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Background:
Systematic Review

Efficacy of Antimicrobial Photodynamic Therapy Mediated by Photosensitizers Conjugated with Inorganic Nanoparticles: Systematic Review and Meta-Analysis

by
Túlio Morandin Ferrisse
1,
Luana Mendonça Dias
1,
Analú Barros de Oliveira
2,
Cláudia Carolina Jordão
1,
Ewerton Garcia de Oliveira Mima
1 and
Ana Claudia Pavarina
1,*
1
Department of Dental Materials and Prosthodontics, School of Dentistry at Araraquara, Universidade Estadual Paulista (UNESP), Araraquara 14801-903, SP, Brazil
2
Department of Morphology, Pediatric Dentistry and Orthodontic, School of Dentistry, São Paulo State University (UNESP), Araraquara 14801-903, SP, Brazil
*
Author to whom correspondence should be addressed.
Pharmaceutics 2022, 14(10), 2050; https://doi.org/10.3390/pharmaceutics14102050
Submission received: 20 August 2022 / Revised: 9 September 2022 / Accepted: 11 September 2022 / Published: 26 September 2022
(This article belongs to the Special Issue Photosensitizers and Drug Delivery Systems for Antimicrobial Photodynamic Therapy)
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Abstract

:
Antimicrobial photodynamic therapy (aPDT) is a method that does not seem to promote antimicrobial resistance. Photosensitizers (PS) conjugated with inorganic nanoparticles for the drug-delivery system have the purpose of enhancing the efficacy of aPDT. The present study was to perform a systematic review and meta-analysis of the efficacy of aPDT mediated by PS conjugated with inorganic nanoparticles. The PubMed, Scopus, Web of Science, Science Direct, Cochrane Library, SciELO, and Lilacs databases were searched. OHAT Rob toll was used to assess the risk of bias. A random effect model with an odds ratio (OR) and effect measure was used. Fourteen articles were able to be included in the present review. The most frequent microorganisms evaluated were Staphylococcus aureus and Escherichia coli, and metallic and silica nanoparticles were the most common drug-delivery systems associated with PS. Articles showed biases related to blinding. Significant results were found in aPDT mediated by PS conjugated with inorganic nanoparticles for overall reduction of microorganism cultured in suspension (OR = 0.19 [0.07; 0.67]/p-value = 0.0019), E. coli (OR = 0.08 [0.01; 0.52]/p-value = 0.0081), and for Gram-negative bacteria (OR = 0.12 [0.02; 0.56/p-value = 0.0071). This association approach significantly improved the efficacy in the reduction of microbial cells. However, additional blinding studies evaluating the efficacy of this therapy over microorganisms cultured in biofilm are required.

1. Introduction

Antimicrobial-resistant infection is responsible for 5 million people’s deaths annually [1]. However, considering that 2 billion people live in countries with unsatisfactory diagnostic capacity, this deaths rates must be greater [2]. In addition, by the year 2050, antimicrobial-resistant pathogens are projected to kill 10 million people each year [3]. The misuse and overuse of antimicrobial agents are the main reasons related to the emergence and spread of antimicrobial-resistant infection [4]. In bacteria, the reduced permeability of antibiotics, the increased efflux pumps, changes in antibiotic targets by mutation, the modification and protection of targets, and the inactivation of antibiotics by hydrolysis or by the transfer of a chemical group are the main molecular mechanisms associated with bacterial resistance [5]. In fungi, the molecular mechanisms associated with acquired resistance are increased efflux pump activity, EGR, ERG11, CYP51, FKS mutations, and decreased membrane ergosterol activity [6].
In addition, the organization of microorganisms in biofilm provides an increase in the tolerance of microorganisms against conventional antimicrobial agents [7]. Biofilms are one of the most widely distributed and successful ways of life, which are defined as aggregates of microorganisms in which cells are frequently embedded in a self-produced matrix of extracellular polymeric substances [7,8]. In this scenario, the search for new therapeutic strategies for the inactivation of pathogenic microorganisms is extremely needed.
Antimicrobial photodynamic therapy (aPDT) is a non-invasive form of treatment based on a combination of a photosensitizer, light with appropriate wavelength, and oxygen dissolved in the application site [9]. As a result of this combination, a photophysical and photochemical mechanism leads to a biological response via the production of reactive oxygen species (ROS), causing the destruction of the target [10]. In addition, the absence of development of microbial resistance to aPDT strengthens further studies for better optimization of this approach [11].
Despite significant results after aPDT application for the reduction of microbial load against many types of microorganisms [12,13,14,15,16,17], studies have been conducted to enhance the efficacy of aPDT [18]. In this context, a diverse type of nanoparticles has been used as a drug delivery system facilitating the photosensitizer uptake in microbial cells and improving bioavailability, solubility, permeability, and selectivity [19]. Inorganic nanoparticles are characterized by physical-chemical stability, good bioavailability, degradation resistance, low toxicity, and improved therapeutic action [20]. The inorganic nanoparticles are divided into metal oxides (iron oxide, zinc oxide, etc.) [21], semiconductors (graphene quantum dots), mesoporous silica, and metallic nanoparticles [22]. Thus, the present study aimed to perform a systematic review and meta-analysis of the effect of aPDT mediated by photosensitizers conjugated with inorganic nanoparticles to reduce microbial load.

2. Materials and Methods

2.1. Protocol and Registration

The Preferred Reporting Items for Systematic Reviews (PRISMA) statement [23] was used to conduct the planning and running of the present systematic review and meta-analysis. In addition, the register was made in the Open Science Framework (OSF)—registration doi: 10.17605/OSF.IO/XNCGD.

2.2. Data Extraction and Research Question

The research question was based on the PICO strategy for systematic reviews, where P = microbial load evaluated in any type of study (e.g., in vitro, animal studies, clinical trials), I = aPDT associated with photosensitizers conjugated with inorganic nanoparticles, C = isolated therapy (aPDT) and O = reduction of microbial load. Secondary outcomes, for instance, changes in biofilm matrix, were also extracted. The present study aimed to answer the following focused question “Does the association between aPDT and inorganic nanoparticles increase the efficacy of the therapy for microbial control compared to aPDT only?” Further data on the name of the first author, the date of publication, study design, inorganic nanoparticle used, light dose, irradiation time (min), wavelength (nm), photosensitizer, pre-irradiation time, microorganism, culture type, sample size, and main outcomes were extracted from the articles included in this systematic review after the screening.

2.3. Eligibility Criteria

The inclusion criteria for this systematic review were the use of aPDT associated with inorganic nanoparticles for microbial control. There were no restrictions on the type of study design (e.g., the inclusion of in vitro and in vivo studies, observational human studies, and randomized clinical trials), language, and microorganisms. Studies that did not evaluate the isolated therapy (aPDT) as the control group, review articles, case reports, other modalities of treatment using inorganic nanoparticles, and aPDT combined with other modalities of treatment (e.g., photochemical therapy) were excluded.

2.4. Search Strategy

Firstly, two independent examiners were calibrated to perform all processes related to article selection. PubMed, Web of Science, Science Direct, Scopus, Cochrane Library, SciELO, and Lilacs databases were searched. For this end, we build the following search terms:
  • (((antimicrobial photodynamic therapy) AND (Drug delivery system)) AND (Metallic nanoparticles)) AND (metal nanoparticles)
  • ((antimicrobial photodynamic therapy) AND (Drug delivery system)) AND (Metal oxides).
  • ((antimicrobial photodynamic therapy) AND (Drug delivery system)) AND (Carbon quantum dots)
  • (((antimicrobial photodynamic therapy) AND (Drug delivery system)) AND (Mesoporous silica) AND (silica nanoparticles)
In addition, a manual search was also made, looking for articles to be included in the eligibility criteria proposed in the present systematic review and meta-analysis. Thus, relevant journals in the field of photodynamic therapy, nanoparticles, drug delivery systems, and ClinicalTrials.gov were searched. Based on the titles and abstracts, the two independent examiners selected and classified the articles as included or excluded from the review (Kappa score = 0.89). In this step, the Rayyan software was used for the selection process and for removing duplicate articles [24]. After the selection process was done, the data were extracted from the articles selected. Then, the articles were analyzed and discussed. Any disagreement during the process was solved by reaching a consensus before proceeding to the next steps.

2.5. Qualitative Analysis

In this step, OHAT Rob toll, adapted for in vitro studies [25,26], was used for the risk of bias assessment. In addition, for the question “Were there no other potential threats to internal validity?” this was considered as bias related to the sample size calculation, normality, and homoscedasticity evaluation and details about the inferential tests used in the statistical approaches [27].

2.6. Meta-Analysis and Quantitative Approaches

Meta-analysis and quantitative approaches were conducted by R software version 3.6.1 with the “META” package. A random effect model was used and the effect measure was the odds ratio (OR), configuring meta-analysis for binary outcomes. In the presence of sparse data, the “Peto” method was used. For n > 10, the publication bias was accessed by using a funnel plot, and for n < 10, a trim-and-fill analysis was conducted. The small-study effect and bias related to meta-analysis were accessed by the trim-and-fill method. High levels of heterogenicity were considered for I-squared > 50%. The presence of microbial cells after treatment was the outcome evaluated. The experimental group was formed by microbial cells that received aPDT with photosensitizer conjugated with inorganic nanoparticles and the control group was formed by microbial cells that received aPDT. When necessary, subgroup analysis was conducted.

3. Results

3.1. Search Results

The article selection process is summarized in the flow diagram presented in Figure 1. The electronic search yielded 574 articles. Accordingly, 359 articles remained in the selection process. After title and abstract screening, 324 articles were excluded because they did not follow the eligibility criteria. A total of 35 articles were eligible for full-text evaluation. Subsequently, for full-text evaluation, 14 articles were included for qualitative analysis and 12 articles could be included in the meta-analysis.

3.2. Synthesis Results

The articles included in the present systematic review and meta-analysis ranged in publication data from 2015 to 2022 [28,29,30,31,32,33,34,35,36,37,38,39,40,41] (Table 1). Most of the studies have been performed in vitro studies. Only one study also performed an animal model assay [41]. The most frequently inorganic nanoparticle evaluated was the metal type, with the same proportion for gold [29,34,38] and for silver [31,36,39]. The second most common was mesoporous silica [28,30,31,32], followed by metallic oxides [37,40,41] and then carbon quantum dots [33,35]. In addition, the most frequently photosensitizer evaluated was the methylene blue [28,29,34,36,38], followed by curcumin [31,35,37], toluidine blue [30,33], phthalocyanines [39,40], rose Bengal [32], and chlorin e6 [41]. Except for curcumin, all photosensitizers evaluated have the same light absorption spectrum. The light dose and the pre-irradiation time showed great different values among the included articles.
Staphylococcus aureus was the microorganism more frequently analyzed [29,30,33,36,37,38,39,40,41], followed by Escherichia coli [28,30,31,36], Pseudomonas aeruginosa [28,33], Staphylococcus epidermis [30], Enterococcus faecalis [34], Aggregatibacter actinomycetemcomitans [35], Porphyromonas gingivalis [35], Prevotella intermedia [35], and Candida albicans [32]. The microorganisms were mainly cultivated in suspension form [28,29,30,31,32,34,36,37,38,39,40,41]. Only five studies evaluated the microorganisms in biofilm [32,33,34,35,41]. Despite the different types of inorganic nanoparticles, significant results for microbial load reduction were reached for all studies included in the present systematic review, independently of the type of microorganism. Moreover, the photosensitizer conjugated with inorganic nanoparticles had significant results for inhibition of biofilm formation [33,34,35].

3.3. Risk of Bias Assessment

For all articles included in the present systematic review, the main source of bias was related to blinding (Were research personnel blinded to the study group during the study? Can we be confident in the outcome assessment (including blinding of assessors?). Moreover, the lack of information about the conduction of the pilot study, sample size estimation, and statistical approaches (e.g., evaluation of outliers, verification of normal distribution, and homoscedasticity) were considered as other potential threats to internal validity. More details can be seen in Table 2.

3.4. Meta-Analysis

Meta-analyses were performed in 12 articles [29,30,31,32,33,34,35,36,37,38,40,41]. Only two studies could not be included in the quantitative approaches due to the lack of sample size reported. Firstly, we performed an overall meta-analysis, including the articles that evaluated microbial cells cultured in suspension (Figure 2). aPDT mediated by conjugated with inorganic nanoparticles has significant results comparing with aPDT for presence of microbial cells (OR = 0.19 [0.07; 0.67/p-value = 0.0019/I-squared = 0%). In addition, a prediction interval for the treatment effect in a future study from a random effects model was calculated (Figure 2A) [42], while a non-publication bias was detected (Figure 2B).
After, subgroup analysis was performed for S. aureus and E. coli (Figure 3). However, significant results for aPDT mediated by photosensitizers conjugated with inorganic nanoparticles was only reached out for E. coli (OR = 0.08 [0.01; 0.52]/p-value = 0.0081/I-squared = 0%) (Figure 3C). In addition, publication bias and consequently meta-analysis bias were detected by trim-and-fill analysis (OR = 0.06 [0.01; 0.30]/p-value = 0.0006/I-squared = 0%) (Figure 3D).
Another subgroup analysis was performed using studies that evaluated methylene blue (MB), but no significant results were found—p-value = 0.1806 (Figure 4A). Despite the publication bias being detected and the meta-analysis bias being corrected, no significant result was found—p-value = 0.0692 (Figure 4B). One more meta-analysis was conducted for the viability of microbial cells cultured in biofilm; however, no significant result was found—p-value = 0.1270 (Figure 4A); non-publication and meta-analysis biases were also found (p-value = 0.1270) (Figure 4B).
Lastly, subgroups meta-analyses were performed for Gram-positive (Figure 5A,B) and Gram-negative bacteria (Figure 5C,D) cultured in suspension and treated based on aPDT with photosensitizers conjugated with inorganic nanoparticles and aPDT only. Non-significant results were found for Gram-positive bacteria (Figure 5A) and no publication bias was detected (Figure 5). Nonetheless, significant results were found for Gram-negative bacteria (OR = 0.12 [0.02; 0.56]/p-value = 0.0071/I-squared = 0%) (Figure 5C) and after detection of publication and meta-analysis biases, the significant result remained (OR = 0.07 [0.02; 0.27]/p-value = 0.0001/I-squared = 0%) (Figure 5D).

4. Discussion

In front of traditional antimicrobials agents, pathogenic microorganisms have developed different pathways in the field of persistence, tolerance, and resistance [5,6,43,44], leading to the emergence of multiple drug-resistant microorganisms and grating one of the major challenges in the medical field in the current society [45]. In addition, biofilm formation is one of the main reasons related to microbial resistance to drugs as bacteria as much as fungi have an innate tendency to cling onto biotic and abiotic surfaces and ensconce themselves in a self-produced matrix mainly containing extracellular polymeric substances (EPS), which are comprised of polysaccharides, extracellular DNAs, lipids, and proteins [7]. In this context, several approaches to combat biofilm have been developed, such as antimicrobial coating modification, antimicrobial peptides, quorum sensing inhibition, bioelectric and bioacoustics effects, and aPDT [43]. Multiple targets are involved and damaged in oxidative stress resulting from aPDT; microbial resistance is unlikely to occur and until now, it was not reported [11].
In this present systematic review and meta-analysis, we evaluated the use of photosensitizers conjugated with inorganic nanoparticles to enhance the aPDT efficacy. The scientific literature reported a wide type of natural and synthetic photosensitizers (PS) used as antimicrobial agents, such as chlorophyll, rose Bengal, crystal violet, methylene blue (MB), Toluidine blue, and psolaren [46]. In the present systematic review, we did not establish any restriction for the type of PS used by the included articles.
The results observed in the present study are promising and can cooperate to better evaluation of this approach against pathogenic microorganisms. Most of the articles included in the systematic review highlighted significant improvements in the aPDT mediated by inorganic nanoparticles compared to aPDT only. These results comply with the overall results of the meta-analysis for microorganisms cultured in suspension and for E. coli also cultured in suspension. Although chemical and biochemical procedures were not evaluated in the present study, special attention should be given to this issue as the preparation of photomaterials with inorganic nanoparticles is complex and may modulate the results when applied in microbiology [46].
E. coli is a commensal bacterium of the gastrointestinal tract of humans as well as other mammals and birds. There are several pathogenic strains of E. coli that can cause diarrhea, enteric infections, urinary tract infections, meningitis, and septicemia [47,48]. In addition, the virulence mechanism related to this gram-negative bacterium involves adhesin expression, toxin secretion, iron acquisition factors, lipopolysaccharide structure, the presence of polysaccharide capsules, and invasion factors [47]. The biofilm formation of E. coli occurs in followed phases; reversible attachment, irreversible attachment, maturation, and dispersion [48]. In particular, the maturation phase is characterized by the final architecture and arrangement of the biofilm conferred by the matrix formation [49]. The matrix provides biofilm stability, promotes intercellular interaction, and enables the transport of nutrients and waste through the biofilms. Lastly, the matrix serves as a protective barrier against antimicrobial agents, antibodies, and host immune response [50,51]. The results of the present systematic review and meta-analysis highlighted that both approaches, aPDT with photosensitizers linked to inorganic nanoparticles and aPDT only, conferred significant results against E. coli viability cultured in a suspension model; however, the associated approach was significantly more efficient. Further studies should be designed to evaluate the efficacy of the therapy in E. coli cultivated in biofilm by the two options of treatment.
As opposed to E. coli, S. aureus is a Gram-positive opportunistic bacterium, catalase-positive, being considered a principal cause of nosocomial infections [52]. S. aureus is frequently found on mucosal surfaces (e.g., the nares, the throat, and the rectum) and in most regions of skin (e.g., axilla, groin, and perineum) [52]. These bacteria can be classified as Methicillin-sensitive S. aureus and Methicillin-resistant S. aureus, and both are relevant and associated with nosocomial infections [53]. Beyond skin and mucosal infections, S. aureus can be responsible for osteoarticular infections, medical devices-related infections, pneumonia, infective endocarditis, and bacteremia. Due to these broader aspects, S. aureus is associated with considerable morbidity, mortality, and economic costs for healthcare institutions [54]. The S. aureus biofilm development can be divided chronologically into four steps; attachment, multiplication, maturation, and detachment [55]. Similarly, as E. coli is in the maturation process of S. aureus biofilm, EPS is produced by covering the multicellular aggregation and granting survival aspects for the microorganism by hindering the function of the host immune system and acting as a multifunctional barrier against antimicrobial agents [55,56].
In the meta-analysis, no significant results were found for the viability of S. aureus in suspension when microorganisms were treated with aPDT mediated by photosensitizers linked to inorganic nanoparticles or aPDT only. The large standard deviation, as well as the small sample size leading to imprecision effects [57], may be the main reason for it. Therefore, these results should be interpreted carefully, as it is expected small sample sizes for in vitro studies compared to other types of studies (e.g., epidemiological studies and clinical trials), and consequently, in further meta-analysis studies involving a larger number of studies, significant results might be reached out. This explanation can also be stipulated for the other non-significant results found in the present meta-analysis, such as viability microorganisms cultured in biofilm and MB.
Correlating the results found for E. coli and S. aureus with the results from Gram-positive and Gram-negative bacteria, we might hypothesize that photosensitizers conjugated with inorganic nanoparticles have an affinity with Gram-negative cell walls. In particular, the cell wall of this bacteria is mainly composed of lipopolysaccharide, while N-acetyl-muramic acid is the most common component of the Gram-positive cell wall [58].
MB can be used as a photosensitizer agent and is classified as a phenothiazine type with strong absorption between 630–680 nm [59]. Even though MB can be widely used as a photosensitizer for aPDT and there are no potential lethal adverse effects related to systemic administration, there are a few studies designed as clinical trials [59,60]. In addition, to enhance the efficacy of aPDT, nanoparticles can be conjugated with photosensitizers. Once nanoparticles can act as a drug-delivery system and consequently facilitate the internalization of photosensitizers, this approach confers to aPDT the lowest concentration of photosensitizers and the shortest light exposure time [61].
Nanoparticles based on metal and silica offer advantages over organic nanoparticles, such as having easy-to-control particle sizes, shape, porosity, and monodispersibility; however, these inorganic nanoparticles do not readily degrade in the biological system [62]. Among all metallic nanoparticles used in photodynamic therapy, gold nanoparticles are the most studied [63,64]. Gold and silver nanoparticles show a special optical phenomenon named localized surface plasmon resonance (LSPR) [63]. LSPR occurs when light interacts with conductive metallic nanoparticles that are smaller than the incident wavelength. Consequently, a rapid energy transfer from the metal surface to molecular O2 (oxygen molecule) with high efficiency occurs and forms 1O2 (singlet molecular oxygen), inducing aPDT even without the involvement of PS [63,64]. Silica nanoparticles are biocompatible, easy to produce, and show high photosensitizer loading capacities [65], and when loaded with antimicrobial compounds, silica nanoparticles have been shown to be capable of reversing antibiotic resistance [66]. In the present systematic review and meta-analysis, the gold and silver nanoparticles, as well as silica nanoparticles, were the inorganic materials most evaluated in conjugation with photosensitizers.
In all articles included in the systematic review, bias related to blinding was detected. Although blinding approaches are fundamental for clinical trials, in in vitro studies, their use is not often. However, the blinding application can eliminate and/or reduce biases related to effect sizes, turning the results more reliable [67]. Moreover, the absence of pilot studies and details about statistical approaches were considered potential threats for internal validity. The conduction of pilot studies can clearly identify a wide source of problems that directly affects the performance of the study and consequently affects the results found. In addition, the application of correct statistical tests, mainly based on the confirmation of normal distribution and homoscedasticity, are highly crucial for understanding the data [68].
Essentially, photosensitizers conjugated with inorganic nanoparticles enhance the effectivity of aPDT in the reduction of microbial load compared to aPDT mediated by classical photosensitizers. Thus, more studies should be planned to evaluate these approaches in other species of bacteria and fungi. Additionally, the evaluation of EPS after this therapeutic approach [69] will provide a wide window of understanding of the role of aPDT mediated by photosensitizers conjugated with inorganic nanoparticles in biofilm formation.

5. Conclusions

Photosensitizers conjugated with inorganic nanoparticles are an effective approach for the reduction of microbial load, especially for E. coli Gram-negative bacteria. Hence, this combined treatment has shown better results than compared to aPDT application only. However, additional blind studies are required to precisely evaluate the efficiency of the photosensitizers conjugated with inorganic nanoparticles as well as, and more studies are required to evaluate this approach in microorganisms cultured in biofilm.

Author Contributions

Conceptualization, T.M.F., L.M.D. and A.C.P.; methodology, T.M.F., L.MD. and A.C.P.; software, T.M.F. and A.B.d.O.; validation, T.M.F., L.M.D., A.C.P., A.B.d.O., C.C.J. and E.G.d.O.M.; formal analysis, T.M.F., L.M.D., A.C.P., A.B.d.O. and C.C.J.; investigation, T.M.F., L.M.D., A.B.d.O. and C.C.J.; resources, T.M.F.; data curation, T.M.F.; writing—original draft preparation, T.M.F., L.M.D., A.B.d.O. and C.C.J.; writing—review and editing, T.M.F. and. A.C.P.; visualization: T.M.F. and. A.C.P.; supervision, A.C.P. and E.G.d.O.M.; project administration, T.M.F. and. A.C.P.; funding acquisition, T.M.F., L.M.D., A.C.P., A.B.d.O., C.C.J. and E.G.d.O.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the São Paulo Research Foundation [Fundação de Amparo à Pesquisa do Estado de São Paulo FAPESP#2013/07276-1 (CePID CePOF)] and FAPESP#2019/27634-6 to C.C.J.; FAPESP#2020/16227-8 to L.M.D.; FAPESP#2020/07110-0 to A.B.O and FAPESP#2021/01191-0 to T.M.F.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet 2022, 399, 629–655. [Google Scholar] [CrossRef]
  2. Oldenkamp, R.; Schultsz, C.; Mancini, E.; Cappuccio, A. Filling the gaps in the global prevalence map of clinical antimicrobial resistance. Proc. Natl. Acad. Sci. USA 2021, 118, e2013515118. [Google Scholar] [CrossRef] [PubMed]
  3. O’Neill, J. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations. London: Review on Antimicrobial Resistance. 2016. Available online: https://apo.org.au/sites/default/files/resource-files/2016-05/apo-nid63983.pdf. (accessed on 20 July 2020).
  4. Tiseo, G.; Brigante, G.; Giacobbe, D.R.; Maraolo, A.E.; Gona, F.; Falcone, M.; Giannella, M.; Grossi, P.; Pea, F.; Rossolini, G.M.; et al. Diagnosis and management of infections caused by multidrug-resistant bacteria: Guideline endorsed by the Italian Society of Infection and Tropical Diseases (SIMIT), the Italian Society of Anti-Infective Therapy (SITA), the Italian Group for Antimicrobial Stewardship (GISA), the Italian Association of Clinical Microbiologists (AMCLI) and the Italian Society of Microbiology (SIM). Int. J. Antimicrob. Agents 2022, 60, 106611. [Google Scholar] [CrossRef] [PubMed]
  5. Blair, J.M.A.; Webber, M.A.; Baylay, A.J.; Ogbolu, D.O.; Piddock, L.J.V. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol. 2015, 13, 42–51. [Google Scholar] [CrossRef]
  6. Berman, J.; Krysan, D.J. Drug resistance and tolerance in fungi. Nat. Rev. Genet. 2020, 18, 319–331. [Google Scholar] [CrossRef]
  7. Flemming, H.-C.; Wingender, J.; Szewzyk, U.; Steinberg, P.; Rice, S.A.; Kjelleberg, S. Biofilms: An emergent form of bacterial life. Nat. Rev. Microbiol. 2016, 14, 563–575. [Google Scholar] [CrossRef]
  8. Stoodley, P.; Sauer, K.; Davies, D.G.; Costerton, J.W. Biofilms as complex differentiated communities. Annu. Rev. Microbiol. 2002, 56, 187–209. [Google Scholar] [CrossRef]
  9. Allison, R.R.; Moghissi, K. Photodynamic Therapy (PDT): PDT Mechanisms. Clin. Endosc. 2013, 46, 24–29. [Google Scholar] [CrossRef]
  10. Surova, O.; Zhivotovsky, B. Various modes of cell death induced by DNA damage. Oncogene 2013, 32, 3789–3797. [Google Scholar] [CrossRef]
  11. Hamblin, M.R.; Abrahamse, H. Can light-based approaches overcome antimicrobial resistance? Drug Dev. Res. 2019, 80, 48–67. [Google Scholar] [CrossRef] [Green Version]
  12. Nunes, L.; Nunes, G.P.; Ferrisse, T.M.; Strazzi-Sahyon, H.B.; Cintra, L.T.Â.; Dos Santos, P.H.; Sivieri-Araujo, G. Antimicrobial photodynamic therapy in endodontic reintervention: A systematic review and meta-analysis. Photodiagnos. Photodyn. Ther. 2022, 39, 103014. [Google Scholar] [CrossRef] [PubMed]
  13. Sales, L.S.; Miranda, M.L.; de Oliveira, A.B.; Ferrisse, T.M.; Fontana, C.R.; Milward, M.; Brighenti, F.L. Effect of the technique of photodynamic therapy against the main microorganisms responsible for periodontitis: A systematic review of in-vitro studies. Arch. Oral Biol. 2022, 138, 105425. [Google Scholar] [CrossRef] [PubMed]
  14. Ferrisse, T.M.; Dias, L.M.; de Oliveira, A.B.; Jordão, C.C.; Mima, E.G.O.; Pavarina, A.C. Efficacy of curcumin-mediated antibacterial photodynamic therapy for oral antisepsis: A systematic review and network meta-analysis of randomized clinical trials. Photodiagnos. Photodyn. Ther. 2022, 39, 102876. [Google Scholar] [CrossRef] [PubMed]
  15. de Oliveira, A.B.; Ferrisse, T.M.; Marques, R.S.; de Annunzio, S.R.; Brighenti, F.L.; Fontana, C.R. Effect of Photodynamic Therapy on Microorganisms Responsible for Dental Caries: A Systematic Review and Meta-Analysis. Int. J. Mol. Sci. 2019, 20, 3585. [Google Scholar] [CrossRef]
  16. Teixeira, C.G.D.S.; Sanitá, P.V.; Ribeiro, A.P.D.; Dias, L.M.; Jorge, J.H.; Pavarina, A.C. Antimicrobial photodynamic therapy effectiveness against susceptible and methicillin-resistant Staphylococcus aureus biofilms. Photodiagnos. Photodyn. Ther. 2020, 30, 101760. [Google Scholar] [CrossRef]
  17. Trigo-Gutierrez, J.; Vega-Chacón, Y.; Soares, A.; Mima, E. Antimicrobial Activity of Curcumin in Nanoformulations: A Comprehensive Review. Int. J. Mol. Sci. 2021, 22, 7130. [Google Scholar] [CrossRef]
  18. Dias, L.M.; Ferrisse, T.M.; Medeiros, K.S.; Cilli, E.M.; Pavarina, A.C. Use of Photodynamic Therapy Associated with Antimicrobial Peptides for Bacterial Control: A Systematic Review and Meta-Analysis. Int. J. Mol. Sci. 2022, 23, 3226. [Google Scholar] [CrossRef]
  19. Silvestre, A.L.P.; Di Filippo, L.D.; Besegato, J.F.; de Annunzio, S.R.; de Camargo, B.A.F.; de Melo, P.B.G.; Rastelli, A.N.D.S.; Fontana, C.R.; Chorilli, M. Current applications of drug delivery nanosystems associated with antimicrobial photodynamic therapy for oral infections. Int. J. Pharm. 2020, 592, 120078. [Google Scholar] [CrossRef]
  20. Kango, S.; Kalia, S.; Celli, A.; Njuguna, J.; Habibi, Y.; Kumar, R. Surface modification of inorganic nanoparticles for development of organic–inorganic nanocomposites—A review. Prog. Polym. Sci. 2013, 38, 1232–1261. [Google Scholar] [CrossRef]
  21. Dias, H.B.; Bernardi, M.I.B.; Ramos, M.A.D.S.; Trevisan, T.C.; Bauab, T.M.; Hernandes, A.C.; Rastelli, A.N.D.S. Zinc oxide 3D microstructures as an antimicrobial filler content for composite resins. Microsc. Res. Tech. 2017, 99, 14434–14643. [Google Scholar] [CrossRef]
  22. Sábio, R.M.; Meneguin, A.B.; Ribeiro, T.D.C.; Silva, R.R.; Chorilli, M. New insights towards mesoporous silica nanoparticles as a technological platform for chemotherapeutic drugs delivery. Int. J. Pharm. 2019, 564, 379–409. [Google Scholar] [CrossRef] [PubMed]
  23. Shamseer, L.; Moher, D.; Clarke, M.; Ghersi, D.; Liberati, A.; Petticrew, M.; Shekelle, P.; Stewart, L.A.; The PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: Elaboration and explanation. BMJ 2015, 349, g764. [Google Scholar] [CrossRef] [PubMed]
  24. Ouzzani, M.; Hammady, H.; Fedorowicz, Z.; Elmagarmid, A. Rayyan—A web and mobile app for systematic reviews. Syst. Rev. 2016, 5, 210. [Google Scholar] [CrossRef] [PubMed]
  25. NTP-OHAT. OHAT Risk of Bias Rating Tool for Human and Animal Studies; Office of Health Assessment and Translation: Morrisville, NC, USA, 2015.
  26. NTP-OHAT. Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration; National Toxicology Program-Office of Health Assessment and Translation: Morrisville, NC, USA, 2019.
  27. Ferrisse, T.M.; de Oliveira, A.B.; Surur, A.K.; Buzo, H.S.; Brighenti, F.L.; Fontana, C.R. Photodynamic therapy associated with nanomedicine strategies for treatment of human squamous cell carcinoma: A systematic review and meta-analysis. Nanomed. Nanotechnol. Biol. Med. 2021, 40, 102505. [Google Scholar] [CrossRef] [PubMed]
  28. Planas, O.; Bresolí-Obach, R.; Nos, J.; Gallavardin, T.; Ruiz-González, R.; Agut, M.; Nonell, S. Synthesis, Photophysical Characterization, and Photoinduced Antibacterial Activity of Methylene Blue-loaded Amino- and Mannose-Targeted Mesoporous Silica Nanoparticles. Molecules 2015, 20, 6284–6298. [Google Scholar] [CrossRef]
  29. Tawfik, A.A.; Alsharnoubi, J.; Morsy, M. Photodynamic antibacterial enhanced effect of methylene blue-gold nanoparticles conjugate on Staphylococcal aureus isolated from impetigo lesions in vitro study. Photodiagnos. Photodyn. Ther. 2015, 12, 215–220. [Google Scholar] [CrossRef]
  30. Perni, S.; Drexler, S.; Ruppel, S.; Prokopovich, P. Lethal photosensitisation of bacteria using silica-TBO nanoconjugates. Colloids Surf. A Physicochem. Eng. Asp. 2016, 510, 293–299. [Google Scholar] [CrossRef]
  31. Kuthati, Y.; Kankala, R.K.; Busa, P.; Lin, S.-X.; Deng, J.-P.; Mou, C.-Y.; Lee, C.-H. Phototherapeutic spectrum expansion through synergistic effect of mesoporous silica trio-nanohybrids against antibiotic-resistant gram-negative bacterium. J. Photochem. Photobiol. B Biol. 2017, 169, 124–133. [Google Scholar] [CrossRef]
  32. Paramanantham, P.; Antony, A.P.; Lal, S.S.; Sharan, A.; Syed, A.; Ahmed, M.; Alarfaj, A.A.; Busi, S.; Maaza, M.; Kaviyarasu, K. Antimicrobial photodynamic inactivation of fungal biofilm using amino functionalized mesoporus silica-rose bengal nanoconjugate against Candida albicans. Sci. Afr. 2018, 1, e00007. [Google Scholar] [CrossRef]
  33. Anju, V.T.; Paramanantham, P.; Sruthil Lal, S.B.; Sharan, A.; Syed, A.; Bahkali, N.A.; Alsaedi, M.H.; Kaviyarasu, K.; Busi, S. Antimicrobial photodynamic activity of toluidine blue-carbon nanotube conjugate against Pseudomonas aeruginosa and Staphylococcus aureus-Understanding the mechanism of action. Photodiagnos. Photodyn. Ther. 2019, 27, 305–316. [Google Scholar] [CrossRef]
  34. Maliszewska, I.; Wróbel, J.; Wanarska, E.; Podhorodecki, A.; Matczyszyn, K. Synergistic effect of methylene blue and biogenic gold nanoparticles against Enterococcus faecalis. Photodiagnos. Photodyn. Ther. 2019, 27, 218–226. [Google Scholar] [CrossRef]
  35. Pourhajibagher, M.; Parker, S.; Chiniforush, N.; Bahador, A. Photoexcitation triggering via semiconductor Graphene Quantum Dots by photochemical doping with Curcumin versus perio-pathogens mixed biofilms. Photodiagnos. Photodyn. Ther. 2019, 28, 125–131. [Google Scholar] [CrossRef] [PubMed]
  36. Belekov, E.; Kholikov, K.; Cooper, L.; Banga, S.; Er, A.O. Improved antimicrobial properties of methylene blue attached to silver nanoparticles. Photodiagnos. Photodyn. Ther. 2020, 32, 102012. [Google Scholar] [CrossRef] [PubMed]
  37. de Santana, W.M.O.S.; Caetano, B.L.; de Annunzio, S.R.; Pulcinelli, S.H.; Ménager, C.; Fontana, C.R.; Santilli, C.V. Conjugation of superparamagnetic iron oxide nanoparticles and curcumin photosensitizer to assist in photodynamic therapy. Colloids Surf. B Biointerf. 2020, 196, 111297. [Google Scholar] [CrossRef]
  38. Monteiro, J.S.; Rangel, E.E.; de Oliveira, S.C.; Crugeira, P.J.; Nunes, I.P.; Fagnani, S.R.D.A.; Sampaio, F.J.; de Almeida, P.F.; Pinheiro, A.L. Enhancement of photodynamic inactivation of planktonic cultures of Staphylococcus aureus by DMMB-AuNPs. Photodiagnos. Photodyn. Ther. 2020, 31, 101930. [Google Scholar] [CrossRef]
  39. Sen, P.; Nyokong, T. Enhanced Photodynamic inactivation of Staphylococcus Aureus with Schiff base substituted Zinc phthalocyanines through conjugation to silver nanoparticles. J. Mol. Struct. 2021, 1232, 130012. [Google Scholar] [CrossRef]
  40. Sen, P.; Nyokong, T. Promising photodynamic antimicrobial activity of polyimine substituted zinc phthalocyanine and its polycationic derivative when conjugated to nitrogen, sulfur, co-doped graphene quantum dots against Staphylococcus aureus. Photodiagnos. Photodyn. Ther. 2021, 34, 102300. [Google Scholar] [CrossRef]
  41. Jin, Y.; Zhao, B.; Guo, W.; Li, Y.; Min, J.; Miao, W. Penetration and photodynamic ablation of drug-resistant biofilm by cationic Iron oxide nanoparticles. J. Control. Release 2022, 348, 911–923. [Google Scholar] [CrossRef] [PubMed]
  42. Higgins, J.P.T.; Thompson, S.G.; Spiegelhalter, D.J. A re-evaluation of random-effects meta-analysis. J. R. Stat. Soc. Ser. A Stat. Soc. 2009, 172, 137–159. [Google Scholar] [CrossRef]
  43. Ciofu, O.; Moser, C.; Jensen, P.Ø.; Høiby, N. Tolerance and resistance of microbial biofilms. Nat. Rev. Microbiol. 2022, 20, 621–635. [Google Scholar] [CrossRef]
  44. Eisenreich, W.; Rudel, T.; Heesemann, J.; Goebel, W. Link Between Antibiotic Persistence and Antibiotic Resistance in Bacterial Pathogens. Front. Cell. Infect. Microbiol. 2022, 12, 900848. [Google Scholar] [CrossRef] [PubMed]
  45. Ramakrishnan, R.; Singh, A.K.; Singh, S.; Chakravortty, D.; Das, D. Enzymatic Dispersion of Biofilms: An Emerging Biocatalytic Avenue to Combat Biofilm-Mediated Microbial Infections. J. Biol. Chem. 2022, 102352. [Google Scholar] [CrossRef] [PubMed]
  46. Mesquita, M.Q.; Dias, C.J.; Neves, M.G.P.M.S.; Almeida, A.; Faustino, M.A.F. Revisiting Current Photoactive Materials for Antimicrobial Photodynamic Therapy. Molecules 2018, 23, 2424. [Google Scholar] [CrossRef] [PubMed]
  47. Kaper, J.B.; Nataro, J.P.; Mobley, H.L.T. Pathogenic Escherichia Coli. Nat. Rev. Microbiol. 2004, 2, 123–140. [Google Scholar] [CrossRef] [PubMed]
  48. Ezzraimi, A.E.; Hannachi, N.; Mariotti, A.; Rolain, J.-M.; Camoin-Jau, L. Platelets and Escherichia coli: A Complex Interaction. Biomedicines 2022, 10, 1636. [Google Scholar] [CrossRef]
  49. Ballén, V.; Cepas, V.; Ratia, C.; Gabasa, Y.; Soto, S.M. Clinical Escherichia coli: From Biofilm Formation to New Antibiofilm Strategies. Microorganisms 2022, 10, 1103. [Google Scholar] [CrossRef]
  50. Schooling, S.R.; Beveridge, T.J. Membrane Vesicles: An Overlooked Component of the Matrices of Biofilms. J. Bacteriol. 2006, 188, 5945–5957. [Google Scholar] [CrossRef]
  51. Rabin, N.; Zheng, Y.; Opoku-Temeng, C.; Du, Y.; Bonsu, E.; Sintim, H.O. Biofilm formation mechanisms and targets for developing antibiofilm agents. Future Med. Chem. 2015, 7, 493–512. [Google Scholar] [CrossRef]
  52. Tong, S.Y.C.; Davis, J.S.; Eichenberger, E.; Holland, T.L.; Fowler, V.G. Staphylococcus aureus infections: Epidemiology, pathophysiology, clinical manifestations, and management. Clin. Microbiol. Rev. 2015, 28, 603–661. [Google Scholar] [CrossRef]
  53. Gajdács, M. The Continuing Threat of Methicillin-Resistant Staphylococcus aureus. Antibiotics 2019, 8, 52. [Google Scholar] [CrossRef] [Green Version]
  54. Zhen, X.; Lundborg, C.S.; Zhang, M.; Sun, X.; Li, Y.; Hu, X.; Gu, S.; Gu, Y.; Wei, J.; Dong, H. Clinical and economic impact of methicillin-resistant Staphylococcus aureus: A multicentre study in China. Sci. Rep. 2020, 10, 3900. [Google Scholar] [CrossRef] [PubMed]
  55. Sedarat, Z.; Taylor-Robinson, A.W. Biofilm Formation by Pathogenic Bacteria: Applying a Staphylococcus aureus Model to Appraise Potential Targets for Therapeutic Intervention. Pathogens 2022, 11, 388. [Google Scholar] [CrossRef] [PubMed]
  56. Serra, D.O.; Hengge, R. Stress responses go three dimensional–the spatial order of physiological differentiation in bacterial macrocolony biofilms. Environ. Microbiol. 2014, 16, 1455–1471. [Google Scholar] [CrossRef] [PubMed]
  57. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004, 328, 1490. [Google Scholar] [CrossRef] [PubMed]
  58. Feezor, R.J.; Oberholzer, C.; Baker, H.V.; Novick, D.; Rubinstein, M.; Moldawer, L.L.; Pribble, J.; Souza, S.; Dinarello, C.A.; Ertel, W.; et al. Molecular Characterization of the Acute Inflammatory Response to Infections with Gram-Negative versus Gram-Positive Bacteria. Infect. Immun. 2003, 71, 5803–5813. [Google Scholar] [CrossRef] [PubMed]
  59. Bacellar, I.O.; Pavani, C.; Sales, E.M.; Itri, R.; Wainwright, M.; Baptista, M.S. Membrane damage efficiency of phenothiazinium photosensitizers. Photochem. Photobiol. 2014, 90, 801–813. [Google Scholar] [CrossRef]
  60. Boltes Cecatto, R.; Siqueira de Magalhães, L.; Fernanda Setúbal Destro Rodrigues, M.; Pavani, C.; Lino-Dos-Santos-Franco, A.; Teixeira Gomes, M.; Fátima Teixeira Silva, D. Methylene blue mediated antimicrobial photodynamic therapy in clinical human studies: The state of the art. Photodiagnos. Photodyn. Ther. 2020, 31, 101828. [Google Scholar] [CrossRef]
  61. Castano, A.P.; Demidova, T.N.; Hamblin, M.R. Mechanisms in photodynamic therapy: Part one-photosensitizers, photochemistry and cellular localization. Photodiagnos. Photodyn. Ther. 2004, 1, 279–293. [Google Scholar] [CrossRef]
  62. Lucky, S.S.; Soo, K.C.; Zhang, Y. Nanoparticles in photodynamic therapy. Chem. Rev. 2015, 115, 1990–2042. [Google Scholar] [CrossRef]
  63. Krajczewski, J.; Rucińska, K.; Townley, H.E.; Kudelski, A. Role of various nanoparticles in photodynamic therapy and detection methods of singlet oxygen. Photodiagnos. Photodyn. Ther. 2019, 26, 162–178. [Google Scholar] [CrossRef]
  64. George, B.P.; Chota, A.; Sarbadhikary, P.; Abrahamse, H. Fundamentals and applications of metal nanoparticle- enhanced singlet oxygen generation for improved cancer photodynamic therapy. Front. Chem. 2022, 10, 964674. [Google Scholar] [CrossRef] [PubMed]
  65. Tang, F.; Li, L.; Chen, D. Mesoporous silica nanoparticles: Synthesis, biocompatibility and drug delivery. Adv. Mater. 2012, 24, 1504–1534. [Google Scholar] [CrossRef] [PubMed]
  66. Capeletti, L.B.; de Oliveira, L.F.; Gonçalves Kde, A.; de Oliveira, J.F.; Saito, Â.; Kobarg, J.; dos Santos, J.H.; Cardoso, M.B. Tailored silica-antibiotic nanoparticles: Overcoming bacterial resistance with low cytotoxicity. Langmuir 2014, 30, 7456–7464. [Google Scholar] [CrossRef]
  67. Saltaji, H.; Armijo-Olivo, S.; Cummings, G.G.; Amin, M.; Da Costa, B.R.; Flores-Mir, C. Influence of blinding on treatment effectsize estimate in randomized controlled trials of oral health interventions. BMC Med Res. Methodol. 2018, 18, 42. [Google Scholar] [CrossRef]
  68. Vetter, T.R. Fundamentals of Research Data and Variables: The Devil Is in the Details. Anesth Analg. 2017, 125, 1375–1380. [Google Scholar] [CrossRef] [PubMed]
  69. Abreu-Pereira, C.A.; Klein, M.I.; Lobo, C.I.V.; Gorayb Pereira, A.L.; Jordão, C.C.; Pavarina, A.C. DNase enhances photodynamic therapy against fluconazole-resistant Candida albicans biofilms. Oral Dis. 2022; Epub ahead of print. [Google Scholar] [CrossRef]
Pharmaceutics 14 02050 g001 550
Figure 1. Flowchart based on the PRISMA statement.
Figure 1. Flowchart based on the PRISMA statement.
Pharmaceutics 14 02050 g001
Pharmaceutics 14 02050 g002 550
Figure 2. Illustration of meta-analysis and quantitative approaches. The experimental group was formed by aPDT mediated by photosensitizers conjugated inorganic nanoparticles and the control group was formed by aPDT only. (A) The results of the meta-analysis are illustrated in a forest plot for the overall viability of microbial cells. (B) Funnel plot analysis shows the absence of publication bias. OR = odds ratio; CI = confidence interval; W: weight [29,30,31,32,34,36,37,38,40,41].
Figure 2. Illustration of meta-analysis and quantitative approaches. The experimental group was formed by aPDT mediated by photosensitizers conjugated inorganic nanoparticles and the control group was formed by aPDT only. (A) The results of the meta-analysis are illustrated in a forest plot for the overall viability of microbial cells. (B) Funnel plot analysis shows the absence of publication bias. OR = odds ratio; CI = confidence interval; W: weight [29,30,31,32,34,36,37,38,40,41].
Pharmaceutics 14 02050 g002
Pharmaceutics 14 02050 g003 550
Figure 3. Illustration of meta-analysis and quantitative approaches. The experimental group was formed by aPDT mediated by photosensitizer conjugated inorganic nanoparticles and the control group was formed by aPDT only. (A) The results of the meta-analysis are illustrated in a forest plot for the viability of S. aureus. (B) Trim-and-fill results for the viability of S. aureus show the presence of publication biases. (C). The results of the meta-analysis are illustrated in a forest plot for the viability of E. coli. (D) Trim-and-fill results for the viability of E. coli show the presence of publication and meta-analysis biases. OR = odds ratio; CI = confidence interval; W: weight. TE = estimated mean; seTE = estimated standard deviation [29,30,31,36,38,40,41].
Figure 3. Illustration of meta-analysis and quantitative approaches. The experimental group was formed by aPDT mediated by photosensitizer conjugated inorganic nanoparticles and the control group was formed by aPDT only. (A) The results of the meta-analysis are illustrated in a forest plot for the viability of S. aureus. (B) Trim-and-fill results for the viability of S. aureus show the presence of publication biases. (C). The results of the meta-analysis are illustrated in a forest plot for the viability of E. coli. (D) Trim-and-fill results for the viability of E. coli show the presence of publication and meta-analysis biases. OR = odds ratio; CI = confidence interval; W: weight. TE = estimated mean; seTE = estimated standard deviation [29,30,31,36,38,40,41].
Pharmaceutics 14 02050 g003
Pharmaceutics 14 02050 g004 550
Figure 4. Illustration of meta-analysis and quantitative approaches. The experimental group was formed by aPDT mediated by photosensitizers conjugated inorganic nanoparticles and the control group was formed by aPDT only. (A) The results of meta-analysis illustrated in a forest plot for the viability of microbial cells cultured in suspension and treated with MB-mediated aPDT with or without photosensitizers conjugated with inorganic nanoparticles. (B) Trim-and-fill results for the viability of microbial cells cultured in suspension and treated with MB-mediated aPDT with or without photosensitizers conjugated with inorganic nanoparticles show the presence of publication and meta-analysis biases. (C) The results of meta-analysis illustrated in a forest plot for viability microbial cells cultured in biofilm. (D) Trim-and-fill results for viability microbial cells cultured in biofilm show the absence of publication bias. OR = odds ratio; CI = confidence interval; W: weight. TE = estimated mean; seTE = estimated standard deviation [29,32,33,34,35,36,38,41].
Figure 4. Illustration of meta-analysis and quantitative approaches. The experimental group was formed by aPDT mediated by photosensitizers conjugated inorganic nanoparticles and the control group was formed by aPDT only. (A) The results of meta-analysis illustrated in a forest plot for the viability of microbial cells cultured in suspension and treated with MB-mediated aPDT with or without photosensitizers conjugated with inorganic nanoparticles. (B) Trim-and-fill results for the viability of microbial cells cultured in suspension and treated with MB-mediated aPDT with or without photosensitizers conjugated with inorganic nanoparticles show the presence of publication and meta-analysis biases. (C) The results of meta-analysis illustrated in a forest plot for viability microbial cells cultured in biofilm. (D) Trim-and-fill results for viability microbial cells cultured in biofilm show the absence of publication bias. OR = odds ratio; CI = confidence interval; W: weight. TE = estimated mean; seTE = estimated standard deviation [29,32,33,34,35,36,38,41].
Pharmaceutics 14 02050 g004
Pharmaceutics 14 02050 g005 550
Figure 5. Illustration of meta-analysis and quantitative approaches. The experimental group was formed by aPDT mediated by photosensitizers conjugated inorganic nanoparticles and the control group was formed by aPDT only. (A) The results of the meta-analysis illustrated in a forest plot for the viability of Gram-positive bacteria cultivated in suspension. (B) Trim-and-fill results for the viability of Gram-positive bacteria cultured in suspension show the absence of publication and meta-analysis biases. (C) The results of the meta-analysis illustrated in a forest plot for viability Gram-negative bacteria cultivated in suspension. (D) Trim-and-fill results for Gram-negative bacteria cultivated in suspension presence of publication and meta-analysis biases. OR = odds ratio; CI = confidence interval; W: weight. TE = estimated mean; seTE = estimated standard deviation [29,30,31,33,34,36,38,40,41].
Figure 5. Illustration of meta-analysis and quantitative approaches. The experimental group was formed by aPDT mediated by photosensitizers conjugated inorganic nanoparticles and the control group was formed by aPDT only. (A) The results of the meta-analysis illustrated in a forest plot for the viability of Gram-positive bacteria cultivated in suspension. (B) Trim-and-fill results for the viability of Gram-positive bacteria cultured in suspension show the absence of publication and meta-analysis biases. (C) The results of the meta-analysis illustrated in a forest plot for viability Gram-negative bacteria cultivated in suspension. (D) Trim-and-fill results for Gram-negative bacteria cultivated in suspension presence of publication and meta-analysis biases. OR = odds ratio; CI = confidence interval; W: weight. TE = estimated mean; seTE = estimated standard deviation [29,30,31,33,34,36,38,40,41].
Pharmaceutics 14 02050 g005
Table
Table 1. Summary finds of data extraction from included articles.
Table 1. Summary finds of data extraction from included articles.
Study (year)Study DesignInorganic Nanoparticle (np)Light Dose Irradiation TimeWaveLengthPhotoSensitizerPre-Irradiation TimeMicroorganismCulture TypeSample SizeOutcomes
Planas et al., 2015 [28]In vitroMesoporous Silica Nanoparticle (MSNP) modified with mannose sugars or amino groups16 J/cm2ND652 nmMethylene Blue (MB)30 minEscherichia coli
Pseudomonas
aeruginosa		SuspensionNDColony forming units (CFU)
E. coli = reduction of 7 log10 using MB (10 µM) alone or associated with MSNP.
P. aeruginosa = reduction of 8 log10 using MB (10 µM) alone or associated with MSNP targeting motifs with mannose sugars. Reduction of 5 log10 was observed using MB associated with MSNP targeting with amino groups.
Tawfik et al., 2015 [29]In vitroGold nanoparticles
(AuNPs)		24 J/cm²2 min660 nmMethylene blue (MB)NDStaphylococcus aureusSuspension3Cell viability after treatment
S. aureus
Inhibition of 95% for MB+np and 40% after MB.
Perni et al., 2016 [30]In vitroSilica nanoparticleND0.5 min
1 min
2 min
3 min		630 nmToluidine blue (TB)
NDStaphylococcus aureus (MRSA), Staphylococcus epidermidis, and Escherichia coliSuspension3Colony forming units (CFU)
E. coli = Reduction of 2 log10 after 3 min of irradiation
S. epidermidis = Reduction of 2 log10 after 2 min of irradiation, and after 3 min, the CFU fell below the limit detection.
S. aureus = reduction of 2 log10 after 2 min of irradiation, and after 3 min, the CFU fell below the limit detection.
Kuthati et al., 2017 [31]
In vitroMesoporous silica (MSN) and silver nanoparticles (SNP)72 J/cm2300 seg470 nmCurcumin
(Cur)		NDEscherichia coliSuspensions6Cell viability (log CFU/mL)
-Cur: reduction of 6 log10
-Cur+np: total microbial reduction
Paramanantham et al., 2018 [32]In vitro Mesoporous silica (MSN)50 mW5 min540 nm = Rose Bengal (RB) free
532 nm = MSN-RB		Rose Bengal (RB)3 hCandida albicansSuspensions and biofilm Reductions in microbial suspension
-RB = 40.96 ± 2.71%
-RB+np = 88.62 ± 3.4%
Reductions in microbial biofilm
-RB = 42.2 ± 2.6%
-RB+np = 79.64 ± 3.05%
Anju et al., 2019 [33]In vitroCarbon nanotubes58.49 J/cm²3 min630 nmToluidine blue (TB)3 hStaphylococcus aureus
Pseudomonas aeruginosa		Biofilm3Biofilm inhibition (crystal violet)
S. aureus: Reduction of 75% for TB+np and 47% after TB
P. aeroginosa: Reduction of 70% for TB+np and 32% after TB
Cell viability inhibition (CFU/mL)
S. aureus: inhibition of 65% for TB+np and 34% after TB
P. aeroginosa: inhibition of 58% for TB+np and 30% after TB
Inhibition of exopolysaccharide production
S. aureus: inhibition of 53% for TB+np and 30% after TB.
P. aeroginosa: inhibition of 50% for TB+np and 27% after TB.
Maliszewska et al., 2019 [34]In vitro Gold nanoparticles (AuNPs)55, 108, and
179 mW/cm2		5, 10, 15, 30, and 45 min660 nmMB120 minEnterococcus
faecalis		Suspensions and biofilm5Cell viability in suspension
(log10CFU/mL)
-MB ~ 4.5 log10 of reduction
-MB+np ~ 5.5 log10 of reduction
Cell viability in biofilm
(log10CFU/mL)
-MB ~ 3 log10 of reduction
-MB+np ~ 4 log10 of reduction
Pourhajibagher et al., 2019 [35]In vitroGraphene quantum dots (GQD)60–80 J/cm²
1 min435 ± 20 nmCurcumin (CUR)5 minAggregatibacter actinomycetemcomitans,
Porphyromonas gingivalis,
and Prevotella
intermedia		Biofilm3Cell viability inhibition
Reduction of 93% for GQD-CUR and 82% after CUR
Biofilm formation
Reduction of 76% for GQD-CUR and 61.3% after CUR
Belekov et al., 2020 [36]In vitroSilver nanoparticleND5 min660 nmMethylene blue (MB)NDStaphylococcus aureus
Escherichia coli		Suspension2Colony forming units (CFU)
S. aureus: Reduction of 90 % for MB+np and 75% for MB
E. coli: Reduction of 100 % for MB+np and 75% for after MB
de Santana et al., 2020 [37]In vitroSuperparamagnetic iron oxide nanoparticles (SPIONPs)3.12 J/cm²29 seg450 nmCurcumin (CUR)5 minStaphylococcus aureusSuspension3Colony forming units (CFU)
SPIONPs + aPDT promoted the complete elimination of S. aureus.
aPDT mediated by CUR promoted complete elimination using the same parameters.
Monteiro et al., 2021 [38]In vitroGold nanoparticles
(AuNPs)		125 mW;
12 J/cm2		192 seg630 nm ± 20 nm1,9-Dimethyl-Methylene Blue zinc chloride double salt (DMMB)5minStaphylococcus aureus (MRSA)Suspensions3Colony forming units(log CFU/mL)
-DMBMB: reduction of 9 log10.
-DMMB-AuNPs: reduction of 8 log10
Sen et al., 2021 [39] (a)In vitroSilver nanoparticlesND80 min680 nmPhthalocyanines (complexes 2 and 3). NDStaphylococcus aureusSuspensionNDColony forming units (CFU)
100% elimination of S. aureus employing light and the conjugate.
87.85% and 58.33% of reduction employing the Phthalocyanines complex numbers 2 and 3, respectively.
Sen et al., 2021 [40] (b)In vitroNitrogen, sulfur co-doped GQDs (3@N,S-GQDs, 4@N,S-GQDs) ND80 min687 and 685 nmPhthalocyaninesNDStaphylococcus aureusSuspension3Colony forming units (CFU)
ZnPC 3 + LED = 99.91% of reduction.
ZnPC 4 + LED = 100% of reduction.
Conjugated 3@N,S-GQDs + LED = 100% of reduction.
Conjugated 4@N,S-GQDs + LED = 100% of reduction.
Jin et al., 2022 [41]In vitro/ in vivoCe6@WCS-IONP100 mW/cm215 min660 nmChlorin e6NDStaphylococcus aureus (MRSA)Suspension and Biofilm3Colony forming units (log10 CFU/mL) (suspension)
Reduction of 4.25 log10 for Ce6@WCS-IONP and 3.8 log10 after Chlorin e6
Cells in biofilm
Reduction of 37.5% for Ce6@WCS-IONP and no reductions after Chlorin e6
Bacterial viability in an animal model
Reduction of 85% for Ce6@WCS-IONP and 50% after Chlorin e6
ND: not documented; min: minutes, seg: seconds; h: hour.
Table
Table 2. Risk of bias assessment according to the OHAT criteria for in vitro studies.
Table 2. Risk of bias assessment according to the OHAT criteria for in vitro studies.
QuestionWas Administered Dose or Exposure Level Adequately Randomized?Was Allocation to Study Groups Adequately Concealed?Were Experimental Conditions Identical across Study Groups?Were Research Personnel Blinded to the Study Group during the Study?Were Outcome Data Complete without Attrition or Exclusion from the Analysis?Can We Be Confident in the Exposure Characterization?Can We Be Confident in the Outcome Assessment (Including Blinding of Assessors?)Were There No Other Potential Threats to Internal Validity?
Study
Planas et al., 2015 [28]++++++--++++---
Tawfik et al., 2015 [29]++++++--++++---
Perni et al., 2016 [30]++++++--++++---
Kuthati et al., 2017 [31]++++++--++++---
Paramanantham et al., 2018 [32]++++++--++++---
Anju et al., 2019 [33]++++++--++++---
Maliszewska et al., 2019 [34]++++++--++++---
Pourhajibagher et al., 2019 [35]++++++--++++---
Belekov et al., 2020 [36]++++++--++++---
de Santana et al., 2020 [37]++++++--++++---
Monteiro et al., 2021 [38]++++++--++++---
Sen et al., 2021 [39] (a)++++++--++++---
Sen et al., 2021 [40] (b)++++++--++++---
Jin et al., 2022 [41]++++++--++++---
++: direct evidence of positive finding; -: indirect evidence of negative finding; --: direct evidence of negative finding.
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MDPI and ACS Style

Ferrisse, T.M.; Dias, L.M.; de Oliveira, A.B.; Jordão, C.C.; Mima, E.G.d.O.; Pavarina, A.C. Efficacy of Antimicrobial Photodynamic Therapy Mediated by Photosensitizers Conjugated with Inorganic Nanoparticles: Systematic Review and Meta-Analysis. Pharmaceutics 2022, 14, 2050. https://doi.org/10.3390/pharmaceutics14102050

AMA Style

Ferrisse TM, Dias LM, de Oliveira AB, Jordão CC, Mima EGdO, Pavarina AC. Efficacy of Antimicrobial Photodynamic Therapy Mediated by Photosensitizers Conjugated with Inorganic Nanoparticles: Systematic Review and Meta-Analysis. Pharmaceutics. 2022; 14(10):2050. https://doi.org/10.3390/pharmaceutics14102050

Chicago/Turabian Style

Ferrisse, Túlio Morandin, Luana Mendonça Dias, Analú Barros de Oliveira, Cláudia Carolina Jordão, Ewerton Garcia de Oliveira Mima, and Ana Claudia Pavarina. 2022. "Efficacy of Antimicrobial Photodynamic Therapy Mediated by Photosensitizers Conjugated with Inorganic Nanoparticles: Systematic Review and Meta-Analysis" Pharmaceutics 14, no. 10: 2050. https://doi.org/10.3390/pharmaceutics14102050

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