Safety and Efficacy of Recombinant Human Bone Morphogenetic Protein-2 in Multilevel Posterolateral Lumbar Fusion in a Prospective, Randomized, Controlled Trial.

OBJECTIVE: This study is an investigator-initiated, prospective, randomized, controlled study to evaluate the efficacy and safety of the combined use of recombinant human BMP-2 (rhBMP-2) and a hydroxyapatite (HA) carrier in multilevel fusion in patients with adult spinal deformity (ASD). METHODS: Thirty patients underwent posterolateral fusion for lumbar spinal deformities at 3 to 5 segments between L1 and S1. The patients received rhBMP-2+HA or HA on the left or right side of the transverse processes. They were followed up regularly at 1, 3, 6, and 12 months postoperatively. Fusion was defined according to the bone bridging on computed tomography scans. The fusion rate per segment was subanalyzed. Function and quality of life as well as pain in the lower back and lower extremities were evaluated. RESULTS: The union rate for the rhBMP-2+HA group was 100% at 6 and 12 months. The union rate for the HA group was 77.8% (21 of 27) at 6 months and 88.0% (22 of 25) at 12 months (p = 0.014 at 6 months; not significant at 12 months). All segments were fused at 6 and 12 months in the rhBMP-2+HA group (p < 0.001). In the HA group, 108 of 115 segments (93.5%) were fused at 6 months and 105 of 109 segments (96.3%) at 12 months. Other clinical parameters (visual analogue scale, 36-item Short Form Health Survey, and Scoliosis Research Society-22 scores) improved compared to baseline. CONCLUSION: Combining rhBMP-2 and an HA carrier is a safe and effective method to achieve multilevel fusion in patients with ASD.

Generation of an rhBMP-2-loaded beta-tricalcium phosphate/hydrogel composite and evaluation of its efficacy on peri-implant bone formation.

Dental implant insertion on a site with low bone quality or bone defect should be preceded by a bone graft or artificial bone graft insertion to heal the defect. We generated a beta-tricalcium phosphate (ß-TCP) and poloxamer 407-based hydrogel composite and penetration of the ß-TCP/hydrogel composite into the peri-implant area of bone was evaluated by porous bone block experiments. The maximum penetration depth for porous bone blocks and dense bone blocks were 524 µm and 464 µm, respectively. We report the in-vivo performance of a composite of ß-TCP/hydrogel composite as a carrier of recombinant human bone morphogenetic protein (rhBMP-2), implanted into a rabbit tibial defect model. Three holes drilled into each tibia of eight male rabbits were (1) grafted with dental implant fixtures; (2) filled with ß-TCP/hydrogel composite (containing 5 µg of rhBMP-2), followed by grafting of the dental implant fixtures. Four weeks later, bone-implant contact ratio and peri-implant bone formation were analyzed by radiography, micro-CT and histology of undecalcified specimens. The micro-CT results showed a significantly higher level of trabecular thickness and new bone and peri-implant new bone formation in the experimental treatment compared to the control treatment. Histomorphometry revealed a significantly higher bone-implant contact ratio and peri-implant bone formation with the experimental treatment. The use of ß-TCP/poloxamer 407 hydrogel composite as a carrier of rhBMP-2 significantly promoted new bone formation around the dental implant fixture and it also improved the quality of the new bone formed in the tibial marrow space.

The effects of recombinant human bone morphogenetic protein-2-loaded tricalcium phosphate microsphere-hydrogel composite on the osseointegration of dental implants in minipigs.

Bone formation in tooth defect areas and the osseointegration of dental implants are very important for successful dental implant surgery. The aim of the present study was to assess the strengthening effect of a ß-TCP microsphere-hydrogel composite containing recombinant human bone morphogenetic protein-2 (rhBMP-2) on bone healing and implant osseointegration. The molars and premolars on the left and right sides of the maxilla were extracted from six male minipigs, and dental implants were placed using either the ß-TCP microsphere-hydrogel carrier alone or the carrier loaded with rhBMP-2 (500 µg). The animals were kept alive for a further 8 weeks. The molars and premolars from the left and the right sides of the mandibles of another six minipigs were extracted, and the animals were kept alive for 4 weeks. Two 5-mm-diameter bone defects were then made on both sides of the mandible. The defects were filled with saline, ß-TCP microsphere-hydrogel carrier, or the carrier loaded with rhBMP-2 (300 µg), and dental implant fixtures were inserted. The animals were kept alive for a further 4 weeks. Bone formation was examined using plane radiographs, micro-CT, and the histology of undecalcified specimens. The group treated with the rhBMP-2-loaded carrier composite showed a significantly higher percentage bone volume and a greater trabecular thickness for the newly formed bone in the tooth defect areas when compared to the group treated with the carrier alone. The rhBMP-2 group had a significantly higher osseointegration, a larger percentage bone volume, greater trabecular thickness in the newly formed bone in tooth defect areas, a larger newly formed bone fraction in the fixture pitch, and a greater number of newly formed trabecular bones when compared to the other groups. We confirmed that the rhBMP-2-loaded carrier composite promotes new bone formation after tooth extraction and strengthens osseointegration of dental fixtures by improving the degree of osseointegration around the dental implant fixture.

Effects of porous beta-tricalcium phosphate-based ceramics used as an E. coli-derived rhBMP-2 carrier for bone regeneration.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) requires carriers for clinical effectiveness. In this study, whether porous beta-tricalcium phosphate (ß-TCP)-based ceramics are ideal carriers for rhBMP-2 was investigated. Hydroxyapatite (HA), ß-TCP, TCP/HA (80 %/20 %), HA with rhBMP-2, TCP with rhBMP-2, and TCP/HA (80 %/20 %) with rhBMP-2 were manufactured by a sponge method with a pore size of 300 µm or more and macro-porosity of 83 %. The alkaline phosphatase (ALP) activity and ALP expression of the cells with 100 % ß-TCP granules were more increased than the those of cells with 100 % HA and TCP/HA (80 %/20 %) at the baseline or when treated with 15 ng/ml of rhBMP-2. In an SD rat calvarial defect model, new bone formation was evidently shown in the TCP 100 %-rhBMP-2 and TCP/HA (80 %/20 %)-rhBMP-2 groups, showing that the most affected area was filled with newly-formed bone, that the percent bone volume and trabecular number were larger when compared to the groups without rhBMP-2 treatment at both 4 and 8 weeks after surgery using micro-CT and histology. Porous TCP-based ceramic granules enhanced the osteoblastic differentiation in the hMSC system when treated with 15 ng/ml of rhBMP-2 and accelerated bone-healing by trabecular number in a rat calvarial defect model. Thus, in this study it was proposed that TCP-based ceramics might be useful carriers of rhBMP-2.

Fabrication and evaluation of porous beta-tricalcium phosphate/hydroxyapatite (60/40) composite as a bone graft extender using rat calvarial bone defect model.

Beta-tricalcium phosphate ( ß -TCP) and hydroxyapatite (HA) are widely used as bone graft extenders due to their osteoconductivity and high bioactivity. This study aims to evaluate the possibility of using porous substrate with composite ceramics ( ß -TCP: HA = 60% : 40%, 60TCP40HA) as a bone graft extender and comparing it with Bio-Oss. Interconnectivity and macroporosity of ß -TCP porous substrate were 99.9% and 83%, respectively, and the macro-porosity of packed granule after crushing was 69%. Calvarial defect model with 8 mm diameter was generated with male Sprague-Dawley rats and 60TCP40HA was implanted. Bio-Oss was implanted for a control group and micro-CT and histology were performed at 4 and 8 weeks after implantation. The 60TCP40HA group showed better new bone formation than the Bio-Oss group and the bone formation at central area of bone defect was increased at 8 weeks in micro-CT and histology. The percent bone volume and trabecular number of the 60TCP40HA group were significantly higher than those of Bio-Oss group. This study confirms the usefulness of the porous 60TCP40HA composite as a bone graft extender by showing increased new bone formation in the calvarial defect model and improved bone formation both quantitatively and qualitatively when compared to Bio-Oss.