Bacterial Species Associated with Peri-Implant Disease—A Literature Review

Abstract

Peri-implantitis is a pathological condition in dental medicine that manifests as an inflammatory process affecting the tissues surrounding dental implants. Peri-implantitis occurs when the soft and hard tissues surrounding these implants become inflamed, leading to progressive destruction of the supporting bone. The etiology of peri-implantitis is multifactorial, involving microbial, host-related, and environmental factors. Microbial involvement in peri-implantitis can be explained either by direct in-situ virulence activation leading to pathogenicity, or by induction of low-grade chronic immune activation, leading to long-term persistence of a pro-inflammatory status. Understanding peri-implantitis is pivotal in maintaining the long-term success of dental implants and improving patient outcomes in implantsupported restorations. Recognizing the etiological factors, including particular bacterial species, genetic predispositions, and environmental influences, is very important for devising effective preventive strategies and targeted interventions.

Introduction

1Dental implants have revolutionized the field of dentistry by providing a predictable and lasting solution for replacing missing teeth. A systematic review demonstrated a mean survival rate of dental implants of 94.6%, over a period of up to 20 years of followup.[1] This is a very promising result, and each year the number of implants placed is getting higher, as the materials and clinical protocols evolve. However, as with any medical procedure, complications can arise. One such complication is peri-implantitis, a condition that affects dental implants. Peri-implantitis is a challenging problem in dentistry, as it can lead to implant failure and significant oral health issues.[2] The prevalence of peri-implantitis described in literature varies, but has a mean of 19.53% at the patient-level and 12.53% at the implant-level.[3]

The etiology of peri-implantitis is multifactorial, involving microbial, host-related, and environmental factors.[4] Microbial biofilms on implant surfaces play a crucial role, triggering a local immune response, inflammation and subsequent tissue breakdown.[5] The clinical presentation varies, ranging from early signs such as gingival bleeding and inflammation (periimplant mucositis) to advanced stages marked by bone loss, suppuration, and implant mobility.[6] Understanding peri-implantitis is pivotal in maintaining the long-term success of dental implants and improving patient outcomes in implant-supported restorations.

Review

Etiological factors of peri-implantitis

Peri-implantitis, a complex inflammatory condition, stems from a myriad of etiological factors that collectively contribute to its onset and progression in dental medicine. Environmental and behavioral factors further contribute to periimplantitis risk:[4]

• smoking[7,8,9,10]
• history of periodontal disease[7,10]
• poor oral hygiene [11]
• systemic diseases [12]
• treatment-related causes (for example persistence of cement in the peri-implant
• soft tissue) [13,14,15,16]
• lack of keratizined gingiva [17,18]
• history of previous implant failure.

Smoking, a well-established risk factor,[7,8,9,10] adversely affects vascularity and immune function in the peri-implant tissues, impeding the body’s ability to mount an effective defense. Poor oral hygiene practices, including inadequate plaque control and irregular dental visits, create an environment conducive to bacterial colonization and biofilm formation.[11] These behavioral aspects emphasize the importance of patient education and compliance with oral hygiene measures to mitigate peri-implantitis risk.

Microbial factors play a pivotal role, with bacterial biofilms forming on the implant surfaces, akin to dental plaque around natural teeth.[19] Specific pathogens, including Staphylococcus epidermidis, Porphyromonas gingivalis, and Tannerella forsythia,[20,21,22] appear to be implicated in periimplantitis, fostering an environment conducive to tissue destruction. Host-related factors also significantly influence susceptibility, with individual immune responses varying.[23,24,25] Immune dysregulation may compromise the ability to combat microbial challenges, exacerbating inflammation and tissue breakdown.[25] Moreover, genetic predispositions underscore the importance of an individual’s genetic makeup in determining their vulnerability to peri-implantitis.

Bacterial involvement in peri-implantitis

The contribution of bacteria to periimplantitis can be explained either by direct in-situ virulence activation leading to pathogenicity, or by induction of low-grade chronic immune activation, leading to long-term persistence of a pro-inflammatory status.[26]

In-situ pathogenicity

Specific microorganisms can transition from commensal to pathogenic by activating their virulence traits, by secreting endo- or exo-toxins, and enzymes, thereby determining in-situ tissue destruction. Examples include expression of extracellular enzymes such as elastases,[27] collagenases, hyaluronidases, proteases, lipases, fibrinolysins, and many more. The regulation of pathogenicity and the switch from niche colonization to upregulation of virulence traits is mainly controlled by population density-based quorum sensing communication.

In-situ immune activation

Pro-inflammatory programmed cell death, or pyroptosis, is one of the hallmarks of periodontal diseases and is a driving factor of local inflammation, in-situ collagen breakdown, and bone resorption.[26] Caspases are the most important effectors of pyroptosis, and their role in peri-implantitis is a subject of continued study.[26] Importantly, pyroptosis is a type of cell death associated with plasma membrane leakage, which leads to inflammation of the surrounding tissue through release of pro-inflammatory mediators.[28] Pyroptosis can occur as a response to the presence of bacterial antigens, slow continued release of bacterial metabolism byproducts, exotoxins, endotoxins (in particular lipopolysaccharides released by Gram-negative bacteria),[26] and even as a response to mechanical stress per se, factors which can all lead to the assembly of inflammasomes thereby initiating pyroptosis.[28]

Bacterial-driven upregulation of proinflammatory cytokines is an important mechanism associated with peri-implantitis.[29] Wang et al. have assessed the microbial and host protein profiles in peri-implant crevicular fluid, comparatively between healthy peri-implant tissues and tissues exhibiting peri-implantitis; they have found increased levels of biomarkers suggestive for periodontal tissue inflammation, matrix degradation and regulation, as well as alveolar bone turnover and resorption.[30] Specifically, in samples from patients with periimplantitis, significantly higher crevicular fluid concentrations were noted for interleukin (IL)-1β, tissue inhibitor of metalloproteinase-2 (TIMP-2), vascular endothelial growth factor (VEGF), and osteoprotegerin (OPG), as well as numerically higher levels of bacterial DNA for pathogens such as P. gingivalis, Prevotella intermedia, Treponema denticola, T. forsythia, and Aggregatibacter actinomycetemcomitans.[30] Based on these results, the authors proposed an algorithm for identifying peri-implantitis by combined detection of T. denticola together with IL-1β, VEGF, and TIMP-2 levels.[30] Similar results were reported by Renvert et al., who described an important role of profuse bleeding and suppuration in peri-implantitis, associated with higher crevicular fluid concentrations of IL-1β, IL-8, tumor necrosis factor (TNF)-α and VEGF.[29]

Bacterial species frequently associated with peri-implantitis

A recent systematic review and meta-analysis has identified the main bacterial species consistently associated with peri-implantitis; these include Staphylococcus epidermidis, Fusobacterium nucleatum, T. denticola, T. forsythia, P. intermedia, and P. gingivalis, but not Aggregatibacter actinomycetemcomitans, Staphylococcus aureus or Campylobacter rectus.[20] We will briefly describe each of these species below.

Staphylococcus epidermidis

Staphylococcal species are part of the Grampositive commensal human flora, and many of them can also become pathogenic when appropriate microenvironmental conditions arise. Among microorganisms associated with periimplantitis, S. epidermidis is one of the best characterized. S. epidermidis is part of the larger group of coagulase-negative staphylococci, and it has an important biofilm-formation capacity.[31] Generally being regarded as a commensal, in most clinical infections, S. epidermidis is initially considered as contaminant, and is only confirmed to be pathogenic when repeatedly isolated from relevant clinical samples, in the absence of the identification of another more typical pathogen. However, when focusing on peri-implantitis, it is frequently retrieved from peri-implant samples,[20,32] and is considered to contribute to pathogenicity, either directly or indirectly.

When regulating their aggressiveness traits, staphylococci often have to choose between expressing adhesion molecules for surface colonization with formation of biofilms,[33] or expressing resistance traits and soluble virulence factors such as hemolysins, lipase, lecithinase, caseinase, amylase, of esculin hydrolysis, which all contribute to the rapid progression towards a fulminant acute infectious process.[34] Furthermore, S. epidermidis has the capacity to induce a particular protein profile when cultivated in the presence of a titanium substrate; these specifically expressed proteins also serve as adherence factors and include surface protein accumulation-associated protein (Q8CQD9), bifunctional autolysin (O33635) and glutamyl endopeptidase (P0C0Q1).[35]

Isolates of S. epidermidis are more frequently identified in patients with peri-implantitis compared to patients with healthy dental implants.[32] Furthermore, S. epidermidis isolates retrieved from subgingival samples of patients with peri-implantitis have also been shown to harbor specific genetic elements at a significantly higher frequency compared to isolates retrieved from orally healthy participants or from patients with healthy dental implants.[32] O’Connor et al. have specifically demonstrated this pattern in S. epidermidis isolates from peri-implantitis, for the arginine catabolic mobile element (ACME), which is involved in enhancing staphylococcal colonization and survival in specific host environments, by allowing metabolic adaptation to utilize arginine as carbon and energy source.[32]

Staphylococci have also been described to contribute to the pro-inflammatory milieu of periimplantitis by inducing cytokines such as IL-1β, which displays higher levels in peri-implant crevicular fluid in the presence of S. epidermidis.[29]

Fusobacterium nucleatum

Fusobacterium nucleatum is a Gram-negative anaerobic bacterium that is part of the normal flora of the oral cavity, where it can be found in dental plaque, gingival crevices, and other oral surfaces, but it has also been associated with various oral diseases, including peri-implantitis[20,36] and systemic diseases, including severe lifethreatening infections.[37]

It has a strong ability to form biofilms and it contributes to the complex microbial communities in the oral cavity. It produces a series of important virulence factors, including proteases, adhesins (secreted or membranebound), invasins, and hemolysins, that contribute to its ability to colonize oral surfaces and potentially invade host tissues, as well as lipopolysaccharides and an outer membrane protein, Fap2, which suppresses cytotoxic activities of natural killer cells, ensuring evasion from host defenses.[38]

Treponema denticola

Treponema denticola is a spirochete found in the oral cavity, particularly in the subgingival region. It is microaerophilic and is one of the key pathogens associated with peri-implantitis.[20,36] T. denticola is often found in close association with other periodontal pathogens within biofilms and it has the ability to produce virulence factors, including adhesins, hemolysins, collagenases, proteases and other enzymes that can degrade host tissues and contribute to the breakdown of periodontal structures.

The dentilisin complex is among the best described virulence factors of T. denticola. This is an outer membrane-associated complex composed of a PrtP protease and two lipoproteins, PrcB and PrcA.[39] Dentilisin contributes to nutrient uptake, coaggregation with other bacteria, complement activation, evasion of human host defenses, hemostasis inhibition, and cell invasion.[40]

Tannerella forsythia

Tannerella forsythia is a Gram-negative anaerobic bacterium that is also considered a key contributor to the initiation and progression of peri-implantitis. It can produce several virulence factors including proteases such as gingipains, miropsin-1, miropsin-2, mirolase, karilysin and mirolysin.[41] Among these proteases, karilysin can degrade elastin, fibrinogen and fibronectin, and both karilysin and mirolysin inhibit complement pathways, protecting the bacteria from human host defenses.[41] T. forsythia also produces an important protease inhibitor from the serpin superfamily (miropin), which is specifically associated with peri-implant disease,[41] as well as sialidases, which allow the bacteria to colonize, adhere to and invade host tissues.[42,43] Interestingly, the capacity of substrate adhesion appears to be significantly higher for T. forsythia when cultured on titanium compared to dentin,[44] which explains its propensity for developing peri-implantitis.

Prevotella intermedia

Prevotella intermedia is a Gram-negative anaerobic bacterium that is also part of the oral microbiota, often found in dental plaque, and contributing to periodontal diseases and periimplantitis.[20]

P. intermedia produces various virulence factors that drive its ability to colonize tissues and potentially cause disease, including enzymes that contribute to tissular damage and evasion of host immune responses, such as adhesins, proteases, hemagglutinins, hemolysins, lipopolysaccharides, and capsular antigens, and it displays important capacity for within-host adaptation.[45] Of particular importance is the capacity of several P. intermedia types of strains to produce viscous exopolysaccharides, which are associated with induction of abscess lesions and antiphagocytic properties.[46]

Porphyromonas gingivalis

Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that plays a significant role in the development of periodontal diseases and periimplantitis. It can form complex biofilms on tooth surfaces and in periodontal pockets, making it more resistant to the host immune response and conventional antimicrobial treatments. It also possesses various virulence factors that contribute to its pathogenicity, including enzymes that break down host periodontal structures, and the best characterized examples include proteases such as gingipains as well as collagenases, to name only a few.[47] The production of these enzymes by Porphyromonas gingivalis contributes to tissue destruction, immune evasion, and the establishment of a favorable environment for the bacterium in the periodontal pockets. Furthermore, together with lipopolysaccharides and pilli, gingipains contribute to the host’s inflammatory response mediated by Toll-like receptors.[47]

Fibroblasts harvested from patients with periimplantitis express higher pro-inflammatory patterns, and a further enhanced inflammatory response when challenged with P. gingivalis, compared to fibroblasts from periodontallyhealthy donors. This was demonstrated through the identification of higher levels of IL-1β, IL-8, IL6, monocyte chemotactic protein (MCP-1), and matrix metalloproteinases (MMP)-1 immediately following P. gingivalis challenge, but the induction was also sustained over longer periods of time after dechallenge for IL-1β, MCP-1 and MMP-1 in fibroblasts from peri-implantitis.[48]

Higher crevicular fluid levels of lectin-type oxidized LDL receptor 1 (LOX-1), IL-1β, MMP2 and MMP9 were reported in patients with periimplantitis, and this increase was also demonstrated in vitro, after challenge of THP-1 macrophages with P. gingivalis, suggesting that LOX-1 may trigger an IL-1β-mediated inflammatory pathway as well as a breakdown of the extracellular matrix[49] mediated through an MMP9 signaling pathway.[50]

Synergistic multispecies interactions in periimplantitis

The pathogenesis of peri-implantitis is marked by important synergistic interactions between the different microbial species mentioned above, and many other contributors. These collaborative microbial interactions ensure the survival and the growth of the different bacterial species, as well as the formation of strong multispecies biofilms.

For example, P. gingivalis and T. denticola display strong synergy in formation of polymicrobial biofilms, leading to increased biovolume and increased biofilm thickness compared to monomicrobial biofilms, and these interactions appear to be mediated by P. gingivalis gingipains.[51] Furthermore, gingipains also play the role of ligands in the coaggregation of P. gingivalis with other oral bacteria, such as T. denticola.[47]

Co-infection with P. gingivalis and T. denticola has a pro-inflammatory effect, demonstrated by synergistic increase in IL-6 production, and the same effect is seen for P. gingivalis and T. forsythia.[52] Furthermore, a nutritional advantage is seen in coinfection, whereby growth of P. gingivalis is enhanced by cell extracts from T. forsythia.[53] Coinfection with P. gingivalis and T. forsythia also displays synergistic virulence enhancement, leading to more pronounced induction of lesion formation in a murine abscess model.[53,54]

While these findings are interesting from a research point of view, they also carry important clinical implications. For example, disease severity in peri-implantitis can be measured by the identification of both P. gingivalis and T. forsythia, and by peri-implant sulcular fluid levels of IL-8 and IL-1β.[41]

Prognosis and long-term outcomes

The prognosis for peri-implantitis treatment varies depending on the severity of the condition, the patient’s compliance with oral hygiene, and the effectiveness of the chosen treatment approach. With early diagnosis and appropriate intervention, peri-implantitis can be managed successfully, and implant survival rates can be maintained.

Studies show that treatment initiated in the stage of peri-implant mucositis has yielded the best results,[4] even though non-surgical treatment alone was not always able to completely heal the mucositis site.[55] There were no statistically significant differences between adding chlorhexidine or azithromycin gels compared to non-surgical debridement alone.[55,56] Interestingly, it seems that improvement in the general oral hygiene is crucial to the resolution of peri-implant mucositis symptoms.[55,56,57]

However, in advanced cases where significant bone loss has occurred, the long-term prognosis may be less favorable. Treatment of cases with bone loss can be done with conservative or resective methods.

Conservative methods include non-surgical curettage of implant surfaces, either with hand instruments,[58,59] or with piezoelectric instruments.[60,61,62] In addition to curettage, several studies compared the administration of local and systemic antibiotic drugs.[63] Another study compared the addition of either local antibiotic (minocycline with delivery system in the form of microspheres) or photodynamic therapy to nonsurgical mechanical debridement, and found no significant differences between the two adjunctive methods.[64] Local delivery of antibiotic drugs or other substances such as chlorhexidine may have an effect on the progression of peri-implantitis, but only in combination with surgical or nonsurgical debridement of the implant surface.[65]

Different studies have assessed the efficacy of laser therapy as a conservative treatment method for peri-implantitis.[66,67] Schwartz et al. demonstrated an adequate removal of subgingival calculus from the implant surface by using an Er:YAG laser, compared to a control group.[67] Another study comparing Er:YAG laser-assisted decontamination of implant surfaces to airabrasion showed that even though initially there was a reduction in the bacterial count, at 6 months that reduction was insignificant, demonstrating that neither methods could be used as single therapy.[68]

Non-conservative methods include surgical debridement of implant surface, combined with resective or regenerative therapies.

Resective surgery is a combination of ostectomy and osteoplasty with the mechanical decontamination and the smoothing of the implant surface, in order to reduce the roughness which could further help with the adhesion of the bacterial biofilm.[69] Romeo et al. demonstrated that implantoplasty and bone resective surgery significantly reduce postoperative marginal bone loss, compared to resective surgery alone.[70] This means that modifying the implant surface from a rough texture to a smooth polished surface could have a significant impact on bacterial adhesion and recolonization of the implant surface.

Regenerative procedures utilize biomaterials to fill bone defects resulted after the bone resective procedure. A study showed no significant difference between the biomaterials used for filling the bone defects—hydroxyapatite or bovine xenograft, and both methods demonstrated promising results at 6 months postop.[71] Overall, regenerative techniques tend to yield good results, regardless of the type of biomaterial used, as long as the clinical steps of implant surface decontamination, bacterial biofilm removal and bone resection are done thoroughly.[72,73,74,75,76]

However, in cases with important bone loss around the implant, with reduced bone-to-implant contact or implant mobility, the implant may need to be removed, and the site allowed to heal before considering a new implant placement or a bone regenerative procedure.

Understanding the multifaceted nature of peri-implantitis etiology is critical for effective prevention and management strategies. Comprehensive preoperative screening and patient selection are essential to identify individuals with heightened susceptibility. Postoperative maintenance, including regular follow-up appointments and continuous patient education, plays a crucial role in mitigating environmental and behavioral risk factors.

Future perspectives and research directions

As dental implant technology continues to advance, ongoing research seeks to develop improved strategies for preventing and treating peri-implantitis. Promising areas of investigation include:

Advanced imaging techniques: the development of more sophisticated imaging modalities may enhance early detection and monitoring of peri-implantitis.

Biomaterials and surface modifications: research is ongoing to improve implant materials and surface coatings that reduce the risk of bacterial adherence and inflammation.

Regenerative therapies: novel regenerative approaches, such as tissue engineering and growth factors, may offer innovative solutions for restoring lost peri-implant tissues.

Personalized treatment plans: tailoring treatment plans to individual patient factors, including genetics and systemic health, may improve treatment outcomes.

Conclusions

In conclusion, peri-implantitis stands as a significant concern in the field of dentistry due to its potential to compromise the long-term success of dental implant treatments. The intricate interplay of microbial, host-related, and environmental factors underscores the complexity of this inflammatory condition. Recognizing the etiological factors, including specific bacterial species, genetic predispositions, and environmental influences, is pivotal for devising effective preventive strategies and targeted interventions. The diagnosis of peri-implantitis demands meticulous attention, allowing for early intervention and the implementation of management strategies to curb its progression. As dental professionals strive to provide patients with durable and aesthetically pleasing solutions through dental implants, the prevention and effective treatment of peri-implantitis become paramount.

The parallels between peri-implantitis and periodontitis highlight the systemic implications of oral health and underscore the need for a comprehensive, holistic approach to dental care. Not only does peri-implantitis pose a threat to the structural integrity of dental implants, but it also impacts patients’ overall well-being. As ongoing research continues to unravel the complexities of peri-implantitis, it opens avenues for innovative preventive measures and treatment modalities, ensuring the continued success of implantsupported restorations. In essence, understanding and addressing peri-implantitis is not only essential for preserving the health of individual patients but also for advancing the broader field of dental medicine, promoting optimal outcomes, and enhancing the quality of life for those seeking implant-based dental solutions.