Sintered porous hydroxyapatites with intrinsic osteoinductive activity: geometric induction of bone formation

Abstract

Sintered hydroxyapatites induce bone formation in adult baboons via intrinsic osteoinductivity regulated by the geometry of the substratum. Bone is thereby formed without exogenous bone morphogenetic proteins (BMPs), well-characterized inducers of bone formation. Monolithic discs of sintered hydroxyapatite, fabricated with concavities of 800 and 1600 mu m diameter on both planar surfaces, were implanted in the rectus abdominis of the baboon (Papio ursinus). Histology on days 30 and 90 revealed de novo generation of bone exclusively within the concavities of the substratum. Porous hydroxyapatites were subsequently fabricated by impregnating polyurethane foams with slurry preparations of powdered hydroxyapatite, so that porous spaces formed by the coalescence of repetitive sequences of concavities. Artefacts were sintered in rod and disc configurations for implantation in heterotopic intramuscular sites and orthotopic calvarial sites, respectively. In four specimens, bone had formed in concavities of the substratum 30 days after implantation in the rectus abdominis. On day 90, bone morphogenesis with associated marrow had occurred in 33 specimens (41 %). Calvarial specimens showed substantial bone formation, culminating in complete penetration of bone within the porous spaces. On day 30, the immunolocalization of BMP family members (BMP-3 and OP-1/BMP-7) in cellular material at the hydroxyapatite interface suggests that the sintered ceramic may act as a solid-state matrix for adsorption of endogenously produced BMPs. These experiments demonstrate intrinsic osteoinductivity by monolithic and porous sintered hydroxyapatites implanted in heterotopic sites of adult primates, and that the geometry of the substratum profoundly regulates the expression of the osteogenic phenotype. The incorporation of specific biological activities into biomaterials achieved by manipulating the geometry of the substratum, defined as geometric induction of bone formation, will help engineer morphometric responses for therapeutic osteogenesis in clinical contexts.