Implant rehabilitation of edentulous patients is a predictable treatment with high long-term survival rates (90-95%) reported for the major dental implant systems after 5-10 years in function. Throughout recent years, different materials, implant surface technologies, macrodesigns, and surgical techniques have been developed to enhance osseointegration and lessen treatment timeframes, for example allowing immediate or early functional loading in patients with reduced bone density. In regards with implant surface properties, hydrophilicity ensures a more rapid coverage of the implant surface with blood and biological fluids, and a faster blood clot formation; this, in combination with the synergistic effect of micro- and/or nanotopography of the implant surface, lead to faster resolution of inflammation and positive modulation of osteogenesis, in turn enhancing the rate and quality of bone-to-implant contact (BIC). Specifically, a novel modification of sandblasted, dual acid-etched surface (SAE) implants to increase hydrophilicity (SAE-HD) has been suggested to enhance osseointegration during the early healing period in a preclinical in vivo model of rabbit tibia in comparison to the hydrophobic SAE surface. However, its histomorphometrical parameters of osseointegration and biomechanical properties have not been investigated in large animal platforms of low- and high-density bone. Furthermore, there is limited knowledge regarding the possible combined modulatory impact of implant macrogeometry and surface hydrophilicity on osteoclastogenesis. In regards with the surgical technique for implant installation, contemporary practice dictates that the implant site is prepared slightly narrower than the implant diameter as per standard (i.e. there is slight mismatch of the inner and outer implant diameter in relation to the drilled bone walls with the implant threads engaging with the bone in the pursuit of high primary implant stability, as measured by maximum insertion torque values (ITV). However, excessive lateral compression of highly-dense trabecular bone and thick cortex has been shown to cause microdamage and necrosis, triggering extensive interfacial bone remodeling, which in turn negatively affects the biomechanical competence of the implant site throughout the healing period. Recently, an oversized drilling technique has been proposed, where the final drill for site preparation has similar or slightly larger diameter than that of the inner implant diameter; this creates closed “healing chambers” between the inner implant diameter and the surgically instrumented bone wall. It is suggested that in spite of low ITV achieved with this surgical approach, the osteoconductive properties of modified implant surfaces positively modulate host-to-implant interactions and enhance osseointegration. However, research to date appears remarkably controversial on this topic, while studies reporting on marginal peri-implant bone levels (MBL) of highly dense bone are limited. The general aim of the present thesis was to evaluate the possible impact of aspects of current oral implant technology, i.e. surface hydrophilicity, implant macrogeometry, and surgical preparation of the implant recipient site, on implant osseointegration. Specifically, it was hypothesized that:•Implants with a chemically modified micro-rough surface would achieve higher BIC and interfacial shear strength in comparison to hydrophobic implants. •Oversized implant recipient sites, by applying sequential profiling and/or tapping of the bone, would promote higher amount and better quality of osseointegration in comparison to undersized-drilled sites.In study I and II, histomorphometrical parameters (BIC and relative peri-implant bone density [BD]) and biomechanical properties (removal torque value [RTV], removal energy, and connection stiffness]) at SAE (control) and SAE-HD (test) implants were assessed at early stages of osseointegration. Two pairs of SAE and SAE-HD implants, of same microgeometry, were installed bilaterally in the proximal tibia of six Beagle dogs and assessed after 2 and 4 weeks of healing. In study I, histomorphometrical parameters were analyzed on non-decalcified sections. In study II, the removal torque test (RTQ) was conducted on a Shimadzu universal testing machine. Results showed that BIC, BD, RTV, and removal energy increased with time in both SAE and SAE-HD implants. No significant differences were observed between the two groups for any of the evaluated parameters and at any observation time-point but a slight increase over time during the early osseointegration period. In study III, the influence of the implant thread design (trapezoidal vs. triangular threads) and surface hydrophilicity (SAE-HD vs. SAE) on osteoclast (OC) differentiation, activation, and survival was evaluated in vitro in a model of RAW 264.7 cells. Titanium disks with SAE or SAE-HD surface and different macrodesign, comprising of trapezoidal (HLX) or triangular threads (TMX) were used: HLX/SAE-HD, HLX-SAE, TMX/SAE-HD, and TMX/SAE. RAW264.7 macrophages were seeded on the disks, differentiated to OC by RANKL treatment and cultured for 5 days. OC differentiated on polystyrene plates were used as positive controls [CCPC (+)]. OC differentiation and viability were assessed by enzymatic TRAP activity and MTT assays. Expression levels of various OC-related genes were measured at the mRNA level by qPCR. SAE-HD surfaces negatively modulate macrophage/osteoclast viability. Specifically, SAE-HD with triangular threads increases the cellular pro-inflammatory status, while surface hydrophilicity and macrodesign do not seem to have a distinct impact on OC differentiation and activation in vitro in a model of RAW 264.7 cells.In study IV, the current evidence on the effects of oversized surgical preparation of the implant site in terms of biomechanical properties (ISQ, ITV, and RTV) and biological parameters of osseointegration (BIC and BD) was systematically assessed in preclinical animal studies. Electronic databases were searched for preclinical in vivo controlled studies reporting on drilling techniques according to the relative implant-final drill discrepancy (IDD; mm), defined herein as the dimensional mismatch between the outer implant diameter and the bone wall in the implantation bed: (1) control ≥ 0.2 mm (press-fit/standard to undersized implant drilling technique); (2) test OD = 0.0 – 0.1 mm (oversized drilling technique to achieve either nearly or precisely similar dimension between the bone defect and the implant outer diameter); and (3) test GAP ≤ –0.1 mm (oversized drilling technique presenting a gap between the bone defect and the implant outer diameter). Random effects meta-analyses were performed for the outcomes ITV, RTV, BIC, and BD at different healing periods. Evidence from 12 studies indicate that oversized surgical preparation of the implant site appears to minimize marginal bone resorption characterized by fast rates of new bone formation in the healing chambers through an intramembranous-type healing mode. However, in terms of biological and biomechanical parameters of osseointegration, oversized implant sites does not seem to provide any additional benefit compared to narrower implant sites, neither at the time of implant placement nor during the early healing period, yielding comparable results at the late post-operative period in different experimental animal models. In study V, the effect of oversized surgical preparation of the implant site on histomorphometrical parameters of osseointegration (BIC and BD) and marginal peri-implant bone level (MBL) of tapered implants with a progressive thread geometry was evaluated following 12 weeks in vivo in the mandible of minipigs. Ten implants with hydrophilic surface (SAE-HD) were inserted in the edentulous mandible of each of 5 female minipigs, by applying different drilling protocols (standard [SD, control] vs. oversized [OD, test]). SD included a 3-step series of drills without profiling of the cortical bone (IDD = 0.3 mm). OD included a 5-step series of drills and profiling of the cortical bone which resulted, respectively, in two IDD along the implant axis: (1) IDD = 0.1 mm in the 8-mm central apical length of the osteotomy; and (2) IDD = 0.0 mm in the 3.5-mm coronal length. Maximum ITV was recorded and non-submerged healing was allowed for 12 weeks (n = 5). Oversized surgical preparation of the implant site yielded low ITV at tapered implants with a progressive thread geometry, but enhanced osseointegration and peri-implant bone density, and preserved better the MBL.