An umbrella review of systematic reviews/meta-analyses evaluating the antimicrobial activity of various nanoparticles on orthodontic materials & components

Abstract

Introduction

White spot lesions (WSLs) are a prevalent issue during fixed orthodontic treatment. Orthodontic materials, such as wires, brackets, and adhesives, often create an environment that promotes microbial growth, particularly from acidogenic bacteria like Streptococcus mutans, leading to enamel demineralization. Traditional preventive measures include fluoride treatments and meticulous oral hygiene, but integrating antimicrobial nanoparticles into orthodontic materials offers a promising alternative. This umbrella review evaluates the antimicrobial efficacy of nanoparticles incorporated into orthodontic materials by assessing evidence from systematic reviews and meta-analyses. Various nanoparticles, including ZnO, Ag, and TiO₂, were studied for their potential to reduce microbial colony formation and adherence to orthodontic materials.

Materials and method

A literature search was conducted across PubMed, Google Scholar, The Cochrane Library, and LILACS, yielding one hundred and sixty-seven articles after removing duplicates. Following abstract and title screening, twenty-seven studies were selected for full-text review, and nine were included in the qualitative analysis. This review adheres to PRISMA guidelines and is registered with PROSPERO (CXXXXXXXXXXXX2).

Results

The studies indicate that incorporating AgNP into orthodontic adhesives enhances antimicrobial activity but exhibits high heterogeneity, necessitating more in vivo studies. TiO₂-coated brackets show antimicrobial properties against various pathogens. Nanoparticle-coated archwires with AgNP, N-doped TiO₂, graphene oxide, and zinc oxide reduce demineralization, are biocompatible, and reduce surface roughness, showing good to fair antimicrobial activity. Results should be interpreted cautiously, and further clinical and long-term studies are required to confirm the effectiveness of these nanoparticles in preventing white spot lesions.

Graphical abstract

1. Introduction

The development of white spot lesions (WSL) or enamel demineralization during fixed orthodontic treatment continues to be a prevalent challenge for clinicians. A meta-analysis on the incidence and prevalence of white spot lesions (WSLs) reported that 45.8 %¹ patients developed new WSLs during orthodontic treatment. Additionally, 68.4 % had existing WSLs at the time of evaluation.

Using orthodontic wires, brackets, adhesives, and other materials in the oral cavity paves the way for an environment that facilitates microbial growth. The presence of acidogenic bacteria like Streptococcus mutans, increased plaque retention due to poor hygiene accessibility, and pH imbalance in the oral cavity all contribute to demineralization^2, which is unwarranted in an orthodontic case, bearing aesthetic and health implications.

While recent times have incorporated fluoride, mouthwashes, meticulous oral hygiene, and other measures, incorporating nanoparticles that mitigate biofilm accumulation and enamel demineralization³ may prove pivotal as a preventive intervention measure in orthodontic therapy.

Nanoparticles are particles that are smaller than 100 nm in size. In dentistry, nanoparticles are used for their antimicrobial, remineralizing, and drug delivery capabilities, revolutionizing treatments for dental caries, periodontal diseases, and orthodontic appliances.⁴ While researchers have assessed the antimicrobial efficacy of incorporating such nanoparticles in orthodontic materials and components, current literature has a paucity of reviews leading to conclusive evidence.

The decision to undertake this umbrella review was driven by the need to systematically consolidate and evaluate high-level evidence regarding the antimicrobial efficacy of nanoparticles in orthodontic materials. Several key factors justify the necessity of this approach.

1.1. Fragmentation and inconsistencies in the existing literature

The application of nanoparticles in orthodontic materials has been explored in multiple systematic reviews and meta-analyses; however, these studies are often narrow in scope, focusing on specific nanoparticle types (e.g., silver, titanium dioxide, zinc oxide) or isolated orthodontic materials (e.g., adhesives, brackets, or wires). As a result, the current body of evidence remains fragmented, limiting a holistic understanding of how nanoparticles function across various orthodontic applications. An umbrella review is essential to integrate these findings and provide a comprehensive synthesis, offering a more complete and unified assessment of antimicrobial effectiveness.

1.2. Conflicting evidence and scientific Controversy

Existing systematic reviews and meta-analyses have reported heterogeneous findings regarding the antimicrobial efficacy of nanoparticles in orthodontic materials. While some studies demonstrate significant bacterial inhibition, others suggest limited or inconsistent antimicrobial effects, which may be influenced by differences in nanoparticle composition, concentration, or incorporation methods. These discrepancies create scientific uncertainty and hinder clinical translation. By synthesizing and critically evaluating these high-level studies, an umbrella review allows for a more reliable assessment of nanoparticle efficacy, helping to clarify inconsistencies and resolve existing controversies.

1.3. Need for systematic bias evaluation

Systematic reviews and meta-analyses, while considered high-level evidence, are not immune to methodological limitations, selective reporting, or publication bias. Many reviews in this domain vary in quality, with differences in study selection criteria, outcome measures, and statistical analyses potentially influencing conclusions. This umbrella review provides an objective appraisal of the methodological rigor of these studies, identifying potential biases and enhancing the reliability of the synthesized evidence.

1.4. Clinical and research implications

Nanoparticle-modified orthodontic materials hold significant promise for reducing microbial adhesion and preventing biofilm formation. However, no consolidated evidence base has been available to inform clinical decision-making. By systematically integrating data from multiple systematic reviews, this umbrella review.

• 1.Provides a comprehensive overview of antimicrobial nanoparticle efficacy across different orthodontic materials.
• 2.Identifies research gaps that warrant further investigation, particularly in areas with conflicting results or limited high-quality studies.
• 3.Offers a more structured and evidence-based framework for the future development of nanoparticle-enhanced orthodontic materials.

2. Objectives

To assess systematic reviews with or without meta-analyses for.

• 1.The amount of evidence that assesses the antimicrobial activity of nanoparticles on orthodontic materials and components
• 2.Risk of bias
• 3.To evaluate the antimicrobial efficacy i.e. the difference in microbial colony formation/adherence to the orthodontic material after the addition of nanoparticles as measured by zone inhibition, chemical indicators, biofilm formation, colony forming units, microbial adhesion by weight change, RT-PCR, caloric method, disc agar diffusion test, or other antimicrobial assays.

3. Materials and Methods

This umbrella review addresses the following PICO question:

In orthodontic materials and components (population), does the addition of nanoparticles (investigated condition) result in more effective inhibition of bacterial growth (outcome) compared to orthodontic materials or components without any modifications (comparison condition)?

Population/problem: Studies involving the use of orthodontic archwires, brackets, and bracket adhesives (including materials like NiTi, Copper NiTi, stainless steel, composite archwires, ceramic, and others).

Intervention: Studies incorporating additional nanoparticles in orthodontic materials. These nanoparticles include but are not limited to ZnO, Ag, TiO2, Cu-Zn02, silver platinum alloy, quaternary ammonium polyethyleneimine (QPEI) particles, graphene oxide, Curcumin (Cur), Curcumin-Zinc oxide (Cur-ZnO), Cu, CuO, Silver-Hydroxyapatite (Ag-HA).

Comparator: Non-modified orthodontic materials.

Outcome: Antimicrobial effectiveness, primarily measured as inhibition of bacterial growth, biofilm formation, or reduction in colony-forming units (CFUs). Secondary outcomes include changes in bacterial adhesion, long-term antimicrobial stability, and any reported clinical or laboratory measures of sustained antimicrobial activity over time.

4. Study registration

This umbrella review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on January 15, 2024, with registration number CXXXXXXXXXXXX2. It complies with PRISMA (Preferred Reporting Items for SRs and Meta-Analyses (PRISMA) guidelines, expanded with the guideline for SRs of SRs).

5. Study designs

Systematic reviews of randomized and non randomized studies, with or without meta-analyses.

6. Inclusion and exclusion criteria

Only full-text systematic reviews/meta-analyses published in English (or with an accompanying English translation) were included from inception to January 31, 2024. Additionally, reference lists of identified studies were also screened.

We excluded literature reviews, scoping reviews, case reports, case series, descriptive studies, and opinion articles. Moreover, studies exclusively evaluating the mechanical or other properties of orthodontic materials were excluded, emphasizing our primary interest in assessing the antimicrobial efficacy of nanoparticles, with a secondary consideration for other properties.

7. Search strategy

A thorough literature search was conducted on PubMed, Google Scholar, The Cochrane Library, and LILACS databases to identify eligible articles based on the population, intervention, comparison, and outcome question. The search used keywords and MeSH terms such as orthodontics, orthodontic brackets, adhesive agents, antimicrobials, antibacterials, and nanoparticles, with various permutations and combinations and the Boolean operators OR and. After obtaining the results on every database, ‘Systematic reviews’ and ‘meta-analysis’ filters were applied.

A total of 175 articles were identified, out of which 167 were screened after removing duplicates.

Zotero (version 6.0.36) software was used to remove duplicates. After abstract and title screening, 21 studies were selected for full-text screening. 12 studies were excluded, ^{5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16} 6 of which had different PICO criteria, 5 were not systematic reviews, and full-text was not available for 1 study. Finally, 9 ^{17, 18, 19, 20, 21, 22, 23, 24, 25} relevant articles were selected for qualitative analysis (Fig. 1).

Fig. 1.

PRISMA flowchart illustrating the systematic process of study selection for this review.

8. Critical appraisal and quality assessment

All the included studies were evaluated using the PRISMA checklist for systematic reviews. The risk of bias and quality assessment was done with the help of AMSTAR-2 (Measurement Tool to Assess Systematic Reviews) critical appraisal tool, which comprises sixteen checklist items. Table 2 shows the AMSTAR-2 responses of each study (see Table 3).

Table 1.

Individual study characteristics.

SR NO.	AUTHORS	COUNTRY OF ORIGIN	NO. OF STUDIES	STUDY DESIGNS	PICO	DATABASES SEARCHED	DATE RANGE OF STUDIES	TYPE OF REVIEW/METHOD OF ANALYSIS	SAMPLE	NANOPARTICLES USED	OUTCOME ASSESSMENT	MAIN RESULTS
1	Mathew T. Maliael, Remmiya M. Varghese, Aravind K. Subramanian	India	5 studies included	In-vitro studies, microbiological assays	P—Orthodontic archwires I—Nanoparticle-coated orthodontic archwire C—Non/uncoated orthodontic archwires Primary outcome—Antibacterial activity Secondary outcome—Anti-adherent activity	PubMed, Google Scholar, Cochrane Library, LILACS, Scopus	1990 to December 2021	Qualitative systematic review	SS, NiTi, Cu-NiTi wires	ZnO, Ag	The studies utilized zone inhibition, chemical indicators, biofilm formation, and colony-forming units to assess the antibacterial activity.	Maliael et al. concluded that nanoparticle-coated archwires do appear to have some effect on antimicrobial activity and adherence (Hammad et al. Mhaske et al., Kachoei et al. Espinosa Cristobal et al.). However, this could differ depending on the brand used (Goncalves et al.) and the size of nanoparticles (Espinosa-Cristobal et al.), i.e., smaller sized nanoparticles (8.1 nm) exhibited significantly (p < 0.05) better antimicrobial activity as compared to larger (20.1 nm) nanoparticles. Surface modification of orthodontic archwires by coating with nanoparticles (ZnO and Ag) appears to offer significant level of antibacterial and anti-adherent acitivity when compared to uncoated control archwires.
2	Nishanth Sivakumar, Dilip Srinivasan, Sushil Chakravarthi, Krishnaraj Rajaram, Ravi Kannan	India	6 studies included: 5 in-vitro studies and 1 prospective clinical study	Prospective controlled clinical trial, in vitro studies	P— Studies involving the use of an orthodontic arch wire. I—-: Studies involving nanocoating of orthodontic archwires. Comparator Studies comparing uncoated archwires with nanocoated archwires. Studies comparing two nanocoated archwires are not included in the study. O— Studies evaluating antimicrobial activity or colony counts as their primary outcomes and friction and roughness as secondary outcomes were included.	PubMed, Google Scholar, Cochrane Clinical Trials, Scopus, Web of Science, Embase, Medline	The initial search was carried out on August 2020 and was repeated on September 2020 to finalise before writeup.	Qualitative systematic review	SS, NiTi, CAW	Ag, TiO2, ZnO, N-doped TiO2	CFU, Microbial adhesion by weight change, S. mutans adhesion by RT-PCR, Antibacterial activity by calorimetric method, MIC, Antibacterial activity by inhibition zone	Most studies showed a reduction in microbial load, weight and friction contributing to the anti-adherence property of the coating. However, some studies did not specify the reason for anti-adherence property.
3	Mohammad Khursheed Alam, Rayan Alsuwailem, Ahmed Ali Alfawzan	Saudi Arabia	10 studies included, 3 in vivo and 7 in vitro studies	Invitro and invivo	The focused PICO question that was answered is as follows: “Whether orthodontic bracket adhesives (Population [P]) containing AgNPs (Intervention [I]) are superior to non-modified orthodontic bracket adhesives (Comparison [C]) in terms of antibacterial activity and shear bond strength (Outcome [O]) for the prevention of WSLs around brackets.”	Dissertations and Theses Global, Web of Science, LILACS, Cochrane, Medline/PubMed, Scopus	From the inception date through May 1, 2021: (1) Dissertations and Theses Global [ProQuest; 1637 – May 2021]; (2) Clarivate Analytics' Web of Science [All Databases; 1900–May 2021]; (3) LILACS [VHL Regional Portal; 1936–May 2021]; (4) Wiley's Cochrane Central Register of Controlled Trials [through May 2021]; (5) Elsevier's Scopus [1966–May 2021]; and (6) MEDLINE/PubMed [including non-MEDLINE and Pre-MEDLINE; 1945–May 2021]. The ISRCTN registry and ClinicalTrials.gov were also searched on April 31, 2021.	A quantitative meta-analysis was carried out using a fixed-effect model if an I2 statistics ≤50 % without significant methodological and clinical heterogeneities were found. Contrarily, in the case of an I2 was found to be >50 %, a random-effect model was applied. If significant statistical heterogeneity was found and noticed methodological and clinical heterogeneities, a meta-analysis will not be performed. This is accompanied by a qualitative review.	Human non-carious molar, premolar, rat non-carious premolar, incisor brackets, incisors, composite discs, bovine incisors; Experimental composite adhesive, LightBond, Blugloo, Transbond XT, Fuji Ortho LC, RGIC, Transbond nano-adhesive.	Ag	Disc agar diffusion test	According to the included articles, it might be suggested that the incorporation of varying concentrations of AgNPs into orthodontic bracket adhesives can be efficacious in the eradication of different microorganisms and does not significantly affect SBS. Ten articles were included and a meta-analysis was performed. The bacterial growth inhibition was assessed in 7/10 included studies. Out of them, 2 studies showed no bacterial growth inhibition zone adjacent to orthodontic bracket adhesives supplementing AgNPs, while 5 articles exhibited a significant microbial growth inhibition zone diameter against varying bacteria. Streptococcus mutans was the main bacteria considered by the included studies (n = 10). In the included studies, the mean SBS scores of control group adhesives ranged between 5.48 ± 1.98 MPa and 24.53 ± 4.1 MPa, while the mean SBS scores of experimental group adhesives ranged between 5.22 ± 1.16 MPa and 17.63 ± 3.2 MPa. Low risk of bias of the included articles was observed in the meta-analysis.
4	Lichi Ashwin Solankia, S.P. Saravana Dinesha, Ravindra Kumar Jaina, Arthi Balasubramaniamb	India	Total 11: 11 studies for qualitative and 5 for quantitative.	Only in-vitro studies	P—- Orthodontic brackets I—Titanium oxide coating C—-: uncoated orthodontic brackets O—-Primary: Antimicrobial activity Secondary: Surface roughness, Cytotoxic activity and bacterial adhesion.	Google Scholar, PubMed MEDLINE, Web of Science, SCOPUS	Articles till September 2022.	Meta-analysis of the primary outcomes was performed. The overall effects were calculated using a random effects model (DerSimonian- Laird random effects pooling method). A subgroup meta-analysis with pooled mean difference was done for the antimicrobial effect of TiO2 coated brackets against S. mutans, L. Acidophilus, C. albicans at 24 h incubation period.	Brackets: Ceramic, SS	Anatase phase, Rutile phase, N-doped TiO2-xNy, N-doped TiO2 coated-annealed at 350 and 450°.	No. of CFU, SE, AFM, XRD, Optical density for AA, INSTRON	On qualitative analysis, a significant antimicrobial effect of TiO2 coating on orthodontic brackets against Streptococcus mutans, Candida albicans and Lactobacillus acidophilus was reported. The meta analysis revealed a significant overall antimicrobial effect with a high heterogeneity. (SMD: 3.5; p < 0.00001; i2 - 99.2 %)
5	Joanna Rygas, Jacek Matys, Magdalena Wawrzyńska, Maria Szymonowicz and Maciej Dobrzyński	Poland	12 studies: all in-vitro.	In vitro and in vivo studies, studies published in English, and studies with a control group.	In the case of orthodontic materials (population), will the addition of graphene oxide (investigated condition) cause a change in their properties (outcome) compared to orthodontic materials without the addition of graphene (comparison condition)?	PubMed, Scopus, Web of Science, Cochrane	On February 1, 2023,	Qualitative systematic review	Transbond XT, GOG solution, TransBond Supreme low-viscosity light cure adhesive, GSEC SS archwire, PMMA, NiTi alloy	GO		Nine studies demonstrated the antibacterial properties of graphene oxide, which can reduce the demineralization of enamel during orthodontic treatment. Seven studies showed that it is biocompatible with oral tissues. Three studies presented that graphene oxide can reduce friction in the arch-bracket system. Two studies showed that it can improve the mechanical properties of orthodontic adhesives by reducing ARI (Adhesive Remnant Index). Three studies demonstrated that the use of graphene oxide in the appropriate concentration can also increase the SBS (shear bond strength) parameter. One research study showed that it can increase corrosion resistance. One research study suggested that it can be used to accelerate orthodontic tooth movement.
6	Maryam Pourhajibagher, Ahmad Sodagar, Abbas Bahador	Iran	13 studies	Study (S): Experimental studies	P—Orthodontic adhesives; I— Antimicrobial nanoparticle C—Mechanical properties of orthodontic adhe-sives containing antimicrobial nanoparticles; O—Effectiveness and/or not defectiveness on shear bond strength, as well as, observation and/or increase in inhibition zone of bacterial growth	MEDLINE, SCOPUS, EMBASE	Up to March 2019	Statistical analysis was performed by Comprehensive MetaAnalysis Software Version 2.0 (Biostat, Englewood, NJ). The prevalence was reported with 95 % confidence intervals (CIs). The heterogeneity comparison was assessed using the I 2 and Chi 2 test. After checking the heterogeneity comparison, random or fixed-effects models were used.	Orthodontic adhesives	Ag, TiO2, Cu, Cur, QPEI, Cu-ZnO2, Ag-HA, ZrO2-Ti02	Disc agar diffusion test	The results indicated no drastic changes in mechanical properties (0.812, 95 % CI [0.750, 0.861], P = 0.000). The Ag-HA, Cur, Cur-ZnO, and TiO2 in concentration ≥1 % showed a statistically significant difference, where the control groups had higher shear bond strength. Nine studies assessed the antimicrobial properties of nanoparticles. 1 wt% Cu and 5 wt% TiO2 not only did not affect shear bond strength but also showed more antimicrobial activity against Streptococcus mutans. The analysis demonstrated the absence of heterogeneity (Q value = 44.014; df (Q) = 12; and I2 = 72.736) in shear bond strength of orthodontic adhesives with nanoparticles, with low risk of bias.
7	De Almeida, C. M., da Rosa, W. L. O., Meereis, C. T. W., de Almeida, S. M., Ribeiro, J. S., da Silva, A. F., & Lund, R. G.	Brazil	32 Qualitative, 22 of which for meta-analysis	In vitro studies	P—in vitro specimens of orthodontic bonding systems with poten-tial antimicrobial activity; I—antimicro-bial agents in orthodontic bonding systems; C— materials without the presence of antimicrobial agents; O—antimicrobial activity and bond strength.	PubMed (Medline), Web of Science, Scopus, Lilacs, Ibecs, BBO, Scielo and Google Scholar	The studies were published between 2002 and 2016.	The global analysis was carried out using a random-effects model, and pooledeffect estimates were obtained by comparing the standardized mean difference of each antimicrobial orthodontic adhesive with the respective control group. A p-value <0.05 was considered as statistically significant.	Transbond XT, Enlight, Lightbond, Monolok2, Transbond Plus, Fuji ORTHO LC, Multi-cure, Blugloo, Clearfil Protect Bond, iBond, Clearfil self etching bond, Transbond Plus Self-Etching Prime, Vitremer, 4-META/MMA-TBB) resin, Fluroide microfilled composite, orthodontic fill magic, fluoride nanofilled composite orthocem, Reliance Phase 2 chemical cure composite, Superbond C&B resin, Composite, Experimental orthodontic adhesive	Cetylpyridinium chloride (CPC), Galla chinensis extract (GCE), titanium oxide (TiO2), triclosan, ursolic acid (1 study); dimethylaminododecyl methacrylate (DMADDM), dimethylaminohexadecylmethacrylate (DMAHDM), 1,3,5-triacryloylhexahydro-1,3,5-triazine (TAT) (2 studies); BAC, zinc oxide (ZnO) (3 studies); chlorhexidine, 2-methacryloyloxyethyl phosphorylcholine (MPC) (4 studies); silver nanoparticles (7 studies) in orthodontic bonding systems and 6 studies with only commercial materials.	Agar diffusion test was used to evaluate the antimicrobial activity in 15 studies, the bacterial optical densities in 2 studies and biofilm in 17	Thirty-two studies were included in the qualitative analysis; of these, 22 studies were included in the meta-analysis. Antimicrobial agents such as silver nanoparticles, benzalkonium chloride, chlorhexidine, triclosan, cetylpyridinium chloride, Galla chinensis extract, acid ursolic, dimethylaminododecyl methacrylate, dimethylaminohexadecyl methacrylate, 2-methacryloyloxyethyl phosphorylcholine, 1,3,5-triacryloylhexahydro-1,3,5-triazine, zinc oxide and titanium oxide have been incorporated into orthodontic bonding systems. The antimicrobial agent incorporation in orthodontic bonding systems showed higher antimicrobial activity than the control group in agar diffusion (overall standardized mean difference: 3.71; 95 % CI 2.98 to 4.43) and optical density tests (0.41; 95 % CI −0.05 to 0.86) (p < 0.05). However, for biofilm, the materials did not present antimicrobial activity (6.78; 95 % CI 4.78 to 8.77). Regarding bond strength, the global analysis showed antimicrobial orthodontic bonding systems were statistically similar to the control.
8	Elena Ferrando-Magraner, Carlos Bellot-Arcís, Vanessa Paredes-Gallardo, José Manuel Almerich-Silla, Verónica García-Sanz, Mercedes Fernández-Alonso and José María Montiel-Company	Spain	82 studies in qualitative, 11 studies in quantitative	In-vitro studies	Does the incorporation of nanoparticles into dental restorative materials increase their antibacterial/antimicrobial properties?	PubMed, SCOPUS, Embase	Published upto December 2018	For the meta-analysis, a random-effects model was created, and the effect size was calculated using Hedge's G standardized mean difference. Data were interpreted by ‘rule of thumb’, which took values below 0.5 as a small effect, values of 0.5–0.8 as a medium effect, and values over 0.8 as a large effect. Heterogeneity was evaluated with the Q-test and I-square value. It was considered that heterogeneity was established when the Q-test generated a p-value below 0.1, and when the I-square value was over 50 %. Funnel plots and the classic fail-safe number were used to assess publication bias. Qualitative analysis was also done.	Transbond XT, NeoBond, dental restorative materials	Ag, ZnO, TiO2, Curc, CaP, hydroxyapatite, QAD	Disc agar diffusion test, direct contact test, sterile paper discs	The incorporation of nanoparticles into dental restorative materials was a favorable option; the antibacterial activity of nanoparticle-modified dental materials was significantly higher compared with the original unmodified materials, TiO2 nanoparticles providing the greatest benefits. However, the high heterogeneity among the articles reviewed points to the need for further research and the application of standardized research protocols.
9	Suvetha Siva, Shreyas Kishore, Priyanka Aadhirai Gopinath	India	13	in-vivo studies, in-vitro	Population (P): Orthodontic bracketsIntervention (I): Brackets coated with Nano-particlesComparison (C): Uncoated bracketsOutcome (O): Increase or decrease in the antimicrobial properties and its effect on enamel demineralization or dental caries.	PubMed, Google Scholar, MEDLINE, MEDLINE in-process, Embase	January 2000–June 2021	Qualitative systematic review	Wistar rats with brackets, SS brackets, occlusal splint, metal brackets, SSPEA	Ag, Ag-Pt, TiO2, N doped TiO2-xNY, ZnO, CuO,	CFU, bacterial adherence, bacterial count	Brackets showed adequate antibacterial effect, reducing microbial colony count (see Table 1).

Table 2.

Critical Appraisal using AMSTAR-2.

SR NO	AUTHOR NAME	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	TOTAL YES	QUALITY
1	Mathew T. Maliael, Remmiya M. Varghese, Aravind K. Subramanian	Y	N	N	PY	Y	N	PY	PY	P∗	Y	NO MA CONDUCTED	NO MA CONDUCTED	N	Y	NO MA CONDUCTED	Y	5	Low
2	Nishanth Sivakumar, Dilip Srinivasan, Sushil Chakravarthi, Krishnaraj Rajaram, Ravi Kannan	Y	N	N	PY	Y	Y	Y	PY	PY	N	NO MA CONDUCTED	NO MA CONDUCTED	Y	Y	NO MA CONDUCTED	N	6	Low
3	Mohammad Khurshad Alam, Rayan Alsuwailem, Ahmed Ali Alfawzan	Y	PY	Y	Y	Y	N	Y	Y	PY	Y	Y	Y	Y	Y	Y	Y	13	High
4	Lichi Ashwin Solanki, S.P. Saravana Dinesh, Ravindra Kumar Jain, Arthi Balasubramaniam	Y	PY	Y	PY	Y	Y	Y	Y	Y	Y	Y∗	Y	Y	Y	Y	N	13	High
5	Joanna Rygas, Jacek Matys, Magdalena Wawrzyńska, Maria Szymonowicz and Maciej Dobrzyński	Y	N	N	PY	Y	Y	N	Y	N	Y	NO MA CONDUCTED	NO MA CONDUCTED	Y	N	N	Y	7	Low
6	Maryam Pourhajibagher, Ahmad Sodagar, Abbas Bahador	Y	Y	N	PY	Y	N	N	Y	Y	N	Y	Y	N	N	N	Y	8	Moderate
7	C. M. de Almeida, W. L. O. da Rosa, C. T. W. Meereis, S. M. de Almeida, J. S. Ribeiro, A. F. da Silva & Rafael Guerra Lund	Y	N	N	PY	Y	Y	N	Y	Y	N	Y	N	Y	N	N	Y	8	Moderate
8	Elena Ferrando-Magraner, Carlos Bellot-Arcís, Vanessa Paredes-Gallardo, José Manuel Almerich-Silla, Verónica García-Sanz, Mercedes Fernández-Alonso and José María Montiel-Company	Y	PY	Y	PY	Y	Y	Y	N	N	Y	Y	Y	Y	Y	Y	Y	12	Moderate
9	SUVETHA SIVA, SHREYA KISHORE, PRIYANKA, AADHIRAI GOPINATH	Y	Y	N	PY	Y	Y	N	N	N	Y	NO MA CONDUCTED	NO MA CONDUCTED	Y	N	N	Y	7	Low

Table 3.

Individual risk of bias assessment.

SR NO.	AUTHORS	INDIVIDUAL STUDY QUALITY ASSESSMENT	HETEROGENEITY
1	Mathew T. Maliael, Remmiya M. Varghese, Aravind K. Subramanian	Based on evaluation given by Ehsani et al. 3 studies had good quality methodology, 2 studies had moderate quality methodology. Overall quality: Moderate.	Present- high- exact value not reported.
2	Nishanth Sivakumar, Dilip Srinivasan, Sushil Chakravarthi, Krishnaraj Rajaram, Ravi Kannan	Downs and Black checklist: 5 studies had fair RoB and 1 study had good RoB	Present- high- exact value not reported.
3	Mohammad Khursheed Alam, Rayan Alsuwailem, Ahmed Ali Alfawzan	In-vitro studies: 2 low risk of bias, 2 moderate risk, 3 high risk. 3 In-vivo studies: ARRIVE criteria and SYRCLE tool: Low RoB.	Present
4	Lichi Ashwin Solankia, S.P. Saravana Dinesha, Ravindra Kumar Jaina, Arthi Balasubramaniamb	RoBDEMAT tool	High- I2 = 99.2 %
5	Joanna Rygas, Jacek Matys, Magdalena Wawrzyńska, Maria Szymonowicz and Maciej Dobrzyński	4 high quality, 6 moderate, 2 low quality	Present
6	Maryam Pourhajibagher, Ahmad Sodagar, Abbas Bahador	11 low, 2 moderate	Comparison assessed using fixed-effects model (I2 = 72.736)
7	De Almeida, C. M., da Rosa, W. L. O., Meereis, C. T. W., de Almeida, S. M., Ribeiro, J. S., da Silva, A. F., & Lund, R. G.	Assessed and adapted from another systematic review (Othman et al., 2002; da Rosa et al., 2015; Sedrez-Porto et al., 2016)	Considerable heterogeneity was observed (I2 = 87 %).
8	Elena Ferrando-Magraner, Carlos Bellot-Arcís, Vanessa Paredes-Gallardo, José Manuel Almerich-Silla, Verónica García-Sanz, Mercedes Fernández-Alonso and José María Montiel-Company	Following a protocol adapted from an in vitro systematic review conducted by Sarkis-Onofre et al. 43 studies were classified as at high risk of bias, while the rest showed a medium risk of bias.	High
9	SUVETHA SIVA, SHREYA KISHORE, PRIYANKA, AADHIRAI GOPINATH	NIH quality assessment tool, 11 medium quality, 1 low, 1 high	Not reported

No reviews were excluded based on methodological quality. However, each review is classified as high, medium, or low quality based on the AMSTAR-2 checklist responses. We also evaluated the extent of heterogeneity among the studies included in each systematic review and meta-analysis (where applicable). No studies were excluded from the umbrella review based on their quality. Two studies were of high quality, four of moderate quality and four of low quality i.e. at a higher risk of bias.

Effect size standardization is an essential consideration in umbrella reviews, particularly when dealing with diverse methodologies and outcome measures. However, in the context of our review, several methodological challenges and justifications must be considered regarding the feasibility and applicability of a unified effect size.

8.1. Heterogeneity in effect measures across systematic reviews

The systematic reviews and meta-analyses included in our umbrella review report varied effect measures, including.

• 4.Risk ratios (RRs) and odds ratios (ORs) in clinical outcome-based studies.
• 5.Mean differences (MD) or standardized mean differences (SMD) in vitro studies assessing bacterial adhesion and biofilm inhibition.
• 6.Qualitative narrative syntheses where meta-analysis was not feasible due to high heterogeneity.

Given this diversity in effect size reporting, an attempt to impose a single common effect size may introduce methodological bias, as it could oversimplify complex data and lead to misinterpretation of findings. This is a recognized challenge in umbrella reviews synthesizing heterogeneous studies.

8.2. Limitations in data availability for standardization

Many included systematic reviews/meta-analyses do not provide access to raw data or sufficient statistical parameters (e.g., confidence intervals, standard deviations) to allow for consistent recalculation of effect sizes. In the absence of individual study-level data, recalculating or transforming effect sizes across different systematic reviews would be prone to error and may not yield reliable comparative insights.

8.3. Risk of introducing additional statistical bias

Attempting to convert diverse effect measures into a common metric (such as Cohen's d or Hedges' g) may introduce statistical bias, particularly when dealing with studies of varying designs, sample sizes, and methodologies. Umbrella reviews differ from traditional meta-analyses in that they synthesize aggregated findings from multiple systematic reviews rather than pooling primary study data. As a result, standardizing effect sizes across reviews with different inclusion criteria, study populations, and methodologies may lead to misrepresentation of the true effect.

8.4. Established umbrella review methodology

In line with established umbrella review methodologies, our approach prioritizes qualitative synthesis and comparative interpretation over numerical standardization of effect sizes. Instead of imposing a common effect size metric, we have.

• •Provided a structured comparison of effect sizes as reported in the original reviews, respecting their methodological integrity.
• •Assessed the strength of evidence using predefined quality criteria (e.g., AMSTAR-2, GRADE).
• •Discussed the variability in findings while acknowledging methodological differences between included reviews.

9. Data extraction

Three independent reviewers identified and extracted the data from eligible articles. A predefined table was used, which comprised the author's name, journal, publication year, number of studies included, objective, study designs, PICO question (if applicable), date range, country of origin, outcome assessment, and main results. A fourth reviewer resolved discrepancies. Reviewers were not blind to the journal/authors involved in the study.

10. Results of individual studies

Maliael et al. ²⁰ concluded that nanoparticle-coated orthodontic archwires do appear to have some effect on antimicrobial activity and adherence. However, this could differ depending on the brand used ²⁶ and the size of nanoparticles, ²⁷ i.e., smaller-sized nanoparticles (8.1 nm) exhibited significantly (p < 0.05) better antimicrobial-activity as compared to larger (20.1 nm) nanoparticles. The nanoparticles were coated using electrodeposition, chemical deposition, and thermal evaporation of nanoparticles. However, none of the studies in this systematic review included a sample size calculation, and the overall methodology was moderate. A confounding effect is also possible as all studies included had no standardized assessment to measure the antibacterial effect.

Sivakumar et al.²¹ assessed the antimicrobial activity and estimated roughness/friction for silver, titanium, and zinc oxide nanocoating. Certain studies found a reduction in microbial load ^28,29 and a 34 % reduction in friction, leading to zinc oxide nanocoating's anti-adherent properties. ZnO's mechanical properties reportedly prevent surface adherence, protecting the wire from pitting and corrosion. An 87.2 % reduction was found in N-doped TiO2-coated nanoparticles as compared to a 5.9 % reduction with TiO2 alone, due to the need for UV light for ROS (reactive oxygen species) formation. Stainless steel wires showed 4.08 % increase in weight, whereas NiTi wires showed 4.4 % increase in one study. ³⁰ Friction reduction was also noted, and a bactericidal and static effect less than five-fold compared to chlorhexidine. Most studies were fair in risk of bias assessment.

Bacterial growth inhibition was assessed in 7 studies, 2 of which showed no bacterial growth inhibition zone adjacent to orthodontic adhesives with AgNPs, while 5 showed significant inhibition zone diameter against Streptococcus mutans, Lactobacillus acidophilus, Streptococcus sanguinis and Lactobacillus sorbius. The mean shear bond strength was 5.48+_ 1.98 MPa and 24.53 +_ 4.1 MPa, while that of experimental group was 5.22 +_ 1.16 MPa and 17.63 +_ 3.2 MPa. Thus, addition of nanoparticles did not significantly affect SBS. As per the fixed-effects models, an I2 value of 68.378 indicates moderately fair heterogeneity.

Solanki et al. ²³ performed a meta-analysis of the antimicrobial effect of TiO2-coated brackets and found a high heterogeneity (I2 = 99.2 %). No significant pooled mean difference was found between coated and uncoated brackets for S. mutans and L. acidophilus but was found for Candida albicans. Overall, the antimicrobial effect was significant (p-value: 0.00001), and reduced surface roughness, cytotoxic activity, and bacterial adhesion were reported in TiO2-coated brackets.

Rygas et al. ²⁵ found that graphene oxide nanoparticles reduce demineralization, are biocompatible, reduce friction in arch bracket systems, increase SBS parameters, and may also increase corrosion resistance and tooth movement.

Pourhajibagher et al. ¹⁸ performed a fixed effects model meta-analysis with I2 = 72.736, and the forest plot presented a non-significant difference between the control and experimental group. 1 wt% Cu and 5 wt% TiO2 showed more antimicrobial activity against S. mutans and did not affect shear bond strength. Mechanical properties were not changed drastically. Less than or equal to 5 wt % antimicrobial NPS to an adhesive is less conducive to microbial growth than the unmodified adhesive and does not influence bracket-enamel bond strength.

Almeida et al. ^24, in their global analysis, used a random effects model to evaluate antimicrobial activity and bond strength. I2 more than 90 % was observed in all analyses with considerable heterogeneity, and The antimicrobial agents in orthodontic bonding systems showed higher antimicrobial activity than the control group in agar diffusion (overall standardized mean difference: 3.71; 95 % CI 2.98 to 4.43), optical density tests (0.41; 95 % CI −0.05 to 0.86) (p < 0.05)and for the subgroup S. mutans. The materials did not present antimicrobial activity for biofilms (6.78; 95 % CI 4.78 to 8.77). Bond strength was not affected.

In the meta-analysis conducted by Elena et al. ²² using four studies, a significant decrease in antibacterial activity was seen in orthodontic bonding materials (Hedge's G SMD of −4.91- CI 95 % from 5.99 to −3.83, p-value <0.001). An I2 value of 85.4 was reported, indicating high heterogeneity. For resin materials, Hedge's G SMD of −1.78 (CI 95 % from −2.60 to −0.97 at p-value <0.001) was found, along with I2 value of 87.15. Forest plot on dental restorative materials based on ten studies also showed a Hedge's G SMD of −1.32 at 95 % CI from −1.66 to −0.98 and an I2 value of 79.7. No significant effect was found for subgroup CaP, CaP/Ag, but for curcumin and TiO2, there were significant improvements. A meta-regression based on these found that nanoparticle concentration had no significant effect, with R2 being 0 for the two analyses.

As for the qualitative analysis, most studies found better antimicrobial capabilities for nanoparticle-modified components and materials, albeit with the possibility of bias. Magalhaes et al.‘s study ³¹ reported no change in activity on adding Ag NPS to resin-based cement, and Garcia-Contreras et al. ³² found no increase in antibacterial activity for two materials, except for TiO2. Sterilization protocols, commercially acquired NPS, manufacturer details, sample polishing, incubation period, sample size calculation, and number of operators involved in testing must be considered.

In the study by Suvetha et al., ¹⁷ most studies found that Ag nanoparticle-coated brackets exhibit significant antibacterial properties. Ag/TiO2 coated brackets also have good biocompatibility. ZnO-coated brackets showed less antimicrobial activity than CuO and CuO-ZnO groups. N-doped TiO2-xNY particles also have good antimicrobial activity because of lesser bacterial adherence.

While formal de-duplication or redundancy-checking methods were not explicitly applied, this decision is methodologically justified based on the following key considerations.

10.1. The primary aim of umbrella reviews is comparative synthesis, not pooled data analysis

Unlike meta-analyses, where redundancy can lead to an overestimation of effects due to duplicate inclusion of primary studies, umbrella reviews function at a higher level of evidence synthesis. The objective is to compare and contrast systematic reviews and meta-analyses, rather than to conduct a cumulative data synthesis. Thus, the focus remains on evaluating the concordance of findings, differences in conclusions, and methodological rigor rather than removing potentially overlapping studies.

Systematic reviews and meta-analyses inherently interpret and weigh primary studies differently based on their inclusion/exclusion criteria, risk of bias assessments, and statistical methodologies. Filtering out reviews with overlapping primary studies may artificially distort the breadth of existing evidence rather than improving reliability.

10.2. The diversity of included systematic reviews mitigates redundancy impact

The systematic reviews and meta-analyses included in this umbrella review exhibit substantial variability in: Inclusion criteria (e.g., orthodontic material types, specific nanoparticles, experimental conditions) - Outcome measures (e.g., bacterial adhesion, biofilm inhibition, clinical efficacy). - Analytical methods (e.g., different effect size metrics, subgroup analyses).

Given these differences, even if the same primary study appears in multiple systematic reviews, it is often analyzed differently—contributing to distinct interpretations and conclusions. Removing studies based solely on overlap would introduce selection bias by disproportionately favoring certain reviews over others and potentially omitting nuanced analytical perspectives.

Previous research on umbrella review methodology emphasizes that inclusion of multiple systematic reviews, even with some degree of overlap, provides a more comprehensive assessment of available evidence than selective exclusion.

10.3. Avoiding selection bias through systematic comparative analysis

Instead of filtering out systematic reviews based on overlapping primary studies, we employed structured comparative analysis to ensure that conclusions were drawn from a broad, unbiased synthesis. This was achieved by: Cross-referencing key primary studies across systematic reviews to identify any potential overrepresentation of specific findings. Highlighting inconsistencies or variations in conclusions among systematic reviews to ensure balanced reporting. Using standardized quality assessment tools (e.g., AMSTAR-2) to evaluate the reliability of included reviews and weigh their findings accordingly.

The Cochrane Handbook advises that in umbrella reviews, selection bias can be minimized by critically appraising and comparing reviews rather than excluding overlapping ones, as exclusions based on overlap alone may introduce subjective bias in evidence synthesis.

10.4. Preserving the integrity of the evidence base without artificial filtering

Applying strict redundancy filters in an umbrella review can lead to artificial narrowing of the available evidence, particularly when systematic reviews employ different methodologies. Instead, we adhered to best-practice approaches by.

• 7.Synthesizing findings across all included systematic reviews rather than focusing on any single review's conclusions.
• 8.Ensuring transparency by reporting the overlap of primary studies where relevant, rather than using exclusionary measures that may distort the comprehensive nature of our review.

Current guidance on umbrella reviews suggests that methodological heterogeneity between systematic reviews is a strength rather than a limitation, as it allows for a broader, more representative synthesis of findings.

11. Discussion

The contact points between orthodontic components and teeth allow bacteria to colonize, resulting in enamel demineralization. These irreversible changes demand intervention as they are aesthetically unappealing and lead to the commencement of dental caries. Studies have reported that stainless steel brackets have high critical surface tension and energy, thus paving the way for plaque formation, retention, and colonization by cariogenic bacteria like Streptococcus mutants and Lactobacillus.

Since WSLs are often formed around brackets and not beneath them, the evaluation of the antimicrobial effects due to the release of nanoparticles is critical. The leading cause for plaque retention is bacterial adherence, and this adherence can be detected by changing the surface characteristics of orthodontic components. This concept used antibacterial nanoparticles like Ag, ZnO, TiO2, etc., to modify surface topography.

While many primary studies have demonstrated an association between nanoparticle addition and increased antimicrobial action, the results across many such studies remain ambivalent. Thus, this umbrella review was used to analyze current literature and identify the potentials and limitations that may improve the reporting standards in the future.

As reported by L.A. Solanki et al., ²³ orthodontic brackets coated with TiO₂ nanoparticles had a lesser surface roughness, less bacterial adhesion, and less cytotoxic activity compared to uncoated brackets. Based on the studies they included in their systematic review, they reported that coated brackets have significantly higher antimicrobial activity than uncoated brackets. TiO2 has high photocatalytic activity, which generates ROS under UV-A light exposure that allows easy penetration into the cell walls and cell membranes and causes oxidative damage. TiO₂ exhibited this property either by UV light illumination or by N-doping with the visible light spectrum, proving to be more clinically accepted. These changes were observed because of the release of hydroxyl ions from TiO2 that react with surface molecules of bacteria, causing surface decomposition and the formation of a fragile wall.

AgNPs are reported to have better contact with microorganisms due to their larger surface area than other salts. Cell death is caused by disrupting the respiratory chain and leakage via holes in cell wall. ZnO also increases oxidative stress and disrupts lipids, proteins, carbohydrates and DNA. Graphene oxide is known to have its action via 3 potential mechanisms-formation of reactive oxygen species, nano-sharpening effect and wrapping effect. Graphene oxide nanoparticles were found to have increased biofilm inhibition without compromising SBS. They also reduce friction and contribute to corrosion resistance in the archwire-bracket system. However, a higher coating could compromise the biocompatibility of GO-coated NiTi wires.

Two studies ^33,34 included in M.K. Alam et al.‘s paper did not show any bacterial growth inhibition zone for bracket adhesives with AgNPs, indicating poor diffusion and insolubility of AgNPs. Solanki et al. ²³ also reported no significant antimicrobial activity when subjected to meta-analysis of TiO2 on orthodontic brackets (P value = 0.15).

Maghalaes et al. ³¹ concluded that AgNP incorporation in resin-based cement did not increase its antibacterial activity but led to a color change and greater sorption than its control. In a study analyzing three types of materials, only one produced increased antibacterial activity by adding TiO2. The addition of ZnO nanoparticles in Glass Ionomer Cement did not show any changes. (Medicina). However, these studies had shorter incubation periods compared to others. ²²

In general, no significant relation was found between antimicrobial activity and shear bond strength scores after the addition of nanoparticles, except for adhesives with >1 wt %.

However, all systematic reviews conclude that the addition of nanoparticles, irrespective of the type used, enhances the antibacterial efficacy of orthodontic components and materials and may prove pivotal in the prevention of WSLs around them. However, the certainty of evidence is questionable. Only two studies included were of high quality, and the high heterogeneity reported in most of these systematic reviews is a critical point to be assessed. Due to the high variability in the nine studies reviewed, a meta-analysis could not be possible. Moreover, there was a lack of standardized assessment in the reviews. Different tests were used to assess the antimicrobial activity, such as Colony Forming Units, zone inhibition, chemical indicators, biofilm formation, PCR, calorimetric tests, disc agar diffusion tests, etc. Techniques such as electrodeposition, physical vapor deposition and others were used to coat such nanoparticles on the components. This invariability between the selected studies could contribute to a huge risk of bias.

11.1. Strengths of the umbrella review

This umbrella review presents a novel and timely synthesis of the rapidly expanding literature on the antimicrobial enhancement of orthodontic materials via nanoparticle incorporation—an area of growing interest due to the persistent challenges of biofilm formation and enamel demineralization during fixed orthodontic treatment. To our knowledge, this is the first umbrella review that systematically compiles, evaluates, and integrates findings from existing systematic reviews and meta-analyses in this niche yet clinically important field. By applying a structured framework, we ensure methodological transparency, reproducibility, and critical appraisal of the evidence base. The breadth of nanoparticle types, orthodontic components, and antimicrobial outcomes assessed further enhances the depth and scope of the review, offering a strategic knowledge synthesis that can inform both clinical decision-making and material innovation.

11.2. Limitations of the study

Despite its comprehensive nature, this umbrella review is limited by the inherent variability and heterogeneity in the included systematic reviews, particularly in the type of nanoparticles, concentration used, testing conditions, microbial strains assessed, and measurement techniques. A majority of the evidence remains laboratory-based (in vitro), which may not fully predict clinical outcomes. Furthermore, although potential overlap of primary studies across reviews is acknowledged, no formal de-duplication algorithm was applied due to the descriptive nature of the synthesis; this is a recognized methodological limitation in many umbrella reviews and was mitigated by careful manual screening. While each review employed different coating methods, we cannot conclude the superiority of any coating method. We summarized all nanoparticles in general, further studies on the salient characteristics of each nanoparticle is recommended.

11.3. Generalizability and relevance

The findings of this review offer broad translational value for researchers, material scientists, and orthodontic clinicians. By synthesizing diverse data on multiple nanomaterials and orthodontic substrates, the review provides a strategic, high-level overview of where the field currently stands and where future innovations can be directed. This work bridges the gap between nanotechnology, microbiology, and clinical orthodontics, paving the way for future interdisciplinary research and product development. Moreover, in an era where antimicrobial resistance and biofilm-associated infections pose increasing clinical challenges, this review provides evidence-informed direction for the development of next-generation, antimicrobial orthodontic devices. It holds public health relevance by potentially reducing the risk of caries and periodontal complications in orthodontic patients, particularly adolescents—a population highly vulnerable to poor oral hygiene.

12. Conclusions

Within the limitations of this umbrella review, the following conclusions can be deduced.

• ●Incorporating AgNP into orthodontic adhesives enhances its antimicrobial activity, but high degree of heterogeneity exists due to deficits in the in vitro model. Their clinical use must be reconsidered after introducing more in vivo studies.
• ●TiO₂ coated brackets have shown antimicrobial properties against S. Mutans, L. Acidophilus, C. Albicans but with high heterogeneity.
• ●Nanoparticle-coated orthodontic archwires using electrodeposition, chemical deposition, and thermal evaporation of nanoparticles appear to have little antimicrobial activity.
• ●Archwire nanocoating with AgNP, N-doped TiO₂-coated nanoparticles, graphene oxide, and zinc oxide has been shown to reduce demineralization, is biocompatible, and reduces surface roughness in the archwire-bracket system. Thus, these nanoparticles have demonstrated good to fair antimicrobial activity.
• ●Results should be interpreted with caution. Clinical and long-term studies are still necessary to confirm the effectiveness of the antimicrobial properties of nanoparticles on orthodontic materials and components in preventing white spot lesions.

Patient/guardian consent

As this research was an umbrella review of existing literature, patient/guardian consent was not applicable.

Contribution details

Conceptualization, V.K. and A.S. and R.S; Methodology, M.J, A.S. and M.V.; formal analysis, M.V and R.S.; Data curation, A.S.; Writing—original draft preparation, A.S, M.J, V.K; Writing—review and editing, R.S, M.V; Supervision, M.V and V.K.

PROSPERO registry number

This umbrella review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on January 15, 2024, with registration number CRD42024499092.

Ethical statement

This umbrella review used data from published studies and did not require ethical approval, as no new data was collected. The Institutional Ethics Committee thereby waived off ethical approval.

Source(s) of support

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.