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European Journal of Dentistry logoLink to European Journal of Dentistry
. 2022 Nov 18;17(4):974–999. doi: 10.1055/s-0042-1757582

Impact of Dentine Pretreatment with Matrix Metalloproteinase Inhibitors on Bond Strength of Coronal Composite Restorations: A Systematic Review and Meta-analysis of In Vitro Studies

Hasan Jamal 1,2,✉, Rayan Yaghmoor 2,3,4, Hassan Abed 5, Anne Young 2, Paul Ashley 1
PMCID: PMC10756735  PMID: 36400108

Abstract

Matrix metalloproteinase (MMP) enzymes participate in collagen matrix degradation, including in dentine, potentially compromising bond strength. Therefore, MMP inhibitors have been hypothesized to improve restoration bond strength and stability. This systematic review aimed to evaluate the influence of different MMP inhibitors applied as dentine surface pretreatments on the immediate (24 hours) and longer term (months) bond strength of direct coronal composite restorations. This systematic literature review followed the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. A systematic literature search of three databases (Ovid MEDLINE, Ovid Embase, and Google Scholar) was conducted independently by two reviewers from inception to April 2022. An adapted quality assessment tool was independently applied by two reviewers for risk of bias assessment. RevMan v5.4 software was used for meta-analyses. A randomeffectsmodel was used to generatemean differences with 95% confidence intervals for treatment and control comparisons. The Q-test and I2-test were used to test for heterogeneity. The proportion of total variance across studies attributable to heterogeneity rather than chance was calculated. Overall effects were tested using the Z-test, while subgroup differences were tested using Chi-squared tests. Of 934 studies, 64 studies were included in the systematic review and 42 in the meta-analysis. Thirty-one MMP inhibitors were reported, three of which were included in the meta-analysis: 2% chlorhexidine (CHX), 0.3M carbodiimide (EDC), and 0.1% riboflavin (RIBO). Pretreatment with 2% CHX for 30 and 60 seconds did not significantly improve bond strength compared with controls either immediately or after long-termageing. However, pretreatment with 0.3MEDC and 0.1% RIBO (but not CHX) significantly improved bond strength compared with control groups both immediately and over time. Most studies showed a medium risk of bias. These in vitro findings pave the way for rationale clinical trialing of dentine surface pretreatment with MMP inhibitors to improve clinical outcomes.

Keywords: restorations, bond strength, matrix metalloproteinase inhibitors, enzymes, caries, dentine.

Introduction

Since their introduction around six decades ago, restorative adhesives have undergone numerous improvements. 1 2 Despite these advances, adhesive restorations often lose their bond strength over time, leading to their failure. 3 4 Adhesive restorations critically rely on their bond with the tooth structures for strength, with the interface—the hybrid layer—crucial in determining the bond's longevity and stability. 5 6 The collagen fibrils in dentine (mainly type 1 collagen) are key to establishing a strong bond, and their deterioration is thought to be the main reason underlying bond failure to dentine. 7

Recent studies have examined the role of endogenous enzymes present within the dentine extracellular matrix (ECM) and their effect on bond stability. Among these enzymes, matrix metalloproteinases (MMPs) represent a group of calcium- and zinc-dependent host-derived enzymes. 8 MMPs are divided into six subgroups: collagenases (MMP-1 and MMP-8), stromelysins (MMP-3, MMP-10, MMP-11, and MMP-20), gelatinases or type-IV collagenases (MMP-2 and MMP-9), matrilysin (MMP-7), metalloelastase (MMP-12), and membrane-type metalloproteinases (MMP-14, MMP-15, MMP-16, and MMP-17). 9 Of these, four MMPs have been identified within the dentine extracellular matrix: MMPs-2, -8, -9, and -20, with MMP-2 and -9 as the most abundant. 10 11 These enzymes are secreted by odontoblasts during odontogenesis and remain silenced and inactive within the dentine ECM. 12 However, these MMPs are activated either by biological acids produced by cariogenic bacteria 13 or acids introduced during acid etching. 14 15 When activated, they start to degrade the exposed collagen fibrils within the dentine. 16 Therefore, inhibiting MMPs could help to preserve the hybrid layer and, therefore, bond stability.

Several types of MMP inhibitor (synthetic and natural) have been described including benzalkonium chloride, 17 18 chlorhexidine, 18 19 20 21 galardin, 22 green tea extract, 23 24 and zinc. 25 MMP inhibitors can be administered either as dentine surface pretreatments or those incorporated into the adhesive. The current systematic review and meta-analysis aimed to collect and analyze the available in vitro evidence on the influence of different MMP inhibitors applied as dentine surface pretreatments on the immediate and long-term bonding strength of coronal composite restorations. The null hypothesis was that there would be no difference in bond strength after MMP inhibitor use compared with controls.

Methods

Eligibility Criteria

The systematic review was developed according to the PICO scheme ( Table 1 ) 26 and was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) guidelines 27 :

Table 1. Keywords and the strategy used in MEDLINE and Embase.

Medline (Ovid) Embase
P 1. Extracted human teeth.mp./OR Human teeth.mp.
2. Sound dentine.mp./OR healthy dentine.mp.
3. Carious affected dentine.mp./OR Caries affected dentine.mp./OR affected dentine.mp.
4. Dentine$.mp.
5. 1 OR 2 OR 3 OR 4		 1. Extracted human teeth.mp./OR Human teeth.mp.
2. Sound dentine.mp./OR healthy dentine.mp.
3. Carious affected dentine.mp./OR Caries affected dentine.mp./OR affected dentine.mp.
4. Dentine$.mp.
5. 1 OR 2 OR 3 OR 4
I 6. Matrix metalloproteinase inhibitors/OR MMP inhibitors.mp. 6. Matrix metalloproteinase inhibitors/OR MMP inhibitors.mp.
C 7. No matrix metalloproteinase inhibitors/OR No MMP inhibitors 7. No matrix metalloproteinase inhibitors/OR No MMP inhibitors
O 8. Bond strength/OR Bond stability 8. Bond strength/OR Bond stability
Combined 1 OR 2 OR 3 OR 4 AND 6 AND 7 AND 8) 1 OR 2 OR 3 OR 4 AND 6 AND 7 AND 8)
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Abbreviation: MMP, matrix metalloproteinase.

Population: all studies examining extracted human teeth, caries-free dentine, healthy dentine, sound dentine, carious-affected dentine, or affected dentin.

Interventions: all studies examining MMP inhibitors as dentine surface pretreatments prior to direct coronal composite restoration placement. Therefore, studies that used luting cements and glass ionomer cements were excluded.

Comparator(s)/control(s): teeth without intervention (i.e., without the addition of MMP inhibitor). Studies that included no comparator were excluded.

Outcome: the main outcome was bond strength or bond stability at the microscale (by microtensile and microshear testing). Studies that tested bond strength at the macroscale were excluded. Included studies needed to have aged the samples for at least 24 hours in water or artificial saliva. Thus, studies with ageing up to 24 hours only and/or studies that used ageing solutions other than water or artificial saliva were excluded.

Search Strategy

Types of Searched Studies

The search included published, peer-reviewed in vitro studies presenting the results (means and standard deviations [SDs]) quantitively and numerically in the English language. Thus, studies that reported the results in graphs or figures only were excluded. Non–peer reviewed studies, conference posters, letters, theses, reviews, and editorials were excluded.

Period of Reviews (Timing) and Databases

A systematic literature search was conducted in three databases: Ovid MEDLINE (1946–April 2022), Embase (1974–April 2022; see Table 1 ), and Google Scholar (up to April 2022).

With respect to the search strategy for Google Scholar, the following terms were used: “Extracted human teeth” OR “human teeth” OR “Sound dentine” OR “healthy dentine” OR “affected dentine” OR “Carious affected dentine” OR “Caries affected dentine” OR “Dentine” AND “Matrix metalloproteinase inhibitors” OR “MMP inhibitors” AND “Bond strength” OR “Bond stability.”

Data Selection and Collection Processes

Full texts of all eligible studies were uploaded to reference management software (EndNote X9.3.1) and duplicate publications were removed automatically. Two authors (H.J. and R.Y.) screened the titles and abstracts, and the full text of studies meeting the inclusion criteria was read. Two evaluators (H.J. and R.Y.) independently screened each full-text paper based on the eligibility criteria. In case of discrepancies about study eligibility between the two reviewers, a further evaluator was involved (H.A. or P.A.). A data extraction form included the following: authors' names, year of publication, type of MMP inhibitor used, duration of MMP inhibitor used as dentine pretreatment, substrate condition, type of bonding agent, type of ageing solution, period of ageing, type of bond strength test, and bond strength means. Two reviewers (H.J. and R.Y.) were independently involved in data collection. An experienced third reviewer (P.A.) independently extracted data from 10% of studies to check process consistency. Conflicts of opinion were resolved through consensus by consulting a further reviewer (H.A. or A.Y.).

Risks of Bias and Quality Assessment

A quality assessment tool adapted from a previous study 28 was independently used by two reviewers (H.J. and R.Y.). The tool evaluated bias in terms of sample randomization, substrate condition, duration of dentine pretreatment, the use of materials according to the manufacturer's instructions, storage medium, interface surface area, restorative and bond tests performed by a single operator, sample size calculation (power analysis), and blinding of the operator during bond strength testing. Minor modifications were added to the risk of bias evaluation tool, which are “dentine pretreatment duration” and “storage medium”. For each component of the tool, the letter “Y (yes)” was assigned if the author reported the item and “N (no)” if it was not reported. The grading judgement of “low,” “medium,” or “high” for the study was based on the total number of “Ys” as follows: one to five (high), six, or seven (medium), and eight or nine (low).

Data Synthesis

Findings were summarized narratively using text and tables. For example, findings were summarized according to type of MMP inhibitor used, duration of dentine pretreatment, substrate condition (caries-free or caries-affected), type/mode of bonding agent, type of ageing solution, period of ageing, type of bond strength test, and mean bond strength.

Meta-analysis

Review Manager (RevMan) version 5.4 software from the Cochrane Collaboration was used for meta-analyses using the following information: the average difference in outcome measures between the intervention and control groups, the number of teeth in each treatment group, and the standard deviations. These data were categorized into three time periods: 24 hours, 6 months, and 12 months, where applicable, and further divided into the type of MMP inhibitor, the adhesive application method used (self-etching or etch and rinse), and the pretreatment duration. Only MMP inhibitors applied for 30 and 60 seconds were included as they contained enough data for the meta-analysis.

The mean differences (MDs) and their 95% confidence intervals (CIs) were calculated. Findings from all comparisons were generally pooled according to the three time periods (24 hours, 6 months, and 12 months). After establishing the pooled MDs according to time, additional pooling was carried out depending on the various parameters indicated. A positive MD supports the experimental group, whereas a negative MD favors the control group. A random-effects model was used to generate MDs with 95% CIs for treatment and control comparisons.

The Q -test and I 2 -test were used to test for heterogeneity. The I 2 statistics was interpreted according to the Cochrane guidelines, with 0 to 29% as being low, 30 to 50% as moderate, and 50 to 90% as considerable heterogeneity. 29 The proportion of total variance across studies attributable to heterogeneity rather than chance was calculated. Finally, the overall effects were tested using the Z -test, while subgroup differences were tested using Chi-squared tests.

The following analyses were carried out:

  1. 2% chlorhexidine (CHX) versus control at baseline (24 hours).

  2. 2% CHX versus control at 6 months.

  3. 2% CHX versus control at 12 months.

  4. 0.3 M 1-Ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) versus control at baseline.

  5. 0.3 M EDC versus control at 12 months.

  6. 0.1% riboflavin (RIBO) versus control at baseline.

  7. 0.1% RIBO versus control at 6 months.

  8. 2% CHX versus control at baseline (according to pretreatment duration of 30 seconds).

  9. 2% CHX versus control at 6 months (according to pretreatment duration of 30 seconds).

  10. 2% CHX versus control at baseline (according to pretreatment duration of 60 seconds).

  11. 2% CHX versus control at 6 months (according to pretreatment duration of 60 seconds).

Results

Study Selection

A flowchart summarizing the selection process according to the PRISMA statement is shown in Fig. 1 . 27 During the initial search, 934 potentially eligible studies were retrieved. After removal of duplicates, 763 studies remained of which 193 remained after reviewing the titles and 163 after reviewing the abstracts. Following reading the full texts, 64 studies were included in the study and 42 were included in the meta-analysis.

Fig. 1.

Fig. 1

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PRISMA 2020 flowchart diagram of study selection. 27 PRISMA, Preferred Reporting Items for Systematic Review and Meta-analyses.

Study Characteristics

The data obtained from the included publications are listed in Table 2 . The 64 included in vitro studies were published between 2009 and 2022.

Table 2. Characteristics of the included studies.

Study/year MMP inhibitor type Pretreatment duration (s) Substrate condition Adhesive system (mode of application) Ageing solution Period of ageing Groups Bond strength means (SD)
Baena et al/2020 30 CS 60 Caries-free Optibond FL (Kerr; etch-and-rinse; OFL)
Scotchbond Universal (3M; self-etch; SBU)		 Artificial saliva 24 hours CS 0.1% + OFL
Control (OFL)
CS 0.1% + SBU
Control (SBU)		 38.0 (7.7)
41.3 (14.5)
28.1 (14.3)
25.0 (16.5)
10,000 thermocycles CS 0.1% + OFL
Control (OFL)
CS 0.1% + SBU
Control (SBU)		 29.2 (14.1)
32.2 (12.9)
33.1 (17.0)
30.4 (11.8)
Balloni et al/2017 31 CHX 60 Caries-free Clearfil SE bond (self-etch) Water 24 hours CHX 2%
Control		 19.24 (11.89)
12.67 (7.43)
6 months CHX 2%
Control		 11.97 (9.95)
10.22 (5.00)
Bravo et al/2017 32 CHX 20 Caries-free Adper Scotchbond 1XT (etch-and-rinse; ASB)
Adper prompt (self-etch; AP)
Single Bond Universal (self-etch; SBU)		 Water 3 days CHX 2% + ASB
Control (ASB)
CHX 2% + AP
Control (AP)
CHX 2% + SBU
Control (SBU)		 26.28 (9.29)
28.56 (5.83)
24.21 (7.52)
20.14 (4.87)
28.43 (9.78)
29.24 (7.90)
3 months CHX 2% + ASB
Control (ASB)
CHX 2% + AP
Control (AP)
CHX 2% + SBU
Control (SBU)		 32.26 (10.33)
19.82 (7.65)
28.51 (13.18)
20.86 (6.13)
44.11 (12.09)
23.54 (12.09)
6 months CHX 2% + ASB
Control (ASB)
CHX 2% + AP
Control (AP)
CHX 2% + (SBU)
Control (SBU)		 31.73 (5.18)
23.39 (5.69)
27.37 (4.40)
20.51 (5.66)
36.88 (6.65)
23.62 (7.07)
de Faria Teixeira et al/2015 33 CHX 60 Not mentioned Clearfil SE bond (self-etch) Water 24 hours CHX 2%
Control		 28.0 (8.4)
24.2 (7.2)
6 months CHX 2%
Control		 33.4 (9.3)
21.8 (7.3)
Comba et al/2020 34 DCC 60 Caries-free Scotch bond universal (SBU) (self-etch) and etch and rinse Artificial saliva 24 hours 0.5M DCC SBU (ER)
Control SBU (ER)
0.5M DCC SBU (SE)
Control SBU (SE)		 46.0 (5.3)
37.1 (12.5)
39.4 (11.1)
26.3 (11.4)
12 months 0.5M DCC SBU (ER)
Control SBU (ER)
0.5M DCC SBU (SE)
Control SBU (SE)		 33.5 (13.9)
31.0 (11.0)
35.3 (13.9)
13.4 (9.1)
Czech et al/2019 24 CHX
EGCG		 60 Caries-affected Adper Single Bond 2 (etch and rinse) Water 24 hours EGCG 200 μg/mL
CHX 2%
Control		 24.08 (7.20)
14.64 (7.74)
23.43 (7.73)
6 months EGCG 200 μg/mL
CHX 2%
Control		 18.67 (8.51)
11.20 (4.79)
16.28 (9.58)
12 months EGCG 200 μg/mL
CHX 2%
Control		 16.77 (5.50)
10.17 (3.02)
14.91 (6.92)
Dávila-Sánchez et al/2020 35 QUE
HES
RUT
NAR
PAC		 60 Caries-affected Scotchbond Universal (3M; etch and rinse) Water 24 hours HES 6.5%
PAC 6.5%
QUE 6.5%
NAR 6.5%
RUT 6.5%
Control		 18.41 (5.30)
20.66 (3.92)
24.58 (4.90)
24.64 (3.70)
26.00 (5.51)
14.42 (4.43)
25,000 thermocycles HES 6.5%
PAC 6.5%
QUE 6.5%
NAR 6.5%
RUT 6.5%
Control		 15.73 (6.07)
17.20 (2.72)
12.02 (5.21)
22.12 (2.92)
21.08 (4.75)
9.43 (4.29)
Costa et al/2019 36 CHX
EGCG		 60 Eroded (ERO) and non-eroded (non-ERO) Clearfil SE bond (self-etch) Water 24 hours CHX 2% (non-ERO)
CHX 2% (ERO)
EGCG 0.1% (non-ERO)
EGCG 0.1% (ERO)
Control (non-ERO)
Control (ERO)		 40.87 (10.23)
49.30 (9.42)
53.67 (6.10)
61.61 (3.17)
52.44 (8.47)
59.25 (5.91)
6 months CHX 2% (non-ERO)
CHX 2% (ERO)
EGCG 0.1% (non-ERO)
EGCG 0.1% (ERO)
Control (non-ERO)
Control (ERO)		 32.77 (10.67)
36.91 (9.88)
50.02 (3.42)
44.63 (13.26)
47.64 (11.67)
45.16 (11.87)
El Baz and Aboulenien/2018 37 EGCG 60 Caries-free Primer and Bond one (Dentsply; etch and rinse) Water 24 hours EGCG 0.1%
Control		 18.8 (0.2)
15.4 (0.7)
6 months EGCG 0.1%
Control		 17.6 (0.3)
12.2 (0.9)
5,000 thermocycles EGCG 0.1%
Control		 22.1 (0.7)
8.8 (0.8)
Fang et al/2017 38 MAP
GM6001		 60 Caries-free Gluma Comfort Bond (etch and rinse) Water 24 hours MAP 1 mg/mL
GM6001 10μM
Control		 19.31 (4.48)
18.86 (4.2)
19.25 (4.21)
2,500 thermocycles MAP 1 mg/mL
GM6001 10μM
Control		 12.22 (4.49)
10.87 (4.27)
6.08 (3.12)
Fernandes et al/2021 39 CHX
EGCG		 60 Caries-free Clearfil SE Bond Primer (self-etch) Artificial saliva 24 hours CHX 2%
EGCG 0.01%
Control		 44.16 (6.81)
42.76 (7.36)
40.65 (6.51)
12 months CHX 2%
EGCG 0.01%
Control		 33.58 (10.49)
34.91 (7.84)
33.85 (9.27)
Fialho et al/2019 40 CHX
EGCG		 60 Caries-affected Adper Single Bond 2 (3M; etch and rinse) Water 24 hours EGCG 0.2%
EGCG 2%
EGCG 0.5%
CHX 2%
Control		 32.65 (9.97)
29.16 (11.52)
28.57 (6.30)
33.33 (11.26)
35.81 (8.25)
12 months EGCG 0.2%
EGCG 2%
EGCG 0.5%
CHX 2%
Control		 22.75 (9.38)
17.15 (10.61)
23.65 (7.19)
19.98 (7.01)
26.17 (12.28)
Gerhardt et al/2016 41 CHX
EGCG
GT		 60 Caries-free Clearfil SE Bond (self-etch) Water 24 hours CHX 2%
EGCG 2%
GT 2%
Control		 13.31 (3.36)
6.93 (3.43)
10.60 (4.69)
8.64 (5.52)
6 months CHX 2%
EGCG 2%
GT 2%
Control		 11.09 (4.98)
15.96 (5.32)
17.82 (12.20)
16.69 (7.20)
Campos et al/2019 42 CHX Not mentioned Caries-affected Clearfil SE Bond (self-etch) Water 24 hours CHX 2%
Control		 19.84 (8.11)
24.89 (9.44)
12 months CHX 2%
Control		 17.59 (8.85)
28.30 (11.54)
Giacomini et al/2020 43 CHX 30 Caries-free Adper Single Bond 2 (etch and rinse)
Adper Single Bond Universal (etch and rinse)
Adper Single Bond Universal self-etch (self-etch)		 Artificial saliva 24 hours CHX 2% (ASB)
Control
CHX 2% (ASU-ER)
Control
CHX 2% (ASU-SE)
Control		 28.41 (7.64)
33.35 (9.01)
33.66 (7.79)
31.62 (8.20)
37.47 (10.68)
45.62 (12.39)
6 months CHX 2% (ASB)
Control
CHX 2% (ASU-ER)
Control
CHX 2% (ASU-SE)
Control		 31.55 (6.15)
32.59 (9.44)
33.79 (6.24)
32.05 (7.04)
34.25 (11.21)
40.15 (14.77)
Grandizoli and Pinheiro/2018 44 CHX 60 Caries-affected Clearfil SE bond (self-etch) Water 24 hours CHX 2%
Control		 21.7 (16.3)
19.3 (11.9)
6 months CHX 2%
Control		 1.9 (1.8)
2.5 (1.2)
Karrabi and Danesh Kazemi/2016 45 CHX 120 Caries-free Adper Single Bond (etch and rinse) Artificial saliva 6 months CHX 2%
Control		 52.67 (6.86)
28.84 (6.23)
Kasraei et al/2017 46 RIBO 120
Light activation		 Caries-free Adper Single Bond (etch and rinse) Water 5,000 thermocycles RIBO 0.1%
Control		 12.79 (3.64)
12.64 (2.35)
Lenzi et al/2014 47 CHX 60 Caries-free and caries-affected Adper Single Bond (etch and rinse) Water 24 hours CHX 2%
Control
CHX 2% (CA)
Control (CA)		 32.8 (3.8)
30.7 (2.2)
25.1 (4.0)
24.3 (3.8)
6 months CHX 2%
Control
CHX 2% (CA)
Control (CA)		 31.3 (2.6)
24.2 (3.6)
23.2 (5.2)
14.3 (5.8)
Li et al/2018 48 BAI
GD		 120 Caries-free Adper Single Bond 2 (etch and rinse) Artificial saliva 24 hours GD 5%
BAI 2.5 μg/mL
Control		 58.86 (4.29)
58.32 (3.95)
41.89 (5.18)
3 months GD 5%
BAI 2.5 μg/mL
Control		 56.10 (5.89)
52.43 (5.43)
34.46 (6.22)
6 months GD 5%
BAI 2.5 μg/mL
Control		 51.86 (6.42)
52.43 (5.43)
26.82 (5.30)
Loguercio et al/2016 49 CHX 60 Caries-free Primer & Bond NT (etch-and-rinse; PB)
Adper Single Bond 2 (etch and rinse)		 Water 24 hours CHX 2% (PB)
Control
CHX 2% (ASB)
Control		 33.1 (2.8)
35.1 (3.1)
43.5 (3.5)
40.2 (3.3)
5 years CHX 2% (PB)
Control
CHX 2% (ASB)
Control		 22.1 (2.2)
11.0 (2.7)
31.3 (2.7)
16.1 (2.1)
Loguercio et al/2009 50 CHX 15/60 Caries-free Primer & Bond (etch and rinse)
Adper Single Bond (SB; etch and rinse)		 Water 24 hours CHX 2% (PB) 15 s
CHX 0.002% (PB) 15 s
Control 15 s
CHX 2% (SB) 15 s
CHX 0.002% (SB) 15 s
Control 15 s
CHX 2% (PB) 60 s
CHX 0.002% (PB) 60 s
Control 60 s
CHX 2% (SB) 60 s
CHX 0.002% (SB) 60 s
Control 60 s		 33.1 (6.5)
25.7 (2.4)
28.3 (4.3)
43.5 (4.1)
41.4 (4.8)
39.2 (5.4)
31.3 (5.1)
29.2 (3.4)
32.4 (5.4)
41.2 (4.2)
43.2 (6.1)
41.5 (6.4)
6 months CHX 2% (PB) 15 s
CHX 0.002% (PB) 15 s
Control 15 s
CHX 2% (SB) 15 s
CHX 0.002% (SB) 15 s
Control 15 s
CHX 2% (PB) 60 s
CHX 0.002% (PB) 60 s
Control 60 s
CHX 2% (SB) 60 s
CHX 0.002% (SB) 60 s
Control 60 s		 27.3 (4.2)
23.2 (4.1)
20.1 (4.2)
40.1 (5.7)
37.2 (6.1)
27.9 (6.2)
28.1 (4.4)
27.0 (3.6)
21.2 (3.8)
37.6 (3.3)
40.1 (3.7)
25.4 (4.1)
Maravic et al/2018 51 ACR 60 Caries-free Adper Scotchbond 1XT (etch and rinse) Artificial saliva 24 hours ACR 0.01%
Control		 46.6 (3.1)
46.0 (4.9)
12 months ACR 0.01%
Control		 39.9 (3.3)
24.8 (2.4)
Mazzoni et al/2013 52 EDC 60 Caries-free Optibond (OB) FL (etch and rinse)
Scotchbond (SB) 1XT (etch and rinse)		 Artificial saliva 24 hours EDC 0.3M + OB
Control
EDC 0.3M + SB
Control		 44.5 (9.8)
43.3 (9.4)
38.8 (9.8)
40.5 (10.3)
12 months EDC 0.3M + OB
Control
EDC 0.3M + SB
Control		 41.2 (10.1)
33.1 (7.9)
32.5 (9.6)
24.8 (8.8)
Mazzoni et al/2018 53 EDC 60 Caries-free Clearfil SE primer (self-etch)
XP Bond (etch and rinse)		 Artificial saliva 24 hours EDC 0.3M + (Clearfil)
Control
EDC 0.3M + (XP bond)
Control		 30.1 (6.3)
32.8 (4.4)
36.5 (7.1)
37.6 (5.9)
12 months EDC 0.3M + (Clearfil)
Control
EDC 0.3M + (XP bond)
Control		 26 (8.0)
21.4 (5.7)
28.6 (6.4)
18.1 (4.9)
Mohamed et al/2020 54 CS 60 Caries-free Universal Single Bond adhesive (self-etch) Water 24 hours CS 0.2%
CS 2.5%
Control		 39.16 (38.62)
15.63 (14.64)
20.82 (21.43)
3 months CS 0.2%
CS 2.5%
Control		 23.95 (25.08)
16.89 (17.79)
21.1 (21.03)
6 months CS 0.2%
CS 2.5%
Control		 25.1 (25.73)
21.36 (20.94)
28.76 (28.15)
Mosallam et al/2018 55 GT
MA
MN		 60 Caries-free Tetric N-Bond Universal (etch and rinse) Water 24 hours GT 20 mg/mL (WE)
GT 5 mg/mL (AE)
MA 20 mg/mL (WE)
MA 5 mg/mL (AE)
MN 20 mg/mL (WE)
MN 5 mg/mL (AE)
Control		 29.22 (6.29)
16.70 (5.30)
4.01 (1.92)
26.68 (5.81)
24.90 (6.74)
26.68 (5.81)
28.38 (6.68)
1,000 thermocycles GT 20 mg/mL (WE)
GT 5 mg/mL (AE)
MA 20 mg/mL (WE)
MA 5 mg/mL (AE)
MN 20 mg/mL (WE)
MN 5 mg/mL (AE)
Control		 18.97 (6.66)
12.73 (6.63)
2.64 (2.27)
17.93 (4.82)
17.83 (6.57)
17.93 (4.82)
17.39 (1.71)
Mosallam et al/2019 56 MA
MN		 60 Caries-free Scotch Bond Universal (etch and rinse) Water 24 hours MA 20 mg/mL (WE)
MA 5 mg/mL (AE)
MN 20 mg/mL (WE)
MN 5 mg/mL (AE)
Control		 29.30 (7.31)
17.39 (1.63)
35.03 (5.24)
19.72 (8.82)
28.38 (6.68)
1,000 thermocycles MA 20 mg/mL (WE)
MA 5 mg/mL (AE)
MN 20 mg/mL (WE)
MN 5 mg/mL (AE)
Control		 20.55 (8.85)
10.26 (8.28)
20.60 (5.97)
18.05 (7.84)
17.39 (1.71)
Ou et al/2018 57 CHX
MMP8-I inhibitor		 30 Caries-free Adper Single Bond 2 (etch and rinse) Water 24 hours CHX 2%
MMP8-I
Control		 42.14 (8.83)
55.29 (9.71)
47.18 (11.69)
6 months CHX 2%
MMP8-I
Control		 41.83 (15.52)
54.70 (13.66)
39.06 (9.88)
12 months CHX 2%
MMP8-I
Control		 39.92 (16.08)
54.29 (15.26)
35.82 (19.14)
Paulose and Fawzy/2018 58 EDC 60 Caries-free Adper Scotchbond multipurpose (etch-and-rinse: SBM)
Single bond Universal adhesive (etch and rinse)		 Water 24 hours EDC 0.3M + SBM
Control
EDC 0.3M -dry + SBU
Control
EDC 0.3M -wet + SBU
Control		 40.7 (9.3)
43.2 (8.1)
39.7 (5.3)
36.9 (8.7)
30.9 (5.7)
33.6 (6.1)
12 months EDC 0.3M + SBM
SMP Control
EDC 0.3 -dry + SBU
Control
EDC 0.3M -wet + SBU
Control		 30.8 (7.4)
22.3 (7.3)
26.7 (4.9)
18.8 (5.9)
11.2 (4.6)
13.7 (4.6)
Pedrosa et al/2018 59 CA 60 Caries-free Adper Scotchbond multipurpose (etch-and-rinse)
Clearfil SE bond (self-etch)		 Water 24 hours CA 0.05% (ASB)
CA 0.1% (ASB)
Control
CA 0.05% (CSE)
CA 0.1% (CSE)
Control		 34.40 (7.75)
36.58 (6.16)
40.67 (8.90)
23.47 (6.91)
25.73 (5.55)
31.74 (8.05)
12 months CA 0.05% (ASB)
CA 0.1% (ASB)
Control
CA 0.05% (CSE)
CA 0.1% (CSE)
Control		 26.97 (9.88)
22.88 (4.44)
25.24 (9.72)
24.20 (7.78)
26.21 (7.33)
25.99 (6.79)
Perote et al/2015 60 CHX
EPE
APE		 60 Caries-free Adper Single Bond 2 (etch and rinse) Artificial saliva 24 hours CHX 0.2%
EPE 10%
APE 10%
Control		 31.6 (7.0)
29.1 (6.9)
33.0 (6.7)
28.6 (5.3)
6 months CHX 0.2%
EPE 10%
APE 10%
Control		 26.5 (4.4)
23.1 (3.9)
25.1 (4.8)
24.0 (3.9)
Porto et al/2018 61 CHX
QUE
Res		 60 Caries-free Single Bond Universal (etch and rinse) Water 24 hours CHX 2%
Que (μg mL 1 ) 100
250
500
1,000
Res (μg mL 1 ) 100
250
500
1,000
Que + Res (μg mL 1 ) 3:1 100
250
500
1,000
Que + Res 1:1 100
250
500
1,000
Que + Res 1:3 100
250
500
1,000
Control		 27.78 (6.88)
32.06 (8.90)
27.51 (8.70)
31.21 (9.93)
31.30 (10.33)
18.81 (6.07)
23.90 (7.46)
23.74 (5.98)
20.11 (5.31)
27.40 (7.19)
19.33 (6.02)
28.44 (7.07)
31.38 (8.45)
18.78 (3.63)
23.93 (7.20)
23.29 (5.23)
19.10 (5.49)
22.73 (6.37)
20.83 (6.61)
25.99 (7.89)
23.76 (5.76)
23.62 (6.71)
3 months CHX 2%
Que (μg mL 1 ) 100
250
500
1,000
Res (μg mL 1 ) 100
250
500
1,000
Que + Res (μg mL 1 ) 3:1 100
250
500
1,000
Que + Res 1:1 100
250
500
1,000
Que + Res 1:3 100
250
500
1,000
Control		 30.68 (8.71)
25.29 (8.01)
34.68 (16.17)
42.37 (13.59)
37.40 (11.37)
31.03 (11.25)
37.90 (10.11)
29.77 (7.34)
26.18 (7.77)
30.48 (10.16)
35.38 (13.54)
31.14 (10.31)
32.32 (8.39)
37.13 (12.29)
32.80 (14.05)
32.36 (11.43)
28.13 (8.54)
28.56 (11.45)
30.82 (8.77)
26.55 (7.93)
31.66 (10.92)
26.47 (8.26)
Prasansuttiporn et al/2020 62 RA 5 Caries-affected Clearfil SE Bond (self-etch) Artificial saliva 24 hours RA 100 μM
Control		 35.4 (5.5)
35.1 (5.3)
12 months RA 100 μM
Control		 34.2 (4.3)
30.3 (4.2)
Prasansuttiporn et al/2017 63 RA 5 Caries-free Clearfil SE Bond (self-etch) Artificial saliva 24 hours RA 100 μM
Control		 54.8 (3.9)
55.2 (4.1)
12 months RA 100 μM
Control		 52.6 (4.7)
45.8 (4.0)
Ruksaphon and Pisol/2017 64 CHX
RA		 60 Caries-free OptiBond FL (etch and rinse)
OptiBond Solo (solo) (etch and rinse)		 Artificial saliva 24 hours CHX 2% + (solo)
CHX 2% + (FL)
RA 100 μM + (solo)
RA 100 μM + (FL)
Control (solo)
Control (FL)		 38.42 (8.04)
38.46 (7.82)
36.00 (8.04)
41.27 (6.76)
39.60 (7.50)
37.27 (8.45)
3 months CHX 2% + (solo)
CHX 2% + (FL)
RA 100 μM + (solo)
RA 100 μM + (FL)
Control (solo)
Control (FL)		 40.75 (7.12)
41.26 (5.51)
39.43 (10.12)
41.27 (6.76)
32.13 (7.32)
29.45 (8.12)
6 months CHX 2% + (solo)
CHX 2% + (FL)
RA 100 μM + (solo)
RA 100 μM + (FL)
Control (solo)
Control (FL)		 32.83 (6.82)
29.33 (6.66)
31.37 (10.24)
32.79 (7.37)
30.54 (8.05)
26.46 (6.39)
12 months CHX 2% + (solo)
CHX 2% + (FL)
RA 100 μM + (solo)
RA 100 μM + (FL)
Control (solo))
Control (FL)		 22.85 (11.72)
27.82 (11.54)
28.98 (7.68)
28.04 (9.09)
3.10 (8.22)
3.91 (9.20)
Sacramento et al/2012 65 CHX 60 Caries-affected Clearfil protect Bond (self-etch)
Clearfil SE Bond (self-etch)		 Water 24 hours CHX 2% (SE)
CHX 2% (PB)
Control (SE)
Control (PB)		 12.39 (2.37)
14.60 (3.65)
12.28 (2.91)
16.24 (2.71)
6 months CHX 2% (SE)
CHX 2% (PB)
Control (SE)
Control (PB)		 2.88 (1.30)
3.09 (0.92)
2.95 (0.77)
2.32 (0.60)
12 months CHX 2% (SE)
CHX 2% (PB)
Control (SE)
Control (PB)		 1.76 (0.35)
2.34 (0.76)
1.36 (0.22)
1.11 (0.59)
Sadeghi et al/2017 66 CHX 60 Caries-free Optibond Solo Plus (etch and rinse)
Single Bond Universal (SBU; etch and rinse)		 Water 1 week CHX 0.2% + OSP
Control
CHX 0.2% +SBU
Control		 29.84 (5.43)
34.57 (8.22)
35.75 (8.58)
58.17 (10.25)
6 months CHX 0.2% + OSP
Control
CHX 0.2% +SBU
Control		 20.59 (5.52)
22.51 (3.55)
23.28 (3.90)
33.42 (7.04)
Santiago et al/2013 67 CHX
EGCG		 60 Caries-free Adper Single Bond 2 (etch and rinse) Water 24 hours EGCG 0.02%
EGCG 0.1%
EGCG 0.5%
CHX 2%
Control		 31.39 (7.82)
34.74 (9.14)
27.11 (7.78)
34.68 (7.30)
34.17 (7.75)
6 months EGCG 0.02%
EGCG 0.1%
EGCG 0.5%
CHX 2%
Control		 31.75 (10.58)
35.99 (10.91)
31.18 (9.29)
31.62 (5.78)
27.67 (6.98)
Shen et al/2020 68 CHX 60 Caries-free Single Bond 2 (etch and rinse) Water 24 hours CHX 2%
Control		 37.43 (5.29)
33.00 (3.95)
6 months CHX 2%
Control		 33.31 (3.28)
28.36 (4.01)
Venigalla et al/2016 69 RIBO
EDC
PAC		 120 Caries-free Adper Single Bond water wet bonding (etch and rinse)
Ethanol wet bonding (etch and rinse)		 Artificial saliva 24 hours RIBO 0.1% + WWB
EDC 1M +WWB
PAC 6.5% +WWB
Control
RIBO 0.1% + EWB
EDC 1M + EWB
PAC 6.5% + EWB
Control		 46.94 (2.17)
45.14 (1.76)
41.71 (1.63)
31.76 (1.51)
52.12 (0.46)
47.50 (0.78)
44.38 (0.69)
41.61 (1.13)
6 months RIBO 0.1% + WWB
EDC 1M +WWB
PAC 6.5% +WWB
Control
RIBO 0.1% + EWB
EDC 1M + EWB
PAC 6.5% + EWB
Control		 45.14 (1.50)
42.58 (1.24)
34.30 (1.21)
23.96 (1.43)
51.80 (0.32)
45.27 (0.50)
41.90 (0.79)
37.37 (0.58)
Xu et al/2020 70 BAC
PVPA
PAC		 30 Caries-free Clearfil SE bond (self-etch) Water 24 hours MDP 5% + BAC 1%
MDP 5% + PVPA 1,000 μm/mL
MDP 5% + PAC 15%
Control
MDP 15% + BAC 1%
MDP 15% + PVPA 1,000 μm/mL
MDP 15% + PAC 15%
Control		 29.2 (6.6)
27.9 (4.1)
26.5 (6.9)
26.9 (5.8)
31.7 (4.0)
30.4 (6.7)
30.3 (3.5)
29.3 (3.8)
12 months MDP 5% + BAC 1%
MDP 5% + PVPA 1,000 μm/mL
MDP 5% + PAC 15%
Control
MDP 15% + BAC 1%
MDP 15% + PVPA 1,000 μm/mL
MDP 15% + PAC 15%
Control		 25.9 (5.2)
26.8 (6.3)
25.6 (4.7)
26.3 (6.2)
35.2 (6.1)
31.8 (5.3)
29.7 (3.6)
31.5 (6.4)
Kazemi-Yazdi et al/2020 71 CHX 60 Caries-free Clearfil SE Bond (self-etch) Water 24 hours CHX 2%
Control		 14.58 (5.04)
18.00 (5.54)
3,000 thermocycles CHX 2%
Control		 14.36 (7.44)
16.71 (8.00)
Da Silva et al/2015 72 CHX 60 Caries-free Single Bond 2 (etch and rinse)
Ambar (etch and rinse)		 Water 24 hours CHX 2% (SB)
Control
CHX 2% (Ambar)
Control		 21.7 (6.7)
11.4 (3.6)
11.2 (5.9)
12.5 (7.6)
15 days CHX 2% (SB)
Control
CHX 2% (Ambar)
Control		 11.1 (3.6)
6.3 (2.5)
6.8 (4.2)
7.7 (3.6)
Zheng et al/2015 73 CHX
GT
FeSO 4
Galardin		 60 Caries-free Optibond FL (etch and rinse)
Clearfil SE Bond (self-etch)		 Artificial saliva 9 months CHX 2% (FL)
GT 0.05% (FL)
FeSO 4 1 mM (FL)
Galardin 0.2 mM (FL)
Control
CHX 2% (SE)
GT 0.05% (SE)
FeSO 4 1 mM (SE)
Galardin 0.2 mM (SE)
Control		 32.9 (11.3)
33.2 (14.0)
25.3 (10.5)
33.6 (10.5)
25.3 (11.8)
32.9 (11.3)
26.1 (14.2)
25.3 (10.5)
33.6 (14.1)
20.3 (13.6)
Sadek et al/2010 74 CHX 60 Not mentioned Scotchbond multipurpose (self-etch)
Single Bond 2 (self-etch)
Experimental ethanol wet-bonding adhesive (self-etch)		 Artificial saliva 24 hours CHX 2% + EWB
Control
CHX 2% + MP
Control
CHX 2% + SB
Control		 46.8 (5.1)
45.8 (7.2)
41.3 (8.1)
44.2 (3.5)
42.6 (5.2)
42.3 (7.4)
9 months CHX 2% + EWB
Control
CHX 2% + MP
Control
CHX 2% + SB
Control		 44.6 (5.6)
44.4 (6.9)
37.4 (5.6)
37.4 (3.5)
38.2 (4.7)
44.4 (4.9)
18 months CHX 2% + EWB
Control
CHX 2% + MP
Control
CHX 2% + SB
Control		 43.6 (5.5)
44.2 (7.8)
30.5 (8.0)
32.6 (7.1)
28.8 (8.3)
31.5 (4.3)
Breschi et al/2010 22 Galardin 30 Caries-free Adper Scotchbond 1XT (etch and rinse) Artificial saliva 24 hours Galardin 0.2 mM
Control		 44.1 (7.3)
41.4 (5.9)
12 months Galardin 0.2 mM
Control		 32.4 (6.6)
22.6 (5.4)
Stanislawczuk et al/2009 75 CHX 60 Caries-free Prime & Bond NT (etch and rinse)
Single Bond (SB) 2 (etch and rinse)		 Water 24 hours CHX 2% + Prime & Bond
Control
CHX 2% + (SB)
Control		 21.9 (4.7)
22.0 (9.7)
23.4 (2.1)
14.6 (3.1)
6 months CHX 2% + Prime & Bond
Control
CHX 2% + (SB)
Control		 31.1 (3.1)
27.2 (6.1)
31.1 (2.6)
20.4 (2.1)
Firouzmandi et al/2020 76 SDF 180 Caries-free
and
Caries-affected (CA)		 Adper single Bond 2 (etch and rinse) Water 24 hours SDF 30%
Control
SDF 30% (CA)
Control		 17.08 (4.88)
18.37 (4.71)
17.63 (4.19)
12.20 (2.34)
6 months SDF 30%
Control
SDF 30% (CA)
Control		 15.72 (2.34)
14.72 (3.51)
10.30 (3.78)
11.53 (2.66)
Giacomini et al/2017 77 CHX
E-64		 60 Caries-free
Eroded (ERO)
and
Caries-affected (CA)		 Adper Single Bond Universal (etch and rinse) Artificial saliva 24 hours CHX 2%
CHX 2% (ERO)
CHX 2% (CA)
E-64 5 μM
E-64 5 μM (ERO)
E-64 5 μM (CA)
Control
Control (ERO/water)
Control (CA/water)		 28.36 (5.88)
22.53 (4.76)
18.31 (3.50)
28.33 (5.42)
30.23 (6.51)
24.51 (4.41)
35.32 (5.30)
29.85 (4.77)
23.42 (4.95)
6 months CHX 2%
CHX 2% (ERO)
CHX 2% (CA)
E-64 5 μM
E-64 5 μM (ERO)
E-64 5 μM (CA)
Control
Control (ERO/water)
Control (CA/water)		 16.50 (3.89)
20.13 (4.62)
16.50 (3.90)
20.80 (3.71)
27.70 (5.32)
20.80 (3.71)
27.45 (5.33)
26.07 (4.96)
20.28 (3.55)
Sabatini et al/2014 78 CHX
BAC		 60 Caries-free Adper Single Bond Plus (etch and rinse) Artificial saliva 24 hours CHX 2%
BAC 0.5%
BAC 1.0%
Control		 38.3 (10.3)
36.4 (8.4)
51.4 (7.9)
34.3 (7.8)
6 months CHX 2%
BAC 0.5%
BAC 1.0%
Control		 34.3 (5.2)
36.6 (6.2)
53.9 (6.9)
27.4 (6.2)
Carvalho et al/2016 79 CHX
EGCG		 60 Caries-affected Adper Single Bond 2 (etch-and-rinse) Water 24 hours EGCG 2%
CHX 2%
Control		 23.0 (6.3)
23.3 (6.0)
24.3 (8.6)
6 months EGCG 2%
CHX 2%
Control		 35.7 (8.4)
23.0 (7.2)
21.6 (6.4)
Loguercio et al/2016 80 CHX 15 Caries-free Prime & Bond NT (etch and rinse)
Adper Single Bond 2 (etch and rinse)		 Water 24 hours CHX 2% (PB)
Control
CHX 2% (SB)
Control		 44.2 (4.3)
42.3 (3.4)
50.3 (5.6)
46.2 (4.7)
2 years CHX 2% (PB)
Control
CHX 2% (SB)
Control		 36.3 (5.1)
23.6 (5.3)
43.3 (3.5)
32.3 (4.5)
Cova et al/2011 99 RIBO 60 Caries-free XP Bond adhesive (etch and rinse) Artificial saliva 24 hours RIBO 0.1%
Control		 44.4 (10.4)
37.3 (10.3)
6 months RIBO 0.1%
Control		 35.6 (11.2)
22.0 (7.0)
12 months RIBO 0.1%
Control		 30.9 (12.2)
17.7 (9)
Mobarak/2011 81 CHX 60 Caries-free
and
Caries-affected (CA)		 Self-etch primer adhesive (Clearfil SE Bond; self-etch) Artificial saliva 24 hours CHX 2%
CHX 5%
Control
CHX 2% (CA)
CHX 5% (CA)
Control		 23.79 (5.9)
25.94 (6.4)
24.33 (5.1)
20.84 (6.2)
20.59 (5.1)
21.73 (6.0)
2 years CHX 2%
CHX 5%
Control
CHX 2% (CA)
CHX 5% (CA)
Control		 8.74 (3.2)
10.98 (3.3)
9.46 (3.4)
9.99 (3.4)
14.67 (4.5)
9.97 (3.5)
Manso et al/2014 82 CHX 30 Caries-free All Bond 3 (Bisco) (etch and rinse)
Excite (Ivoclar Vivadent) (etch and rinse)		 Water 24 hours CHX 2%/water (Bisco)
Control
CHX 2%/ethanol (Bisco)
Control
CHX 2%/water (Excite)
Control
CHX 2%/ethanol (Excite)
Control		 46.96 (3.6)
51.07 (3.6)
54.67 (3.6)
59.41 (3.6)
40.05 (5.4)
49.51 (5.4)
53.37 (5.4)
49.67 (5.4)
6 months CHX 2%/water (Bisco)
Control
CHX 2%/ethanol (Bisco)
Control
CHX 2%/water (Excite)
Control
CHX 2%/ethanol (Excite)
Control		 50.69 (3.6)
57.13 (3.6)
52.17 (3.6)
56.41 (3.6)
36.78 (5.4)
42.10 (5.4)
57.47 (5.4)
44.56 (5.4)
15 months CHX 2%/water (Bisco)
Control
CHX 2%/ethanol (Bisco)
Control
CHX 2%/water (Excite)
Control
CHX 2%/ethanol (Excite)
Control		 46.07 (4.4)
47.29 (4.4)
39.58 (4.4)
44.41 (4.4)
40.87 (6.6)
45.51 (6.6)
49.55 (6.6)
42.48 (5.4)
Breschi et al/2010 19 CHX 30 Caries-free Adper Scotchbond 1XT (etch and rinse) Artificial saliva 24 hours CHX 2%
CHX 0.2%
Control		 41.2 (9.6)
39.2 (9.3)
40.8 (8.7)
2 years CHX 2%
CHX 0.2%
Control		 28.5 (7.2)
32.6 (8.3)
13.4 (4.9)
Montagner et al/2015 83 CHX 60 Caries-free Adper Single Bond 2 (etch and rinse) Water 24 hours CHX 2%
Control		 25.3 (6.2)
26.7 (10.0)
18 months CHX 2%
Control		 20.1 (10.3)
14.8 (9.4)
Li et al/2020 84 DMA 60 Caries-free Adper Single Bond 2 (etch and rinse) Water 24 hours DMA 0.1 mM
DMA 1.0 mM
DMA 10 mM
Control		 28.73 (5.19)
30.76 (7.57)
27.06 (7.53)
29.96 (6.43)
1,000 thermocycles DMA 0.1 mM
DMA 1.0 mM
DMA 10 mM
Control		 23.84 (7.06)
29.19 (6.58)
23.34 (7.36)
16.24 (6.90)
Hass et al/2016 98 PAC
RIBO
GD		 60 Caries-free Adper Single Bond 2 (etch and rinse)
Tetric N-Bond (etch and rinse)		 Water 24 hours PAC 6.5% (SB)
RIBO 0.1% (SB)
GD 5% (SB)
Control
PAC 6.5% (TN)
RIBO 0.1% (TN)
GD 5% (TN)
Control		 36.2 (5.5)
37.1 (9.7)
38.5 (2.4)
39.5 (7.9)
29.2 (1.2)
31.5 (6.9)
35.7 (1.9)
36.8 (4.7)
18 months PAC 6.5% (SB)
RIBO 0.1% (SB)
GD 5% (SB)
Control
PAC 6.5% (TN)
RIBO 0.1% (TN)
GD 5% (TN)
Control		 31.9 (4.3)
31.6 (3.5)
29.7 (2.6)
13.9 (1.8)
27.6 (6.3)
25.1 (1.3)
24.2 (1.4)
13.9 (1.8)
Kalagi et al/2020 85 CHX 5 Caries-free Adper Scotchbond multipurpose (etch and rinse) Water 24 hours CHX 2%
Control		 66.4 (8.8)
49.1 (12.6)
6 months CHX 2%
Control		 71.9 (14.7)
41.6 (10.6)
Tekçe et al/2016 86 CHX 60 Caries-free Single Bond Universal (self-etch)
All Bond Universal (self-etch)		 Water 24 hours CHX 2% (SBU)
Control
CHX 2% (ABU)
Control		 45.22 (6.32)
43.33 (3.41)
38.92 (4.01)
43.81 (3.61)
12 months CHX 2% (SBU)
Control
CHX 2% (ABU)
Control		 41.19 (3.98)
37.67 (3.40)
31.37 (5.97)
38.54 (6.19)
de Moura et al/2021 87 GT 60 Caries-affected Adper Single Bond 2 (etch-and-rinse) Water 24 hours GT 0.05%
GT 0.2%
GT 2%
Control		 14.42 (6.20)
17.80 (6.49)
11.04 (2.94)
11.29 (4.78)
6 months GT 0.05%
GT 0.2%
GT 2%
Control		 9.53 (4.83)
13.25 (5.82)
7.09 (4.14)
8.82 (6.23)
Li et al/2021 88 DMA 60 Caries-free Adper Single Bond 2 (etch-and-rinse) Water 24 hours DMA 1 mM
DMA 5 mM
DMA 10 mM
Control		 33.16 (8.41)
32.59 (8.70)
32.73 (7.39)
30.08 (7.55)
10,000 thermocycles DMA 1 mM
DMA 5 mM
DMA 10 mM
Control		 30.40 (8.10)
31.46 (7.31)
31.85 (8.10)
22.63 (6.40)
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Abbreviations: ACR, acrolein; AE, alcohol extract; APE, aqueous propolis extract; BAI, baicalein; BAC, benzalkonium chloride; CA, caffeic acid; CS, chitosan; CHX, chlorhexidine; DCC, N,N'-dicyclohexylcarbodiimide; DMA, dopamine methacrylamide; EDC, carbodiimide; EGCG, epigallocatechin gallate; EPE, ethanolic propolis extract; FeSO 4 , ferrous sulfate; GD, 5% glutaraldehyde; GT, green tea; HES, hesperidin; MA, Morus alba leaves; MAP, mussel adhesive protein; MN, Morus nigra leaves; NAR, naringin; PAC, proanthocyanidin; PVPA, polyvinylphosphonic acid; QUE, guercetin; RA, rosmarinic acid; Res, resveratrol; RIBO, riboflavin; RUT, rutin; SDF, silver diamine fluoride; WE, water extract.

Thirty-one different types of MMP inhibitors were used, 14 synthetically derived and 17 naturally derived. The microtensile bond strength test was used in all included studies except for five studies that used microshear bond strength testing. Most studies ( n  = 53) used caries-free dentine substrate, 13 used caries-affected dentine, two studies used eroded dentine, and one study used dentine without mentioning its condition. All studies used permanent teeth except for one study that used primary teeth.

With respect to storage medium, the majority of studies used distilled water (40 studies) and 22 used artificial saliva. Two studies used both distilled and deionized water. The majority of the studies applied MMP inhibitor for 60 s ( n  = 47), six studies applied it for 30 seconds, four for 120 seconds, three for 5 seconds, two for 15 seconds, and one each for 20 and 180 seconds. One study did not report the application duration. Only MMP inhibitors applied for 30 and 60 seconds were included in the meta-analysis, as they contained enough data.

Ageing periods ranged from 24 hours to 5 years, and various thermocycling ageing protocols were also used. The majority of studies ( n  = 62) aged samples for 24 hours as an immediate ageing period. With respect to long-term ageing, 31 studies aged the samples for 6 months, 19 aged them for 12 months, five aged them for 3 months, three for 2 years, three for 18 months, two for 9 months, and one study each for 3 days, 1 week, 15 days, 15 months, and 5 years. Eleven studies used thermocycling for ageing: four used 1,000 cycles, two used 5,000 cycles, and one study each used 2,500, 3,000, 10,000, and 25,000 cycles.

Risk of Bias Evaluation

Table 3 shows the evaluated risk of bias of the included studies. Overall, almost half of included studies showed a medium risk of bias (33 of 64), 17 of 64 studies showed a high risk of bias, and 14 studies were classified as a low risk of bias.

Table 3. Quality assessment and risk of bias.

Study/year Randomization Substrate condition Dentine pretreatment duration Manufacturer instruction Storage medium Interface surface area Single operator Sample size calculation Blinding of operator Risk of bias
Baena et al / 2020 30 N Y Y Y Y Y N N N High
Balloni et al / 201 7 31 Y Y Y Y Y Y N N Y Medium
Bravo et al / 2017 32 Y Y Y Y Y Y N N N Medium
de Faria Teixeira et al / 2015 33 Y N Y Y Y Y N N N High
Comba et al / 2020 34 Y Y Y Y Y Y N N N Medium
Czech et al / 2019 24 Y Y Y Y Y Y Y N N Medium
Dávila-Sánchez et al / 2020 35 Y Y Y Y Y Y Y Y N Low
Costa et al / 2019 36 Y Y Y Y Y Y N N N Medium
El Baz, and Aboulenien/2018 37 N Y Y Y Y Y N Y N Medium
Fang et al / 2017 38 N Y Y Y Y Y N N N High
Fernandes et al / 202 1 39 Y Y Y Y Y Y N Y N Medium
Fialho et al / 2019 40 Y Y Y Y Y Y Y Y N Low
Gerhardt et al / 2016 41 Y Y Y Y Y N N N N High
Campos et al / 2019 42 Y Y N Y Y Y Y N N Medium
Giacomini et al / 2020 43 Y Y Y Y Y Y N Y N Medium
Grandizoli and Pinheiro/2018 44 Y Y Y Y Y Y N Y N Medium
Karrabi and Danesh Kazemi/ 2016 45 Y Y Y Y Y Y N N N Medium
Kasraei et al/ 2017 46 Y Y Y N Y Y N N N High
Lenzi et al / 2014 47 Y Y Y N Y Y N N N High
Li et al / 2018 48 Y Y Y N Y Y N N N High
Loguercio et al / 2016 49 Y Y Y N Y Y N N N High
Loguercio et al / 2009 50 Y Y Y Y Y Y Y N N Medium
Maravic et al / 2018 51 Y Y Y Y Y Y N N N Medium
Mazzoni et al / 2013 52 Y Y Y Y Y Y N N N Medium
Mazzoni et al / 2018 53 Y Y Y Y Y Y N N N Medium
Mohamed et al / 2020 54 N Y Y Y Y Y N N N High
Mosallam et al / 2018 55 Y Y Y Y Y Y N N N Medium
Mosallam et al / 2019 56 Y Y Y Y Y N N N N High
Ou et al / 2018 57 Y Y Y Y Y N N N N High
Paulose and Fawzy / 2018 58 Y Y Y Y Y Y N N N High
Pedrosa et al / 2018 59 Y Y Y Y Y Y N N N Medium
Perote et al / 2015 60 Y Y Y Y Y Y N N N Medium
Porto et al/ 2018 61 Y Y Y Y Y Y N N N Medium
Prasansuttiporn et al / 2020 62 Y Y Y Y Y Y N N N Medium
Prasansuttiporn et al / 2017 63 Y Y Y Y Y Y N N N Medium
Ruksaphon and Pisol/ 2017 64 Y Y Y Y Y Y N N N Medium
Sacramento et al / 2012 65 Y Y Y Y Y Y N N N Medium
Sadeghi et al/ 2017 66 Y Y Y Y Y Y N N N Medium
Santiago et al / 2013 67 Y Y Y Y Y Y N N N Medium
Shen et al / 2020 68 Y Y Y N Y Y N N N High
Venigalla et al / 2016 69 Y Y Y Y Y N N N N High
Xu et al / 2020 70 Y Y Y N Y Y N N N High
Kazemi-Yazdi et al / 2020 71 Y Y Y Y Y Y N N N Medium
Da Silva et al / 2015 72 Y Y Y Y Y Y N N N Medium
Zheng et al / 2015 73 Y Y Y Y Y Y N N N Medium
Sadek et al / 2010 74 Y N Y Y Y Y N N N High
Breschi et al / 2010 22 Y Y Y Y Y Y N N N Medium
Stanislawczuk et al / 2009 75 Y Y Y N Y Y Y N N Medium
Firouzmandi et al / 2020 76 N Y Y Y Y N N N N High
Giacomini et al / 2017 77 Y Y Y Y Y Y N N N Medium
Sabatini et al / 2014 78 Y Y Y Y Y Y N N N Medium
Carvalho et al / 2016 79 Y Y Y Y Y Y N N N Medium
Loguercio et al / 2016 80 Y Y Y Y Y Y Y N N Medium
Cova et al / 2011 99 Y Y Y Y Y Y N N N Medium
Mobarak / 2011 81 N Y Y Y Y N N N N High
Manso et al / 2014 82 Y Y Y Y Y Y N N N Medium
Breschi et al / 2010 19 Y Y Y Y Y Y N N N Medium
Montagner et al / 2015 83 Y Y Y Y Y Y Y N N Medium
Li et al / 2020 84 Y Y Y Y Y Y N N N Medium
Hass et al / 2016 98 Y Y Y Y Y Y N N N Medium
Kalagi et al / 2020 85 Y Y Y Y Y Y N N N Medium
Tekçe et al / 2016 86 Y Y Y Y Y Y Y N N Medium
de Moura et al / 2021 87 Y Y Y Y Y Y Y Y N Low
Li et al / 2021 88 Y Y Y Y Y Y N N N Medium
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Abbreviations: N, no; Y, yes.

Note: This table demonstrates the quality assessment and risk of bias as reported in the materials and methods section.

Meta-Analysis

Of the 64 studies, data from 42 studies were subjected to further evaluation in meta-analyses ( Figs. 2 3 4 5 6 ). In the first analysis (2% CHX vs. control in the baseline, immediate bond strength values), 16 etch-and-rinse studies were included, representing 28 datasets considered. There was no statistically significant difference between groups ( Z -test = 1.26, p  = 0.21), and there was considerable heterogeneity ( I 2  = 54%). Eight self-etching studies were included, with 11 datasets considered. There was no significant difference between groups ( Z -test = 0.76, p  = 0.45), and there was moderate heterogeneity ( I 2  = 35%). Overall (self-etching and etch-and-rinse), there was no statistically significant difference between groups ( Z -test = 1.51, p  = 0.13), with moderate heterogeneity observed between subgroups ( I 2  = 49%; Fig. 2A ).

Fig. 2.

Fig. 2

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Forest plots according to MMP inhibitor type. 2% CHX vs. control at 24 hours ( A ), 6 months ( B ), and 12 months ( C ). CHX, chlorhexidine; CI, confidence interval; MMP, matrix metalloproteinase; SD, standard deviation.

Fig. 3.

Fig. 3

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Forest plots according to MMP inhibitor type. 0.3 M EDC vs. control at 24 hours ( A ) and 12 months ( B ). CI, confidence interval; EDC, carbodiimide; MMP, matrix metalloproteinase; SD, standard deviation.

Fig. 4.

Fig. 4

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Forest plots according to MMP inhibitor type: 0.1% RIBO vs. control at 24 hours ( A ) and 6 months ( B ). CI, confidence interval; MMP, matrix metalloproteinase; RIBO, riboflavin; SD, standard deviation.

Fig. 5.

Fig. 5

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Forest plots according to pretreatment duration for 30 seconds: pretreatment with 2% CHX vs. control group at 24 hours ( A ) and 6 months ( B ). CHX, chlorhexidine; CI, confidence interval; SD, standard deviation.

Fig. 6.

Fig. 6

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Forest plots according to pretreatment duration for 60 seconds: pretreatment with 2% CHX vs. control group at 24 hours ( A ) and 6 months ( B ). CHX, chlorhexidine; CI, confidence interval; SD, standard deviation..

The second analysis (2% CHX vs. control at 6 months of ageing) included 14 etch-and-rinse studies, representing 25 datasets. There was overall a higher bond strength for the experimental group compared with controls, but this was not statistically significant ( Z -test 1.81, p  = 0.07) and heterogeneity was considerable ( I 2  = 88%). Six self-etching studies were included, with nine datasets considered. There was no statistically significant difference between groups ( Z -test = 0.86, p  = 0.39), and again there was considerable heterogeneity ( I 2  = 73%). Tests for overall effect showed significantly higher bond strength in the experimental group compared with controls ( Z -test = 2.33, p  = 0.02), with considerable heterogeneity between subgroups ( I 2  = 86%; Fig. 2B ).

The third analysis (2% CHX vs. control at 12 months of ageing) included five etch-and-rinse studies with seven datasets. There were overall higher bond strength values in the experimental group compared with the control group. but this was not statistically significant ( Z -test = 1.09, p  = 0.28) and heterogeneity was considerable ( I 2  = 91%). For self-etching, three studies were included with four datasets considered, and there was no statistically significant difference between groups ( Z -test = 0.18, p  = 0.86) but with considerable heterogeneity ( I 2  = 84%). Tests for overall effect favored the experimental group over the control group but without statistical significance ( Z -test = 1.66, p  = 0.10) and with considerable heterogeneity between subgroups ( I 2  = 90%; Fig. 2C ).

For the fourth analysis (0.3 EDC vs. control at baseline), only etch-and-rinse studies met the inclusion criteria. Three studies were included, representing six datasets. Overall, the effect was not statistically significant ( Z -test = 0.33, p  = 0.74). Heterogeneity between groups was low ( I 2  = 0%; Fig. 3A ).

For the fifth analysis (0.3 EDC vs. control at 12 months), again, three etch-and-rinse studies representing six datasets were included. Overall, there were significantly higher bond strength values in the experimental group compared with the control group ( Z -test = 2.58, p  = 0.01) but with considerable heterogenicity ( I 2  = 66%; Fig. 3B ).

For the sixth analysis (0.1% RIBO vs. control at baseline), only two etch-and-rinse studies met the criteria, representing three datasets. There was overall a significant difference favoring the experimental group over the control group ( Z -test = 3.12, p  = 0.002), with considerable heterogeneity ( I 2  = 99%; Fig. 4A ).

For the seventh analysis (0.1% RIBO vs. control at 6 months), two studies representing three datasets showed significantly higher bond strengths in the experimental group than the control group ( Z -test = 5.78, p  < 0.00001) but with considerable heterogeneity I 2  = 98% ( Fig. 4B ).

For the eighth analysis of pretreatment for 30 seconds (2% CHX vs. control at baseline), only four etch-and-rinse studies were included, representing seven datasets. There was overall a statistically significant difference favoring the control group over the experimental group ( Z  = 2.42, p  = 0.02), and heterogeneity was low ( I 2  = 0%; Fig. 5A ).

For the ninth analysis of pretreatment for 30 seconds (2% CHX vs. control at 6 months), only three etch-and-rinse studies met the criteria, representing six datasets. There was overall no statistically significant difference between groups ( Z  = 0.28, p  = 0.78), and heterogeneity was considerable ( I 2  = 55%; Fig. 5B ).

For the 10th analysis of pretreatment for 60 seconds (2% CHX vs. control at baseline), 14 etch-and-rinse studies were included, representing 19 datasets. There was overall no statistically significant difference between groups ( Z -test = 0.07, p  = 0.95), but there was considerable heterogeneity between groups ( I 2  = 63%). For self-etching, six studies were included with six datasets. Again, there was no statistically significant difference between groups ( Z -test = 0.01, p  = 0.89) and moderate heterogeneity ( I 2  = 41%). Tests for overall effect showed no statistically significant difference between groups ( Z -test = 0.01, p  = 0.99) and considerable heterogeneity between subgroups ( I 2  = 58%; Fig. 6A ).

For the 11th and final analysis of pretreatment for 60 seconds (2% CHX vs. control at 6 months), 11 etch-and-rinse studies were included, representing 16 datasets. Overall, the experimental group was slightly, but not significantly, favored over the control group ( Z -test = 1.73, p  = 0.08), with considerable heterogeneity ( I 2  = 91%). Five self-etching studies were included representing five datasets. Overall, the experimental group was slightly, but not significantly, favored over the control group ( Z -test = 1.22, p  = 0.22), with considerable heterogeneity ( I 2  = 83%). The tests for overall effect favored the experimental group but this was not statistically significant ( Z -test = 2.35, p  = 0.73). Heterogeneity between subgroups was considerable ( I 2  = 90%; Fig. 6B ).

Discussion

This meta-analysis revealed that at least some MMP inhibitors significantly alter bond strength, both immediately and over the longer term. Accordingly, the null hypothesis was rejected.

Of all MMP inhibitors considered for meta-analysis, two MMP inhibitors improved bond strength: 0.3 M EDC and 0.1% RIBO. The 0.3 M EDC did not improve bond strength immediately (24 hours) but showed benefit after ageing for 12 months, while 0.1% RIBO showed statistically significant increases in bond strength both immediately (24 hours) and over the long term (6 months) compared with controls. Conversely, 2% CHX showed a slight but nonsignificant improvement in bond strength after 6 months of ageing but not immediately (24 hours) or after 12 months. The lack of immediate benefit with 2% CHX is consistent with two previous meta-analyses, 28 89 but the long-term results differ, possibly due to the different concentration of CHX used in previous studies. It has been suggested but not consistently proven that MMP inhibition by CHX is dose dependent. 90 91 It is worth noting that, of the few clinical trials evaluating pretreatment with CHX, no improvement in bond strength was observed over time. 92 93 94 95 96 97 With respect to adhesive systems, a previous systematic review 28 found that both types of adhesive system (self-etching and etch and rinse) benefited from 2% CHX in vitro . This, however, was also not consistent with the current meta-analysis results, since we found no significant difference according to the adhesive system used.

EDC and RIBO have a different mechanism of MMP inhibition to CHX through their cross-linking action. Generally, collagen cross-linkers protect collagen fibrils from further degradation by enhancing both the chemical and mechanical properties of collagen. 98 99 100 These additional functions could explain their superiority in maintaining adhesive interface integrity.

Pretreatments of 30 and 60 seconds with 2% CHX met the inclusion criteria for meta-analysis. Generally, neither pretreatment protocol significantly improved bond strength either immediately (24 hours) or over the long term (6 months). Indeed, when 2% CHX was applied for 30 seconds, there was a significant negative effect on bond strength over 24 hours. After 6 months of aging, there was a slight improvement in bond strength, still favoring the control group. With pretreatments of 60 seconds, 2% CHX showed no effect on bond strength and was similar to controls and, while slightly improved bond strength was observed with CHX after 6 months, it was nevertheless not statistically significant.

Our results show some inconsistencies with previous systematic reviews which might be due to differences in the inclusion criteria. For example, Montagner et al 28 and Kiuru et al 89 included different concentrations of CHX other than 2%, as well as various bond strength tests other than microtensile bond strength testing.

Limitations

There are a few limitations to our study. This review only included in vitro studies since there have been very few in vivo studies or clinical trials in the literature. More in vivo studies will ultimately be crucial for providing high-quality evidence of the safety, toxicity, and efficacy of a given intervention in a complex model. Furthermore, although strict measures were taken during the search of the articles included for meta-analysis, several data demonstrated high heterogeneity. It is worth mentioning that most of the results with high heterogeneity were observed in the long-term ageing periods, unlike the immediate ageing periods which showed lower heterogeneity. Factors that could influence this may include the different brands of adhesive systems used and the ageing methods utilized. Similar findings were observed in the study by Montagner et al 28 which found that the aging methods were the greater influencing factor in the high heterogeneity. It is also worth noting that there are no standardized protocols for evaluating bond strength which previously shown will inevitably increase the heterogeneity of results 101 . To improve the reliability and quality of future bond strength testing studies, robust and strict guidelines for laboratory testing must be developed and implemented.

Many of the studies carried a risk of bias, and only one study mentioned blinding of the operator testing the bond strength; this parameter will be important to include in future studies to reduce the risk of bias. Moreover, only six studies calculated the sample size and reported a power analysis.

Nevertheless, these in vitro findings pave the way for rationale clinical trialing of dentine surface pretreatment with MMP inhibitors to improve clinical outcomes.

Conclusion

The data suggest that using 2% CHX had no significant positive effect on bond strength either immediately or over the longer term. Pretreatments with 2% CHX for either 30 or 60 seconds do not improve the bond strength. Both 0.3 M EDC and 0.1% RIBO improve bond strength immediately and over time. There was considerable heterogeneity between the different adhesive systems used, limiting our meta-analysis. Given the limited clinical evidence available, more research is required to confirm the beneficial use of MMP inhibitors.

Acknowledgment

The authors would like to thank Kalvin Balucanag for support with meta-analyses.

Funding Statement

Funding The authors would like to thank the Deanship of Scientific Research at Umm Al-Qura University for supporting this work by Grant Code: (22UQU4350291DSR06).

Footnotes

Conflict of Interest None declared.

References

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