In the current investigation, we report osseous regeneration in critical-size rat calvarial defects using recombinant human bone morphogenetic protein-2 (rhBMP-2) and novel delivery systems based on biomaterials. The novel systems combine rhBMP-2 with dry powder microparticles of poly(D,L-lactide-co-glycolide) (PLGA). The mixture of rhBMP-2 with PLGA microparticles is added to an aqueous solution of biopolymer to yield a semisolid paste. The biopolymers tested include autologous blood clot, hydroxypropyl methylcellulose, and sodium alginate cross-linked with calcium ion. Insoluble collageneous bone matrix was also studied as a control. Test articles were made at 0-, 10-, and 30-micrograms doses of rhBMP-2 and imiplanted in 8-mm-diameter rat calvarial defects (which will not heal if left untreated). The animals were examined 21 days after implantation by radiography, radiomorphometry, histology, and histomorphometry. All tested materials containing rhBMP-2 restored radiopacity and normal contouring to the calvarial defects. Samples without added rhBMP-2 yielded only soft tissue within the defects. Histology showed restoration of inner and outer bone tables plus marrow constituents. The PLGA microparticles were significantly resorbed at the 21-day time point. Although small differences between delivery systems were evident at 0- and 10-micrograms rhBMP-2 doses, all test articles performed essentially equivalently at the 30-micrograms dose. Thus, novel delivery systems for rhBMP-2 offer the promise of combining the intrinsic bioactivity of the osteoinductive protein with pharmaceutically acceptable biomaterials.
The purpose of this study was to measure bone-regenerative effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) in rat calvarial critical-size defects (CSDs). CSDs (8 mm in diameter) were treated with either 1) 2.2 micrograms rhBMP-2 combined with insoluble collagenous bone matrix (ICBM), 2) 6.5 micrograms rhBMP-2 plus ICBM, 3) ICBM alone, or 4) demineralized bone matrix (DBM), for 7, 14, or 21 days. Multiple linear regression showed that rhBMP-2 had a significant time- and dose-dependent effect on bone regeneration (P < .05). After 7 days, new calcifying cartilage and remineralizing ICBM, with an occasional zone of new woven bone, was evident in defects treated with rhBMP-2/ICBM. By 14 days, both doses of rhBMP-2 reconstituted with ICBM had induced more bone formation than ICBM alone or DBM, and 6.5 micrograms was superior to 2.2 micrograms. There was no evidence of adverse cellular response. This study shows for the first time that rhBMP-2 could restore osseous form to a calvarial defect. In addition, osteoregeneration was accelerated by the higher dose of rhBMP-2.
Trauma, disease, developmental deformities, and tumor resection frequently cause bone defects that seriously challenge the skills of orthopedic and maxillofacial surgeons. Currently, repairing osseous deficiencies involves various medical surgical techniques, including autogenous grafts, allografts, internal and external fixation devices, electrical stimulation, and alloplastic implants. The existing technology, though effective in many cases, still is beset with numerous difficulties and disadvantages. A critical need for improved treatment methods exists today. Biotechnology now provides access to new bone repair concepts via administration of protein growth and morphogenic factors. Implantable device and drug delivery system technologies also have advanced. The converging biopharmaceutical, device, and delivery technologies represent an opportunity to improve the quality of health care for individuals with orthopedic and maxillofacial deficiencies. This report reviews current concepts in fracture healing and bone repair and examines existing treatment modalities. It also addresses novel protein drugs that stimulate osseous regeneration and delivery systems for these drugs.
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