Peri‐Implant Diseases: The Past, the Present, the Future

1. Introduction

Peri‐implant disease is a collective term for inflammatory reactions in the tissues surrounding a dental implant. This definition was proposed in a consensus report from session IV of the 1st European Workshop on Periodontology, held in Ittingen, Switzerland in February 1993. The consensus report also identified two distinct disease entities among peri‐implant diseases. Peri‐implant mucositis was described as a reversible inflammatory condition in the soft tissues surrounding an implant, while peri‐implantitis was characterized as inflammatory reactions with loss of supporting bone in the tissues surrounding a functioning implant. The importance of peri‐implant diseases as an integrated and central part of periodontology was strengthened in subsequent European Workshops and in the 2017 World Workshop on Classification of Periodontal and Peri‐implant diseases and Conditions in Chicago, organized by the European Federation of Periodontology and the American Academy of Periodontology. Although research in the field of peri‐implant diseases embraces thousands of publications extending over 35 years, the time perspective in relation to periodontology overall appears short. The present review highlights milestones in clinical and experimental research on peri‐implant diseases from the past to the present time. Perspectives on the future are also presented.

In a historical view, it is logical to assume that the term peri‐implant diseases became a reality in dentistry concomitant with the introduction of dental implants. This is, however, not entirely true. In the early days of implant dentistry, the appreciation among clinicians using dental implants in restorative therapy was largely relying on the firm anchorage of the titanium device in the mandibular or maxillary bone, while less attention was paid to the soft tissue surrounding the implant. Although not proven, it was even suggested that the titanium surface of the implant exhibited protective features to the accumulation of bacteria and the formation of a biofilm. Speculations of this kind led to the assumption that the soft tissue surrounding a dental implant, that is, the peri‐implant mucosa, had a lower propensity to develop inflammatory reactions than the gingiva around teeth. Results obtained from experiments performed in human and pre‐clinical models in the early 1990s, however, opposed such theories [1, 2, 3, 4, 5]. Again, it is important to realize that the focus in research on peri‐implant tissues at that time was mainly on the bone tissue and the osseointegration process, while studies on the peri‐implant mucosa were rare. Research initiatives were therefore taken to improve the understanding of the structure and function of the peri‐implant mucosa.

2. Peri‐Implant Tissues—The Past

Assessment of characteristics of healthy conditions is fundamental for the understanding and recognition of disease. Criteria need to be identified to distinguish health from disease for appraisals of prevalence of disorders and for definitions of relevant endpoints in treatment protocols [6]. Characteristics of healthy peri‐implant tissues were addressed in a review by Araujo & Lindhe [7]. The review was conducted in conjunction with the 2017 World Workshop on Classification of Periodontal and Peri‐implant diseases and Conditions in Chicago and provided clinical and histological characteristics for the definition of peri‐implant health in a consensus report [8]. Araujo & Lindhe [7] reported that most information on the structure and composition of the peri‐implant mucosa comes from pre‐clinical in vivo studies using the canine model. Studies published between 1991 and 2002 demonstrated that the vertical dimension of the peri‐implant mucosa is about 3–4 mm and that the tissue portion that faces the transmucosal part of the implant is comprised of a 2‐mm high junctional epithelium and a 1–1.5 mm zone of “connective tissue integration” that extends between the epithelium and the crestal bone [4, 5, 9, 10, 11, 12, 13, 14]. In addition, the connective tissue zone apical of the junctional epithelium of the peri‐implant mucosa is rich in collagen fibers and presents with a lower density of blood vessels than the corresponding connective tissue area at teeth [15].

The formation of the peri‐implant mucosa is the result of a wound healing process, as is the establishment of osseointegration between the peri‐implant bone and the dental implant. The morphogenesis of the peri‐implant mucosa starts immediately following flap closure at the surgical installation procedure and continues over several weeks. The sequences of the mucosal wound healing process from day 0 to 12 weeks were described in detail in a pre‐clinical study by Berglundh et al. [16]. It was reported that during the initial stages of healing, inflammatory cells infiltrated and degraded the coagulum that resided in the space between tissue and the implant device. Access was thereby provided for fibroblasts to enter the compartment and to start forming connective tissue with collagen fibers and a matrix. While first signs of a junctional epithelium were detected at 1–2 weeks of healing, a mature and complete soft tissue adhesion with defined epithelial and connective tissue portions was established to the implant component after 6–8 weeks. Concomitantly, collagen fibers of the peri‐implant mucosa became organized after 4–6 weeks of healing. Like the morphogenesis of the peri‐implant mucosa, the sequential wound healing process in the bone tissue following implant placement was analyzed in pre‐clinical models [17, 18]. Thus, the initially formed blood clot in voids between the bony wall of the osteotomy preparation and the implant device became infiltrated and degraded by neutrophils and macrophages during the first week of healing. Active resorption of the old bone that was in contact with the implant directly after the installation procedure was initiated early and continued at 2 weeks of healing. A provisional connective tissue occupied the void areas around the implant and was subsequently replaced with woven bone. First signs of osseointegration were detected at 1 week. Remodeling of the immature bone with the formation of lamellar bone and bone marrow occurred between 6 and 12 weeks. It is evident that the healing processes in the soft and hard peri‐implant tissues in the canine model follow similar patterns and that mature tissues become established within a 3‐month period. While the use of pre‐clinical models in studies on peri‐implant tissues was justified by the need to harvest block biopsies that comprised the implant and its surrounding hard and soft tissues, interpretation of results on, for example, healing time, must be made with care. Similar considerations should be made regarding pre‐clinical models on peri‐implant diseases. For this reason, it would be desirable to obtain data from analysis of human tissue samples, although access to representative specimens is associated with obvious limitations and ethical concerns.

3. Peri‐Implant Tissues—The Present and Future Perspectives

Research on peri‐implant tissues in the past was predominantly based on pre‐clinical models, whereas more recent studies incorporated new technology to be applied on human tissue samples. Tomasi et al. [19, 20] introduced a novel biopsy technique on tissues around custom‐made abutments to study the early healing process of the peri‐implant mucosa. Thus, without jeopardizing the outcome of treatment in patients who were enrolled in the studies, circular‐shaped soft tissue biopsies of the peri‐implant mucosa were cut and removed together with custom‐made abutments and placed in a fixative. Permanent abutments were connected to the implants immediately after biopsy and prosthetic treatment was finalized. The biopsies were separated from the custom‐made abutments and processed using different techniques for scanning electron microscopy (SEM), histological analysis and immunohistochemistry (IHC). While overall findings from the analysis of the human samples were consistent with observations made in previous pre‐clinical studies, additional knowledge was acquired from both SEM and IHC evaluations regarding alterations in cells, vascular structures and collagen fibers in the connective tissue, and the formation of a junctional epithelium during the early stages of healing. In the future, the development of human models in research on peri‐implant tissues will be fundamental for further understanding of interactions between tissues and biomaterials. Human models may not only provide clinically representative target samples since they also allow the possibility for the use of novel techniques to assess key mechanisms in the morphogenesis of peri‐implant tissues and preservation of health.

In summary, peri‐implant soft tissues present with vertical dimensions of about 3–4 mm and adhere to the transmucosal part of the implant device with an about 2 mm high junctional epithelium and a zone of connective tissue containing high densities of collagen fibers aligned parallel with the implant surface. The connective tissue/implant interface is the most conspicuous difference between the peri‐implant mucosa and the gingiva around teeth. The lack of root cementum with inserting attachment fibers and a periodontal ligament around implants is an important difference and results in different mechanical functions of implants as opposed to teeth. The deficiency of fibrous attachment at implants also leads to a diminished ability to wall off an apical and lateral spread of inflammatory reactions in the connective tissue during the progression of peri‐implant disease. It is evident that the sealing function of the peri‐implant mucosa towards the implant is critical for maintaining peri‐implant tissue health.

4. Peri‐Implant Mucositis—The Past

Like teeth, the supra‐mucosal part of dental implants and implant‐supported crowns is consistently exposed to the accumulation of microorganisms. While bacteria colonizing the oral epithelium of the peri‐implant soft tissues are constantly removed by cellular desquamation, implant components and crowns, like teeth, have non‐shedding surfaces and lack such protective mechanisms. The build‐up of a microbial biofilm on implant components follows essentially similar patterns to those on teeth [21, 22]. It needs to be kept in mind, however, that the surface microstructure of implants and implant components influences the formation of biofilms and the ability to remove the biofilm during treatment of peri‐implant diseases.

The clinical features and diagnosis of peri‐implant mucositis were summarized in a review by Heitz‐Mayfield and Salvi [23]. Also, this review was performed for the 2017 World Workshop on Classification of Periodontal and Peri‐implant Diseases and Conditions and the consensus report stated that peri‐implant mucositis is an inflammatory lesion of the soft tissues surrounding an endosseous implant in the absence of loss of supporting bone [8]. In addition to the descriptive disease definition, the proposed case definition of peri‐implant mucositis in the consensus report included the detection of bleeding on probing and absence of bone loss.

Pre‐clinical and clinical studies using the classical experimental gingivitis model [24] demonstrated that clinical and histopathological characteristics of peri‐implant mucositis are similar to those of gingivitis around teeth. The studies evaluated the response to de novo plaque formation on implants and teeth following a preceding period of plaque control to disclose the pattern of a shift from a healthy to an inflamed state of peri‐implant and gingival tissues. Pre‐clinical studies demonstrated a “proof of concept” of similar clinical, microbiological and histopathological outcomes of undisturbed plaque formation for 3 weeks and 3 months at implants and teeth [1, 2]. Another proof of concept was shown by Pontoriero et al. [3] in a clinical study on 3 weeks of plaque formation in 20 patients with implants. Zitzmann et al. [25] also used the experimental gingivitis model and collected soft tissue biopsies around implants and teeth in 12 patients before and after 3 weeks of plaque formation. It was reported that the size of the inflammatory lesion in the connective tissue and the number of immune cells indicated by immunohistochemistry were similar in peri‐implant mucosa and gingiva around teeth. Salvi et al. [26] and Meyer et al. [27] analyzed plaque and crevicular fluid samples from patients of different age groups and showed that peri‐implant mucositis, like gingivitis, is a reversible condition that resolves following the reinstitution of oral hygiene measures.

Although not making comparisons with teeth and gingival tissues, other studies evaluated the outcome of long‐standing biofilm formation on implants. It was reported that the inflammatory lesions in peri‐implant mucosa that were formed after 5–9 months of plaque formation, remained stable and did not extend apical of the junctional epithelium [4, 5, 28]. Histological evaluations made on human biopsies obtained from implant sites with long‐standing peri‐implant mucositis also revealed well‐defined inflammatory infiltrates lateral of the junctional epithelium [29, 30].

5. Peri‐Implant Mucositis—The Present and Future Perspectives

Pre‐clinical models on peri‐implant mucositis in the past were justified to establish proof of concept and cause‐and ‐effect relationship between plaque formation on implants and inflammatory response in peri‐implant mucosa [23]. The documentation in terms of histopathological evidence on the location of the inflammatory lesion in relation to epithelial structures and the crestal bone and the tissue response to long‐term exposure to plaque formation prompted the use of pre‐clinical models. On the other hand, experimental mucositis in humans is a feasible research model to study tissue reactions to biofilm formation on implants. Outcomes may include clinical observations, analysis of key markers in crevicular fluid and, when ethically feasible, evaluations of inflammatory cells and mediators in soft tissue specimens. The knowledge obtained from pre‐clinical and clinical studies in this field has been fundamental for the understanding of the importance of oral hygiene measures in day‐to‐day clinical practice to prevent the development of peri‐implant diseases.

The future perspective on research on peri‐implant mucositis is directed towards well‐controlled experimental studies in humans. While the advantage of evaluating tissue reactions in humans is obvious, there are important ethical and practical limitations to consider. Investigations on, for example, potential anti‐bacterial effects of implant materials or coatings would ideally be performed using the experimental peri‐implant mucositis model in humans with a preceding meticulous plaque control period to unravel effects on biofilm formation and the ensuing tissue response in peri‐implant mucosa. While short‐term effects in experimental designs may be evaluated using outcomes that incorporate assessments of biofilm on implant components and inflammatory markers in crevicular fluid and/or connective tissue lesions, long‐term effects should be assessed using clinical outcomes in large patient groups.

In summary, peri‐implant mucositis, like gingivitis around teeth, may remain stable for long periods of time and in many subjects never progress. The question of why some individuals with implants develop peri‐implantitis and some do not, is fundamental and reflects the parallel issue regarding gingivitis and periodontitis around teeth. The critical point is the understanding of mechanisms involved in the conversion of peri‐implant mucositis to peri‐implantitis. As mentioned above, a pre‐clinical study on long‐standing peri‐implant mucositis around implants of 3 different systems demonstrated that the inflammatory lesion resided in a connective tissue compartment immediately lateral to the pocket epithelium [4, 5]. Since the apical extension of the lesions consistently coincided with that of the pocket epithelium, the “connective tissue integration” zone apical to the epithelium remained unaffected. There are reasons to suggest that the preservation of the integrity of the “connective tissue integration” zone in peri‐implant mucositis is a key mechanism in avoiding disease progression.

Peri‐implant mucositis is the precursor for peri‐implantitis, as is gingivitis for periodontitis. Treatment of peri‐implant mucositis is therefore the logical strategy in preventing peri‐implantitis [31, 32]. The EFP S3 level clinical practice guideline on prevention and treatment of peri‐implant diseases provided a comprehensive and detailed series of recommendations [33]. The aim of treatment of peri‐implant diseases is to arrest the inflammatory processes within the peri‐implant tissues and to control local and systemic risk factors that may sustain it. Disruption of the locally accumulating microbial biofilms is a key target.

6. Peri‐Implantitis—The Past

Peri‐implantitis represents the most severe form of peri‐implant diseases and is characterized by inflammation in peri‐implant soft tissues and destruction of supporting bone. Diagnosis and characteristics of peri‐implantitis were presented in a review by Schwarz et al. [34], which was prepared for the 2017 World Workshop on Classification of Periodontal and Peri‐implant diseases and Conditions. The disease definition of peri‐implantitis in the consensus report from the workshop emphasized that peri‐implantitis is a plaque‐associated pathological condition, characterized by inflammation in the peri‐implant mucosa and progressive loss of supporting bone [8]. The case definitions of the condition covered recommendations for diagnosis based on clinical recordings of bleeding on probing, increased probing depth, and bone loss assessed in radiographs.

Peri‐implantitis was presented as a disease entity at the first European Workshop on Periodontology in 1993 [35, 36]. While the relevance of peri‐implantitis has been debated for many years, the disease is currently recognized as one the most challenging problems in implant dentistry and dentistry overall. This is illustrated by the following. Meta‐analyses of data from studies on the prevalence of peri‐implantitis in different patient samples revealed results varying between 20% and 22% [37, 38]. In a nation‐wide study on a large random patient sample, it was reported that moderate/severe peri‐implantitis (bleeding on probing and bone loss > 2 mm) occurred in 14.5% of patients [39]. When case definitions used by Derks et al. [39] were applied on data from other cross‐sectional studies, the prevalence of moderate/severe peri‐implantitis ranged from 16% to 20% [40]. In addition, recent registry data from Sweden showed that 5.6% of 3.3 million individuals had ≥ 1 implants [41]. Taken together, since about 1 out of 5 subjects with implants has moderate/severe peri‐implantitis, the disease seems to affect > 1% of a random adult population and may therefore be considered a public health concern.

In the consensus report from the 2017 world workshop [8] it was stated that peri‐implantitis may occur early and that it progresses in a non‐linear and accelerating pattern [42, 43]. As disease progression in peri‐implantitis also appears to be faster than that in periodontitis, critical differences in host defense mechanisms need to be addressed.

The pre‐clinical models that were used in early studies on peri‐implantitis were based on concepts established in classical experiments on periodontitis. Thus, a combination of ligatures placed in a submarginal/subgingival position and plaque formation was applied to induce a large inflammatory infiltrate in the connective tissue and loss of supporting bone around implants and teeth [44, 45]. It was reported that bone loss was more pronounced around implants than around teeth and that the inflammatory infiltrates in the peri‐implant mucosa, in contrast to the lesion in the gingiva, extended to the crestal bone. It should be pointed out, however, that in accordance with classical experimental periodontitis protocol, the ligatures were removed 1 month prior to the termination of the experiment and biopsy [44]. While periodontal tissues at teeth recovered after ligature removal and formed a “self‐limiting” zone of connective tissue attachment that separated the lesion from the bone crest, a similar limiting process did not occur around implants due to the deficiency of a fibrous attachment. As mentioned above, the lack of a fibrous attachment at implants may lead to a diminished ability to wall off an apical and lateral spread of inflammatory lesions in the connective tissue in peri‐implantitis and further progression of disease. This hypothesis was addressed in a pre‐clinical study on experimental peri‐implantitis by Zitzmann et al. [46]. After an initial period of inflammation and tissue breakdown, the ligatures were removed and plaque formation continued for 12 months. The final examination revealed that most implant sites showed additional bone loss in combination with inflammatory lesions extending to the crestal bone. In the remaining few implant sites, no further bone loss had occurred, and the lesions were encapsulated and separated from the bone crest. The “spontaneous progression” model of experimental peri‐implantitis introduced by Zitzmann et al. [46] was subsequently used to study potential differences between implants with varying surface structures, including custom‐made and commercially available surface preparations. Berglundh et al. [47] reported that spontaneous progression of experimental peri‐implantitis was more pronounced around implants with a moderately rough surface than at implants with an identical geometry but with a smooth surface. In a similar study on 4 commercially available implant types with varying geometry and surface characteristics, Albouy et al. [48, 49] showed that 6 months of spontaneous progression of experimental peri‐implantitis resulted in varying degrees of bone loss and large inflammatory lesions that extended apically to the pocket epithelium. The influence of implant surface characteristics on spontaneous progression of peri‐implantitis was further demonstrated by Albouy et al. [50]. They compared implants with identical geometry but with either smooth, non‐modified surfaces or moderately rough, modified surfaces. It was reported that the amount of bone loss that occurred during the 6‐month period and the size of the inflammatory lesions in the connective tissue were larger around implants with modified surfaces. Although the number of implant types used in the pre‐clinical studies on spontaneous progressions of experimental peri‐implantitis was limited, the observations on the influence of implant surface characteristics on progression of disease are important and call for further investigations in clinical settings.

In addition to pre‐clinical models, analysis of human biopsy material has been fundamental for the understanding of periodontitis lesions around teeth. Likewise, human biopsy material from patients with peri‐implantitis has been an invaluable source for adding information to observations made in the pre‐clinical studies reported above. The retrieval of human biopsies from peri‐implantitis sites for research purposes is in most cases carried out in conjunction with surgical treatment of the condition. This approach justifies the biopsy procedure from an ethical perspective and, for the same reason, also limits the specimen to the soft tissue component. In this context, the advantage of the pre‐clinical model is evident since the biopsy encompasses both hard and soft tissue components in addition to the implant. On the other hand, the techniques that were used for the analysis of specimens obtained in pre‐clinical studies on canine models, were predominantly based on morphological approaches and evaluation of immunohistochemical (IHC) markers of key components in the connective tissue. Human specimens, confined to the soft tissue part of peri‐implantitis sites, however, were analyzed using techniques that combined conventional morphology and IHC for assessments of phenotype characteristics and molecular biology approaches for appraisals of functional features.

Results from analysis of human peri‐implantitis lesions have been reviewed previously [34, 40, 51]. Descriptive observations in early studies included the detection of a large inflammatory cell infiltrate that occupied a major part of the tissue sample [30, 52, 53]. Results from comparisons between human peri‐implantitis and periodontitis specimens were in line with observations made in pre‐clinical studies. Thus, the inflammatory lesions were larger in peri‐implantitis and extended to a position that was apical to the pocket epithelium [54, 55, 56]. The relative proportions of plasma cells, macrophages and neutrophils were larger in peri‐implantitis than in periodontitis lesions [54]. In addition, macrophages demonstrating M1‐polarization were more common in peri‐implantitis than in periodontitis sites [57]. Peri‐implantitis samples also exhibit higher densities of cells demonstrating antimicrobial activity and DNA damage than periodontitis specimens [56].

7. Peri‐Implantitis—The Present and Future Perspectives

The balance between pre‐clinical research and examination of human samples from peri‐implantitis sites has shifted over the past 30 years from an early predominance of experimental models to an extended and wider approach to advanced techniques in the analysis of human biopsy material. The models used in pre‐clinical studies in the past have diminished mostly due to ethical reasons. Other models, such as mice, have gradually been introduced to replace previous experimental protocols [58, 59, 60, 61]. While the small size of mice and the need for using custom‐made implants may be shortcomings of the new pre‐clinical models, there are several advantages of access to advanced techniques in the analysis of tissue samples. Provided that experimental peri‐implantitis in mice can be controlled and mimic natural diseases in a way that was achieved in previous canine models, the new pre‐clinical models may be valuable in future research.

As mentioned above, morphological assessments and IHC for detection of cell markers were the most used procedures in the analysis of human biopsy material. While such techniques preserved tissue orientation and provided information on the position of key elements in lesions, other methods that target functional features of cells required homogenization of the tissue samples. Although studies using, for example, RT‐qPCR and transcriptome profiling techniques provided information on mRNA levels for specific cytokines, the relevance of findings is not fully understood since the spatial orientation of gene expression in the tissue samples is lost during processing [62, 63, 64, 65, 66]. Techniques that both provide access to novel methods of assessing functional features on the cellular level, for example, proteomics and transcriptomics, and preserve the spatial orientation would therefore be desirable. Such a technique has been established and is termed “spatial transcriptomics” [67]. The method was recognized as the “method of the year” in Nature Methods [68] and provides gene‐expression analysis with large‐scale data visualization at the cellular level on intact tissue sections. The technique has been acknowledged to bridge the gap between spatial organization and molecular biology [69]. Recently, Dionigi et al. [70] analyzed gene expression profiles in human samples from sites with and without peri‐implantitis by integrating spatial transcriptomics, bulk RNA‐sequencing and IHC. The key finding was the evident association between distinct gene clusters and specific tissue compartments. The clusters of gene signatures within tissue sections were visualized by the spatial transcriptomic method and the subsequent analysis of gene expression was thereby limited to the clusters of interest. The analysis demonstrated that several biological pathways linked to the activation of the host response towards bacterial insults were dysregulated in peri‐implantitis specimens. While the observations made in the study by Dionigi et al. [70] provided a significant contribution to the understanding of the pathogenesis of peri‐implantitis, it should be kept in mind that the combination of novel methods in the study by Dionigi et al. [70] required considerable investments in terms of financial and time resources. Future research on human biopsy material in the field should nevertheless integrate novel techniques, provided that accessibility to relevant infrastructure is improved and costs reduced.

Dental implants are mainly comprised of titanium and micro‐particles from the implant surface may be dislodged during the surgical installation procedure and become trapped in the supra‐crestal connective tissue during healing. It has therefore been suggested that the micro‐particles may interact with inflammatory reactions that occur in peri‐implant lesions. Although reports on the analysis of human biopsy material indicated that titanium micro‐particles may occasionally occur in tissue samples obtained from implant sites with peri‐implantitis [71, 72, 73, 74], the importance of the findings remains unclear. Since the evaluations were confined to peri‐implantitis lesions, there is no information on the occurrence of titanium micro‐particles in tissue samples obtained from implant sites with no signs of peri‐implantitis. This deficiency prompted the investigation recently presented by Dionigi et al. [75]. They collected soft tissue specimens from implants with and without peri‐implantitis in 21 patients. Micro Proton‐induced X‐ray Emission (μ‐PIXE) was used to assess the occurrence and localization of titanium micro‐particles and RNA sequencing was carried out to examine the potential association between densities of metal particles and gene expression profiles. The analysis revealed that titanium micro‐particles occurred in all specimens but varied among patients. The relative density of particles, however, did not vary between implants with and without peri‐implantitis within the same patient. The inter‐individual variation in titanium micro‐particles between individuals was explained by differences in implant systems between patients. The observations by Dionigi et al. [75] indicate that titanium micro‐particles are common in peri‐implant soft tissues and that their occurrence is not associated with peri‐implantitis. It was also reported that differences in gene expression between peri‐implantitis specimens with high or low volumetric densities were small. The 14 genes that were dysregulated were all associated with the regulation of the immune response and epithelial development.

One of the strengths in the paper by Dionigi et al. [75] was the study design. The use of an intra‐individual control site eliminated potential variations in aspects related to the dental implant, for example, geometry and surface characteristics, function/exposure time and installation protocols, in addition to inter‐subject variations in host response. The introduction of relevant controls in the design of studies on peri‐implant diseases facilitates interpretation of findings. Researchers should therefore strive for optimal protocols including relevant controls in future studies. This is particularly important in appraisals of different procedures in the treatment of peri‐implant diseases.

In summary, findings from pre‐clinical studies and analysis of human biopsy material have shown that peri‐implantitis lesions present with a dysregulated host response. In contrast to periodontitis lesions around teeth, the pocket epithelium in peri‐implantitis does not cover the entire dimension of the pocket and, hence, there is no epithelial lining between the microbial biofilm and the apical part of the inflammatory cell infiltrate. Furthermore, peri‐implantitis lesions extend beyond the pocket epithelium and reach the crestal bone, whereas periodontitis lesions remain within the dimensions of the pocket epithelium and are separated from the crestal bone by a zone of connective tissue attachment. The structural and functional characteristics of peri‐implantitis lesions indicate an active and ceaseless inflammatory process, which leads to the non‐linear and accelerating pattern of disease progression. Future research using novel techniques in assessments of gene expression profiles on the cellular level in human peri‐implantitis lesions may provide further understanding of key mechanisms involved in disease onset and progression.

Disclosure

AI statement: This manuscript did not use artificial intelligence in any capacity.

Data Availability Statement

The author has nothing to report.