## 3 Discussion
Thus, 6% sodium hypochlorite is related to a significant reduction in survival and dentin sialophosphoprotein gene expression, while these effects can be prevented with the use of lower NaCl concentrations [37]. Further studies should follow standardized and evidence-based protocols. The papilla apical is a soft tissue rich in mesenchymal stem cells (stem cells from apical papilla--SCAPs) that are able to survive even after a prolonged periapical infection [38; 39]. The epithelial-mesenchymal interaction between the apical papilla and the Hertwig epithelial root sheath (HERS), the proliferation of epithelial cells located at the cervical loop of the enamel organ, coordinates the radicular development of the immature teeth. Thus, radicular development requires the survival and interaction of such embryological structures. It has been reported that in all cases treated with RET, trauma is the most frequent etiology for pulp necrosis, followed by developmental dental anomalies [40]. In the included studies in this systematic review, the cause of pulp necrosis was trauma in all except one tooth that had a _dens evaginatus_, while caries was the cause of pulp necrosis in no teeth. A previous study suggested that trauma was associated with worse outcomes after regenerative endodontics compared to _dens evaginatus_, possibly due to the damage to the Hertwig epithelial root sheath and apical papilla stem cells [41]. Although this was rejected in a recent systematic review and meta-analysis that found no statistical differences in the success rate related to the cause of pulp necrosis [42], further studies should assess whether this also applies to teeth previously treated with regenerative endodontics that undergo orthodontic treatment. Despite the high prevalence of adverse effects and need for further intervention in the included studies, one of the case reports with a remarkably compromised tooth was successful [31]. Before treatment, the tooth had a history of triple trauma, root fracture, and a sinus tract that had not completely healed when orthodontic treatment was initiated. The teeth presented with no adverse effects and no need for further intervention after 5.5 years of the orthodontic treatment. Moreover, the sinus tract and root fracture were healed after the orthodontic treatment. There is a lack of comparative studies to establish whether teeth treated with RET in the past and subjected to orthodontic treatment are at higher risk of adverse effects comparedwith non-RET treated teeth. Should that association exist, there is a need to establish the factors influencing the outcomes. Possible factors that would need further investigation are related to the characteristics of the tooth, such as the cause of pulp necrosis, type of teeth, presence of preexisting periapical lesions, and others; the regenerative endodontic procedure, such as the medications used and the time lapse between RET and orthodontic treatment; and the characteristics related to the orthodontic treatment, such as the duration of the treatment and the direction and magnitude of the forces applied to the tooth, among others. Apparently, there is a high prevalence of adverse effects and a need for further intervention in teeth previously treated with regenerative endodontics that undergo orthodontic treatment, although tooth survival is high. However, all the review findings should be taken with caution, since the certainty of the evidence is very low. The evidence is insufficient to advise clinicians whether orthodontic treatment affects the survival and morbidity of these teeth. Until a higher level of evidence is achieved and whenever possible, clinicians may avoid the inclusion of these teeth in the archive during the orthodontic treatment or submit these teeth to a low magnitude of orthodontic force. If such teeth are included in the orthodontic treatment, follow-up intervals should be shortened in order to detect possible adverse effects early.