Antibacterial Effects of Cavity Lining a Systematic Review and Network

8/15/2019 Antibacterial Effects of Cavity Lining a Systematic Review and Network

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Review article

Antibacterial effects of cavity lining: A systematic review and networkmeta-analysis

Falk Schwendickea,*, Yu-Kang Tub, Le-Yin Hsub, Gerd Göstemeyera

aDepartment of Operative and Preventive Dentistry, Charité—Universitätsmedizin Berlin, Aßmannshauser Str. 4-6, 14197 Berlin, Germanyb Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan

A R T I C L E I N F O

Article history:

Received 21 March 2015Received in revised form 26 June 2015

Accepted

1

July

2015

Keywords:

Bacteria

Bayesian

Calcium hydroxide

Dental

Dental caries

Mineral

Trioxide

Aggregate

A B S T R A C T

Objectives: Cavity liners are frequently used prior placing a restoration, with one main aim being to

reduce the number of remaining bacteria.We systematically appraised studies comparing antibacterialeffects of different liners against each other or no liner.

Data studies: reporting the number of sterile cavities before/after lining or sealing, or the reduction in

bacterial numbers (colony-forming-units) in two or more treatment groups were included. Treatments

were categorized as: no/placebo liner, calcium hydroxide, mineral trioxide aggregate, antibiotic/

disinfectant, calcium phosphates, zinc oxide eugenol, black copper cement, and glass ionomer cement

liners. Pairwise and network meta-analyses were performed.

Study selection: From113 identied studies,14 (500 treated lesions) were included. Risk of biaswas high

or unclear.Based on 11 studies, network meta-analysis foundmineral trioxide lining toyield thegreatest

probability of achieving sterile cavities after a lining/sealing period (73%), followed by antibiotic/

disinfectant (8%) and zinc oxide eugenol (7%). Only six studies assessed bacterial reduction after lining/

sealing, and zinc oxide eugenol was found to have the highest probability of achieving a bacterial

reduction. In both analyses, not providing any lining was found to have low antibacterial effects.

Conclusion: Within the limitations of this review and the included studies, certain liners seem more

suitable to achievesterile cavities or reducebacterialnumbers thanothers. Given thepaucity of data and

the unclear impact of remaining bacteria on clinical outcomes, further recommendations for speciccavity treatments prior a restoration are not possible.

Clinical signi cance: There is insuf cient evidence to generally recommendcavity liningor the useof any

specic liner based on their antibacterial effects. Dentists might continue to use liners, but should be

aware that such use is not strongly supported by clinical studies.

ã 2015 Elsevier Ltd. All rights reserved.

1.

Introduction

For treating pulpo-proximal dentin after excavation of deeper

caries lesions, the use of cavity liners has been recommended for

decades [1]. As liners are thought to induce the development of

reactionary dentin [2,3], reduce post-operative pulpal inam-

mation [4], or isolate the pulp from chemical irritants like

hydroxyethyl methacrylate [5], they are commonly used for pulp

protection. However, clinical studies do not necessarily support

these arguments, with only few trials evaluating for example the

risk of post-operative hypersensitivity or the need for endodontic

follow-up treatments in teeth with versus without cavity lining

[6–8]. A second reason why the use of liners has been advocated

was their remineralizing effects, especially when selective

(incomplete) or stepwise excavation was performed prior to

restoration. Some studies demonstrated such remineralization

induced by cavity liners [9,10], whilst others indicate that such

mineral gain in the residual caries lesion might well be mediated

by the pulp, and does not seem to require the application of a liner

prior to restoration [11,12]. Last, lining materials are used as they

might reduce bacterial numbers, i.e. acting as cavity disinfection:

This has been especially postulated for the most widely used

material, calcium hydroxide, whose alkaline pH is supposed to

exert strong antibacterial effects [13–15]. Such effects have also

been shown for other lining materials, for example glass ionomer

cements [16,17], whilst it remains unclear which material is most

* Corresponding author at: Charité Centre for Dental Medicine, Department for

Operative and Preventive Dentistry, Aßmannshauser Str. 4–6, 14197 Berlin,

Germany. Fax: +49 30 450 7562 556.

E-mail address: [email protected] (F. Schwendicke).

http://dx.doi.org/10.1016/j.jdent.2015.07.001

0300-5712/ã 2015 Elsevier Ltd. All rights reserved.

Journal of Dentistry 43 (2015) 1298–1307

Contents

lists

available

at

ScienceDirect

Journal

of

Dentistry

j ourna l homepage : www.int l .e lse vie rheal th.com/journals / jden

mailto:[email protected]://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001http://www.sciencedirect.com/science/journal/03005712http://www.intl.elsevierhealth.com/journals/jdenhttp://www.intl.elsevierhealth.com/journals/jdenhttp://www.intl.elsevierhealth.com/journals/jdenhttp://www.intl.elsevierhealth.com/journals/jdenhttp://www.intl.elsevierhealth.com/journals/jdenhttp://www.intl.elsevierhealth.com/journals/jdenhttp://www.sciencedirect.com/science/journal/03005712http://dx.doi.org/10.1016/j.jdent.2015.07.001http://dx.doi.org/10.1016/j.jdent.2015.07.001mailto:[email protected]://crossmark.crossref.org/dialog/?doi=10.1016/j.jdent.2015.07.001&domain=pdf


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suitable for reducing the bacterial load prior to restoration. More

importantly, a changed understanding of the pathology of caries

and the pathogenic effects of cariogenic bacteria has raised doubts

regarding the need for such cavity disinfection via liners: a growing

number of studies show that the sealing of the remaining bacteria

via adhesive restorations has signicant antibacterial effects [18],

and the relevance of an additional treatment of the cavity needs to

be questioned [11,19–23].

Nevertheless, the majority of practical dentists rely on the use

of liners, with one of the most cited reasons being the fear of

remaining viable bacteria harming the pulp [24,25]. Given the

discussed uncertainties, this study aimed at systematically

appraising clinical trials investigating the antibacterial effects of

different liners in comparison with each other or with restorations

without any liner. Given the variety of available lining materials,

we applied network meta-analysis for comparing the bacterial

reductions in different treatment groups. Network meta-analysis

allows indirect comparison and provides ranking of treatments

according to their probability of having benecial (or harmful)

effects, in this case of having antibacterial effects. Based on this

review, the most potent antibacterial treatment should be

identied. The results of this review could then either be

contrasted with clinical outcomes [26,27] to inform practitioners,

or could be used for guiding future research regarding dental liningmaterials.

2.

Materials

and

methods

This review followed international guidelines for performing

and reporting systematic reviews and pairwise or network meta-

analysis [28–30], and assessed if, in human patients with cavities

resulting from caries removal, cavity lining compared with another

cavity liner or no liner has different effects on the remaining

number of bacteria (sterility of the cavity, reduction of bacterial

numbers within the dentin). Assessing how antibacterial effects

translate into clinical outcomes (pain, clinical success) was beyond

the scope of this review. Similarly, we did not assess the effects of

different antibacterial restoration materials, but focussed on the

comparison of different liners or lining versus no lining.

2.1. Participants and intervention

Clinical trials investigating children or adults with primary

caries lesions receiving operative treatment involving caries

removal and restoration were included, with minimum two

treatment groups comparing the antibacterial effects of different

cavity treatment (i.e. different liners, or liner versus restoration

without liner). We did not separate primary from permanent or

anterior from posterior teeth, and did not dene the depth or the

location or extension of the lesion a priori. Treatment groups

should differ only with regards to the lining/restorative material,

whilst the treatment procedure like excavation should have

been identical to limit potential biases introduced by including

non-randomized trials.

2.1.1. Selection criteria

Whilst both randomized and non-randomized trials were

included, only studies which allocated treatments independently

from the cavity depth or the baseline bacterial load were eligible

for inclusion to avoid selection bias by indication. Studies shouldhave reported on the bacterial reduction associated with different

cavity treatments, i.e. should have evaluated the bacterial load

after excavation and after a certain effect period. Bacterial

reduction should have been determined by assessing bacterial

numbers, e.g. via cultivation or polymerase chain reaction, in

dentin samples.

2.1.2. Search strategy

Three electronic database (Medline via PubMed, Embase,

Cochrane Central Register of Controlled Trials) were searched at

September 23rd 2014. Screening procedures used a three-pronged

approach (Fig. 1), and cross-referencing from the bibliographies of

Fig.

1.

Screening

process.

Different

domains

(boxes)

of

the

search

sequence

were

combined

using

the

Boolean

operator

‘

AND’

(example

for

medline

search).

F. Schwendicke et al. / Journal of Dentistry 43 (2015) 1298–1307 1299


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full-text studies was used for identifying further articles. Grey

literature was searched electronically (www.opengrey.eu), and

ongoing trials screened using clinicaltrials.gov. No restrictions with

regard to language or publication date were applied. Neither

authors nor journals were blinded. Title and abstract of identied

studies were screened by two calibrated reviewers (FS, GG) for

eligibility. Consensus was obtained by discussion. Inclusion of

studies was independently decided by both reviewers; consensus

was again achieved by discussion.

2.1.3. Data extraction and evaluation

Duplicative data extraction was performed independently by

two calibrated reviewers (FS, GG) using a jointly developed

spreadsheet which had been piloted on ve studies a priori.

Disagreement was solved by discussion. Data was recorded

according to guidelines outlined by the Cochrane Collaboration

[31]. We recorded setting, study type, source of funding, risk of

bias, description of the sample, performed excavation (selective,

stepwise, complete), treatment of the cavity oor, restoration,

attrition, follow-up, and outcomes. Outcomes were recorded either

dichotomously (number of positive samples) or continuously

(reduction of colony forming units [CFUs]).

2.1.4. Risk of bias assessment Selection bias (sequence generation, allocation concealment),

performance and detection bias (blinding of operators, or

participants and personnel), bias due to incomplete data, and

reporting bias (selective reporting, unclear withdrawals, missing

outcomes) were recorded, assessed and classied according to

Cochrane guidelines [31].

2.1.5. Outcome measures and statistical analysis

Our primary outcome was the number of positive bacterial

dentin samples remaining in a cavity, i.e. the proportion of cavities

with cultivable bacteria. Effects were estimated as odds ratio (OR),

with the odds of harbouring positive bacterial samples (i.e. not

being sterile) in the test compared with the control group being

assessed. Superiority was dened if a treatment yielded signi-cantly fewer positive samples than the comparator. Our secondary

outcome was the reduction in the numbers of bacteria remaining

in the cavity, with colony forming units as effect measure. For

bacterial reduction, log CFU reported by some studies were back

transformed into original values, and bacterial reduction calculat-

ed as standardized mean differences (SMD: before and after lining)

as effect estimate. Superiority was dened if a treatment induced a

signicantly greater bacterial reduction than the comparator.

The unit of analysis was the sample, i.e. the evaluated lesion or

lesion site; no adjustment for the possible effects of clustering was

undertaken as not all studies reported the number of treated

patients for each group. Treatments were classied into the

following categories being used: (1) No active liner/material, i.e.

direct

restoration

using

composite/amalgam/compomer,

or(wax/gutta-percha) placebo being used as liner, (2) calcium

hydroxide (both setting and not setting), (3) glass ionomer cement

(standard or resin-modiedGIC used as liner; in case GIC and other

lining materials like antibiotics were mixed, we considered this

treatment not as GIC, but the other lining material), (4) mineral

trioxide aggregate (MTA), (5) calcium phosphates (hydroxyl apatite

[HA] or tricalcium phosphate [TCP]), (6) antibiotic [ATB] or

disinfectant (triclosan, thymol, chlorhexidine, stannous uoride),

(7) black copper cement (BCC), (8) zinc oxide eugenol [ZOE] liner.

Note that for comparison reasons, we summarized certain groups

(e.g. calcium phosphates) and combined restorative materials and

liners where applicable (e.g. for GIC). If the same study compared

the same group of treatment, but different products, only one

product

was

chosen

at

random

for

statistical

evaluation.

Networks constructed by plotting different treatments (as

nodes) and comparisons (as edges) were inspected for geometry

and asymmetry [32,33]. Random-effects pairwise meta-analysis

were performed using STATA,with OR or SMD as effect sizes. STATA

command metan was used to obtain the forest plot, and command

netfunnel and networkplot were used to obtain the network funnel

plots and the network plots. Network meta-analyses were

performed using Bayesian random-effects models and a Markov

Chain Monte Carlo simulation using Bayesian software package

WinBugs and GeMTC 0.6 [34] implemented in R 3.0.3 (R

foundation, Vienna, Austria).

For the number of positive bacterial samples after different

lining treatments, the Bayesian network meta-analysis rst used

the binomial likelihood to model the data:

r j;k Binomialð p j;k;n j;kÞ

where r j,k is the number of events in treatment group k of the jth

trial, n j,k is the number of observations and P i,k the corresponding

probability of the event for treatment k. Then it was modeled on

the logit scale as

log itð p j;kÞ ¼ m j þ d j;b;kI ðk 6¼ AÞ; b > k

d j;b;k N ðdAk dAb;s 2Þ

where b is the baseline treatment for the jth trial, dAk is the

estimated difference in treatment effect between A and k, and dAbis the estimated difference between A and b, The variance of d jbk is

s 2. For the bacterial reduction, a normal likelihood was used to

model the data instead [35,36].

To t the model, we used a non-informative priors for the

basic parameters from a normal distribution: N(0,104), and a

at prior U(0,2) for the random-effects standard deviation.

The convergence was assessed based on the Brooks–Gelman–

Rubin criteria [37] and inspection of trace plots. The rst

50000 iterations were discarded as “burn-in” and then a further

50000 iterations were undertaken for 2 chains at a thinningintervals of 5. We reported posterior medianOR or SMD and their

95% credible intervals (95% CrI). Credible intervals are the range

of estimated parameters after exclusion of extreme values [38].

Different treatments were ranked according to their probability

of having the lowest versus the highest odds or differences [39],

and the surface under the cumulative ranking (SUCRA) line

plotted and calculated.

Heterogeneity within pairwise comparisons was assessed

quantitatively using I 2-statistics [40]. Loop inconsistency, i.e. the

difference between direct and indirect estimates for three

treatments within a loop, was evaluated by the inconsistency

factor (IF) for the loop [41,42]. Within each loop, the IF value was

dened as IF = E direct E indirect (E : estimate). We rejected the null

hypothesis

that

the

evidence

is

consistent

(H0:IF

=

0),

when

IF

wassignicantly greater or smaller than 0. Funnel plot analysis was

performed to assess small study effects or publication bias of

pairwise estimates. Trim-and-ll was used to evaluate the effects

of such bias [43]. Given the limited available data and the lack of

detailed reporting (see below), no sensitivity or subgroup analyses

were performed to assess the potential impact of effect modiers

on our ndings [44].

3. Results

3.1. Results of the search and risk of bias

Using electronic databases, 113 studies were found to be

possibly

eligible.

43

studies

were

analysed

full-text,

with

14

studies

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odontoblastic differentiation and mineralization [47]. MTA has been

introduced to resin compositematerials, possiblyallowing to omit its

separate use as a liner, which could improveclinical results, since the

material itself has only low compressive strength and could

compromise the restoration placed above [45]. The inferior effects

of calcium hydroxide compared with MTA have been found in other

regards as well, with lower successchances after direct cappingusing

calciumhydroxide compared with MTA [48–50]. A direct comparison

of the clinical effects of both materials used as liners has been

performed in a recent randomized trial and conrmed the benetsof

MTA [51]. In general, the suitability of calcium hydroxide for cavity

lining is increasingly questioned, and our results might partially

support thesegrowing doubts.However,we found calcium hydroxide

to exert stronger antibacterial effects than other materials also

commonly used for lining (especially GIC), and to reduce bacterial

numbers much more effectively than only sealing the cavity.

Fig. 2. The number of positive bacterial samples after different lining treatments. Overall, seven treatments were compared: no or placebo lining, calcium hydroxide (CH),

mineral trioxide aggregate (MTA), glass ionomer cement (GIC), mineral liners (tri-calcium phosphate [TCP] or hydroxyl apatite [HA]), antibiotic (ATB) or disinfectant liners, or

zinc

oxide

eugenol

(ZOE)

liner.

(a)

Pairwise

meta-analysis

was

used

to

compare

the

probability

of

positive

dentin

samples

after

different

liner

treatments.

Odds

Ratios

and

95%

Condence

Intervals

were

calculated;

heterogeneity

was

assessed

using

I

2

-statistics.

(b)

Funnel

plot

analysis

to

assess

potential

publication

bias.

(c)

Network

of

thecomparisons for the Bayesian network meta-analysis. For each node (lining treatment), the number of treated cavities or cavity sites is indicated by the width of each circle.

Direct

comparisons

are

indicated

by

lines

between

nodes,

with

the

width

of

lines

being

proportional

to

the

number

of

trials

comparing

connected

treatments.

Indirect

comparisons are not shown. (d) Strategy ranking according to network meta-analyses. Strategies were ranked for having the highest chance of no positive bacterial samples,

i.e. sterility of the cavity. The probability of being ranked 1st, 2nd etc. of each strategy (different colours) is given. (e) Cumulative ranking probability plots. On the horizontal

axis is the possible rank of each treatment (from rst best rank to worse). On the vertical axis is the cumulative probability for each treatment to be the best, second best etc.

option (11). (For interpretation of the references to colour in this gure legend, the reader is referred to the web version of this article.)

1304 F. Schwendicke et al. / Journal of Dentistry 43 (2015) 1298–1307


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In this review, zinc oxide eugenol was highly ranked for

achieving sterility of the cavity, which conrms the high

antibacterial potential of ZOE compared with CH, GIC or MTA

[52,53]. Other studies found ZOE to reduce biolm adhesion [54],

which supports the notion of it being suitable for exerting

antibacterial effects within the oral environment. Similarly, our

secondary analysis found ZOE to have only limitedly antibacterial

effects if measured via reduction in bacterial units remaining in

the cavity. This nding was based on a single study, and caution is

required when interpreting it.

GIC was ranked low with regards to its probability of achieving

total bacteria elimination and for reducing bacterial numbers.

However, GIC has been shown to have antibacterial properties

[17,55,56] and to be suitable for suppressing the cariogenic

activity of remaining bacteria by releasing uoride ions [57]. It

was further reported to allow remineralisation of the remaining

carious dentin and to actively bond to dental hard tissues, which

could have mechanical advantages [10,58]. Moreover, clinical

studies found teeth lined with GIC to have highchances of success

compared with other lining materials [11,51]. In consequence,

there seems to be a conict between clinical studies, which found

GIC or providing no lining highly successful, and the studies

included in this review, which found MTA or antibacterial liners

more suited for exerting antibacterial effects. It can be deducted

that reducing the number of remaining bacteria might not be as

relevant as commonly thought, especially when considering

the demonstrated antibacterial effects of a tight seal [18]. Here,

again, our results are in obvious conict with existing studies,

which found sealing itself to drastically reduce the number of

bacteria within the cavity [18], which was not conrmed by our

review.

There are several reasons for these discrepancies. First, we did

not mainly assess the bacterial reduction itself, but the relative

differences of this reduction between different groups: It might be

that sealing is ef cacious for reducing bacterial numbers, but the

use of liners might further increase this effect. Second, all but one

included study did not only seal the cavity without any liner (direct

adhesion), but used placebo liners (wax, gutta-percha) instead. It

could be hypothesized that the remaining space beneath the

restoration is detrimental, since it might allow biolm re-

formation. One effect of sealing, which has not been extensively

assessed so far, might thus not only be the starvation of bacteria by

carbohydrate deprivation, but also the inhibition of biolm

formation due to lack of space. The remaining bacterial units

within dentin tubules or the hybrid layer might not achieve a

critical mass to survive or to be harmful. However, it is also possible

Figure 3. Bacterial reduction by lining and/or sealing. Six treatments were compared: no or placebo lining, calcium hydroxide (CH), glass ionomer cement (GIC), antibiotic

(ATB) or disinfectant liners, zinc oxide eugenol (ZOE), or black copper cement (BCC) liner. (a) Pairwise meta-analysis compared the standardized mean difference (SMD)

reduction of bacterial numbers at the cavity oor in different treatment groups. A negative SMD indicates a lower reduction in the test compared with the control group,

whilst positive SMDs indicate a higher reduction. SMD, 95% condence intervals and I2-values are shown. (b) Funnel plot analysis to assess potential publication bias. (c)

Network of the comparisons for the Bayesian network meta-analysis. (d) Strategy ranking according to network meta-analyses. Strategies (different colours) were ranked for

having the highest chance of bacterial reduction, i.e. those with the lowest reduction were ranked lowest. (e) Cumulative ranking probability plots. On the horizontal axis is

the

possible

rank

of

each

treatment

(from rst best rank to worse). On the vertical axis is the cumulative probability for each treatment to be the best, second best etc. option

(11). (For interpretation of the references to colour in this gure legend, the reader is referred to the web version of this article.)



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