Clinical efficacy and the antimicrobial potential of silver formulations in arresting dental caries: a systematic review

Present strategies of deep-caries management include selective caries removal, to lessen the risk of pulp exposure and consequent complications, that can compromise the longevity of the tooth [11]. However, up until now, there is no consensus on the quantity of the affected dentine in the carious lesion that should be removed. Clinical criteria indicative of caries-free status after debridement are rather crude and are currently based on naked-eye, subjective assessment of the color of residual caries, hardness on probing, and moisture content of the dentine [12‐16].

Employing contemporary partial removal philosophy, the success related to partial caries removal can occur if a hermetic restoration is placed to avoid microbial proliferation. It is currently surmised that viable microbes entombed within a placed restorations undergo a process of prolonged starvation leading to microbial dormancy and death, thus resulting in lesion arrest [17, 18]. On the contrary, several reports have now described the ability of such entombed microbes are capable of proliferation and survival, even with a limited supply of nutrients [19]. Entrapped microbial species within a restoration can survive within this nutrient-starved ecosystem by procuring glycoproteins and amino acid supplies from the pulpal fluids [20]. It has been suggested that the survival and growth of residual bacteria in such an adverse eco-system depend upon the ‘baseline’ pulpal health, remaining dentine thickness, the core composition of the residual microbiota, and the microbial load at the time of restoration [19, 21, 22]. For instance, in a recent seminal study, Marggraf and et al., [21] performed a kinetic assessment of S. sobrinus and L. rahmnosus beneath different restorative materials in stressed environments and noted that the survival kinetics of residual microbes were both strain-, and sealing- material-dependent.

The preceding, therefore, implies that a) microbes can survive and proliferate in stressed ecosystems even under sealed restorations, b) the composition, the load, and the species specificity of the residual microbiota determine their survival lifespan, c) the quality of the lesional floor and the dentine that entombs the restoration may be crucial for the microbial viability, and finally, d) the quality of the restorative material is an essential determinative factor. However, contemporary best practice does not, as yet, have any standardized microbiological-grounded approach in its caries management guidelines.

Given the variety of factors that affect the microbial survival within restorations, and the inability of the widely used restorative materials to destroy all the residual microbes in such locales, novel material formulations are imperative. The development and evaluation of this chemical armamentarium available in dentistry is necessary to tackle the issue of worldwide prevalence of rampant dentinal caries.

Elemental silver has been used as a biocide in a variety of biomedical applications for many a decade [23‐26]. Indeed, silver in various formulations have been used since early 1900 to treat and arrest dental caries, and the metallic element incorporated in several dental products [27‐29].

The exact mechanisms by which particulate silver kills bacteria and fungi are not precise, but several probable ways by which it may cause microbial destruction have been postulated [30, 31]. These include electrostatic bonding of silver ions to the anionic components of the microbial cell membranes, which appear to cause cell content leakage, abrogation of cell motility (in motile bacteria), and cell death. Second, Ag + ions appear to be toxic and thus poison the metabolic enzymes and block electron transport systems. Finally, they also seem to inactivate bacterial DNA and RNA via yet unknown pathways [32, 33].

Perhaps the earliest use of silver in dentistry was in the form of dental amalgam, which is a liquid mercury and metal alloy comprising mercury (50%), silver (22–32%), tin (14%), copper (8%) and other trace metals [34]. Another silver-containing compound, silver diamine fluoride (SDF), was introduced more than a decade ago to manage caries in primary and permanent teeth but was not particularly favored by the dental profession and gradually fell into disuse [35]. However, there has been a current resurgence of SDF usage, particularly for arresting and preventing dental caries progression in children [36, 37]. Interestingly, the Federal Drug Administration of the USA has approved the use of SDF for the dental and related purpose since 2014 [38].

Recent advances in manufacturing and biomaterial technology have led to the development of ‘second generation’ of silver products, and these include nano-molecules and nano-scaled silver nanoparticles (AgNPs). The particle size of nanomaterials ranges between 1 and 100 nm, and they appear to exhibit size-dependent physicochemical properties [39]. The bactericidal effect of AgNP is highest in the 1–10 nm size range, whence they exhibit highly reactive surface interactions [40].

The very small size and large contact area of nanoparticles have a remarkable effect on viable eukaryotic cells, influencing uptake efficiency, permeating cell membranes, and internalization, eventually leading to intracellular cytotoxicity and cell death, at high concentrations, [41] The high degree of cytotoxicity appears to be related to their nanoscale size, shape, surface area per unit mass, surface charge, and nonspecific oxidative damage [42, 43].

AgNP compounds currently used in dentistry include nanocomposites, adhesives, implant coatings, orthodontic material, and intracanal medicaments [29, 37, 38]. Due to the intense penetrative capacity and the microbicidal effects of AgNP, they appear to be good candidate chemicals for sanitization and disinfection of deep dentinal lesions, mainly to destroy the residual bacterial burden, after conservative caries removal (e.g., Atraumatic restorative treatment (ART).

Numerous in vitro and in vivo studies are available where silver compounds have been used in the management of human dental caries [27, 30, 36, 44‐48]. However, to our knowledge, we are unaware of a systematic review that attempts to answer the question, “How effective is silver against cariogenic microbes in dentin biofilm?”

Hence, the primary objective of the present review was to systematically review the clinical application and antimicrobial potential of silver-containing formulation for caries arrest. Our secondary goal was to summarize the available in vitro evidence of microbicidal efficacy of silver-containing formulations against ‘cariogenic’ microbiota in dentine.

We believe that our findings reported here provide a state-of-the-art summary on the potency and the effectiveness of silver-compounds used in dentistry in eradicating cariogenic microbes in infected-dentine.

Two investigators (LPS and KSF) performed an electronic search of English language manuscripts using Ovid MEDLINE, EBSCO host, Web of Science, and Cochrane Library databases. Published in vitro and in vivo studies were accessed between January 2009 and May 2019. A specific review question was formulated using the PICO framework as follows. Do silver-containing compounds (SDF/SDF + KI/AgNO₃, nanosilver) (I) compared to distilled water/saline/Chlorhexidine (C) result in an efficient microbial reduction (O) in (P) dentin caries? The search keywords and combination of keywords were organized according to the PICO model, as illustrated in Table 1.

Pre-determined inclusion criteria were:

Clinical (in vivo)application: 1) English language articles, 2) dentine/dentinal caries, 3) primary teeth, 4) permanent teeth, 5) ‘cariogenic’ microbes/bacteria, 6) antimicrobial effect, 7) pre-post microbial/bacterial reduction (caries arrest), 8) silver-based cavity disinfectants/formulations, and 9) asymptomatic dentine lesion.

The exclusion criteria included: 1) review articles lacking related clinical data, 2) reports that do not allow extraction of data required to meet the set objectives, 3) enamel caries, 4) bovine dentin, 5) silver-based dental biomaterials, 6) studies with incomplete outcome details, 7) recruits (patient) on antibiotics, and 8) poster/conference presentation/abstracts. Grey literature and unpublished information through reading, were neither considered nor used; country or date enforced no limitations.

The identified research articles were compiled using bibliographic software, Endnote version 9. (Clarivate Analytics, USA).

To ensure a systematic and comprehensive process, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines-PRISMA [49, 50]. The employed search strategy and results are summarized in Fig. 1.

The electronic data search and analysis were carried out in three stages. In stage one, the titles and abstracts of all identified relevant studies meeting predetermined inclusion criteria were screened. The full-text review was considered to have complete details of the data to make a precise decision. For the full-text review, the investigators (using spreadsheets) ensured that the eligibility criteria were met and that the outcomes meeting the study objectives were reported and retrievable. References were checked as a backward search of the included studies. To identify other studies that could be considered, a manual search of the listed references from the included articles was performed. In the third and final stage, the reviewer extracted and analyzed the data.

Using the Cochrane Collaboration risk of the bias assessment tool, the risk of bias was assessed to evaluate the methodological quality of the study [51]. This included an assessment of the method of randomization, allocation concealment, blinding of outcome assessment, selective reporting, and other sources of biases. Any discrepancies were discussed until mutual consensus was reached between the reviewers and the paper documented as low, unclear, or high risk.

A total of 326 articles were identified after screening the different electronic databases, after which 43 duplicate publications were removed, leading to 283 studies that were initially reviewed. Of these, a total of 29 articles were identified and selected for full-text review as per the selection criteria for further analysis. The remaining publications were not considered as they were studies on enamel caries, caries prevention, erosion, or AgNP infused dental materials, that were unrelated to the present investigation. The employed search strategy and results are summarized in Fig. 1.

After reviewing the full text, in-depth detail of the characteristics of each study was recorded using the Cochrane pattern. This facilitated identifying the study design, setting and country, funding sources, specimen preparation, and test-microbes. Moreover, the type of intervention, comparator, evaluation time, assessment methods, sample size, statistical analysis, and study outcomes were comprehensively examined.

After an extensive review of the characteristics of the articles and drawing details from the tables evaluating the risk of bias of each trial, 14 studies were deemed suitable for the current systematic review (Table 2). Of 14-included studies, only three in vivo and five in vitro trials investigated the antimicrobial effectiveness of SDF, SDF/KI, AgNPs, AgNO₃ in caries affected dentine of primary and permanent teeth. Summary of the characteristics of included studies and the reported results of antimicrobial efficacy of silver-compounds in these trials are summarized in Tables 3 and 4. Information detailing risk of bias assessment of each trial are given in Table 5.