BMP-2-Mediated Regeneration of Large-Scale Cranial Defects in the Canine: An Examination of Different Carriers
ABSTRACT Recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered on an absorbable collagen sponge is a U.S. Food and Drug Administration-approved therapy shown to be an effective means of generating bone formation in multiple clinical settings. However, the optimum dose and delivery of rhBMP-2 to the calvaria are undetermined. The aim of the authors' study was to investigate the use of rhBMP-2 in addressing calvarial defects in a large-animal model through a variety of modifications to this U.S. Food and Drug Administration-approved therapy.
Twenty-three adult canines underwent the creation of a standard calvarial defect and received either no treatment, 0.2 mg/ml rhBMP-2 in an absorbable collagen sponge, 0.2 mg/ml rhBMP-2 in an absorbable collagen sponge with corticocancellous chips, 0.2 mg/ml rhBMP-2 in an absorbable collagen sponge with MasterGraft Granules, or 0.4 mg/ml rhBMP-2 in a compression-resistant matrix carrier. Direct comparisons of defect radiopacity were performed at 0, 8, 16, and 24 weeks postoperatively before the animals were euthanized. All specimens were evaluated qualitatively with histology.
Surgical control animals had an average defect radiopacity of 32.7 percent at study completion compared with an average of 99.95 percent across all treatment groups. Ectopic bone formation was found consistently in all treatment groups with varying degrees of severity. Regenerated bone thickness, compactness, and organization varied qualitatively between groups.
Treatment with 0.2 mg/ml rhBMP-2 in an absorbable collagen sponge with MasterGraft Granules showed the least amount of ectopic bone formation and the most compact bone formation within the defect, and produced reasonably consistent bony thickness across the defect. Future studies should focus on spatial regulation of rhBMP-2 to minimize unwanted bone formation.
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ABSTRACT: Commercially available recombinant human bone morphogenetic protein 2 (rhBMP2) has demonstrated efficacy in bone regeneration, but not without significant side effects. In this study, we utilize rhBMP2 encapsulated in PLGA microspheres (PLGA-rhBMP2) placed in a rabbit cranial defect model to test whether low-dose, sustained, delivery can effectively induce bone regeneration. rhBMP2 was encapsulated in 15% poly (lactic-co-glycolic acid), using a double emulsion, solvent extraction/evaporation technique, and its release kinetics and bioactivity were tested. Two critical-size defects (10mm) were created in the calvarium of New Zealand White rabbits (5-7 mos of age, M/F) and filled with a collagen scaffold containing one of four groups: 1) no implant, 2) collagen scaffold only, 3) PLGA-rhBMP2(0.1ug/implant), or 4) free rhBMP2 (0.1ug/implant). After 6 weeks, the rabbits were sacrificed and defects were analyzed by µCT, histology, and finite element analysis. RhBMP2 delivered via bioactive PLGA microspheres resulted in higher volumes and surface area coverage of new bone than an equal dose of free rhBMP2 by µCT and histology (p=0.025, 0.025). FEA indicated that the mechanical competence using the regional elastic modulus did not differ with rhBMP2 exposure (p=0.70). PLGA-rhBMP2 did not demonstrate heterotopic ossification, craniosynostosis, or seroma formation. Sustained delivery via PLGA microspheres can significantly reduce the rhBMP2 dose required for de novo bone formation. Optimization of the delivery system may be a key to reduce the risk for recently reported rhBMP2 related adverse effects. Animal Study.Plastic and Reconstructive Surgery 03/2014; 134(1). DOI:10.1097/PRS.0000000000000287 · 3.33 Impact Factor
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ABSTRACT: Background : A major problem in craniofacial surgery is non-healing bone defects. Autologous reconstruction remains the standard of care for these cases. Bone morphogenetic protein-2 (BMP-2) therapy has proven its clinical utility, although non-targeted adverse events occur due to the high milligram-level doses used. Ongoing efforts explore the use of different growth factors, cytokines, or chemokines, as well as co-therapy to augment healing. Methods : Here we utilize inkjet-based biopatterning to load acellular DermaMatrix delivery matrices with nanogram-level doses of BMP-2, stromal cell-derived factor-1β (SDF-1β), transforming growth factor-β1 (TGF-β1), or co-therapies thereof. We tested the hypothesis that bioprinted SDF-1β co-delivery enhances BMP-2 and TGF-β1-driven osteogenesis both in-vitro and in-vivo using a mouse calvarial critical size defect (CSD) model. Results : Our data showed that BMP-2 bioprinted in low-doses induced significant new bone formation by four weeks post-operation. TGF-β1 was less effective compared to BMP-2, and SDF-1β therapy did not enhance osteogenesis above control levels. However, co-delivery of BMP-2 + SDF-1β was shown to augment BMP-2-induced bone formation compared to BMP-2 alone. In contrast, co-delivery of TGF-β1 + SDF-1β decreased bone healing compared to TGF-β1 alone. This was further confirmed in vitro by osteogenic differentiation studies using MC3T3-E1 pre-osteoblasts. Conclusions : Our data indicates that sustained release delivery of a low-dose growth factor therapy using biopatterning technology can aid in healing CSD injuries. SDF-1β augments the ability for BMP-2 to drive healing, a result confirmed in vivo and in vitro; however, because SDF-1β is detrimental to TGF-β1-driven osteogenesis, its' effect on osteogenesis is not universal.Bone 10/2014; 67. DOI:10.1016/j.bone.2014.07.007 · 4.46 Impact Factor
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ABSTRACT: Objective To document cumulative initial experience and long-term follow-up of the use of rhBMP-2/CRM for reconstruction of large mandibular defects (≥5 cm) in dogs. Study DesignRetrospective case series. AnimalsDogs (n = 5). Methods Medical records (October 1999–April 2011) of dogs that had mandibular reconstruction for defects/resections of ≥5 cm using rhBMP-2/CRM were reviewed. Signalment, preoperative assessment/rationale for mandibular reconstruction, surgical methods, postoperative assessment of the reconstruction (evaluation of occlusion), and complications were recorded. A definitive histologic diagnosis was obtained in dogs that had mandibular resection for mass removal. Long-term complications were determined. A minimum time frame of 2-year in-hospital follow-up was required for case inclusion. ResultsMandibular reconstruction was successfully performed in all dogs' defects where gaps of 5–9 cm were bridged. Surgical reconstruction rapidly restored cosmetic appearance and function. All dogs healed with new bone formation across the gap. New bone formation was present within the defects as early as 2 weeks after surgery based on palpation, and new bone formation bridging the gap was documented radiographically by 16 weeks. Minor complications occurred in all dogs in the early postoperative period, and included early firm swelling and gingival dehiscence in 1 dog; late plate exposure in 3 dogs; and exuberant/cystic bone formation in 2 dogs (related to concentration/formulation of rhBMP-2/CRM). Two dogs had minor long-term complications of late plate exposure and a non-vital canine tooth; the plates and the affected canine tooth were removed. Long-term in-hospital follow-up was 5.3 years (range, 2–12.5 years); further long-term telephone follow-up was 6.3 years (range, 2–12.5 years). All owners were pleased with the outcome and would repeat the surgery again under similar circumstances. Conclusion The efficacy and success of this mandibular reconstruction technique, using rhBMP-2/CRM with plate fixation, was demonstrated with bridging of large mandibular defects regardless of the underlying cause, and with excellent cosmetic and functional results. Complications were common, but considered minor and easily treated. The complications encountered revealed the importance of tailoring the use of BMPs and fixation methods to this specific anatomic location and indication.Veterinary Surgery 02/2014; 44(4). DOI:10.1111/j.1532-950X.2014.12171.x · 0.99 Impact Factor