Advances in Dental Research

Randomized control trial (RCT) methodology has compared interventions for the prevention and management of dental caries since the late 1960s. Despite almost 50 years and evidence of significant wastage within the wider biomedical research field, there has been little investigation into what works well and where weaknesses lie. This paper aims to draw attention to areas for improvement within cariology clinical trial methodology by summarizing systematic reviews on interventions and outcomes, and using examples to illustrate some challenges with intervention delivery fidelity, outcome analyses, and intervention co-production. Trial design stage choices are critical to ensure that optimum information is obtained when testing interventions. Intervention choice, outcome choice, and analyses are particularly important, and cariology trials have specific issues associated with them. A systematic search and review of cariology RCTs found 650 RCT reports. Social Network Analysis of interventions revealed a high degree of separation between prevention and management trials, gaps in clinically important comparisons, and a tendency for there to be comparisons within groups; e.g., comparison of interventions within the same, rather than different, levels of invasiveness. Outcomes measured for the same trial reports show: a focus on restoration performance and individual/population caries burden; the growing use of carious lesion activity and economic-related outcomes; and sparse, although an increase in the use of, patient-reported/patient-centered outcomes. Fidelity of adherence to complex interventions can be challenging to measure but is important in interpreting trial findings. Involving target populations in intervention design, delivery, and relating it to the planned rollout, are opportunities to ensure intervention relevance and improved uptake. Outcomes analyses should consider the minimum clinically important differences and outcome relevance measures for the target population. Factors underlying trialists’ comparator and outcome choices need to be identified, and there is a need to ensure that a minimum dataset of outcomes allow for combination and comparisons of trial data for systematic review.

A system for Caries Management by Risk Assessment (CAMBRA^®) has been developed in California. The purpose of this article is to summarize the science behind the methodology, the history of the development of CAMBRA, and the outcomes of clinical application. The CAMBRA caries risk assessment (CRA) tool for ages 6 y through adult has been used at the University of California, San Francisco (UCSF), for 14 y, and outcome studies involving thousands of patients have been conducted. Three outcomes assessments, each on different patient cohorts, demonstrated a clear relationship between CAMBRA-CRA risk levels of low, moderate, high, and extreme with cavitation or lesions into dentin (by radiograph) at follow-up. This validated risk prediction tool has been updated with time and is now routinely used at UCSF and in other settings worldwide as part of normal clinical practice. The CAMBRA-CRA tool for 0- to 5-y-olds has demonstrated similar predictive validity and is in routine use. The addition of chemical therapy (antibacterial plus fluoride) to the traditional restorative treatment plan, based on caries risk status, has been shown to reduce the caries increment by about 20% to 38% in high-caries-risk adult patients. The chemical therapy used for high-risk patients is a combination of daily antibacterial therapy (0.12% w/v chlorhexidine gluconate mouth rinse) and twice-daily high-concentration fluoride toothpaste (5,000 ppm F), both for home use. These outcomes assessments provide the evidence to use these CRA tools with confidence. Caries can be managed by adding chemical therapy, based on the assessed caries risk level, coupled with necessary restorative procedures. For high- and extreme-risk patients, a combination of antibacterial and fluoride therapy is necessary. The fluoride therapy must be supplemented by antibacterial therapy to reduce the bacterial challenge, modify the biofilm, and provide prevention rather than continued caries progression.

To demonstrate that Caries Management by Risk Assessment (CAMBRA) can be successfully implemented in dental practice, 30 dentists were recruited to perform a 2-y CAMBRA trial. Twenty-one dentists (18 private practices, 3 community clinics) participated in a randomized, controlled, parallel-arm, double-blind clinical trial with individual-level assignment of 460 participants to standard of care (control) versus active CAMBRA treatment (intervention). Control or active antimicrobial and remineralizing agents were dispensed at baseline and 6-, 12-, 18-, and 24-mo recall visits according to risk level and assigned treatment arm. Primary outcome measure was dentist-determined caries risk level at recall. Among initially high-risk participants, secondary outcomes were recorded disease indicators. Generalized estimating equations were used to fit log-linear models for each outcome while accounting for repeated measurements. At 24 mo, follow-up rates were 34.3% for high-risk participants (32.1% intervention, 37.1% control) and 44.2% for low-risk participants (38.7% intervention, 49.5% control). Among 242 participants classified as high caries risk at baseline (137 intervention, 105 control), a lower percentage of participants remained at high risk in the intervention group (statistically significant at all time points). At 24 mo, 25% in the intervention group and 54% in the control group remained at high risk (P = 0.003). Among 192 participants initially classified as low risk (93 intervention, 99 control), most participants remained at low risk. At 24 mo, 89% in the intervention group and 71% in the control group were low caries risk (P = 0.18). The percentage of initially high-risk participants with recorded disease indicators decreased over time in both intervention and control groups, being always lower for the intervention group (statistically significant at the 12- and 18-mo time point). In this practice-based clinical trial, a significantly greater percentage of high-caries-risk participants were classified at a lower risk level after CAMBRA preventive therapies were provided. Most participants initially assessed at low caries risk stayed at low risk (ClinicalTrials.gov NCT01176396).

Expanded partnership with the medical community is an important strategy for reducing dental caries disparities. The purpose of this study was to assess the relationship between fluoride (F) “in office” (drops/tablets and/or varnish), as prescribed or applied by a health care professional by age 1 y, and 1) caries development and 2) presence of other caries risk factors or mediators (e.g., socioeconomic status). Child–primary caregiver (PCG) pairs (N = 1,325) were recruited in Indiana, Iowa, and North Carolina as part of a longitudinal cohort study to validate a caries risk tool for primary health care settings. PCGs completed a caries risk questionnaire, while children received caries examinations per the criteria of the International Caries Detection and Assessment System at ages 1, 2.5, and 4 y. Baseline responses regarding children’s history of F in office were tested for association with other caries risk variables and caries experience at ages 2.5 and 4 y via generalized estimating equation models applied to logistic regression. The sample was 48% female, and many children (61%) were Medicaid enrolled. The prevalence of cavitated caries lesions increased from 7% at age 2.5 y to 25% by age 4 y. Children who received F in office were likely deemed at higher caries risk and indeed were significantly (P < 0.01) more likely to develop cavitated caries lesions by ages 2.5 and 4 y, even after F application (odds ratios: 3.5 and 2.3, respectively). Factors significantly associated with receiving F included the following: child being Medicaid enrolled, not having an employed adult in the household, child and PCG often consuming sugary drinks and snacks, and PCG having recent caries experience. Increased F in office from a health care provider by age 1 y was associated with known caries risk factors. Most (69%) children had never been to the dentist, suggesting that risk factors could be alerting medical providers and/or parents, thereby affecting in-office F recommendations. Differences among states could also be related to state-specific F-varnish reimbursement policies (ClinicalTrials.gov NCT01707797).

Over 1 in 5 dental patients report moderate to severe dental fear. Although the efficacy of cognitive-behavioral treatment (CBT) for dental fear has been examined in over 20 randomized controlled trials—with 2 meta-analyses finding strong average effect sizes (d > 1)—CBT has received almost no dissemination beyond the specialty clinics that tested it. The challenge, then, is not how to treat dental fear but how to disseminate and implement such an evidence-based treatment in a way that recognizes the rewards and barriers in the US health care system. This mixed-method study investigated the potential of disseminating CBT through care from a mental health provider from within the dental home, a practice known as evidence-based collaborative care (EBCC). Two preadoption studies were conducted with practicing dentists drawn from a self-organized Practice-Based Research Network in the New York City metropolitan area. The first comprised 3 focus groups (N = 17), and the second involved the administration of a survey (N = 46). Focus group participants agreed that CBT for dental fear is worthy of consideration but identified several concerns regarding its appeal, feasibility, and application in community dental practices. Survey participants indicated endorsement of factors promoting the use of EBCC as a mechanism for CBT dissemination, with no factors receiving less than 50% support. Taken together, these findings indicate that EBCC may be a useful framework through which an evidence-based treatment for dental fear treatment can be delivered.

Modern approaches in caries treatment involve lesion management without tissue removal. Regenerative medicine focuses on replacing damaged tissues with biologically similar tissues. This article discusses the scientific evidence and clinical results for self-assembling peptides in modern caries management. The biomimetic remineralization promoted by self-assembling peptide P11-4 has been proven in vitro as an effective therapy for initial caries. P11-4 was rationally designed to promote formation of hydroxyapatite on its surface. The formulation was optimized to ensure the ability of monomeric P11-4 to penetrate past the subsurface lesions and assembly into a biomatrix within. Furthermore, P11-4 has shown that it assembles into fibers within carious lesions, and promotes the remineralization thereof. In a recent clinical study, the safety and efficacy of P11-4 in treatment of initial caries were evaluated. The additional effect of the application of P11-4 (Curodont Repair) was compared to the application of fluoride varnish (Duraphat) alone in active occlusal initial caries lesions on erupting permanent molars. In the 3- and 6-month recalls, the test group showed, both in the laser fluorescence readings and in the clinical assessment of the caries stage and activity, significantly superior lesion regression compared to the control group. No adverse events, medical complications, or allergic reactions related to the treatments were reported. Clinical applicability of treatment was regarded as satisfactory. Patients were happy to receive noninvasive caries treatments. In conclusion, biomimetic mineralization facilitated by P11-4 in combination with fluoride may present a simple, safe, and effective noninvasive treatment for early carious lesions.

This article aims to outline the early development of a King’s College London dental spinout company, Reminova, formed to commercialize a novel clinical method of caries remineralization: electrically accelerated and enhanced remineralization (EAER). This method is being developed to address the unmet clinical need identified by modern caries management strategies to keep enamel “whole” through remineralization of clinical caries as a form of nonoperative caries treatment for initial-stage and moderate lesions. A progressive movement within dentistry is shifting away from the restorative-only model, which, it is suggested, has failed. The high prevalence of initial-stage caries across populations provides a significant opportunity to prevent restorations and reduce repeat restorations over a patient’s lifetime. Reminova has set out to provide a method to repair lesions without drilling, filling, pain, or injections. The article outlines the rationale for and the chronological stages of the technology and company development. It then outlines corroborative evidence to show that EAER treatment can, in this preliminary in vitro investigation, remineralize clinically significant caries throughout the depth of the lesion as measured by Knoop microhardness and corroborated by scanning electron microscopy. Furthermore, the presented data show that EAER-treated enamel is harder than the healthy enamel measured nearby in each sample and is very similar in appearance to healthy enamel from the subjective interpretation made possible by scanning electron microscopy imagery. The data presented also show that this more “complete” remineralization to a high hardness level has been achieved with 2 remineralizing agents via in vitro human tooth samples. The broad clinical potential of this new treatment methodology seems to be very encouraging from these results. Reminova will strive to continue its mission, to ensure that, in the future, dental teams will not need to drill holes for the treatment of initial-stage and moderate caries lesions.

Remineralization of caries lesions is naturally achieved by salivary ions, and it can be enhanced by external factors or elements such as fluoride. Numerous studies have demonstrated the remineralizing efficacy of fluoride therapies as well as the limitations with some groups of the population. Consequently, developing new remineralization therapies to close this gap in efficacy has been a priority for the last 2 decades. In this review, we summarize and briefly discuss some of the latest advances in remineralization therapies. Most new therapies try to enhance the effect of fluoride by adding other potentially active ingredients to the formulation, such as calcium, phosphate, stannous, xylitol, and arginine. Other remineralization strategies have focused on creating remineralizing scaffolds within the lesions (e.g., self-assembling peptides). While several of the new remineralization strategies have progressed significantly in recent years, for most of them, the evidence is still insufficient to assess their true clinical potential.

The oral microbiome is natural and has a symbiotic relationship with the host by delivering important benefits. In oral health, a dynamic balance is reached between the host, the environment, and the microbiome. However, the frequent intake of sugar and/or reductions in saliva flow results in extended periods of low pH in the biofilm, which disrupts this symbiotic relationship. Such conditions inhibit the growth of beneficial species and drive the selection of bacteria with an acid-producing/acid-tolerating phenotype, thereby increasing the risk of caries (dysbiosis). A more detailed understanding of the interdependencies and interactions that exist among the resident microbiota in dental biofilms, and an increased awareness of the relationship between the host and the oral microbiome, is providing new insights and fresh opportunities to promote symbiosis and prevent dysbiosis. These include modifying the oral microbiome (e.g., with prebiotics and probiotics), manipulating the oral environment to selectively favor the growth of beneficial species, and moderating the growth and metabolism of the biofilm to reduce the likelihood of dysbiosis. Evidence is provided to suggest that the regular provision of interventions that deliver small but relevant benefits, consistently over a prolonged period, can support the maintenance of a symbiotic oral microbiome.

Technological advances in DNA sequencing have provided unprecedented insights into the composition of the oral microbiome in health and disease, and RNA-sequencing and metabolomics-related technologies are beginning to yield information on the activities of these organisms. Importantly, progress in this area has brought the scientific community closer to an understanding of what constitutes a health-associated microbiome and is supporting the notion that the microbiota in healthy sites assumes an active role in promoting health and suppressing the acquisition, persistence, and activities of overt and opportunistic pathogens. It is also becoming clear that a significant impediment to developing a conclusive body of evidence that defines a healthy microbiome and the mechanisms by which beneficial bacteria promote health is that an inherent characteristic of the most abundant members of the oral flora, those that potentially play the greatest roles in health and disease, is intraspecies genomic diversity. In particular, individual isolates of abundant commensal and pathogenic streptococci show tremendous variability in gene content, and this variability manifests in tremendous phenotypic heterogeneity. Analysis of the consequences of this diversity has been complicated by the exquisite sensitivity these bacteria have evolved to environmental inputs, inducing rapid and substantial fluctuations in behaviors, and often only within subpopulations of the organisms. Thus, the conditions under which the oral microbiota is studied can produce widely different results within and between species. Fortunately, continually diminishing costs and ongoing refinements in sequencing and metabolomics are making it practical to study the oral microbiome at a level that will create a sufficiently robust understanding of the functions of individual organisms and reveal the complex interrelationships of these microbes (“the known unknowns”) in a way that researchers will be able to engage in the rational design of reliable and economical risk assessments and preventive therapies.

Understanding the microbiology of dental caries is not a mere academic exercise; it provides the basis for preventive, diagnostic, and treatment strategies and gives the dentist a theoretical framework to become a better professional. The last years have seen the development of new research methodologies, ranging from high-throughput sequencing or “omics” techniques to new fluorescence microscopy applications and microfluidics, which have allowed the study of the oral microbiome to an unprecedented level of detail. Those studies have provided new insights about oral biofilm formation, biomarkers of caries risk, microbial etiology, appropriate sampling, identification of health-associated bacteria, and new anticaries strategies, among others. Several pitfalls are associated with the new technologies, including a small number of samples per study group, elevated cost, and genus- or species-based analyses that do not take into consideration intraspecies variability. However, the new data strongly suggest that saliva may not be an appropriate sample for etiological studies or for bacterial caries-risk tests, that microbial composition alone may be insufficient to predict caries risk, and that antimicrobial or immunization strategies targeting single species are unlikely to be effective. Strategies directed toward modulation of the oral biofilm, such as pre- and probiotics, emerge as promising new approaches to prevent tooth decay.

The oral microbiome plays a critical role in maintaining oral health. Frequent dietary carbohydrate intake can lead to dysbiosis of the microbial community from overproduction of acid with selection for increases in acidogenic, acid-tolerant bacteria. Knowledge of the caries-associated microbiome is key in planning approaches to reverse the dysbiosis to achieve health. For risk assessment and treatment studies, it would be valuable to establish whether microbial monitoring requires assay of multiple species or whether selected key species would suffice. Early investigations of the oral microbiota relied on culture-based methods to determine the major bacteria in health and disease. Microbial monitoring using gene probes facilitated study of larger populations. DNA probe methods confirmed and expanded the importance of transmission of bacteria from mother to infant and association of preselected species, including mutans streptococci and lactobacilli with caries in larger populations. 16S ribosomal RNA (rRNA) probes confirmed the wide diversity of species in oral and caries microbiomes. Open-ended techniques provide tools for discovery of new species, particularly when strain/clone identification includes gene sequence data. Anaerobic culture highlighted the caries association of Actinomyces and related species. Scardovia wiggsiae, in the Actinomyces/Bifidobacterium family, and several Actinomyces species have the cariogenic traits of acid production and acid tolerance. Next-generation sequencing combined with polymerase chain reaction methods revealed a strong association with mutans streptococci in a high caries population with poor oral hygiene and limited access to care. A population with a lower caries experience generally had lower or no Streptococcus mutans detection but harbored other acidogenic taxa in the microbiome. Study of the microbiome suggests a role for the assay of selected putative cariogenic species in more aggressive diseases. For many populations with caries progression, however, assay of multiple species will likely be warranted to determine the caries profile of the population and/or individuals under study.

Cariogenic biofilms are highly structured microbial communities embedded in an extracellular matrix, a multifunctional scaffold that is essential for the existence of the biofilm lifestyle and full expression of virulence. The extracellular matrix provides the physical and biological properties that enhance biofilm adhesion and cohesion, as well as create a diffusion-modulating milieu, protecting the resident microbes and facilitating the formation of localized acidic pH niches. These biochemical properties pose significant challenges for the development of effective antibiofilm therapeutics to control dental caries. Conventional approaches focusing solely on antimicrobial activity or enhancing remineralization may not achieve maximal efficacy within the complex biofilm microenvironment. Recent approaches disrupting the biofilm microbial community and the microenvironment have emerged, including specific targeting of cariogenic pathogens, modulation of biofilm pH, and synergistic combination of bacterial killing and matrix degradation. Furthermore, new “smart” nanotechnologies that trigger drug release or activation in response to acidic pH are being developed that could enhance the efficacy of current and prospective chemical modalities. Therapeutic strategies that can locally disrupt the pathogenic niche by targeting the biofilm structure and its microenvironment to eliminate the embedded microorganism and facilitate the action of remineralizing agents may lead to enhanced and precise anticaries approaches.

Dental caries remains a world-wide disease despite the global distribution of fluoride. It has become apparent that the introduction of significant levels of sugar (fermentable carbohydrate) into the diet has resulted in a change in the biofilm, encouraging acid formation. Further, there has been a shift in the microbiota in the biofilm to a flora that produces acid, and thrives and reproduces in an acidic environment. The management of caries activity under these conditions has focused on brushing to remove the biofilm with fluoride pastes, and high-dose fluoride treatments. Kleinberg, in the 1970s, identified an arginine-containing compound in saliva that several oral biofilm bacterial species metabolize to produce base. Multiple in situ and in vivo studies have been conducted, and have discussed the ability of multiple bacteria to increase the resting pH of the biofilm and even reduce the decrease in pH when the biofilm is challenged with glucose. This shift in resting pH can shift the level of caries formation by the biofilm. Here, we present 8 clinical studies, with different clinical designs, measuring different clinical outcomes, for a diverse, world-wide population. Each of these studies demonstrates reductions in caries formation beyond that seen with fluoride alone and several demonstrate the reversal of early caries lesions. Significant clinical research has been shown that 1.5% arginine combined with fluoride toothpaste has superior anti-caries efficacy to toothpaste containing fluoride alone.

Carious lesions develop in tooth surfaces where there is an imbalance of the processes of acid and alkali production by supragingival biofilms. Since low pH is the main driving factor in the development of carious lesions, most efforts to identify an effective anticaries therapy have focused on targeting the acid-producing bacteria and their mechanisms of acid production. An expanding area of oral microbiology has now been devoted to explore microbial metabolic activities that help to neutralize biofilm pH and thus inhibit the caries process. Arginine metabolism via the arginine deiminase pathway (ADS) produces alkali in the form of ammonia that counteracts the effects of biofilm acidification from bacterial glycolysis. ADS also functions as an adaptive strategy used by certain bacteria to thrive in oral biofilms. Substantial evidence accumulated from laboratory and clinical observations supports the hypotheses that measurements of arginine metabolism via ADS may serve as an important caries risk assessment criterion and that providing arginine regularly to supragingival biofilms can be an effective therapy for caries intervention. This article reviews the potential of arginine-based therapies such as the use of arginine as prebiotic, ADS⁺ strains as probiotics, and oral care formulations containing arginine for prevention and management of dental caries.

Erythritol belongs chemically to the family of polyols (or sugar alcohols), yet it is metabolized by animals and humans very differently compared to all other polyols. While polyols have been used traditionally (for about 80 y) to replace sugar in sweet foods to reduce demineralization of tooth enamel and to reduce postprandial blood glucose levels, benefits achieved merely through the absence of sugar, emerging evidence shows that erythritol can play a number of functional roles to actively support maintenance of oral and systemic health. Oral health studies revealed that erythritol can reduce dental plaque weight, reduce dental plaque acids, reduce counts of mutans streptococci in saliva and dental plaque, and reduce the risk for dental caries better than sorbitol and xylitol, resulting in fewer tooth restorations by dentist intervention. Systemic health studies have shown that erythritol, unlike other polyols, is readily absorbed from the small intestine, not systemically metabolized, and excreted unchanged within the urine. This metabolic profile renders erythritol to be noncaloric, to have a high gastrointestinal tolerance, and not to increase blood glucose or insulin levels. Published evidence also shows that erythritol can act as an antioxidant and that it may improve endothelial function in people with type 2 diabetes. This article reviews the key research demonstrating erythritol’s oral and systemic health functionalities and underlying mechanisms.

Dental caries is a disease that results from microbiome dysbiosis with the involvement of multiple cariogenic species, including mutans streptococci (MS), lactobacilli, Scardovia wiggsiae, and several Actinomyces species that have the cariogenic traits of acid production and acid tolerance. Sugar consumption also plays an important role interacting with microbiome dysbiosis, determining the fate of caries development. In addition, the MS transmission that encompasses multiple sources can have long-term impacts on the oral microbiome and caries development in children. Intervention in MS transmission in early childhood may promote effective long-term caries prevention. Anticaries regimens aimed against the above mechanisms will be important for successful caries management. Xylitol and erythritol may serve as good components of anticaries regimens as oral microbiome modifiers, sugar substitutes, and agents to prevent MS transmission in early childhood with both oral and systemic benefits. Further studies are needed to elucidate the mechanism of the anticaries effects of xylitol and erythritol with consideration of their impacts on the microbiome and bacterial virulence, in addition to cariogenic bacteria levels as well as their benefits for overall health. On the other hand, the anticaries agent C16G2, specifically targeting Streptococcus mutans, the most common cariogenic bacterial species, has shown good safety for short-term oral topical use and promising effects in reducing S. mutans in vitro and in vivo with the promotion of oral commensal bacteria. Future study on its anticaries effect will need to include its long-term impact on the oral microbiome and effects on other important cariogenic bacteria.

A novel silver nanoparticle (AgNP) formulation was developed as a targeted application for the disinfection of carious dentine. Silver nitrate (AgNO₃) was chemically reduced using sodium borohydrate (NaBH₄) in the presence of sodium dodecyl sulfate (SDS) to form micelle aggregate structures containing monodisperse 6.7- to 9.2-nm stabilized AgNPs. AgNPs were characterized by measurement of electrical conductivity and dynamic light scattering, scanning electron microscopy, transmission electron microscopy, and inductively coupled plasma mass spectrometry. Antimicrobial activity of AgNPs was tested against planktonic cultures of representative gram-positive and gram-negative oral bacteria using well diffusion assays on tryptic soy broth media and monoculture biofilms grown with brain heart infusion ± sucrose anaerobically at 37°C on microtiter plates. Biofilm mass was measured by crystal violet assay. Effects were compared to silver diamine fluoride and chlorhexidine (negative controls) and 70% isopropanol (positive control) exposed cultures. In the presence of AgNPs, triplicate testing against Streptococcus gordonii DL1, C219, G102, and ATCC10558 strains; Streptococcus mutans UA159; Streptococcus mitis I18; and Enterococcus faecalis JH22 for planktonic bacteria, the minimum inhibitory concentrations were as low as 7.6 µg mL^–1 and the minimum bacteriocidal concentrations as low as 19.2 µg mL^–1 silver concentration. Microplate readings detecting crystal violet light absorption at 590 nm showed statistically significant differences between AgNP-exposed biofilms and where no antimicrobial agents were used. The presence of sucrose did not influence the sensitivity of any of the bacteria. By preventing in vitro biofilm formation for several Streptococcus spp. and E. faecalis, this AgNP formulation demonstrates potential for clinical application inhibiting biofilms.

A genome-wide transcriptional analysis was performed to elucidate the bacterial cellular response of Streptococcus mutans and Actinomyces viscosus to NaF and SnF₂. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of SnF₂ were predetermined before microarray study. Gene expression profiling microarray experiments were carried out in the absence (control) and presence (experimental) of 10 ppm and 100 ppm Sn²⁺ (in the form of SnF₂) and fluoride controls for 10-min exposures (4 biological replicates/treatment). These Sn²⁺ levels and treatment time were chosen because they have been shown to slow bacterial growth of S. mutans (10 ppm) and A. viscosus (100 ppm) without affecting cell viability. All data generated by microarray experiments were analyzed with bioinformatics tools by applying the following criteria: 1) a q value should be ≤0.05, and 2) an absolute fold change in transcript level should be ≥1.5. Microarray results showed SnF₂ significantly inhibited several genes encoding enzymes of the galactose pathway upon a 10-min exposure versus a negative control: lacA and lacB (A and B subunits of the galactose-6-P isomerase), lacC (tagatose-6-P kinase), lacD (tagatose-1,6-bP adolase), galK (galactokinase), galT (galactose-1-phosphate uridylyltransferase), and galE (UDP-glucose 4-epimerase). A gene fruK encoding fructose-1-phosphate kinase in the fructose pathway was also significantly inhibited. Several genes encoding fructose/mannose-specific enzyme IIABC components in the phosphotransferase system (PTS) were also downregulated, as was ldh encoding lactate dehydrogenase, a key enzyme involved in lactic acid synthesis. SnF₂ downregulated the transcription of most key enzyme genes involved in the galactose pathway and also suppressed several key genes involved in the PTS, which transports sugars into the cell in the first step of glycolysis.

Silver diamine fluoride (SDF) is a solution containing ionic silver, fluoride, and ammonia that arrests the progress of carious lesions and prevents the development of future caries. The silver particle extends into the dentin tubules and could create some bonding problems for subsequent composite resin restorations placed over SDF-treated darkened tooth structures. The fluoride penetrates deeper into the tooth with SDF as compared with other fluoride solutions, creating a fluoride reservoir in the tooth structure. The fluoride component of SDF contributes to remineralization and fluorapatite formation, producing harder, more caries-resistant tooth structures. The silver provides the antimicrobial activity for the material and inhibits biofilm formation. It has been evaluated in >20 clinical studies and reviewed in systemic reviews. The material was recently approved by the Food and Drug Administration for desensitizing cold-sensitive teeth and has been used off-label to treat carious lesions. SDF will produce a caries lesion darker (brown to black) than the original, which is the major criticism of the material. A nanoparticle-sized silver material was recently developed that may retain the antimicrobial properties of the larger-sized ion silver material without the discoloring effects. The application of SDF is easily adapted for field use. The lesion is isolated, and the solution is painted onto the clean caries lesion and dried. This simple application process requires little equipment, and its low cost per application makes the material ideal for large populations.

Medical management of caries is a distinct treatment philosophy that employs topical minimally invasive therapies that treat the disease and is not merely prevention. This strategy is justified as an alternative or supplement to traditional care by significant disease recurrence rates following comprehensive operative treatment under general anesthesia. Silver diamine fluoride (SDF) is one agent to enable effective noninvasive treatment. The announcement of breakthrough therapy designation by the Food and Drug Administration (FDA) suggests that SDF may become the first FDA-approved drug for treating caries. Since our systematic review performed in April 2015, 4 clinical trials have been completed, which inform an update to the application protocol and frequency regimen. Suggestions from these studies are to skip the rinsing step due to demonstration of safety in young children, start patients with high disease severity on an intensive regimen of multiple applications over the first few weeks, and continue with semiannual maintenance doses as previously suggested. Breakthroughs in elucidating the impact of SDF on the dental plaque microbiome inform potential opportunities for understanding caries arrest. SDF can be added to the set of evidence-based noninvasive methods to treat caries lesions in primary teeth, such as the Hall crown technique and sealing lesions with accessible margins.