The effect of the release behavior of simvastatin from different PLGA particles on bone regeneration in vitro and in vivo: Comparison of simvastatin-loaded PLGA microspheres and nanospheres

Abstract

Simvastatin is a cholesterol-lowering drug known to affect bone formation in vivo and its sustainable administration into localized areas is of particular interest in the dental field. Two simvastatin-loaded poly(lactic-co-glycolic acid) (PLGA) formulations (PLGA microspheres and PLGA nanospheres) were compared to investigate whether a sustainable supply of simvastatin from a PLGA-based carrier is effective for bone regeneration. PLGA microspheres successfully presented sustained release of simvastatin for one month, whereas simvastatin was continuously released from PLGA nanospheres for one week. The difference of drug release pattern between two PLGA particles was confirmed by Korsmeyer–Peppas mathematical model. PLGA microspheres and simvastatin alone (no carrier) induced the proliferation MC3T3-E1 cells and increased alkaline phosphatase (ALP) activity, a differentiation marker of MC3T3-E1 cells, whereas PLGA nanospheres did not. These results suggested that PLGA nanospheres had an adverse effect on bone generation in vitro due to the production of PLGA metabolized products. Both PLGA microspheres and PLGA nanospheres provided a bone formation effect in an in vivo rat calvaria bone defect model and PLGA microspheres were superior to PLGA nanospheres. Our data suggest that simvastatin-loaded PLGA microspheres can release simvastatin sustainably and induce bone formation more efficiently than PLGA nanospheres, thus promoting bone regeneration.