title: Bone healing in the rat and dog with nonglycosylated BMP-2 demonstrating low solubility in fibrin matrices.
abstract: 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 microg 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 microg/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.
authors.affiliation: Department of Materials and Institute for Biomedical Engineering, Swiss Federal Institute of Technology (ETH) Zurich and the University of Zurich, Zurich 8000, Switzerland. hugo.schmoekel@kkh.unibe.ch
authors.forename: Hugo
authors.initials: H
authors.lastname: Schmoekel
authors.forename: Jason C
authors.initials: JC
authors.lastname: Schense
authors.forename: Franz E
authors.initials: FE
authors.lastname: Weber
authors.forename: Klaus W
authors.initials: KW
authors.lastname: Grätz
authors.forename: Dania
authors.initials: D
authors.lastname: Gnägi
authors.forename: Ralph
authors.initials: R
authors.lastname: Müller
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
mesh_terms: D000818:Animals; D001174:Arthrodesis; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology*; D002350:Carpus, Animal / Q000187:drug effects* / Q000293:injuries / Q000473:pathology / Q000601:surgery; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005337:Fibrin; D017102:Fracture Healing / Q000187:drug effects*; D006031:Glycosylation; D016348:Osseointegration / Q000187:drug effects*; D011446:Prospective Studies; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D012886:Skull / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D012995:Solubility / Q000187:drug effects; D016212:Transforming Growth Factor beta
chemical_list: C525718:BMP2 protein, human; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D005337:Fibrin