Introduction

The term peri-implantitis was first appeared in the French literature in 1965 and described as a biofilm associated biological complications [1]. That was well before the term resurfaced again in the seminal work of Mombelli in 1987 where the term peri-implantitis was described as a site-specific infectious disease with many features common to periodontitis [2]. Over the past three decades, multiple definitions describing peri-implant diseases appeared in the implant literature with several proposals for treatment strategies of varied extents. The lack of uniformity in defining peri-implant diseases, from a clinical perspective, seems to result from the use of different threshold measures to assess bone loss and the lack of defined follow-up periods among the different studies.

Despite the ambiguity of definition, peri-implant disease has been recognized as the most common complication associated with dental implant therapy [3]. The frequency of occurrence of peri-implant diseases was summarized in a systematic review [4•] where 63.4% of patients and 30.7% of individual implants encountered peri-implant mucositis, while the frequency of peri-implantitis was in 18.8% of the patients and in 9.6% of the individual implants. With these numbers in mind and considering the staggering number of dental implants placed worldwide, the need to understand the multifaceted etiology of peri-implant disease, its case definition, and characteristics cannot be overemphasized. It is only through this process of understanding that the true impact of peri-implant disease on the individual dental implant performance and on the implant therapy in continuum can be estimated and effective treatment strategies can be instituted. In the present review, the current literature on the case definitions and etiopathogenesis of peri-implant mucositis and peri-implantitis was summarized.

Evolution of Case Definitions

Since 1993, several world forums have described the etiology, pathogenesis, and progression of peri-implant diseases. A clinical scenario devoid of mucosal inflammation and erythema of soft tissues surrounding dental implants is regarded as a state of heath. The clinical presentation of both peri-implant mucositis and peri-implantitis was first discussed at the First European Workshop on Periodontology [5]. The case definitions have since evolved through deliberations at various workshops. The discussions were based on emerging evidences on the prevalence, manifestations, and treatment outcomes of different management strategies. In 2008, the definitions adopted by the Sixth European Workshop on Periodontology [6] were based on a review paper by Zitzmann and coworkers [7]. Peri-implant mucositis was defined as the presence of bleeding on probing and inflammation of peri-implant tissues without signs of supporting bone loss, while peri-implantitis included the loss of supporting bone. The Seventh European Workshop on Periodontology referred to the presence of bleeding on probing as the key feature of peri-implant mucositis [8]. Recently, the World Workshop on the classification of periodontal and peri-implant diseases, in 2017, confirmed the case definitions proposed by the Sixth and Seventh European Workshops on Periodontology [7, 8] but referred to the progressive bone loss as the one that exceeds initial bone remodeling during healing [9•].

Etiopathogenesis of Peri-Implant Mucositis

The degradation of healthy soft tissues around dental implants leading to mucositis has been attributed to the presence and accretion of microbial biofilms around osseointegrated implants. This etiological factor pertaining to establishing mucosal inflammation has been investigated and confirmed in various animal and human studies. The classical study of experimental gingivitis in man [10] formed the basis for experimental peri-implant mucositis studies in man which evaluated the association between biofilm and peri-implant mucositis [11, 12]. The known methodology in these experiments involved asking patients to stop any oral home care regimen for a period of 3 weeks followed by reinstitution of optimum oral health. Clinical data, including periodontal indices and probing depths, were collected around osseointegrated dental implants prior and after the period of undisturbed plaque formation. In addition, soft tissue biopsies were harvested, and microbial composition around dental implants and natural teeth was evaluated. The clinical data revealed visible cardinal signs of mucosal inflammation (i.e., redness, bleeding, and swelling) at the time of abolishing oral home care. Increased levels of T and B cells were noticed in the inflammatory infiltrate at dental implants and natural teeth with no significant difference in the microbial composition. The experimental studies in man also showed similar patterns of disease initiation around dental implants and natural teeth and confirmed the direct cause and effect relationship between biofilm accumulation and peri-implant mucositis [11, 12].

The inflammatory soft tissue reactions to plaque formation have also been evaluated around relatively new implant materials. In a recent prospective cohort study, clinical, microbiological, and host-derived factors were assessed in experimental mucositis around natural teeth and titanium and zirconia implants [13, 14]. The authors examined the pro-inflammatory parameters such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-⍺), and interleukin 1b (IL-1b). The deepest probing site around each unit (implant and tooth) was selected to evaluate the inflammatory response. The immunological response to biofilm-induced mucosal inflammation was evaluated by examining the compositional changes in the mucosal/gingival crevicular fluid. Any changes associated with inflammation were transient, and levels of different markers revert back to baseline upon resolution of inflammation.

Several animal studies confirmed the alteration of peri-implant mucosa following biofilm accumulation with migration of leukocytes through the sulcular and junctional epithelium, formation of inflammatory infiltrate, and increased proportions of T and B cells in the adjacent connective tissue around dental implants and natural teeth [15, 16]. It is worth noting that despite similarities in inflammatory response, the apical extent of inflammatory infiltrate at dental implants was more pronounced compared with the one observed at natural teeth.

Etiopathogenesis of Peri-Implantitis

The known differences and similarities in the anatomy of surrounding supporting tissues around teeth and implants have influenced the host response to infection and consequently natural history, pathogenesis, and clinical appearance of periodontitis and peri-implantitis. One of the fundamental differences is the lack of periodontal fibers and cementum at implant surface. In contrast, natural teeth’s supporting structure is mainly made of complex network of collagen fiber that support gingival tissue and connect teeth to teeth and alveolar bone. A series of experimental studies using a dog model demonstrated that collagen fibers are not inserted into the implant surface but rather run parallel to it [15, 17, 18]. However, the mean dimensions of the junctional epithelium and supra-crestal connective tissue were similar to the ones reported around natural teeth [19].

The pathogenesis of periodontitis has been described by Page and Schroeder [20], and many of its immunohistochemical features have been explored. The comparison of clinical, radiographic, microbiological, and histological features of periodontitis and peri-implantitis remain the mainstream of many studies investigating the pathogenesis of peri-implantitis. Analyzing human autopsy material and animal experiments forms the basis of our current understanding of the pathogenesis of peri-implantitis.

Animal Studies

Several animal studies [18, 21,22,23,24, 25, 26, 27•, 28,29,30,31] showed more pronounced clinical and radiographic signs of tissue destruction around dental implants compared with natural teeth (Table 1). The most commonly used methodology is the placement of cotton or silk ligatures around the neck of the implant in dogs, monkeys, and mini-pigs along with undisturbed plaque buildup to induce peri-implant tissue breakdown in an attempt to mimic a natural peri-implantitis lesion.

Table 1 Characteristics of the experimental animal studies
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In a dog model in which ligatures were applied to implants and teeth, Lindhe and colleagues [18] showed that the infiltrated connective tissue extended to peri-implant bone level, while the advanced lesions of periodontitis are guarded by a band of non-infiltrated connective tissue. The parallelly directed collagen fibers to implant surface may allow greater expansion of the inflammatory infiltrate [18]. Histological findings showed a more pronounced bone loss around implants compared with teeth with increased number of osteoclasts on the bone crest [26, 28]. Moreover, the type of mucosa was investigated in a monkey model and showed a greater recession around implants with non-keratinized mucosa compared with those with keratinized tissue [30]. In both monkey and dog models, histological analysis also showed that occlusal orthodontic forces and lateral static load did not increase the bone loss in sites of peri-implantitis [24, 25].

To assess the progression of peri-implantitis, several studies [21, 22, 31, 32] used a spontaneous progression model of experimental peri-implantitis by removing the ligatures when 40% of supporting bone is lost and then allowing undisturbed plaque buildup. Continuous breakdown was noticed among the majority of implants with inflammatory infiltrate extending apical to the pocket epithelium and close to the bone crest. In addition, implants with rough surfaces had greater bone loss than smooth-surfaced implant [22]. In interpreting the findings of animal research, one must take into consideration that ligature-induced model of peri-implantitis causes severe and acute inflammatory reaction that does not truly resemble peri-implantitis lesion seen in humans which is chronic in nature.

Human Autopsy Studies

Human autopsy studies provide an opportunity to study the pathology of peri-implant diseases in humans [33,34,35,36,37,38] (Table 2). However, histological investigations of peri-implantitis in humans did not provide elaborated details as those reported in animal models. Ethical concerns of inducing and leaving peri-implantitis without treatment will always limit histological descriptions in humans. Nevertheless, the surrounding tissues of failing implants were histologically examined [33, 39]. The inflammatory infiltrate of peri-implantitis contained mostly plasma cells which resembled plasm cell lesion of periodontitis [33, 40]. In addition, the infiltrated connective tissues lacked collagen which was mostly replaced by increased vascularity and inflammatory cells [33]. Another resemblance to periodontitis lesion is the thin and ulcerated apical portion and thick marginal portion of pocket epithelium with rete pegs extending into the infiltrated connective tissues [33]. Inflammatory infiltrate in peri-implantitis sites had both B and T lymphocytes. In one study [34], T cells outnumbered the B cells, while an immunohistochemistry analysis showed a higher level of B lymphocytes than T lymphocytes in peri-implantitis lesions [36]. In addition, higher number of IL-1⍺ and IL-6 positive cells and smaller number of cells positive for TNF-⍺ were observed in peri-implantitis compared with periodontitis lesions [37].

Table 2 Characteristics of human autopsy studies
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Microbiology of Peri-Implant Diseases

The microbiology of peri-implant tissues bears resemblance to that associated with natural teeth. Plaque associated with healthy implant abutments consists predominately of gram-positive facultative cocci and rods [41]. Quirynen and colleagues [42] investigated the microbial composition of plaque around teeth and implant after initial exposure. A similarity in the microbial composition was shown. Likewise, implants with peri-implantitis lesions had over 50% of gram-negative anaerobes [2] and considerable amounts of periodontal pathogens including Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Tannerella forsythia [43], which resembles the microbial composition of periodontitis lesions.

Concluding Remarks

Experimental studies in man, human autopsy studies, and animal studies confirmed that the microbial biofilm is an initiator and sustainer of peri-implant diseases. While human autopsy studies provided direct information on peri-implantitis lesions, they are limited in that they do not permit us to obtain specimens at various levels of severity. On the other hand, the information gathered from animal studies allowed histological examination of the whole lesion including bone, but the findings may not truly represent the course of human peri-implant disease.

Moreover, there are several similarities in the histopathological characteristics of peri-implantitis and periodontitis as demonstrated in human autopsy and animal studies. Nevertheless, differences do exist, namely, the extension of inflammatory infiltrate apical to pocket epithelium with relatively increased levels of neutrophil granulocytes and macrophages in peri-implantitis lesions. Moreover, peri-implantitis lesions differ in the structure of the granulation tissue compared with that observed in periodontitis lesions. Such differences have implications in treatment planning for peri-implant diseases.