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Although alveolar bone resorption after the tooth extraction is unavoidable, the preservation of alveolar ridge has been expected. The dihydropyridine-type calcium channel blocker, benidipine (BD) has been widely used as an antihypertensive, and recently some reports indicated the anabolic effect of BD on bone. We novelly developed BD-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres with sustained-release characteristics as a possible socket preservative. The aim of the present study was to examine the effect of BD on bone healing using rodent tooth extraction model with newly-developed drug delivery system. In parallel, the effect of BD on the gene expression of hard and soft tissue cells was examined using culture study. The maxillary right first molars of 5-week-old Wistar rats were extracted and immediately injected the suspension of BD-loaded (or non-loaded as a control) PLGA microspheres once, into the gingivobuccal fold just proximal to the socket. At days 1, 3, 7 and 28 after the injection, the extraction socket healing was histologically evaluated. As culture studies, the effect of BD on the proliferation of osteoblast (MC3T3-E1), osteocyte (MLO-Y4), fibroblast (NIH3T3) and gingival epithelial cell (GE1) was measured at the concentrations of 0, 0.1, to 10000 nM. The effect of BD on cell migration was also observed in fibroblastic and gingival epithelial cell culture. Real-time RT-PCR array assay was performed using osteoblastic and osteocytic cell culture with the concentration of 100 nM BD. Animal study revealed that the single injection of BD-loaded PLGA microspheres significantly augmented bone volume and density at the extraction socket. In vitro study demonstrated that BD significantly promoted the proliferation of every tested cell. BD also enhanced the cell migration of NIH3T3 and GE1. RT-PCR assay indicated that BD up-regulated the mRNA expressions of Ahsg and Csf-2 in MC3T3-E1 and Bmp4 and Bmp6 in MLO-Y4. This study demonstrated that a single topical application of BD-loaded PLGA microspheres promoted extraction socket healing in vivo. Culture study exhibited the BD accelerating both proliferation and migration of bone and soft tissue cells. The expressions of some genes were activated, consistent with the evidence that BD group had an anabolic effect on bone metabolism. These results presented possibilities of BD as a locally-administrable socket-preservative or anti-bone resorption agent.
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