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Comparative evaluation of biomaterial-based and fluoride toothpastes for enamel remineralization: a PRISMA-compliant systematic review
1Department of Dentistry, Cardenal Herrera-CEU University, 46115 Valencia, Spain
2Department of Operative Dentistry, Tohoku Graduate School of Dentistry, Tohoku University, 980-8575 Sendai, Japan
3Clinical Sciences Department, Centre of Medical and Bio-Allied Health Science Research, College of Dentistry, Ajman University, P.O. Box 346, Ajman, United Arab Emirates
4Department of Therapeutic Dentistry, I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
*Corresponding Author(s):v.venkataiah@ajman.ac.ae (Venkata Suresh Venkataiah); salvatore.sauro@uchceu.es (Salvatore Sauro)
| History | Submitted: 30 October 2025 | Accepted: 09 February 2026 | Published: 03 July 2026 |
| Copyright: | ©2026 The Author(s). Published by MRE Press. |
Background: Fluoride remains the benchmark for caries prevention due to its well-established capacity to enhance enamel remineralization. However, growing concerns regarding fluoride overexposure have stimulated interest in biomaterial-based alternatives. Ingredients such as calcium phosphate derivatives, nano-hydroxyapatite (nHAP), casein phosphopeptide–amorphous calcium phosphate (CPP-ACP), calcium silicate, and bioactive glass (BG) have been proposed to support enamel repair through biomimetic or ion-releasing mechanisms. Methods: This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review searched PubMed, ScienceDirect, EBSCO, and LILACS for studies published between January 2020 and March 2025 comparing biomaterial-based toothpastes with conventional fluoride formulations using human permanent teeth. Eligible in vitro, in situ, and in vivo studies were screened independently in duplicate. The risk of bias was assessed using Faggion’s checklist for in vitro studies and the Cochrane Risk of Bias (RoB) 2 tool for in vivo and in situ studies. Results: Of 294 records identified, 11 studies met the inclusion criteria. Biomaterials evaluated included calcium silicate, calcium phosphate derivatives, nano-hydroxyapatite, CPP-ACP, and bioactive glass. Several biomaterial formulations demonstrated remineralization outcomes comparable to fluoride under controlled experimental conditions. Some fluoride–biomaterial combinations have been suggested to exhibit potential synergistic effects. However, interpretation is limited by substantial methodological heterogeneity, short intervention periods, and a limited number of well-designed in vivo trials. Conclusions: Biomaterial-based toothpastes show promise as adjuncts or potential alternatives to fluoride for enamel remineralization. Nonetheless, the current evidence base is dominated by in vitro and short-term in situ studies. High-quality, long-term in vivo trials are required to establish clinical effectiveness and inform evidence-based preventive strategies. The PROSPERO registration: The protocol for this systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420251027747.
Cite this article
Wei-Chung Hsueh, Po-Kai Huang, Anika Renee Toothman, Rebecca May Wilkinson, Pei-Jung Wu, Deepak Mehta, Venkata Suresh Venkataiah, Salvatore Sauro. Comparative evaluation of biomaterial-based and fluoride toothpastes for enamel remineralization: a PRISMA-compliant systematic review. Journal of Clinical Pediatric Dentistry. 2026; 50(4): 45-53. doi: 10.22514/jocpd.2026.090
1. Introduction
Oral diseases affect nearly 3.5 billion people worldwide, with untreated dental caries representing the most common condition and affecting over a quarter of the global population [1]. Dental caries is a multifactorial disease influenced by socioeconomic, behavioral, biological, and dietary factors, with high sugar intake being the most significant modifiable risk [2, 3]. These determinants interact with local factors, such as frequent exposure to fermentable carbohydrates, acidogenic biofilm, inadequate oral hygiene, reduced salivary flow, and limited fluoride availability, to drive sustained demineralization. When pathological processes outweigh natural protective mechanisms like salivary buffering and remineralization, early enamel lesions develop [4]. Such lesions remain reversible with appropriate preventive measures, including regular toothbrushing [5].
Dentin hypersensitivity, which affects nearly 30% of the population, is another condition linked to demineralization or exposed dentinal tubules [6]. Its management often relies on agents that promote mineral deposition or occlude tubules [7].
Toothbrushing remains central to plaque control—the primary etiological factor for both caries and periodontal disease [8, 9]. Fluoride-containing toothpastes are considered the gold standard for caries prevention because of their ability to inhibit demineralization, promote remineralization, and exert antibacterial effects [10, 11]. Nevertheless, concerns regarding excessive fluoride exposure—including dental and skeletal fluorosis—highlight the need for effective fluoride-sparing or fluoride-free alternatives [12, 13, 14].
Several biomaterial-based agents have emerged as potential substitutes [15]. Calcium phosphate derivatives increase calcium and phosphate availability for remineralization [15, 16], nano-hydroxyapatite (nHAP) mimics the natural enamel apatite structure [16, 17], bioactive glass (BG) releases mineral ions that form a hydroxycarbonate apatite layer [17], and casein phosphopeptide (CPP) stabilizes calcium ions more efficiently than salivary proteins [18]. These biomaterials offer biologically compatible mechanisms that may support enamel repair.
Despite growing interest in these alternatives, there is limited consolidated evidence comparing their remineralization performance with that of conventional fluoride toothpastes across in vitro, in situ, and in vivo models. Therefore, this systematic review aimed to evaluate and compare the remineralizing potential of biomaterial-based toothpastes versus fluoride formulations to inform evidence-based strategies for preventive oral care.
2. Materials and methods
2.1 Overview
This systematic review was designed per the guidelines of PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [19]. The completed PRISMA 2020 checklist is provided as Supplementary material 1. The protocol for this systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD420251027747. The research question was developed using the Population, Intervention, Comparator, Outcomes, and Study Design (PICOS) framework, where the population included demineralized human permanent teeth studied under in vitro, in vivo, or in situ conditions. The intervention of interest was biomaterial-based toothpaste formulations, compared against conventional fluoride-based toothpastes. The primary outcome evaluated was the remineralization capacity of the intervention. Studies of any design that addressed these criteria were considered eligible for inclusion.
2.2 Eligibility criteria
Studies were included in this review if they investigated the remineralization potential of toothpaste formulations using permanent human teeth under in vitro, in vivo, or in situ conditions. Only studies published in English between January 2020 and March 2025 with full-text availability were considered. Exclusion criteria were defined to maintain focus on the core objective. Studies were excluded if they did not conform to the predefined PICOS framework, lacked clarity in the intervention or evaluation methods description, or primarily focused on properties, such as toxicity or adhesion, unrelated to remineralization. To minimize potential commercial bias, studies authored by individuals with direct affiliations to toothpaste manufacturers or studies reporting undisclosed industry funding were excluded. This approach reduces the influence of conflicts of interest, but may also limit the inclusion of some relevant datasets. The eligibility criteria are summarized in Table 1.
| Criterion Type | Description |
| Population | Permanent human teeth (in vitro, in vivo, or in situ) |
| Intervention | Biomaterial-based toothpaste formulations |
| Comparator | Conventional fluoride toothpaste |
| Outcome | Remineralization capacity |
| Language | English |
| Publication Date | January 2020 to March 2025 |
| Exclusions | Studies focusing on toxicity, adhesion, or non-remineralizing properties; unclear methodology; brand-affiliated authorship; undisclosed funding |
2.3 Data sources and search strategy
In April 2025, a comprehensive electronic search was conducted across four databases: PubMed, ScienceDirect, EBSCO, and LILACS. The search strategy employed a combination of controlled vocabulary (where applicable) and free-text terms, including “remineralization”, “toothpastes”, “fluorides”, and “biomaterial-based toothpaste”, linked using Boolean operators AND & OR. The full search syntax for each database is detailed in Supplementary Table 1.
The search was restricted to studies published in English, with full text available, and within the January 2020 to March 2025 publication window. All retrieved citations were exported to the reference management software Zotero for organization and duplicate removal. Following deduplication, a three-stage screening process was undertaken: initial title screening and abstract and full-text evaluations. Articles meeting the inclusion criteria were retained for qualitative synthesis and, where applicable, quantitative analysis.
2.4 Selection of studies
The selection process was conducted in three sequential stages: title screening, abstract review, and full-text evaluation. All records retrieved through database searches were initially imported into Zotero, and duplicate entries were identified and removed. Two reviewers (WCH and PKH) independently screened the titles of the remaining articles to assess their potential relevance. Articles that appeared eligible or unclear based on the title alone were then screened for the abstract. The same two reviewers then independently assessed the abstracts to determine whether they aligned with the predefined eligibility criteria. Any discrepancies or uncertainties during this stage were resolved through discussion or consultation with a third reviewer (SS). Full-text versions of potentially eligible studies were retrieved and thoroughly evaluated against the inclusion and exclusion criteria. Studies meeting all criteria were selected for final inclusion in the review and entered into the data extraction and risk-of-bias assessment phases.
2.5 Data extraction
Data from the included studies were extracted independently by two reviewers using a standardized and pre-piloted data extraction form. Extracted information included the first author’s name, year of publication, country of origin, study design (in vitro, in vivo, or in situ), type and number of samples used, description of the test and control toothpaste formulations, intervention protocols, outcome assessment methods, and key findings related to remineralization capacity. Particular attention was given to the type of the biomaterial incorporated in the test formulations, the presence and concentration of fluoride, and the specific remineralization metrics used (such as surface microhardness, lesion depth, or mineral content analysis). Any discrepancies between the reviewers during the extraction process were resolved through discussion, and when necessary, by involving a third reviewer.
2.6 Risk-of-bias assessments
Two assessors (WCH and PKH) independently assessed the methodological quality of the included studies, using tools appropriate to each study type. For in vitro studies, the Faggion’s checklist was employed. This tool evaluates six key domains across the study sections—abstract, methods, results, discussion, and other relevant information—to determine potential bias.
For in vivo and in situ studies, the Cochrane Risk of Bias Tool (RoB 2) was applied. This tool assesses bias across seven domains, including the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of reported results. Each domain was judged as presenting “low risk of bias”, “some concerns”, or “high risk of bias”. Any assessor disagreements were resolved through discussion and, if needed, consensus with the other authors.
3. Results
3.1 Study selection
The database search identified 294 records related to toothpastes containing remineralizing agents. After screening titles and abstracts, 45 studies underwent full-text assessment. Eleven studies met the predefined eligibility criteria and were included in the final review. The study selection process is summarized in the PRISMA flow diagram (Fig. 1).
Fig. 1.PRISMA flow diagram.
3.2 Characteristics of included studies
The included studies evaluated various biomaterials—including calcium phosphate derivatives, calcium silicate, hydroxyapatite (HAP), casein phosphopeptide–amorphous calcium phosphate (CPP-ACP), and bioactive glass—compared against conventional fluoride-containing toothpastes. Study designs comprised in vitro, in situ, and in vivo approaches using human permanent teeth, enamel slabs, or dentine specimens. Key characteristics, intervention protocols, and outcome measures are presented in Table 2 (Ref. [20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30]).
| Study | Design | Sample | Material | Outcome Measure | Follow-up | Best Material | Main Outcome |
| Cagetti et al. [20] (2022) | In vivo | 306 children (HAF = 152; NaF = 154) | HAF (1450 ppm), NaF (1450 ppm) | ICDAS | 12 and 24 mon | HAF | After two years, HAF showed significantly lower caries risk than NaF. |
| Ashour et al. [21] (2021) | In vivo | 51 participants (n = 17/group) | CPP-ACP, CPP-ACFP, fluoridated toothpaste | VistaCam, pH meter, ion electrode | T1 to T6 (6 mon) | CPP-ACFP | CPP-ACFP showed highest remineralization, pH improvement, and fluoride release. |
| Farooq et al. [22] (2021) | In vitro | 72 premolars (n = 24/group) | Distilled water, NaF (1450 ppm), BG-F (530 ppm) | VHN, Ra, Micro-CT | 1 cycle | BG-F | BG-F group had highest Vickers hardness and lowest surface roughness. |
| Ionescu et al. [23] (2022) | In vitro | 18 extracted wisdom teeth (n = 36 slices) | F-HAP + MgSrCHA-Chi, ZnCHA, NaF (1450 ppm) | SEM, EDX | 1 wk | F-HAP + MgSrCHA-Chi, ZnCHA | All except NaF showed enamel remineralization and dentin occlusion. |
| Li et al. [24] (2020) | In vitro | Coronal dentine (n = 3) | CSSP (1450 ppm), NaF (1450 ppm) | SEM, EDX, TEM, SAED | 2–14 cycles | CSSP | CSSP fully occluded dentinal tubules and formed hydroxyapatite layer. |
| Buzalaf et al. [25] (2021) | In vitro | 48 human third molars | Non-fluoride, NaF (1450 ppm), CaSi (1450 ppm MFP) | Contact profilometry | 3 and 7 d | CaSi | CaSi toothpaste showed significantly better enamel protection than NaF and non-fluoride. |
| Amaechi et al. [26] (2022) | In situ | 15 patients, 60 MIH enamel blocks | 20% HAP, NaF (1450 ppm) | Micro-CT | 14 d | HAP | HAP group had higher remineralization than NaF for MIH lesions. |
| Guntermann et al. [27] (2022) | In vitro | 19 wisdom teeth | Untreated, acid only, fluoride-free HAP, amine fluoride (1400 ppm), fluoride- and HAP-free | SEM | 1 cycle | Amine fluoride | Fluoride toothpaste showed best remineralization and protection after demineralization. |
| de Oliveira et al. [28] (2022) | In situ | 10 adults; 160 enamel slabs (n = 20/group) | Silica (no F), CPP-ACP, CPP-ACP + NaF (900 ppm), NaF (1100 ppm) | KHN, %SH | 10 d | CPP-ACP + NaF, NaF | Both treatments showed significant hardness recovery. |
| Chen et al. [29] (2023) | In vitro | 23 extracted teeth (n = 15 root segments) | BG-F (540 ppm), 1450 ppm F, 5000 ppm F, deionized water | ICP-OES, KHN, XRD, 19F-MAS-NMR, F-ISE | 13 d | BG-F | BG-F showed higher Ca and P ion release; 1450 F and 5000 F had more fluorapatite formation. |
| Chen et al. [30] (2024) | In vitro | 3 extracted teeth (n = 3) | BG (540 ppm), NaF (1450, 5000 ppm), deionized water | XMT, SEM, 19F-MAS-NMR | 13 d | BG (540 ppm) | BG showed mineral gain and fluoride apatite formation; NaF caused subsurface loss. |
d: day; mon: month; wk: week; NaF: Sodium fluoride; CaSi: Calcium silicate; HAF: Fluoride-substituted hydroxyapatite; BG: Bioactive glass; CSSP: Calcium silicate and sodium phosphate; HAF + MgSrCHA-Chi: Fluoride-hydroxyapatite, Magnesium-Strontium-Carbonate Hydroxyapatite conjugated with Chitosan; ZnCHA: Zinc carbonate hydroxyapatite; CPP-ACFP: Casein Phosphopeptide–Amorphous Calcium Fluoride Phosphate; HAP: Hydroxyapatite; ICDAS: International Caries Detection and Assessment System; KHN: Knoop hardness test; F-ISE: Fluoride-Ion Selective Electrode; ICP-OES: Inductively Coupled Plasma-Optical Emission Spectroscopy; XRD: X-ray Diffraction; 19F-MAS-NMR: 19F Magic Angle Spinning-Nuclear Magnetic Resonance Spectroscopy; SEM: Scanning Electron Microscopy; EDX: Energy Dispersive X-ray Spectroscopy; TEM: Transmission Electron Microscopy; SAED: Selected Area Electron Diffraction; Ra: Surface Roughness; micro-CT: Micro-Computed Tomography; VistaCam: Light-Induced Fluorescence Intraoral Camera; XMT: X-ray Microtomography; %SH: Microhardness Recovery; ACP: amorphous calcium phosphate; MFP: Monofluorophosphate; VHN: Vickers Hardness Number; MIH: Molar Incisor Hypomineralization. |
The methodological quality of in vitro studies was assessed using Faggion’s checklist [31], which evaluates reporting transparency, procedural detail, and analytical rigor (Supplementary Table 2, Ref. [22, 23, 24, 25, 26, 27, 28, 29, 30]). Most studies met several quality criteria, although information on randomization, allocation concealment, and blinding—typically rare in laboratory designs—was commonly missing.
Two studies were randomized controlled trials [20, 21] and were evaluated using the Cochrane RoB 2 tool [32]. Both trials demonstrated low risk of bias across key domains, including randomization process, blinding where applicable, completeness of outcome data, and selective reporting (Table 3, Ref. [20, 21]).
| Study | Random sequence generation (selection bias) | Allocation concealment (selection bias) | Blinding of participants and personnel (performance bias) | Blinding of outcome assessment (detection bias) | Incomplete outcome data (attrition bias) | Selective reporting (reporting bias) | Other bias |
| Cagetti Maria Grazia et al. [20] (2022) | Low | Low | Some concern | Some concern | Low | Low | Low |
| Ashour Doaa Gamal, et al. [21] (2021) | Low | Low | Low | Low | Low | Low | Low |
3.3 Qualitative synthesis of findings
3.3.1 Calcium phosphate derivatives
Calcium phosphate forms the primary inorganic structure of enamel [33]. During demineralization, replenishment of calcium and phosphate ions is essential for enamel repair [34, 35]. Ionescu et al. [23] reported that calcium phosphate nanoparticles induced epitaxial mineral growth on demineralized enamel surfaces, forming a crystallographic pattern resembling native hydroxyapatite—an effect less evident in sodium fluoride controls. These findings indicate that nano-scaled calcium phosphate formulations may achieve remineralization outcomes comparable to fluoride under controlled laboratory conditions. However, limited in vivo validation restricts conclusions regarding clinical performance.
3.3.2 Calcium silicate derivatives
Calcium silicate (CaSi) promotes hydroxyapatite formation on both eroded and sound enamel surfaces [24, 36]. Li et al. [24] observed that CaSi–sodium phosphate (CSSP) toothpaste occluded dentinal tubules more effectively than 1450 ppm fluoride, supported by focused ion beam-TEM (Transmission Electron Microscopy) and SAED (Selected Area Electron Diffraction) evidence of intratubular HAP formation. Buzalaf et al. [25] reported greater protection against enamel erosion with CaSi toothpaste than with fluoride after short-term exposure. Although these in vitro findings suggest that CaSi can perform as well as, or better than, fluoride in specific experimental setups, the absence of long-term or in vivo data limits generalizability.
3.3.3 Hydroxyapatite (HAP)
Hydroxyapatite is widely recognized for its biocompatibility and structural similarity to natural enamel [37]. Amaechi et al. [26] demonstrated that a 20% micro-HAP toothpaste improved remineralization of MIH (Molar Incisor Hypomineralization) lesions more than 1450 ppm fluoride in situ. Ionescu et al. [23] also found that HAP-based formulations produced a uniform remineralized layer resembling native tissue, with performance comparable to fluoride. In a clinical study, Cagetti et al. [20] reported a reduction in caries incidence among children after prolonged use of HAP toothpaste. However, Guntermann et al. [27] presented divergent findings, noting that fluoride outperformed HAP in initial and repeated remineralization cycles in vitro. Collectively, evidence indicates that HAP can produce remineralization outcomes similar to fluoride, but the relative effectiveness varies across lesion types, concentrations, and experimental conditions.
3.3.4 Casein phosphopeptide–amorphous calcium phosphate (CPP-ACP)
CPP-ACP stabilizes calcium and phosphate ions at the tooth surface, supporting remineralization [38]. Ionescu et al. [23] reported that CPP-ACP induced remineralization, but was less effective than nanohydroxyapatite. In situ findings by de Oliveira et al. [28] showed that both CPP-ACP and CPP-ACP combined with fluoride (CPP-ACFP) increased enamel microhardness, with CPP-ACFP performing similarly to 1100 ppm NaF toothpaste. Ashour et al. [21] showed that CPP-ACP alone had a limited effect, whereas its combination with fluoride improved white-spot lesion progression and salivary pH. These results suggest that CPP-ACP is an effective adjunct, but its performance is more variable than HAP or CaSi, and it appears to benefit substantially from co-administration with fluoride.
3.3.5 Bioactive glass
Bioactive glass (BG) releases calcium and phosphate ions that form a hydroxycarbonate apatite layer upon contact with saliva [39]. Farooq et al. [22] found that fluoride-containing BG toothpaste improved enamel hardness and reduced surface roughness more than fluoride alone. Chen et al. [29] reported enhanced ion release and surface rehardening with BG-fluoride formulations, although 5000 ppm fluoride paste demonstrated higher fluorapatite crystallinity. A later study by Chen et al. [30] showed that BG-fluoride toothpaste offered better protection against demineralization than fluoride-only formulations despite residual subsurface mineral loss across all groups. Overall, BG-fluoride toothpastes demonstrate remineralization performance comparable to fluoride alone, with possible advantages in ion release dynamics and surface conditioning.
4. Discussion
The findings of this systematic review align with an emerging body of research evaluating biomaterial-based alternatives to fluoride for enamel remineralization. Across included studies, several agents—such as calcium phosphate derivatives, calcium silicate, hydroxyapatite (HAP), CPP-ACP, and bioactive glass, demonstrated remineralization outcomes comparable to fluoride under specific laboratory or short-term clinical conditions [21, 23, 25, 26]. However, the consistency of these effects varied across materials, study designs, lesion types, and methodological approaches, warranting cautious interpretation.
Calcium phosphate derivatives, particularly in nanoparticle form, have shown promising remineralization behavior. Ionescu et al. [23] demonstrated epitaxial mineral growth resembling native hydroxyapatite, and Hamba et al. [40] reported deeper mineral penetration than fluoride in a pH-cycling model. While these findings suggest potential advantages under controlled conditions, evidence remains primarily in vitro, and the extent to which these outcomes reflect clinical situations is uncertain.
Calcium silicate derivatives also showed favorable performance, with studies reporting dentinal tubule occlusion and enamel surface protection [24, 25]. Li et al. [24] observed intratubular hydroxyapatite formation, whereas Tavangar et al. [41] demonstrated mineralizing potential in caries-affected dentin. These results indicate that CaSi may be a useful adjunct in managing early enamel and dentine lesions, although long-term clinical validation remains limited.
Hydroxyapatite (HAP) continues to attract interest because of its biomimetic properties. Studies by Amaechi et al. [26] and Ionescu et al. [23] reported HAP-associated remineralization comparable to fluoride, and clinical data suggest possible benefits in reducing caries incidence [20]. Conversely, other investigations reported greater remineralization with fluoride [27, 42], highlighting the variability in outcomes. Taken together, HAP appears capable of achieving fluoride-like performance in certain contexts, but the evidence does not support a consistent advantage over conventional fluoride formulations.
CPP-ACP demonstrated mixed results. Although it facilitated remineralization, it was generally less effective than HAP or CaSi and performed inconsistently compared to fluoride [21, 23]. Studies evaluating CPP-ACP–fluoride combinations reported enhanced outcomes compared with either agent alone, suggesting that synergistic effects may depend on the co-presence of fluoride [28, 38]. CPP-ACP, therefore, appears to function best as an adjunctive material, rather than a standalone alternative.
Bioactive glass (BG) formulations showed improved surface rehardening and ion release when combined with fluoride [22, 29, 39]. BG-fluoride toothpastes demonstrated comparable or enhanced remineralization outcomes relative to fluoride alone in several studies. However, in highly acidic or high-challenge conditions, high-concentration fluoride pastes produced greater fluorapatite crystallinity [30]. BG may represent a potentially valuable complementary agent, but comparative long-term evidence remains sparse.
Beyond material-specific findings, several methodological considerations limit the overall strength of the available evidence. The predominance of in vitro experiments constrains ecological validity, as these models do not replicate salivary flow, oral microbiota, dynamic pH changes, or dietary influences. Short study durations, single-modality assessment methods, and limited reporting of randomization and blinding further restrict interpretation. Some studies were affected by external disruptions, such as the COVID-19 pandemic, which affected participant adherence. Additionally, heterogeneity in lesion creation methods, remineralization protocols, and outcome metrics complicates direct comparisons across studies.
This review also has limitations inherent to its scope. The scarcity of well-designed in vivo trials restricts clinical conclusions, and extraction-based analysis is often not feasible in clinical settings. Differences in fluoride chemistry, ion availability, and kinetic behavior across formulations add complexity to comparative assessment. Most included studies evaluated only one alternative agent at a time, limiting head-to-head comparisons among biomaterials. Furthermore, studies with industry involvement were excluded to minimize commercial bias; although this enhances neutrality, it may also omit potentially informative datasets.
Despite these constraints, the collective evidence indicates that several biomaterial-based toothpastes can achieve remineralization outcomes comparable to fluoride in controlled settings, and some may offer complementary benefits when used in combination with fluoride. These materials, particularly when incorporated into accessible over-the-counter formulations, have the potential to support non-invasive management of early carious lesions, especially in populations at risk for fluorosis or with limited fluoride exposure.
This review also excluded studies with company sponsorship or authorship affiliations to specific toothpaste brands to minimize the risk of commercial bias. While this approach enhances the methodological neutrality of the evidence synthesis, it may introduce selection bias by excluding some potentially relevant data. The findings should, therefore, be interpreted with an awareness of this trade-off between reducing conflict-of-interest influence and maintaining comprehensive inclusion of available studies.
Future research should prioritize standardized, adequately powered in vivo trials with longer follow-up periods, consistent lesion models, and multimodal assessment techniques. Comparative studies examining particle size, material composition, and interactions among formulations—particularly fluoride–biomaterial combinations—will be essential for determining optimal clinical applications. Evaluating affordability, accessibility, and patient-centred outcomes will further support integration of these agents into preventive dental care.
5. Conclusions
In summary, this systematic review indicates that several biomaterial-based toothpastes—including calcium phosphate derivatives, calcium silicate, hydroxyapatite, CPP-ACP, and bioactive glass—show potential as alternatives or adjuncts to fluoride for supporting enamel remineralization. Across included studies, these materials produced remineralization outcomes that were generally comparable to fluoride under specific experimental conditions, and some fluoride–biomaterial combinations suggested possible additive or complementary benefits. However, the evidence base is dominated by in vitro and short-term in situ studies, and substantial methodological heterogeneity limits the ability to draw strong clinical conclusions. Well-designed, longer-duration in vivo studies with standardized protocols are needed to clarify the clinical relevance of these materials and to determine their appropriate role within evidence-based caries prevention strategies.
Availability of data and materials
This study is a systematic review and does not involve generating or analysing primary data. All data supporting the findings of this review are derived from previously published studies, which are cited within the manuscript. Further details can be obtained from the corresponding author upon reasonable request.
Author contributions
SS, WCH, PKH, VSV—conceptualisation. ART, RMW, PJW—data curation. WCH, ART, PJW—formal analysis. RMW, WCH, PKH, DM—investigation. SS, ART, PKH, VSV—methodology. SS, DM, VSV—project administration; validation; writing–review & editing. SS, WCH, RMW—supervision; visualisation. WCH, PKH, DM, VSV—roles/writing–original draft. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval and informed consent were not required for this study, which is a systematic review of previously published literature and does not involve new experiments with human participants or animals.
Acknowledgment
We acknowledge the use of artificial intelligence tools for proofreading and refining the English, which contributed to improving the manuscript’s clarity, coherence, and overall quality. During the preparation of this work, the authors used Grammarly AI for language editing. Following the use of this tool, the authors carefully reviewed and edited the content as necessary and took full responsibility for the publication’s content.
Funding
This study was supported by the grants PUENTE, GIR, and INDI (2024–2026) from Universidad CEU Cardenal Herrera, Valencia, Spain, awarded to the principal investigator, Dr. Salvatore Sauro (SS).
Conflict of interest
The authors declare no conflict of interest.
Supplementary material
Supplementary material associated with this article can be found, in the online version, at https://oss.jocpd.com/files/article/2072885708412862464/attachment/Supplementary%20material.zip.
