## 4 Discussion  
Considering that bone regeneration is still a challenge in oral and maxillofacial surgeries, the search for biomaterials and predictable techniques that enhance bone regeneration continues [26]. Since SIM has been proposed to support bone formation, drug delivery systems were evaluated [27; 28]. This systematic review evaluates the SIM dose embedded into PLGA-based scaffolds necessary to promote bone regeneration in preclinical models. We observed that, from the six included studies, five studies confirmed SIM embedded into PLGA-based scaffolds promotes bone formation. The required dose ranged from 8 to 50 \(\upmu\)g SIM/scaffold in rodents, and 100 \(\upmu\)g SIM/scaffold in rabbit. In one study, SIM failed to support bone regeneration. This review may contribute to the experimental design of future studies on SIM in bone regeneration.  
Adequate drug release from scaffolds is critical for bone formation, and efforts to find an appropriate SIM dosing and delivery system are made [29]. High SIM doses are associated with an exacerbated inflammatory responses and impaired bone formation [24; 30; 31], also due to cytotoxicity and blocked cholesterol synthesis [32; 33]. Conversely, low SIM doses may not reach the pharmacologically relevant concentration. In this context, three articles evaluated SIM release varying from 4% (1 day) [8], 15% (2 days) [18], to >60% (7 days) [25]. Moreover, SIM release of approximately 30% in 30 days [8], 23% in 56 days [18], and 100% in 21 days [25] was reported. Drug release from PLGA can be controlled by varying the molecular weight and the ratio of lactic to glycolide [11]. Different ratios of lactic to glycolide were used to produce the PLGA scaffolds. The proportion most often used was 50:50 [23; 25; 28], followed by 82:18 [22], 85:15 [18], and 75:25 [24]. One article did not report the lactic to glycolic ratio [8]. Thus, the lactic-to-glycolic rations may affect the SIM release kinetic and, consequently, the bone regeneration capacity in vivo.  
Concerning the RoB judgment, a low RoB was attributed to most items evaluated. Low RoB judgments denote that none or minor methodological flaws occurred in the assessed studies. Consequently, none or small deviations from the true effect estimation befallen, providing confidence in interpreting the results [34]. No study reports whether or not the allocation sequence was adequately generated and applied, as well as whether or not the caregivers/investigators and outcome assessors were blinded to the intervention [8; 18; 22; 24; 25]. The animals selected at random for outcome assessment also remained unclear [8; 18; 22; 24; 25]. Future studies should put more emphasis on reporting methodological details.  
Regarding the limitations of this review, only PLGA-based scaffolds were evaluated. Thus, further studies assessing the dose and release of SIM embedded into different scaffolds are required. The included studies used \(\upmu\)CT, histological, and radiographical analysis to quantify the bone regeneration. Due to high-resolution 3D information, \(\upmu\)CT is the most reliable to evaluate bone regeneration [35; 36]. Moreover, \(\upmu\)CT provides information concerning the volume, texture, and external and internal structures of the implanted scaffold. Histological analysis, however, is ideal to study the cellular aspects of bone regeneration, hence any potential adverse effects of the scaffold [37]. Further studies assessing the dose of SIM embedded into scaffolds with different chemical compositions than PLGA are suggested. Additionally, the evaluation of SIM doses used clinically is proposed.