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SUMMARY Over the last decade, the focus of clinical implant research shifted from predominately survival orientated to peri-implant health and patient-centred outcomes. A stable peri-implant bone level is a prerequisite to achieve long-term implant success. Peri-implant bone level is affected by patient-, implant-, and site-specific factors. In addition, the success of an implant treatment could also be determined by the improvement in Oral Health-Related Quality of Life (OHRQoL). The introduction (Chapter 1) scrutinizes and clarifies the current literature focusing on these factors. The existing literature gives an ambiguous effect of implant-related and site-specific factors on peri-implant bone stability, showing the need for more research. Chapter 2 presents the aims of this dissertation. This thesis's first two literature studies (Chapter 3 and 4) systematically assessed the available scientific evidence. The assessment focused on whether commonly used biological parameters correspond to long-term outcomes of implant survival and reported peri-implantitis prevalence. Additionally, it also examined whether long-term peri-implant bone loss is affected by implant surface roughness. The clinical studies in this thesis (Chapter 5, 6, and 7) aimed to evaluate the effect of implant related factors such as implant micro-design (implant surface roughness), macro-design (microthreads and implant-abutment connection), and site-specific factors (soft-tissue thickness) on long-term peri-implant bone stability and peri-implant health. Additionally, we paid attention to the Oral Health-Related Quality of Life in patients restored with mandibular implant-retained overdentures. Chapter 3 (Study I) is a critical review of the literature published between 2011 and 2017, regarding the biological peri-implant parameters bleeding on probing, probing pocket depth, and bone loss. The search algorithm highlighted 4,173 papers available for further analysis, 255 papers for full article reading, and 41 fulfilled the inclusion criteria. In these 41 articles, 15 different case definitions for peri-implantitis were used. The reported prevalence of peri-implantitis ranged between 0% and 39.7%, with an overall mean weighted implant survival rate of 96.9% (89.9% - 100%). Based on 8,182 implants, the overall weighted mean bone loss was 1.1 mm after a loading time ranging from 5 to 20 years. The mean bone loss did not correlate with the reported prevalence of peri-implantitis, and the diagnostic parameters mean probing pocket depth and mean bleeding on probing. Moreover, the reported peri-implantitis prevalence did not correlate with mean probing pocket depth. However, a strong correlation was found between the reported prevalence of peri-implantitis and bleeding on probing. The survival rate showed a substantial correlation with function time, showing minor implant loss over time. We concluded that the case definition for peri-implantitis varied significantly between studies, indicating that an unambiguous definition based on a specified threshold for bone loss is not agreed upon in the literature. Chapter 4 (Study II) scrutinized the literature on long-term peri-implant bone loss and the relation with implant surface roughness and patient-related factors such as smoking and history of periodontitis. Implant systems are categorised based on the surface roughness expressed in Sa-value; minimally rough (Sa value: 0.5 – 1 μm), moderately rough (Sa value: 1 – 2 μm), and rough (Sa value: > 2 μm). In implant dentistry's early days, only minimally rough and microporous titanium plasma-sprayed rough implant systems were available. However, over time several implant modifications were done by sandblasting, acid-etching, anodic oxidation, or hydroxyapatite coating resulting in a moderately rough implant system. These modifications improved the osteoconductive and osteoinductive properties of the implant. The surface of the moderately rough implant system showed better blot cloth stabilisation, enhanced production of biological mediators, stimulate osteogenic maturation leading to higher bone-to-implant contact, and increased bonding strength of the bone to the implant. On the other hand, rougher implant systems are linked to increased bacterial adhesion with a higher risk of being affected by peri-implantitis. The search yielded 2,566 studies and 156 were selected for further reading. Only 87 reported information about surface roughness of the implants and mean bone loss after at least five years of function. In these papers in total 15,695 implants were inserted in 6,755 patients. The average weighted survival rate for these implants was 97.3% after at least 5 years of function. If 3 mm bone loss was used as a threshold to quantify peri-implantitis, less than 5% of the implants were affected. Regarding implant surface roughness, the systematic review suggests that peri-implant bone loss around minimally rough implant systems was statistically significantly less than the moderately rough and rough implant systems. No statistically significant difference was observed between moderately rough and rough implant systems. The meta-analyses showed less average peri-implant bone loss around smoother surfaces. However, due to the heterogeneity of the papers and the multifactorial cause for bone loss, the impact of surface roughness alone seems somewhat limited and of minimal clinical importance. In addition, the meta-analysis showed that smoking and history of periodontitis increased the risk for bone loss. Chapter 5 (Study III) includes two prospective split-mouth studies. Both studies included edentulous patients in need of a two-implant-supported overdenture in the mandible. The first part of Study III described the effect of the site-specific factor ‘soft-tissue thickness’ on crestal bone remodeling and peri-implant health. Twenty-six patients received two moderately rough implants. According to the manufacturer's guidelines, the control implant was installed equicrestally. The test implant was placed below crestal level to ensure at least 3 mm space for biologic width establishment on the abutment part. Initially, 26 patients were treated with one equicrestally and one subcrestally placed implant. After 36 months, 24 patients were available for follow-up. The second part of Study III determined the effect of implant surface roughness on crestal bone remodeling. As concluded in Study II, crestal bone loss might be related to the implant surface roughness. The existing literature suggests higher survival rates for moderately rough implants compared to minimally rough implants. On the other hand, recent literature and the findings of Study II suggest that implants with a minimally rough surface yield less long-term crestal bone loss. An implant with a hybrid surface combines the benefit of a moderately rough implant body and a minimally rough implant neck. To determine the effect of implant surface roughness on crestal bone loss, 23 patients received two implants: an implant with a moderately rough surface (Sa value: 1.3 μm) and a hybrid implant with a minimally rough coronal neck of 3 mm (Sa value: 0.9 μm) combined with a moderately rough body (Sa value: 1.3 μm). Apart from the difference in implant surface roughness, the two implants were identical. After 36 months, 21 patients were available for follow-up. The implant survival rate was 100% after 36 months. No differences were observed in crestal bone remodeling between the hybrid and moderately rough implant. However, initial bone remodeling was affected by initial soft tissue thickness because the equicrestal implants had implant threads exposed above bone level. Anticipating the biological width re-establishment by adapting the vertical position of the implant in relation to the available soft tissue thickness may prevent that implant threads are not fully covered by peri-implant bone. However, long-term follow-up of the study is necessary to determine the influence of early implant surface exposure and implant surface roughness on crestal bone loss, biological parameters, and implant survival. Study III also included Oral Health-Related Quality of Life for edentulous patients restored with a two-implant-supported mandibular overdenture. This patient-centred outcome was assessed with the Oral Health Impact Profile-14 (OHIP-14). The study concluded that a two-implant-supported mandibular overdenture in comparison with a conventional removable denture yields a significant improvement in the quality of life. Chapter 6 (Study IV) presented the five-year follow-up of the first part of study III, determining the effect of soft tissue thickness on crestal bone remodeling and peri-implant health. Twenty-four patients were available for the five-year follow-up. The survival rate was 100%, and only one implant showed a mean bone level higher than 2 mm. During initial bone remodeling equicrestal placement yielded 0.68 mm additional surface exposure compared to subcrestal placement. Afterwards, bone level and peri-implant health were comparable in both treatment conditions and stable up to five years. Hence, Study IV concluded that adapting the vertical position of the implant concerning the soft tissue thickness prevents early implant surface exposure caused by initial bone remodeling. However, in a well-maintained population, this has no impact on long-term prognosis. In addition, the Oral Health-Related Quality of Life was assessed using the Oral Health Impact Profile-14 (OHIP-14), concluding a stable Oral Health-Related Quality of Life over time. Chapter 7 (Study V) determines the effect of implant neck (microthreaded versus non-microthreaded) as well as the type of connection (internal conical versus external flat-to-flat) on peri-implant bone stability and peri-implant health. According to the literature, peri-implant bone loss is minimized on implants with microthreaded neck design and internal type of abutment connection, albeit that many clinical studies are biased due to confounding factors. Twenty-five patients were treated with a maxillary implant-supported bar-retained overdenture on four different implant types. Each patient received one implant with an internal connection with microthreads (I MT), one with an internal connection without microthreads (I NMT), one with an external connection with microthreads (E MT), and one with an external connection without microthreads (E NMT). Other design features, as well as surgical and prosthetic protocol, were consistent. After at least 36 months, the survival rate was 96%. It was concluded that the implant-abutment connection type (internal vs external) and the implant neck design (microthreaded vs non-microthreaded) have no clinical effect on peri-implant bone remodeling, peri-implant bone level after the initial remodeling. Furthermore, it also had no clinical effect on peri-implant health parameters, at least when implants are installed according to soft tissue thickness. Chapter 8 is the general discussion and includes clinical and future research recommendations. In addition, it highlights the social relevance of the undertaken scientific work in conjunction with a personal reflection. This PhD thesis concludes that: 1. Various peri-implantitis definitions are used in the literature, and reporting of biological parameters is often incomplete. Consistent reporting of peri-implantitis is required for scientific purposes as well as for clinical practice. 2. The peri-implantitis prevalence based on various case definitions did not correlate with the diagnostic parameters ‘mean probing pocket depth’, ‘mean bleeding on probing’, and ‘mean bone loss’. The survival rate showed a substantial correlation with function time, but implant loss over time is low. 3. In the current literature, less than 5% of the implants showed bone loss above 3 mm after at least five years in function. This result was independent of surface or implant brand, suggesting that currently reported peri-implantitis prevalence is exaggerated. 4. Rough implant systems are more prone to crestal bone loss. However, the multifactorial cause for bone loss and the heterogeneity of the studies make it difficult to draw firm conclusions. Nevertheless, more papers show less bone loss in favour of minimally rough implant systems. 5. Co-factors such as smoking or a history of periodontal disease increase the risk of bone loss. 6. The implant neck design (microthreaded vs non-microthreaded) has no influence on peri-implant bone remodeling when implants are installed in relation to soft tissue thickness allowing the formation of a 3 to 4 mm biological seal. 7. The implant-abutment connection type (internal vs external) has no influence on peri-implant bone remodeling when implants are installed in relation to soft tissue thickness allowing the formation of a 3 to 4 mm biological seal. 8. Implant surface roughness (minimally rough vs moderately rough) influences peri-implant bone remodeling nor additional bone loss when implants are installed in relation to soft tissue thickness allowing the formation of a 3 to 4 mm biologic seal. 9. Peri-implant health parameters (probing pocket depth, bleeding on probing, and plaque score) are not affected by implant design, surface texture, or abutment-connection features when implants are installed in relation to soft tissue thickness. 10. Anticipating biologic width re-establishment by adapting the vertical position of the implant in relation to the available soft tissue thickness may prevent initial peri-implant bone loss. 11. In a well-maintained population, the effect of early implant surface exposure caused by initial bone remodeling on peri-implant bone stability and biological parameters seems to be limited. 12. Implant-supported mandibular overdentures significantly improve the quality of life, with little biological complications and a high survival rate of the implants.