Clinical Performance of Nano-Coated Orthodontic Materials In Vivo: A Systematic Review

Abstract

Background: Nanotechnology-based surface coatings show promise in enhancing the antibacterial activity and mechanical performance of orthodontic materials. Although numerous in vitro studies suggest some benefits, the clinical relevance of these effects in vivo remains uncertain. Objectives: The aim of this systematic review was to assess whether nanocoated orthodontic materials improve clinical and clinically derived laboratory outcomes in in vivo human studies, including microbial adhesion, enamel mineralization, surface characteristics and other treatment-related parameters. Materials and Methods: An electronic literature search was conducted up to 31 July 2025, yielding 15,330 records after duplicate removal. Only in vivo studies using nanocoated materials in patients undergoing orthodontic treatment were included. Study selection, data extraction, risk-of-bias assessment and certainty-of-evidence assessment were performed independently by two reviewers. Risk of bias was assessed using RoB 2 and ROBINS-I, and certainty of evidence was evaluated using GRADE. Results: A total of 13 studies were included in the qualitative synthesis. The comparative appliances were coated and uncoated brackets, tubes, archwires, miniscrews and modules. Most studies primarily assessed microbial outcomes. Overall, nanocoated orthodontic appliances showed promising antimicrobial properties and lower bacterial adhesion in several studies. Other studies assessed enamel demineralization, surface characteristics, bond failure, orthodontic miniscrew success rate and rate of canine retraction. Conclusions: Although the included studies indicate promising results, confidence is limited by heterogeneity in nanoparticle types, coating protocols and outcome measures. Safety outcomes, including coating degradation and long-term local or systemic effects, were not adequately assessed. Further well-designed randomized trials with standardized and clinically meaningful outcomes are needed before routine clinical implementation can be supported.

1. Introduction

Nanotechnology refers to the manipulation of matter on a scale ranging between 1 and 100 nanometers, where materials exhibit unique physicochemical properties not observed in their bulk form [1]. These nanoscale characteristics include a high surface area-to-volume ratio, increased chemical reactivity, and enhanced interaction with biological and microbial environments. In dentistry, these properties have catalyzed significant progress across diagnostics, restorative materials, drug delivery, and regenerative applications [2].

Orthodontic treatment, especially with fixed orthodontic appliances, is highly associated with the risk of caries, enamel demineralization and the development of white-spot lesions (WSLs) [3,4]. Bracket, band and archwire surface characteristics, particularly surface roughness and the bracket–archwire frictional interface, affect sliding mechanics and clinical efficiency, with efforts aimed at lowering resistance to sliding and reducing chairside time [5]. The application of nanotechnology advancements in the field of orthodontics seems to have the potential to transform the clinical everyday practice. Several studies already exhibit the ability of different nanoparticles (NPs) to overcome the barriers of enhancing or preserving bond strength between bracket and tooth surface, lowering bacterial colonization and microbial adhesion during treatment and reducing caries formation [6].

Modifying the surface of orthodontic materials via nanoparticle coatings may have a positive impact on their clinical performance addressing the above-mentioned difficulties. A wide spectrum of nanoparticles such as silver (Ag), titanium dioxide (TiO₂) and zinc oxide (ZnO) NPs have been tested for their antibacterial and anticaries properties [7,8]. Experimental studies demonstrated more promising long-term antibacterial effects and adequate surface roughness [9,10,11]. Results also exhibit decreased dependence on oral hygiene maintenance and increased biocompatibility of nanocoated orthodontic appliances in vitro [12]. However, limitations exist due to lack of consistency in laboratory studies regarding coating protocols, nanoparticle types and measurement methods in combination with the unique conditions in the oral environment.

Despite the presence of a great number of in vitro studies presenting the potential benefits of nanoparticle coatings, only a small number of in vivo trials have been conducted. Thus, the assumption that the outcomes arriving from experimental conditions are similar to the clinical performance of the modified materials is not safe.

Thus, the aim of this systematic review was to synthesize existing evidence from in vivo studies in order to evaluate whether nanocoated orthodontic materials used during fixed orthodontic appliance treatment provide superior clinical and clinically derived laboratory performance compared to conventional uncoated devices, with outcomes prespecified and analyzed in distinct domains (microbial outcomes, enamel demineralization, surface characteristics and other treatment-related performance outcomes).

2. Materials and Methods

2.1. Protocol

This systematic review followed the PRISMA 2020 guidelines for the implementation of systematic reviews [13]. The completed PRISMA checklist is provided in Supplementary Materials. The completed PRISMA checklist is provided in Supplementary Materials. An internal protocol was developed before study selection and specified the review question, eligibility criteria, information sources, search strategy, study selection process, data extraction, risk-of-bias assessment, outcome domains, and planned narrative synthesis. The protocol was not prospectively registered in a public registry. No major deviations from the original protocol were introduced during the conduct of the review.

2.2. Eligibility Criteria

Eligibility criteria were structured using the PICO framework and further specified by using Study design (S) and Effect/Endpoint (E).

• Population: Patients undergoing orthodontic treatment with fixed appliances (in vivo studies only). No restrictions were applied regarding sex, age, clinical or community status.
• Intervention: Use of nanocoated orthodontic materials (e.g., brackets, archwires, tubes, miniscrews) applied during orthodontic treatment.
• Comparators: Conventional uncoated orthodontic materials.
• Outcomes:

  ○

  Primary: Microbial assessment, enamel demineralization, surface characteristics

  ○

  Secondary: Bond failure rate, success rate of orthodontic miniscrews, rate of canine retraction

Outcomes were prespecified and grouped into clinically relevant domains to anticipate expected heterogeneity across materials, nanoparticle types and measurement methods.

• Study Design: Eligible study designs included controlled in vivo human clinical studies comparing nanocoated with uncoated orthodontic materials in patients undergoing orthodontic treatment. These included randomized controlled clinical trials, quasi-randomized controlled clinical studies, non-randomized controlled clinical studies and prospective controlled clinical studies. Both parallel-group and split-mouth designs were eligible. Quasi-randomized studies were defined as studies in which allocation was based on a non-random or predictable method, whereas non-randomized controlled studies were defined as controlled clinical studies without random allocation. Prospective controlled clinical studies were defined as studies in which the intervention and comparator were assessed prospectively in treated patients. In vitro, ex vivo and animal studies, case reports, reviews, editorials, studies without a comparator group, and completed or ongoing trials without available results were excluded.
• Effect/Endpoint: Any measurable clinical effect of nanoparticle coatings on the prespecified outcomes, at any time point, extracted as reported in the included studies.

2.3. Information Sources and Search Strategy

An electronic literature search was conducted up to 31 July 2025 without restriction on year, setting or geographic location, according to the predefined search protocol. The search included 15 information sources, grouped as bibliographic databases, trial registries, grey-literature sources and search engines. The bibliographic databases included PubMed, Scopus, Web of Science Core Collection, Cochrane Library, Virtual Health Library, ScienceDirect, Ovid, CRD University of York and ProQuest. Trial registries included ClinicalTrials.gov, the EU Clinical Trials Register and ISRCTN. Grey-literature sources included OpenGrey through DANS Data Station Life Sciences and NIHR Be Part of Research. Google Scholar was searched as a search engine. The complete search strategy, including the exact search strings, search dates and number of records retrieved for each information source, is provided in Supplementary Table S1.

2.4. Study Selection

Zotero software (version 7.0.24; Roy Rosenzweig Center for History and New Media, George Mason University, Fairfax, VA, USA) was used to manage and de-duplicate records [14,15]. Two reviewers independently screened the titles, the abstracts, and then the full texts. Disagreements were resolved by consensus. Reasons for exclusion at full-text stage were recorded. Authors were contacted for missing or unclear data. A PRISMA flow diagram was used to summarize the selection process [13].

2.5. Data Collection and Data Items

Two reviewers independently extracted data using a pre-defined customized data extraction form.The information gathered included authors, year of publication, country, type of study, sample size, details of the intervention and outcome metrics. For split-mouth studies, the number of participants was distinguished from the number and type of experimental units, such as treated sides, arches, brackets, archwires, orthodontic miniscrews, molar tubes or modules, where applicable. Finally, the studies were grouped for synthesis in two ways: according to their primary and secondary outcomes, as well as according to the type of orthodontic material under examination.

2.6. Risk-of-Bias Assessment

The Cochrane RoB 2 tool was utilized for randomized clinical trials [16] while the Cochrane ROBINS-I tool was used for non-randomized clinical trials [17]. Again, two reviewers assessed the risk of bias independently, and disagreements were resolved by consensus.

For split-mouth studies, the paired and intra-individual nature of the design was specifically considered during risk-of-bias assessment and interpretation of the findings. For randomized split-mouth studies assessed with RoB 2, attention was given to the randomization of the coated side or orthodontic component, possible deviations from the intended intervention, outcome measurement and whether the statistical analysis accounted for paired data. For quasi-randomized or non-randomized split-mouth studies assessed with ROBINS-I, additional attention was given to predictable allocation, possible side-, site- or arch-level confounding, classification of interventions and outcome measurement. When studies did not clearly account for the paired design or treated sides, arches, orthodontic miniscrews, brackets, archwires, tubes or modules as non-independent observations, this was considered a methodological limitation and was taken into account in the interpretation of the results and certainty-of-evidence assessment. Finally, the robvis tool web app was used to summarize the risk-of-bias assessments and generate the figures, which were subsequently edited only for typographical formatting according to journal style [18].

2.7. Certainty of Evidence

The certainty of the evidence for each major outcome domain was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [19]. The assessment included five domains: risk of bias, inconsistency, indirectness, imprecision and publication bias. The certainty of evidence was classified as high, moderate, low or very low. Randomized controlled clinical trials initially contributed high-certainty evidence. Quasi-randomized and non-randomized controlled clinical studies were considered non-randomized evidence and initially contributed low-certainty evidence. When randomized and non-randomized studies contributed to the same outcome domain, findings were not statistically pooled but were integrated narratively. In these cases, the starting certainty was determined by the study design providing the most direct and methodologically robust evidence for that outcome, while evidence from quasi-randomized or non-randomized studies was considered in the overall judgment of risk of bias, inconsistency and imprecision. Certainty was downgraded when important limitations were identified in one or more GRADE domains. No upgrading was applied because the available evidence did not demonstrate a large effect, a dose-response gradient or a situation in which all plausible residual confounding would reduce the observed effect. The detailed GRADE domain-specific judgments and reasons for downgrading are provided in Supplementary Table S3.

2.8. Summary Measures and Synthesis of Results

As studies presented substantial clinical and methodological heterogeneity, a meta-analysis was not performed. The included studies differed in the type of orthodontic material, nanoparticle composition, coating method, follow-up duration, study design, outcome definition and measurement method. Formal subgroup analyses by nanoparticle type or orthodontic material were considered; however, they were not appropriate because most subgroups included only one or two studies and frequently used different outcome metrics. Therefore, a structured narrative synthesis was performed instead, with findings summarized according to orthodontic material and outcome domain, while considering nanoparticle type, direction of effect, follow-up duration and methodological limitations. No pooled effect estimate was calculated, and the narrative synthesis should be interpreted as describing patterns and direction of findings rather than pooled or generalized treatment effects.

3. Results

3.1. Study Selection

The initial search through electronic databases retrieved 20,959 records. After the removal of the 5629 duplicates, 15,330 remained for further evaluation. Following title/abstract and full text evaluation a total of 13 studies were identified for inclusion in this systematic review (Figure 1).

3.2. Study Characteristics

Table 1 summarizes the general characteristics of all studies, grouped according to the type of orthodontic material evaluated:

• Four studies compared coated and uncoated archwires [20,21,22,23],
• four studies compared coated and uncoated brackets [24,25,26,27],
• one study compared cohorts including coated and uncoated brackets and archwires [28],
• one study compared coated and uncoated orthodontic molar tubes [29],
• two studies compared coated and uncoated orthodontic miniscrews [30,31], and finally,
• one study compared coated and uncoated modules [32].

Further, Table 2, Table 3 and Table 4 present the primary outcomes as classified in the Materials and Methods section. More specifically, Table 2 displays the microbial assessment analyzed in 10 out of 13 studies. Most studies presented antiadhesion properties and antimicrobial effects of coated orthodontic materials, mainly against Streptococcus mutans. However, four studies also provided information on gingival indices, and one study included molecular analysis. Table 3 presents the extracted data regarding enamel demineralization. Overall, the studies evaluated different materials, including archwires, modules and brackets, used different nanoparticles, including TiO₂, ZnO and Ag, and relied on different assessment methods, including DIAGNOdent, SEM and EDS. Table 4 summarizes the surface characteristics of coated stainless-steel and NiTi archwires. Again, there was diversity in nanoparticle types, outcome metrics and follow-up duration.

Finally, Table 5 summarizes the secondary outcomes. Only one study reported the bond failure rate of orthodontic molar tubes, two studies referred to the success rate of orthodontic miniscrews and two studies assessed the rate of canine retraction. Where available, key numerical comparisons between coated and uncoated materials are summarized in the corresponding evidence tables, while additional methodological details are provided in Supplementary Table S2.

Table 1. General characteristics of included studies.

Study ID (Author, Year)	Country	Design	Sample Size	Age/Sex (M/F)	Material and Coating	Comparator Material	Study Outcome
Al-Murshady and Al-Groosh, 2025 [29]	Iraq	Multi-center DB, SM RCT	18	N.A. /N.A.	Coated Orthodontic Molar Tube (COMT)/ZnO	Uncoated Orthodontic Molar Tube (OMT)	1. Bond failure 2. Microbial assessment 3. Plaque and gingival indices	Tubes
Chowdhary, 2020 [25]	India	Prospective, Quasi-randomized, SM clinical trial	11	>15 years old/N.A	022 MBT coated stainless-steel brackets/ZrO2	022 MBT Uncoated stainless-steel brackets	1. Rate of canine retraction 2. Plaque accumulation	Brackets
Alam et al., 2024 [26]	Saudi Arabia	RCT	30	12–18 years old/N.A.	Coated brackets/N.A.	Uncoated brackets	1. Biofilm formation
Monica and Padmanabhan, 2022 [27]	India	One-center, parallel-group, SM RCT	30	16 to 23 years (F) 16 to 29 years (M)/19 (F) 11 (M)	Coated stainless-steel brackets/(nitrogen-doped) TiO2	Uncoated stainless-steel brackets	1. Streptococcus mutans concentration
Hashem et al., 2022 [24]	Egypt	RCT	32	13–16 years old/N.A.	Coated stainless-steel brackets/Ag	Uncoated stainless-steel brackets	1. Enamel demineralization
Raval et al., 2025 [20]	India	SM, DB; randomization of coated side	30	N.A./N.A.	Coated stainless-steel archwires/Ag	Uncoated stainless-steel archwires	1. Surface characteristics (frictional resistance, surface roughness) 2. Microbial assessment	Archwires
Mollabashi et al., 2020 [21]	Iran	In Vivo clinical study	68	12–25 years old/40 (F) 8 (M)	Coated stainless-steel archwires/TiO2	Uncoated stainless-steel archwires	1. Antiadhesion and 2. Antibacterial properties of TiO2-coated stainless-steel orthodontic archwires against S. mutans bacteria
Venkatesan et al., 2020 [22]	India	Prospective clinical study	12	14–25 years old/N.A.	Coated NiTi archwires/TiO2	Uncoated NiTi archwires	1. Streptococcus mutans adhesion 2. Enamel demineralization 3. Surface roughness
Amini et al., 2017 [23]	Iran	In Vivo clinical study	20	15–25 years old/10 (F) 10 (M)	Coated stainless-steel archwires-TiN	Uncoated stainless-steel archwires	1. Bacterial adhesion
Fahmy et al., 2024 [28]	Egypt	SM RCT	21	N.A./N.A.	Cohort A: coated wire and coated brackets Cohort B: coated wire and uncoated brackets Cohort C: uncoated wire and coated brackets/ZrO2	Uncoated wire (other part) and uncoated brackets	1. Rate of canine retraction per month	Brackets and Archwires
Al-Hilaly and Alhuwaizi, 2025 [30]	Iraq	Multicenter, DB, SM RCT	40	13–18 years old/N.A.	Coated orthodontic miniscrews (OMSs)/Chlorhexidine Hexametaphosphate NPs	Uncoated orthodontic miniscrews	1. Success rate 2. Peri-implant health 3. Post-operative Pain 4. OMS mobility	Orthodontic Miniscrews
Mk et al., 2023 [31]	India	DB, SM clinical study	18	mean age 22.58 ± 3.52/4 (M) 14 (F)	Coated infra zygomatic crest (IZC) miniscrews/Ag	Uncoated infra zygomatic crest (IZC) miniscrews	1. Success rate 2. Molecular Analysis (bacterial assessment)
Hemashree and Padmanabhan, 2025 [32]	India	SM RCT	16	15–30 years old/N.A.	Coated Orthodontic Modules/ZnO	Uncoated Orthodontic Modules	1. Streptococcus mutans concentration 2. Enamel mineralization	Modules

Abbreviations: RCT, randomized controlled trial; DB, double-blind; SM, split-mouth; N.A., not available.

Table 1. General characteristics of included studies.

Study ID (Author, Year)	Country	Design	Sample Size	Age/Sex (M/F)	Material and Coating	Comparator Material	Study Outcome
Al-Murshady and Al-Groosh, 2025 [29]	Iraq	Multi-center DB, SM RCT	18	N.A. /N.A.	Coated Orthodontic Molar Tube (COMT)/ZnO	Uncoated Orthodontic Molar Tube (OMT)	1. Bond failure 2. Microbial assessment 3. Plaque and gingival indices	Tubes
Chowdhary, 2020 [25]	India	Prospective, Quasi-randomized, SM clinical trial	11	>15 years old/N.A	022 MBT coated stainless-steel brackets/ZrO2	022 MBT Uncoated stainless-steel brackets	1. Rate of canine retraction 2. Plaque accumulation	Brackets
Alam et al., 2024 [26]	Saudi Arabia	RCT	30	12–18 years old/N.A.	Coated brackets/N.A.	Uncoated brackets	1. Biofilm formation
Monica and Padmanabhan, 2022 [27]	India	One-center, parallel-group, SM RCT	30	16 to 23 years (F) 16 to 29 years (M)/19 (F) 11 (M)	Coated stainless-steel brackets/(nitrogen-doped) TiO2	Uncoated stainless-steel brackets	1. Streptococcus mutans concentration
Hashem et al., 2022 [24]	Egypt	RCT	32	13–16 years old/N.A.	Coated stainless-steel brackets/Ag	Uncoated stainless-steel brackets	1. Enamel demineralization
Raval et al., 2025 [20]	India	SM, DB; randomization of coated side	30	N.A./N.A.	Coated stainless-steel archwires/Ag	Uncoated stainless-steel archwires	1. Surface characteristics (frictional resistance, surface roughness) 2. Microbial assessment	Archwires
Mollabashi et al., 2020 [21]	Iran	In Vivo clinical study	68	12–25 years old/40 (F) 8 (M)	Coated stainless-steel archwires/TiO2	Uncoated stainless-steel archwires	1. Antiadhesion and 2. Antibacterial properties of TiO2-coated stainless-steel orthodontic archwires against S. mutans bacteria
Venkatesan et al., 2020 [22]	India	Prospective clinical study	12	14–25 years old/N.A.	Coated NiTi archwires/TiO2	Uncoated NiTi archwires	1. Streptococcus mutans adhesion 2. Enamel demineralization 3. Surface roughness
Amini et al., 2017 [23]	Iran	In Vivo clinical study	20	15–25 years old/10 (F) 10 (M)	Coated stainless-steel archwires-TiN	Uncoated stainless-steel archwires	1. Bacterial adhesion
Fahmy et al., 2024 [28]	Egypt	SM RCT	21	N.A./N.A.	Cohort A: coated wire and coated brackets Cohort B: coated wire and uncoated brackets Cohort C: uncoated wire and coated brackets/ZrO2	Uncoated wire (other part) and uncoated brackets	1. Rate of canine retraction per month	Brackets and Archwires
Al-Hilaly and Alhuwaizi, 2025 [30]	Iraq	Multicenter, DB, SM RCT	40	13–18 years old/N.A.	Coated orthodontic miniscrews (OMSs)/Chlorhexidine Hexametaphosphate NPs	Uncoated orthodontic miniscrews	1. Success rate 2. Peri-implant health 3. Post-operative Pain 4. OMS mobility	Orthodontic Miniscrews
Mk et al., 2023 [31]	India	DB, SM clinical study	18	mean age 22.58 ± 3.52/4 (M) 14 (F)	Coated infra zygomatic crest (IZC) miniscrews/Ag	Uncoated infra zygomatic crest (IZC) miniscrews	1. Success rate 2. Molecular Analysis (bacterial assessment)
Hemashree and Padmanabhan, 2025 [32]	India	SM RCT	16	15–30 years old/N.A.	Coated Orthodontic Modules/ZnO	Uncoated Orthodontic Modules	1. Streptococcus mutans concentration 2. Enamel mineralization	Modules

Abbreviations: RCT, randomized controlled trial; DB, double-blind; SM, split-mouth; N.A., not available.

Table 2. Microbial assessment.

Study ID (Author, Year)	Material/Coating	Follow-Up/Time Points	Measurement Method	Bacterial Species Assessed	Additional Notes
Al-Murshady and Al-Groosh, 2025 [29]	stainless-steel molar tubes/ZnO	2 weeks/T0: baseline T1: 2 weeks	CFU plate counts: blood agar; Mitis Salivarius; MRS; Gram; catalase; oxidase	Streptococcus mutans; Lactobacillus acidophilus; total anaerobic bacteria	Plaque and Gingival indices
Chowdhary, 2020 [25]	0.022 MBT stainless-steel canine brackets/ZrO2	3 months/Τ0: Start of retraction T1: 1 month T2: 3 months	Visual plaque scoring	N.A.	Extraction cases (first premolars)
Alam et al., 2024 [26]	brackets/N.A.	6 months/T0: Baseline T1: 3 months T2: 6 months	Plaque index score (biofilm quantification)	N.A.	/
Monica & Padmanabhan, 2022 [27]	stainless-steel brackets/N-doped TiO2	60 days/T1: 30 days T2: 60 days	Real-time PCR (SYBR Green); Ct value quantification; 7900HT system; SmF5/SmR4 primers	Streptococcus mutans	/
Raval et al., 2025 [20]	stainless-steel archwire/Ag	6 weeks (intraoral exposure)/6 weeks (wire retrieval)	Columbia Sheep Agar culture; 35–37 °C for 24–48 h; identification/CFU via Automated Vitek2 System	Streptococcus mutans; Lactobacillus acidophilus	Extraction cases (first premolars); MBT brackets 0.022 × 0.028-in
Mollabashi et al., 2020 [21]	stainless-steel wire/TiO2	four weeks/four groups = 1 week; 2 weeks; 3 weeks; 4 weeks	CFU counting on S. mutans-specific mitis-salivarius agar	Streptococcus mutans	Canine-to-canine segment; maxilla and mandible; MTT cell viability; Ti release
Venkatesan et al., 2020 [22]	nickel–titanium archwire/TiO2	1 month/baseline and 1 month	Real-time PCR (SYBR Green); Ct value quantification (7900HT system)	Streptococcus mutans	/
Amini et al., 2017 [23]	stainless-steel archwire/TiN	4 weeks/4 weeks (wire retrieval)	CFU counts on blood agar; incubated 37 °C for 24 h; reported in ×104 units	N.A.	Both jaws (full archwires)
Mk et al., 2023 [31]	stainless-steel IZC bone miniscrews/Ag	6–8 months/at screw retrieval (end of use)	Molecular analysis/terminal restriction fragment length polymorphism (T-RFLP); cloning-based 16S rDNA sequencing; GeneMapper 4.1 analysis	Prevotella oris strain NCTC13071; Uncultured Prevotella sp.; Capnocytophaga leadbetteri; Capnocytophaga sp.; Uncultured bacterium; Uncultured bacterium clone 069096_35	Placement: infra-zygomatic crest (IZC) region/ Requiring bilateral IZC anchorage to correct Class II
Hemashree and Padmanabhan, 2025 [32]	elastomeric modules (orthodontic ligatures) on fixed appliances/ZnO	1 year/T0: Immediately after bonding T1: 3 months T2: 1 year	Real-time PCR (qPCR) for S. mutans; Ct value quantification (Applied Biosystems)	Streptococcus mutans	Plaque samples surrounding the maxillary lateral incisors were collected at T1 and T2/ coating integrity evaluated weekly over 1 month

Table 2. Microbial assessment.

Study ID (Author, Year)	Material/Coating	Follow-Up/Time Points	Measurement Method	Bacterial Species Assessed	Additional Notes
Al-Murshady and Al-Groosh, 2025 [29]	stainless-steel molar tubes/ZnO	2 weeks/T0: baseline T1: 2 weeks	CFU plate counts: blood agar; Mitis Salivarius; MRS; Gram; catalase; oxidase	Streptococcus mutans; Lactobacillus acidophilus; total anaerobic bacteria	Plaque and Gingival indices
Chowdhary, 2020 [25]	0.022 MBT stainless-steel canine brackets/ZrO2	3 months/Τ0: Start of retraction T1: 1 month T2: 3 months	Visual plaque scoring	N.A.	Extraction cases (first premolars)
Alam et al., 2024 [26]	brackets/N.A.	6 months/T0: Baseline T1: 3 months T2: 6 months	Plaque index score (biofilm quantification)	N.A.	/
Monica & Padmanabhan, 2022 [27]	stainless-steel brackets/N-doped TiO2	60 days/T1: 30 days T2: 60 days	Real-time PCR (SYBR Green); Ct value quantification; 7900HT system; SmF5/SmR4 primers	Streptococcus mutans	/
Raval et al., 2025 [20]	stainless-steel archwire/Ag	6 weeks (intraoral exposure)/6 weeks (wire retrieval)	Columbia Sheep Agar culture; 35–37 °C for 24–48 h; identification/CFU via Automated Vitek2 System	Streptococcus mutans; Lactobacillus acidophilus	Extraction cases (first premolars); MBT brackets 0.022 × 0.028-in
Mollabashi et al., 2020 [21]	stainless-steel wire/TiO2	four weeks/four groups = 1 week; 2 weeks; 3 weeks; 4 weeks	CFU counting on S. mutans-specific mitis-salivarius agar	Streptococcus mutans	Canine-to-canine segment; maxilla and mandible; MTT cell viability; Ti release
Venkatesan et al., 2020 [22]	nickel–titanium archwire/TiO2	1 month/baseline and 1 month	Real-time PCR (SYBR Green); Ct value quantification (7900HT system)	Streptococcus mutans	/
Amini et al., 2017 [23]	stainless-steel archwire/TiN	4 weeks/4 weeks (wire retrieval)	CFU counts on blood agar; incubated 37 °C for 24 h; reported in ×104 units	N.A.	Both jaws (full archwires)
Mk et al., 2023 [31]	stainless-steel IZC bone miniscrews/Ag	6–8 months/at screw retrieval (end of use)	Molecular analysis/terminal restriction fragment length polymorphism (T-RFLP); cloning-based 16S rDNA sequencing; GeneMapper 4.1 analysis	Prevotella oris strain NCTC13071; Uncultured Prevotella sp.; Capnocytophaga leadbetteri; Capnocytophaga sp.; Uncultured bacterium; Uncultured bacterium clone 069096_35	Placement: infra-zygomatic crest (IZC) region/ Requiring bilateral IZC anchorage to correct Class II
Hemashree and Padmanabhan, 2025 [32]	elastomeric modules (orthodontic ligatures) on fixed appliances/ZnO	1 year/T0: Immediately after bonding T1: 3 months T2: 1 year	Real-time PCR (qPCR) for S. mutans; Ct value quantification (Applied Biosystems)	Streptococcus mutans	Plaque samples surrounding the maxillary lateral incisors were collected at T1 and T2/ coating integrity evaluated weekly over 1 month

Table 3. Enamel Demineralization.

Study ID (Author, Year)	Venkatesan et al., 2020 [22]	Hemashree and Padmanabhan, 2025 [32]	Hashem et al., 2022 [24]
Material/Coating	NiTi archwires/TiO2	Elastomeric modules on fixed appliances/ZnO	Stainless-steel brackets/Ag
Follow-up/time points	1 month/T0 = baseline T1 = 1 month	1 year/T0 = baseline T2 = 1 year	2 months/assessed at 1 month and 2 months
Outcome Metrics	DIAGNOdent laser fluorescence values of enamel	DIAGNOdent laser fluorescence (enamel demineralization index)	EDS calcium wt%; EDS phosphorus wt%; SEM enamel surface topography
Main Finding	No significant difference in DIAGNOdent values was found between TiO2-coated and uncoated NiTi archwires after 1 month	ZnO-coated modules showed significantly lower DIAGNOdent values than uncoated modules at 1 year	Ag-coated brackets preserved enamel calcium and phosphorus content and showed more favorable SEM enamel surface features compared with uncoated brackets

Table 3. Enamel Demineralization.

Study ID (Author, Year)	Venkatesan et al., 2020 [22]	Hemashree and Padmanabhan, 2025 [32]	Hashem et al., 2022 [24]
Material/Coating	NiTi archwires/TiO2	Elastomeric modules on fixed appliances/ZnO	Stainless-steel brackets/Ag
Follow-up/time points	1 month/T0 = baseline T1 = 1 month	1 year/T0 = baseline T2 = 1 year	2 months/assessed at 1 month and 2 months
Outcome Metrics	DIAGNOdent laser fluorescence values of enamel	DIAGNOdent laser fluorescence (enamel demineralization index)	EDS calcium wt%; EDS phosphorus wt%; SEM enamel surface topography
Main Finding	No significant difference in DIAGNOdent values was found between TiO2-coated and uncoated NiTi archwires after 1 month	ZnO-coated modules showed significantly lower DIAGNOdent values than uncoated modules at 1 year	Ag-coated brackets preserved enamel calcium and phosphorus content and showed more favorable SEM enamel surface features compared with uncoated brackets

Table 4. Surface Characteristics.

Study ID (Author, Year)	Venkatesan et al., 2020 [22]	Raval et al., 2025 [20]
Material/Coating	NiTi archwires/TiO2	Stainless-steel archwire/Ag
Follow-up/time points	1 month (intraoral exposure)/T0 = as received T1 = 1 month	6 weeks (intraoral exposure)/post-6-week retrieval; measurements at “load at limit” and “maximum load”
Outcome Metrics	Surface roughness Ra (nm); SEM topography; coating thickness (nm)	Frictional resistance (load at limit; maximum load; deflection); SEM surface roughness (qualitative)
Measurement Method	3D surface profilometer (Wyko NT1100); SEM (Zeiss Ultra 55 “Gemini”)	UTM for friction; SEM (15 kV; ×3000)
Main Findings	TiO2-coated NiTi archwires showed lower surface roughness at baseline; however, after 1 month, roughness increased in both groups and no significant difference was found between coated and uncoated archwires. The TiO2 coating also showed deterioration after intraoral use.	Ag-coated stainless-steel archwires showed no significant difference in frictional resistance compared with uncoated archwires. SEM evaluation indicated lower surface roughness in the silver-coated portion

Table 4. Surface Characteristics.

Study ID (Author, Year)	Venkatesan et al., 2020 [22]	Raval et al., 2025 [20]
Material/Coating	NiTi archwires/TiO2	Stainless-steel archwire/Ag
Follow-up/time points	1 month (intraoral exposure)/T0 = as received T1 = 1 month	6 weeks (intraoral exposure)/post-6-week retrieval; measurements at “load at limit” and “maximum load”
Outcome Metrics	Surface roughness Ra (nm); SEM topography; coating thickness (nm)	Frictional resistance (load at limit; maximum load; deflection); SEM surface roughness (qualitative)
Measurement Method	3D surface profilometer (Wyko NT1100); SEM (Zeiss Ultra 55 “Gemini”)	UTM for friction; SEM (15 kV; ×3000)
Main Findings	TiO2-coated NiTi archwires showed lower surface roughness at baseline; however, after 1 month, roughness increased in both groups and no significant difference was found between coated and uncoated archwires. The TiO2 coating also showed deterioration after intraoral use.	Ag-coated stainless-steel archwires showed no significant difference in frictional resistance compared with uncoated archwires. SEM evaluation indicated lower surface roughness in the silver-coated portion

Table 5. Secondary Outcomes.

Outcome Domain	Study ID (Author, Year)	Main Finding
Bond Failure Rate	Al-Murshady and Al-Groosh, 2025 [29]	The same number of bond failures was reported for ZnO-coated and uncoated molar tubes, with 2/36 failures in each group over 3 months.
Success Rate of Orthodontic Miniscrews	Al-Hilaly and Alhuwaizi, 2025 [30]	CHX-HMP-coated miniscrews did not show higher success than uncoated miniscrews after 4 months.
Success Rate of Orthodontic Miniscrews	Mk et al., 2023 [31]	Ag-coated IZC miniscrews showed a higher reported success rate than uncoated IZC miniscrews after 6–8 months.
Rate of Maxillary Canine Retraction	Chowdhary, 2020 [25]	ZrO2-coated brackets were associated with a higher rate of canine retraction than uncoated brackets over 3 months.
Rate of Maxillary Canine Retraction	Fahmy et al., 2024 [28]	The effect depended on the coated component: coated wire alone was associated with faster retraction, whereas coated brackets alone or combined coated brackets and wire were associated with slower retraction.

Table 5. Secondary Outcomes.

Outcome Domain	Study ID (Author, Year)	Main Finding
Bond Failure Rate	Al-Murshady and Al-Groosh, 2025 [29]	The same number of bond failures was reported for ZnO-coated and uncoated molar tubes, with 2/36 failures in each group over 3 months.
Success Rate of Orthodontic Miniscrews	Al-Hilaly and Alhuwaizi, 2025 [30]	CHX-HMP-coated miniscrews did not show higher success than uncoated miniscrews after 4 months.
Success Rate of Orthodontic Miniscrews	Mk et al., 2023 [31]	Ag-coated IZC miniscrews showed a higher reported success rate than uncoated IZC miniscrews after 6–8 months.
Rate of Maxillary Canine Retraction	Chowdhary, 2020 [25]	ZrO2-coated brackets were associated with a higher rate of canine retraction than uncoated brackets over 3 months.
Rate of Maxillary Canine Retraction	Fahmy et al., 2024 [28]	The effect depended on the coated component: coated wire alone was associated with faster retraction, whereas coated brackets alone or combined coated brackets and wire were associated with slower retraction.

3.3. Risk-of-Bias Assessment

Figure 2 and Figure 3 display the risk-of-bias assessment for randomized clinical trials (using the RoB 2 tool) and Figure 4 and Figure 5 for non-randomized clinical trials (using ROBINS-I tool). The study of Chowdhary is a prospective split-mouth quasi-randomized clinical trial but the RoB 2 tool was not applicable because the allocation of side of intervention was predetermined rather than truly randomized [25]. Following the same pattern, the study of Venkatesan et al. is a prospective split-mouth (arch-level) non-randomized controlled clinical study (12 patients; one arch received TiO₂-coated NiTi wire, the opposing arch an uncoated wire; allocation done by alternate assignment)—ROBINS-I was applied [22].

Among the randomized clinical trials assessed using RoB 2, only one study was judged to be at low risk of bias while the other ten studies raised some concerns. The domains most frequently contributing to some concerns were the randomization process, deviations from the intended interventions and selection of the reported results. Among the non-randomized studies evaluated using ROBINS-I, both studies were judged to be at moderate risk. The principal sources of bias in these studies were confounding, classification of interventions, deviations from intended interventions, measurement of outcomes and selection of reported results.

These findings indicate that most included studies had methodological limitations, which should be considered when interpreting the reported benefits of nanocoated orthodontic materials.

3.4. Certainty of Evidence

The certainty of evidence was rated as low for microbial outcomes and very low for enamel demineralization, surface characteristics, bond failure rate, orthodontic miniscrew success rate and rate of maxillary canine retraction. The certainty for microbial outcomes was downgraded because of risk of bias and imprecision, although most studies showed a favorable direction of effect for nanocoated materials. For enamel demineralization, surface characteristics, orthodontic miniscrew success rate and rate of maxillary canine retraction the certainty was further reduced because the findings were inconsistent across studies. Evidence regarding bond failure was based on only one small study with four failure events and was therefore considered very imprecise. Overall, the main factors reducing the certainty of the evidence were methodological limitations, small sample sizes, lack of confidence intervals, differences in interventions and outcome measurements, and the limited number of studies available for several outcomes. More specifically, inconsistency reflected variation in the direction or magnitude of effects for outcomes assessed in more than one study, while imprecision was mainly related to small sample sizes, few events for some outcomes, and the absence of confidence intervals. The main reasons for downgrading are summarized in

Table 6. Summary of findings and main reasons for downgrading.

Outcome Domain	Studies and Participants/Orthodontic Components	Main Findings	Main Reasons for Downgrading	Overall Certainty
Microbial assessment	10 studies; 252 participants analyzed; orthodontic components varied across studies	Most studies reported lower plaque accumulation, bacterial adhesion, colony counts or S. mutans concentration with nanocoated orthodontic materials, although the effect was not significant for every microorganism or at every follow-up period.	Risk of bias and imprecision	Low
Enamel demineralization	Three studies; 60 participants	Findings were inconsistent. One study found no difference in DIAGNOdent values after 1 month, whereas two studies suggested potential reduction of enamel mineral loss or more favorable enamel surface/mineral findings with nanocoated orthodontic materials. The studies used different coatings, orthodontic components, follow-up periods and measurement methods.	Risk of bias, inconsistency and imprecision	Very low
Surface characteristics	Two studies; 42 participants; archwires/archwire segments	Nanocoated archwires showed different surface effects depending on coating material and follow-up period. TiO2-coated NiTi archwires showed lower roughness at baseline, but this advantage was lost after 1 month. Ag-coated stainless-steel archwires appeared smoother after 6 weeks, while frictional resistance did not differ significantly.	Risk of bias, inconsistency, indirectness and imprecision	Very low
Bond failure rate	One study; 18 participants; 72 molar tubes	Bond failure occurred in two of thirty-six ZnO-coated molar tubes and two of thirty-six uncoated molar tubes during 3 months of follow-up. The small number of events does not establish equivalence.	Risk of bias and very serious imprecision	Very low
Success rate of orthodontic miniscrews	Two studies; 58 participants; 116 orthodontic miniscrews	Findings were inconsistent. One study reported higher success with Ag-coated IZC orthodontic miniscrews, whereas another found no benefit of CHX-HMP-coated orthodontic miniscrews.	Risk of bias, inconsistency and imprecision	Very low
Rate of maxillary canine retraction	Two studies; 31 participants analyzed; 62 treated canine sides	Findings were inconsistent. One study reported faster canine retraction with ZrO2-coated brackets. In the second study, coating the archwire alone increased retraction, whereas coating the bracket alone or both the bracket and archwire reduced the rate compared with the uncoated side.	Risk of bias, inconsistency and imprecision	Very low

Note: For split-mouth studies, participants and experimental units are distinguished where applicable. Participants are reported as analyzed participants when the number analyzed differed from the number recruited.

, while the detailed GRADE domain-specific judgments for risk of bias, inconsistency, indirectness, imprecision and publication bias are provided in Supplementary Table S3.

4. Discussion

The different effects of coated orthodontic materials with nanoparticles have been illustrated in several laboratory studies. There are also some systematic reviews of in vitro studies summarizing the existing evidence. A recent systematic review of in vitro studies supports the reduction in frictional resistance in the bracket–wire interface during tooth movement [33]. Another systematic review published in 2024 collected data regarding the antimicrobial efficacy of silver nanoparticles when used as coatings of brackets, archwires and micro-implants. Authors investigated in vitro studies, and they showed the ability of silver-coated devices to present antimicrobial action [34]. Although several studies reported on the in vitro behavior of nanocoated orthodontic materials there is a lack in the literature regarding their in vivo performance.

In this systematic review we examined 13 studies that investigated orthodontic materials used clinically in patients either during active treatment or under treatment conditions. A coated orthodontic material was placed and compared to the same uncoated conventional one. Overall, the primary outcomes were associated with antimicrobial properties, enamel demineralization and changes in surface characteristics. Success rate of orthodontic miniscrews, rate of canine movement and bond failure rate of orthodontic second molar tubes were also analyzed as secondary outcomes. Thus, our results extend the knowledge derived from previous reviews, as they synthesize all the existing evidence of the use of coated orthodontic materials in human beings.

Microbial assessment was the most frequently investigated outcome. Overall, most studies reported lower bacterial adhesion, colony counts, S. mutans concentration, plaque accumulation or gingival index values with nanocoated orthodontic materials, although the effects were not consistent for every microorganism or follow-up period. One study also used molecular profiling to assess bacterial profiles around coated and uncoated infrazygomatic miniscrews. Because the studies differed in material type, nanoparticle composition, follow-up duration and measurement method, these findings should be interpreted as preliminary. Despite these results, the included studies did not directly compare different nanoparticles, and therefore the clinical superiority of silver cannot be confirmed. The variable findings with TiO₂ may be related to its dependence on photocatalytic activation, while ZnO coatings may act through reactive oxygen species [8,35,36]. However, these mechanisms were not directly tested in the included clinical studies and should be considered possible explanations rather than confirmed clinical mechanisms. In all cases, the duration of the antimicrobial effect may depend on coating stability, since saliva, plaque and mastication may gradually cover or damage the active surface.

Across the three studies regarding enamel demineralization, nanoparticle coatings showed mixed findings, with some studies suggesting potential anti-demineralization effects. In the study of Venkatesan et al., there was no significant difference in enamel mineralization between TiO₂-coated and uncoated sides of the archwire by DIAGNOdent, suggesting that archwires alone may have a limited impact on demineralization [22]. In contrast, ZnO-nanocoated elastomeric modules, evaluated over one year, were associated with significantly lower laser fluorescence values [32]. Likewise, in the study of Hashem et al., nanosilver-coated stainless-steel brackets preserved enamel mineral content, whereas teeth bonded with uncoated brackets showed early demineralization changes [24]. This difference may be related to the position of the coating, as brackets and modules are located directly next to the enamel and may create areas where plaque is accumulated. However, these findings are based on only three small and heterogeneous studies with very low certainty of evidence and should therefore be interpreted cautiously. The findings regarding surface characteristics showed that nanoparticle coatings may improve wire surface smoothness initially, but this advantage was not always maintained after intraoral exposure. In the study of Raval et al., silver-coated stainless-steel archwires showed lower surface roughness on SEM than their uncoated segments after 6 weeks, with no significant change in frictional resistance versus uncoated wire [20]. In contrast, Venkatesan et al. reported that TiO₂-coated NiTi archwires started significantly smoother, but after 1 month both coated and uncoated atchwires roughened and no longer differed [22]. The oral environment can explain these changes, as saliva, pH fluctuations and repeated bracket–wire contact may increase roughness and cause wear or partial loss of the coating [37,38].

A small study also presented data about the bond failure rate of coated and uncoated orthodontic molar tubes, reporting no significant difference [29]. Silver-nanoparticle coating on infra-zygomatic miniscrews achieved a higher success rate than uncoated orthodontic miniscrews, but this finding was only presented in one study [31]. By contrast, coating miniscrews with chlorhexidine-hexametaphosphate nanoparticles did not improve success rates compared with controls over the study period [30]. Overall, these findings suggest that miniscrew stability is not only affected by coating alone, as other factors, such as bone quality and insertion technique may determine it. Zirconia-nanoparticle coatings showed mixed effects on canine retraction. In a randomized split-mouth clinical trial, coating the archwire alone was associated with faster retraction, whereas coating the brackets—either alone or together with the wire—was linked to slower movement [28]. In contrast, a separate study comparing coated and uncoated brackets found faster retraction with the coated brackets [25]. These conflicting findings may be explained by differences in coating thickness, altered bracket-slot dimensions, surface irregularities, and binding. Therefore, favorable laboratory measurements may not necessarily translate into faster clinical tooth movement.

The methodological limitations of the included studies should be considered when interpreting the reported benefits of nanocoated orthodontic materials. Most randomized studies raised some concerns in the RoB 2 assessment, and both non-randomized studies were judged to have moderate risk of bias. Together with small sample sizes, inconsistent findings, limited follow-up and the absence of confidence intervals in several studies, these limitations contributed to low certainty for microbial outcomes and very low certainty for the remaining outcome domains. Therefore, although several studies reported favorable findings, firm conclusions cannot be drawn and further well-designed clinical trials are needed.

From a clinical point of view, nanocoated orthodontic materials might help reduce bacterial adhesion and limit enamel changes during fixed appliance treatment. However, the current evidence is mostly based on surrogate outcomes, small sample sizes, and short follow-up periods. As a result, these materials should not be viewed as a replacement for standard preventive measures, including good oral hygiene instruction, fluoride use, and regular monitoring throughout orthodontic treatment.

4.1. Safety and Toxicity Considerations

Safety remains an important consideration before nanocoated orthodontic materials can be adopted routinely in clinical practice. In the clinical studies included in this review, safety outcomes were not assessed consistently. Nanoparticle release into saliva, local tissue reactions, systemic absorption and long-term accumulation were generally not evaluated. Therefore, the absence of reported adverse events should not be interpreted as confirmation of long-term local or systemic safety.

External experimental and toxicological evidence has raised safety considerations regarding specific nanoparticles. For TiO₂ nanoparticles, a recent systematic review identified mechanistic findings relevant to pulmonary carcinogenicity, particularly following inhalation exposure; however, the evidence remained insufficient to establish TiO₂ nanoparticle-induced lung carcinogenicity [39]. ZnO nanoparticles may be absorbed and distributed to systemic organs after different routes of exposure and various distribution patterns, although the detected zinc may represent dissolved ions or transformed compounds rather than intact nanoparticles [40]. Silver nanoparticles also require safety consideration, as experimental toxicological reviews have reported that Ag nanoparticle biodistribution and toxicity may depend on particle size, dose, surface coating and route of exposure [41]. These findings are relevant because orthodontic appliances remain in the oral cavity for prolonged periods, and coating degradation may lead to repeated local exposure or ingestion of released material. However, they should be interpreted cautiously because the exposure conditions differ substantially from those associated with clinical orthodontic use. In one animal study, repeated oral administration of TiO₂ did not produce treatment-related general toxicity, relevant titanium accumulation in systemic organs or DNA damage under the tested conditions [42]. An oral biodistribution study of ZnO demonstrated increased total zinc concentrations mainly in the liver, lungs and kidneys but did not establish whether the zinc was present as intact nanoparticles, dissolved ions or transformed compounds [43]. Conventional orthodontic archwires may also release metal ions into artificial saliva, indicating that intraoral corrosion and degradation can release material constituents [44]. However, this should not be interpreted as direct evidence of intact nanoparticle release from nanocoated orthodontic appliances. Overall, the included clinical studies are insufficient to establish long-term local or systemic safety, and future trials should assess coating stability, material release, local tissue responses and systemic exposure.

4.2. Limitations

Despite the abovementioned advanced properties of nanocoated orthodontic materials that align with the results of in vitro studies, one should consider the various limitations.

• Firstly, most included studies had small sample sizes, and formal sample-size justification was not consistently reported. This likely contributed to imprecision and reduced confidence in the estimated effects.
• Secondly, studies lack standardization in nanoparticle types, coating methods and duration of intervention.
• Following this, there is great heterogeneity in measurement methods and outcome metrics, thus cross-comparisons are challenging.
• Follow-up periods also varied considerably across studies, ranging from short-term assessments to one-year follow-up. Therefore, outcomes measured at different time points may not be directly comparable, especially for antimicrobial activity, enamel demineralization and coating degradation.
• In addition, several outcomes, such as microbial counts, bacterial adhesion, DIAGNOdent values and surface roughness, represent surrogate or clinically derived laboratory outcomes rather than direct patient-centered clinical endpoints.
• Furthermore, there is a need for biocompatible materials with long-lasting effects, but the small number of existing studies undermines clinical translation.
• Finally, modern orthodontics require the selection of each biomaterial in alignment with individual risk profiles. For instance, a patient may present high risk of caries and at the same time orthodontic movements should be achieved in a specific treatment time [45,46].

This review also has some methodological limitations. A meta-analysis could not be performed because of substantial heterogeneity in nanoparticle types, coated orthodontic components, outcome definitions, measurement methods and follow-up periods. Formal subgroup analyses were also not feasible because most material or nanoparticle-specific subgroups included very few studies and did not use comparable effect measures. Publication bias could not be assessed reliably because only a small number of studies contributed to each outcome. In addition, the protocol was not prospectively registered in a public registry. Although an internal protocol was developed before study selection, the absence of prospective public registration reduces methodological transparency and prevents independent verification that the eligibility criteria, outcomes and synthesis decisions were established prospectively. To reduce this risk, study selection, data extraction and risk-of-bias assessment were performed independently by two reviewers, and the search strategy is provided in the Supplementary Material.

Thus, in the future more robust randomized clinical trials are needed to produce safer conclusions about material properties and clinical outcomes. Moreover, interdisciplinary collaboration among clinicians and scientists is urgently needed to create safe biomaterials with long lasting effects that may upgrade clinical everyday practice.

5. Conclusions

Nanocoated orthodontic materials showed promising antimicrobial findings in several clinical studies, while limited evidence suggested potential anti-demineralization effects. However, the certainty of evidence was low or very low across the evaluated outcomes, mainly because of methodological limitations, small samples, heterogeneous interventions and limited follow-up. Current evidence remains insufficient to support routine clinical implementation until larger, high-quality randomized clinical trials confirm their efficacy, coating stability and long-term local and systemic safety.