Table 1.

Summary of studies related to periodontitis, peri-implantitis, and L/SDD and level of MMP-8 in oral fluids.

	Study title and reference	Reference (year)	Objective	Sample source	Smoker	Form of detected MMP-8 and other markers	Study population	Diagnosis	Result
1	Collagenases in different categories of peri-implant vertical bone loss [21]	Ma et al. (2000) [21]	To investigate if level of collagenase-2 and collagenase-3 in PISF act as mediators in the process of bone destruction in peri-implantitis	PISF samples	N/A	aMMP-8 by IFMA	13 subjects aged from 23 to 89 years old	Peri-implantitis	Gingival Index is not a clinically important marker for bone loss, but aMMP-8 and MMP-13 in PISF are. They might participate in peri-implant osteolysis
2	Levels and molecular forms of MMP-7 (matrilysin-1) and MMP-8 (collagenase-2) in diseased human peri-implant sulcular fluid [22]	Kivelä-Rajamäki et al. (2003) [22]	To identify various isoforms of MMP-8 in PISF and its relationship with MMP-7	PISF samples	N/A	aMMP-8 levels were determined by the western immunoblot method with polyclonal anti-human-MMP-8	13 subjects aged from 21 to 86 years old	Peri-implantitis	The elevated levels of aMMP-8 and MMP-7 were identified in active forms in diseased PISF, but MMP-7 was less prominent. MMP inhibitors, potential future tissue protective drugs, seemingly do not interfere with the defensive antibacterial action of MMP-7 but can inhibit aMMP-8
3	Laminin-5 gamma2-chain and collagenase-2 (MMP-8) in human peri-implant sulcular fluid [23]	Kivelä-Rajamäki et al. (2003) [23]	To investigate the forms and concentration of MMP-8 and laminin-5 gamma2-chain in PISF and to find correlation of these two with clinical parameters (i.e., the recorded gingival and bone resorption) of peri-implantitis	PISF samples	N/A	aMMP-8 levels were determined by western immunoblot	13 subjects aged from 21 to 86 years old	Peri-implantitis	aMMP-8 is a important biomarker of peri-implantitis, but longitudinal studies are required to assess their use, either alone or in combination as molecular biochemical PISF markers, to predict the risk of progression of peri-implantitis, as well as to monitor the impact of treatment of the disease
4	Gingival crevicular fluid collagenase-2 (MMP-8) test stick for chair-side monitoring of periodontitis [24]	Mäntylä et al. (2003) [24]	To develop a test stick for detection of MMP-8 in GCF, to evaluate its diagnostic potential as point-of-care/chair-side test, and to monitor the response to treatment of periodontitis	GCF samples	N/A	aMMP-8 levels were determined by IFMA, and chair-side dip-stick was performed	29 subjects, age not applicable	Healthy, gingivitis, and chronic periodontitis	aMMP-8 GCF levels and chair-side test differentiated periodontitis from gingivitis, and healthy control sites. Scaling and root planing could be followed successfully by both PoC-/chair-side and IFMA
5	The effect of adjunctive low-dose doxycycline therapy on clinical parameters and GCF MMP-8 levels in chronic periodontitis [25]	Emingil et al. (2004) [25]	To compare effectiveness of LDD combined with nonsurgical periodontal therapy alone in reducing levels of MMP-8 in GCF and improving clinical parameters in patients with chronic periodontitis	GCF	12 nonsmokers. none of the subjects was a heavy smoker (i.e., not more than 10 cigarettes/day)	aMMP-8 levels determined by the immunofluorometric assay	30 subjects, 37 to 61 years of age	Chronic periodontitis	Randomized, double blind, placebo-controlled, parallel arm study. LDD improved the effects of nonsurgical periodontal therapy
6	Longitudinal analysis of metalloproteinases, tissue inhibitors of metalloproteinases and clinical parameters in GCF from periodontitis-affected patients [26]	Pozo et al. (2005) [26]	Assessment of periodontal disease performed through measurement of extracellular MMP-8, MMP-9, and their TIMP-1 and TIMP-2 in GCF	GCF samples	N/A	aMMP-8 levels were determined by immune-western blotting (Cat. MAB 3316, Chemicon International, Temecula, CA, USA), MMP-9 by zymography, and dot blot of TIMP-1 and TIMP-2 (Cat. sc-6832 and sc-6835, respectively, Santa Cruz Biotechnology, Santa Cruz, CA, USA)	24 subjects, 30 to 35 years old	Healthy, and chronic periodontitis	A different pattern of aMMP-8 in control and patient site was found. The study has established the significant correlation between the severity of periodontal disease and the actual aMMP-8. aMMP-8 and the low level of both TIMP-1 and TIMP-2 were found
7	Is the excessive inhibition of matrix metalloproteinases (MMPs) by potent synthetic MMP inhibitors (MMPIs) desirable in periodontitis and other inflammatory diseases? That is: “Leaky” MMPIs vs excessively efficient drugs [27]	Sorsa and Golub (2005) [27]	Comparison between SDD and tetracycline (non-antibacterial composition) with more potent MMP inhibitors	N/A	N/A	N/A	N/A	N/A	Letter to editor: beneficial clinical efficiency observed only with LDD
8	Monitoring periodontal disease status in smokers and nonsmokers using a gingival crevicular fluid matrix metalloproteinase-8-specific chair-side test [28]	Mäntylä et al. (2006) [28]	To evaluate the efficacy of the aMMP-8-specific chair-side dip-stick test in longitudinally monitoring the periodontal status of smoking and nonsmoking patients with chronic periodontitis, using aMMP-8 concentration in GCF	GCF samples	11 smokers and 5 nonsmokers were included in the study	aMMP-8 levels were determined by chair-side lateral-flow immunotests and IFMA	16 subjects, age not applicable	chronic periodontitis	Persistently elevated GCF aMMP-8 concentration were identified, and they indicated sites at enhanced risk; patients with inadequate response to conventional treatment were identified by PoC/chair-side test and IFMA
9	Matrix metalloproteinases: contribution to pathogenesis, diagnosis and treatment of periodontal inflammation [3]	Sorsa et al. (2006) [3]	To understand the role of MMPs and their inhibitors in pathogenesis, diagnosis, and treatment of periodontal inflammation	N/A	N/A	N/A	N/A	N/A	Review: beneficial LDD adjunctive medical can be monitored/followed by aMMP-8 PoC/chair-side test
10	Salivary biomarkers of existing periodontal disease: a cross-sectional study [29]	Miller et al. (2006) [29]	To determine the correlation between salivary biomarkers specific for periodontal tissue inflammation, collagen degradation, bone turnover, and clinical features of periodontitis	Unstimulated whole expectorated saliva samples	33.3 case subjects and 27.6 control subject smokers were included in the study	Total MMP-8 levels were determined by the ELISA kit (Quantikine, R&D Systems, minneapolis, MN, USA)	57 subjects, 28 to 61 years of age	Healthy, and chronic periodontitis	A salivary level of MMP-8 appears to serve as biomarker of periodontitis
11	Characteristics of collagenase-2 from gingival crevicular fluid and peri-implant sulcular fluid in periodontitis and peri-implantitis patients: pilot study [30]	Xu et al. (2008) [30]	To identify the difference in collagenolytic activity between healthy subjects and subjects with peri-implantitis and to find the correlation between severity of peri-implantitis and collagenase activity	GCF and PISF samples	Nonsmokers were included in the study	Both aMMP-8 and total MMP-8 levels were determined by western blot and DNP-octapeptide assay	29 subjects, 4 healthy, 5 gingivitis patients, 10 chronic periodontitis patients, 5 implants patients, 5 peri-implantitis patients, the age range 23 to 72 years old	Healthy, gingivitis, chronic periodontitis and peri-implantitis	Peri-implantitis PISF contained higher active aMMP-8 levels and activity than GCF from similar deep chronic periodontitis sites. GCF and PISF from severe chronic periodontitis and peri-implantitis exhibited the highest aMMP-8 from PMNs and fibroblasts
12	Host-response therapeutics for periodontal diseases [31]	Giannobile (2008) [31]	To study factors affecting hard and soft tissue degradation around the teeth and dental implants.	N/A	N/A	N/A	N/A	N/A	Review: SSD is a useful/beneficial adjunctive medication in periodontitis
13	Host response modulation in periodontics [32]	Preshaw (2008) [32]	To study the role of SDD in modulation of host response in periodontal disease management	N/A	N/A	N/A	N/A	N/A	Review: MMP-8 is a potential biomarker at periodontitis and LDD is a useful adjunctive medication
14	Matrix metalloproteinase levels in children with aggressive periodontitis [33]	Alfant et al. (2008) [33]	To figure out the MMP-1, -2, -3, -8, -9, -12, and -13 levels in a cohort of African American children with and without aggressive periodontitis	GCF samples	17 nonsmokers were included in the study	Total MMP-1, -2, -3, -8, -9, -12, and -13 levels were determined by the ELISA kit (SenzoLyte 520, AnaSpec, San Jose, CA, USA)	44 subjects with AgP, 7 to 19 years of age, and 12 healthy controls. 17 adults with chronic periodontitis 35 to 65 years of age	Healthy, chronic periodontitis, and aggressive periodontitis	MMP-8 levels were elevated in AgP sites relative to nondiseased sites in the same subjects, in siblings and controls and subjects with chronic periodontitis. MMPs associated with the AgP sites in children were generally elevated compared to an adult cohort with a history of chronic periodontitis
15	Matrix metalloproteinase-8 concentration in shallow crevices associated with the extent of periodontal disease [34]	Passoja et al. (2008) [34]	To study association between MMP-8 levels in shallow, gingival crevices and the extent of periodontal disease	GCF samples	20 nonsmokers and 28 smokers were included in the study	Total MMP-8 levels were determined by the ELISA kit (Quantikine, R&D Systems, Minneapolis, MN, USA)	48 subjects, 22 to 75 years old	Chronic periodontitis	Statistically significant association between MMP-8 concentration from shallow crevices and the extent of attachment level (AL) ≥ 4 mm (p=0.028) and AL ≥ 6 mm (p=0.001), in subjects with moderate to high plaque scores
16	Identification of pathogen and host-response markers correlated with periodontal disease [35]	Ramseier et al. (2009) [35]	To find out the ability of putative host and microbially derived biomarkers to identify periodontal disease status from whole saliva and plaque biofilm	Unstimulated whole saliva samples	0% healthy, 19% gingivitis, 36% mild chronic periodontitis, and 81% severe chronic periodontitis smokers were included in the study	Total MMP-8 and -9, calprotectin, and OPG levels were determined by the ELISA kit (Quantikine, R&D Systems, Minneapolis, MN, USA). A.actinomycetemcomitans, C. rectus, F. nucleatum, P. intermedia, P. gingivalis, T. forsythia, and T. denticola with a quantitative PCR assay, IL-1β, -2, -4, -5, -6, -10, and -13, TNF-α, (FN-γ by protein microarray (Whatman, Florham Park, NJ), and ICTP by radioimmunoassay (Immunodiagnostic Systems, Fountain Hills, AZ)	100 subjects, aged ≥ 18 years old	Healthy, gingivitis, and chronic periodontitis	Multiple combinations of biomarkers especially MMP-8, 9, and osteoprotegerin combined with red complex bacteria provided highly accurate predictions of periodontal diseases.
17	Association of GCF biomarkers during periodontal maintenance with subsequent progressive periodontitis [36]	Reinhardt et al. (2009) [36]	To find correlation between GCF biomarkers of inflammation and bone resorption and loss of periodontal attachment and bone	GCF	N/A	Total MMP-8 level was determined by the ELISA kit (Biosource, Camarillo, CA)	128 osteopenic postmenopausal females (not taking estrogen) 45 to 70 years of age	Good general health, from healthy and chronic periodontitis patients'	Placebo-controlled clinical trial: SDD targets elevated aMMP-8 with beneficial clinical outcome
18	Oral salivary MMP-8, TIMP-1, and ICTP as markers of advanced periodontitis [37]	Gursoy et al. (2010) [37]	To detect potential markers of advanced periodontitis in saliva. In addition, we compared two MMP-8 detection methods using IFMA and ELISA to differentiate periodontitis subjects from controls	Stimulated whole saliva samples	17.2% healthy and 52.3% chronic periodontitis smokers were included in the study	aMMP-8 levels were determined by IFMA, total MMP-8, MMP-14, and TIMP-1 levels were determined by the ELISA kit (Amersham, GE Healthcare, Buckingamshire, UK) and ICTP levels were measured by enzyme immunoassay (Orion Diagnostica Oy, Espoo, Finland)	165 subjects, aged ≥ 30 years old	Healthy and chronic periodontitis	Salivary aMMP-8, when used in combination with TIMP-1 and ICTP is a potential biomarker in the detection of advanced periodontitis. The detection of total MMP-8 by the traditional ELISA method technique is less accurate than the aMMP-8 IFMA technique
19	Associations between matrix metalloproteinase-8 and -14 and myeloperoxidase in gingival crevicular fluid from subjects with progressive chronic periodontitis: a longitudinal study [13]	Hernández et al. (2010) [13]	To associate the levels, molecular forms, isoenzyme distribution, and degree of activation of MMP-8 and MMP-14, MPO, and TIMP-1 in GCF from patients with progressive periodontitis at the baseline and after periodontal therapy	GCF samples	N/A	aMMP-8 levels were determined by western blot and IFMA. MPO levels were determined by the ELISA kit (Immundiagnostik, Bensheim, Germany). MMP-14 and TIMP-1 levels were determined by the ELISA kit (Biotrak, GE healthcare, amersham, Slough, UK)	25 subjects, 35 to 62 years old	Chronic periodontitis	High aMMP-8 and MPO levels and a high MPO/MMP-8 positive correlation were found in active and inactive sites at baseline. After treatment, decreases in MPO and aMMP-8 were seen, except for active sites in which MMP-8 differences were not significant
20	Smoking affects diagnostic oral salivary periodontal disease biomarker levels in adolescents [38]	Heikkinen et al. (2010) [38]	To investigate the association between salivary aMMP-8 and PMN elastase with commonly used periodontal health indices in a birth cohort of adolescents accounting for their smoking habits	Stimulated whole saliva samples	61 boys and 66 girls were smokers. 197 boys and 177 girls were nonsmokers	Active MMP-8 levels were determined by IFMA	501 subjects, 15 to 16 years old	Most subjects were chronic periodontitis	Smoking significantly decreased both biomarkers, including aMMP-8 studied
21	Detection of gingival crevicular fluid MMP-8 levels with different laboratory and chair-side methods [6]	Sorsa et al. (2010) [6]	To compare four methods for detection of MMP-8 in GCF	GCF samples	Smokers were included in the study, but exact number of smokers is not mentioned	aMMP-8 levels were determined by DentoAnalyzer (Dentognostics GmbH, Jena, Germany), IFMA, and chair-side lateral-flow immunotests (Medix Biochemica Ltd, Espoo, Finland).Total MMP-8 levels were determined by the ELISA kit (Amersham, GE healthcare, Buckingamshire, UK)	10 subjects, age not applicable	Healthy, gingivitis and chronic periodontitis	IFMA (aMMP-8) and DentoAnalyzer (aMMP-8) results can detect MMP-8 from GCF samples, and these methods are comparable. The chair-side dip-stick test (aMMP-8) results were well in line with these assays. The Amersham ELISA (total MMP-8) results were not in line with tests.
22	Gingival crevicular fluid levels of MMP-8, MMP-9, TIMP-2, and MPO decrease after periodontal therapy [39]	Marcaccini et al. (2010) [39]	To compare the levels of MMP-8, MMP-9, TIMP-1, TIMP-2, and MPO in GCF of chronic periodontitis patients and controls at the baseline and three months after nonsurgical therapy	GCF samples	N/A	Total MMP-8, MMP-9, TIMP-1, and TIMP-2 levels were determined by the ELISA kit (DuoSet R&D Systems, Inc., Minneapolis, MN, USA), and MPO levels were determined (Sigma chemical, Co., St. Louis, MO, USA)	42 subjects, 35 to 55 years old	Healthy, and chronic periodontitis	Level of all the markers except TIMP-1 was found to be higher in GCF of patients compared with controls. The elevated level decreased three months after periodontal therapy
23	Use of host-and bacteria-derived salivary markers in detection of periodontitis: a cumulative approach [40]	Gursoy et al. (2011) [40]	The salivary concentration of three different salivary markers P. gingivalis, IL-1β, and MMP-8 were calculated together to obtain the cumulative risk score for detection of periodontitis	Stimulated whole saliva samples	N/A	P. gingivalis with a quantitative real-time PCR assay, IL-1β levels were determined by the ELISA kit (Amersham), and aMMP-8 levels were determined by IFMA	165 subjects, aged ≥ 30 years old	Healthy, and chronic periodontitis	The results point to that a cumulative risk score, calculated from the three salivary biomarkers, detects periodontal status more accurately than any of the markers individually. However, it is still sufficient to distinguish the periodontitis patient from the healthy group. However, aMMP-8 is reliable when used alone
24	Smoking and matrix metalloproteinases, neutrophil elastase and myeloperoxidase in chronic periodontitis [41]	Özçaka et al. (2011) [41]	To investigate the possible relationship between smoking and serum concentration of aMMP-8, MMP-9, TIMP-1, MPO, and neutrophil lactase in chronic periodontitis patients relative to periodontally healthy subjects	Serum samples	Healthy subjects (17 smokers) and chronic periodontitis patients (16 smokers) were included in the study	aMMP-8 levels were determined by IFMA; MMP-9 levels were determined by Biotrak ELISA Systems, Amersham Biosciences Ltd, Buckinghamshire, UK; TIMP-1 levels were measured by Duoste ELISA Development Systems, R&D systems, MN, USA; MPO levels were measured by Immunodiagnostic AG, Bensheim, Germany; and neutrophil elastase by Bender MedSystems GmbH, Vienna, Austria	111 subjects, 33 to 65 years	Healthy, and chronic periodontitis	aMMP-8 concentration and aMMP-8/TIMP-1 molar ratios in chronic periodontitis group were not found to be significantly different from those in the periodontally healthy group
25	Oral rinse MMP-8 point-of-care immuno test identifies patients with strong periodontal inflammatory burden [42]	Leppilahti et al. (2011) [42]	To determine if MMP-8 (measured by three different methods), TIMP-1, and elastase activity differentiate subjects with the different periodontal conditions, and second, to find out if MMP-8 levels were comparable among the methods used	Oral-rinse samples	Smokers were included in study, but the exact number of smokers is not mentioned	aMMP-8 levels were determined by DentoELISA (Dentognostics GmbH, Jena, Germany) and IFMA; total MMP-8 levels were measured by the ELISA kit (Amersham, GE Healthcare, Buckingamshire, UK); TIMP-1 levels were determined by the ELISA kit (Amersham); and elastase activity by Sigma Co., St Louis, MO, USA	214 subjects, 44 to 78 years old	Chronic periodontitis	aMMP-8 testing of oral-rinse samples may be beneficial in periodontal diagnostics. Total MMP-8 levels were not useful in diagnosis
26	Salivary biomarkers of periodontal disease in response to treatment [43]	Sexton et al. (2011) [43]	To check utility of salivary biomarkers in the monitoring of periodontal disease over time in subjects who received localized periodontal therapy	Unstimulated whole saliva samples	23% of the SRP group, and 33% of the OHI group smokers were included in the study	Total MMP-8 and OPG levels were determined by the ELISA kit (Quantikine, R&D Systems, Minneapolis, MN, USA) and IL-1β, IL-8, MIP-1α, and TNF-α levels were measured by Luminex human cytokine/chemokine multiplex kits (Millipore, St. Charles, MO, USA)	68 subjects, aged ≥ 18 years old	Chronic periodontitis	Salivary levels of biomarkers, i.e., IL-1β MMP-8, OPG, and MIP-1α reflected disease severity and response to therapy suggesting their potential utility for monitoring periodontal disease status
27	Full-mouth profile of active MMP-8 in periodontitis patients [44]	Kraft-Neumärker et al. (2011) [44]	To investigate whether there was a relationship between clinical diagnostic parameters and the concentration of aMMP-8 in GCF in the site level full-mouth analysis	GCF samples	Nonsmokers were included in the study	aMMP-8 levels were determined by IFMA	9 subjects, 35 to 66 years old	Chronic periodontitis	A statistically significant relationship found between level of aMMP-8 and pocket depth
28	Matrix metalloproteinase-8 is the major potential collagenase in active peri-implantitis [45]	Arakawa et al. (2012) [45]	To compare levels of MMP-1, -8, and -13 in PISF of both healthy and diseased sites and to find correlation between these MMPs with bone loss	PISF samples	N/A	Total MMP-8, MMP-1, and MMP-13 levels were determined by Fuji Chemical Industry, Takaoka, Japan	64 subjects, the aged range 59 to 78 years old	Peri-implantitis	This study also showed MMP-8 as a possible marker for progressive bone loss in peri-implantitis
29	Matrix metalloproteinases and inflammatory cytokines in oral fluid of patients with chronic generalized periodontitis and various construction materials [46]	Kushlinskii et al. (2012) [46]	To compare oral fluid of practically healthy subjects with intact periodontium and patient with chronic generalized periodontitis with various structural materials of dental restorations	Oral fluid samples	N/A	Total MMP-8 levels were determined by the ELISA kit (Quantikine, R&D Systems, Minneapolis, MN, USA)	105 subjects, 18 to 52 years old	Chronic periodontitis	The MMP-8 level in oral fluid was found to be higher than the normal only in patients with chronic generalized periodontitis with metal restorations. No significant difference was found in the level of MMP-8 in patients of chronic generalized periodontitis without metal restoration
30	Effect of scaling and root planing on interleukin-1β, interleukin-8 and MMP-8 levels in gingival crevicular fluid from chronic periodontitis patients [47]	Konopka et al. (2012) [47]	To determine amounts of MMP-8, IL-8, and IL-1β in GCF from patients with chronic periodontitis in relation to clinical parameters	GCF samples	Nonsmokers were included in the study	Total MMP-8 and IL-8 and IL-1β levels were determined by the ELISA kit (Quantikine, R&D Systems, Minneapolis, MN, USA)	51 subjects, 30 patients (mean age 48.7 ± 9.1 years old), and 21 healthy subjects (mean age 33.7 ± 8.2 years)	Healthy, and chronic periodontitis	Short-term nonsurgical therapy resulted in significant improvement in periodontal indices and a marked decrease of MMP-8, IL-8, and IL-1β in GCF. However, the level of humoral factors was still higher than those in control group
31	Associations of periodontal microorganisms with oral salivary proteins and MMP-8 in gingival crevicular fluid [19]	Yakob et al. (2012) [19]	To investigate in subjects with and without periodontitis, the levels of salivary proteins and aMMP-8 in GCF in relation to the presence of specific periodontal pathogens	Unstimulated and stimulated whole saliva, and GCF samples	15 healthy, and 30 chronic periodontitis smokers were included in the study	aMMP-8 levels were determined by IFMA, A.actinomycetemcomitans, P. intermedia, P. gingivalis T. forsythia, and T. denticola with a quantitative PCR assay; Albumin was analyzed using an immunoturbidometric Tina-Quant® kit (Roche, Basel, Switzerland); the salivary immunoglobulin concentrations were then analyzed by ELISA [87]; and salivary total protein was measured using the colorimetric Lowry method [49]	101 subjects, mean age 59.2 ± SD 2.9	Healthy, and chronic periodontitis	Salivary albumin and protein concentration were significantly higher in subjects with T. denticola. Level of aMMP-8 was significantly higher in subjects with T. denticola and T. forsythia
32	Treponema denticola associates with increased levels of MMP-8 and MMP-9 in gingival crevicular fluid [50]	Yakob et al. (2013) [50]	To assess the association between the presence of site-specific subgingival microorganisms and the level of aMMP-8 and MMP-9 in GCF	GCF samples	15 healthy and 30 chronic periodontitis were included in the study	aMMP-8 levels were determined by IFMA, A.actinomycetemcomitans, P. intermedia, P. gingivalis, T. forsythia, and T. denticola with a quantitative PCR assay; MMP-9 levels were determined by the ELISA kit (Amersham, Biosciences UK Ltd, Buckinghamshire, UK)	99 subjects, mean age 59.2 ± 2.9	Healthy, and chronic periodontitis	The presence of T. forsythia and T. denticola was associated with increased levels of aMMP-8 in the test sites
33	Cytokine and matrix metalloproteinase expression in fibroblasts from peri-implantitis lesions in response to viable porphyromonas gingivalis [51]	Irshad et al. (2013) [51]	To analyze inflammatory reactions of fibroblasts after in vitro challenge with P. gingivalis	Fibroblasts	All subjects' nonsmokers were included in the study	Total MMP-8, -1 levels were determined by the ELISA kit (Quantikine Human, Pharmacia Biotech, Buckinghamshire, UK), TIMP-1 immunoassay (R&D Systems, Minneapolis, MN, USA), and P. gingivalis with a quantitative real-time PCR assay	Five patients periodontally healthy 54.4 ± (±18.7) years old, nine patients (II) 57.8 (±12.4) years old, seven peri-implantitis patients 54.4 (±9.2) years old	Peri-implantitis	Fibroblasts from peri-implantitis and periodontitis lesions gave a more pronounced inflammatory response to the P. gingivalis challenge than fibroblasts from healthy donors. They may therefore be involved in the development of inflammation in peri-implantitis and periodontitis. Moreover, the sustained upregulation of inflammatory mediators and MMP-1 in peri-implantitis fibroblasts may play a role in the pathogenesis of peri-implantitis
34	Salivary biomarkers of oral health: a cross-sectional study [52]	Rathnayake et al. (2013) [52]	Aimed to investigating if known salivary biomarkers could be used for epidemiological studies for detection of periodontitis	Stimulated whole saliva samples	75 smokers were included in the study	Active MMP-8 levels were determined by IFMA; TIMP-1 levels were measured by the ELISA kit; (Amersham); TNF-α, IL-1β, IL-6, and IL-8 were measured by Luminex Chemokine multiplex); lysozyme levels were measured the ELISA kit (Quantikine, R&D Systems, Minneapolis, MN, USA)	966 subjects, 20 to 89 years old	Chronic periodontitis	aMMP-8 could be used as marker of periodontal disease in more significant patient populations
35	Oral salivary type I collagen degradation end-products and related matrix metalloproteinases in periodontitis [53]	Gursoy et al. (2013) [53]	Type I collagen degradation end products and related MMPs were examined aiming at detecting potential markers of periodontitis in saliva with high sensitivity and specificity	Stimulated whole saliva samples	86 smokers were included in the study	Active MMP-8 levels were determined by IFMA; MMP-9 and MMP-13 levels were measured by the ELISA kit (Amersham, GE Healthcare, Buckinghamshire, UK); TRACP-5b levels were measured by BoneTRAP® assay, Immunodiagnostic Systems Ltd, Boldon, UK); ICTP levels were measured by enzyme immunoassay; (Orion Diagnostica UniQ ICTP, EIA; Orion Diagnostica, Espoo, Finland); CTx levels were measured by Serum CrossLaps® ELISA assay (Immunodiagnostic, Systems Ltd, Boldon, UK); and NTx levels were measured by OSTEOMARK® NTx; serum levels were measured by Wampole Laboratories (Princeton, NJ, USA)	230 subjects of ≥30 years old	Chronic periodontitis	aMMP-8 is a reliable biomarker candidate for detecting alveolar bone destruction
36	Periodontal treatment reduces matrix metalloproteinase levels in localized aggressive periodontitis [54]	Gonçalves et al. (2013) [54]	To evaluate MMP-1, -2, -3, -8, -9, -12 and -13 levels in the GCF after treatment of LAgP and to correlate these levels with clinical response	GCF samples	Nonsmokers were included in the study	Total MMPs levels were determined by the ELISA kit (SensoLyte 520, AnaSpec, Fremont, CA)	29 subjects of 5 to 21 years old	Aggressive periodontitis	Treatment of LAgP with Conventional mechanical treatment and systemic antibiotics reduced specific MMPs levels effectively. The significant association was observed between MMP-1, -2, -3, -8, -9, -12 and -13 and percentage of sites with PD > 4 mm
37	Patterns of salivary analytes provide diagnostic capacity for distinguishing chronic adult periodontitis from health [55]	Ebersole et al. (2013) [55]	To determine to analyze expression levels in unstimulated whole saliva samples collected from multiple occasions from 30 healthy adults and 50 chronic adult periodontitis patients	Unstimulated whole saliva samples	Only nonsmokers were included in study	Total MMP-8 levels were determined by the ELISA kit (Quantikine, R&D Systems, minneapolis, MN, USA)	80 subjects of 18 to 45 years old	Healthy and chronic periodontitis	Salivary levels of MMP-8 were significantly elevated in periodontitis patients compared with the daily variation observed in healthy adults
38	Clinical correlates of a lateral-flow immunoassay oral risk indicator [18]	Nwhator et al. (2014) [18]	To investigate the clinical correlates of a lateral-flow immunoassay with BOP, oral hygiene, and periodontal probing depth on the first time	Oral-rinse samples	5 smokers and 71 nonsmokers were included in the study	aMMP-8 levels were determined by chair-side lateral-flow immunotests (Dentognostics GmbH, Jena, Germany)	76 subjects, age not applicable	Healthy, and chronic periodontitis	The chair-side aMMP-8 immunoassay showed a high (82.6%) sensitivity for at least two sites with BOP and periodontal pockets. It showed a lower relationship with single-site periodontal pockets and BOP
39	Crevicular fluid biomarkers and periodontal disease progression [56]	Kinney et al. (2014) [56]	Assess the ability of a panel of GCF biomarkers as predictors of periodontal disease progression	Unstimulated whole saliva samples	0% was healthy, 19% were gingivitis, 36% were mild chronic periodontitis, and 81% were severe chronic periodontitis smokers were included in the study	Total MMP-8 levels were determined by the ELISA kit (Quantibody human cytokine array by RayBiotech, Inc., Norcross, GA, USA)	100 subjects, aged ≥ 18 years old	Healthy, gingivitis, and chronic periodontitis	MMP-8 was significantly higher in periodontal disease progression group compared to stable patients
40	Salivary biomarkers associated with gingivitis and response to therapy [57]	Syndergaard et al. (2014) [57]	The primary aim was to compare the concentrations of IL-1β, IL-6, PGE2, MMP-8, and MIP-1α in the whole saliva from patients with gingivitis with concentrations of these substrates in the saliva of patients with a clinically healthy periodontium	Unstimulated whole saliva samples	N/A	Total MMP-8, IL-1β, IL-6, PGE2, and MIP-1α levels were determined by ELISA kit, assay design, Ann Arbor, MI & EMD, millipore, Billerica, MA	80 subjects of 23 to 38 years old	Healthy and gingivitis	Concentrations of IL-1β, IL-6, and MMP-8 cannot distinguish gingivitis from health
41	Oral salivary biomarkers of bacterial burden, inflammatory response, and tissue destruction in periodontitis [58]	Salminen et al. (2014) [58]	To investigate the association of selected salivary biomarkers with periodontal parameters and validate the use of a novel salivary diagnostic approach, the cumulative risk score (CRS), in detection of periodontitis in subjects with angiographically verified coronary artery disease diagnosis	Stimulated whole saliva samples	58 were current smokers and 202 former smokers were included in the study	aMMP-8 levels were determined by IFMA, IL-1β was measured by flow cytometry-based Luminex kits, Milliplex, Map Kit; MPXHCYTO-60k, Millipore, Billerica, MA, USA, and P. gingivalis with a quantitative PCR assay was performed	493 subjects, age nonapplicable	Chronic periodontitis	The high salivary concentration of aMMP-8, IL-1β, and P. gingivalis was associated with deepened periodontal pockets and alveolar bone loss. aMMP-8 performed better compared to BOP%
42	Matrix metalloproteinases and myeloperoxidase in GCF provide site-specific diagnostic value for chronic periodontitis [59]	Leppilahti et al. (2014) [59]	To identify the diagnostic accuracy of GCF candidate biomarkers to discriminate periodontitis from inflamed and healthy sites and to compare the performance of two independent MMP-8 immunoassays	GCF samples	5 subjects healthy (nonsmokers), 3 nonsmokers with gingivitis, and 3 nonsmokers with chronic periodontitis were included in the study	aMMP-8 levels were determined by IFMA, and total MMP-8 was measured by ELISA kits, GE Healthcare, Amersham	25 subjects, healthy (mean age, 48.2 ± 11.2 years) gingivitis (mean age, 35.7 ± 15.4 years) and periodontitis patients (mean age, 46.0 ± 5.0 years)	Healthy, gingivitis, and chronic periodontitis	MMPs are highly discriminatory biomarkers for site-specific diagnosis of periodontitis. The comparison of two quantitative MMP-8 methods demonstrated IFMA to be more accurate than ELISA
43	Gingival crevicular fluid matrix metalloproteinase-8 levels predict treatment outcome among smokers with chronic periodontitis [60]	Leppilahti et al. (2014) [60]	To explore different GCF aMMP-8 patterns in smokers and nonsmokers with chronic periodontitis and test the utility of baseline GCF aMMP-8 levels in predicting categorically assessed treatment outcomes	GCF samples	10 smokers and 5 nonsmokers were included in the study	aMMP-8 levels were determined by IFMA	15 subjects, aged 28 to 64 years	Chronic periodontitis	Baseline aMMP-8 level in GCF strongly predicts how aMMP-8 levels behave during the maintenance period. In this regard, aMMP-8 analysis can be considered more useful than BOP. In smokers' sites, high baseline aMMP-8 levels indicate and predict weak treatment response
44	Targeted salivary biomarkers for discrimination of periodontal health and disease(s) [61]	Ebersole et al. (2015) [61]	Saliva-based diagnostic approach for periodontal health and disease based upon the abundance of salivary analyses coincidence with the disease	Unstimulated whole saliva samples	28 current smokers were included in the study	Total MMP-8 levels were determined by ELISA kit, the MILLIPLEX MAP Kit, EMD millipore, Billerica, MA, USA	209 subjects, aged ≥ 18 years	Healthy, gingivitis, and chronic periodontitis	Demonstrated the utility of MMP-8 in differentiating periodontitis from health
45	Activated matrix metalloproteinase-8 in saliva as diagnostic test for periodontal disease? a case-control study [62]	Izadi Borujeni et al. (2015) [62]	To evaluate sensitivity and specificity of a chair-side test for aMMP-8 to detect periodontitis	Oral-rinse samples	25 smokers were included in the study	aMMP-8 levels were determined by chair-side lateral-flow immunotests, Dentognostics GmbH, Jena, Germany	60 subjects, aged ≥ 18 years	Healthy and chronic periodontitis	Positive results of the aMMP-8 test significantly correlate with generalized chronic periodontitis. The test shows 87% sensitivity and 60% specificity in the diagnosis of chronic periodontitis
46	The utility of gingival crevicular fluid matrix metalloproteinase-8 response patterns in prediction of site-level clinical treatment outcome [63]	Leppilahti et al. (2015) [63]	To study different response patterns of MMP-8 among smoker and nonsmoker subjects with CP and GAgP to test its utility in predicting site level treatment outcome	GCF samples	86 smokers were included in the study	aMMP-8 levels were determined by IFMA	158 subjects, aged 27 to 49 years	Chronic periodontitis and aggresive periodontitis	Distinct types of MMP-8 response patterns were obtained for smokers and nonsmokers. Optimal cutoff levels of aMMP-8 defined for smokers and nonsmokers, which indicate risk for compromised treatment outcome at baseline and during maintenance
47	Pilot study on oral health status as assessed by an active matrix metalloproteinase-8 chair-side mouth rinse test in adolescents [64]	Heikkinen et al. (2016) [64]	To investigate whether a PoC mouth rinse test based on aMMP-8 immunoassay could identify patients with oral inflammatory burden among adolescents with early pathologic findings	Mouth rinse samples	5 smokers, and 42 nonsmokers were included in the study	aMMP-8 levels were determined by chair-side lateral-flow immunotests (Dentognostics GmbH, Jena, Germany)	47 subjects, aged 15 to 17 years	Chronic periodontitis	PoC/chairside was found to be useful in the online detection/diagnosis of oral inflammatory burden, i.e., periodontitis in adolescents with early, initial signs of periodontitis. Detection of caries is also possible but with less efficiency. The test shows 76.5% sensitivity and 96.7% specificity in the diagnosis of initial chronic periodontitis
48	Host-derived biomarkers at teeth and implants in partially edentulous patients. A 10-year retrospective study [65]	Ramseier et al. (2016) [65]	To compare host-derived biomarkers in PISF and in GCF from adjacent teeth and to analyze their level in both periodontal disease and healthy condition	PISF and GCF samples	Smokers were included in study but exact number of smokers is not mentioned	IL-1β, MMP-3, MMP-8, MMP-1, and MMP-1/TIMP-1 levels were determined by ELISA kits, R&D systems, Europe Ltd, Abingdon, UK	Total 997 samples were evaluated	chronic periodontitis and peri-implantitis	Increased levels of MMP-8 and IL-1β in PISF or GCF may be associated with inflammation around teeth and implants while lower levels of MMP-8/TIMP-1 may be an indicator of disease progression around implants and eased levels of MMP-8 and IL-1β in PISF or GCF may be associated with inflammation around teeth and implants while lower levels of MMP-1/TIMP-1 may be an indicator of disease progression around implants
49	Non-antibacterial tetracycline formulations: host-modulators in the treatment of periodontitis and relevant systemic diseases [66]	Golub et al. (2016) [66]	To address the evidences supporting adjunctive use of host modulation therapy with scaling and root planning in the long-term management of periodontal disease	N/A	N/A	N/A	N/A	N/A	Review: aMMP-8 PoC test is suitable to monitor the adjunctive beneficial SDD in periodontitis
50	Analysis of matrix metalloproteinases, especially MMP-8, in GCF, mouth rinse, and saliva for monitoring periodontal diseases [7]	Sorsa et al. (2016) [7]	To review recent studies related to monitoring of periodontal and peri-implant diseases by analyzing systemic and oral fluid biomarkers	N/A	N/A	N/A	N/A	N/A	Review: SDD targets increased aMMP-8 beneficial clinical outcome and no development bacterial resistance
51	Protein biomarkers and microbial profiles in peri-implantitis [67]	Wang et al. (2016) [67]	To assess diagnostic ability of biomarkers when combined with microbial profiles	PICF samples	4 current smokers and 21 past smokers were included in the study	Total MMP-8, OPG, IL-1β, TIMP-2, and vascular endothelial growth factor levels were determined by ELISA kits, custom human Quantibody, arrays, RayBiotech, Inc., Norcross, GA, USA, and A.actinomycetemcomitans, P. intermedia, P. gingivalis, T. forsythia, and T. denticola with a quantitative PCR assay	68 subjects, age range: 37 to 83 years	Peri-implantitis	The present data suggest that the increased levels of the selected PICF-derived biomarkers of periodontal tissue inflammation, matrix degradation/regulation, and alveolar bone turnover/resorption combined with site-specific microbial profiles may be associated with peri-implantitis and could have potential as predictors of peri-implant diseases
52	Peri-implant sulcus fluid (PISF) matrix metalloproteinase (MMP) -8 Levels in peri-implantitis [14]	Thierbach et al. (2016) [14]	To assess MMP-8 levels in PISF from diseased sites in both smokers and nonsmokers	PISF samples	17 smokers were included in the study	aMMP-8 levels were determined by DentoELISA immunoassay (Dentognostics, Jena, Germany)	29 subjects, 8 healthy patients, 3 gingivitis, and 18 chronic periodontitis	Peri-implantitis	aMMP-8 levels increase in peri-implantitis affected implants both in nonperiodontitis and periodontitis patients, but levels still after treatment of the condition reflect intensified host response around implants and indicate challenges of controlling peri-implantitis with any treatment modality
53	Correlation between peri-implant sulcular fluid rate and expression of collagenase2 (MMP8) [68]	Janska et al. (2016) [68]	To identify correlation between PISF and collagenase-2 level in superficial and fundus area of PI sulcus	PISF samples	N/A	aMMP-8 levels were determined by DentoELISA immunoassay (Dentognostics, Jena, Germany)	15 subjects, the age range 43 to 75 years	Peri-implantitis	Examination of aMMP-8 is a sensitive method when examining early inflammatory changes but depends from the depth of the sample collection in the gingival pocket
54	Rapid assessment of oral salivary MMP-8 and periodontal disease using lateral flow immunoassay [15]	Johnson et al. (2016) [15]	To determine the efficacy of a novel POCID for detecting MMP-8 concentration in oral fluids in comparison with a gold standard laboratory-based immunoassay	Unstimulated whole saliva samples	10 smokers were included in the study	Total MMP-8 levels were determined by rapidassays, ApS, Copenhagen-S, Denmark, EMD Millipore, Billerica, MA and luminex, Austin, TX, USA	41 subjects, aged 18 years or older	Healthy and chronic periodontitis	MMP-8 can be detected by POCID and concentration correlates with luminex for both saliva and rinse fluids. This study confirmed and further extended the original studies of Nwhator et al. [18] and Heikkinen et al. [64]
55	Diagnostic accuracy for apical and chronic periodontitis biomarkers in gingival crevicular fluid: An exploratory study [69]	Baeza et al. (2016) [69]	Assessment of level and diagnostic accuracy of an asset of potential biomarkers in GCF from patients with chronic periodontitis and AAP	GCF samples	19 smokers were included in the study	aMMP-8 levels were determined by IFMA, MPO levels were determined by ELISA kit, immunodiagnostik, AG, Bensheim, Germany. IL-1β, IL-6, TNF-α, Dkk-1, ON, PTN, TRAP-5, and OPG levels were determined by Multiplex detection panels Millipore, St. Charles, MO, USA, Magpix, Millipore, St. Charles, MO, USA, and MMP-2 and -9 levels were determined by gelatin zymography.	106 subjects, aged 44 to 52 years	Chronic periodontitis	aMMP-8 shows diagnostic potential for both chronic periodontitis and AAP. aMMP-8 was found to be higher in chronic periodontitis, followed by AAP
56	Pilot study on the genetic background of an active matrix metalloproteinase-8 test in finnish adolescents [70]	Heikkinen et al. (2017) [70]	To determine whether aMMP-8 chair-side test can detect initial periodontitis and caries with genetic background in adolescents	Oral fluid and DNA samples	5 smokers and 42 nonsmokers were included in the study	aMMP-8 levels were determined by chair-side lateral-flow immunotests (Dentognostics GmbH, Jena, Germany)	47 subjects aged 15 to 17 years	Chronic periodontitis	The aMMP-8 chair-side test has potential to detect initial periodontitis in adolescents with predisposing genetic background. aMMP-8 PoC/chair-side test acts as a gene test
57	Association of oral fluid MMP-8 with periodontitis in swiss adult subjects [12]	Mauramo et al. (2017) [12]	To find association between periodontitis and levels of aMMP-8 in saliva and GCF	Stimulated whole saliva and GCF	Never smokers were 150 (58.1%). Former smokers were 70 (27.1%). Current smokers were 38 (14.7%)	aMMP-8 levels were determined by IFMA	258 subjects, mean age 43.5 (21–58) years	Healthy and chronic periodontitis	Elevated levels of aMMP-8 in saliva and GCF are significantly associated with periodontitis in a systemically healthy adult
58	Association between serum and oral matrix metalloproteinase-8 levels and periodontal health status association between serum and oral matrix metalloproteinase-8 levels and periodontal health status association between serum and oral matrix metalloproteinase-8 levels and periodontal health status [71]	Noack et al. (2017) [71]	To identify the association between extent of circulating aMMP-8 and status of periodontal disease and aMMP-8 levels in oral fluids	Unstimulated whole saliva, stimulated whole saliva, GCF, and serum samples	Smokers were included in study but exact number of smokers is not mentioned	aMMP-8 levels were determined by IFMA, PerioSafe plus, (Dentognostics GmbH, Jena, Germany), and A.actinomycetemcomitans, P. intermedia, P. gingivalis, T. forsythia, and T. denticola with a semiquantitative PCR assay	59 subjects, aged 23 to 58 years	Healthy, gingivitis, and chronic periodontitis	The serum levels correlated significantly with oral aMMP-8 as well as with clinical periodontal parameters in a dose-dependent manner in systematically healthy subjects
59	Influence of different forms and materials (zirconia or titanium) of abutments in peri-implant soft-tissue healing using matrix metalloproteinase-8: a randomized pilot study [72]	Kumar et al. (2017) [72]	To compare peri-implant connective tissue response around titanium and zirconia abutments	PISF samples	Nonsmokers were included in the study	Total MMP-8 levels were determined by ELISA, Boster Biological Technology Co Ltd	12 subjects, the age range 20 to 45 years	Healthy	This study suggests the presence of more remodeling and/or inflammatory phenomena around titanium implant abutments than around zirconia abutments of a different design during the early stages but not at 1 year
60	Microbiological and aMMP-8 findings depending on peri-implant disease in patients undergoing supportive implant therapy [73]	Ziebolz et al. (2017) [73]	To study relation of microbiological findings and aMMP-8 level with peri-implant mucositis and peri-implantitis in subjects receiving periodontal or implant therapy	PISF samples	17 smokers with 43 implant sites	aMMP-8 levels were determined by DentoELISA (Dentognostics GmbH, Jena, Germany)	89 subjects with 171 implants. Mean age: 52 ± years, 116 dental implants were healthy, 39 dental implants had mucositis, and 16 dental implant had peri-implantitis	Peri-implantitis, peri-mucositis around implants, and chronic periodontitis	Within the limitations of this study, microbiological findings and aMMP-8 levels are not suitable for a differentiation between healthy, peri-mucositis, and peri-implantitis in patients all undergoing SIT/SPT. No healthy and disease patients without SIT/SPT were involved. Only smoking and the presence of Pi appear to be potential parameters associated with peri-implant disease in SIT/SPT patients. SIT/SPT intervention downregulated aMMP-8 during maintenance
61	Diagnosing peri-implant disease using the tongue as a 24/7 detector [49]	Ritzer et al. (2017) [49]	Anyone, anywhere, and anytime diagnostics were developed for peri-implant disease. The sensors responded to MMPs and provided proof of concept in statistically differentiating patients with peri-implant disease from healthy volunteers	Oral fluid	No-smokers were included in the study	aMMP-8 levels were determined by DentoELISA (Dentognostics GmbH, Jena, Germany) and MMP-8 analyzed by 24/7 chewing gum	33 subjects saliva or sulcus fluid collected from patients with peri-implant disease (defined as mucositis or peri-implantitis; n=19) and healthy control (n=14)	Peri-implantitis	Elevated MMP-8 could be detected in peri-implantitis, oral fluid vs. healthy oral fluid