Bone healing in the rat and dog with nonglycosylated BMP-2 demonstrating low solubility in fibrin matrices

• Published in: Journal of orthopaedic research 2004-03, Vol.22 (2), p.376-381
• Main Authors: Schmoekel, Hugo, Schense, Jason C, Weber, Franz E, Grätz, Klaus W, Gnägi, Dania, Müller, Ralph, Hubbell, Jeffrey A
• Format: Article
• Language: English
• Subjects: Animals; Arthrodesis; BMP-2; Bone defect; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins - metabolism; Bone Morphogenetic Proteins - pharmacology; Carpus, Animal - drug effects; Carpus, Animal - injuries; Carpus, Animal - pathology; Carpus, Animal - surgery; Controlled release; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Fibrin; Fracture Healing - drug effects; Glycosylation; Osseointegration - drug effects; Precipitation; Prospective Studies; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Skull - drug effects; Skull - injuries; Skull - pathology; Solubility - drug effects; Transforming Growth Factor beta
• ISSN: 0736-0266; 1554-527X
• DOI: 10.1016/S0736-0266(03)00188-8

A novel form of recombinant human bone morphogenetic protein-2 (BMP-2) was explored for effective incorporation and long-term retention into fibrin ingrowth matrices. The solubility of native BMP-2 is greatly dependent on its glycosylation. To enhance retention of BMP-2 in fibrin matrices, a nonglycosylated form (nglBMP-2), which is less soluble than the native glycosylated protein, was produced recombinantly and evaluated in critical-size defects in the rat calvarium (group n=6). When 1 or 20 μg nglBMP-2 was incorporated by precipitation within the matrix, 74 ± 4% and 98 ± 2% healing was observed in the rat calvarium, respectively, as judged radiographically by closure of the defect at 3 weeks. More soluble forms of BMP-2, used as controls, induced less healing, demonstrating a positive correlation between low solubility, retention in vitro, and healing in vivo. Subsequently, the utility of nglBMP-2 was explored in a prospective veterinary clinical trial for inter-carpal fusion in dogs, replacing the standard-of-care, namely autologous cancellous autograft, with nglBMP-2 in fibrin. In a study of 10 sequential canine patients, fibrin with 600 μg/ml nglBMP-2 performed better than autograft in the first weeks of bone healing and comparably thereafter. Furthermore, a greater fraction of animals treated with nglBMP-2 in fibrin demonstrated bone bridging across each of the treated joints at both 12 and 17 weeks than in animals treated with autograft. These results suggest that evaluation in a human clinical setting of nonglycosylated BMP-2 in fibrin matrices might be fruitful.