THE CRITICAL ROLE OF GEOMETRY OF POROUS HYDROXYAPATITE DELIVERY SYSTEM IN INDUCTION OF BONE BY OSTEOGENIN, A BONE MORPHOGENETIC PROTEIN

The collagenous extracellular matrix of bone obtained after dissociative extraction with 4 M guanidine-HCI is an optimal substratum for bone induction by osteogenin, a bone morphogenetic protein. As a proteinaceous substratum, this matrix and other collagen-based materials may be immunogenic. Thus, the search and discovery of a non-immunogenic substratum is a necessary prerequisite for the therapeutic application of the principle of bone induction to skeletal repair. Bovine osteogenin, purified greater than 50,000-fold and with an apparent molecular mass of 28-42 kilodaltons, was delivered into nonresorbable porous hydroxyapatite in granular and disc configuration. A total of 328 preparations were bioassayed for osteogenic activity by subcutaneous implantation into 164 Long-Evans rats. Specimens were harvested at day 7, 11 and 21 after implantation and subjected to alkaline phosphatase activity determination and histologic analysis. Osteogenin combined with discs of porous hydroxyapatite induced in vivo differentiation of the osteogenic phenotype in mesenchymal cells invading the three-dimensional porous space of the inorganic substratum. The geometry of the substratum had a profound influence on bone induction, since the expression of the osteogenic phenotype was solely confined in porous hydroxyapatite with disc configuration. Osteogenin did not induce bone differentiation when combined with granules of porous hydroxyapatite with identical pore dimensions. The finding that the biological activity of osteogenin can be restored and delivered by a substratum with defined geometry other than the insoluble collagenous matrix may form the basis of the potential therapeutic application of bone morphogenetic proteins.