Analyzing the Effectiveness of Different Delivery Methods for Remineralization Agents in Pediatric Dental Health: A Systematic Review
Dental caries remains one of the most prevalent chronic diseases among children worldwide, posing a significant public health challenge . Despite advances in preventive and therapeutic strategies, caries management in pediatric patients continues to demand innovative approaches, especially during the early stages of enamel demineralization . Early-stage caries, characterized by non-cavitated lesions, represent a critical window for intervention, as timely remineralization can reverse the progression of demineralization, preserving tooth structure and minimizing the need for invasive treatments . Addressing this challenge involves not only identifying effective remineralization agents but also determining the optimal delivery methods to maximize clinical outcomes . Remineralization agents such as fluoride-based products, casein phosphopeptides (CPP), calcium phosphates, and other biomimetic materials have shown promise in promoting enamel repair and preventing caries progression . These agents work by replenishing lost minerals in the enamel matrix, strengthening its structure, and reducing the susceptibility to acid attacks from cariogenic bacteria . While the efficacy of these agents has been well-documented, the mode of delivery (as varnishes, gels, foams, sprays, or other forms) can influence their clinical effectiveness, ease of application, and patient compliance . The pediatric population presents unique challenges in the management of dental caries. Children aged 3-15 years are particularly vulnerable to caries due to developing oral hygiene habits , frequent exposure to cariogenic diets, and the physiological characteristics of primary and newly erupted permanent teeth, which are less mineralized than adult teeth . Additionally, pediatric patients often have behavioral and psychological considerations that impact their acceptance of dental procedures . Thus, selecting a delivery method that balances efficacy with practicality and patient comfort is critical for achieving favorable outcomes. Different delivery methods offer distinct advantages and limitations in clinical practice. Varnishes, for instance, are widely used due to their ease of application and prolonged contact time with enamel, which enhances fluoride uptake . Gels and foams, often applied in dental trays, can provide high concentrations of remineralizing agents but may pose challenges in younger children who have difficulty tolerating prolonged tray placement . Sprays, while less commonly studied, represent a promising alternative for their simplicity and minimal invasiveness. Each method also varies in its ability to distribute the agent uniformly, maintain therapeutic concentrations, and penetrate enamel lesions effectively. Understanding these differences is essential for tailoring interventions to the specific needs of pediatric patients. For instance, in high-caries-risk populations, a more intensive delivery method, such as varnish or gel, may be preferable. Conversely, in children with behavioral challenges or dental anxiety, less invasive options like sprays or quick-application foams may improve compliance and treatment acceptance. However, the existing literature lacks comprehensive comparisons of these delivery methods, particularly in the context of their relative effectiveness in pediatric populations. What is the relative effectiveness of different delivery methods of remineralization agents in enhancing enamel remineralization, preventing caries progression, and improving oral health outcomes in pediatric patients? While numerous studies have evaluated the efficacy of individual remineralization agents, relatively few have focused on comparing their delivery methods in pediatric populations. The existing evidence is fragmented, often limited to single-center studies or narrow comparisons that do not account for variations in patient demographics, dental conditions, or application protocols . Moreover, the methodological quality of these studies varies, with many failing to include appropriate control groups or standardized outcome measures. This lack of robust evidence complicates the task of establishing clinical guidelines for the use of remineralization agents in children. Furthermore, the heterogeneity in study designs, including variations in age groups, intervention protocols, and outcome measures, has made it challenging to synthesize findings into actionable insights. For example, while fluoride varnishes are a mainstay in pediatric caries prevention, their relative performance compared to emerging delivery methods, such as biomimetic foams or sprays, remains underexplored . Additionally, most studies have focused on short-term outcomes, such as immediate increases in enamel mineral content, without adequately assessing long-term effects on caries prevention or overall oral health improvement. This systematic review aims to address these gaps by synthesizing existing evidence on the impact of different delivery methods of remineralization agents on dental health outcomes in pediatric patients. Specifically, the review will compare delivery methods such as varnishes, gels, foams, and sprays in terms of their effectiveness in enhancing enamel remineralization, preventing caries progression, and improving oral health indicators. 

Methods Eligibility Criteria This systematic literature review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The research question was: What is the relative effectiveness of different delivery methods of remineralization agents in enhancing enamel remineralization, preventing caries progression, and improving oral health outcomes in pediatric patients? The review included randomized controlled trials (RCTs), cohort studies, and case-control studies focusing on treatment outcomes with different remineralization agents on pediatric patients aged 3-15 years with early-stage dental caries or enamel demineralization (incipient or non-cavitated lesions). Eligible studies had to assess remineralization agents delivered via varnishes, gels, foams, or sprays, with outcomes related to enamel remineralization, caries prevention, or general oral health improvement published in peer-reviewed journals. Exclusion criteria included any other type of article, studies with a split-mouth design in which the investigators were studying remineralizing therapy (because there is always the risk that the agent can migrate through saliva and contaminate the control side), conducted on non-pediatric population or children with advanced caries or severe systemic diseases. Studies with a high risk of bias or significant methodological flaws and non-English language studies without verified translations were also excluded. The search was conducted based on the PICOS (Problem/Patient, Intervention/Indicator, Comparison, Outcome, and Study Design) criteria, which are presented in Table . Search Strategy A comprehensive search was conducted in four databases: PubMed, the Cochrane Library, Google Scholar, and Web of Science. The following filters were applied to all databases: publication date within the past 10 years, English language, and studies of humans. We then searched the references cited in all the articles located to identify any additional articles. For the search, we made sure we did not miss any relevant studies by using a combination of Medical Subject Headings (MeSH) and non-MeSH terms together with Boolean operators (AND and OR) related to demineralization (tooth demineralization, white spot lesion, early/incipient caries lesion, non-cavitated enamel lesion, early carious lesion, and decalcification), pediatric dentistry (pediatric, children, child and pediatric dental health outcomes), treatment (caries prevention, tooth remineralization, cariostatic agents, fluorides, fluoride varnish, caseins, calcium phosphate, CPP-(amorphous calcium phosphate) ACP, CPP-amorphous calcium fluoride phosphate (ACFP), remineralizing agents, remineralization techniques, and minimally invasive treatment), delivery methods (varnish, foam, spray, gel, tablets, and application methods), study type (RCT, cohort, case-control, observational studies, clinical trials) and participants (human and in vivo). The search strings used in the different databases are given in Table . Articles published between April 2014 and November 2024 were included in the search. Discrepancies in selection were resolved through discussion or by consulting a third reviewer. A PRISMA flow diagram (Figure ) shows the selection process. Data Collection and Analysis Data extraction and assessment of bias: Two independent reviewers conducted the same search independently and screened titles and abstracts for relevance, followed by a full-text review of eligible studies. Data were extracted using a standardized form that included study characteristics (author, year, location, design), population details (age, health status), interventions (type and delivery method of remineralization agents), comparators, and reported outcomes. Discrepancies in selection were resolved through discussion or by consulting a third reviewer. Data Synthesis and Statistical Analysis A narrative synthesis was performed to summarize findings, supported by tables and figures. Data was visualized using Microsoft Excel (Microsoft Corporation, Redmond, Washington, United States), and separate sheets were maintained and collaborated on by the reviewers during data extraction. Quality Assessment The methodological quality of the 10 included studies was evaluated independently by two reviewers using the Cochrane ROB-2 tool as shown in Figure . Studies were categorized as low, moderate, or high risk of bias based on factors such as randomization, blinding, and completeness of outcome data. Any disagreements were resolved by consensus. Out of the 10 studies, eight exhibited an overall low risk of bias, with most domains (D1-D5) judged favorably. However, concerns about randomization (D1) or deviations from the intended intervention (D2) were noted in studies by Keratibumrungpong et al.  and Mendes et al. . Notably, Unal and Oztas's study  had a high risk of bias, particularly in deviations from intervention (D2) and overall assessment. This variation may stem from inadequate blinding or intervention inconsistencies. Results Ten RCTs were included in the analysis, conducted across diverse countries, including Germany , Italy , Turkey [ - ], China , Thailand , Iran , and Brazil , and encompassing a total sample size of 743 participants. Table summarizes the characteristics of the studies. Sample sizes ranged from 21 to 240 participants, with interventions tailored to specific populations. Alkilzy et al. , Pardo et al. , and Almaz et al.  explored fluoride varnishes combined with innovative agents (e.g., self-assembling peptides, biorepair pastes). Güçlü et al. , He et al. , and Memarpour  targeted white spot lesions using fluoride, CPP-ACP, or a combination. Keratibumrungpong et al.  and Mendes et al.  compared fluoride gels and pastes against control groups. Sitthisettapong et al.  emphasized daily CPP-ACP application for high caries-risk preschool children, while Unal and Oztas  investigated fissure sealants with or without ozone. The participants were primarily children, with ages ranging from 12 months to 20 years, depending on the study. All studies focused on pediatric populations with specific dental conditions such as early occlusal caries, molar-incisor hypomineralization (MIH), white spot lesions (WSLs), or high caries risk. Male predominance was noted in some studies, though gender distribution varied. The mean ages of participants spanned from 21 months to 15 years, with the highest mean age observed in orthodontic patients with WSLs. As mentioned earlier, interventions varied widely across studies. Most employed remineralization agents like fluoride varnishes, self-assembling peptides, or CPP-ACP formulations, with some studies comparing these agents or assessing different application methods. Comparisons included control groups receiving no treatment, placebos, or alternative preventive interventions. Delivery methods included varnishes, gels, films, pastes, and even fissure sealants combined with or without ozone. The patient populations showed significant variation in health conditions and dental needs. Inclusion criteria ranged from children with early caries and non-cavitated lesions to those undergoing orthodontic treatment. All studies stratified participants into intervention and control groups, aiming to evaluate the efficacy of novel and conventional remineralization methods in improving oral health outcomes in pediatric populations. Table summarizes the delivery methods and remineralization agents used, along with their effectiveness. The Grading of Recommendations Assessment Development and Evaluation (GRADE) approach was utilized to determine the certainty of the evidence in this systematic review. The certainty of the evidence was evaluated based on three domains: Studies included, Number of participants, and Effectiveness. It was classified as very low, low, moderate, or high certainty of evidence. Our results are summarized in Table along with the GRADE assessment of each outcome. Discussion Comparison of Delivery Methods The studies analyzed in this systematic review demonstrate that the mode of delivery significantly influences the effectiveness, patient compliance, and overall practicality of remineralization agents for pediatric dental care. The four delivery methods reviewed, varnishes, gels, foams, and sprays, each present unique advantages and limitations. A summary of the comparison can be seen in Table . By comparing these methods, this section highlights their strengths and weaknesses to guide clinical decision-making. Varnishes: Fluoride varnishes, such as Duraphat and Clinpro, are a mainstay in caries prevention and remineralization due to their high fluoride content and ability to provide prolonged contact with enamel . Their semi-viscous consistency allows easy application, even in uncooperative pediatric patients, and their rapid drying minimizes ingestion risks . Studies, including Alkilzy et al.  and Memarpour et al. , consistently demonstrated that fluoride varnishes significantly reduced caries progression and enhanced remineralization of early lesions. However, their efficacy is limited by the application frequency and the dependence on professional administration, which can increase costs and reduce accessibility in underserved areas . Gels: Gels such as 1.23% APF gel and CPP-ACP formulations often require tray applications, which provide a controlled environment for high-concentration agents to interact with the enamel . Their advantages include the ability to deliver higher doses of fluoride or other remineralizing agents over a short period . However, as observed in studies like Mendes et al. , their use in pediatric populations is complicated by discomfort during tray placement and challenges with patient cooperation, particularly among younger children. Foams: Emerging as a novel delivery system, foams are lightweight and easy to distribute, making them particularly suitable for patients with behavioral challenges . While limited evidence is available, foams are hypothesized to enhance compliance due to their simplicity and minimal invasiveness. Their ability to penetrate deep lesions is still under investigation. Foams show promise for routine preventive care but require further research to validate their efficacy compared to more established methods. Sprays: Sprays offer a highly convenient and patient-friendly approach. They are ideal for rapid application and can be self-administered, providing an advantage in settings where professional application is not feasible. However, studies like He et al. suggest that sprays may suffer from uneven distribution and lower adherence to enamel surfaces, potentially reducing their remineralization capacity . Advantages of Combining Delivery Methods A notable finding from the review was the synergistic effect observed in combining delivery methods or agents. For example, Alkilzy et al. demonstrated improved outcomes when fluoride varnish was paired with self-assembling peptides . Such combinations allow for the strengths of one delivery method to complement the limitations of another. Future clinical protocols could consider hybrid approaches to optimize treatment efficacy. High Risk vs. Low Risk Caries Patients and Choice of Delivery Method The choice of an ideal delivery method should also account for the patient's caries risk. High-caries-risk patients, who often require intensive and frequent remineralization therapy, benefit from delivery methods that ensure prolonged agent retention, such as fluoride varnishes or CPP-ACP gels . These methods allow sustained release of active ingredients, providing long-lasting protection against demineralization. On the other hand, low-caries-risk patients might achieve sufficient preventive outcomes with less intensive methods, such as sprays or foams, which are easier to apply but may require more frequent applications to maintain effectiveness. Stratifying delivery methods based on caries risk enables clinicians to tailor treatments to patient needs, optimizing resource allocation while maintaining clinical efficacy. Ideal Delivery Method and Proper Isolation The application method significantly influences remineralization agents' effectiveness, particularly in the context of proper isolation techniques like rubber dam usage. Rubber dam isolation creates a dry, uncontaminated field, enhancing the adhesion and penetration of agents like FVs, CPP-ACP pastes, and self-assembling peptides into enamel microstructures. Studies have demonstrated that the absence of moisture or saliva contamination during application increases the efficacy of these agents by facilitating a more uniform layer deposition and prolonged agent retention on the tooth surface . Furthermore, methods such as varnishes, which adhere well in dry conditions, often exhibit superior outcomes when combined with proper isolation. The use of rubber dams is particularly crucial for younger patients, where maintaining a saliva-free environment can be challenging. Behavioral and Psychological Considerations One key challenge in pediatric dental care is ensuring patient compliance, which varies significantly with the invasiveness and duration of treatment. Varnishes and sprays are better tolerated by anxious children or those with shorter attention spans, while gels, requiring extended contact time, may be less acceptable . The choice of delivery method should balance efficacy with patient comfort to improve adherence and treatment outcomes. How Patient Behavior Influences Delivery Method Used As outlined in Table , patient behavior plays a pivotal role in determining the feasibility and success of various delivery methods. Cooperative patients, who can remain still and follow instructions, are suitable candidates for methods requiring precision, such as tray-based gel applications or fissure sealants combined with remineralization agents. Potentially uncooperative patients, often younger children or those with anxiety, may respond better to faster and less invasive methods like fluoride varnishes or sprays, which can be applied quickly with minimal discomfort. For completely uncooperative patients, such as those with special needs or severe dental fear, methods like varnishes combined with behavior management techniques or even sedation may be necessary. Understanding patient behavior not only aids in selecting the most effective delivery method but also enhances patient comfort and compliance during dental procedures. Clinical Implications and Recommendations The clinical decision on the optimal delivery method should consider the patient’s age, caries risk level, and behavioral profile. High-risk populations may benefit from professional-grade varnishes or intensive gel applications to achieve maximum remineralization. Younger or behaviorally challenging patients may respond better to foams or sprays due to their ease of application. Additionally, accessibility and cost-effectiveness play a significant role, particularly in low-resource settings. Spray and foam methods, given their potential for self-application, could be more feasible alternatives in such contexts. However, the lower efficacy observed with these methods suggests the need for further optimization or combination with adjunctive therapies. Several limitations in the existing literature hinder the ability to make definitive recommendations about the best delivery methods for remineralization agents. Short follow-up periods in many studies limit the understanding of long-term efficacy in preventing caries and maintaining enamel health. Furthermore, significant heterogeneity exists across studies regarding application protocols, including differences in agent concentrations and frequencies of use, making direct comparisons challenging. Emerging delivery methods such as foams and sprays have also received limited attention, with few robust trials exploring their potential advantages or optimal application in pediatric populations. Addressing these gaps requires future research to focus on long-term studies that assess sustained caries prevention and enamel durability across various delivery methods. Conducting head-to-head trials under standardized conditions could provide clearer clinical guidelines by enabling more reliable comparisons. Moreover, examining the behavioral aspects of these interventions such as strategies to enhance patient compliance will be crucial for improving their real-world effectiveness, particularly among pediatric patients. 

This systematic review highlights the significant impact of delivery methods on the effectiveness of remineralization therapies in pediatric dental care. While varnishes continue to be the gold stander for high-risk caries populations, sprays and foams offer valuable alternatives, particularly for children with behavioral challenges. Ultimately, personalizing remineralization treatments to the specific needs of each patient is key to maximizing the success of these therapies and improving long-term pediatric dental health outcomes. 

