Journal of International Oral Health

REVIEW ARTICLES
Year
: 2021  |  Volume : 13  |  Issue : 3  |  Page : 214--226

Classical versus non-classical strategies for remineralization of early enamel lesions: Systematic review and meta-analysis


Mennatallah N Salem1, Raneen Ahmed Gohar2, Shereen I Hafez3, Bassam Ahmed Abulnoor4,  
1 Conservative Dentistry Department, Operative Division, Faculty of Oral and Dental Medicine, Misr International University, Cairo, Egypt; Conservative Dentistry Department, Faculty of Dentistry, Cairo University, Cairo, Egypt
2 Conservative Dentistry Department, Faculty of Dentistry, Cairo University, Cairo, Egypt; Conservative Dentistry Department, Faculty of Dentistry, Suez University, Suez, Egypt
3 Conservative Dentistry Department, Faculty of Dentistry, Cairo University, Cairo, Egypt
4 Fixed Prosthodontics Department, Faculty of Dentistry, Ain Shams University, Cairo, Egypt

Correspondence Address:
Dr. Mennatallah N Salem
Conservative Dentistry Department, Operative Division, Faculty of Oral and Dental Medicine, Misr International University, P.O. Box Heliopolis 01, KM 28 Cairo-Ismailia Road, Ahmed Orabi District, Cairo.
Egypt

Abstract

Aim: The aim of this paper was to assess the clinical performance of self-assembling peptide (SAP) in comparison to fluoride varnish in treatment of early enamel lesions. Materials and Methods: The literature search covered the electronic databases such as PubMed, Google Scholar, EBSCOhost, and Cochrane from 2010 to 2020. Only articles published in English were included. In vivo studies, involving human subjects in whom SAP was delivered, were included. Results: Eight hundred and sixty articles were identified from the search after excluding duplicates. Abstracts of articles were reviewed independently. Eight hundred and twenty-four articles were excluded after reading the abstracts. Full-text articles were retrieved for 36 relevant studies. After reviewing articles independently, 25 were excluded after full-text reading. Finally, 11 studies were selected based on the eligibility criteria. All 11 articles reviewed SAP, seven of them compared SAP to fluoride, one compared SAP to no treatment, and three were case series studies. Conclusion: For the treatment of early enamel lesions, non-classical remineralization using SAP whether used alone or in combination with fluoride showed a positive outcome that was superior to that of fluoride varnish. Future studies are speculated to show higher probability to detect a positive effect with SAP.



How to cite this article:
Salem MN, Gohar RA, Hafez SI, Abulnoor BA. Classical versus non-classical strategies for remineralization of early enamel lesions: Systematic review and meta-analysis.J Int Oral Health 2021;13:214-226


How to cite this URL:
Salem MN, Gohar RA, Hafez SI, Abulnoor BA. Classical versus non-classical strategies for remineralization of early enamel lesions: Systematic review and meta-analysis. J Int Oral Health [serial online] 2021 [cited 2021 Jul 30 ];13:214-226
Available from: https://www.jioh.org/text.asp?2021/13/3/214/318451


Full Text

 Introduction



Dental caries is the most common disease worldwide.[1] It leads to the destruction of dental hard tissues. The process of caries formation begins by dissolving the minerals from enamel, due to the organic acids produced by bacteria accumulated on the surface of the tooth. Prolonged acid attack creates a subsurface, demineralized lesion, known as white spot lesion (WSL).

Remineralization is the process of restoring minerals to the hydroxyapatite’s lattice structure.[2] Fluoride varnishes have been the most commonly used agents for treatment of WSLs.[3] Several mechanisms have been suggested to achieve remineralization by fluoride-containing products, which include the formation of fluorapatite—which is more acid-resistant than hydroxyapatite—and reduction of pellicle formation, as fluoride varnishes have shown to be effective in minimizing bacterial adherence and subsequent biofilm formation to fluoride-coated surfaces.[4],[5] The use of fluoride encompasses a “classical,” ion-based, crystallization concept. This means that the pathway taken for enamel crystal formation starts with ions that act as building units or nuclei for further crystal aggregation and cluster formation with eventual crystal growth occurring by ion-to-ion attachment.[6] However, remineralization by fluoride is dependent on the residual crystals, in which fluoride ions replace OH- ions by adsorbing to the crystal surface of demineralized enamel. These surface ions then attract calcium ions, followed by phosphate ions, resulting in new mineral formation (fluorapatite). Moreover, for every two fluoride ions, six phosphate ions and 10 calcium ions are needed. This means that not only does this process rely on the remaining crystals for crystal growth but also on the availability of calcium and phosphates, which can limit the whole process.[7]

A new approach for reversing and repairing WSLs has been suggested to overcome the drawback of fluorides. Biomimetic remineralization entitles a concept in which enamel is formed as it would, during tooth formation and amelogenesis.

The application of the self-assembling peptides (SAPs), also known as P11-4, has been advocated for enamel regeneration. SAPs are biocompatible, small molecules consisting of 11 amino acids. This material utilizes a “non-classical” pathway for enamel repair, where first the small protein molecules self-assemble to form a 3-D prenucleation cluster or scaffold in the subsurface lesion, mimicking the protein that is laid by ameloblasts during tooth formation. This 3-D scaffold has great affinity to tooth minerals. Secondly, the attachment of calcium and phosphate from saliva takes place and subsurface remineralization is likely to happen in a bottom-up direction of growth, ensuring full depth remineralization and repair of the lesion.[3],[8]

The aim of this systematic review was to assess the clinical performance of SAP in comparison to fluoride varnish in treatment of early enamel lesions.

 Materials and Methods



Search criteria

We reported this systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria.[9] The research question was as follows: Do SAPs provide similar clinical performance to fluoride for treatment of early enamel lesions? The eligibility criteria were set as studies written in English language, published within the past 10 years, from 2010 to April 2020, since CurodontTM, which is the only material presenting SAP, has been available in the dental market since June 2016. Only in-vivo trials, involving human population, were considered of all ages and both sexes; subjects must have had early carious enamel lesion. The studies assessing post-orthodontic treatment WSLs were also taken in consideration. Editorials, review articles, in-vitro studies, animal studies, and non-English articles were excluded from this systematic review. We registered this systematic review on the PROSPERO International Prospective Register of Systematic Reviews, registration ID: CRD42020182583.

Structured question

Do SAPs provide similar clinical performance to fluoride for treatment of early enamel lesions?

PICO analysis

Population: Subjects having early enamel lesions;

Intervention: SAP;

Comparison: fluoride varnish or no treatment (negative control);

Outcome: primary outcome: remineralization of early enamel lesions;

Secondary outcome: adverse effects related to materials used.

Search strategy

The literature search covered the electronic databases such as PubMed, Google Scholar, EBSCOhost, and Cochrane clinical trials. String of English search (MeSH) terms was used to search through different databases. The string of English search terms is as follows: (biomimetic remineralization OR enamel remineralization OR enamel repair OR enamel regeneration) AND (curodont OR P11-4 OR self-assembling peptides) AND (sodium fluoride OR fluoride Varnish) AND (enamel demineralization OR early enamel lesion OR early enamel caries OR WSLs OR post orthodontic WSLs OR incipient caries). In addition, hand searching through the references of relevant articles was done.

Data extraction

Two calibrated reviewers checked the titles and abstracts of all identified studies independently. Once the publication met the inclusion criteria, the full-text articles were obtained and reviewed. Any disagreement during the study selection and data extraction process was solved by discussion and consultation with a third reviewer.

Risk of bias assessment

Risk of bias assessment was done by the investigators using the Cochrane Collaboration tool for assessment of bias.[10] In the other bias section, it was assessed whether follow-up times were sufficient, the investigators had performed a sample size calculation, and the investigators had specified sample inclusion and exclusion criteria. According to the recommendations of the Cochrane Collaboration manual risk of bias, high, unclear, or low risks of bias were taken and shown in [Table 1].{Table 1}

 Results



A total of 860 articles were identified from the search after excluding duplications. Eight hundred and twenty-four articles were excluded after reading titles and abstracts. Abstracts of 36 articles were reviewed independently. Twenty-five articles were excluded after reading their full text, one of those articles by Mannaa et al.[11] was found as an abstract in a conference without any further data and therefore was counted ineligible to be included in this systematic review. Finally, 11 studies were selected based on the eligibility criteria. All 11 articles reviewed SAP, seven of them compared SAP with fluoride, one compared SAP with no treatment, and three were case series studies. The PRISMA flow diagram in [Figure 1] shows the complete selection process.{Figure 1}

Study characteristics

The following characteristics were extracted from all the studies included in the present systematic review to facilitate comparison among them: lesions tested, authors’ names and publication year, study design, age of participants, number of participants and/or lesions in the study, control group, intervention group, measured outcomes, and follow-up period, and finally conclusions are shown in [Table 2].{Table 2}

The primary outcome for assessment was considered as the remineralization potential of self-assembling peptides on early non-cavitated carious enamel lesion. All the studies showed significant remineralization of early non-cavitated carious lesion with the use of SAPs.

The secondary outcome evaluated in this systematic review was adverse effects and side effects in conjunction with the use of SAPs. In total, seven studies measured this outcome.[12],[13],[14],[15],[16],[17],[18] The reported adverse effects were dental sensitivity[15] and increase in salivary pH.[16],[17] However, an increase in salivary pH is not considered as an adverse effect.

Quantitative analysis

Statistical analysis was performed with R statistical analysis software[19] version 4.0.3 for Windows using meta,[20] dmetar,[21] and ggplot2[22] packages. The significance level was set at p ≤0.05 within all tests. Twelve studies were chosen to determine the effect of SAP application on treating early carious lesions in comparison to fluoride. Values used were those measured in the last follow-up interval of each study, and all studies with no control group were excluded. Summary data for the included studies coupled with their respective effect sizes (i.e. standardized mean difference (SMD) for studies with continuous outcomes and odds ratio for studies with binary outcomes) were presented in [Table 3] and [Table 4]. Signs of (SMD) values were reversed for outcomes in which lower means indicate a positive effect (i.e. fluorescence imaging and VAS).{Table 3} {Table 4}

A random-effects model utilizing inverse variance method was chosen to study the intervention effect due to the non-uniformity in the studies’ populations. (SMD) values were converted to natural logs of odds ratios following the method proposed by Hasselblad and Hedges[23] in order to measure the pooled effect. Results of the model was presented in [Table 5] and [Figure 2].{Table 5} {Figure 2}

Due to the high level of heterogeneity between studies 75.8% [57.6%; 86.2%], an influence analysis was run to detect any potential outliers using difference in fits (DFFITS) cutoff value calculated based on Viechtbauer and Cheung.[24] Results of the analysis presented in [Figure 3] showed three possible studies to be responsible for the heterogeneity (Doberdoli et al.[13] measuring fluorescence imaging and both outcomes measured by Gözetici et al.[14]). A follow-up cluster analysis of graphic display of heterogeneity (GOSH) plot is presented in [Figure 4] using K-means, density-based spatial clustering (DBSCAN), and Gaussian mixture model algorithms. Two of the three algorithms detected four studies (three of which were detected by the influence analysis plus the radiodensity outcome measured by Metwally et al.[39]) to be outliers. A Baujat plot[25] presented in [Figure 5] showed contribution of different studies to the overall heterogeneity.{Figure 3} {Figure 4} {Figure 5}

A second model was built with the four extreme studies excluded, and its results were presented in [Table 6] and [Figure 6]. There was no detected heterogeneity between the remaining studies 0.0% [0.0%; 30.8%] and the combined effect of the intervention was positive and statistically significant (OR=2.62 [1.81; 3.79]; z=5.14; p<0.001). The model weights ranged from 24.3% (Bröseler et al.[40] measuring VAS) to 4.7% (Doberdoli et al.[13]) measuring ICADS). The effect in all studies was positive, yet it was only significant in three studies (Bröseler et al.[40] and Alkilzy et al.[12] measuring VAS and Jablonski-Momeni et al.[31] measuring fluorescence imaging). The prediction interval [1.66; 4.15] indicated the higher probability of future studies to detect a significant positive effect. Analysis of the funnel plot presented in [Figure 7] showed symmetry of the studies’ distribution indicating no publication bias. The symmetry was confirmed using Egger’s test,[26] which was not statistically significant (t=0.313; p=0.765).{Table 6} {Figure 6} {Figure 7}

 Discussion



The primary objective of this systematic review was to determine the remineralization potential of non-classical crystal growth using SAP through studying the published, in human studies available in the literature. In the present systematic review, four clinical trials out of 11 revealed a low risk of bias on the effect of SAP on early enamel carious lesions, suggesting that SAP has a greater remineralizing effect on early caries lesions in clinical trials in comparison to fluoride varnish.

Early carious enamel lesions appear clinically as white, opaque spots. Those lesions are slightly softer than the surrounding sound enamel and their whiteness increases with air drying. They are characterized by defects with some subsurface damage and a relatively intact enamel surface. The progressive subsurface demineralization, if not reversed, will lead to mechanical failure of enamel and cavitation with subsequent commencement of the detrimental restoration cycle. Therefore, considering the preferred conservative approach, remineralizing agents can be used to promote the mechanism of ion-exchange instead of invasive techniques.[27]

The aim of enamel remineralization nowadays does not only encompass inhibition of progression of early enamel lesions, but also “true regeneration” of hydroxyapatite crystals in the subsurface lesion while utilizing the natural remineralization process of saliva. This can be achieved through a guided enamel regeneration approach by the use of SAP, also called P11-4.[28] The proof of concept that SAPs facilitate biomimetic enamel remineralization was first published by Kirkham et al.[29] SAPs have the capability of diffusing into the subsurface carious lesions, acting as building blocks creating a 3D bio-matrix scaffold in the form of fibers, guiding the regeneration of enamel tissue. The 3D biomatrix contains clusters of negative charges, presenting potential calcium binding sites. In other words, SAP is characterized by having high affinity to calcium and phosphate with a potential to nucleate de novo hydroxyapatite crystals.[1],[18] Those calcium and phosphate ions are delivered from saliva, thus supporting the concept of natural remineralization mechanism driven by saliva.[30]

SAP used in the included studies was marketed under the trade names of “CurodontTM Repair” and “CurodontTM Protect” (Credentis; Windisch, Switzerland). The fluoride varnishes used were under the trade names of Enamelast 5% sodium fluoride, 22,600ppm F (Ultradent, South Jordan, UT, USA) Duraphat, 22600ppm F (Colgate Palmolive, New York, NY, USA), and Fluor Protector S (7′700ppm Fluoride, Ivoclar Vivadent, Schaan, Liechtenstein) and in a form of paste marketed as Lunos® Polierpaste paste Two in One (Durr Denta AG, Bietigheim-Bissingen, Germany).

The difference between both Curodont products lies in the composition. CurodontTM Repair is a monomeric form of SAP, which is mainly applied in clinical settings, whereas CurodontTM Protect is a polymeric form of self-assembling peptide matrix (SAPM) containing 1000 ppm P11-4 and 900 ppm fluoride and calcium phosphate, intended for clinical or home use.[13],[31],[32]

There seems to be an agreement on the enhanced efficacy of SAP on enamel repair and regeneration in cases of early enamel lesions. This has been elaborated through the included studies in this systematic review. In cases of post-orthodontic WSLs, SAP showed superior remineralization properties when mineral content was measured through radiodensity and digital subtraction radiography, as in the case series by Abdel Aziz et al.[16] and Schlee et al.[18] The authors presented results showing in-depth remineralization of lesions after 6 months follow up and up to 1 year from Curodont Repair application. Another method to assess mineral content is through quantitative analysis, as that presented by Jablonski-Momeni et al.[31] in their in-situ clinical trial, in which micro-CT was used to quantitatively measure amount of minerals after the at-home application of Curodont Protect over demineralized bovine enamel discs, with and without orthodontic brackets, placed on removable appliances intraorally. This study design simulated enamel demineralization patterns occurring in high caries risk patients, as those receiving orthodontic appliances. Micro-CT results showed significant increase in mineralization when compared with the fluoride control group after just 1 week of Curodont Protect application and remained stable for the following 2–3 weeks.

Impedance measurement is another method utilized to measure the effectiveness of SAP on post-orthodontic WSLs. Welk et al.[30] recorded a marked decrease in impedance readings (using CarieScan) after 3 months of SAP application; the readings remained stable up to 6 months from application.

The presence of WSLs significantly affects the esthetic appearance of the teeth and quality of life of patients who are suffering from them.[33] Although fluoride has been considered the gold standard for the arrest of WSLs,[34] yet, concentrated fluoride applied on the labial surfaces of teeth maintains the whiteness of the lesion. This was explained by the presence of a hypermineralized surface layer.[35] Moreover, fluoride might cause permanent brown organic staining, which might further endanger the esthetic treatment outcome.[36] To effectively evaluate reversal of WSLs, visual and photographic assessments are very important to track lesion changes for aesthetic purposes.[37] Brunton et al.[15] conducted a clinical study that is considered to be the first-in-man clinical safety trial to detect the safety and efficacy of SAP on class V WSLs. Single application of SAP on early carious lesions led to a significant reduction of the lesion size within 30 days, as assessed on clinical photographs. The results remained stable for a follow-up period of 6 months.

When SAP was compared with fluoride, SAP showed statistically significant superior results in enamel repair. This was attributed to the ability of SAP to penetrate into the subsurface lesion and build newly formed hydroxyapatite crystals from bottom to top, unlike fluoride, which cannot remineralize beyond the surface zone.[38] This was demonstrated by Kamh et al.[17] who measured early enamel lesion changes visually, via ICDAS II scoring. SAP showed a statistically significant enhancement in lesion reversal, over fluoride after 3 months of application. This was emphasized when some lesions (13.3%) had reverted from ICDAS scores 2 and 3 to an ICDAS score 0 upon SAP application, whereas no lesions showed reversal below ICDAS score 1 in the fluoride group. This was in agreement with Metwally et al.[39] who stated that although both SAP and fluoride showed a gradual decrease in the ICDAS score from baseline, reaching the lowest score after 6 months, SAP showed greater lesion regression than fluoride. Similarly, Bröseler et al.[40] assessed the morphometric changes through comparing photographs of early buccal carious lesion after application of P11-4 and fluoride varnish after 30, 90, 180, and 360 days. The investigators reported lesion regression and reversal in the SAP group, whereas the fluoride group remained stable. When diagnostic aids were used for quantitative analysis, Jablonski-Momeni et al.[31] reported lower laser fluorescence values with Curodont Protect using DIAGNOdent, in comparison to the fluoride control group, in this in-situ clinical trial. On the contrary, Gözetici et al.[14] found no significant difference between SAP and fluoride test groups when measured using laser fluorescence (LF pen), over the course of 6 months.

SAPs have been tested with different combinations, showing a greater outcome on early enamel lesions. This was explained by the complementary mechanism of the remineralizing agents used. Doberdoli et al.[13] used ICDAS-II codes and Nyvad criteria to evaluate the effect of combination therapy with SAP. They concluded that SAP, when used in combination with fluoride varnish or twice weekly application of Curodont Protect, had a statistically significant improvement in enamel repair and lesion arrest over fluoride varnish alone. However, there was no statistically significant difference between both SAP groups. This was in agreement with Alkilzy et al.[12] who stated that there was a statistically significant overpowering from SAP in combination with fluoride, over the use of fluoride alone, when measured using ICDAS-II scoring and Nyvad criteria. Moreover, further proof was provided in this study via quantitative analysis, in which there was a statistically significant decrease in laser fluorescence readings in the test group (combination of SAP and fluoride), in comparison to the control group (fluoride varnish only), at 3 and 6 months of follow-up when measured using DIAGNOdent.

Some authors recommend remineralizing agents’ application more than once for further carious lesion arrest and regression.[41] However when Metwally et al.[39] tested single and double applications of SAP and fluoride, there was no statistically significant difference between the number of applications in both groups, when assessed by ICDAS and radiodensity, over a period of 6 months.

It is worth mentioning that three of the assessed studies in this systematic review are case series studies[15],[30] which represent weaker evidence than randomized clinical trials according to the hierarchy of study designs.[42] Two of the included studies are split-mouth clinical trials, in which a carryover effect might have taken place and affected the results of the study; moreover, this carryover effect puts split-mouth trials at risk of bias.[43] Furthermore, most studies investigated the effect of SAP and fluoride using indirect measurements of remineralization, such as laser fluorescence, ICDAS-II scoring system, visual analog scale (VAS), and radiographic assessment. Although those methods are the most commonly used assessment strategies for WSLs in the literature, yet, further investigations using direct measurements of net mineral gain by the tooth structure would yield more accurate results to define quantitatively the remineralization power of remineralizing agents in the treatment of WSLs.

The secondary outcome evaluated in this systematic review was the occurrence of adverse effects in conjunction with SAP. No unwanted adverse effects were recorded by four studies.[12],[13],[14],[18] Yet, Bruton et al.[15] reported the occurrence of dental sensitivity after treatment with SAP in their clinical safety trial, which could possibly be related to this material. Moreover, Abdel Aziz et al.[16] and Kamh et al.[17] reported an increase in salivary pH after the application of SAP. However, this is not considered as an adverse effect.

Saliva is one of the key players for adequate remineralization of early enamel lesions. Therefore, using remineralization agents to maintain a higher plaque pH than the critical pH is the best approach for caries management.[44] Abdel Aziz et al.[16] and Kamh et al.[17] recorded salivary pH with the use of SAP for 6 and 3 months, respectively, and the results showed that there was an increase in salivary pH with time. This helps enamel to resist the acidic challenge and makes it capable for net remineralization of early carious lesions. In contrast, Metwally et al.[39] recorded no change in salivary pH in both SAP and fluoride groups, throughout the follow-up period. P11-4 has a chemical formula of C72H98N20O22, which is a synthetic material that consists of naturally occurring amino acids (glutamine, glutamic acid, phenylalanine, tryptophan, and arginine). Those amino acids are carbonated elements with a controlled pH. SAP builds a 3-D biomatrix on the enamel surface that has high affinity to calcium and phosphate in saliva; thus binding occurs between those ions and the tooth surface via the binding sites for calcium ions on the tooth structure, and those sites serve as nucleation point for hydroxyapatite formation. This matrix formation is pH-controlled, which induces localized buffering on the tooth surface.[45],[46] It has also been claimed that patients suffering from xerostomia could demonstrate compromised outcomes on the overall treatment using SAP.[47] However, the effect of SAP on the buffering effect of saliva should be further investigated.

 Conclusion



For the treatment of early enamel lesions, non-classical remineralization using SAP, whether used alone or in combination with fluoride, showed a positive outcome that was superior to that of fluoride varnish. Future studies are speculated to show higher probability to detect a positive effect with SAP.

Recommendation

Further studies are recommended to use methods for measurement of amount of mineral uptake by enamel in conjunction with application of SAP, with longer follow-up periods to conclusively evaluate its regenerative capabilities in treatment of WSLs, especially lesions scoring 3 in ICDAS-II scoring system and its effect on salivary buffering capacity.

Acknowledgements

Not applicable.

Financial support and sponsorship

This research was self-funded.

Conflict of interest

There is no conflict of interest to declare.

Author contributions

All authors contributed in study conception, data collection, data acquisition and analysis, data interpretation, and manuscript writing. All the authors approved the final version of the manuscript for publication.

Ethical policy and Institutional Review board statement

Not applicable.

Patient declaration of consent

Not applicable.

Data availability statement

The data set used in the current study is available on request from Raneen Ahmed Gohar (raneen.aboelgheit[email protected]).

References

1Kind L, Stevanovic S, Wuttig S, Wimberger S, Hofer J, Müller B, et al. Biomimetic remineralization of carious lesions by self-assembling peptide. J Dent Res 2017;96:790-7.
2Cochrane NJ, Cai F, Huq NL, Burrow MF, Reynolds EC. New approaches to enhanced remineralization of tooth enamel. J Dent Res 2010;89:1187-97.
3Wang H, Xiao Z, Yang J, Lu D, Kishen A, Li Y, et al. Oriented and ordered biomimetic remineralization of the surface of demineralized dental enamel using [email protected] nanoparticles guided by glycine. Sci Rep 2017;7:1-13.
4Rao A, Malhotra N. The role of remineralizing agents in dentistry: A review. Compend Contin Educ Dent 2011;32:26-33; quiz 34, 36.
5Chau NP, Pandit S, Jung JE, Jeon JG. Evaluation of Streptococcus mutans adhesion to fluoride varnishes and subsequent change in biofilm accumulation and acidogenicity. J Dent 2014;42:726-34.
6He L, Hao Y, Zhen L, Liu H, Shao M, Xu X, et al. Biomineralization of dentin. J Struct Biol 2019;207:115-22.
7Juntavee A, Sinagpulo AN, Juntavee N. Modern approach to pediatric dental caries prevention and treatment. Ann Pediatr Child Heal 2017;5:1127-35.
8Wierichs RJ, Kogel J, Lausch J, Esteves-Oliveira M, Meyer-Lueckel H. Effects of self-assembling peptide P11-4, fluorides, and caries infiltration on artificial enamel caries lesions in vitro. Caries Res 2017;51:451-9.
9Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:e1000097.
10Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al. Chapter 8. Assessing risk of bias in a randomized trial. In: Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al, editors. Cochrane Handbook for Systematic Reviews of Interventions. Version 6. Cochrane; 2019: ebook.
11Mannaa A, Sedlakova P, Bommer C, di Bella E, Krejci I. Mannaa unfound reference.pdf. In: IADR Vol. 96th General Session, London, UK; 2018.
12Alkilzy M, Tarabaih A, Santamaria RM, Splieth CH. Self-assembling peptide P11-4 and fluoride for regenerating enamel. J Dent Res 2018;97:148-54.
13Doberdoli D, Bommer C, Begzati A, Haliti F, Heinzel-Gutenbrunner M, Juric H. Randomized clinical trial investigating self-assembling peptide P11-4 for treatment of early occlusal caries. Sci Rep 2020;10:4195.
14Gözetici B, Öztürk-Bozkurt F, Toz-Akalın T. Comparative evaluation of resin infiltration and remineralisation of noncavitated smooth surface caries lesions: 6-month results. Oral Health Prev Dent 2019;17:99-106.
15Brunton PA, Davies RP, Burke JL, Smith A, Aggeli A, Brookes SJ, et al. Treatment of early caries lesions using biomimetic self-assembling peptides—A clinical safety trial. Br Dent J 2013;215:E6.
16Abdel Aziz F, Marei TH, Elmalt MA. Assessment of self-assembling peptide P-11–4 in the treatment of white spot lesions after orthodontic treatment. Egypt Orthod J 2016;50:35-48.
17Kamh RA, Niazy MA, El-Yasaky MA. Clinical performance and remineralization potential of different biomimitic materials on white spot lesions. Al-Azhar Dent J 2018;5:349-58.
18Schlee M, Schad T, Koch JH, Cattin PC, Rathe F. Clinical performance of self-assembling peptide P 11-4 in the treatment of initial proximal carious lesions: A practice-based case series. J Investig Clin Dent 2018;9:e12286.
19Team RC. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2013.
20Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: A practical tutorial. Evid Based Ment Health 2019;22:153-60.
21Harrer M, Cuijpers P, Furukawa T, Ebert DD. dmetar: Companion R Package for the Guide Doing Meta-Analysis in R. Published online 2019.
22Wickham H. Programming with ggplot2. In: ggplot2. Use R! Cham: Springer; 2016.
23Hasselblad V, Hedges LV. Meta-analysis of screening and diagnostic tests. Psychol Bull 1995;117:167-78.
24Viechtbauer W, Cheung MW. Outlier and influence diagnostics for meta-analysis. Res Synth Methods 2010;1:112-25.
25Baujat B, Mahé C, Pignon JP, Hill C. A graphical method for exploring heterogeneity in meta-analyses: Application to a meta-analysis of 65 trials. Stat Med 2002;21:2641-52.
26Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.
27Philip N. State of the art enamel remineralization systems: The next frontier in caries management. Caries Res 2019;53:284-95.
28Alkilzy M, Santamaria RM, Schmoeckel J, Splieth CH. Treatment of carious lesions using self-assembling peptides. Adv Dent Res 2018;29:42-7.
29Kirkham J, Firth A, Vernals D, Boden N, Robinson C, Shore RC, et al. Self-assembling peptide scaffolds promote enamel remineralization. J Dent Res 2007;86:426-30.
30Welk A, Ratzmann A, Reich M, Krey KF, Schwahn C. Effect of self-assembling peptide P11-4 on orthodontic treatment-induced carious lesions. Sci Rep 2020;10:6819.
31Jablonski-Momeni A, Korbmacher-Steiner H, Heinzel-Gutenbrunner M, Jablonski B, Jaquet W, Bottenberg P. Randomised in situ clinical trial investigating self-assembling peptide matrix P11-4 in the prevention of artificial caries lesions. Sci Rep 2019;9:269.
32Ceci M, Mirando M, Beltrami R, Chiesa M, Colombo M, Poggio C. Effect of self-assembling peptide P11-4 on enamel erosion: AFM and SEM studies. Scanning 2016;38:344-51.
33Gu X, Yang L, Yang D, Gao Y, Duan X, Zhu X, et al. Esthetic improvements of postorthodontic white-spot lesions treated with resin infiltration and microabrasion: A split-mouth, randomized clinical trial. Angle Orthod 2019;89:372-7.
34González-Cabezas C, Fernández CE. Recent advances in remineralization therapies for caries lesions. Adv Dent Res 2018;29:55-9.
35Chen H, Liu X, Dai J, Jiang Z, Guo T, Ding Y. Effect of remineralizing agents on white spot lesions after orthodontic treatment: A systematic review. Am J Orthod Dentofacial Orthop 2013;143:376-382.e3.
36Sonesson M, Bergstrand F, Gizani S, Twetman S. Management of post-orthodontic white spot lesions: An updated systematic review. Eur J Orthod 2017;39:116-21.
37Markowitz K, Carey K. Assessing the appearance and fluorescence of resin-infiltrated white spot lesions with caries detection devices. Oper Dent 2018;43:E10-8.
38Zhang X, Li Y, Sun X, Kishen A, Deng X, Yang X, et al. Biomimetic remineralization of demineralized enamel with nano-complexes of phosphorylated chitosan and amorphous calcium phosphate. J Mater Sci Mater Med 2014;25:2619-28.
39Metwally NI, Niazy MA, El-malt MA. Remineralization of early carious lesions using biomimetic self-assembling peptides versus fluoride agent (in vitro and in vivo study). Al-Azhar Dent J 2017;4:179-88.
40Bröseler F, Tietmann C, Bommer C, Drechsel T, Heinzel-Gutenbrunner M, Jepsen S. Randomised clinical trial investigating self-assembling peptide P11-4 in the treatment of early caries. Clin Oral Investig 2020;24:123-32.
41Marinho VCC, Worthington HV, Walsh T, Clarkson JE. Fluoride varnishes for preventing dental caries in children and adolescents (review). Cochrane Database Syst Rev2013:CD002279.
42Ismail AI, Bader JD; ADA Council on Scientific Affairs and Division of Science. Evidence-based dentistry in clinical practice. J Am Dent Assoc 2004;135:78-83.
43Smaïl-Faugeron V, Fron-Chabouis H, Courson F, Durieux P. Comparison of intervention effects in split-mouth and parallel-arm randomized controlled trials: A meta-epidemiological study. BMC Med Res Methodol 2014;14:64.
44Khijmatgar S, Reddy U, John S, Badavannavar AN, D Souza T. Is there evidence for Novamin application in remineralization?: A systematic review. J Oral Biol Craniofac Res 2020;10:87-92.
45Alkilzy M, Tarabaih A, Splieth C. Efficacy, clinical applicability and safety, of CurodontTM repair in children with early occlusal caries. Caries Res 2015;49:311.
46Chen X, Gillam D, Lysek D, Hill R. Dentine tubule occlusion of a novel self-in vitro evaluation of dentine remineralisation by a self-assembling peptide using scanning electron microscopy. Caries Res 2014;48:402.
47Bonchev A, Vasileva R, Dyulgerova E, Yantcheva S. Self-assembling peptide P11-4: A biomimetic agent for enamel remineralization. Int J Pept Res Ther2020. doi: 10.1007/s10989-020-10136-1.