improving oral health: a short-term split-mouth randomized

QUINTESSENCE INTERNATIONAL | volume 51 • number 9 • October 2020696

Improving oral health: a short-term split-mouth randomized clinical trial revealing the superiority of resin infiltration over remineralization of white spot lesionsAhmed Youssef/Mohamed Farid, PhD/Mohamed Zayed, PhD/Edward Lynch, PhD/

Mohammad K. Alam, PhD/Andrej M. Kielbassa, Prof Dr med dent Dr h c

Objectives: To evaluate masking effects of resin infiltration on

labial white spot lesions (WSL), by comparing the latter with a

remineralization approach (using hydroxyapatite and fluor-

ides) and conventional oral care (using fluoride-free tooth-

paste). Method and materials: Fifteen patients with at least

three WSL were enrolled for a within-person randomized con-

trolled trial, thus allowing for intrapersonal comparisons. Each

WSL per tooth in every patient was randomly assigned to one

of the following groups. Group 1: lesions were resin-infiltrated

with Icon (RI; DMG); Group 2: Remin Pro (RP; VOCO) was used

as remineralizing agent; and Group 3 (control): affected teeth

were brushed with Complete Care toothpaste (CC; Himalaya).

RP and CC were applied by means of a polishing brush, using a

low-speed handpiece (5 min), and these procedures were re-

peated chairside thrice daily for 7 consecutive days. Digital

photographs were captured before and after lesion treatment

under standardized conditions. The CIE L*a*b* color system

was used to analyze the optical outcome, and intrapersonal

color differences were statistically evaluated. Results: Com-

pared to RP and CC, RI showed prompt and subjectively satis-

factory color improvements, and this was primarily driven by L*

and b* shifts. Statistical analysis of the objective color differ-

ences (ΔE*) between the three groups revealed significant difEE -ff

ferences for RI vs RP (P = .029), RI vs CC (P < .001), and RP vs CC

(P = .001). Conclusion: Resin infiltration is considered a

time-effective treatment option for esthetically camouflaging

WSL, while RP and CC failed to improve lesion appearance and

oral health in the current short-term trial. (Quintessence Int

2020;51:696–709; doi: 10.3290/j.qi.a45104)

Key words: dental health, enamel caries, health care quality, improvement of oral health, remineralization, resin infiltration,

white spot lesion

From a cariologic point of view, white spot lesions (WSL) on

smooth surfaces of teeth occur as a consequence of undis-

turbed and prolonged biofilm accumulation with a concomi-

tant acid production, thus resulting in subsurface enamel

demineralization. The latter is characterized by a mineral disso-

lution frequently starting at the prism cores; ongoing acid

attacks will result in increasing mineral loss (of mainly calcium

phosphates) at the interprismatic areas and from the prism

peripheries, thus leading to an increased subsurface porous

volume of the WSL without macro-cavitation.1 Along with

organic debris,2 yeasts,3 and bacteria,4,5 these increased porosi-

ties may be filled either with water or air, both showing refrac-

tive indices (1.33 and 1.00, respectively) differing from sound

enamel (1.62); thus, reduced refractive indexes do alter optical

properties, and indicate mineral loss with initial and advanced

enamel lesions with intact surfaces.6 Previous experiments

have led to the development of a low-viscous resin being able

to infiltrate these lesions, to occlude the porous volume, and to

build a 3D network consisting of the infiltrant resin enwrapping

the demineralized enamel remnants.1,7,8

Since the first report revealing the clinical feasibility of

masking WSL by means of this Infiltration concept,1 several

RESTORATIVE DENTISTRY

QUINTESSENCE INTERNATIONAL | volume 51 • number 9 • October 2020 697

Youssef et al

case series,9-11 clinical efficacy (non-randomized) studies,12-17

and randomized controlled trials (RCTs)18-28 have confirmed

that using Icon (DMG) frequently will result in clinically satisfac-

tory alterations of these initially demineralized and esthetically

disfiguring lesions, usually revealing a milky or chalky appear-

ance. However, whitish opacities of labial enamel surfaces are

not only the result of demineralization; fluorosis, hypomineral-

ization/hypomaturation, and enamel hypoplasia are consid-

ered developmental malformations or maturation distur-

bances, and are responsible for mineral-deficient changes or

nonmineralized opacities considered treatable with resin infil-

tration (as has been shown with previous case series and

RCT).12,29,30 These camouflaging effects are mainly due to the

favorable refractive index of the resin infiltrant (1.51);31,32 the

partially dissolved enamel crystals will be enwrapped by the

non-filled, low-viscosity, and light-polymerizable resin, thus

closing the pores,33 forming an enamel hybrid layer,34 and lead-

ing to a decreased light-scattering of the infiltrated lesion.32

There is no doubt that a thorough and patient-centered,

individual determination of the respective etiology is consid-

ered mandatory to successfully manage these mineral-defi-

cient areas; this must include lesion width and lesion depth.35

Any treatment decision of the dental professional must meet

the patients’ expectations, and it seems obvious that the latter

frequently aim for both tissue preservation and esthetic

improvement. From a medical perspective, it seems clear that

with true WSL the demineralization process has to be arrested

(or even reversed),36 to prevent any progress of these lesions;

indeed, regular brushing and professional tooth cleaning have

been shown to be effective for preventing any progress of WSL

on labial surfaces in the long run.18

Hence, with already existing WSL, a wide variety of thera-

peutic options is available, ranging from antiseptics and topi-

cally applied fluorides to microabrasion.37 Notwithstanding, a

clear and indisputable ranking of the various available treat-

ments according to their efficacy has not been elaborated so

far,38 even if an expert panel convened by the American Dental

Association Council on Scientific Affairs and the Center for Evi-

dence-Based Dentistry has prioritized either acidulated phos-

phate fluoride gels (1.23%) with moderate certainty, or sodium

fluoride varnish (5%) with low certainty for the treatment of

noncavitated caries lesions on facial or lingual surfaces.39 This

has recently been corroborated by means of a network

meta-analysis.40 Surprisingly, resin infiltration has been recom-

mended for proximal surfaces (thus following the original idea

of the infiltration concept1,41), while no reference to resin infil-

tration was made with regard to labial smooth surfaces.39,40

From laboratory studies, it is known that with regard to pro-

viding esthetic improvements of WSL resin infiltration is more

effective than fluorides or alternative remineralizing agents.42-44

However, while some authors have concluded that there is a

lack of clinical evidence to sufficiently support either reminer-

alizing or camouflaging strategies in managing postorthodon-

tic WSL,45,46 others clearly have stated that resin infiltration

using triethylene glycol dimethacrylate (TEGDMA) might

enhance the esthetic improvement of these lesions, even with

moderate- to high-caries-risk individuals (like patients with

fixed orthodontic appliances).18

To overcome these uncertainties documented in the litera-

ture, the current study aimed to provide a reliable basis for

treatment decisions with WSL. The treatment approach using

resin infiltration by means of the commercially available prod-

uct Icon (DMG) was compared to an established remineralizing

agent (Remin Pro, VOCO; based on a watery cream containing

hydroxyapatite, fluorides, and xylitol) recommended for treat-

ment of WSL.47,48 A herbal toothpaste (Complete Care, Hima-

laya), known to positively affect salivary glucose levels, salivary

pH,49 and with a documented anti-plaque efficacy,50 was used

as a non-fluoride control without active properties promoting

remineralization.

The objectives of the present split-mouth RCT were to clini-

cally evaluate the short-term effects of these treatment

approaches by using standardized digital photography, and the

CIE (Commission Internationale de l’Éclairage) L*a*b* color sys-

tem was utilized to assess and to compare the esthetic improve-

ments, with the difference in color (ΔE*) as the primary outcome EE

(and with ΔL*, Δa*, and Δb* as the subanalytical points of inter-

ests). With the background presented above, the null hypothe-

sis (H0) assumed that all treatment regimens were equally effec-

tive with regard to esthetic improvement of WSL, and this was

tested against the alternative hypothesis (H1) of a difference.

Method and materials

Sample size estimation

The sample size estimation for the present split-mouth RCT was

based on recently published laboratory31,43 and clinical stud-

ies19 having investigated perceived color differences (CIE L*a*b*

ΔE*) of initially demineralized enamel (WSL) and resin infilEE -

trated WSL. Thus, pre- and posttreatment ΔE* values ranging EE

from 16.1 (± 5.0) to 2.0 (± 1.3),19,31,43 respectively, were used to

carefully assess the standard deviations (SDs) of the within-per-

son differences (μ1 − μ2), thereby following previous recom-



mendations.51 Considering a type I error risk of .05 (α) and a

90% power (1 − γ) to detect a true difference, and taking into

account an estimated sample loss of at least 30%,52 a total of 45

treatment sites (or 15 patients contributing three comparable

WSL) was specified.

Ethical considerations and participation consent

Prior to the start of the study, full ethical approval of the study

protocol was obtained from the Ethical Committee of the Minia

University/Faculty of Dentistry (vote number 255/2018; date of

approval 12 June 2019). Treatments were performed in accor-

dance with the Code of Ethics of the World Medical Association

(Declaration of Helsinki, 7th revision/version 2013) for experi-

ments involving humans. The CONSORT (http://www.con-

sort-statement.org) and SQUIRE 2.0 statements (http://www.

squire-statement.org) for reporting of RCTs were followed.

From October 2019 to January 2020, a total of 25 participants

attending the outpatient Clinic of Restorative and Orthodontic

Dentistry at the University of Minia (study setting location)

were screened for eligibility (Fig 1). All participants were pro-

vided with a full explanation of the study (including objectives,

risks, and benefits), and written informed consent was obtained

from each patient to voluntarily take part.

Outcome measures

The primary outcome of the current investigation was the

amount of lesion color change in terms of ΔE*, from the white EE

opaque perception to a natural color mimicking the sound sur-

rounding enamel. Failure was defined as no or only low color

improvement after WSL management. Color measurements of

L*, a*, and b* values before and after the various treatments

were done, and changes of lightness (ΔL*, black/white) as well

Fig 1 Study flowchart (CONSORT).

1


Youssef et al

as those of the opposing-color axes Δa* (green/magenta) and

Δb* (blue/yellow) were assessed as secondary outcome mea-

sures, and were collected as means and SDs.

Patient eligibility

The main inclusion criteria were patients with (at least) three

noncavitated, post-orthodontic WSL, located on smooth surfaces

of maxillary or mandibular permanent teeth, and comparable in

size, opacity, and whitish appearance. Further aspects were: ■ age (a range from 15 to 30 years of age was determined) ■ good general health (absence of disease/no handicaps, to

ensure oral care at home) ■ preserved pulp vitality of the teeth to be included as deter-

mined by clinical and radiographic observations (to control

for internal discolorations) ■ finished orthodontic therapy ■ consolidated oral care on a daily basis ■ agreement by patient and parents (or guardians) to partic-

ipate in the study.

Patients with periodontal diseases (periodontal pockets or den-

tal mobility) or radiologically identified pathologies (periapical

radiolucencies) were not considered eligible. Teeth revealing

any kind of restorations were excluded from the current study.

Moreover, any kind of previous or planned WSL treatment was

considered as an exclusion criterion.

Enrollment of patients and concealment of allocation

In total, three patients refused to take part in the investigation,

and seven potential participants did not meet the inclusion cri-

teria; in all cases, a regular treatment was administered to these

patients. Finally, 15 patients suffering from post-orthodontic

WSL and, meeting the inclusion criteria, were enrolled for the

present split-mouth RCT. All participants were of legal age, and

signed their consent forms (no written consent from the par-

ents/guardians was necessary). A flowchart describing the par-

ticipants’ enrollment is given in Fig 1.

Due to the nature of the present study design, this trial

could not be blinded. Thus, to reduce any selection bias, an ade-

quate allocation concealment of the lesions had to be assured,

and randomization of the three scheduled treatments was per-

formed within the three studied sites of each patient (but not

within the patients). With multiple eligible lesions, a standard-

ized process was stipulated to single out the study lesions, and

WSL were preferably selected according to (1) comparable

lesion widths, (2) similar tooth types (incisors or canines), and

(3) neighboring lesions. Due to the short-term character of the

current trial, no interim analysis or early termination was

planned, and no monitoring or audits were scheduled.

In Group 1 (RI), the lesions were resin infiltrated (Icon,

DMG), whereas the lesions of Group 2 (RP) were actively

treated using a remineralizing agent (Remin Pro, VOCO);

lesions of Group 3 (CC) received a nonremineralizing tooth-

paste (Complete Care, Himalaya), and served as control

(Table 1). Using a computer-generated and concealed block

randomization allocation sequence (www.randomization.

com; patient #1 RP-CC-RI; #2 RI-CC-RP; #3 RI-RP-CC, and so

on), both a strict running order and a uniform distribution of

the intervention modes were guaranteed. This way, the vari-

ous treatments were randomly assigned to the lesions, with

the first therapeutic approach allocated to the lowest number

of the included tooth (according to the Universal Tooth Num-

bering System).

Table 1 Materials (including their main compositions and manufacturers) used in the various study groups of the current investigation

Study group Material Composition Manufacturer

Group 1 (RI) Icon Icon Etch: hydrochloric acid, pyrogenic silicic acid, surface-active substances

DMG

Icon dry: 99% ethanol

Icon infiltrant: methacrylate-based resin matrix, initiator

Group 2 (RP) Remin Pro Water-based cream containing hydroxyapatite (calcium and phosphate), fluoride (1,450 ppm), and xylitol

Voco

Group 3 (CC) Complete Care Extracts from pomegranate, neem bark, Indian gum arabictree’s fresh twigs, bishop’s weed, five-leaved chaste tree, false black pepper, triphala

Himalaya



Interventions

With each new patient, the next sealed envelope containing

the allocation sequence was opened. In Group 1, resin infiltra-

tion (Icon vestibular, DMG) of WSL was accomplished according

to the manufacturer’s instructions. Briefly, after rubber dam

isolation and cleaning, the etching (Icon Etch, 2 minutes; DMG)

and drying steps using air and alcohol (Icon-Dry, 30 seconds;

DMG) were assured, and the lesion was controlled. Then, the

resin (Icon-Infiltrant, 3 minutes; DMG) was applied to the lesion

twice, and each step was completed by a sufficient polymeriza-

tion (> 800 mW/cm2, 60 seconds; Elipar FreeLight, 3M Espe).

Remin Pro was used as a remineralizing agent for the WSL

of Group 2. This cream containing fluoridated hydroxyapatite

was applied chairside on the enamel surfaces using a polishing

brush (Jiffy Composite Polishing Brush, Ultradent Products;

DURAtec 2068D, KaVo) and a low-speed handpiece for 5 min-

utes. These procedures were repeated three times per day for 7

consecutive days.

The WSL of Group 3 were treated in a similar way, but using

the herbal toothpaste (Complete Care). Again, the dentifrice

was applied with a low-speed polishing brush (Jiffy Composite

Polishing Brush; DURAtec 2068D) for 5 minutes. This procedure

was repeated three times per day, and was continued for 7 con-

secutive days (Fig 1). Moreover, detailed oral hygiene instruc-

tions were given to the patients, along with a manual tooth-

brush (Oral-B PRO-EXPERT CrossAction, Procter & Gamble), a

nonprescription fluoride-free toothpaste (Parodontax Classic,

GlaxoSmithKline), and dental floss (Oral-B Glide Floss, Procter &

Gamble). Compliance was tested by questions about the home

care practices at the follow-up visit. All patients were motivated

by the resin infiltration approach (and showed some curiosity

with the teeth to be remineralized).

Color measurement

Digital photographs were captured under fixed conditions using

a digital camera (Nikon D7200, Nikon), equipped with a macro

lens (Rokkor-X, 100 mm, Minolta) and a macro ring flash (ML-150,

GODOX Photo Equipment) placed at a standard focal distance

from the patient.16 All intraoral photographs were taken with

fixed camera settings after configuring the white balance, using

the same focal length (50), shutter speed (1/200), flashlight

exposure time (1/64), and sensor adjustment (ISO 200), to ensure

reproducible conditions. With these standard settings matching

the operator distance, three standardized color patches were

measured, and L*a*b* values were compared (R2 > .98).

The participating patients were photographed in a dark-

ened room to remove any room light variables. To eliminate

and to standardize all possible interferences of the background

contrast, lip/cheek retractors (DynaFlex) were used. Before cap-

turing the images in large RAW format to preserve the quality

of the photographs, tooth surfaces were dried to avoid any

influence of moisture on the WSL appearance. Images were

taken before starting (T1) and after the end of the treatments

(T2, after 7 days). To evaluate the digital images, a graphics edi-

tor (Photoshop CS5, Adobe) was used to convert the digital

images (RAW format) to TIFF format with 16-bits image resolu-

tion. CIE L*a*b* color system was used to analyze the optical

results. Demineralized WSL were outlined and analyzed by the

same investigator (AY) on the same computer screen (S2719H

Dell 27 Monitor, Dell Technologies).

2a 2b

Figs 2a and 2b (a) Preoperative view of a study participant. Clearly visible is the whitish appearance of the labial surfaces. (b) Postoperativeview, 1 week after treatment. The maxillary lateral incisor has been resin infiltrated, while the canine has been treated with Remin Pro.


Youssef et al

This way it was ensured that there were no incomplete out-

come data, and any attrition bias could be avoided. Although

blinding was not possible, this shortcoming was considered

surmountable (or even negligible), since the primary outcome

(ΔE*) was an exclusively computer-based result, thus beingEE

affected neither by subjective inter- and intra-examiner differ-

ences,53,54 nor by measurement bias.

Statistical analysis

Lightness and color data (L*a*b* values) of the respective WSL

were recorded and entered into Excel sheets (Microsoft). Color

changes between T1 and T2 were calculated from the ΔL*, Δa*,

and Δb* values, and was expressed as ΔE* for each group. StatEE -

istical analysis was performed using SPSS for Windows (version

19.0, SPSS, IBM). To determine statistically significant differ-

ences between the three independent groups, the nonpara-

metric Kruskal-Wallis H-test (“one-way ANOVA on ranks”) was

used. To clarify which specific means were significantly differ-

ent from the others, pairwise calculations between the groups

were computed using Dunn post-hoc test for multiple compar-

isons. With all statistical comparisons, a significance level of 5%

(α = .05) was adopted, and this level indicated differences con-

sidered unlikely to have arisen by chance.

Results

In total, 15 patients (8 women, 7 men; mean ± SD age 23 ±

3.3 years) participated in the current investigation. All patients

suffered from post-orthodontic WSL, and orthodontic therapy

had been successfully finalized (mean duration between com-

pletion of orthodontic treatment and start of the study was

4 ± 2.5 months). Mainly maxillary teeth were treated (15 out

the 45 lesions were mandibular teeth). No patient was lost in

this trial, and no adverse events were observed.

Subjective outcome (patients’ and operator’s appraisal)

At baseline, all WSL showed subjectively perceived color dis-

similarities compared with the surrounding sound enamel, and

all patients complained of the detrimental appearance of those

WSL. As a basic outcome, resin infiltration resulted in subjective

satisfaction of all patients, even if not all lesions could be com-

pletely masked from the operator’s perspective. This has been

confirmed with the objective CIE L*a*b* evaluation. However,

while 10 lesions from Group 1 (RI) revealed decreased color dif-ff

ferences and complete camouflaging outcomes of WSL (com-

pared to the preoperative condition and compared to adjoin-

ing normal enamel), three teeth showed a partial (but still

satisfactory) masking only, and two infiltrated lesions were not

rated satisfactory by the operator. In contrast, teeth from Group

2 (RP) and Group 3 (CC) revealed an insignificant improvement

of color, rated clearly inferior to that of the resin infiltration

group (Fig 2). All patients voted for resin infiltration of their

non-altered teeth.

Lightness values (L*)

With a mean L* value of 86.49 ± 4.63, baseline values of Group 1

(RI) were comparable with Group 2 (RP; L* = 87.97 ± 4.01) and

Group 3 (CC; L* = 88.45 ± 2.73) (P > .05). With Group 1 (RI), mean

Table 2 L*) between the various study groups according to CIE L*a*b* results before and after WSL treatments

ΔL* Group 1 (RI) (n = 15) Group 2 (RP) (n = 15) Group 3 (CC) (n = 15) H-test P

Minimum 12.74 3.90 1.07NA

Maximum −1.08 −0.70 −0.09

Mean ± SD 7.07 ± 3.70 2.10 ± 0.79 −0.54 ± 0.31 45.311* < .001*

Median (IQR) 7.39 (9.86 to 3.29) −2.21 (2.47 to 1.76) −0.49 (0.81 to 0.25) NA

Group differences P1

= .047*; P2

< .001*; P3

< .001* NA

Lightness of color (L* = 0 = darkest black, and L* = 100 = brightest white); IQR, interquartile range; NA, not applicable; P1

= Group 1 vs Group 2; P2


= Group 2 vs Group 3 (Dunn test).



lightness decreased to 79.56 ± 6.01 after resin infiltration, while

the values of Group 2 (RP; 86.07 ± 3.93) and Group 3 (CC;

87.91 ± 2.66) remained unaffected after their respective treat-

ments. Intergroup comparisons revealed significant differences

between the three groups (Table 2); with a mean ΔL* value of

7.07 ± 3.70, the effects of resins infiltration in Group 1 (RI) were

considerably increased if compared to Group 2 (RP; ΔL* = 2.10 ±

0.79) and Group 3 (CC; −0.54 ± 0.31). Thus, the disappearance of

the whitish WSL was strongly influenced by the L* component.

Magenta-green range (a* channel)

Mean baseline a* values were low, but negative (Group 1 [RI],

a* = −2.08 ± 3.16; Group 2 [RP], a* = −0.60 ± 1.88; and Group 3

[CC], a* = −0.08 ± 2.32), thus indicating some negligible propor-

tions of the green component (P > .05). Posttreatment inter-

group comparisons revealed nonsignificant differences (P > .05)

between Group 2 (RP; Δa* = 0.21 ± 0.80) and Group 3 (CC;

Δa* = −0.06 ± 0.43), again not revealing any treatment effects,

and emphasizing a neutral outcome. In contrast, a more pro-

nounced effect was observed with Group 1 (RI; Δa* = 2.15 ±

1.92); these means indicated a slight shift to the red compo-

nent, and this was significantly different (P < .05) both from

Group 2 (RP) and from Group 3 (CC) (Table 3).

Yellow-blue axis (b* value)

Baseline comparability could also be observed with regard to

the b* values of the various groups (Group 1 [RI], b* = −1.87 ±

3.40; Group 2 [RP], b* = 2.31 ± 5.21; and Group 3 [CC], b* =

−5.11 ± 2.21). Posttreatment effects again were negligible

(P > .05) between Group 2 (RP; Δb* = 0.88 ± 1.47) and Group 3

(CC; Δb* = 0.11 ± 0.53), thus indicating neither considerable

yellow nor major blue shifts. However, these groups both dif-ff

fered significantly (P < .05) from Group 1 (RI; Δb* = 7.70 ± 4.76),

and these increased means revealed a strong tendency towards

yellow, thus again approximating the surrounding sound

enamel well (Table 4).

Perceived difference in color (ΔE*)

With a ΔE* value exceeding 3.7, the perceived color differenceEE

between pre and post resin infiltration with the lesions of

Group 1 (RI) was clearly observable by the naked eye (Table 5).

In contrast, Group 2 (RP; ΔE*EE = 2.80 ± 0.84) and Group 3 (CC;

0.88 ± 0.28) revealed subperceptible color changes, thus indi-

cating failed treatment effects from a clinical perspective. Inter-

group comparisons are given with Table 5, and means ± SD of

Group 1 (RI) differed significantly from the other groups

(P < .05). With three daily applications of Remin Pro provided

over 7 days, ΔE* values of Group 2 (RP) and Group 3 (CC) difEE -ff

fered significantly (P = .001) at the end of this study.

Discussion

The present investigation aimed to document the instant out-

come of a split-mouth efficacy RCT on the optical effects of WSL

infiltrated with resin. A balanced randomization protocol

assigning the respective teeth of the patients ensured that

selection and allocation bias could be minimized, even if the

basic conditions for inclusion of participants was considered

selective per se. The implemented intra-personal study design

aimed at precise comparisons of lesion behavior within the

same patient (serving as his/her own control), and allowed for a

stringent removal of inter-subject variability from the observed

treatment effects as the main advantage, thus ensuring an

increase of the statistical efficiency. This set-up usually requires

approximately half of the patients if compared to a parallel-arm

trial with the same power,51,55 and it should be stressed that no

systematic differences regarding the outcome of intervention

could be derived from split-mouth and parallel-group RCT.56

However, intra-subject designs encompass some uncertainty

with regard to contamination between sites, in particular, since

assessment of the extent of carry-across effects in a split-mouth

trial would not seem possible; in the present investigation, this

risk of bias was eliminated by strictly treating the tooth surfaces

assigned by the randomization scheme. While Group 1 (RI) would

not seem critical with this respect, some diffusion of fluorides

from Group 2 (RP) cannot be ruled out. It is known, however, that

Remin Pro has only negligible effects on tooth color.57 Thus, no

carry-over effect was to be expected in this regard; most proba-

bly due to the short-term observation, mean ΔE* was 2.80EE ± 0.84

in Group 2, and this was neither significant nor clinically observ-

able. Notwithstanding, an influence of remineralization (trig-

gered by the ingredients,47,48 and by the nonfluoride home care)

should have affected all (study) teeth in a comparable way, and

from the outcome it seems clear that this theoretically conceiv-

able effect is negligible. In Group 3 (CC), a herbal dentifrice con-

taining pomegranate, neem, and ayurvedic triphala was used. By

releasing tannins, polyphenols, and astringents, these ingredi-

ents have shown antimicrobial effects.49,58 Consequently, some

clinical effects on biofilm growth (but not on remineralization)

have been described, and this toothpaste served as a control with

placebo characteristics,50 and without any possible response bias.


Youssef et al

Finally, split-mouth trials are considered at risk of bias when

finding matching sites is impossible in subjects; this risk could

be avoided with the present study, since all lesions treated were

considered comparable with respect to age and size. Due to the

intrinsic characteristics of the current study, blinding was not

possible, both with the patients and with the operators, thus

increasing the performance bias. However, even if a good cor-

relation between visual (subjective) and spectrophotometric

(objective) evaluation has been described,12 the current set-up

used a standardized computer-based shade determination, thus

eliminating any additional observer bias due to possible mis-

judgment, and allowing for a significantly more reproducible

and objective evaluation than with solely visual assessments.53,54

In this manner, demonstrating the generalizable outcome

benefit of Group 1 (RI) over the remineralization intervention of

Group 2 (RP) and the control Group 3 (CC) became possible with

the current explanatory RCT. By assessing the visually perceived

color difference, it was found that the color of lesions consider-

ably improved in Group 1 after resin infiltration (see Fig 2), and

the altered lesion appearance was clinically recognizable

Table 3 a* (value changes from green to magenta) between the various study groups according to CIE L*a*b*results before and after WSL treatments

Δa* Group 1 (RI) (n = 15) Group 2 (RP) (n = 15) Group 3 (CC) (n = 15) H-test P

Minimum 1.65 −0.96 −0.99NA

Maximum 5.36 1.81 0.49

Mean ± SD 2.15 ± 1.92 0.21 ± 0.80 −0.06 ± 0.43 22.221* < .001*

Median (IQR) 1.76 (0.90 to 4.07) −0.01 (0.21 to 0.50) −0.07 (0.27 to 0.20) NA


< .001*; P2

< .001*; P3

= .464 NA

Values of the green/magenta coordinate (a*; negative values indicate green, and positive values indicate red/magenta); NA, not applicable; P1




Table 4 b*) between the various study groups according to CIE L*a*b* results before and after WSL treatments

Δb* Group 1 (RI) (n = 15) Group 2 (RP) (n = 15) Group 3 (CC) (n = 15) H-test P

Minimum −0.26 −2.74 −1.05NA

Maximum 14.18 2.89 0.85

Mean ± SD 7.70 ± 4.76 0.88 ± 1.47 0.11 ± 0.53 21.635* < .001*

Median (IQR) 8.44 (4.81 to 11.82) 0.68 (0.02 to 2.29) 0.15 (0.01 to 0.51) NA


= .012*; P2

< .001*; P3

= .116 NA

Changes of color coordinate b*, representing blueness (negative) or yellowness (positive direction); IQR, interquartile range; NA, not applicable; P1


= Group 1 vs Group 3;P

3= Group 2 vs Group 3 (Dunn test).

Table 5 E* ) between the various study groups according to CIE EE L*a*b* results before and after WSL treatments

ΔE* Group 1 (RI) (n = 15) Group 2 (RP) (n = 15) Group 3 (CC) (n = 15) H-test P

Minimum 2.97 1.27 0.36NA

Maximum 19.68 4.53 1.37

Mean (± SD) 11.29 ± 5.05 2.80 ± 0.84 0.88 ± 0.28 49.352* < .001*

Median (IQR) 12.90 (8.20 to 14.81) 2.76 (2.20 to 3.51) 0.96 (0.68 to 1.04) NA


= .029*; P2

< .001*; P3

= .001* NA

Perceived difference in color (ΔE*), calculated as [(ΔE L*)2 + (Δa*)2 + (Δb*)2]½; IQR, interquartile range; NA, not applicable; P1






(ΔE*EE > 3.7). Moreover, final outcome of resin infiltration was sig-

nificantly different from the other treatment groups (see Table 5).

Thus, the null hypothesis stating that with regard to any esthetic

improvements of the studied WSL there would be no difference

between the various treatment regimens was rejected. The

dense polymer network,59 completely occluding the porous

enamel surface,33,60,61 and primarily consisting of a TEGDMA/

enamel hybrid layer,34 successfully masked the incipient lesions.

However, measurement of color improvement as provided with

the present outcome would seem to prove treatment success

only, and must be classified as a surrogate outcome, but should

not be compared to clinical endpoints in terms of true remineral-

ization. Surrogate endpoints, however, are useful tools to detect

potential success or failure of treatment, and may allow for early

treatment decisions, in particular when preservation of healthy

conditions is considered mandatory.

The current investigation applied the CIE L*a*b* color space

to measure the color differences. This standard system employs

a lightness value (L*, light to dark) as well as the two color chan-

nels a* (green-to-red component) and b* (blue-to-yellow com-

ponent). Usually, WSL are characterized by increased opacity,

and loss of normal translucency of the enamel due to absorp-

tion and light-scattering (at the roughened surface and within

the porous lesion) is the main esthetic problem. With the resin

infiltrated WSL, all three values used to describe the color index

of the treated lesions changed significantly in the present

study, with ΔL* and Δb* revealing the most prominent differ-

ences (see Tables 2 and 4). This supports the outcome of a

recent paper which showed that the resinous infiltrant itself

displayed comparably high ΔL* values, even after accelerated

aging or bleaching, thus confirming that the infiltration regi-

men is visualized as a lightening procedure.59,61 Due to the

inherent material properties, slight color changes should be

expected over time, with Δb* accounting for the visual alter-

ations.59 In laboratory studies, however, no changes have been

observed, and infiltrated lesions proved stable; untreated

lesions, however, revealed clear alterations over time.43,44,62 This

indeed would be in accordance with clinical reports that

showed a satisfactory optical durability over 6 months20,26 and

1 year;1,9,14,25 even after longer observation periods (lasting up

to 4 years) of exposure to the oral environment, neither the

color of the resin infiltrated WSL nor their esthetic camouflage

was altered.21,22,63

This esthetic effect has been confirmed, with the present

investigation having shown esthetically improved resin infil-

trated WSL (Group 1). Moreover, the nonfavorable results

observed with Group 2 (RP) obviously are in accordance with

previous clinical trials showing significant differences between

resin infiltrated WSL and other study groups. From a cariologic

point of view, resin infiltration (along with additional regular

fluoride varnish treatments) has revealed a clearly superior out-

come with significantly more arrested lesions (if compared to

fluoride varnish treatment alone) in an RCT treating facial

smooth surfaces of primary teeth.24 While resin infiltration

turned out to be superior if compared to microabrasion,19 other

RCT using actively supported remineralization regimens by

means of fluoride varnishes clearly have favored the infiltration

approach, both from an esthetic and from a clinico-medical

perspective.18,22,23,28 The patient preferences revealed in the

present study would seem to confirm these observations.

In contrast, reduced esthetic improvements have been

observed with Group 3 (CC; control) as well, and this corrobo-

rated two independent RCTs26,27 revealing a significant super-

iority of the infiltration concept over nontreated controls; the

latter were also been infiltrated with Icon after 6 months (as

part of an agreement with the patients), so no longer compar-

isons were possible.21 When considering these aspects, a closer

look into the natural fate of WSL on smooth surfaces might

seem helpful. The pioneering Backer Dirks study has shown

that 51% of early smooth surface WSL disappeared (while 36%

kept stable) after 7 years,64 and similar observations have been

published by other authors, again with predominantly stable

(and low progressing) lesion numbers.65,66 From previous clin-

ical investigations, it would seem clear that neither daily brush-

ing with various fluoride toothpastes67 nor an additional use of

highly concentrated fluoride gels (on a weekly basis)68 would

significantly alter (long-existing) WSL size or appearance over

periods of 6 months. After appreciating the outcome of infil-

trated teeth, the present patients enquired about (while some

even insisted on) treating the other lesions the same way; thus,

for ethical reasons, the current study was not prolonged, and

this was comparable to a previous RCT.21

As discussed above, post-orthodontic WSL only gradually

reduce in size69 (or even regress in some cases70) within the first

few years, and this will not be influenced by using low-level

fluoride formulations of mouthrinse and toothpaste.69 Conse-

quently, Backer Dirks64 assumed, that “The disappearance of

white opaque spots can take place by remineralization or sur-

face abrasion, or both.” Indeed, WSL are characterized by a

reduced mineral content resulting in a decreased microhard-

ness, and, thus, a gradual regression as a result of surface abra-

sion of WSL (if compared to sound enamel) has been observed

clinically;71 similarly, a significant surface substance loss of WSL

after brushing either with acidic or with abrasive oral care prod-


Youssef et al

ucts could be confirmed in highly standardized, laboratory

experiments.72 It should be noted that a considerable increase

of enamel surface roughness has been reported after the use of

acidulated phosphate fluorides, thus indicating a weakened

substrate, susceptible to abrasion.73 In contrast, a recently pub-

lished systematic review compiling the previous studies on

surface microhardness of resin-infiltrated WSL has revealed a

considerable increase.74 These effects are coupled with a

decrease in roughness of demineralized and infiltrated enamel

surfaces,33,60 and with an initially reduced microbial adhe-

sion,75,76 thus presenting an elevated protection against demin-

eralization if compared to nontreated WSL, and an increased

resistance to the challenges of mechanical abrasion.77

It should be emphasized that fluoride treatment is not con-

sidered capable of elevating microhardness by a comparable

extent,78,79 and, accordingly, highly concentrated fluoride gels

or lacquers (supplemental to daily tooth brushing) failed to

completely remineralize and mask WSL to an esthetically

acceptable dentofacial appearance within reasonable time

periods.48,80-83 Consequently, systematic reviews have indicated

a predominantly modest effect not considered clinically rele-

vant to support the effectiveness of an enduring camouflaging

treatment of these WSL.38,46,84,85 Thus, it seems clear that a treat-

ment renunciation (like in Group 3 [CC] of the present study)

would not have the capacity for any beneficial change, since

even in the case of well-maintained mouth hygiene many

(severe) post-orthodontic WSL will not regain their pretreat-

ment level for up to 12 years after debracketing,86 while other

cases would reveal either surface abrasion or cavitation.64,66 It

should be borne in mind, however, that resin infiltration has

been introduced as a preventive regimen, with the main inten-

tion to stop or reduce progression of WSL.1

In the past, some insecurity and confusion has been created

on when to infiltrate WSL, and this has been documented in

personal communications as well as in the scientific litera-

ture.9,27,87 This mainly refers to recommendations aiming to infil-

trate WSL as soon as possible after the removal of fixed ortho-

dontic treatment,9 to avoid any surface breakdown, or to

hamper any occlusion of the tiny pores of the latter. In contrast,

others have recommended an elapse time of even more than

3 months, to wait for a spontaneous recovery.17,19 While the

pseudointact surface layer has a varying thickness of some

40 μm and a mineral content of up to 82 vol%,72 these values

may vary, in particular with arrested and inactive lesions reveal-

ing a smooth and shiny surface (indicating some precipitation

of minerals within the pores of the pseudointact surface layer).

However, from the literature it seems clear that lesions up to

1 year old will be successfully infiltrated.27,88 In these cases, and

this is comparable to resin infiltration of fluorotic or otherwise

hypomineralized teeth,12,22,89 it may become mandatory to

tailor conditioning times (up to several minutes)25,26 and to

increase infiltration times90 and/or frequencies,91 depending on

the lesion history and characteristics;30,91 consequently, the

required dental competence is high, and some well deliberated

and substantiated deviation from the manufacturer’s routinely

propagated protocol would seem advisable in all cases requir-

ing a personalization of the intervention.

Accordingly, in the present study, some teeth of Group 1 (RI)

needed prolonged drying and several applications of the resin-

ous infiltrant to mask the lesion completely, while other lesions

showed a well-pronounced and subjectively satisfactory, but

objectively only partial color improvement after a treatment

sequence following the protocol. This is in concordance with

previous studies also having reported non-complete infiltra-

tion effects in some cases.15,17,22,26 Possible reasons would seem

manifold, but longevity as well as depth and width of lesions,26

along with microorganisms3-5 and external and salivary pro-

teins and lipids2 (occluding both the lesion surface and the

porous lesion volume) have to be considered as primary causes,

at least with patients not suffering from hyposalivation.92

Therefore, a thorough cleaning procedure, along with a depro-

teinization treatment of the lesions by chemically dissolving

organic debris is strongly recommended,93 and this should be

applied prior to etching. Finally, water content also has to be

taken into account, and lesion dryness has to be assured with

utmost care.60 All these aspects must be taken into consider-

ation, and it should be clear that in some reported cases the

clinicians might have missed adopting the desired practice

effectively; thus, a well-developed treatment regimen must

cover not only the option of whether the resin infiltration

would have an effect, but also how to ensure the latter.

It should be emphasized that the chemistry of the resinous

infiltrant differs from former infiltration attempts, and, as has

been shown with the introductory papers on the infiltration

concept,1,7,8 allows for multiple combination therapies. With an

increasing popularity, infiltration treatment has been success-

fully combined with conventional adhesives and composite

resins to improve fissure sealing,94 to restore cavities,1,95 or to

bond orthodontically,96 and other approaches like internal tun-

nel restorations (including internal and external infiltration)97 of

proximal lesions have been introduced. Additionally, supple-

mental applications (like treatment of developmental defects,

or combinations with bleaching approaches30,90) have consider-

ably expanded the initially proposed indications.



As has been elucidated above, post-orthodontic WSL have

to be considered as a long-lasting cariologic problem,86 even if

the demineralization process can be interrupted and some

repair is possible, in particular with mild lesions.20,83 From a

medical perspective, it seems clear that arrested and inactive

lesions do not necessitate any interventions, and progression

to cavitated caries should not be a concern with regularly

implemented oral hygiene;27 however, these lesions may

change to brown spots during remineralization, due to ingress

of colorants from exogenous sources, and these changes will

be even more unpleasant if compared to the chalky appear-

ance of WSL. Not astonishingly, patients suffering from the

compromised esthetics call for a clinically relevant (and at best

optically perfect) harmonization of their whitish spots, and this

will not be swiftly and satisfactorily achieved by exclusively fol-

lowing the published recommendations for using either acidu-

lated phosphate fluoride gels (1.23%) or sodium fluoride var-

nish (5%).39,40 Meanwhile, a considerable number of clinical

studies9-28 published in the past decade has provided a con-

vincing data basis for a valid estimate of the long-term durabil-

ity of the resin infiltration approach as an enduring esthetic

improvement,25 arresting the caries process.98

In contrast, various systematic reviews have repeatedly indi-

cated a lack of reliable evidence to support camouflaging or rem-

ineralizing strategies for smooth surface WSL,38,45,46,84,85,87,89,99 again

and again paraphrasing that “there would be a need for long-

term studies to confirm the effectiveness.” This should not be

excoriated from a scientific point of view. However, each of the

studies included in the various systematic reviews do comple-

ment and add some specific value to each other (even if all the

studies have some shortcomings to a certain extent, as does the

present one), thus providing validation and additional under-

standing of the masking effect of resin infiltration. It should be

remembered that the latter is of paramount importance for most

patients, in particular since the caries-arresting resin infiltration

may be successfully combined with a substantial caries remin-

eralization program;36 preferably, regular fluoride varnish appli-

cations should be used.24 Thus, with the accumulated knowledge

and the respective medico-ethical considerations in mind, fur-

ther long-term comparative investigations would not seem enti-

tled anymore.87 In other words, how many patients would be

willing to wait for several-year studies, in particular in those cases

with a significant treatment decision? Patients will favor the most

convenient therapeutic approach; beyond that, the micro-inva-

sive resin infiltration not only is considered a simple treatment

regimen, but also has gained an essential position in dentistry,

and, thus, clearly contributes to improved health care.

With the acceptable clinical and esthetic outcomes of resin

infiltration, a recovery of the patients’ self-esteem seems possi-

ble35 within one highly effective treatment session.12,28,35 By

complementing the concept of minimum intervention den-

tistry,1 the therapeutic benefits of resin infiltration as discussed

above should considerably decrease both long term (re-)

restorative needs and costs,36 and this is considered clinically

relevant, in particular when promoting patient-centered treat-

ment decisions in oral health care. With the available body of

literature in mind, it is not surprising that the infiltration con-

cept has recently been labeled as “gold standard,”20 and others

have recommended resin infiltration as a viable option99 and an

alternative to fluoride treatment of incipient lesions,23 in partic-

ular if these lesions are deemed not to regress naturally.27

Conclusion

From the current RCT identifying color differences by means of

the CIE L*a*b* color coordinates, it is concluded that WSL neces-

sitating a treatment decision will not be satisfactorily redressed

by brushing with a herbal (non-fluoride) toothpaste. When

applying remineralizing agents on a daily basis, an only minor

and clinically irrelevant improvement should be expected

within the short-term period of 1 week. In contrast, resin infiltra-

tion of WSL reveals a significant increase in luminance (ΔL*),

along with a shift in the blue/yellow axis towards yellow (Δb*),

thus resulting in favorable perceived total color alterations (ΔE*). EE

This color-neutralizing impact (if compared to the adjacent

sound enamel) contributes to the camouflaging effect of resin

infiltration, along with mimicking a natural recovery of WSL.

Together with the well-known strengthening of the demineral-

ized enamel, resin infiltration of WSL is considered a prob-

lem-solving regimen, clearly promoting dental and oral health.

Acknowledgments

The authors thank Dr Shereen Osama (Department of Restora-

tive Dentistry, Outpatients Clinics, Ministry of Health, Alexandria.

Egypt) for her clinical assistance. This investigator-driven RCT

was supported by the authors and their respective institutions

only, without any external funding. The manufacturer of the resin

infiltrant (DMG, Hamburg, Germany) has licensed international

patents for the infiltration technique for caries lesions; these pat-

ents are held by Charité - Universitätsmedizin Berlin (Germany),

with Andrej M. Kielbassa being appointed as inventor and receiv-

ing royalties. The authors declare no potential conflict of interest

with respect to authorship and/or publication of this trial.


Youssef et al

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Ahmed Youssef

Ahmed Youssef PhD candidate, Department of Restorative Den-tistry, Faculty of Dentistry, Minia University, Minia, Egypt

Mohamed Farid Professor, Department of Restorative Dentistry,Cairo University, Cairo, Egypt

Mohamed Zayed Assistant Professor, Department of RestorativeDentistry, Faculty of Dentistry, Minia University, Minia, Egypt

Edward Lynch Adjunct Professor, University of Nevada, Las Vegas,NV, USA; and Honorary Professor, De Montford University, Leicester, UK

Mohammad K. Alam Associate Professor, Department of Preventive Dentistry, College of Dentistry, Jouf University, Aljouf, KSA

Andrej M. Kielbassa Professor and Head, Centre for OperativeDentistry, Periodontology, and Endodontology, University of Den-tal Medicine and Oral Health, Danube Private University (DPU),Krems, Austria

Correspondence: Prof Dr Dr h c Andrej M. Kielbassa, Centre for Operative Dentistry, Periodontology, and Endodontology, University of Dental Medicine and Oral Health, Danube Private University (DPU), Steiner Landstraße 124, A – 3500 Krems, Austria. Email: [email protected]

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