Structure, biology, and function of peri-implant soft tissues in health and disease: a comprehensive review of the literature

Abstract

The morphogenesis of peri-implant soft tissues following surgical trauma, along with the nature, topography, and design of implant-prosthetic material surfaces, leads to peri-implant tissues that exhibit unique histological and morphological characteristics. It has been shown that mucosal phenotypes with a mucosal thickness of at least 2 mm and a keratinised mucosa width of at least 2 mm promote proper integration and a biological seal at the mucosa-implant interface. This seal prevents pathogen penetration, protects the underlying peri-implant bone, and reduces susceptibility to inflammatory peri-implant diseases (IPDs). Furthermore, even under ideal conditions, peri-implant soft tissues demonstrate less mechanical resistance, stability, and hermeticity compared to periodontal tissues. These deficiencies are directly associated with both the onset and progression of IPDs such as peri-implant mucositis (PM) and peri-implantitis (PI). Over recent decades, the prevalence of PM and PI has risen, making them the primary causes of implant failure. Given that the characteristics of peri-implant mucosa are closely linked to the progression of these diseases, a deep understanding of the biology of peri-implant soft tissues is crucial for developing strategies to either avoid or minimise the impact of IPDs on implant therapy outcomes. This comprehensive review of the literature aims to provide a precise and detailed description of the structure, biology, and function of peri-implant soft tissues, starting from their formation process and linking their morphogenic characteristics to the establishment and evolution of IPDs. Additionally, the composition of the microbiome and the most relevant anti/pro-inflammatory mediators involved in the development of IPDs are summarised.

Graphical Abstract

INTRODUCTION

The high predictability and acceptance of implant therapy have led to a significant increase in the use of dental implants for prosthetic oral rehabilitation [1]. Recent studies have reported survival rates ranging from 89% to 94.4% over follow-up periods of up to 16 years [1,2]. The reported failure rates vary between 1.9% and 3.6% [2].

Over the last decade, the prevalence of inflammatory peri-implant diseases (IPDs)—peri-implant mucositis (PM) and peri-implantitis (PI)—has increased, becoming the primary etiological factors for implant therapy failure [2]. Lee et al. [3] systematically analysed the prevalence of these peri-implant diseases, both implant-based and subject-based. They reported that the weighted prevalence of implant-based and patient-based PM was 29.48% (confidence interval [CI], 22.65–36.32) and 46.83% (CI, 38.30–55.36), respectively. Similarly, the weighted prevalence of implant-based and patient-based PI was 9.25% (CI, 7.57–10.93) and 19.83% (CI, 15.38–24.27), respectively [3]. These findings indicate that the health of peri-implant tissues and the biological conditions at their interface with dental implants significantly influence the long-term success rates of implant therapy.

The biological seal (BS) at the interface between the soft tissue (peri-implant mucosa) and the implant is formed by epithelium and connective tissue (CT). Various authors have noted that a deficient keratinised mucosa width (KMW) of less than 2mm is linked to increased microbial plaque accumulation and soft tissue inflammation, primarily at the mucosa-implant interface. This, in turn, leads to mucosal recession, attachment loss, and the development of IPDs [4]. Consequently, the KMW influences the dimensions of the BS [5]. It has also been suggested that an adequate peri-implant mucosal thickness (MT) of ≥2 mm is vital for maintaining the health of peri-implant tissues [6]. Kim et al. [7] and Linkevicius et al. [8] have shown that peri-implant phenotypes with a thin MT of <2 mm are susceptible to crestal bone loss during the formation of the peri-implant BS [7,8]. Other researchers have indicated that a thin MT tends to exacerbate the severity of IPDs, with observed increases in bleeding and recession of the peri-implant mucosa [9]. Therefore, an adequate KMW, along with a thick peri-implant mucosal biotype, is crucial in protecting peri-implant supporting tissues from the onset of IPDs. This facilitates proper integration and BS at the mucosa-implant interface, which in turn prevents pathogen penetration, protects the underlying peri-implant bone, and reduces susceptibility to IPDs [4,5,6,7,8,9]. However, even under optimal conditions, the peri-implant BS exhibits less mechanical resistance, stability, and hermeticity compared to that formed between periodontal tissues and dental surfaces. This difference is directly related to the biological characteristics of the peri-implant mucosa, as well as the onset and progression of IPDs [4,5,6,7,8,9]. Therefore, a thorough understanding of the biological nature of peri-implant soft tissues is essential to fully comprehend the progression of IPDs.

Since it is widely acknowledged that the scar-like nature of peri-implant soft tissues is one of the primary causes of the biological deficiencies that promote the emergence and progression of IPDs, numerous studies—mainly animal and in-vitro—have focused on elucidating the nature of peri-implant mucosa, the structural, functional, and molecular properties of the BS, and the immune mechanisms at the interface between the peri-implant mucosa and the implant. However, it is crucial to summarise, associate, and comprehensively analyse this heterogeneous information to identify the biological factors in peri-implant soft tissues that are key to the emergence and progression of PM and PI. This analysis aims to develop strategies to avoid or minimise the impact of IPDs on implant therapy outcomes [10]. Given this context, this comprehensive literature review summarises the most relevant information related to the structure, biology, and function of peri-implant soft tissues and explores how these characteristics may relate to the emergence of IPDs. Additionally, the composition of the microbiome, the inflammatory pathway, and the most relevant anti/pro-inflammatory mediators for the development of IPDs are summarised.

PART 1: HEALTH

Morphogenesis of peri-implant mucosa

Berglundh et al. [11] detailed the morphogenesis of peri-implant mucosa in a canine model, beginning with the placement of dental implants and their respective transmucosal abutments, following a single-stage implant/abutment placement protocol [11]. The process initiates with the formation of a blood clot between the implant, the mucosa, and the alveolar process, noticeable 2 hours post-surgery. By the fourth day, this clot is infiltrated by numerous granulocytic neutrophils, and a dense fibrin mesh containing leukocytes forms an initial peri-implant mucosal seal [11,12]. Subsequently, the clot starts to degrade due to the extensive leukocyte infiltration, triggering angiogenesis through the activation of epithelial, endothelial, and fibroblast cells. This promotes healing and epithelial proliferation, eventually leading to the development of the peri-implant epithelium (PIE) [11,12]. One week post-implantation, the initial mucosal seal remains, albeit with reduced fibrin and leukocyte content, confined to the marginal portion of the soft tissue-implant interface and predominantly composed of fibroblasts and collagen in its most apical part [11,12]. Two weeks after the procedure, the mucosa begins to adhere to the implant surface through a CT rich in fibroblasts and vascular structures, showing early signs of PIE formation, analogous to the junctional epithelium (JE) found in periodontal tissues [11,12]. Between 6 and 12 weeks post-surgery, complete healing of the PIE is evident, along with a dense layer of fibroblasts aligned parallel to the implant surface, forming part of the subepithelial peri-implant connective tissue (PCT). The bone crest establishes itself approximately 3 mm below the soft tissue margin (mucosal margin [MM]) [11,12,13]. Histologically, the PIE is longer than the JE, akin to a long JE, and the PCT resembles scar-like CTs [14].

Structure of peri-implant soft tissues

During the healing process following the placement of a dental implant, 2 main phenomena can be identified, which are independent yet highly related: osseointegration and periointegration, both of which occur as a foreign body response [15]. Osseointegration is defined as a direct structural and functional connection between newly formed bone and the implant surface, synonymous with the biomechanical concept of secondary stability [16]. This process involves a cascade of complex physiological mechanisms similar to those seen in the direct healing of a bone fracture and typically takes about 3 to 6 months after the implant is inserted into the alveolar bone [15]. From a genetic perspective, osseointegration appears to be associated with significant deregulation of the immune-inflammatory response, which in turn promotes the over-expression of genes related to osteogenesis, angiogenesis, and neurogenesis during the early stages of the healing process [15,17]. Periointegration refers to the formation and maturation of peri-implant soft tissues around a transmucosal abutment, establishing a direct connection between the intraosseous implant and the oral cavity. This usually occurs between 8 and 12 weeks after the installation of the transmucosal abutment [15]. It is important to note that even after successful osseointegration and periointegration, peri-implant tissues exhibit considerable differences from periodontal tissues [15,18]. Unlike periodontal tissues, which develop concurrently with dental eruption, peri-implant tissues arise from a healing process following surgical trauma [15,18]. These differences in morphogenesis lead to specific structural and morphological characteristics in the peri-implant tissues, such as the absence of a periodontal ligament, a deeper peri-implant sulcus (PS), poor vascular supply due to its scar-like nature, and marked differences in histological and functional terms at the level of the PIE and PCT responsible for creating the BS around dental implants. Consequently, these biological structures have a lower capacity for integration and adhesion around dental implants compared to the BS generated by periodontal tissues [15,19]. However, it is crucial to emphasise that there are still many gaps in our understanding of the biology and mechanisms of the BS of peri-implant soft tissues (Figure 1) [19].

Figure 1. Parallel comparison of the anatomical structure in periodontal tissues (A-C) vs. peri-implant tissues (B-D). (A-C) JE, SE, GM, GS, OE. (B-D) MM, PISE, PIE, PCT, OE.

JE: junctional epithelium, SE: sulcular epithelium, GM: gingival margin, GS: gingival sulcus, OE: oral epithelium, MM: mucosal margin, PISE: peri-implant sulcular epithelium, PIE: peri-implant epithelium, PCT: peri-implant connective tissue.

PIE

The epithelium surrounding dental implants exhibits differentiation and functional patterns akin to those of gingival tissue [19]. This epithelium is composed of 3 types of stratified squamous epithelia: (i) the PIE, (ii) the peri-implant sulcus epithelium (PISE), and (iii) the oral epithelium (OE) [19]. Unlike the PISE and OE, the PIE is characterised by its non-keratinised nature, featuring wide intercellular spaces and weak intercellular contacts [19]. The PIE develops from the OE within 2–3 weeks after the installation of a transmucosal abutment [19,20]. Initially, the PIE may be in close contact with both the dental implant and the transmucosal abutment. However, over time, the interface between the implant and abutment can become a site for infection and inflammation, leading to peri-implant bone resorption. This typically results in the PIE shifting to a more apical position, where it contacts only the implant surface [19].

Animal studies have defined the PIE as a histological structure consisting of several layers of flattened epithelial cells. These cells lack keratin in their stratum corneum, making the PIE similar to the JE found in periodontal tissues [19,20]. Like the JE, the PIE is encased by a basal membrane (BM), which is composed of structural proteins such as type IV collagen, fibronectin, and laminin [19]. This BM includes 2 layers: the internal basal laminae (IBL) and the external basal laminae (EBL). Each of these laminae is further divided into a lucid lamina (LL) and a dense lamina (DL), facilitating the adherence of epithelial cells to various surfaces [19,20]. The IBL, primarily made up of laminin 332 and type VIII collagen, connects the PIE to the implant surface [19,20,21,22]. The LL of the IBL is directly inserted into the plasma membrane of the PIE cells, supported by hemidesmosomes (HDs) and epithelial adhesion plates. Meanwhile, the DL of the IBL connects directly to the implant surface through HDs, forming a BS between the epithelium (PIE) and the implant surface [19,20]. Consequently, PIE cells attach to the titanium surface via the IBL and HDs, mirroring the attachment between the JE and the surface of natural teeth [19,20]. HDs, a family of integrins including integrin β6α, plectin, CD151, BP230, and BP180 (type XVII collagen), specialise in epithelial adhesion. This allows cells to firmly attach to the surface of dental implants and establishes connections between the keratin in the epithelial cells' cytoskeleton and the LL [22]. However, it has been reported that the IBL (LL and DL) and HDs are only found in the most apical region of the PIE-titanium interface, unlike in periodontal tissues where the presence of IBL and HDs is evident along the entire JE-tooth interface [15,19,20]. Furthermore, the presence of certain molecules associated with epithelial adhesion and migration, such as laminins (LMNs)—a family of high molecular weight glycoproteins consisting of 3 heterotrimeric chains (γ, β, α) linked by disulphide bridges—has been studied. These molecules, which constitute the majority of the basal laminae’s extracellular proteins and are highly expressed in the laminae between the JE and the tooth surface, enhance the hermetic seal. Their expression has also been analysed at the peri-implant tissue level [21,22]. Some authors have identified an IBL, 100 nm wide, positive for LMN-1, LMN 332 (LMN-5), and HDs as adhesion structures at the apical portion of the IBL at the PIE-implant interface [21]. These findings suggest a suboptimal insertion of the PIE onto the titanium surface [21]. The EBL, rich in extracellular matrix proteins, links the PIE to the CT surface of the peri-implant mucosa [19,20]. The LL of the EBL directly anchors to the basal cells of the PIE via HDs, while the DL connects to a fibroreticular lamina or sub-dense lamina (Figure 2) [19,20,21,22].

Figure 2. Schematic representation of the PIE. Left: PIE’s BM consists of IBL and EBL. Notably, the IBL only encompasses the PIE at its most apical level. Middle: The IBL and EBL are divided into LL and DL, through which the epithelial cells adhere to different surfaces. The inter-epithelial cell adhesive junctions are mediated by DSMs. Right: The IBL adheres to the implant surface via HDs and LMNs [19,20,21,22].

PIE: peri-implant epithelium, BM: basement membrane, IBL: internal basal laminae, EBL: external basal laminae, LL: lucid lamina, DL: dense lamina, DSM: desmosome, HD: hemidesmosome, LMN: laminin.

PCT

The CT located apical to the PIE and JE around implants and teeth, respectively, plays a crucial role in protecting against various noxious agents, such as bacterial penetration and irritants. It also facilitates the acquisition of nutrients from its vascular supply [19,22]. Positioned just apical to the PIE, the PCT is essential for stabilizing the apical migration of the PIE and preventing bone resorption. However, the peri-implant mucosa’s morphogenesis and scar-like nature result in the PCT having a lower vascular supply compared to the periodontal CT. This leads to peri-implant epithelia that are less vascularised and have reduced nutritional support [19,22].

In natural teeth, the main component of the periodontal CT, located apical to the JE, consists predominantly of type III collagen fibres produced by fibroblasts. These fibres are organised into bundles with various orientations, including dento-gingival, dento-periosteal, alveolo-gingival, and transseptal, among others. These bundles attach to the root cementum surface, creating a tight seal between the CT and the dental surface [23]. The PCT located under the PIE is primarily composed of type I and III peri-implant collagen fibres (PICF), whereas the supra-crestal PCT consists mainly of type I-PICF [22]. Both subepithelial type I and III PICF predominantly exhibit a parallel orientation to the implant surface, without attaching to it [19,22]. Human histological studies have also revealed the presence of PICF bundles arranged in a circular pattern around the transmucosal abutment and the implant platform, which may contribute to the stability of the soft tissue [24].

The lamina propria of the peri-implant mucosa is notably rich in type V collagen fibres, which are resistant to collagenase. This suggests that the CT surrounding dental implants resembles scar-like tissue, resulting from a chronic inflammatory phenomenon, rather than acting as a sealing or defensive structure like periodontal CT. Such a composition could lead to accelerated horizontal recessions [19,22].

Moon et al. [25] examined a 200-μm-wide zone of PCT adjacent to the implant surface using a scanning electron microscope. The analysis revealed that PCT adhesion consists of 2 distinct layers: (i) an inner layer, approximately 40 μm in width, which lacks vascular supply and contains a high concentration of flattened fibroblasts (32% of the volume). These fibroblasts, interspersed with thin PICF, appear to be in close contact with the implant surface. Within this layer, both the fibroblasts and the collagen molecules are oriented parallel to the implant surface, extending from the periosteum to the OE [25]. Notably, the CT cells and PICF bundles are separated from the titanium oxide (TiO₂) surface by a 20nm layer of proteoglycans [26]. Consequently, the mechanical strength of the PCT’s adhesion to the implant surface is inferior to that of natural teeth. (ii) An outer layer, about 160 μm in width, predominantly comprises PICF (83%), fibroblasts (11%), and vascular structures (3%) (Figures 3 and 4) [25].

Figure 3. Schematic comparison of the PCT and periodontal CT. Left: while periodontal tissues have a broad blood flow from the PL, the PO, and the CT, the vascular supply of the peri-implant mucosa is predominantly from its CT [19,22]. Middle: Histological zones of the PCT, separated from the implant surface by a 20-nm proteoglycan layer [25,26]. Right: schematic representation of collagen fibres running through the periodontal CT (DGF, DPF, AGF, PF) and PCT, PICF) running parallel to de dental implant [19,22,23].

PCT: peri-implant connective tissue, CT: connective tissue, PL: periodontal ligament, PO: periosteum, DGF: dento-gingival, DPF: dento-periosteal, AGF: alveolo-gingival, PF: periodontal fibres, PCT: peri-implant connective tissue, PICF: peri-implant collagen fibres.

Figure 4. Orientation of PICFs. Left: Circular PICFs running around the dental implant. PICFs parallel to the dental implant (blue dots) (axial view). PICFs fail to attach to the implant surface [19,22,24].

PICF: peri-implant collagen fibre.

PS

The PS shares structural, ultrastructural, and functional characteristics with the gingival sulcus (GS) from periodontal tissues [27]. The PS is anatomically defined as the space between the dental implant surface and the PISE, histologically extending from the MM to the PIE. However, when the depth of the PS is assessed with a periodontal probe, the PIE may be displaced apically or even penetrated by the probe before resistance from the PCT at the bottom of the sulcus is detected [28,29]. Studies have shown that the depth of clinical probing under a pressure of 0.5N is typically greater around implants than around natural teeth [27,29]. In terms of health, periodontal probing around teeth is <3 mm, compared to 2.5 to 4 mm around dental implants [27]. However, unlike with natural teeth, increased peri-implant probing measurements cannot always be considered a diagnostic test for peri-implant pathology [30]. Long-term clinical studies have conclusively shown that the probing depth of healthy peri-implant mucosa tends to be >4 mm (60% to 63%), and greater than 6 mm (15% to 23%) [30,31,32]. Furthermore, implants deemed successful after more than 18 years of function could exhibit probing depths of up to 9 mm, leading some authors to suggest that probing depth levels are a poor indicator of peri-implant pathology [31,32]. Peri-implant probing depth is influenced by various factors such as the peri-implant phenotype at the time of implant placement, anatomical conditions, implant design, and the position of the implant platform relative to the crestal bone [30,33,34]. Therefore, no specific peri-implant probing depth conclusively indicates the presence of peri-implant pathologies, as specified in the new classification scheme of periodontal and peri-implant diseases and conditions: “it is not possible to define a range of probing depths compatible with peri-implant health” [35]. Additionally, some authors have suggested that the fragile connection between the PIE and the implant surface means the epithelial seal can be easily disrupted by slight pressure from the periodontal probe, often inducing bleeding; thus, bleeding on probing (BOP) is also considered a poor indicator of peri-implant pathology [19,30]. Moreover, the disruption of the epithelial seal during peri-implant probing allows bacteria to infiltrate deep areas of the peri-implant biological space, accelerating the physical destruction of the PIE and the PCT [19,30]. Given these considerations, peri-implant probing appears to offer limited and often counterproductive benefits. Therefore, a visual inspection of the peri-implant soft tissues, assessing colour, tone, consistency, and the flow of crevicular fluid, should be additional factors considered when evaluating the health of the peri-implant mucosa [19].

Similar to the GS, the PS contains an inflammatory exudate known as peri-implant crevicular fluid (PCF), which primarily originates from the vessels of the peri-implant mucosa plexus. The PCF plays a crucial role as an antimicrobial defence mechanism, essential for maintaining the integrity of various structures within the peri-implant mucosa, including the biological width [27,36]. The PCF comprises serum, locally produced substances from CT and bone proteins (such as laminin, osteonectin, osteocalcin, peptidases, and haemoglobin peptides), glycosaminoglycans (including hyaluronic acid, chondroitin sulphate, dermatan sulphate, hydroxyproline, and fibronectin fragments), inflammatory mediators and biological response modifiers (such as cytokines, tumour necrosis factor, interferon alpha, substance P, interleukin E2, leukotrienes, and acute phase proteins like lactoferrin, transferrin, and C-reactive protein), antibodies against dental plaque microorganisms (IgG, IgM, IgA), and host-derived enzymes such as elastases, collagenases (MMP-1, -8, -13), gelatinases (MMP-2, -9), myeloperoxidases, and stromelysins (MMP-3, -10, -13), along with their respective inhibitors, including elastase inhibitors (alpha-2 macroglobulin and alpha-1 antitrypsin) and MMP inhibitors (TIMP-1) [27]. Additionally, PCF is rich in leukocytes, particularly polymorphonuclear leukocytes (PMNs), which are drawn to the crevicular fluid by various chemotactic gradients [27,36]. After crossing the BM, the PIE serves as the primary diffusion pathway for PCF into the PS [27,36]. Clinically healthy implants typically exhibit a higher volume of PCF and a greater concentration of pro-inflammatory cytokines compared to the GS of periodontally healthy teeth [27,37]. Several human biomarkers in PCF associated with a healthy PS have been identified, including angiotensinogen, clusterin, thymidine phosphorylase, the β-defensin family, cathelicidin (LL-37), calprotectin, and adrenomedullin, among others [15]. During inflammatory conditions such as PM and/or PI, there is a significant increase in the volume of PCF, accompanied by elevated levels of pro-inflammatory mediators and enzymatic activity. This leads to a substantial increase in the inflammatory infiltrate, characterised by a higher proportion of plasma cells, macrophages, and neutrophils compared to those found in periodontitis (Figure 5) [27,37].

Figure 5. (A) CF at the gingival sulcus. (B) Similar to CF, the PCF is composed of serum, products derived from the PCT, bone proteins, glycosaminoglycans, leukotrienes, acute phase proteins, antibodies against dental plaque microorganisms (IgG, IgM, IgA), host-derived enzymes, myeloperoxidases, stromelysins with their respective inhibitors, MMP, inammatory mediators, and biological response modiers, among others [27].

CF: crevicular fluid, PCF: peri-implant crevicular fluid, PCT: peri-implant connective tissue, Ig: immunoglobulin, MMP: matrix metalloproteinase, LMN: laminin, PMN: polymorphonuclear leukocyte, TNF: tumor necrosis factor, CRP: C-reactive protein, TIMP: tissue inhibitors of metalloproteinase.

Peri-implant biological width (supra-crestal tissue attachment)

Based on the work of Gargiulo et al. [38], the term “biological width” is used to describe the apico-coronal dimensions of the dento-gingival attachment apparatus (JE and supra-crestal CT) surrounding a natural tooth. In 2017, during the World Workshop on the Classification of Periodontal and Peri-Implant Disease and Conditions, “biological width” was redefined as “supra-crestal tissue attachment” [39]. Research has shown that the dimensions of the supra-crestal tissue attachment in natural teeth range from 1.7 to 2.7 mm, with the JE component measuring between 0.71 and 1.35 mm and the CT component between 1.06 and 1.99 mm [22,38]. Studies on dental implants in animal models indicate that the dimensions of the supra-crestal tissue attachment are slightly larger than those in natural teeth. The peri-implant supra-crestal tissue attachment dimensions have been found to vary from 3 to 4 mm, with the PIE component ranging from 2.02 to 2.3 mm and the PCT component from 1.1 to 1.49 mm across various studies (Figure 6) [22,40,41].

Figure 6. Parallel comparison of anatomical structures and their dimensions in periodontal tissues vs. peri-implant tissues. Left: periodontal structures (OSE, JE, periodontal CT, OE, PL, RC. Middle: biological width dimension. Right: peri-implant structures (PISE, PIE, PCT, OE [22,40,41].

OSE: oral sulcular epithelium, JE: junctional epithelium, CT: connective tissue, OE: oral epithelium, PL: periodontal ligament, RC: radicular cement, PISE: peri-implant sulcular epithelium, PIE: peri-implant epithelium, PCT: peri-implant connective tissue, OE: oral epithelium.

Some factors that regulate the stability of the peri-implant MM include the dimensions of the soft tissues that make up the supra-crestal tissue attachment. Peri-implant phenotypes with thin MT are more prone to having a smaller supra-crestal tissue attachment, which can lead to crestal bone loss and recessions of the peri-implant MM, thereby affecting the effective dimension of the supra-crestal tissue attachment [22]. Additionally, the presence of keratinised mucosa positively influences the health of peri-implant tissues and helps maintain the position of the peri-implant MM by accelerating the formation of the peri-implant BS (PIE + PCT) [22]. It is also important to note that the dimensions of the peri-implant supra-crestal tissue attachment can vary based on the design of the dental implants and their surface treatments. For example, in conical implants with an internal hex, the dimensions of the supra-crestal tissue attachment range from 3.13 to 3.34 mm (PIE = 1.64−1.93/PCT=1.21−1.32) [22,42]. In monobloc implants, the supra-crestal tissue attachment measures approximately 2.55±0.16 mm, compared to 3.26±0.15 mm in 2-component implants [22]. Furthermore, the dimensions of the peri-implant supra-crestal tissue attachment can vary from 2.84 to 3.80 mm (PIE=1.33−2.31/PCT=1.28−1.70), depending on different surface treatments such as sand-blasting and acid etching [22,43].

In periodontal tissues, the supra-crestal tissue attachment serves as a natural protective barrier—both biological and mechanical—shielding the underlying periodontal ligament and alveolar bone from the penetration and/or invasion of particles and microorganisms from the oral cavity. Such invasions could potentially trigger infectious and inflammatory phenomena [19]. This attachment performs several crucial immunological functions: (i) the endocytosis and decomposition of exogenous substances by neutrophils, (ii) the endocytosis and decomposition of exogenous factors by the JE itself, (iii) the antibacterial action of crevicular fluid, and (iv) the exfoliation of the JE cell layer [19]. It has been suggested that, due to the biological similarities between the tissues forming the supra-crestal tissue attachment in both teeth and implants, the peri-implant supra-crestal tissue attachment also serves as a defence mechanism. This mechanism protects the underlying bone, prevents the development of peri-implant inflammatory pathologies, ensures healthy conditions, and facilitates stable osseointegration [22,44].

Studies using animal models to evaluate the immune functions of the peri-implant supra-crestal tissue attachment have shown an increase in leukocyte migration and accumulation through the PIE in response to continuous bacterial plaque accumulation, compared to non-infected implants (1.9% vs. 0.9% respectively). This suggests an immune response to infectious phenomena [44,45]. Additionally, models that combined uninterrupted bacterial plaque accumulation with mechanical damage to the peri-implant supra-crestal tissue attachment demonstrated an accelerated loss of peri-implant crestal bone [44]. This contrasts with studies where implants were subjected to continuous plaque formation without mechanical damage to the supra-crestal tissue attachment over various periods, which resulted in only minor bone loss and mild peri-implant mucosal inflammation [44,45]. Human histological studies have also revealed a greater transmigration and density of inflammatory cell populations such as PMN, T and B lymphocytes, plasma and mononuclear cells, and cells positive for elastase (a biomarker indicating pathological stimulation of granulocytes [PMN]), through the PIE in implants with established infectious phenomena compared to healthy implants [44,46].

It has been demonstrated that peri-implant pathologies progress more severely than periodontal pathologies, particularly in terms of bacterial plaque accumulation, and the rate and extent of tissue destruction (including damage to the peri-implant mucosa, bone resorption, and the formation of peri-implant pockets) [19]. Peri-implant pockets form due to epithelial down-growth at the interface between the soft tissue and the implant [47], creating a niche for anaerobic bacteria that can exacerbate inflammatory conditions [19]. Given these issues, it is crucial to acknowledge the limited sealing capacity of peri-implant soft tissues and to ensure that patients receive regular follow-ups after implant therapy.

PART 2: DISEASE

IPDs: overview

PM and PI are 2 inflammatory conditions that contribute to the failure of osseointegrated implants. The European Federation of Periodontology and the American Academy of Periodontology have introduced a recent classification for peri-implant diseases and conditions. This classification defines peri-implant health as a state where immune surveillance maintains homeostasis and the clinical health of the peri-implant mucosa. This health is characterised by the absence of erythema, BOP, inflammation, and/or suppuration in the tissues surrounding a dental implant [48]. It also notes that a specific range of probing depths indicating health cannot be defined, and peri-implant health may even exist around implants with reduced bone support [48]. The primary clinical indicator of PM is BOP. BOP is an early sign of underlying inflammation and is considered a key symptom of PM [15,48]. In 98.8% of clinical cases, an absence of BOP correlates with healthy PS. BOP is present in 67%–90% of PM cases and in over 97% of PI cases [15]. Other common clinical signs of PM include erythema, inflammation, and/or suppuration. During PM, inflammatory phenomena lead to decreased resistance to probing, often resulting in increased probing depth levels (Figure 7) [48]. If the etiological factors causing these inflammatory phenomena are not controlled early in the IPD, PM can progress to PI. PI is a plaque-associated pathological condition that occurs in tissues around dental implants, characterised by progressive bone loss after the functional loading of the implants, which is evident radiographically. PI also presents clinical signs similar to those of PM, including BOP and/or suppuration, increased probing depths, and/or MM recession [48]. Additionally, the diagnosis of PI is associated with signs such as progressive peri-implant bone loss greater than 2mm per year, or exposure of more than 2–3 mm from the implant-abutment connection to the oral cavity due to marginal bone resorption, or the exposure of more than 3 intraosseous screw threads [15].

Figure 7. (A) Healthy vs. (B) inflammatory peri-implant disease.

Several risk factors have been proposed for the onset of both IPDs, which can be grouped into 6 categories: (i) general factors associated with the patient, (ii) local factors associated with the patient, (iii) factors related to the implant designs, (iv) microbiological factors, (v) prosthodontic/implant conditions, and (vi) the biology/nature of the peri-implant tissues [15,49,50,51]. The interplay of these closely related factors predisposes the onset and progression of IPDs [15]. Albrektsson et al. [52] suggested that marginal bone loss associated with IPDs results from the combined effects of several factors with immuno-osteolytic capabilities. These factors synergistically disrupt the delicate balance between osteoblasts and osteoclasts, thereby inducing pathological bone resorption processes [52].

Risk factors for peri-implant diseases

Patient-related general factors

General patient-related factors are those that threaten or lead to the loss of previously established osseointegration. Such factors are commonly associated with the development of chronic infectious phenomena with a high immunogenic capacity [15]. Multivariate analysis studies have indicated that a history of chronic periodontitis is significantly associated with PI (adjusted odds ratio [OR], 2.55; 95% CI, 1.14−5.70; P=0.02) [53]. Patients with a history of mild, moderate, and severe chronic periodontitis show a significantly higher prevalence of IPDs compared to those without such a history (8.7%, 22.2%, and 35% vs. 10.9%, respectively) [53]. Poorly controlled diabetes mellitus, indicated by an haemoglobin A1c level greater than 8%, is linked to deeper probing depths, BOP, and peri-implant bone resorption [54]. Certain genetic traits may influence the host's immune-inflammatory response, which in turn affects colonization patterns and specific changes in the oral biofilm [15]. Individuals carrying the IL-1RN VNTR polymorphism, IL-6−174 polymorphism (G allele and GG genotype), and specific interleukin-17 (IL-17, a pro-inflammatory cytokine) polymorphism are at an increased risk of PI [55]. Similarly, polymorphisms in bone morphogenetic protein/retinoic acid-inducible neural-specific 3 (BRINP3) and low levels of BRINP3 expression are associated with a higher risk of PI. Specific haplotypes of FGF10 and BMP4 have also been linked to a predisposition for IPD [55]. It has been reported that smoking, even under clinically healthy conditions, can alter the peri-implant microbiome by promoting the growth of pathogenic species and reducing commensals [15]. A recent systematic review and meta-analysis examining the impact of smoking on the incidence of PI revealed a significant difference in risk between smokers and nonsmokers (implant-based [P<0.0001] and patient-based [P=0.003]). Additionally, a strong association was observed between smoking and the risk for PI at both the implant level (relative risk [RR], 2.04; 95% CI, 1.46−1.85) and patient level (RR, 2.79; 95% CI, 1.42−5.50) [56].

Patient-related local factors

Local factors are those that can serve as focal points for the formation and maturation of supra-mucosal bacterial plaque, which is considered the primary event in the development of IPDs [15]. Patients with PM and PI exhibited a significantly higher frequency of poor oral hygiene (P<0.05, χ² post hoc pairwise-comparison test) [57]. Additionally, it has been noted that a pre-existing periapical inflammatory condition related to infectious endodontic pathology in an adjacent tooth may initiate a specific type of PI known as retrograde PI. This condition primarily affects the apical portion of the implant while the coronal portion remains osseointegrated. The reported incidence of retrograde PI is 7.8% [58].

Implants diagnosed with PM and PI exhibit a significantly higher incidence of preoperative alveolar ridge deficiencies, including horizontal, vertical, or combined defects (P<0.05, χ² test) [57]. Furthermore, predictive models, demonstrating an accuracy of 82.35%, have identified failed bone reconstruction—characterised by the resorption of augmented bone and exposed implant surfaces (OR, 2.35)—as a critical risk factor for the development of peri-implant pathologies [49].

Prosthodontic/implant conditions

When prosthetic design does not ensure adequate cleanability, the risk of developing IPDs increases. Features such as a middle implant splinted to both the mesial and distal adjacent implants, convex emergence profiles, and an implant-abutment emergence angle of 30° or more, may complicate the patient’s daily hygiene routines [51,59]. Placing the implant closer to the buccal area can provide a more natural contour and emergence profile. Additionally, a smaller emergence angle of the restoration could result from using a wider diameter or placing the implant deeper. This adjustment would elevate the proximal contact point, expand the interproximal area, and simplify plaque maintenance [51,59]. Tissue-level implants are associated with a lower prevalence of IPDs and show no significant correlation with emergence angle and emergence profile [51]. Unlike bone-level implants, tissue-level implants do not have an implant-abutment interface at the bone crest, eliminating the micro-gap at the bone level and preventing early bacterial contamination. Moreover, because the implant platform is at the tissue level, larger emergence angles and convex emergence profiles may not affect the peri-implant tissues [51]. Conversely, implants with a platform-matched flat-flat implant-abutment connection have demonstrated post-osteointegration bone remodelling, characterised by a crater-like loss of bone around the implant platform. This loss exposes the implant’s rough surface into the PS, jeopardizing long-term peri-implant health. Consequently, the platform-switching concept has been recently recommended [50]. Ortiz-Echeverri et al. [57], in a retrospective cross-sectional study of 379 implants placed in 155 patients, found that the OR of PM was significantly increased (P<0.01, Wald test) in cases where the implant length was 11.0 mm or less [57]. Excessive overload on dental implants can cause microfractures in the marginal bone area around the implant, leading to a local inflammatory response that may result in the loss of osseointegration at the implant platform. However, the impact of occlusal overload on PI remains a topic of debate [60].

Biology of peri-implant tissues

The scar-like nature and biology of peri-implant tissues contribute to the susceptibility to developing IPDs [15]. Morphogenic characteristics of peri-implant tissues, such as the absence of a periodontal ligament, poor vascular supply, a deeper PS, poor integration of the PIE, and weak adhesion of PCT to the titanium surface, facilitate the penetration of highly pathogenic bacteria into the depths of the peri-implant mucosa and the underlying alveolar bone [15,21]. Traditionally, it has been suggested that peri-implant phenotypes with an adequate KMW (≥2 mm) around dental implants can facilitate proper oral hygiene measures, reduce bacterial plaque accumulation rates, and thus minimise the incidence of IPDs [61]. However, a recent meta-analysis reported that adequate KMW does not influence probing depth, soft tissue recession, or marginal bone loss compared to deficient KMW [61]. It has also been reported that bone-level implants placed in naturally thick mucosal tissues (>2 mm) experience less peripheral bone loss than those surrounded by peri-implant phenotypes with thin MT (bone loss of 0.25 mm and 1.38 mm, respectively) [6,7,8,9,62]. If an ideal peri-implant MT is not achieved at the time of implant placement, the formation of the supra-crestal tissue attachment, which involves bone loss, will occur [62]. Therefore, in the long term, thin MT could favour the exposure of implant surfaces, food impaction, and facilitate bacterial colonization [6,7,8,9,62].

Physicochemical characteristics of the implant surface

The physicochemical characteristics of dental implant surfaces are directly linked to patterns of bacterial colonization. The formation of an acquired pellicle (AP) on the surface of dental implants, which occurs before bacterial colonization, is a crucial step for the subsequent development of bacterial biofilm [15,63]. The AP, primarily composed of proteins and glycoproteins from saliva, enhances the adherence and coaggregation of oral bacteria. It can cover all implant surfaces almost immediately after exposure to the oral environment, regardless of surface wettability or roughness [15,63]. The attachment of various bacterial species to the AP is facilitated by trans-membranous proteins known as adhesins, predominantly lectins [15,63]. Bacterial colonization on the AP begins roughly 30 minutes after the implant's exposure to the oral environment [15]. Factors such as free-energy (which describes the interaction of adhesion and cohesiveness forces affecting the wetting property or the spread of a liquid across a surface), wettability/hydrophobicity, and the roughness of the implant surface primarily influence bacterial adhesion to the AP [15,63]. Implants with high levels of surface free-energy (SFE) exhibit increased bacterial colonization [64]. Al-Radha et al. [64] concluded that zirconia's ability to reduce bacterial adhesion is due to its lower SFE compared to titanium, suggesting that SFE is a key determinant in initial bacterial adherence to the implant surface [64]. Similarly, the kinetics of cell adherence to the implant surface are thought to be influenced by aspects of surface wettability/hydrophobicity. Bacterial plaque accumulates more on hydrophobic surfaces than on hydrophilic ones. Most oral bacterial species possess hydrophobic cell walls, enabling them to attach to similarly hydrophobic surfaces [15]. Additionally, the rough surface of dental implants promotes bacterial mechanical retention/adhesion. Surface roughness (Ra >0.2 μm) is the primary cause of peri-implant breakdown due to its role in accelerating biofilm development [63]. If pathogenic bacteria colonise the implant surface in sufficient numbers, a host immune-inflammatory peri-implant response becomes inevitable [15].

Bacterial-related factors

Microorganisms and their products are significant triggers in the peri-implant inflammation process. The microbiome associated with dental implant surfaces has been studied using traditional microbiological methods, including bacterial cultures [65,66], conventional polymerase chain reaction (PCR) [65,67], quantitative PCR [65,68], nested PCR [65,69], and DNA hybridization [65,70]. Additionally, next-generation sequencing technologies [65,71] have facilitated the identification of phylotypes that are undetectable by classical in vitro bacterial culturing techniques. These uncultivable bacteria constitute approximately 60% of the more than 700 bacterial species identified in the oral cavity [72]. Despite the diversity of methods and sequencing strategies, the different populations studied, and the high sensitivity in terms of methodological and result analysis, these studies produce a wide variety of information. This variety complicates the precise definition of the microbiome associated with dental implants. However, a significant proportion of the bacterial sequences obtained from implant biofilms in various studies appear to be similar, suggesting the existence of distinct “core microbiota” associated with “healthy” and “diseased” conditions [15,71].

Gram-positive cocci, comprising 45% to 86% of the population, along with nonmotile bacilli and a small number of gram-negative anaerobic species, predominantly constitute the supra- and subgingival dental plaque in the early stages of biofilm formation [15,73]. Diaz et al. [74] identified early colonisers as including Streptococcus sanguinis, Streptococcus infantis, Streptococcus oralis, and Streptococcus thermophilus, followed by Gemella haemolysans and Neisseria pharynges. These bacterial species form a core group that establishes the foundation for subsequent colonization by facultative and obligate anaerobes [74].

Uninterrupted plaque accumulation and maturation on the implant surface lead to PM, which in turn causes an increase in spirochetes, cocci, and motile bacilli. This results in a higher proportion of periodontopathogenic bacteria, primarily Porphyromonas gingivalis, Tannerella forsythia, Prevotella intermedia, Fusobacterium nucleatum, and Eubacterium species. These bacteria play crucial roles in the transition from a healthy implant status to peri-implant disease due to their biotic interactions with other bacteria in the early stages of the disease [15,75,76,77]. Additionally, there is often a decrease in Actinomyces and Streptococci species. Notably, bacteria from the orange complex, known to be periodontopathogenic, can occasionally colonise a healthy PS without causing any signs of inflammation [15,75,76,77]. Schincaglia et al. [37] evaluated the microbiome, inflammatory biomarkers, and clinical parameters at implant sites in response to experimental plaque accumulation over 21 days, transitioning from healthy peri-implant sockets to PM. The composition of the implant biofilm did not show any statistically significant changes until the 21st day, when a gradual shift associated with the over-expression of IL-1α, IL-8, increased microbiota diversity, and clinical inflammation became evident. The main drivers of microbial variability at the genus level, based on the θ_YC distance, were Tannerella, Treponema, Fretibacterium, Fusobacterium, TM7[G-1], Eubacterium, Prevotella, Atopobium, Streptococcus, Rothia, and Granulicatella. However, variations in microbiome succession patterns were observed among the subjects [37]. Zheng et al. [68], using a subsample of 8,000 16s-metagenomic reads from each dataset (healthy implant [HC], PM, PI sites), calculated the alpha diversity values to compare the overall microbial diversity among the groups. Diversity increased (in terms of observed OTUs, Chao1, Shannon index, and phylogenetic diversity) in both PI and PM compared to HC. Notably, there were no statistical differences (P>0.05) between PM and PI, implying that PM is a crucial early stage of transition before the development of PI [68]. The development of PI may result from persistent inflammation that spreads further and reaches deeper areas of the peri-implant region. PI is caused by a heterogeneous mixed infection involving uncultivable asaccharolytic Gram-positive rods, other anaerobic Gram-negative rods, and periodontopathic microorganisms. Opportunistic bacteria such as enteric rods and Staphylococcus aureus are infrequently observed [65]. An increase in pathogenic bacteria from the orange and red complexes is typically associated with PI. However, the bacterial species associated with PI and those involved in periodontal disease significantly differ, with the PI microbiome being more diverse than that in periodontitis [15,77]. Additionally, several Eubacterium species have been proposed to have a direct correlation with the onset of PI. PI also exhibits a high abundance of Eubacterium minutum in the co-occurrence analysis alongside Prevotella intermedia [68,77]. Figure 8 summarises the core microbiome of different peri-implant statuses (HC, PM, PI) [15,37,65,68,73,74,75,76,77]. Figure 9 summarises, groups, and represents the co-occurrence of the main risk factors linked with the onset and progression of implant-related diseases [15,49,50,51,53,54,55,56,57,58,59,60,61,62,63,64,71].

Figure 8. Core microbiome of different peri-implant statuses identified by sequencing (HC, PM, PI) [15,37,65,68,73,74,75,76,77].

HC: implant health, PM: peri-implant mucositis, PI: peri-implantitis.

Figure 9. Co-occurrence of the main risk factors linked to the onset and progression of inflammatory peri-implant diseases [15,49,50,51,53,54,55,56,57,58,59,60,61,62,63,64,71].

The inammatory pathway of peri-implant diseases

The formation of bacterial biofilm on the surface of dental implants involves various stages, including adhesion, growth, maturation, and dispersion [77]. Initially, microorganisms adhere to the implant surface through electrostatic attractions and then secrete extracellular polymeric substances, which are crucial for the biofilm's functional and structural integrity. Standard antibiotic therapy and human immune responses are generally ineffective against these co-aggregated bacteria within biofilms [77,78]. A transition from a healthy PS to an infected peri-implant pocket is triggered by bacterial pathogenic activity during the biofilm's maturation phase [15,77,78]. This persistent biofilm leads to hyper-inflammation, causing collateral damage to the neighbouring host tissues [78]. Initially, PMN migration through CTs is chemotactically stimulated by bacterial products in the PS [15,79]. In response, the host’s immune system releases pro-inflammatory soluble mediators, including cytokines (IL-1β, IL-6, IL-8, IL-17, IL-18, IL-23, tumor necrosis factor [TNF]-α, MIP-1α, ICTP, MMPs-1-2-7-8-9-13, cathepsins, and TNF-related weak inducer of apoptosis [TWEAK]), anti-inflammatory cytokines (IL-4, IL-10, IL-1RN, IL-1α, tissue inhibitors of metalloproteinases [TIMPs] 1 and 2, and serine protease inhibitors [SERPIN-Bs] B1, B3, B4, and B5), chemokines, eicosanoids, prostanoids, enzymes, and toxins. These are triggered by endotoxins (such as lipopolysaccharides) and virulence factors (such as Gingipains) produced by bacteria (Figures 10 and 11) [15,77,80,81,82,83,84,85,86,87,88,89,90,91]. The physiopathological interaction between peri-implant soft tissues and local leukocytes with dental plaque, oral bacteria, and their by-products results in these soluble mediators of immune reactions, which are contained in the PCF [15,37]. As IPD progresses, the balance of pro/anti-inflammatory cytokines shifts in favour of pro-inflammatory cytokines [83]. This imbalance typically impedes the inflammation repair process, leading to persistent tissue deterioration and disease [89]. If short-term, cytokines can trigger immune responses and initiate wound healing; however, they can also cause significant tissue damage if they are untimely and persistent. There is a substantial correlation between the expression level of pro-inflammatory cytokines and the intensity of the inflammatory response [15,77,80,81,82]. Through microvascular changes in the PIE (vasodilation and vasoproliferation), these pro-inflammatory mediators stimulate the arrival and extravasation of other immune cell types, such as mast cells, dendritic cells, T- and B-cells, and macrophages, in an attempt to contain the infectious phenomenon. However, the initial symptoms of peri-implant mucositis are caused by haemolytic and macrophagic activity established on the host tissue [77].

Figure 10. Main anti-inflammatory cytokines involved in the development of Inflammatory peri-implant diseases [15,77,80,81,82,83,84,85,86,87,88,89,90,91].

TNF: tumor necrosis factor, IL: interleukin, TGF: transforming growth factor, TIMP: tissue inhibitors of metalloproteinase, MMP: matrix metalloproteinase.

Figure 11. Main pro-inflammatory cytokines involved in the development of inflammatory peri-implant diseases [15,77,80,81,82,83,84,85,86,87,88,89,90,91].

IL: interleukin, MMP: matrix metalloproteinase, TNF: tumor necrosis factor, TWEAK: TNF-related weak inducer of apoptosis, PMN: polymorphonuclear leukocyte, PM: peri-implant mucositis, PI: peri-implantitis.

As the inflammatory process progresses, the CT becomes damaged. In a histopathological examination, an inflammatory lesion dominated by plasma cells and lymphocytes can be seen in the CT of the peri-implant mucosa [92]. Advanced PM is characterised by the increased expression of IL-1β, IL-17 and TNF-α which stimulates PMNs to produce enzymes (mainly proteases) and reactive oxygen species and fibroblasts to release MMPs, leading to fibroblast degeneration, CT disruption and increased tissue permeability [15,79]. Pocket deepening, infection propagation into underlying tissues and a pH drop in the PCF are the outcomes of epithelial down-growth into collagen-depleted locations [15,79]. Several human biomarkers (detected in the PCF) such as proteoglycans and fibronectin fragments, keratins, titin, actin- and microtubule-associated proteins, l-plastin, histone H4, H1.2, plasminogen activator (tPA), plasminogen activator inhibitor 2 (PAI-2), and apolipoprotein B-100 related to CT damage have been reported [15,80,81,82,93]. The transition from PM to PI is marked by an upregulated expression of pro-inflammatory cytokines, particularly MMP-8, IL-6, Ig-G1, and PGE-2, which induce a local increase of vasodilation and vascular permeability [15,77,93,94] and a shift (↑ increase/ ↓ decrease) in the expression of certain biomarkers of bone turnover, such as ↓ osteoprotegerin (OPG), ↑ sclerostin, ↑ receptor activator of nuclear factor kappa-β (RANK), ↑ Colony-stimulating factor-1 and ↑ receptor activator of nuclear factor kappa-β ligand (RANKL) [15,77,82,95,96,97]. Furthermore, TNF, IL-1b, and IL-17 control T helper cell development, which results in osteoblast RANKL's expression, thus starting the pre-osteoclast maturation [15,79]. Osteoclastogenesis and bone resorption are the outcomes of this inflammatory cascade. A rise in the expression of particular biomarkers (proteins linked to the degradation of bone tissue) during the peri-implants-related bone resorption process has been reported: cathepsin G, cathepsin K, osteonectin, osteopontin, osteocalcin calprotectin, the C-telopeptide pyridinoline crosslinks of type I collagen and alkaline phosphatase [15,77,82,95,96,97]. Similarly, plasminogen system downregulation (tPA and PAI-2) combined with an elevation in pro-inflammatory cytokine levels is thought to be a powerful predictor of PI [98]. Corrosion and disintegration of the TiO2 layer of the implant body may be triggered by mechanical damage to the implant surface or a pH decrease in the PCF as a result of the advanced inflammation. Macrophages may phagocytose the titanium ions/metallic particles. titanium wear products lead to cytotoxicity, which in turn intensifies the inflammatory process, by a further release of cytokines (mostly IL-8b) and osteolysis of the bone [15,79,99]. Additional data showed that soluble ions, rather than particles, elicit the pro-inflammatory response that increases the RANKL/OPG ratio, which causes alveolar bone resorption (Figure 12) [100].

Figure 12. The Inammatory pathway of peri-implant diseases. The initial bacterial adhesion to the implant surface triggers a transition from a healthy peri-implant sulcus to an infected peri-implant pocket, driven by bacterial pathogenic activity [15,77,78]. This persistent biofilm activates both the innate and adaptive immune systems [78]. Chemotactic stimulation by bacterial products initially prompts the migration of polymorphonuclear cells across connective tissues [15,79]. Early stages of inflammation involve the release of IL-1B, IL-18, and cathepsins, which subsequently lead to histamine release, causing vasodilation and vasoproliferation. This environment supports the migration of macrophages and cells linked to adaptive immunity, such as T and B lymphocytes [15,77,80,81,82,83,84,85,86,87,88,89,90,91]. Advanced PM is marked by elevated levels of IL-1β, IL-17, and TNF, which stimulate PMNs to produce enzymes (primarily proteases) and ROS, and fibroblasts to release MMPs. This results in fibroblast degeneration, disruption of connective tissue, and increased tissue permeability [15,79]. The progression from PM to PI is characterised by an upregulated expression of pro-inflammatory cytokines, notably TNF, MMP-8, IL-6, Ig-G1, PGE-2, IL-17, and IL-1B. These cytokines induce an increase in certain biomarkers of bone turnover and activate RANKL/RANK signaling, leading to osteoclastogenesis and bone resorption as part of this inflammatory cascade [15,77,80,81,82,83,84,85,86,87,88,89,90,91].

Ig: immunoglobulin, IL: interleukin, PMN: polymorphonuclear leukocyte, ROS: reactive oxygen species, MMP: matrix metalloproteinase, TNF: tumor necrosis factor, TGF: transforming growth factor, RANK: receptor activator of nuclear factor kappa-β, RANKL: receptor activator of nuclear factor kappa-β ligand, PM: peri-implant mucositis, PI: peri-implantitis.

CONCLUSION

Peri-implant soft tissues play a crucial role in the success of implant therapy. Their scar-like nature endows them with unique biological properties across various levels (PS, PIE, PCT), rendering them more susceptible to the development and progression of IPDs compared to periodontal tissues. Consequently, a thorough examination of these structures in terms of their structure, biology, and function is essential for understanding the evolution of PM and PI. However, our understanding of the nature of peri-implant mucosa remains limited and is primarily derived from in vitro or animal studies.

To date, it has been suggested that the simultaneous presence of multiple, closely related harmful factors is crucial for the development of IPDs. However, recent theories based on an infectious model now emphasise the significant role of the peri-implant microbiome—encompassing adhesion, growth, maturation, and changes in its composition (including species richness and species evenness)—in the initiation and progression of IPDs. Additionally, it is recognised that the emergence of this infectious condition triggers complex innate and adaptive immune responses, which lead to the destruction of peri-implant supporting tissues as the host attempts to contain the spread of the infection.

In light of the preceding, it is crucial to focus efforts on thoroughly understanding the biological nature of peri-implant soft tissues and their interactions with the materials and surfaces of dental implants. This understanding will enable the development of new strategies aimed at eliminating or minimizing the effects of PM and PI on the success of implant therapy.