Comparative evaluation of biomaterial-based and fluoride toothpastes for enamel remineralization: a PRISMA-compliant systematic review

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.

Dental caries; Fluoride toothpaste; Remineralisation; Biomaterials; Nano-hydroxyapatite; Casein phosphopeptide; Bioactive glass; Calcium phosphate; Systematic review

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