|Year : 2022 | Volume
| Issue : 2 | Page : 95-103
Matrix Metalloproteinase-8 Levels in Peri-Implant Sulcular Fluid in Peri-Implantitis Patients as a Point-of-Care Biomarker: A Systematic Review
Shukra Paralkar, Amit Benjamin, Pooja Naik
Department of Periodontology and Implantology, YMT Dental College and Hospital, Navi Mumbai, Maharashtra, India
|Date of Submission||10-Jan-2022|
|Date of Decision||11-Apr-2022|
|Date of Acceptance||23-Apr-2022|
|Date of Web Publication||22-Aug-2022|
Department of Periodontology and Implantology, YMT Dental College and Hospital, Navi Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Levels of matrix metalloproteinase-8 (MMP-8) in peri-implant sulcular ﬂuid (PISF) increase to pathologically elevated levels in peri-implant diseases as a result of the destruction of peri-implant tissues. Active (a) and not latent (l) MMP-8 is shown to be truly representative of the disease progression. The objective of the study was therefore to evaluate if aMMP-8 levels in PISF predict the severity of peri-implant diseases in peri-implantitis patients and serve as a possible biomarker. A systematic review of the literature was performed using the PubMed/Medline and EBSCOhost databases. Studies concerning the use of aMMP-8 in the diagnosis of peri-implant disease that evaluated its effectiveness as a biomarker for peri-implant diseases were selected. The search strategy provided a total of 687 studies; only seven studies met the eligibility criteria and were included in the present systematic review. The studies demonstrated significantly higher concentrations of aMMP-8 in PISF of peri-implantitis patients than in healthy controls. aMMP-8 was shown to be a more sensitive biomarker with a questionable correlation to gingival index in assessing peri-implant disease activity and progression. These findings imply the potential adjunctive use of aMMP-8 in the diagnosis of peri-implant disease either alone or along with other pro-inflammatory biomarkers.
Keywords: Biomarkers, matrix metalloproteinases, peri-implant disease, peri-implantitis, systematic review
|How to cite this article:|
Paralkar S, Benjamin A, Naik P. Matrix Metalloproteinase-8 Levels in Peri-Implant Sulcular Fluid in Peri-Implantitis Patients as a Point-of-Care Biomarker: A Systematic Review. J Dent Res Rev 2022;9:95-103
|How to cite this URL:|
Paralkar S, Benjamin A, Naik P. Matrix Metalloproteinase-8 Levels in Peri-Implant Sulcular Fluid in Peri-Implantitis Patients as a Point-of-Care Biomarker: A Systematic Review. J Dent Res Rev [serial online] 2022 [cited 2022 Dec 1];9:95-103. Available from: https://www.jdrr.org/text.asp?2022/9/2/95/354194
| Introduction|| |
Dental implants have been most sought-after option for oral rehabilitation owing to its high clinical success rate and thereby enhancing the individual's quality of life. However, peri-implant disease remains to be a major concern to the clinicians as it adversely affects the long-term survival rate of dental implants.
The term “Peri-implantitis” is defined as an inflammatory process affecting soft and hard tissues surrounding an osseointegrated implant associated with the breakdown of the peri-implant epithelial seal, pocket formation, purulence, and progressive bone loss., Peri-implantitis has a similar background to the etiopathogenesis of periodontitis, which is caused by a cascade of host and microbial factors and proteolytic enzymes leading to soft- and hard-tissue destruction. Plaque accumulation can cause peri-implant mucositis which is a reversible inflammation of the soft tissue surrounding functional implants. If left untreated, it may progress to peri-implantitis where the inflammation extends into the deeper tissue and causes bleeding on probing (BOP), mucosal swelling, suppuration, peri-implant pockets formation, alveolar bone loss, and later may lead to a complete loss of osseointegration.
To regenerate peri-implant tissues affected by peri-implantitis, i.e., re-osseointegration remains a challenge to the clinicians; also, unpredictable disease resolution compels to look forth for the early detection and diagnosis which will help arrest the disease progression. Thus, preventing further extensive peri-implant bone loss. to ensure longevity of implants, regular monitoring of peri-implant tissue health is utmost essential. One of the diagnostic challenges is to discriminate bone loss due to infection from bone remodeling. The conventional diagnostic tools, namely probing, implant mobility analysis, and radiographic examination can provide information about the extent of tissue destruction but cannot predict the risk of disease. The extent to which BOP is indicative of the presence or the risk of peri-implantitis is unclear and may have a high false positive.,
Early and sensitive diagnosis of peri-implant mucositis and peri-implantitis can contribute to prolonging the life of dental implants. This could be enabled by the analysis of peri-implant sulcular fluid (PISF) as an inflammatory exudate for specific biomarkers which would accurately predict peri-implant status and disease progression as well as serve as a risk predictor, thus allowing the clinicians to be aware of the individual's susceptibility toward the said disease.
Increasing evidence indicates that pathologically excessive collagenase activity plays a major role in periodontal destruction. The balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) influences the integrity of connective tissues surrounding dental implants. MMP represents a structurally related, but genetically distinct, superfamily of proteases responsible for physiological development and tissue remodeling as well as pathological inﬂammatory and malignant tissue. MMPs can be divided into ﬁve major groups: Collagenases (MMPs 1, 8, and 13); gelatinases (MMPs 2 and 9); stromelysins (MMPs 3, 10 and 11); membrane-type MMPs (MMPs 14, 15, 16 and 17); and others. MMPs can collectively degrade almost all the components of extracellular matrix and basement membrane, and their pathologically excessive activity leads to periodontal and peri-implant tissue destruction. Connective tissue remodeling and tissue matrix destruction are regulated by various cell-cell and cell-matrix interactions, such as the production of enzymes, activators, inhibitors, cytokines, and growth factors. MMPs are controlled and inhibited by the tissue inhibitors of MMPs (TIMPs). Various bioactive nonmatrix substrates are processed by MMPs (cytokines, chemokines, growth factors, and immune mediators) which mediate both anti- and pro-inﬂammatory processes. Therefore, the levels of MMPs should not be interpreted solely as the surrogate markers of tissue destruction but also as the part of physiological or anti-inﬂammatory defense.,,,
MMP-8, also known as collagenase-2 or pmnl collagenase, is considered to be the key enzyme in the extracellular collagen matrix (ECM) degradation during the acute stage of peri-implantitis. It has affinity for type I collagen which is the main component of mucosal ECM, thereby accurately assessing the prevalence of the active disease. MMP-8 is synthesized mainly in polymorphonuclear granulocytes (PMNs) and prestored in the subcellular-specific granules. It is subsequently released in large quantities when PMNs are recruited to a site of inflammation. Gingival ﬁbroblasts, when stimulated by pro-inﬂammatory mediators, such as interleukin (IL)-1 β and tumor necrosis factor-α, can produce collagenolytic MMPs including MMP-8., The level of MMP-8 is described to be slightly activated and increased in the first 2 weeks of dental implantation. However, increased collagenase activity in PISF in the later stage after implantation could be a reliable marker in evaluating inflammation and monitoring the transformation of peri-mucositis to peri-implantitis. Arakawa et al. demonstrated that MMP8 is the major collagenase with severe peri-implantitis and ongoing bone loss.
The level of active, but not latent or total, collagenase-2/MMP-8 reﬂects, predicts, and is related to progressive peri-implant disease activity. Clinical periodontal parameters, i.e., probing pocket depth (PPD), BOP, and clinical attachment loss are found to correlate with the elevated levels of aMMP-8 in oral ﬂuids (saliva, mouthrinse, gingival crevicular ﬂuid [GCF], and PISF). The levels of aMMP-8 have shown to decrease after successful periodontal and peri-implant treatments.,,
A number of studies that have been performed utilize point-of-care (PoC)/chair-side analysis of elevated aMMP-8 in saliva/oral ﬂuids.,, A study comparing a PoC immunoﬂow tool with the standard gold laboratory-based one concluded that the concentration of aMMP-8 in oral ﬂuids is useful in distinguishing periodontal diseases from healthy controls. Lateral ﬂow immunoassay of aMMP-8 has been shown to have high sensitivity for at least two sites with BOP and two sites with deepened periodontal pockets. Immunoﬂuorometric assay (IFMA) and DentoAnalyzer-PoC-test could detect aMMP-8 from GCF samples, and these methods are comparable with the chair-side/PoC aMMP-8 dip-stick test. The Amersham enzyme-linked immunosorbent assay (ELISA) for total MMP-8 immunoactivities was not in line with the PoC/chair-side immune tests, speciﬁc for aMMP-8. Few studies demonstrated the associations of various periodontal pathogens in oral ﬂuids with the levels of aMMP-8 and suggested to the use in combination with aMMP-8 with other pro-inﬂammatory and microbiological biomarkers that may potentially improve the diagnostic accuracy.,
The rationale of the present systematic review is to review the published literature regarding the potential of aMMP-8 in PISF as a biomarker and predictor for peri-implant diseases.
The objectives of the study were as follows:
- Can aMMP-8 levels in PISF predict the severity of peri-implant diseases?
- To evaluate the various diagnostic tests for aMMP-8 evaluation.
| Methods|| |
Registration and protocol
This systematic review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines and was registered a priori in the International Prospective Register of Systematic Reviews (registration number: CRD42020191512).
Eligibility criteria, information sources, and search
A literature search was performed in PubMed and EBSCOhost databases for the papers published from May 2000 to June 2019. The papers published in the English language were selected for the analysis. In addition to this, other relevant studies were identiﬁed by manual searching. The keywords used for the study identiﬁcation in all databases were “collagenase-2 OR matrix metalloproteinase-8 OR MMP-8 OR pmnl collagenase AND peri-implantitis OR peri-implant crevicular fluid OR peri-implant sulcular fluid” and “MMP-8 and peri-implantitis.” The synonyms such as MMP-8, collagenase-2, and neutrophil collagenase were also searched in combination with peri-implantitis. The electronic search was done from June 11, 2019, to November 30, 2019. The systematic review was elaborated according to the PRISMA guidelines.
All identiﬁed studies were screened, and the selection process was done on the basis of following inclusion and exclusion criteria.
- Randomized controlled clinical trials
- Controlled clinical trials
- Cross-sectional studies
- Cohort studies.
- Written in a language other than English
- Case reports
- Animals studies
- In vitro studies
- Systemic/syndromic disease
- Alcoholism, smoking, and pregnant women
- Lack of data regarding the diagnostic method used.
Initially, a screening was performed by evaluating the titles and abstracts resulting from the search. All relevant studies were obtained in full and were analyzed separately by two evaluators. The inclusion criterion was studies involving the use of MMP-8 in the diagnosis of peri-implant disease, evaluating its effectiveness as a biomarker for peri-implant disease. Publications that did not present a compatible methodology for the systematic analysis were excluded (e.g., reviews, editorial letters, opinions, book chapters, brief communications, conferences, abstracts, patents, and studies with insufficient information). In vitro experiments, studies which interfered with the expression of MMP-8 through therapeutic methods, analysis of biomarkers in exogenous biological media were also excluded.
Data collection process
The following information was collected from all studies evaluated: Authors, publication year, country, sample size (number of cases diagnosed with peri-implant disease and controls), extension of peri-implant disease, criteria applied for the diagnosis, MMP-8 evaluation method, detection of biomarkers, relevant conclusion, and results [Table 1].
|Table 1: Summary of the descriptive characteristics of the included studies (n=7)|
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Risk of bias in individual studies
The methodologies used in the selected studies were analyzed by the reviewers through the use of Quality Assessment of Diagnostic Accuracy Studies-2, a tool for assessing bias risk in systematic reviews. The articles were classified as low risk, high risk, or risk of uncertain bias, according to the reviewers' critical analysis.
| Results|| |
The search strategy provided a total of 687 studies. After screening by reading the title and abstracts, 18 studies were considered potentially eligible and were read in full by the evaluators. At the end of the analyses, seven articles published between 2000 and 2019 met all the inclusion criteria and were included in the present systematic review. The flowchart of article screening and selection process is displayed in [Figure 1].
|Figure 1: Flow diagram of the literature search and selection criteria adapted from the Preferred Reporting Items for Systematic Reviews and Meta-analyses|
Click here to view
All the studies were carried out in developed countries. Regarding the design and methodological characteristics, patient samples varied between 6 and 60, with a median of participants and a total sample size of 149 patients [Table 1].
Risk of bias within and across studies
All the studies were evaluated using the same reference list for risk of bias assessment [Table 2]. No double-blinded studies were present in the selected articles. Patients were enrolled by random or consecutive sampling method except in studies of Meissen et al. and Xu et al. where the patient selection could have induced unclear risk of bias. High risk of bias was seen in a study by Kivelä-Rajamäki et al. as the index test and reference standard was not specified.
|Table 2: Quality assessment of the studies included by judging the risk of bias and applicability using the quality assessment of diagnostic accuracy studies-2|
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| Synthesis of results|| |
MMP-8 levels of patients in the studies included in the review are shown in [Table 3].
Qualitative (MMP8) and quantitative evaluation (periotron-PISF volume) of PISF during implant maintenance was evaluated by Janska et al. PISF samples were collected from the mesial and distal aspects of superficial and fundus area of peri-implant sulcus. They demonstrated a positive correlation only between PISF volume and MMP8 level from the fundus and distal area. There was no correlation between PISF volume and MMP8 from the mesial area, nor superficially from the distal area. The 69.5% variation of mesial MMP8 sulcular and fundus was due to correlation, rather than due to chance. This has produced a statistical significance of P < 0.001. The statistical significance for a positive correlation between MMP8 fundus and PISF was also P < 0.05. There was no significant correlation between MMP8 and PISF in the mesial side.
Meissen et al. in their study demonstrated statistically significant differences between the two abutments surfaces, i.e., titanium and zirconium nitride (ZrN) (t1: P < 0.0005; t2: P = 0.001; t3: P < 0.0005). The mean values of aMMP-8 reached 10.3–12.1 ng/mL in titanium abutments, whereas the values of 6.6–7.5 ng/ml were found on ZrN abutments during the 12 months of investigation. Accordingly, a wider spread of the maximum values of aMMP-8 occurred with titanium abutments (44–80 ng/mL) compared with ZrN abutments 25–44 ng/mL).
Maximum aMMP-8 values in cases of titanium abutments (80 ng/mL) as well as in cases of ZrN abutments (44 ng/mL) are most elevated at t1, i.e., 6 weeks after the commencement of the prosthetic restoration. It can therefore be assumed that some patients still exhibit an active healing phase 6 weeks after surgery. Whether the significantly reduced values of the tissue destructive biomarker aMMP-8 were due to less plaque retention or to surface chemistry was not evaluated in the study.
Furthermore, the study was not designed to evaluate whether the obstruction of aMMP-8 refers to less plaque biofilm formation, to improved mechanical stress of the supporting tissues, or to both of these factors.
Xu et al. 2008 demonstrated that the collagenase activity per site is high in peri-implantitis group as compared to healthy implants (P < 0.05). Alveolar bone loss in peri-implantitis could be directly related to the excessive PISF collagenase activity and activation. Both isoenzyme forms (PMN and fibroblast type) of MMP-8 eventually contribute to this PISF collagenase activity.
The level of MMP-8 immunoreactivity in PISF and GCF was enhanced with increased clinical severity of both peri-implantitis and periodontal disease. Furthermore, the degree of PMN-type MMP-8 activation was clearly enhanced along with increased clinical severity of both peri-implantitis and periodontal disease. Fibroblast-type MMP-8 could be detected in partially activated forms only in GCF and PISF from severe chronic periodontitis and peri-implantitis.
In a study by Kivelä-Rajamäki et al., 2003, signiﬁcant correlation was detected between MMP-8 and 45 and 70 kDa laminin-5 g2-chain immunoreactivities (r = 0.787, P < 0.001) when the relationships of 45 and 70 kDa LN-5 g2-chain species and MMP-8 immunoreactivities in PISF were determined. They correlated signiﬁcantly with gingival index (GI) (r = 0.704, r = 0.772, P < 0.001, respectively), but there was no statistically signiﬁcant correlation between these parameters and bone resorption (BR). MMP-8 and LN-5 g2-chain fragments were signiﬁcantly elevated in peri-implant disease groups with elevated GI as compared with the peri-implantitis group without elevated GI or the clinically healthy group. Furthermore, a clear activation of 75 kDa neutrophil (PMN)-type proMMP-8–10 kDa lower molecular size active form was especially detected in PISF from peri-implantitis lesions with elevated GI.
The levels of active forms of MMP-8 and MMP-7 were signiﬁcantly elevated in diseased PISF in relation to healthy PISF. Furthermore, MMP-8 and MMP-7 levels correlated signiﬁcantly to each other and GI.
Ma et al. showed that the GI findings did not correlate with the extent of irreversible bone loss and that peri-implant vertical bone loss did not seem to reflect by the severity of peri-implant mucosal inflammation. Even with a very low GI, possibility of underlying bone loss around the implants persists. Collagenase-2 and collagenase-3 levels were significantly higher in the group with >3 mm of bone loss (collagenase-2, P = 0.049; collagenase-3, P = 0.041) than in those groups that had lost less bone.
Nomura et al. demonstrated the similarity of collagenase and MMP levels between peri-implantitis and periodontitis.
| Discussion|| |
Summary of evidence
Based on the literature, PISF volume assessment, “Periotron reading” of 0–20 indicated that tissue is healthy and shows little or no inflammation; 20–60: Mild inflammation; >60: Considerably severe condition. The results ranged from 0 to 61 in all the studies included.,,
From previous studies, PISF MMP8 levels were categorized as levels <8 ng/ml: Healthy peri-implant sites; 8–20 ng/ml: Peri-implant mucositis; >20 ng/ml: More or less progressive peri-implantitis.,
Janska et al. reported the advantages of MMP-8 evaluation over PISF volume measurement in the early diagnosis of inflammatory changes in peri-implant tissue. The former method was reported to be more sensitive in early detection of inflammatory changes, also it decreased collection time and thereby provided better patient comfort.
The significant correlation was seen between alveolar bone loss and peri-implantitis., However, no statistical correlation was seen between BR and aMMP-8 levels in studies by Kivelä-Rajamäki et al., 2003. Two studies, showed a significant correlation with GI and aMMP-8. No statistically significant correlation was seen in three studies between bone loss and GI.,, These findings suggest that PISF exhibits a potential value for enzyme diagnostics for monitoring the host response in the maintenance phase of dental implant therapy. In order to come to a definite conclusion, further studies are needed involving a greater sample size. Furthermore, there is a need for more longitudinal and not just cross-sectional studies.
For the evaluation of aMMP-8 levels, DentoELISA, specific ELISA,, western immunoblot,,, and IFMA were used in the present review. Due to such heterogeneity in the diagnostic tests used and smaller number of studies, conclusions were found regarding the specificity and sensitivity of the tests. However, MMP-8 in PISF presented the strong potential for the use as a biomarker either as a laboratory or PoC/chair-side test.
Al-Majid et al. reviewed 61 articles on MMP-8 levels in periodontitis and peri-implantitis levels and concluded indicated that aMMP-8 in oral ﬂuids exerts the strong potential to serve as a useful adjunctive diagnostic and preventive biotechnological tool in periodontal and peri-implant diseases.
de Morais et al. included six articles in his systematic review on MMP-8 levels in periodontitis. Significantly, higher concentrations of MMP-8 in patients with periodontal disease were compared with controls, as well as in patients presenting more advanced stages of periodontal disease.
Both the above reviews included studies which evaluated both latent and active mmp8. In this systematic review, we are considering only aMMP8 levels in peri-implantitis which are shown to be truly representative of the disease severity and thus is more specific.
This review shows that aMMP8 levels are more specific than PISF volume assessment. BOP status significantly correlates with aMMP8 levels indicating that it is representative of peri-implant diseases. aMMP8 can be used as a PoC/chair-side test for the early detection of peri-implantitis, although this needs to be supported by more longitudinal studies.
Variations in the antibodies used for the determination of aMMP-8 levels, the index test used in their determination, and nonhomogenous methods of reporting in the levels of MMP-8 affected data interpretation across studies.
| Conclusion|| |
The present systematic review found significantly higher aMMP-8 concentrations in patients with peri-implantitis as compared with controls, as well as in patients presenting more advanced stages of peri-implant disease. The findings imply the potential adjunctive use of MMP-8 in the diagnosis of peri-implant disease.
This systematic review points out the need for studies applying homogeneous methodological processes, thus allowing for a more in-depth analysis of the data presented by the authors in their studies. MMP-8 levels and its effect exclusively on smokers and systemic diseases influencing periodontal conditions should be determined in further reviews.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]