## 4 Discussion  
The present research into the literature aimed at systematically reviewing the existing literature about the use of local doxycycline as an adjunct to standard nonsurgical treatment for the management of peri-implantitis. The lack of comparability among the included studies (also due to the heterogeneity in study protocols) and the absence of a higher number of RCTs prevented the authors from performing a quantitative synthesis of the available data. However, on the basis of the available results, it can be stated that the local application of doxycycline may be considered as a promising treatment option in the nonsurgical phase of management of peri-implantitis, although a larger amount of confirmative research is needed to give more strength to the recommendation. The results of the review should be read in the light of previously published literature also about the use of this antibiotic for treating periodontal disease, to weigh their external validity. The pivotal review of the literature published by [PERSON] and coworkers in 2020 [7] analyzed data from three studies that used local doxycycline for treating periodontal pockets in a total of 232 patients. In the meta-analysis, the test group resulted in a significantly higher PPD reduction than control group, with 0.283 mm on average after 6 to 12 months, and higher CAL gain of 0.408 mm in the same follow-up period. Two of the included studies revealed a significant improvement in the periodontal parameters [15; 16], and one of the studies explored the treatment of function defects during the supportive periodontal care [16]. One of the studies included in the meta-analysis did not find any significant difference between the test and control group, failing to find any adjunctive effect of using local doxycycline applications [17; 18]. In the study by [PERSON] et al., the behavior of tetracyclines is described, with a particular focus on several molecules within this antibiotic class, including doxycycline. Although the article does not specifically address the effect of doxycycline on bacterial biofilm in the oral cavity, a key factor in peri-implant diseases, it provides the mean minimal inhibitory concentration (MIC) of doxycycline against the pathogens most sensitive to this molecule (see Table 2) [19]. The recently published study by [PERSON] and coworkers investigated the influence of locally delivered doxycycline on the inflammatory status of periodontal intrabony defects before periodontal regeneration [20]. The authors could demonstrate that the number of sites presenting bleeding at the end of the nonsurgical phase was significantly lower in the test sites than in control ones and that there was a significant decrease, more evident in the test group, of several inflammatory cytokines, such as IL-1b, MMP-8, and MMP-9,that are very often correlated with the presence of periodontal inflammation [20]. Such an improvement resulted in better soft tissue healing outcomes two weeks after surgeries. In the study published in 2020, [PERSON] and coworkers treated a sample made exclusively of type-2 diabetics with periodontal disease with nonsurgical subgingival instrumentation and adjunctive 20% doxycycline [21]. In this particular cohort, the experimental group showed higher improvements in BoP, PPD, and CAL in the short term as compared to control group. Moreover, confirming the results obtained by [PERSON] et al., the group treated with adjunctive doxycycline presented a significant reduction in periodontal pathogens and inflammatory cytokines. Interestingly, the level of HbA1c decreased more in the treatment group [21]. Considering the studies included in the present review on peri-implant defects, the results obtained, although applied in a slightly different clinical condition, were comparable to those obtained in the previously cited papers on periodontal defects, since both peri-implantitis and periodontitis presented a similar (not identical) inflammatory pattern [22; 23].