Resin infiltration has been widely used to treat white spot lesions because of its ability to restore esthetic promptly. However, because of its potential to mask the lesion rather than remineralize it, its use as an optimal treatment option is controversial and is a cause for concern . So, this study investigated the ability of CPP-ACP coupled with universal adhesive resin to remineralize the white spot lesion and restore its esthetic, proposing an optimal treatment modality.
The findings of the study endorsed the rejection of the null hypothesis. The WSL treatment protocol based on using CPP-ACP paste to remineralize the lesion followed by a universal adhesive resin coat to mask the lesion was a comparable or even better treatment approach than the most commonly used approaches like ICON resin infiltrant or CPP-ACP remineralizing agent separately.
Management of white spot lesions via CPP-ACP alone was not able to restore the esthetic to a non-observable degree as (ΔE ≥ 3.3). On pairing this remineralizing program with universal adhesive resin, the results were very promising (ΔE = 2.35). The universal adhesive alone exhibited the least ability to enhance esthetic (ΔE = 4.23) among the investigated strategies.
The bioactive substance generated from casein milk protein, casein phosphopeptide amorphous calcium phosphate, can function as a reservoir of bio-available calcium and phosphate, allowing their precipitation on the demineralized enamel surface and so considerably improving remineralization [26, 27]. It has been reported that CPP-ACP is able to fill the subsurface enamel pores, decreasing the refractive index difference between the porous demineralized enamel and the sound enamel, thus improving the translucency of the white spot lesion . This is consistent with the finding by Anggani et al., which concluded that CPP-ACP application enhanced the esthetic of white spot lesions because of CPP-ACP's ability to fill the subsurface enamel pores. This supporting study applied CPP-ACP once/a day for 14 days . Alternatively, our finding is in disagreement with a different study that stated the inability of CPP-ACP application to enhance the esthetic of post-debonding white spot lesions and correlated that to the short duration of CPP-ACP application, which was only once with follow-up after 6 weeks . So CPP-ACP effectiveness seems to be treatment duration and follow-up time-dependent. One more investigation recommended the daily application of CPP-ACP and considered it more effective in regression and esthetic improvement of post-debonding WSLs than fluoride-containing pastes and rinses . Also, the results of a 12-week clinical study show that twice daily topical applications of 10% CPP-ACP paste as an important contributor to a standard oral hygiene program, such as fluoridated dentifrice, antimicrobial mouthwash, and xylitol chewing gum, improve the esthetic and remineralization of white spot lesions significantly .
Variations in study design, duration of the treatment protocol application, variances in the activity and severity of lesions, and probable pathological distinctions between orthodontic and non-orthodontic WSLs may all contribute to differences in CPP-ACP efficiency and in-vivo recommendations [33, 34]. This may explain the variability among different studies’ assumptions.
On treating the WSLs with either ICON resin or universal adhesive resin, the esthetic was improved, but not to the same grade with a statistically significant difference in between. Generally, the resin has the same refractive index as enamel and, on application, it infiltrates the pores, obliterating them and thus minimizing the difference in refractive index between the pores and the neighboring sound enamel surface to the point of being negligible. This effect is highly dependent on the degree of resin infiltration into the demineralized enamel [35, 36]. So, ICON resin seems to have better penetration into demineralized enamel surface than universal adhesive resin does.
ICON resin composition is based on a light-curing low-viscosity resin, composed of mixture of Bis-GMA (bisphenol A glycidyl methacrylate) and triethylene glycol dimethacrylate (TEGDMA), which easily infiltrate the enamel pores and block them [37, 38]. ICON-dry, applied before the ICON resin, contains 99% ethanol, and the addition of ethanol increases the penetration coefficient by decreasing the viscosity and contact angle . Also, hydrochloric acid gel erodes the surface layer more efficiently than 37% phosphoric acid and the self-etching adhesives. ICON's use of longer acid conditioning for 2 min by hydrochloric acid could have resulted in deeper resin penetration, thus recording a lower ΔE than universal adhesive resin . As a supporting conclusion to our study, Enan et al. detected that ICON resin could be a potential technique to repair the appearance of demineralized enamel following orthodontic treatment while also protecting it from acidic drinks . The tendency of ICON resin to occlude the pores within the lesion body through infiltration, generating a negligible difference in refractive index with the surrounding sound enamel and increasing the value parameter of the treated lesion, has been concluded by Neuhaus et al. 
Conversely, the higher ΔE of the universal adhesive resin compared to ICON may be related to its lower penetration coefficient relevant to the weaker self-etching strategy. Thus, the enamel treated with ICON offers a clinically acceptable appearance and brings about patient satisfaction. Combining CPP-ACP with universal adhesive resin seems to generate a harmonizing effect wherein CPP-ACP remineralizes the tooth structure and both act synergistically through infiltrating and occluding the porosity within the demineralized surface, thus improving the esthetic through reducing the refractive index [26,27,28, 35, 36]. Although no studies have investigated CPP-ACP combined with resin infiltrant for the management of WSLs yet, relevant studies [26,27,28,29, 31, 35, 36] assessed independently CPP-ACP and resin infiltration effectiveness in WSLs color improvement and their outcomes could be supportive to this investigation complementary treatment protocol.
Surface microhardness results revealed that CPP-ACP and CPP-ACP coupled with universal adhesive resin were the best management protocols to increase the surface microhardness of WSLs. CPP-ACP proved to have the potential to induce remineralization of enamel, causing white spot lesion regression and high surface microhardness recovery. This is assumed to be relevant to free calcium and phosphate ions that were deposited, thereby stimulating remineralization, maintaining a state of supersaturation with regard to tooth minerals, and discouraging enamel demineralization. Also, its ACP nano-clusters are small enough to access demineralized areas [43, 44]. This is consistent with an additional research, concluding that products containing CPP-ACP have a great tendency to regress enamel white spot lesions due to the incorporation of calcium and phosphate of ACP into the demineralized structure [10, 45]. A different supportive meta-analysis determined that CPP-ACP produces excellent remineralization of WSLs, with high surface microhardness regaining, probably through a remineralizing effect. This indicates that CPP-ACP is verified to be effective for the management of WSLs based on both in-vitro and in-vivo records .
The surface microhardness of enamel treated with resin infiltrants is dependent on the degree of enamel demineralization, penetration of the resin, and monomer and solvent compositions of the infiltrants [47, 48]. ICON resin is a Bis-GMA-based infiltrant, and this type of methacrylate resin is known for its high molecular weight, aromatic backbone, and rigid molecular structure. Besides, it contains hydroxyl groups that generate strong hydrogen bonds. All these compositional belongings seem to be responsible for the higher hardness value compared to the preceding demineralized enamel and universal adhesive resin-treated WSLs [49,50,51]. Contrariwise, the type of resin in the experienced universal adhesive (Gluma Bond) is urethane dimethacrylate (UDMA)-based resin. This resin comprises a flexible aliphatic core with two urethane linkages and is capable of forming hydrogen bonds. Yet, these interactions are not as strong as those in Bis-GMA-based resin. The weaker interactions, plus the flexible nature of UDMA resin, are the causative factors for significantly lower surface microhardness values compared to ICON resin-treated lesions [52,53,54].
Concerning the penetration coefficient, those infiltrants with a high penetration coefficient would be able to penetrate more deeply into subsurface lesions, filling the spaces between the leftover enamel crystals of the porous lesion and thus enhancing the surface microhardness of the treated lesions [47, 48]. The higher penetration coefficient of ICON resin due to the powerful etching with hydrochloric acid plus the ethanol containing-ICON dry step before ICON application clarifies the difference in surface microhardness values between ICON resin and the universal adhesive resin-treated lesions [39, 55, 56]. Omar El Meligy et al. concluded that ICON resin increased the hardness of demineralized enamel and the stability of carious lesions, relying on its ability to penetrate the porosity of the WSLs, and this finding is consistent with our result . Another investigation confirmed the ability of ICON resin to restore the surface microhardness of the WSLs to a value close to that of sound enamel . In parallel with our findings, another study revealed that both CPP-ACP and ICON resin therapies enriched the tooth surface mineral content, with the enamel mineral gain potential of CPP-ACP being superior . One more in-vitro long-term study disclosed that both ICON resin and CPP-ACFP (casein phospho peptide amorphous calcium fluorophosphate) were effective in treating WSLs, but the CPP-ACFP was more effective as it was extended for a longer period, producing stabilized remineralization of the lesion .
While the universal adhesive resin alone was not as efficient as ICON resin in regaining the surface microhardness of the WSLs, pairing it with the CPP-ACP remineralizing agent appeared to complement one another and produce a superior impact on the lesion microhardness compared to other considered approaches. This may be due to the remineralizing competency of CPP-ACP augmented by the resin penetration within the porosity left after remineralizing agent application [35, 36, 43, 44]. An extra contributing factor should be considered, which is the acidic functional monomer; 10-methacryloyloxydecyl dihydrogen phosphate incorporated in the universal adhesive, which generates surface micro-retention and chemical interactions with calcium ions either in the tooth hydroxyapatite or those deposited by CPP-ACP .
For CPP-ACP, ICON resin, universal adhesive resin, and CPP-ACP conjugated with universal adhesive-demineralized enamel-treated groups, they were all significantly different from artificially-created WSLs with reference to the surface roughness. CPP-ACP proved to have an excellent ability to smoothen the enamel surface and promote the esthetic. The deposited calcium and phosphorus ions restored the central areas of enamel prisms gradually until the surface became flat and smooth . This consequence is supported by multiple previous analyses, which indicate that CPP-ACP significantly decreases the surface roughness of enamel by the creation of a layer filling the interprismatic cavities and partially covering the enamel prisms [26, 46, 61, 62]. However, our study finding disagreed with Bayram et al. who concluded that CPP-ACP increased the surface roughness of stripped enamel .
In harmonization with other studies, the ability of ICON resin to retain a smoother surface of demineralized enamel was confirmed [41, 64]. Other investigations conflicted with this opinion and reported that the surface roughness of resin-infiltrated enamel was less than ideal [65, 66]. The inability of ICON resin to decrease surface roughness was confirmed by an investigation, suggesting that ICON resin increases plaque accumulation in the proximal area, rendering higher surface roughness values compared to pre-application . Also, Gurdogan et al. disagreed with the potentiality of ICON resin to generate a smoother surface when it infiltrates demineralized enamel surface, where they used sound bovine incisors (smooth buccal surface) in contrast to our study, where sound human premolars were investigated .
Universal adhesive resin is a flexible cross-linked urethane-based resin with higher mobility than Bis-GMA-based resin. It infiltrates the enamel and leaves a resin layer on the top responsible for the smoothing of the demineralized enamel surface . This may be in contrast to another study that compared ICON to UDMA-based infiltrant and concluded that the UDMA-based resin significantly lowered the surface roughness of demineralized enamel compared to ICON . The CPP-ACP conjugated with the universal adhesive resin-treated group had a statistically comparable result, supposed to be attributed to occluding the pores within the WSL and smoothening of the extremely rough demineralized enamel surface.
Coupling the CPP-ACP remineralizing program with subsequent universal adhesive resin infiltration may be an effective treatment for orthodontic post-bonding WSLs. Investigating the effectiveness of the tested protocol, CPP-ACP coupled with universal adhesive resin, when applied pre-bonding of appliances as a preventive strategy, is compulsory. Regarding the methodology, the recommended protocol seems to be easy to be applied in-vivo. However, the clinical application and success may be highly reliant on the patient's compliance, cooperation, and patience as the patient has to apply the CPP-ACP treatment section daily for 6 weeks with monitoring by the clinician. On accomplishment of the remineralizing program, the universal adhesive resin infiltration is applied in one visit with a prompt restoration of the esthetic.
The current study has some limitations that need to be acknowledged. The limited sample size, the use of artificially-created white spot lesions, and the short-term assessment of the investigated protocol are the most noted restrictions of this study.
Further supporting studies are highly recommended to assess the efficacy and long-term stability of the proposed treatment protocol, CPP-ACP remineralizing agent with subsequent universal adhesive resin, particularly in vivo for the naturally occurring white spot lesions. Additionally, testing this protocol as an effective preventive approach before fixation of the orthodontic appliances should be considered.