Thus, high risk of bias should be considered when interpreting the results, due to the above methodological limitations and the overall limited information (four studies) available.

Conventional implant surgery involves osteotomy preparation and insertion of the implant into the alveolar bone. The immediate local effects of this procedure, functionally relevant to subsequent healing processes, are (1) bone trauma, (2) formation of bone debris, (3) hemostasis and clot formation, and (4) hypoxia. These effects involve the release of specific CKs and GFs within the local environment [7], resulting in recruitment of two primary cell types to the site, inflammatory cells and progenitor cells (MSCs and HSCs) [19], which in turn regulate the subsequent healing processes. A summary of differentially regulated genes relating to the involved biological processes is presented in Table 4, while Figure 2 represents an evidence-based illustrative model summarizing these processes.

All studies reported a significant upregulation of genes associated with inflammation during the first time point of observation (day 3 or 4) regardless of the implant surface. Specifically, upregulation regarded pro-inflammatory cytokines of the interleukin (IL), tumor necrosis factor (TNF), and interferon (IFN) families, as well as genes associated with proliferation of lymphocytes and macrophages (MPs). Previous in vitro [40,41] and animal [42] studies have reported the significance of MPs at the bone-implant interface and identified favorable MP activity in relation to modified rough surfaces as demonstrated by in vitro gene expression that was associated with increased in vivo bone formation. Also, the nuclear factor-kB (NF-kB) inflammatory pathway was upregulated at day 4 [34], while macrophage activity and chemokines of the CCL and CXL families in the peri-implant tissues continued to remain prominent at day 7.

However, this inflammatory response was generally downregulated at later time points (day 7 or 14). For example, in one study, genes associated with pro-inflammatory cytokines (IL-1B, IL-1A, IL-1R2) and chemokines (CCL22, CCL18) were downregulated and upregulated, respectively, on day 7, at both implant surface technologies examined (Osseospeed and TiOBlast) [37]. Moreover, the anti-inflammatory response seemed to be modulated by surface properties. In one study, genes related to anti-inflammatory cytokines such as IL-9, IL-22, toll-like receptor inhibitor protein (TOLLIP), and several key chemokines (CCL18, CXCL10, CXCL18) were significantly upregulated on Osseospeed surfaces but not TiOBlast, at day 3 [36]. In another study, genes associated with inflammatory cell proliferation were significantly downregulated earlier on SLActive surfaces compared to the SLA, i.e., at day 7 instead of day 14 [35]. Therefore, the initial inflammatory response seems to be important for the recruitment of cells that govern subsequent healing processes and is regulated by a natural biological immune response which may be further modified by implant surface properties.