Novel, rapidly resorbable bioceramic bone grafts produce a major osteogenic effect - the pre-clinical evidence

摘要

Although autogenous bone grafts are currently the standard of care for bone reconstruction in implant dentistry, bone substitute materials are extensively studied in order to avoid harvesting autogenous bone. Recently, the use of tricalcium phosphate (TCP) and bioactive glass 45S5 particles as alloplastic bone graft materials for alveolar ridge augmentation and sinus floor elevation procedures has received increasing attention in implant dentistry. However, given the clinical findings with these current bone substitute materials there continues to be interest in bone substitute materials which degrade more rapidly, but still stimulate osteogenesis at the same time. As a result considerable efforts have been undertaken to produce rapidly resorbable bone substitute materials, which exhibit good bone bonding behaviour by stimulating enhanced bone formation at the interface in combination with a high degradation rate. This has led to the synthesis of a new series of bioactive, rapidly resorbable calcium alkali phosphate materials. These are glassy crystalline calcium alkali orthophosphates, which exhibit stable crystalline Ca2KNa(PO4)2 phases. These materials have a higher solubility than TCP and therefore they are designed to exhibit a higher degree of biodegradability than TCP. On this basis, they are considered as excellent alloplastic materials for alveolar ridge augmentation. In order to evaluate the osteogenic potential in vitro, we first examined the effect of various rapidly resorbable calcium alkali orthophosphate bone grafting materials on the expression of osteogenic markers characteristic of the osteoblastic phenotype in vitro and compared this behaviour to that of the currently clinically used materials β-tricalcium phosphate (TCP) and bioactive glass 45S5. These studies showed that several calcium alkali orthophosphate materials supported osteoblast differentiation to a greater extent than TCP. In specific, we were able to demonstrate that the glassy-crystalline calium alkali orthophosphate material GB9, which contains the crystalline phase Ca2KNa(PO4)2 and a small amorphous portion containing silica phosphate, had a significantly greater stimulatory effect on osteoblastic proliferation and differentiation when compared to β-TCP, preconditioned bioactive glass 45S5, and other calcium alkali orthophosphate materials of varying composition. Applying this type of in vitro assays is based on the hypothesis that enhanced osteoblastic cell differentiation in vitro leads to more expeditious and more copious bone formation at the bone-biomaterial interface in vivo. In order to test this hypothesis correlation of the in vitro and in vivo data is needed. This includes (1) correlating quantitative expression of the osteogenic markers in vitro with the amount of bone formed after bioceramics implantation. (2) Quantifying the expression of these markers in histological sections obtained from in vivo experiments in comparison to the expression of the various markers in vitro. To this end, we then examined the effect of the same selection of bioactive ceramics (previously studied in vitro) on osteogenic marker expression and bone formation after implantation in the sheep mandible and sinus floor in vivo. Of the various grafting materials studied, GB9 showed the best bone-bonding behavior and had the greatest stimulatory effect on bone formation and expression of osteogenic markers, while exhibiting the highest biodegradability. Consequently, these findings were in accordance with those of the preceding in vitro study, in which GB9 showed the greatest stimulatory effect on osteoblast differentiation in vitro. Since the cell adhesion and intracellular signaling events which lead to this stimulatory effect on osteogenesis are not fully understood, we then elucidated the mechanisms by which these bioactive bone substitutes stimulate the intracellular signalling pathways, which regulate osteoblast differentiation and cell survival. This