins were quantified in immunostained sections. Immunoflurescence colocalization of BMP2 and acetylated low density lipoprotein (AcLDL) was done to detect the source of BMP2. Immediate delivery yielded better bone regeneration. Both BMP2 and VEGF mRNA expression was upregulated only in Gp1 (+7.3, p=0.001; +1.53, p=0.001, respectively). BMP2 protein was significantly higher in the immediate reconstruction group; however, VEGF protein was undetected in the examined sections. Immediate delivery of rhBMP2 seemed to induce endogenous release of BMP2 from the surrounding soft tissues, an effect that was lacking in delayed delivery and may explain the variability of clinical results associated with BMP2 use. Colocalization of BMP2 and endothelial cells (ECs) suggested that ECs could be the source of endogenous BMP2.

Reconstruction of large mandibular bone and soft-tissue defect using bone transport distraction osteogenesis.

Reconstruction of large anterior mandibular defects is a challenging task. The condition can become even more complex if primary reconstruction fails, leading to loss of the entire midline portion of the lower face with massive scarring of the remaining tissues. Bone transport distraction osteogenesis can provide a viable treatment option for these patients. One of such cases will be presented, followed by a discussion of the advantages, disadvantages, and limitations of the technique.