###### Abstract  
Simvastatin embedded into poly(lactic-co-glycolic acid) (PLGA)-based scaffolds can stimulate bone regeneration in preclinical models. However, the ideal pharmacological dose has not been evaluated. This systematic review reports on the simvastatin doses used in preclinical studies and evaluates the regeneration of critical-sized bone defects. References were selected in a two-phase process. Electronic databases (Embase, LILACS, LIVIVO, PubMed, SCOPUS, and Web of Science) and grey literature databases (Google Scholar, Open Grey, and ProQuest) were searched until September 2022. The risk of bias was considered to be low based on the SYRCLE tool. We identified four studies in rat, two in parietal and two in calvaria bone, one in mouse parietal bone, and one in rabbit femur bone. Simvastatin, ranging from 8 to 100 \(\upmu\)g, significantly increased bone formation in five studies, as compared to the scaffold alone based on \(\upmu\)-computed tomography, histomorphometric, and radiography analysis. The median increase in bone formation caused by simvastatin was 2.1-fold compared to the PLGA-based scaffold alone. There was, however, no significant correlation between the relative bone gain and the doses of simvastatin (\(p=0.37\)). The data suggest that relatively lower doses of simvastatin can consistently promote preclinical bone regeneration. However, the interpretation of these data must consider the heterogeneity of the PLGA-scaffolds, the defect anatomy, the observation period, and the evaluation method.  
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that enhance bone regeneration are still lacking in clinical applications. Consequently, vertical bone augmentation is still a challenge in cranioxillofacial region [3; 4; 5].  
Among the biodegradable polymers for drug delivery, the poly(lactic-co-glycolic acid) (PLGA) has shown great potential due to its biocompatibility, biodegradability, flexibility, minimal side effects [6], favorable degradation characteristics, and the ability for sustained drug delivery [7; 8]. Additionally, the US Food and Drugs Administration (FDA) and European Medicine Agency (EMA) approved the use of PLGA in various drug delivery systems [9; 10]. Changes in PLGA proprieties also influence the release and degradation rate of the embedded substances. Therefore, it is possible to tune the overall physical properties of the polymer-substance matrix by controlling relevant parameters, such as the ratio of lactic to glycolide, the polymer molecular weight, and substance dose to achieve the desired dosage and release interval [7; 11].  
Simvastatin (SIM), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is used to reduce blood cholesterol levels [11; 12], and has been extensively investigated due to its pleiotropic effects, such as angiogenic, immunomodulatory, and anti-inflammatory properties [12; 13; 14]. Additionally, SIM promotes osteogenic differentiation and increases bone formation [8; 15; 16; 17]. Furthermore, it is relevant to emphasize that SIM in-site applications require a suitable carrier to allow for its controlled release, thus preventing burst release, drug degradation, and exacerbated inflammatory responses [14; 18].  
Despite several studies reporting the efficacy of SIM embedded into PLGA-based scaffolds for bone formation, the dose of SIM required to promote bone formation through local drug delivery systems is not fully elucidated. This systematic review aimed to critically discuss the available scientific evidence to answer the following focused question: \"What is the appropriate SIM dose embedded into PLGA-based scaffolds required to promote bone formation in critical-sized bone defects?\"