In the present review, a significant simultaneous upregulation of several angiogenesis-related genes was identified at day 7 in all included studies. Pro-angiogenic factors (ANXA2, EPAS-1) were upregulated at TiOBlast and Osseospeed surfaces at day 7 [37]. Genes associated with VEGF and P13K-AKT signaling pathways were upregulated at SLActive (but not SLA) surfaces on day 7 and continued to be upregulated on day 14 [35]. The P13K-AKT pathway is reported to be important for endothelial cell survival, migration, and vessel formation, in addition to aiding VEGF-mediated angiogenesis [68]. Previous in vitro studies have reported the pro-angiogenic effects of SLActive surfaces by promoting VEGF expression in EPCs and osteoblasts [65,69], while enhanced histological osseointegration of SLActive implants has been directly correlated with increased angiogenesis in a dog model [70,71]. Thus, implant surface technology appears to have the possibility to also influence angiogenesis at early stages of wound healing.

Bone innervation includes both myelinated and unmyelinated nerve fibers located in the periosteum, bone cortex, Haversian systems, Volkmann’s canals, and the marrow spaces [72]. An interesting finding in the present review was the significant upregulation of genes associated with neurogenesis, more than any other biological process, on SLActive and SLA surfaces at all time points [34,35]. Specific processes represented were axon formation, growth and differentiation, and the neural signaling pathway. This is consistent with previous in vivo reports of murine fracture healing [73] and calvarial defect regeneration in relation to SLA surfaces [74,75]. Key neurotrophic factors (brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NTF3)), essential for neuronal survival and differentiation during development [76], were significantly upregulated on SLActive versus SLA surfaces at day 7 suggesting an effect of surface modulation. The P13K-AKT pathway, upregulated on SLActive surfaces (in relation to angiogenesis), has also been implicated in neuronal survival and subsequent neural development [77,78] and could have contributed to upregulation of neurogenic genes at these surfaces. Indeed, previous histologic reports have described changes in bone innervation after implant placement (and loading) and the presence of nerve fibers within the peri-implant bone, in animals and humans [79-81].