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Background:
Review

Can New Remineralizing Agents Serve as Fluoride Alternatives in Caries Prevention? A Scoping Review

by
Jekaterina Gudkina
1,*,
Bennett T. Amaechi
2,
Stephen H. Abrams
3 and
Anda Brinkmane
1
1
Conservative Dentistry and Oral Health Department, Riga Stradiņš University, LV-1007 Riga, Latvia
2
Department of Comprehensive Dentistry, School of Dentistry, University of Texas Health Science Center, San Antonio, TX 77030, USA
3
Four Cell Consulting, Cliffcrest Family Dental, Scarborough, ON M1M 1P1, Canada
*
Author to whom correspondence should be addressed.
Oral 2025, 5(3), 47; https://doi.org/10.3390/oral5030047
Submission received: 3 March 2025 / Revised: 19 May 2025 / Accepted: 23 May 2025 / Published: 2 July 2025
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Abstract

Background: Due to limitations of fluoride (F) treatment as a main caries preventive measure, it is important to consider the use of other dental caries preventive measures to reduce caries prevalence, especially in its early stages. Recently, new remineralizing agents appeared on the market, with their commercial availability in a variety of oral care products. Objectives: The purposes include providing a scoping review that represents caries remineralizing efficacies of only commercially available products and their existing adverse effects (if it is presented) and ensuring that only evidence-based approved products are included. Methods: The following databases were used in searching scientific literature on 28 October 2024: PubMed, PubMed Advanced Search, MeSH database, and PubMed Clinical Queries. The study selection criteria were as follows: for laboratory, in vitro, and/or in situ—remineralization of enamel-scanning electron microscopy, spectroscopy, microhardness test, light microscopy, profilometry, transverse microhardness microradiography, integrated mineral loss, light microscopy, photothermal radiometry; if it was a randomized controlled trial—CONSORT protocol, ICDAS system (to detect dental caries), diagnostic additional devices; antibacterial ability-colony forming units, DNA-based sequencing, scanning electron microscopy, crystal violet staining, and confocal laser scanning microscopy. Results: This review includes 98 papers: 14 of them describing the current status of caries patterns in the world, 60 studies (45 laboratory studies and 15 RCTs), and 24 systematic reviews were analyzed in order to detect whether new remineralizing agents can replace fluoride in further caries prevention. Conclusions: All reviewed new remineralization agents could be used without additives to treat early caries lesions, but the combination with F promotes better remineralization. Only HAP demonstrated its potential to serve as an alternative to fluoride in oral care products. However, further clinical studies are needed to prove its role in the remineralizing process of initial caries lesions. One also needs to ensure that both the clinical trials and in vitro lab studies use the best gold standards to validate any changes in the tooth structure, both remineralization and demineralization.

Graphical Abstract

1. Introduction

Rationale: Dental caries is the most common oral disease globally, leading to the destruction of the hard tissue of a tooth via the interaction of bacteria and fermentable carbohydrates [1]. Nowadays, the dental caries rate is increasing, and it has become a major public health challenge worldwide, affecting many children and adult populations, and leading to pain, discomfort, and loss of teeth [2,3,4]. Despite reducing dental caries, due to the daily use of fluoride toothpaste [2], it remains one of the most prevalent diseases affecting children worldwide, and caries still develops in high-risk individuals of all ages, irrespective of the dose of fluoride used [5,6]. Although fluoride interventions have consistent benefits in preventing caries and remineralizing initial caries lesions, other agents are needed to enhance the caries control effects of fluoride, especially in high-risk individuals [5,7,8,9,10,11]. However, the question arises about the safety of water fluoridation, as a major public health measure with its potential adverse effects in high concentration, and its impact on caries prevalence [12,13,14,15]. Unfortunately, the caries reduction effect was reported to be smaller than in previously conducted studies [15]. So, it is important to consider the use of other dental caries preventive measures to reduce caries prevalence [15], especially in its early stages [16]. However, there is a limit to the fluoride dose allowed in oral care products to avoid the risk of fluorosis in children and toxicity in all ages [5]. Also, a higher fluoride dose in remineralization materials results in surface-zone remineralization at the expense of the lesion body, thus preventing fuller and homogenous remineralization of the lesion [5,17]. Recently, new remineralizing agents are commercially available in a variety of oral care products that could be used not only by professionals (e.g., varnishes) but also by patients (gel, toothpastes, and mouthrinses). The efficacy of the active ingredients in these products was carefully investigated by different studies.
Objectives: This review focuses on the remineralizing efficacies of only the agents in commercially available products and their existing adverse effects (if it is reported).

2. Materials and Methods

This scoping review, including the literature search, was based on the Arksey and O’Malley Framework principles (2005) [18].

2.1. Review Objectives

This review concept/research question analyzes different new commercially available remineralizing agents tailored to arrest the initial stages of caries development.

2.2. Eligibility Criteria

The following inclusion and exclusion criteria were used in determining the eligibility of the included studies.

2.2.1. Inclusion Criteria

  • Population: A healthy population (no general disease) with initial stages of dental caries.
  • Interventions: Studies involving interventions with definite enamel remineralizing agents: amorphous calcium phosphate (ACP), polyphosphate systems, STMP, functionalized β-tricalcium phosphate, calcium sodium phosphosilicate (CSP), casein phosphopeptide–amorphous calcium phosphate (CPP-ACP), self-assembling polypeptide, P11-4, nano-hydroxyapatite, and fluoride.
  • Outcomes: Laboratory studies: definite dg criteria: remineralization of enamel-scanning electron microscopy, spectroscopy, microhardness test, light microscopy, profilometry, transverse microhardness microradiography, integrated mineral loss, light microscopy, photothermal radiometry, and microcomputed tomography (MCT); Clinical studies: RCT, CONSORT document, and trial registration.
  • Study design: Randomized controlled trials (RCT, CONSORT document, trial registration), in vitro, in vivo, and in situ studies.
  • Language: English only.
  • Period of search: From the end of August to 28 October 2024.
  • Publication type: Peer-reviewed studies only.

2.2.2. Exclusion Criteria

  • Unhealthy population.
  • Studies reported the effect affecting dentine.
  • Studies not reporting the isolated effect of a definite enamel-remineralizing effect. Also, studies that do not use a definite enamel-remineralizing effect.
  • The outcomes were measured without the use of the outcome criteria.
  • Studies not published in English.
  • Repetitive data.

2.3. Information Sources and Search Strategy

These databases were used in searching scientific literature: PubMed, PubMed Advanced Search, MeSH database, and PubMed Clinical Queries, using the following search terms (single and combination of several terms): remineralizing agents, amorphous calcium phosphate, ACP, polyphosphate systems, STMP, functionalized β-tricalcium phosphate, calcium sodium phosphosilicate, CSP, casein phosphopeptide–amorphous calcium phosphate, CPP-ACP, self-assembling polypeptide, P11-4, nano-hydroxyapatite, fluoride, white spot lesions, early caries lesions, initial caries, oral microflora, and oral biofilm. The following filters applied: peer-reviewed only, dg criteria for laboratory studies (remineralization of enamel-scanning electron microscopy, spectroscopy, microhardness test, light microscopy, profilometry, transverse microhardness microradiography, integrated mineral loss, light microscopy, photothermal radiometry, micro-CT); if it was a randomized controlled trial (RCT)—CONSORT protocol, ICDAS system (to detect dental caries), diagnostic additional devices; antibacterial ability-colony forming units, DNA-based sequencing, scanning electron microscopy, crystal violet staining, and confocal laser scanning microscopy. The data were searched from the end of August to 28 October 2024, and each database was searched for a definite remineralizing agent continuously starting from PubMed and completed with PubMed Clinical Queries. The period of studies included was from 2010 to 2024, when new agents achieved major evidence-based research in the laboratory, and when commercially available products were extensively studied.

2.4. Study Selection, Data Extraction, and Synthesis

Data were extracted by two independent researchers. If any questions arose, then the paper was discussed and submitted to a third researcher to decide whether to include it or not. Anyway, the paper was included only with the approval of all authors.
Based on narrative and descriptive synthesis, all studies were grouped based on the enamel-remineralizing agent, then each group was divided into laboratory studies and clinical ones. Also, the demineralization/mineralization of new remineralizing agents and their antibacterial properties were compared to those of fluoride. Afterward, Table 1 (the Results section) was prepared. All publications used for this review were published in English.
As if it is a scoping review, the following analyses were not conducted: the analysis for heterogeneity (statistical methods), as well as the sensitivity analyses among studies, the confidence in the body of evidence, or the certainty of formal assessment for an outcome. Also, methods to assess the risk of bias cause to missing results were not performed.
Furthermore, this review was prepared in compliance with the PRISMA 2020 guidelines and checklist (https://www.prisma-statement.org/prisma-2020-statement accessed on the 30 August 2024). The PRISMA flow diagram shown in Figure 1 presents the sequence of literature selection for this review (Figure 1). This review was not registered (not applicable); accordingly, the protocol was not conducted.

3. Results

The total number of sources from the Database was 104 papers, where 98 were included in the review, and the analysis consisted only of 57 (42 laboratory studies and 15 RCT) studies, and 24 systemic scoping reviews; 9 papers were excluded for not meeting eligibility criteria before the analysis, where 3 papers were included in the total number of references, but 6 were excluded completely. The main outcomes are represented in Table 1, comparing the remineralizing and antibacterial abilities of different new remineralizing agents to those of fluoride. The formal risk of bias was not included in this scoping review. The following items of the PRISMA 2020 checklist, 18, 19, 20b, 20c, 20d, 21, and 22, were not conducted.
Table 1. The comparison of different abilities of new remineralizing agents to fluoride.
Table 1. The comparison of different abilities of new remineralizing agents to fluoride.
The Name of the Agent Remin/DeminBiofilmAdverse EffectCommercial Product
FluorideRemin↑/Demin↓
A high fluoride dose results in surface-zone remineralization and only prevents fuller and homogenous remineralization of the lesion [5]. Incorporation of fluoride into the tooth surface is at a very low level with no “hardening” of the tooth [19]. Those remineralizing properties of fluorides and their mechanisms of inhibiting demineralization have not yet been fully understood [19].		Reduces saccharolytic organisms and inhibits pathways of sugar fermentation [20,21]; also,
it prevents demineralization without affecting biofilm composition and growth inhibits various bacterial enzymes that are necessary for cell growth, sugar transport, and energy metabolism (e.g., enolase, F-ATPase, sulfatase, catalase, phosphatases, and phosphoglucomutase) [21].		FluorosisA wide range of commercial products available
Amorphous calcium phosphate Insufficiently remineralized sub-surface lesions with dental calculus depositions on teeth [7,22].No studies are available.NoEnamelonTM toothpaste
(https://www.enamelon.com, accessed on the 30 September 2024)
Sodium trimetaphosphate (STMP)Strongly binds to phosphate on enamel (which blocks the release of calcium and phosphate from the crystal) and leads to the formation of a layer on the enamel surface that limits acid ion diffusion, but calcium and phosphate diffusion is not affected; was able to minimize mineral loss even in the presence of low F concentrations [7,22].↓The number of Str. mutans cells, and ↓biofilm metabolism (without F) [23]. Also, STMP+F led to the formation of a less compact biofilm [24,25].
STMP alone had a reducing effect, mainly on the metabolism and the extracellular matrix components of the biofilms [26].		NoOral-B Pro Expert toothpaste
(https://www.oralb.co.uk;
https://oralb.com/en-us, accessed on the 30 September 2024)
Functionalized β-tricalcium phosphate (f β-TCP)Boost F-ion activity on the tooth surface, with remineralization driven mostly by salivary Ca2+ and PO43− ions [7,22].
f-TCP creates barriers to prevent interactions between fluoride and calcium, delivering minerals and fluoride to the teeth’ surface [21]. The minerals produced by the combination of fluoride and fTCP have greater acid resistance potential than F, β-TCP, and f-TCP alone [27].		f-TCP, in addition to AgNO3 and NaF, reduced the damage of dentine caries caused by cariogenic biofilm [28].No3M™ Clinpro™ 5000 1.1% Sodium Fluoride
(https://www.solventum.com/en-us/home/f/b00005767/, accessed on the 30 September 2024)
3M™ Clinpro™ XT Varnish
Durable Fluoride-Releasing Coating
3M
(https://www.3m.com/3M/sl_SI/p/d/v000180763, accessed on the 30 September 2024)
Calcium sodium phosphosilicate (Bioglass) When it interacts with saliva, it releases Na+, Ca2+, and PO43− ions and deposits a crystalline hydroxycarbonate apatite layer like the structure of the natural tooth minerals [7,22].
Remin↑/Demine↓ [28]		It has demonstrated antimicrobial effects against various microbial genera, including S. gordonii, V. parvula, P. aeruginosa, and MRSA (methicillin-resistant, Staphylococcus aureus) [29].NoNovaMin toothpaste, Sensodyne
(https://www.sensodyne.com/en-ca/products/repair-and-protect-original, accessed on the 30 September 2024)
Oravive Revitalizing Toothpaste With Novamin, GSK
(https://www.instacart.com/products/22049256-oravive-toothpaste-revitalizing-classic-regular-strength-double-mint-4-00-oz, accessed on the 30 September 2024)
Casein phosphopeptide–amorphous calcium phosphate (CPP-ACP)↑Remin of subsurface lesions, supplying a high concentration of calcium and phosphate ions [28].↓ The number of Str. Mutans at a higher rate than fluoride toothpaste
alone [30,31,32].		It could not be used in people with an allergy to lactose.MI Paste cremes,
Recaldent, Trident White sugar-free gum,
MI Paste One toothpaste
MI Varnish, GC
(https://www.gc.dental/europe/en/products, accessed on the 30 September 2024)
(https://www.gc.dental/america/products, accessed on the 30 September 2024)
Self-assembling peptides P11-4Forms a 3D scaffold in carious lesions and promotes the new formation of hydroxyapatite
crystals [33].		The self-assembling peptide P11-4 exhibited an inhibitory influence on S. Mutans, which may lead to changes in the formation of cariogenic bacteria biofilm [34].NoCurodont Repair, Straumann
(https://professional.vvardis.com/product/curodont-repair, accessed on the 30 September 2024)
(https://professional.vvardis.us/products/#repair, accessed on the 30 September 2024)
Nano-hydroxyapatite It induces remineralization of initial caries lesions by filling micropores in demineralized tooth surfaces, where it acts as a crystal nucleus and promotes crystal deposition and growth by continuously attracting large amounts of calcium and phosphate ions from the surrounding remineralization solution [5].HAP reduces the initial plaque formation
on enamel surfaces [19]. It acts as an acid buffer and reservoir for calcium and phosphate ions in plaque, leading to significant reduction and inhibition of plaque formation without killing bacteria [19]. The high potential of HAP to adsorb to bacterial cell walls facilitates an antibiofilm effect by inducing coaggregation of bacteria within the HAP particles, aiding biofilm removal from the tooth surfaces, and hindering oral biofilm formation [5].		NoPro-Mineralizer Toothpaste, Great Oral Health;
Kinder Karex Zahnpasta, Dr. Kurt Wolff GmbH and Co. KG, Bielefeld
(https://www.karex.com/en-de/products/kinder-karex-toothpaste, accessed on the 30 September 2024)
APAGARD® M-plus toothpaste
(https://www.sangi-eu.com/en/apagard-m-plus/mpc125n, accessed on the 30 September 2024)
(https://www.sangi-co.com/en/products/apagard_mplus/index.html, accessed on the 30 September 2024)
Desensin® oral rinse, DENTAID technologies
(https://www.dentaid.com/en/countries, accessed on the 30 September 2024)

4. Discussion

4.1. Amorphous Calcium Phosphate

Some decades ago, the commercially available amorphous calcium phosphate technology (Enamelon™) was a dual-chamber system, delivering calcium and phosphate salts separately into the oral cavity via F-containing toothpaste [7,22,35]. Unfortunately, ACP easily and spontaneously transforms into apatite crystals in an aqueous environment into stable hydroxyapatite (HAP) or fluorapatite (FA) [21,22]. This means that the concentrations of bioavailable Ca2+, PO43−, and fluoride ions are insufficient to promote subsurface lesion remineralization [7,36,37]. Since ACP is easy to agglomerate and is unstable in an aqueous solution, the main challenge in applying the ACP for enamel remineralization is its stabilization [37,38].
The most recent scientific literature review has suggested that added stabilizers for ACP may establish methods for enhancing traditional or unconventional mineralization mechanisms [38]. Another existing way to stabilize ACP is if the ACP particles were prepared in an anhydrous dry granular state [37].
Unfortunately, there are no published papers that demonstrate that the EnamelonTM technology could reduce the caries progression in a randomized, controlled caries clinical trial [36]. A recent improvement in the older Enamelon™ gave birth to the current commercially available Enamelon® [22]. This newly developed formulation claimed to deliver statistically significantly more fluoride to caries lesions and reduce enamel solubility due to the combination of stannous fluoride (SnF2) with two polymer complexes of calcium and phosphate salts [22]. Another study in 2019 comparing four different toothpaste formulations, including Enamelon™, failed to show the superiority in the enamel remineralization of any used toothpastes [39]. Unfortunately, oral products based on the ACP remineralization technology have limited clinical applicability [7].

4.2. Polyphosphate Systems (Sodium Trimetaphosphate, Calcium Glycerophosphate, Sodium Hexametaphosphate)

Among the polyphosphates like sodium trimetaphosphate (STMP), calcium glycerophosphate, or hexametaphosphate, STMP is the most effective anti-caries agent and is marketed as Oral-B Pro-Expert toothpaste, reported to inhibit demineralization and promote remineralization [7,22]. The mechanism is based on the ability of STMP (Na3P3O9) to bind to phosphate on the enamel surface, which blocks the release of calcium and phosphate ions from the tooth crystals [7,22]. As a sequence, this layer limits acid ion diffusion without affecting calcium and phosphate diffusion [7,22]. Sodium trimetaphosphate has also been shown to promote intrafibrillar collagen remineralization, phosphate uptake by previously demineralized dentin, and deposition of needle-like crystallites at the intrafibrillar level [40].
The clinical study conducted in 2016—an 18-month double-blinded trial—showed that low-fluoride dentifrice (500 ppm) with STMP was superior to fluoride dentifrice (1100 ppm) in decreasing early caries lesions [41]. These conclusions were stated based on the dmfs (including initial dmfs) calculations [41]. Another study conducted later suggests that the inclusion of nano-sized TMP in fluoride toothpaste significantly enhances its remineralization potential [42].
The recent literature review suggested that nano-enhanced formulations could be particularly beneficial in patients at high risk of dental caries [43].
Major in vitro studies were conducted on its efficacy, using pH-cycling models with surface microhardness tests and transverse microradiology [44,45,46,47].
Recent in vitro studies declared that the addition of STMP to F-containing varnishes and gels significantly increased not only the remineralization of initial carious lesions [47,48,49] but also improved protection against erosive tooth wear measured by the use of surface microhardness test and profilometry [50]. The remineralization of the enamel surfaces was measured using light microscopy, scanning electron microscopy [47,48], and surface microhardness test [50]. Notwithstanding positive results in treating early carious lesions, there is a need for additional long-term clinical studies to ascertain whether STMP can effectively induce remineralization in the absence of fluoride [7,22]. At the same time, TMP has shown rather promising results in preventing dentine demineralization [51,52,53].

4.3. Functionalized β-Tricalcium Phosphate

It was designed primarily to boost fluoride ion activity on the tooth surface, with remineralization driven mostly by salivary Ca2+ and PO43− ions [7,22].
The purpose of functionalizing β-TCP was to create barriers preventing premature fluoride–calcium interactions; at the same time, it acts as a targeted low-dose delivery system when applied to teeth using dentifrices or mouthwashes [7,22]. Also, mineralization is slowed by interactions between β-TCP and components, including those in the content of the dentifrices or mouthwash [7,22].
An in vitro study conducted in 2010 demonstrated that TCP + Fluoride provides statistically superior remineralization compared to β-TCP alone [54]. These conclusions were obtained by the use of surface and longitudinal microhardness measurements [54]. Recent laboratory studies stated that functionalized TCP paste showed a significantly greater increase in mean microhardness than casein phosphopeptide–amorphous calcium phosphate fluoride and the negative control and promoted the incorporation of fluoride into root caries lesions and increased mineral density [55,56]. At the same time, it showed no significant difference in the percentage of remineralization potential and microhardness percentage recovery compared to fluoride toothpaste [55,56]. Recent clinical studies have suggested that fluoride varnish applied with functionalized tricalcium phosphate can reverse a white spot lesion [57], and the test group with functionalized TCP had a higher arrest rate than that without functionalized TCP [55]. Notwithstanding positive findings, clinical recommendations to use β-TCP products will be premature without evidence from well-designed RCTs [7,22,56]. A recent in vitro study showed that β-TCP (500 ppm) combined with F (950 ppm) has better remineralizing potential than β-TCP alone [58]. Another study suggested that toothpaste with functionalized Tri-Calcium Phosphate (f-TCP) provides additional protection against decalcification of enamel compared to fluoride varnish with casein phosphopeptide–amorphous calcium phosphate [59].

4.4. Calcium Sodium Phosphosilicate

Calcium sodium phosphosilicate (CSP) is a bioactive glass material originally developed as a biocompatible bone regenerative agent. Also, it is bioactive [7,22]. When it interacts with saliva, it releases Na+, Ca2+, and PO43− ions and deposits a crystalline hydroxycarbonate apatite layer like the structure of the natural tooth minerals [22]. CSP has been commercialized as NovaMin TM technology in toothpaste such as Oravive toothpaste [22]. Calcium sodium phosphosilicate was initially incorporated into a dentifrice to treat hypersensitive dentin [7,22]. However, the evidence of its remineralizing ability from in vitro and in situ studies was weak and contradictory [7,20], even from a recent clinical trial [60]. It was suggested that future research might be needed to prove its effect on enamel remineralization [7,22]. A recent review showed that Novamin has significantly less clinical evidence to prove its effectiveness as a remineralization agent in treating both carious and non-carious lesions [61]. The recent in vitro study, in 2024 by Joshi et al., has shown that bioactive glass (NovaMin Technology; Sensodyne Repair and Protect, GlaxoSmithKline, London, UK) proved its remineralizing potential, but it is less effective than the CCP-ACP (GC Tooth Mousse; Tokyo, Japan) [62].

4.5. Casein Phosphopeptide–Amorphous Calcium Phosphate (CPP-ACP)

Casein phosphopeptide (CPP)–amorphous calcium phosphate (ACP) nanocomplexes are soluble in saliva and create a diffusion gradient that allows them to be localized in supragingival plaque [7,22]. Low pH during a cariogenic attack facilitates the release of Ca2+ and PO43− ions, favoring the remineralization of the incipient lesion [7,22]. Also, CPP-ACP promotes the remineralization of the subsurface lesion, improving its esthetics, strength, and resistance to subsequent acid attack [7,22,63,64].
Several studies have stated the significant remineralizing effect of CPP-ACP, while others have not reported its priority over F-containing products [7,22]. Published literature and systematic reviews also reach conflicting conclusions, possibly due to a poor understanding of CPP-ACP technology or the fact that the remineralization pattern produced by CPP-ACP is different from that of fluoride. CPP-ACP enhanced remineralization of enamel subsurface lesions compared to surface-only remineralization produced by F-containing products [7,35]. Furthermore, systematic reviews reported that inconsistent conclusions can be due to studies with inadequate statistical power, short-term follow-up periods, and possible conflicts of interest between competing product manufacturers [7,22].
However, fluoride and saliva are not enough to repair the initial lesion, especially in a highly cariogenic environment. CPP-ACP can provide high concentrations of stabilized Ca2+ and PO43− ions [7,22]. Other findings emphasize positive effects on the increase in salivary conditions followed by the application of the CPP-ACP-containing product to the inside surface of a removable denture, working as a potential caries-risk tool when natural dentition remains, especially in patients with xerostomia [65]. In 2024, one study stated that fluoridated groups including solutions and CPP-ACPF ((2% CPP-ACPF, 900 ppm of F−) MI Paste Plus®, CG America®, Alsip, IL, USA) were more effective than CPP-ACP (CPP-ACP emulsion (2% of CPP-ACP, 0 ppm of F−) MI Paste®, CG America®, Alsip, IL, USA) in reducing enamel demineralization around orthodontic brackets even after a single application [66]. These findings were validated by the use of scanning electron microscopy (SEM) [66]. It is worth mentioning that the majority of analyzed studies investigated CPP-ACP in the form of toothpaste or tooth mousse. Studies including CPP-ACP as a remineralizing agent in the forms of a paste or tooth mouse did not demonstrate a superior effect in remineralization of the enamel using ICDAS II criteria [67], the light-induced fluorescence [68], as well as the SEM and microhardness test [69]. The latest review has stressed that the delivery methods influence the success of remineralizing therapies, where fluoride varnishes remain the gold standard, while sprays and foams are viable alternatives for specific patient needs [70]. However, other studies, including CPP-ACP in the form of a varnish, demonstrated its remineralizing ability at a higher level compared to CPP-ACP paste or mousse [65,71,72,73,74,75,76,77,78,79,80,81,82]. At the same time, a study conducted in 2018 showed no difference in changes in caries detection parameters comparing CPP-ACP agents in the forms of paste and varnish [83]. Also, another study conducted recently, in 2024, stated similar results using a micro-CT as a diagnostic measure [84]. The application of MI Varnish before or after in-office bleaching reduced mineral loss, with the after-bleaching application being more effective [79]. Also, a recent literature review suggested that calcium phosphates like CPP-ACP can be used to remineralize MIH-affected teeth and reduce MIH-associated tooth sensitivity [84]. The majority of in vitro studies validated their results by the use of surface microhardness tests, SEM, trans microradiography [73,74,78,79,80], polarized light microscopy [78], and energy-dispersive spectroscopy [73,77]. Another part of the laboratory studies used only DIAGNOdent [71], or quantitative light-induced digital fluorescence combined with other methods [73], Fourier transform infrared spectroscopy (ATR-FTIR), small-angle X-ray scattering (SAXS) [78], and optical coherence tomography [72]. Results of clinical findings were evaluated using ICDAS II criteria [72,82,83], but some of the findings were evaluated by DIAGNOdent pen [80].

4.6. Self-Assembling Polypeptide

The self-assembling polypeptide (SAP) was developed to promote the enamel remineralization of early carious lesions without additional calcium and phosphate [7,22,85,86,87].
The major advantage of self-assembling peptides is their ability to form a biomimetic scaffold within subsurface caries lesions [87]. This scaffold relies on the natural mineralization processes in saliva to promote remineralization and regeneration of the lesion [87]. This approach presents a novel possibility for dentists to treat early stages of carious lesions using a minimally invasive and biologically focused treatment [87]. The increase in the effectiveness of SAP could be achieved in conjunction with a calcium-phosphate additive [87]. As long as SAP promotes the natural remineralization process, its mechanism relies on the individual’s saliva quality, its calcium and phosphate concentration as well as the total mineral content, buffering ability, and, of course, salivary flow rate [87]. The remineralizing efficacy of SAP was qualitatively and quantitatively evaluated using SEM and energy-dispersive X-ray (EDX) [87].
Based on later findings, its high affinity to hydroxyapatite and the ability to nucleate it, SAP has the potential to interact with dentin, strengthening collagen fibers and leading to improved bonding properties between caries-affected dentin and restorative materials [87]. Recent studies reported significantly improved stability of reversed early occlusal and proximal lesions within 6–12 months after treatment, with the application of SAP completed [87]. In addition, the combination of fluoride and SAP has shown a higher remineralizing potential in treating early caries lesions than the F alone, within the 6-month follow-up period [88]. Unfortunately, the insufficient number of clinical studies, their short follow-up period, and the limited evidence may influence further use of SAP regularly in treating early carious lesions [7,22,86,88].

4.7. Nano-Hydroxyapatite (nHA, Crystalline)

Nano-hydroxyapatite (nHA) is considered one of the most biocompatible and bioactive materials, and it has been discussed as an effective anti-caries agent [7,22,89,90]. nHA has a similar morphology and structure to the apatite crystal within the enamel, and its hardness and modulus of elasticity are similar to those of natural enamel. It has also been shown that it is suitable for remineralization of initial submicron enamel erosion with its nanoparticles [7,22,89,91,92]. It works as a source of calcium and phosphate ions that promote remineralization [7,22,89,90]. The enamel surface of the initial caries lesion is highly porous, and as such, it allows greater absorption of nHA in it, where it attracts calcium and phosphate ions, leading to crystal growth and integrity [90]. Nanohydroxyapatite solutions have a higher concentration of calcium, thus leading oral fluids to be saturated with hydroxyapatite, forming new apatite minerals in affected regions, and promoting remineralization [90]. Recent reports suggested that although tooth remineralization is achieved with fluorides, it can be achieved more efficiently by calcium phosphates such as hydroxyapatite and amorphous calcium phosphates [19]. Other reports demonstrated that pure nano-HAP application has a promising remineralization ability on white spot lesions based on surface microhardness and mineral content [93].
Several studies of oral care products suggested HAP to be an alternative to fluoride-containing products, especially in avoiding the risk of fluorosis [92,94]. Hydroxyapatite could be counted not only as a safe and efficient anticaries agent in oral care but also as offering relief from dentin hypersensitivity and reducing biofilm formation, making it a multifunctional agent for preventive oral health care [94,95]. Compared to fluorides, calcium phosphate agents are safe if accidentally swallowed, and calcium and phosphate ions can be released during an acidic attack in the plaque [19]. Low pH during a cariogenic attack facilitates the release of Ca2+ and PO43− ions from HAP in plaque, favoring the remineralization of the incipient lesion and inhibition of tooth demineralization [7,22]. Toothpaste containing 10% HAP achieved comparable efficacy with 500 ppm F− in remineralizing initial caries and preventing demineralization [5]. Another study reported that HAP-containing toothpaste was used successfully to remineralize MIH lesions [96], while an ex vivo study conducted in 2023 showed increased remineralization deep within the tooth and progressed toward the surface when a supersaturated calcium phosphate rinse (SSCPR) was used [83]. However, notwithstanding the positive results reported by studies investigating nHAP remineralizing abilities, further long-term research is needed [55,97,98].
Nevertheless, the remineralizing effect of different agents, including fluorides, could not be achieved without the mechanical removal of the biofilm [24]. However, it should be emphasized that complete removal of dental plaque cannot be achieved, so oral care products should contain active ingredients influencing biofilm formation [24]. The demineralization can be decreased by buffering properties and calcium and phosphate ions release of calcium carbonate and/or (carbonated) hydroxyapatite included in oral care products [24]. Generally, the new remineralizing agents can help to prevent dental caries, but other risk factors that facilitate further caries development, such as diet or oral hygiene, should not be overlooked.

4.8. Main Findings and Limitations

4.8.1. Main Findings

Amorphous Calcium Phosphate (ACP): It has the potential for enamel remineralization, but it is not stable. Maybe the addition of stabilizers could have helped it be used in the future as a remineralizing agent.
Polyphosphate Systems: Sodium trimetaphosphate (STMP) is one of the most effective polyphosphates, showing inhibition of demineralization and promoting remineralization. Notwithstanding its promising laboratory results, clinical trials are required to establish its efficacy in completely preventing caries progression, especially in fluoride-free formulations. Also, trials should have to be long-term.
Functionalized β-Tricalcium Phosphate (β-TCP): Functionalized β-TCP, together with fluoride, has demonstrated superior remineralization potential compared to β-TCP alone. It increases the F inclusion in enamel and raises the density of the mineral. Again, clinical trials are necessary to support its widespread use as an oral care product.
Calcium Sodium Phosphosilicate (CSP): CSP shows promising results, particularly treating dentin hypersensitivity; the evidence for its remineralization potential in enamel is unclear. Further studies are necessary to prove or disprove its remineralizing potential.
Casein Phosphopeptide–Amorphous Calcium Phosphate (CPP-ACP): It was suggested that CPP-ACP can enhance remineralization of subsurface lesions, especially in acidic environments. However, the question of whether it can replace F remains unclear. Also, the delivery form (e.g., paste, mousse, or varnish) significantly influences the effectiveness of CPP-ACP, with varnish formulations being more effective than paste forms.
Self-assembling Polypeptides (SAPs): SAPs are a novel approach that promotes the natural mineralization process in saliva. Unfortunately, clinical evidence is limited. SAP with calcium-phosphate additives may enhance its effectiveness, but, again, additional studies with longer follow-up periods are required to validate these findings.
Nano-hydroxyapatite (nHA): Nano-hydroxyapatite (nHA) is a highly effective, biocompatible material that helps in the remineralization of enamel. Some studies have stated that nHA-based products may compete with F in further caries prevention. However, additional long-term clinical trials are necessary to investigate its role as a routine dental care product.

4.8.2. Limitations of Evidence Included

Study Design and Sample Size
Many studies have small sample sizes and a lack of long-term follow-up, which may not reflect the long-term effects of these remineralization agents. This limits the generalizability of the results and their application to the natural environment.
Methodology
As long as a considerable variability in diagnostic devices was used to assess remineralization (laboratory studies (e.g., SEM, light microscopy) and clinical trials (caries scores)), it was difficult to compare the findings of different studies and assess the true effectiveness of the agents.
Lack of Standardized Outcomes
Also, laboratory studies may have difficulties providing a natural environment (saliva), and the demineralized areas may be created by the application of chemicals (not naturally demineralized enamel). It is very important to have standardized measures for outcomes, notwithstanding the extensively developed diagnostic devices (e.g., enamel-scanning electron microscopy). Concerning RCT, caries diagnostic methods, such as ICDAS II, could improve the reliability of future studies.
Bias and Confounding Factors
The potential for bias, including conflicts of interest, was possible in some studies. In addition, the influence of individual parameters (e.g., diet, oral hygiene habits, and saliva) may affect the possible findings.

4.8.3. Limitations of the Review Processes

This review has the following limitations:
Language—only one language (English) was used as one of the eligibility criteria.
Database selection—all data were searched in PubMed and its related variations.
Grey literature search was not conducted.
Also, the items that help to evaluate the reliability of the evidence, of the PRISMA 2020 checklist, were not included (e.g., risk of bias assessment or certainty) in this scoping review.

4.8.4. Future Directions

Future research should focus on randomized controlled trials (RCTs) with appropriate design, with larger sample sizes and longer follow-up periods to confirm or disprove the long-term effectiveness of these agents. Furthermore, more studies are needed to assess the impact of different delivery systems (e.g., pastes, varnishes, and mouthwashes) on the efficacy of remineralizing agents. The standardization of outcome measures and diagnostic tools needs to be implemented to enable better comparison between studies.

5. Conclusions

All reviewed new remineralization agents could be used without additives to treat early caries lesions, but the combination with F promotes better remineralization. Only HAP demonstrated its potential to serve as an alternative to fluoride in oral care products. However, further clinical studies are needed to prove its role in the remineralizing process of initial caries lesions. One also needs to ensure that both the clinical trials and in vitro lab studies use the best gold standards to validate any changes in the tooth structure, both remineralization and demineralization.

Author Contributions

Conceptualization, methodology, validation, writing, and preparing the original draft—J.G., B.T.A. and S.H.A.; writing review—B.T.A. and S.H.A.; editing—A.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

All authors declare no conflicts of interest. “Cliffcrest Family Dental” and “Four Cell Consulting” are dental clinics of one of the authors (S.H.A.), which do not have any conflict of interest of any sort with the publication or products mentioned in the manuscript.

References

  1. Frencken, J.E.; Peters, M.C.; Manton, D.J.; Leal, S.C.; Gordan, V.V.; Eden, E. Minimal Intervention Dentistry (MID) for managing dental caries a review: Report of a FDI task group. Int. Dent. J. 2012, 62, 223–243. [Google Scholar] [CrossRef] [PubMed]
  2. Tafere, Y.; Chanie, S.; Dessie, T.; Gedamu, H. Assessment of prevalence of dental caries and the associated factors among patients attending dental clinic in Debre Tabor general hospital: A hospital-based crosssectional study. BMC Oral Health 2018, 18, 119–126. [Google Scholar] [CrossRef]
  3. Pitts, N.B.; Zero, D.T.; Marsh, P.D.; Ekstrand, K.; Weintraub, J.A.; Ramos-Gomez, F.; Tagami, J.; Twetman, S.; Tsakos, G.; Ismail, A. Dental caries. Nat. Rev. Dis. Primers 2017, 3, 17030. [Google Scholar] [CrossRef]
  4. Peres, M.A.; Macpherson, L.M.D.; Weyant, R.J.; Daly, B.; Venturelli, R.; Mathur, M.R.; Listl, S.; Celeste, R.K.; Guarnizo-Herreño, C.C.; Kearns, C.; et al. Oral diseases: A global public health challenge. Lancet 2019, 20, 249–260. [Google Scholar] [CrossRef] [PubMed]
  5. Amaechi, B.T.; Abdul Azees, P.A.; Alshareif, D.O.; Shehata, M.A.; de Carvalho Sampaio Lima, P.P.; Abdollahi, A.; Kalkhorani, P.S.; Evans, V. Comparative efficacy of a hydroxyapatite and a fluoride toothpaste for prevention and remineralization of dental caries in children. BDJ Open 2019, 5, 18–29. [Google Scholar] [CrossRef]
  6. Kazeminia, M.; Abdi, A.; Shohaimi, S.; Jalali, R.; Vaisi-Raygani, A.; Salari, N.; Mohammadi, M. Dental caries in primary and permanent teeth in children’s worldwide, 1995 to 2019: A systematic review and meta-analysis. Head Face Med. 2020, 16, 22. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  7. Philip, N. State of the Art Enamel Remineralization Systems: The Next Frontier in Caries Management. Caries Res. 2019, 53, 284–295. [Google Scholar] [CrossRef]
  8. Wen, P.Y.F.; Chen, M.X.; Zhong, Y.J.; Dong, Q.Q.; Wong, H.M. Global Burden and Inequality of Dental Caries, 1990 to 2019. J. Dent. Res. 2022, 101, 392–399. [Google Scholar] [CrossRef]
  9. Dentistry TUKSo. Comprehensive Management of Dental Caries Practice Guidelines; Temple University Kornberg School of Dentistry: Philadelphia, PA, USA, 2019. [Google Scholar]
  10. Campos, P.H.; Gimenez, T.; Rocha, R.S.; Caneppele, T.M.F.; Guaré, R.O.; Lussi, A.; Bresciani, E.; Diniz, M.B. Prevalence of White Spot Caries Lesions in Primary Teeth in Preschool Children: Systematic Review and Meta-analysis. Curr. Pediatr. Rev. 2022, 18, 33–46. [Google Scholar] [CrossRef]
  11. He, S.; Yon, M.J.Y.; Liu, F.; Lo, E.C.M.; Yiu, C.K.Y.; Chu, C.H.; Lam, P.P.Y. Prevalence of caries Patterns in the 21st Century Preschool Children: A Systemic Review and Meta-Analysis. J. Evid. Based Dent. Pract. 2024, 24, 101992. [Google Scholar] [CrossRef]
  12. Yazdanbakhsh, E.; Bohlouli, B.; Patterson, S.; Amin, M. Community water fluoride cessation and rate of caries-related pediatric dental treatments under general anesthesia in Alberta, Canada. Can. J. Pub. Health 2024, 115, 305–314. [Google Scholar] [CrossRef] [PubMed]
  13. Iheozor-Ejiofor, Z.; Walsh, T.; Lewis, S.R.; Riley, P.; Boyers, D.; Clarkson, J.E.; Worthington, H.V.; Glenny, A.M.; O’Malley, L. Water fluoridation for the prevention of dental caries. Cochrane Database Syst. Rev. 2024, 10, CD010856. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  14. Abrams, S.; Beltran-Aguilar, E.; Martinez-Mier, E.A.; Kumar, J.; Slade, G.D.; Gooch, B. Water Fluoridation: Safety, Effectiveness and Value in Oral Health: A Symposium at the 2014 Annual Meeting of the American and Canadian Associations for Dental Research. J. Can. Dent. Assoc. 2015, 80, f16. [Google Scholar] [PubMed]
  15. Goodwin, M.; Walsh, T.; Whittaker, W.; Emsley, R.; Kelly, M.P.; Sutton, M.; Tickle, M.; Pretty, I.A. The CATFISH study: An evaluation of a water fluoridation program in Cumbria, UK. Community Dent. Oral Epidemiol. 2024, 52, 590–600. [Google Scholar] [CrossRef] [PubMed]
  16. Ismail, A.I.; Pitts, N.B.; Tellez, M.; Banerjee, A.; Deery, C.; Douglas, G.; Eggertsson, H.; Ekstrand, K.; Ellwood, R.; Gomez, J.; et al. The International Caries Classification and Management System (ICCMS™) An Example of a Caries Management Pathway. BMC Oral Health 2015, 15, 9–22. [Google Scholar] [CrossRef]
  17. Malcangi, G.; Patano, A.; Morolla, R.; De Santis, M.; Piras, F.; Settanni, V.; Mancini, A.; Di Venere, D.; Inchingolo, F.; Inchingolo, A.D.; et al. Analysis of Dental Enamel Remineralization: A Systematic Review of Technique Comparisons. Bioengineering 2023, 10, 472. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  18. Westphaln, K.K.; Regoeczi, W.; Masotya, M.; Vazquez-Westphaln, B.; Lounsbury, K.; McDavid, L.; Lee, H.L.; Johnson, J.; Ronis, S.D. From Arksey and O’Malley and Beyond: Customizations to enhance a team-based, mixed approach to scoping review methodology. Methods X 2021, 8, 101375. [Google Scholar] [CrossRef]
  19. Meyer, F.; Schulze Zur Wiesche, E.; Amaechi, B.T.; Limeback, H.; Enax, J. Caries Etiology and Preventive Measures. Eur. J. Dent. 2024, 18, 766–776. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  20. López-López, A.; Mira, A. Shifts in Composition and Activity of Oral Biofilms After Fluoride Exposure. Microb. Ecol. 2020, 80, 729–738. [Google Scholar] [CrossRef] [PubMed]
  21. Thurnheer, T.; Belibasakis, G.N. Effect of sodium fluoride on oral biofilm microbiota and enamel demineralization. Arch. Oral Biol. 2018, 89, 77–83. [Google Scholar] [CrossRef] [PubMed]
  22. Grohe, B.; Mittler, S. Advanced non-fluoride approaches to dental enamel remineralization: The next level in enamel repair management. Biomat. Biosyst. 2021, 4, 100029. [Google Scholar] [CrossRef] [PubMed]
  23. Cavazana, T.P.; Hosida, T.Y.; Pessan, J.P.; Sampaio, C.; Monteiro, D.R.; Delbem, A.C.B. Activity of sodium trimetaphosphate, associated or not with fluoride, on dual-species biofilms. Biofouling 2019, 35, 710–718. [Google Scholar] [CrossRef] [PubMed]
  24. Meyer, F.; Enax, J.; Epple, M.; Amaechi, B.T.; Simader, B. Cariogenic Biofilms: Development, Properties, and Biomimetic Preventive Agents. Dent. J. 2021, 9, 88. [Google Scholar] [CrossRef]
  25. Amarante, V.O.Z.; Delbem, A.C.B.; Sampaio, C.; de Morais, L.A.; de Camargo, E.R.; Monteiro, D.R.; Pessan, J.P.; Hosida, T.Y. Activity of Sodium Trimetaphosphate Nanoparticles on Cariogenic-Related Biofilms In Vitro. Nanomaterials 2022, 13, 170. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  26. Zen, I.; Delbem, A.C.B.; Martins, T.P.; de Morais, L.A.; Sampaio, C.; Hosida, T.Y.; Monteiro, D.R.; Pessan, J.P. Evaluation of Solutions Containing Fluoride, Sodium Trimetaphosphate, Xylitol, and Erythritol, Alone or in Different Associations, on Dual-Species Biofilms. Int. J. Mol. Sci. 2023, 24, 12910. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  27. Zhang, O.L.; Niu, J.Y.; Yin, I.X.; Yu, O.Y.; Mei, M.L.; Chu, C.H. Bioactive Materials for Caries Management: A Literature Review. Dent. J. 2023, 11, 59. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  28. Yu, O.Y.; Zhao, I.S.; Mei, M.L.; Lo, E.C.; Chu, C.H. Effect of Silver Nitrate and Sodium Fluoride with Tri-Calcium Phosphate on Streptococcus mutans and Demineralised Dentine. Int. J. Mol. Sci. 2018, 19, 1288. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  29. Zhou, P.; Garcia, B.L.; Kotsakis, G.A. Comparison of antibacterial and antibiofilm activity of bioactive glass compounds S53P4 and 45S5. BMC Microbiol. 2022, 22, 212–224. [Google Scholar] [CrossRef]
  30. Philip, N.; Leishman, S.J.; Bandara, H.M.H.N.; Walsh, L.J. Casein Phosphopeptide-Amorphous Calcium Phosphate Attenuates Virulence and Modulates Microbial Ecology of Saliva-Derived Polymicrobial Biofilms. Car. Res. 2019, 53, 643–649. [Google Scholar] [CrossRef] [PubMed]
  31. Sionov, R.V.; Tsavdaridou, D.; Aqawi, M.; Zaks, B.; Steinberg, D.; Shalish, M. Tooth mousse containing casein phosphopeptide-amorphous calcium phosphate prevents biofilm formation of Streptococcus mutans. BMC Oral Health 2021, 21, 136–146. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  32. Widyarman, A.S.; Udawatte, N.S.; Theodorea, C.F.; Apriani, A.; Richi, M.; Astoeti, T.E.; Seneviratne, C.J. Casein phosphopeptide-amorphous calcium phosphate fluoride treatment enriches the symbiotic dental plaque microbiome in children. J. Dent. 2021, 106, 103582. [Google Scholar] [CrossRef] [PubMed]
  33. Shaalan, O.; Fawzy El-Sayed, K.; Abouauf, E. Evaluation of the remineralization potential of self-assembling peptide P11-4 with fluoride compared to fluoride varnish in the management of incipient carious lesions: A randomized controlled clinical trial. Clin. Oral. Investig. 2024, 28, 438–448. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  34. Gayas, Z.; Azher, U.; Paul, S.T.; Selvan, A.; Reddy, C.D.; Raghu, D.; Uday, V. Comparative Evaluation of Antimicrobial Efficacy of Fluoride-Based and Self-Assembling Peptide P11-4-based Tooth Remineralization Agents on Streptococcus mutans: A Microbiological Study. Contemp. Clin. Dent. 2023, 14, 141–144. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  35. Schemehorn, B.R.; Wood, G.D.; Winston, A.E. Laboratory enamel solubility reduction and fluoride uptake from enamelon dentifrice. J. Clin. Dent. 1999, 10, 9–12. [Google Scholar] [PubMed]
  36. Reynolds, E.C. Calcium phosphate-based remineralization systems: Scientific evidence? Aust. Dent. J. 2008, 53, 268–273. [Google Scholar] [CrossRef] [PubMed]
  37. Yan, J.; Yang, H.; Luo, T.; Hua, F.; He, H. Application of Amorphous Calcium Phosphate Agents in the Prevention and Treatment of Enamel Demineralization. Front. Bioeng. Biotechnol. 2022, 10, 853436. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  38. Lippert, F.; Gill, K.K. Carious lesion remineralizing potential of fluoride- and calcium-containing toothpastes: A laboratory study. J. Am. Dent. Assoc. 2019, 150, 345–351. [Google Scholar] [CrossRef] [PubMed]
  39. Yang, Q.; Zheng, W.; Zhao, Y.; Shi, Y.; Wang, Y.; Sun, H.; Xu, X. Advancing dentin remineralization: Exploring amorphous calcium phosphate and its stabilizers in biomimetic approaches. Dent. Mater. 2024, 40, 1282–1295. [Google Scholar] [CrossRef]
  40. Buzalaf, M.A.R.; Pessan, J.P. New Preventive Approaches Part I: Functional Peptides and Other Therapies to Prevent Tooth Demineralization. Monogr. Oral. Sci. 2017, 26, 88–96. [Google Scholar] [CrossRef] [PubMed]
  41. Freire, I.R.; Pessan, J.P.; Amaral, J.G.; Martinhon, C.C.R.; Cunha, R.F.; Delbem, A.C.B. Anticaries effect of low-fluoride dentifrices with phosphates in children: A randomized, controlled trial. J. Dent. 2016, 50, 37–42. [Google Scholar] [CrossRef]
  42. Danelon, M.; Garcia, L.G.; Pessan, J.P.; Passarinho, A.; Camargo, E.R.; Delbem, A.C.B. Effect of Fluoride Toothpaste Containing Nano-Sized Sodium Hexametaphosphate on Enamel Remineralization: An in Situ Study. Caries Res. 2019, 53, 260–267. [Google Scholar] [CrossRef] [PubMed]
  43. Dipalma, G.; Inchingolo, A.D.; Guglielmo, M.; Morolla, R.; Palumbo, I.; Riccaldo, L.; Mancini, A.; Palermo, A.; Malcangi, G.; Inchingolo, A.M.; et al. Nanotechnology and Its Application in Dentistry: A Systematic Review of Recent Advances and Innovations. J. Clin. Med. 2024, 13, 5268. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  44. Takeshita, E.M.; Exterkate, R.A.M.; Delbem, A.C.B.; ten Cate, J.M. Evaluation of Different Fluoride Concentrations Supplemented with Trimetaphosphate on Enamel De- and Remineralization in vitro. Caries. Res. 2011, 45, 494–497. [Google Scholar] [CrossRef] [PubMed]
  45. Zaze, A.C.S.F.; Dias, A.P.; Sassaki, K.T.; Delbem, B.A.C. The effects of low-fluoride toothpaste supplemented with calcium glycerophosphate on enamel demineralization. Clin. Oral. Investig. 2014, 18, 1619–1624. [Google Scholar] [CrossRef]
  46. Camara, D.M.; Pessan, J.P.; Francati, T.M.; Souza, J.A.S.; Delbem, B.A.l. Fluoride toothpaste supplemented with sodium hexametaphosphate reduces enamel demineralization in vitro. Clin. Oral Investig. 2016, 20, 1981–1985. [Google Scholar] [CrossRef]
  47. Mohammadipour, H.S.; Maghrebi, Z.F.; Ramezanian, N.; Ahrari, F.; Daluyi, R.A. The effects of sodium hexametaphosphate combined with other remineralizing agents on the staining and microhardness of early enamel caries: An in vitro modified pH-cycling model. Dent. Res. J. 2019, 12, 398–406. [Google Scholar] [PubMed] [PubMed Central]
  48. Gonçalves, F.M.C.; Delbem, A.C.B.; Gomes, L.F.; Emerenciano, N.G.; Pessan, J.P.; Romero, G.D.A.; Cannon, M.L.; Danelon, M. Effect of fluoride, casein phosphopeptide-amorphous calcium phosphate and sodium trimetaphosphate combination treatment on the remineralization of caries lesions: An in vitro study. Arch. Oral. Biol. 2021, 122, 105001. [Google Scholar] [CrossRef] [PubMed]
  49. Nagata, M.E.; Delbem, A.C.B.; Báez-Quintero, L.C.; Danelon, M.; Sampaio, C.; Monteiro, D.R.; Wiegand, A.; Pessan, J.P. Effect of fluoride gels with nano-sized sodium trimetaphosphate on the in vitro remineralization of caries lesions. J. Appl. Oral Sci. 2023, 31, e20230155. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  50. Paiva, M.F.; Delbem, A.C.B.; Veri, I.V.; Sampaio, C.; Wiegand, A.; Pessan, J.P. Fluoride varnishes supplemented with nano-sized sodium trimetaphosphate reduce enamel erosive wear in vitro. J. Dent. 2023, 138, 104726. [Google Scholar] [CrossRef] [PubMed]
  51. Gonçalves, R.S.; Scaffa, P.M.C.; Giacomini, M.C.; Vidal, C.M.P.; Honório, H.M.; Wang, L. Sodium Trimetaphosphate as a Novel Strategy for Matrix Metalloproteinase Inhibition and Dentin Remineralization. Caries Res. 2018, 52, 189–198. [Google Scholar] [CrossRef] [PubMed]
  52. Gonçalves, R.S.; Candia Scaffa, P.M.; Giacomini, M.C.; Rabelo Buzalaf, M.A.; Honório, H.M.; Wang, L. Use of sodium trimetaphosphate in the inhibition of dentin matrix metalloproteinases and as a remineralizing agent. J. Dent. 2018, 68, 34–40. [Google Scholar] [CrossRef] [PubMed]
  53. Nunes, G.P.; Danelon, M.; Pessan, J.P.; Capalbo, L.C.; Junior, N.A.N.; Matos, A.A.; Souza, J.A.S.; Buzalaf, M.A.R.; Delbem, A.C.B. Fluoride and trimetaphosphate association as a novel approach for remineralization and antiproteolytic activity in dentin tissue. Arch. Oral Biol. 2022, 142, 105508. [Google Scholar] [CrossRef] [PubMed]
  54. Karlinsey, R.L.; Mackey, A.C.; Walker, E.R.; Frederick, K.E. Preparation, characterization and in vitro efficacy of an acid-modified β-TCP material for dental hard-tissue remineralization. Acta Biomater. 2010, 6, 969–978. [Google Scholar] [CrossRef]
  55. Chen, K.J.; Gao, S.S.; Duangthip, D.; Lo, E.C.M.; Chu, C.H. Randomized Clinical Trial on Sodium Fluoride with Tricalcium Phosphate. J. Dent. Res. 2021, 100, 66–73. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  56. Chen, J.; Zhang, Y.; Yin, I.X.; Yu, O.Y.; Chan, A.K.Y.; Chu, C.H. Preventing Dental Caries with Calcium-Based Materials: A Concise Review. Inorganics 2024, 12, 253. [Google Scholar] [CrossRef]
  57. Salamara, O.; Papadimitriou, A.; Mortensen, D.; Twetman, S.; Koletsi, D.; Gizani, S. Effect of fluoride varnish with functionalized tri-calcium phosphate on post-orthodontic white spot lesions: An investigator-blinded controlled trial. Quintessence Int. 2020, 51, 854–862. [Google Scholar] [CrossRef] [PubMed]
  58. Bhat, D.V.; Awchat, K.L.; Singh, P.; Jha, M.; Arora, K.; Mitra, M. Evaluation of Remineralizing Potential of CPP-ACP, CPP-ACP + F and β TCP + F and Their Effect on Microhardness of Enamel Using Vickers Microhardness Test: An In Vitro Study. Int. J. Clin. Pediatr. Dent. 2022, 15, 221–225. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  59. Handa, A.; Chengappa, D.; Sharma, P.; Handa, J.K. Effectiveness of Clinpro Tooth Crème in comparison with MI Varnish with RECALDENT™ for treatment of white spot lesions: A randomized controlled trial. Clin. Oral Investig. 2023, 27, 1473–1481. [Google Scholar] [CrossRef] [PubMed]
  60. Alexandrino, L.D.; de Melo Alencar, C.; Silva da Silveira, A.D.; Alves, E.B.; Silva, C.M. Randomized clinical trial of the effect of NovaMin and CPP-ACPF in combination with dental bleaching. J. Appl. Oral. Sci. 2017, 25, 335–340. [Google Scholar] [CrossRef]
  61. Khijmatgar, S.; Reddy, U.; John, S.; Badavannavar, A.N.; Souza, D.T. Is there evidence for Novamin application in remineralization?: A Systematic review. J. Oral Biol. Craniofac. Res. 2020, 10, 87–92. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  62. Joshi, S.; Vaidya, N.; Gupta, B.; Pustake, B.; Shinde, G.; Pharande, S. A Comparative Evaluation of Arginine Complex Combined With Flouride and Two Standard Non-Fluoridated Remineralizing Agents: An In Vitro Study. Cureus 2024, 16, e60118. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  63. Reema, S.; Lahiri, P.; Roy, S. Review of Casein Phosphopeptides-Amorphous Calcium Phosphate. Chin. J. Dent. Res. 2014, 17, 7–14. [Google Scholar] [PubMed]
  64. Sleibi, A.; Tappuni, A.R.; Baysan, A. Reversal of Root Caries with Casein Phosphopeptide-Amorphous Calcium Phosphate and Fluoride Varnish in Xerostomia. Car. Res. 2021, 55, 475–484. [Google Scholar] [CrossRef] [PubMed]
  65. Curtis, C.; Qian, F.; Bowers, R.D. CPP-ACP paste’s effect on salivary conditions in patients with removable dentures. J. Prosthodont. 2024, 33, 427–435. [Google Scholar] [CrossRef] [PubMed]
  66. Leite, K.L.F.; Martins, M.L.; Monteiro, A.S.N.; Vieira, T.I.; Alexandria, A.K.; Rocha, G.M.; Fonseca-Gonçalves, A.; Pithon, M.M.; Cavalcanti, Y.W.; Maia, L.C. In-vitro effect of a single application of CPP-ACP pastes and different fluoridated solutions on the prevention of dental caries around orthodontic brackets. Dent. Press J. Orthod. 2024, 28, e2321383. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  67. Sitthisettapong, T.; Phantumvanit, P.; Huebner, C.; Derouen, T. Effect of CPP-ACP paste on dental caries in primary teeth: A randomized trial. J. Dent. Res. 2012, 91, 847–852. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  68. Oliveira, G.M.; Ritter, A.V.; Heymann, H.O.; Swift, E., Jr.; Donovan, T.; Brock, G.; Wright, T. Remineralization effect of CPP-ACP and fluoride for white spot lesions in vitro. J. Dent. 2014, 42, 1592–1602. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  69. Bhadoria, N.; Gunwal, M.K.; Kukreja, R.; Maran, S.; Devendrappa, S.N.; Singla, S. An In Vitro Evaluation of Remineralization Potential of Functionalized Tricalcium Phosphate Paste and CPP-ACPF on Artificial White Spot Lesion in Primary and Permanent Enamel. Int. J. Clin. Pediatr. Dent. 2020, 13, 579–584. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  70. Basheer, B.; Alqahtani, A.A.; Abdullah Alowairdhi, A.; Nuri Alohali, S. Analyzing the Effectiveness of Different Delivery Methods for Remineralization Agents in Pediatric Dental Health: A Systematic Review. Cureus 2024, 16, e76577. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  71. Llena, C.; Leyda, A.M.; Forner, L. CPP-ACP and CPP-ACFP versus fluoride varnish in remineralisation of early caries lesions. A prospective study. Eur. J. Paediatr. Dent. 2015, 16, 181–186. [Google Scholar] [PubMed]
  72. Pithon, M.M.; Dos Santos, M.J.; Andrade, C.S.; Leão Filho, J.C.; Braz, A.K.; de Araujo, R.E.; Tanaka, O.M.; Fidalgo, T.K.; Dos Santos, A.M.; Maia, L.C. Effectiveness of varnish with CPP-ACP in prevention of caries lesions around orthodontic brackets: An OCT evaluation. Eur. J. Orthod. 2015, 37, 177–182. [Google Scholar] [CrossRef] [PubMed]
  73. Savas, S.; Kavrìk, F.; Kucukyìlmaz, E. Evaluation of the remineralization capacity of CPP-ACP containing fluoride varnish by different quantitative methods. J. Appl. Oral Sci. 2016, 24, 198–203. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  74. Wierichs, R.J.; Stausberg, S.; Lausch, J.; Meyer-Lueckel, H.; Esteves-Oliveira, M. Caries-Preventive Effect of NaF, NaF plus TCP, NaF plus CPP-ACP, and SDF Varnishes on Sound Dentin and Artificial Dentin Caries in vitro. Car. Res. 2018, 52, 199–211. [Google Scholar] [CrossRef] [PubMed]
  75. Varma, V.; Hegde, K.S.; Bhat, S.S.; Sargod, S.S.; Rao, H.A. Comparative Evaluation of Remineralization Potential of Two Varnishes Containing CPP-ACP and Tricalcium Phosphate: An In Vitro Study. Int. J. Clin. Pediatr. Dent. 2019, 12, 233–236. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  76. Attiguppe, P.; Malik, N.; Ballal, S.; Naik, S.V. CPP-ACP and Fluoride: A Synergism to Combat Caries. Int. J. Clin. Pediatr. Dent. 2019, 12, 120–125. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  77. Akgun, O.M.; Haman Bayari, S.; Ide, S.; Guven Polat, G.; Yildirim, C.; Orujalipoor, I. Evaluation of the protective effect on enamel demineralization of CPP-ACP paste and ROCS by vibrational spectroscopy and SAXS: An in vitro study. Microsc. Res. Tech. 2021, 84, 2977–2987. [Google Scholar] [CrossRef] [PubMed]
  78. Altınışık, H.; Kedici Alp, C. Evaluation of Enamel Surfaces Treated with a Desensitizing Agent Containing CPP-ACP Before or After In-Office Bleaching. Int. J. Period. Rest. Dent. 2023, 7, 18–25. [Google Scholar] [CrossRef] [PubMed]
  79. Almansouri, N.; Bakry, A.S.; Abbassy, M.A.; Linjawi, A.I.; Hassan, A.H. Evaluation of Resin Infiltration, Fluoride and the Biomimetic Mineralization of CPP-ACP in Protecting Enamel after Orthodontic Inter-Proximal Enamel Reduction. Biomimetics 2023, 8, 82. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  80. Erkmen Almaz, M.; Ulusoy, N.B.; Akbay Oba, A.; Dokumaci, A. Remineralization effect of NaF, NaF with TCP, NaF with CPP-ACP and NaF with CXP varnishes on newly erupted first permanent molars: A randomized controlled trial. Int. J. Dent. Hyg. 2024, 22, 703–710. [Google Scholar] [CrossRef] [PubMed]
  81. Al-Nerabieah, Z.; AlKhouli, M.; Dashash, M. Preventive efficacy of 38% silver diamine fluoride and CPP-ACP fluoride varnish on molars affected by molar incisor hypomineralization in children: A randomized controlled trial. F1000Research 2024, 12, 1052–1088. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  82. Rechmann, P.; Bekmezian, S.; Rechmann, B.M.T.; Chaffee, B.W.; Featherstone, J.D.B. MI Varnish and MI Paste Plus in a caries prevention and remineralization study: A randomized controlled trial. Clin. Oral. Investig. 2018, 22, 2229–2239. [Google Scholar] [CrossRef] [PubMed]
  83. Enax, J.; Amaechi, B.T.; Farah, R.; Liu, J.A.; Schulze Zur Wiesche, E.; Meyer, F. Remineralization Strategies for Teeth with Molar Incisor Hypomineralization (MIH): A Literature Review. Dent. J. 2023, 11, 80. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  84. İlisulu, S.C.; Gürcan, A.T.; Şişmanoğlu, S. Remineralization efficiency of three different agents on artificially produced enamel lesions: A micro-CT study. J. Esthet. Restor. Dent. 2024, 36, 1536–1546. [Google Scholar] [CrossRef] [PubMed]
  85. Silvertown, J.D.; Wong, B.P.Y.; Sivagurunathan, K.S.; Abrams, S.H.; Kirkham, J.; Amaechi, B.T. Remineralization of natural early caries lesions in vitro by P11 -4 monitored with photothermal radiometry and luminescence. J. Investig. Clin. Dent. 2017, 8, e12257. [Google Scholar] [CrossRef] [PubMed]
  86. Shetty, S.S.; Nekkanti, S. Remineralization Potential of a Novel Biomimetic Material (Self-assembling Peptide P11-4) on Early Enamel Caries: An In Vitro Study. J. Contemp. Dent. Pract. 2023, 24, 181–187. [Google Scholar] [CrossRef] [PubMed]
  87. Alkilzy, M.; Qadri, G.; Splieth, C.H.; Santamaría, R.M. Biomimetic Enamel Regeneration Using Self-Assembling Peptide P11-4. Biomimetics 2023, 8, 290. [Google Scholar] [CrossRef]
  88. Inces, G.S.; Ermisr, B.R. The in situ potential of synthetic nano-hydroxyapatite for tooth enamel repair. Bioinsp. Biomim. Nanobiomat. 2021, 10, 78–86. [Google Scholar] [CrossRef]
  89. Pushpalatha, C.; Gayathri, V.S.; Sowmya, S.V.; Augustine, D.; Alamoudi, A.; Zidane, B.; Hassan Mohammad Albar, N.; Bhandi, S. Nanohydroxyapatite in dentistry: A comprehensive review. Saudi Dent. J. 2023, 35, 741–752. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  90. Pepla, E.; Besharat, L.K.; Palaia, G.; Tenore, G.; Migliau, G. Nano-hydroxyapatite and its applications in preventive, restorative and regenerative dentistry: A review of literature. Ann. Stomatol. 2014, 5, 108–114. [Google Scholar] [CrossRef]
  91. Florea, A.-D.; Pop, L.C.; Benea, H.-R.-C.; Tomoaia, G.; Racz, C.-P.; Mocanu, A.; Dobrota, C.-T.; Balint, R.; Soritau, O.; Tomoaia-Cotisel, M. Remineralization Induced by Biomimetic Hydroxyapatite Toothpastes on Human Enamel. Biomimetics 2023, 8, 450. [Google Scholar] [CrossRef]
  92. Alajlan, S.; Baysan, A. The effect of nano-hydroxyapatite on white spot lesions: A systematic review and meta-analysis. J. Dent. 2024, 151, 105402. [Google Scholar] [CrossRef] [PubMed]
  93. O’Hagan-Wong, K.; Enax, J.; Meyer, F.; Ganss, B. The use of hydroxyapatite toothpaste to prevent dental caries. Odontol. 2022, 110, 223–230. [Google Scholar] [CrossRef] [PubMed]
  94. Paszynska, E.; Pawinska, M.; Enax, J.; Meyer, F.; Schulze zur Wiesche, E.; May, T.W.; Amaechi, B.T.; Limeback, H.; Hernik, A.; Otulakowska-Skrzynska, J.; et al. Caries-preventing effect of a hydroxyapatite-toothpaste in adults: A 18-month double-blinded randomized clinical trial. Front. Public Health 2023, 11, 1199728. [Google Scholar] [CrossRef] [PubMed]
  95. Amaechi, B.T.; Farah, R.; Liu, J.A.; Phillips, T.S.; Perozo, B.I.; Kataoka, Y.; Meyer, F.; Enax, J. Remineralization of molar incisor hypomineralization (MIH) with a hydroxyapatite toothpaste: An in-situ study. BDJ Open 2022, 8, 33–43. [Google Scholar] [CrossRef]
  96. Carey, C.M. Remineralization of Early Enamel Lesions with Apatite-Forming Salt. Dent. J. 2023, 11, 182. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  97. Fontana, M.; Gonzalez-Cabezas, C.; Tenuta, L. Evidence-based approaches and considerations for nonrestorative treatments within modern caries management. JADA 2024, 155, 1000–1011. [Google Scholar] [CrossRef]
  98. Pawinska, M.; Paszynska, E.; Amaechi, B.T.; Meyer, F.; Enax, J.; Limeback, H. Clinical evidence of caries prevention by hydroxyapatite: An updated systematic review and meta-analysis. J. Dent. 2024, 151, 105429. [Google Scholar] [CrossRef] [PubMed]
Oral 05 00047 g001
Figure 1. The PRISMA 2020 flow diagram used in the scoping review.
Figure 1. The PRISMA 2020 flow diagram used in the scoping review.
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MDPI and ACS Style

Gudkina, J.; Amaechi, B.T.; Abrams, S.H.; Brinkmane, A. Can New Remineralizing Agents Serve as Fluoride Alternatives in Caries Prevention? A Scoping Review. Oral 2025, 5, 47. https://doi.org/10.3390/oral5030047

AMA Style

Gudkina J, Amaechi BT, Abrams SH, Brinkmane A. Can New Remineralizing Agents Serve as Fluoride Alternatives in Caries Prevention? A Scoping Review. Oral. 2025; 5(3):47. https://doi.org/10.3390/oral5030047

Chicago/Turabian Style

Gudkina, Jekaterina, Bennett T. Amaechi, Stephen H. Abrams, and Anda Brinkmane. 2025. "Can New Remineralizing Agents Serve as Fluoride Alternatives in Caries Prevention? A Scoping Review" Oral 5, no. 3: 47. https://doi.org/10.3390/oral5030047

APA Style

Gudkina, J., Amaechi, B. T., Abrams, S. H., & Brinkmane, A. (2025). Can New Remineralizing Agents Serve as Fluoride Alternatives in Caries Prevention? A Scoping Review. Oral, 5(3), 47. https://doi.org/10.3390/oral5030047

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