Bone induction by BMPs/OPs and related family members in primates - The critical role of delivery systems

Background: In a series of studies in the primate Papio ursinus, we have ex amined the capacity of bone morphogenetic proteins (BMPs/OPs) delivered in a variety of biomaterial carrier systems to elicit bone formation in hetero topic and orthotopic sites. In this review, we compare the osteoinductive e ffects of different biomaterial delivery systems that have or have not been pretreated with BMPs/OPs. In particular, we focus on the geometric inducti on of bone formation by sintered porous hydroxyapatite (SPHA) discs with co ncavities on their planar surfaces, which elicit bone formation without exo genously applied BMPs/OPs. Methods: Heterotopic bone formation was examined by bilaterally implanting 100-mg pellets of a collagenous carrier containing BMPs/OPs in the rectus a bdominis muscle of the adult baboon. Orthotopic bone formation was examined by implanting 1 g of a collagenous carrier containing BMPs/OPs into two fu ll-thickness critical-sized 25-mm-diameter defects on each side of the calv aria of adult baboons. The BMPs/OPs whose effects were examined included re combinant human osteogenic protein-1 (rhOP-1), recombinant human transformi ng growth factor-pr (rhTGF-beta1), rhTGF-beta2, and porcine platelet derive d transforming growth factor-beta1 (pTGF-beta1). Tissue from the rectus abd ominis muscle was harvested 30 or 90 days after implantation. Tissue from t he orthotopic calvarial model was examined at 1, 3, 6, 9, and 12 months aft er implantation. To demonstrate the effect of surface geometry on bone indu ction, hydroxyapatite powders were sintered to form solid discs with a seri es of concavities on the planar surfaces of the SPHA discs. The discs were either pretreated with exogenous rhOP-1 or not treated with exogenous OF-1. They were then implanted heterotopically or orthotopically into calvarial defects. Bone formation was evaluated histologically in undecalcified secti ons stained with Goldner's trichrome stain or 0.1% toluidine blue. Results: Naturally derived BMPs/OPs or rhOP-1 in a collagenous carrier elic it heterotopic bone formation and the complete healing of 25-mm-diameter cr itical-sized defects by day 90 following implantation. Binary applications of TGF-beta1 together with rhOP-1 in the collagen carrier induced massive e ndochondral ossicles in heterotopic sites and bone formation in calvarial d efects. pTGF-beta1, rhTGF-beta1, and rhTGF-beta2 are powerful inducers of h eterotopic endochondral bone formation but elicit limited bone formation in calvarial defects. SPHA discs pretreated with rhOP-1 elicited extensive bo ne formation in both heterotopic and orthotopic sites. However, SPHA withou t rhOP-1 also elicited bone formation in heterotopic and orthotopic sites a nd complete healing of the calvarial defects. Conclusion: We have prepared SPHA discs with concavities on their planar su rfaces that induce bone formation in heterotopic or orthotopic critical-siz ed calvarial defects without exogenously applied BMPs/OPs. This biomaterial induces bone formation by intrinsic osteoinductivity regulated by the geom etry of the substratum. The incorporation of specific biological activities into biomaterials by manipulating the geometry of the substratum, defined as geometric induction of bone formation, may make it possible to engineer morphogenetic responses for therapeutic osteogenesis in clinical contexts. Clinical Relevance: We have implemented a clinical trial using naturally de rived BMPs/OPs extracted and purified from bovine bone matrices and implant ed in craniofacial defects in humans. In addition, the discovery that speci fic geometric and surface characteristics of sintered hydroxyapatites can i nduce intrinsic osteoinductivity in primates paves the way for formulation and therapeutic application of porous substrata designed to obtain predicta ble intrinsic osteoinductivity in clinical contexts.