*5.3. Significance of Prosthetic Design*

Assuming the role of biofilm and its bacterial byproducts in the onset and progression of peri-implantitis, it is conceivable that retentive prosthetic components may promote inflammation (Figure 10). In this regard, Serino and Strom demonstrated that regardless of adequate oral hygiene of the natural dentition in partially edentulous patients, prosthetic design plays a major role in plaque accumulation around implant-supported prostheses. The authors found that adequate oral hygiene could not be performed in 53 out of 58 implants, and that peri-implantitis therefore could be attributed to deficient access for personal oral hygiene [78]. This is a typical scenario in hybrid prostheses, where esthetic requirements are satisfied but long-term implant maintenance is jeopardized owing to poor access for oral hygiene. Similarly, bone-level, implant-supported single crowns with an emergence angle of over 30 degrees and a convex profile have been shown to be factors strongly associated with peri-implantitis. This was not consistent with the findings in tissue-level implants [79]. Hence, convexities and marked emergence profiles should be avoided in the design of single crowns. In any case, patients should be comprehensively instructed to use interproximal brushes to remove food debris or plaque within the implant surroundings [2].

**Figure 10.** A hybrid prosthesis does not facilitate adequate oral hygiene and favors plaque retention, thereby triggering peri-implantitis.

Into the bargain, conceiving that excessive early bone resorption is often associated with greater late bone loss [26], prosthetic factors associated with minimal physiological bone loss should be noted. In this sense, longer transmucosal abutments (>2 mm) [80] and internal connection (including platform-switching [81] and Morse cone connections [82]) have demonstrated efficient preservation of the peri-implant hard tissue levels.

#### **6. Local Precipitant Factors**

The literature describes a few factors (so-called precipitant factors) associated with the triggering of inflammation within the peri-implant sulcus.

#### *6.1. Residual Submucosal Cement*

While screw-retained restorations do not necessarily outperform cement-retained prostheses, the presence of residual cement has been shown to have a deleterious effect upon the peri-implant tissues. Wilson et al. demonstrated the triggering role of residual cement, since 81% of the cases developed peri-implantitis, with spontaneous resolution in 74% following mechanical removal of the excess cement [63]. Likewise, Linkevicius et al. demonstrated the effect of residual cement upon peri-implant tissue response. In this scenario, 85% of the cases developed peri-implant disease [83]. Similar findings were obtained by Korsch et al. in a later study affording further insight into the effect of cement type upon the development of pathological complications. It was seen that while methacrylate cement was present in 62% of the suprastructures, zinc oxide eugenol cement could not be detected [84]. As a matter of fact, it was seen that the clinical and radiographic peri-implant conditions were generally unfavorable for implant-retained suprastructures using methacrylate cement, irrespective of cement excess [84]. In view of the significance of the presence of residual cement upon peri-implant tissue stability, it is advisable to use radiopaque cement if needed, with the aim of promptly detecting and removing it.

#### *6.2. Residual Dental Floss*

The remnants of floss in the peri-implant sulcus have also been regarded as a triggering factor for peri-implantitis. Van Velzen et al. reported 10 cases with progressive peri-implantitis related to floss remnants. Interestingly, in 90% of the cases, the inflammation resolved spontaneously after mechanical removal of the floss remnants [85]. Thus, caution is required when providing personal oral hygiene instructions involving the use of floss, and patients should be further encouraged to employ interproximal brushes.

#### **7. Local Accelerating Factors: Influence of Surface Topography upon Progressive Bone Loss**

In the course of the evolution of implant dentistry, advances in the form of implant surface modifications have led to stronger bone responses and higher implant survival rates [86]. Associations have been reported between significantly greater crestal bone loss and different implant surfaces and topographic features [86]. Furthermore, it has been suggested that surface roughness might have some role in the incidence of peri-implantitis [87] (Figure 11). In contrast, other authors consider that there are no available data confirming an association between implant surface features and the initiation of peri-implantitis or the progression of established peri-implantitis [88]. Ligature animal models have shown an increased risk of peri-implantitis with SLA implants in comparison to machined implants [89], and with TiUnite implants in comparison to machined, SLA, and TiOblast implants [31,90,91]. Similarly, another preclinical study noted significantly greater intrasurgical defect depths, defect widths, probing depths, and radiographic bone loss with TiUnite implants than with Straumann SLA or Biomet T3 implants [92]. Other factors apart from surface features might be relevant in the initial phase; for example, the invaginating grooves and pits on the TiUnite surface might favor bacterial adhesion and protect bacteria from shear forces [92]. Interestingly, a recent systematic review failed to find a long-term association between different surface modifications. Hence, these data in

humans suggest that it is possible to achieve very good long-term results with all types of moderately rough implant surfaces [93].

**Figure 11.** Moderately rough topographic characteristics (RA~1.3 μm) may induce chronification of the inflammatory condition by harboring pathogenic bacteria. This, in turn, may influence the therapeutic outcome. Note the scanning electron microscopic features of the implant surface under high magnification.

Furthermore, the management of established peri-implantitis is possible after surgical treatment, but the therapeutic outcome is also influenced by the implant surface characteristics [90]. In a randomized clinical trial on the effect of adjunctive systemic and local antimicrobial therapy in patients with peri-implantitis, treatment success was reported in 79% of the implants with nonmodified surface features, but in only 34% of the implants with modified surfaces [94]. Similarly, a three-year randomized controlled trial found the surgical treatment of peri-implantitis to be effective, with stable peri-implant marginal bone levels, but here again the nonmodified surfaces yielded significantly better results [95].

Depending on the surface modification methods used, some remnants may persist on the surface and have deleterious effects upon the clinical performance of the implant [87]. These particles and others released from the surface as a result of corrosion and mechanical wear may have cytotoxic effects and stimulate inflammatory reactions [8], leading to osteoclast activation and further peri-implant bone loss. Likewise, it has been recently evidenced that titanium particles derived from implants containing phosphate-enriched titanium oxide, fluoride-modified, and grit-blasted (GB) surface treatments are able to activate CHK2 and trigger the recruitment of BRCA1 in oral epithelial cells. These are markers for detecting activation of the DNA damage response. Accordingly, it can be inferred that titanium particles released into a surgical wound may contribute to the disruption of epithelial homeostasis, and potentially compromise the oral epithelial barrier [96].

### **8. Other Perspectives to Conceive Peri-Implantitis**

Different perspectives to understand peri-implantitis have been further proposed. As such, it has been advocated that peri-implant marginal bone loss might be related to a change in the foreign body equilibrium between the host immune system and the implant device [97]. The biological behavior of the bone cells is mediated by the interaction among immune cells (neutrophils, macrophages, and lymphocytes) and the dental implant (or any kind of foreign body). Briefly, one of the very first interplays around the foreign body is carried out by neutrophils for 24–48 h [98]. The insertion of a dental implant induces a status of hypoxia in the surrounding bone that leads to neutrophil accumulation in order to promote angiogenesis. Also, neutrophil cells may discharge proteolytic

enzymes and reactive oxygen species during their function that can erode the implant surface and release metal particles to the tissues [99]. After 48 h, the population of macrophages is higher around the foreign body and these cells may lead the evolution of the immune response. In fact, these cells promote osteoclastogenesis, matrix deposition, and bone anabolism [100], whereas macrophages' absence might impair osteoblast viability and bone formation [101,102]. Neutrophil apoptosis is mediated by macrophages during the shift between inflammatory phase to the healing phase. Also, the polarization between macrophages M1 to M2 and the length of each phase may have clinical effects, thereby an extended M1 phase may lead to a fibrous encapsulation of the fixture and implant failure [103]. On the contrary, higher presence of M2 macrophages has been reported on commercial pure implants [99,104], leading to bone deposition on the surface to isolate the fixture from the surrounding bone.

In addition, macrophages can differentiate into osteoclasts during bone remodeling and have phagocytosis capabilities until 5 μm of particle size [98]. Under presence of larger particles, macrophages tend to fuse to become foreign body giant cells (FBGCs). FBGCs are more frequent around the implant interface [105] than around healthy tissues and this fact might indicate the presence of a foreign body reaction around the dental fixture or the allogenic material.

Hence, under this concept of foreign body reaction, osseointegration is a mild chronic inflammatory and immunologically driven response where the bone–implant interface remains in a state of equilibrium but susceptible to changes in the environment [7,106]. Macrophages, FBGCs, and others approach this new bone barrier and if any disturbing factor occurs, a reactivation of the immuno-inflammatory cells against the foreign body material takes place. The loss of the foreign body equilibrium may thus stand as one of the reasons for this peri-implant bone loss [98].

#### **9. Conclusions**

Site-specific diseases are often attributable to local predisposing factors. In the case of plaque-associated peri-implantitis, local contributors, including surgical and prosthetic factors, as well as soft and hard tissue characteristics, may be predisposing factors to biofilm adherence around dental implants, thus leading to inflammation. Moreover, two major precipitant or triggering factors can be identified: residual cement and residual floss. In addition, current evidence seems to suggest that certain surface topographies can further accelerate the process of peri-implantitis.

**Funding:** The present review was partially founded by FEDICOM Foundation (Badajoz, Spain).

**Conflicts of Interest:** The authors declare no direct and potential conflict of interest with respect to the authorship or concepts presented in this article.

#### **References**


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