Cells along the osteogenic differentiation pathway may be artificially categorized as (1) undifferentiated MSCs, (2) osteo-chondro-progenitor cells, (3) pre-osteoblasts, and (4) osteoblasts; although in reality, a developmental continuum without distinct boundaries may exist [43]. While pre-differentiated osteoblasts in the marrow compartment only play a minor role in bone wound healing, a more prominent role is that of undifferentiated MSCs which are recruited to the regeneration site where they differentiate into osteoblasts [16]. The recruitment and differentiation of MSCs is regulated by CKs and GFs [17,19]. The GFs most commonly implicated in bone wound healing are BMPs, members of the TGF-β family, PDGF, and IGF-1 [19,20]. Moreover, the bone debris created during implant surgery, the peri-implant blood clot (i.e., platelets) and the differentiating MSCs themselves further contribute to release of GFs at the site [44,45].

All studies reported some evidence of osteogenic differentiation at an early time point (day 3 or 4) via expression of genes associated with key growth factors (bone morphogenetic proteins (BMP4, BMP6, BMP2-kinase), growth and differentiation factor-10 (GDF10), transforming growth factors (TGF-α, TGF-β), platelet-derived growth factor (PDGF), and insulin-like growth factor-1 (IGF1)), transcription factors (Runx2, Osx, Dlx3, Dlx5, Msx1, HOX genes, Sp1, Sp3), and/or osteogenic signaling pathways (TGF-β/BMP signaling, Wnt-receptors, Ras-protein/mitogen-activated protein kinase (Ras/MAPK) signal transduction). In all studies, these genes were further upregulated at day 7. Upregulation of osteogenic factors seemed regulated by implant surface. The key transcription factor osterix (Osx) was upregulated on the Osseospeed surface, but not TiOBlast at day 7 [36], while tissues adjacent to SLActive surfaces demonstrated comparatively greater BMP and Ras/MAPK expression compared to SLA surfaces at day 7 [35]. Previous in vivo animal studies have reported correlations between upregulated osteogenic gene expression in peri-implant tissues and enhanced histological and biomechanical measures of osseointegration during early (1- to 4-week) healing times [27,46]; nevertheless, it is unclear whether upregulation and/or overexpression of genes at a specific time point directly correlates to increased protein production in vivo.