Secondary Alveolar Bone Graft Using Recombinant Human Bone Morphogenetic Protein-2 (rh-BMP2) May Be as Efficacious as Autologous Grafting in Unilateral Cleft Lip and Palate Patients.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Secondary alveolar bone grafting using autologous versus alloplastic material in the treatment of cleft lip and palate patients: systematic review and meta-analysis. Scalzone A, Flores-Mir C, Carozza D, d'Apuzzo F, Grassia V, Perillo L. Prog Orthod 2019;20(6):1-10. SOURCE OF FUNDING: The authors received no financial support for this study. TYPE OF STUDY/DESIGN: Systematic review and meta-analysis.

rhBMP-2 (Recombinant Human Bone Morphogenetic Protein-2) in real world spine surgery. A phase IV, National, multicentre, retrospective study collecting data from patient medical files in French spinal centres.

BACKGROUND: This is a Phase IV, national, multicentre, retrospective study to observe the real-world use of rhBMP-2 in France. HYPOTHESIS: There was no statistical hypothesis, the statistical analyses were descriptive in nature. PATIENTS AND METHODS: Data was collected from patient medical files in 10 French spinal centres. Primary objectives were to understand which patients were treated with rhBMP-2, commercialised in Europe as InductOs™ and how rhBMP-2 was used during spinal fusion surgery in France between 2011 and 2012. RESULTS: Four hundred patients (634 levels) treated with rhBMP-2 were included in the analysis. The most frequent primary diagnostic indication for rhBMP-2 use was degenerative disc disease (DDD; 129/400; 32.3% of patients) followed by spondylolisthesis (119/400; 29.8%), deformity (59/400; 14.8%) and pseudoarthrosis (29/400; 7.3%). The most frequently treated level was L4-L5 (33.8% of levels in 53.5% of patients); followed by L5-S1 (29.8%, 47.3%), L3-L4 (16.7%, 26.5%), and L2-L3 (7.3%, 11.5%), all other levels (less than 5% of patients). No interbody fusion device was used in 42.7% of levels. Wetted matrix of rhBMP-2 was placed in the interbody space in 58.4% of levels (370/634). The most common procedure for rhBMP-2 treatment was posterior lumbar fusion (PLF) (221/634; 34.9% of levels), followed by anterior lumbar interbody fusion (ALIF) (188/634; 29.7%), posterior lumbar interbody fusion (PLIF) (111/634; 17.5%), lateral lumbar interbody fusion (LLIF) (106/634; 16.7%), transforaminal lumbar interbody fusion (TLIF) (4/634; 0.6%) and 'other' (4/634; 0.6%). Thirty-one adverse events of Interest (AEI) were recorded in 27 patients. One AEI was considered related to rhBMP-2. Unplanned secondary spine interventions at index level treated with rhBMP-2 were required in 4 patients. DISCUSSION: In years 2011 and 2012 when the surgeries captured in this retrospective study were done, rhBMP-2 was indicated for single level (L4-S1) anterior lumbar spine fusion as a substitute for autogenous bone graft in adults with DDD. The most common procedure for the treatment with rhBMP-2 was PLF (off-label use), followed by ALIF (on-label use). The safety findings confirm a predictable and manageable safety profile. LEVEL OF EVIDENCE: IV.

The local cytokine and growth factor response to recombinant human bone morphogenetic protein-2 (rhBMP-2) after spinal fusion.

BACKGROUND CONTEXT: The systemic response regarding cytokine expression after the application of recombinant human bone morphogenetic protein-2 (rhBMP-2) in a rat spinal fusion model has recently been defined, but the local response has not been defined. Defining the local cytokine and growth factor response at the fusion site will help explain the roles of these molecules in the fusion process, as well as that of rhBMP-2. Our hypothesis is that the application of rhBMP-2 to the fusion site will alter the local levels of cytokines and growth factors throughout the fusion process, in a manner that is different from the systemic response, given the tissue-specific effects of rhBMP-2. PURPOSE: The purpose of this study was to evaluate the local cytokine and growth factor response after the application of rhBMP-2 in a rat spinal fusion model. STUDY DESIGN/SETTING: This was a basic science animal model study. METHODS: This study was partially funded by a physician-sponsored grant from Medtronic. A total of 135 Wistar rats (age 8 weeks, weighing approximately 300-400 g) underwent L4-L5 posterolateral intertransverse fusion with demineralized bone graft (approximately 0.4-cm3 rat demineralized bone matrix [DBM] per side). In the first group, 10 µg of rhBMP-2 on an allograft collagen sponge (ACS) was added to the fusion site with approximately 0.4-cm3 rat DBM per side. In the second group, 100 µg of rhBMP-2 on an ACS was added to the fusion site with approximately 0.4-cm3 rat DBM per side, and the third experiment was the control group, which consisted of only an ACS plus 0.4-cm3 DBM per side. There were nine groups of five animals each per experiment. Each group was sacrificed at time points up to 4 weeks (1, 6, 24, and 48 hours, and 4, 7, 14, 21, and 28 days after surgery). At sacrifice, the DBM, transverse processes, and any new bone formed were harvested, immediately frozen in liquid nitrogen, and prepared for protein extraction. ELISA was performed to compare the levels of various cytokines (interleukin [IL]-1ß, tumor necrosis factor alpha, IL-6, IL-1RA [IL-1 receptor antagonist], IL-4, and IL-10) and growth factors (vascular endothelial growth factor [VEGF], endothelia growth factor [EGF], insulin-like growth factor-1 [IGF-1], platelet derived growth factor [PDGF], transforming growth factor beta [TGF-ß]) that are known to be involved in the fusion-fracture healing process. Fusion was evaluated on the rats sacrificed at 28 days by manual palpation and microcomputed tomography (microCT) by two independent observers. RESULTS: The expression of cytokines and growth factors varied throughout the fusion process at each time point. In the groups treated with rh-BMP-2, IL-6 and IL-1RA had higher expression in the early time points (1 and 6 hours). Tumor necrosis factor alpha demonstrated significantly lower expression in the groups treated with rhBMP-2 at Days 1, 2, and 4. At the early time points (1 and 6 hours), in the groups treated with rhBMP-2, all of the growth factors IGF-1, VEGF, platelet derived growth factor AB (PDGF-AB), TGF-ß had equal or lower expression compared with controls. At 24 hours, there was a peak in IGF-1, VEGF, and PDGF-AB. These growth factors then declined, with IGF-1 and PDGF-AB having a second peak at Day 7. At 4 weeks, all of the rhBMP-2-treated animals fused based on manual palpation and microCT. The control group had four of five rats fused based on manual palpation and two of five rats based on microCT. CONCLUSIONS: There is significant variability in the expression of cytokines throughout the fusion process after treatment with rhBMP-2. The inflammatory response appears to peak early (1 and 6 hours), followed by a significant decrease with rhBMP-2 treatment. However, the growth factor expression appears to be suppressed early (1 and 6 hours), followed by a peak at 24 hours, and a second peak at Day 7.

A review on carrier systems for bone morphogenetic protein-2.

Bone morphogenetic protein-2 (BMP-2) has unique bone regeneration property. The powerful osteoinductive nature makes it considered as second line of therapy in nonunion bone defect. A large number of carriers and delivery systems made up of different materials have been investigated for controlled and sustained release of BMP-2. The delivery systems are in the form of hydrogel, microsphere, nanoparticles, and fibers. The carriers used for the delivery are made up of metals, ceramics, polymers, and composites. Implantation of these protein-loaded carrier leads to cell adhesion, degradation which eventually releases the drug/protein at site specific. But, problems like ectopic growth, lesser protein delivery, inactivation of the protein are reported in the available carrier systems. Therefore, it is need of an hour to modify the available carrier systems as well as explore other biomaterials with desired properties. In this review, all the reported carrier systems made of metals, ceramics, polymers, composites are evaluated in terms of their processing conditions, loading capacity and release pattern of BMP-2. Along with these biomaterials, the attempts of protein modification by adding some functional group to BMP-2 or extracting functional peptides from the protein to achieve the desired effect, is also evaluated. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 904-925, 2017.

The Use of Bone Morphogenetic Protein in Pediatric Cervical Spine Fusion Surgery: Case Reports and Review of the Literature.

Study Design Case report. Objective There is a paucity of literature describing the use of bone graft substitutes to achieve fusion in the pediatric cervical spine. The outcomes and complications involving the off-label use of bone morphogenetic protein (BMP)-2 in the pediatric cervical spine are not clearly defined. The purpose of this article is to report successful fusion without complications in two pediatric patients who had instrumented occipitocervical fusion using low-dose BMP-2. Methods A retrospective review of the medical records was performed, and the patients were followed for 5 years. Two patients under 10 years of age with upper cervical instability were treated with occipitocervical instrumented fusion using rigid occipitocervical fixation techniques along with conventionally available low-dose BMP-2. A Medline and PubMed literature search was conducted using the terms "bone morphogenetic protein," "BMP," "rh-BMP2," "bone graft substitutes," and "pediatric cervical spine." Results Solid occipitocervical fusion was achieved in both pediatric patients. There were no reported perioperative or follow-up complications. At 5-year follow-up, radiographs in both patients showed successful occipital cervical fusion without evidence of instrumentation failure or changes in the occipitocervical alignment. To date, there are few published reports on this topic. Complications and the appropriate dosage application in the pediatric posterior cervical spine remain unknown. Conclusions We describe two pediatric patients with upper cervical instability who achieved successful occipital cervical fusion without complication using off-label BMP-2. This report underscores the potential for BMP-2 to achieve successful arthrodesis of the posterior occipitocervical junction in pediatric patients. Use should be judicious as complications and long-term outcomes of pediatric BMP-2 use remain undefined in the existing literature.

The use of allograft and recombinant human bone morphogenetic protein for instrumented atlantoaxial fusions.

BACKGROUND: Iliac crest autograft is the historic gold standard for bone grafting, but is associated with a significant patient morbidity. Fusion rates of C1-C2 up to 88.9% using allograft and 96.7% using autologous iliac crest bone graft can be achieved when combined with rigid screw fixation. We sought to determine our fusion rate when combining allograft with recombinant human bone morphogenetic protein-2 (rh-BMP2) and rigid screw fixation. METHODS: We reviewed our experience using allograft, bone morphogenetic protein (rh-BMP2) and screw fixation of C1-C2 in 52 patients and examined indications, surgical technique, fusion rates, and complications. In 28 patients, corticocancellous allograft pieces were laid along decorticated bone after a C2 neurectomy was performed. In 24 patients, unicortical iliac crest allograft was precision-cut to fit between the C1 lamina and C2 spinous processes. RESULTS: Fifty-two C1-C2 fusions were performed with allograft, rh-BMP2, and rigid screw fixation. There were 25 female and 27 male patients ranging in age from 6 to 92 years (mean, 65.8 years). Operative indications included trauma (56%), degenerative disease (21%), rheumatoid arthritis (15%), congenital anomalies (6%), and synovial cyst (2%). The mean follow-up was 23.9 ± 2.1 months (range, 2-55 months). The mean dose of rh-BMP2 used for all patients was 4.5 mg (range, 2.2-12 mg). In patients who achieved sufficient follow-up, 100% achieved solid fusion: 45/50 Lenke A, 5/50 Lenke B. There were no known complications attributable to the use of rh-BMP2. CONCLUSIONS: The use of small doses of rh-BMP2 added to allograft in addition to rigid screw fixation is a safe and highly effective means of promoting a solid fusion of the atlantoaxial complex and spares the patient the morbidity of iliac crest harvest.