UNIVERSIDADE ESTADUAL PAULISTA
“JÚLIO DE MESQUITA FILHO”
Instituto de Ciência e Tecnologia
Campus de São José dos Campos
ORIGINAL ARTICLE DOI: https://doi.org/10.4322/bds.2024.e4419
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Braz Dent Sci 2024 Oct/Dec;27 (4): e4419
This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Efficacy of quercetin nano-emulgel as adjuvant local delivery drug
in non-surgical treatment of periodontitis
Eficácia do nano-emulgel de quercetina como terapia adjuvante de liberação local no tratamento não cirúrgico da
periodontite
Khoshoe Al-mokhtar MOHAMMED1 , Alzahraa A. ALGHRIANY1 , Abdullah Ibrahim Abd Rabbouh ALI2 , Helal F. HETTA3 ,
Ibrahim M. MWAFEY2
1 - Assiut University, Faculty of Dentistry, Department of Oral Medicine, Periodontology, and Oral Diagnosis. Assiut, Egypt.
2 - Al-Azhar University, Assiut Branch, Faculty of Dental Medicine, Department of Oral Medicine, Periodontology, Oral Diagnosis and
Dental Radiology. Assiut, Egypt.
3 - University of Tabuk, Faculty of Pharmacy, Department of Natural Products and Alternative Medicine, Division of Microbiology,
Immunology and Biotechnology. Tabuk, Saudi Arabia.
How to cite: Mohammed KA, Alghriany AA, Ali AIAR, Hetta HF, Mwafey IM. Efcacy of quercetin nano-emulgel as adjuvant local
delivery drug in non-surgical treatment of periodontitis. Braz Dent Sci. 2024;27(4):e4419. https://doi.org/10.4322/bds.2024.e4419
ABSTRACT
Objective: The objective of this study was to assess the impact of quercetin nano-emulgel on clinical and
biochemical markers in patients with stage I and II periodontitis as an adjuvant to scaling and root planing (SRP).
Material and Methods: Two groups were randomly assigned to 20 test sites from patients with stage I and II
periodontitis: Group I, in which 10 sites got scaling and root planing, and Group II, in which 10 sites received
scaling and root planing alongside quercetin nano-emulgel. Clinical parameters were recorded at baseline, 1
month, and 3 months; these included plaque index (PI), gingival index (GI), probing depth (PD), and clinical
attachment level (CAL). Biochemical evaluations were conducted to measure the gingival crevicular uid (GCF)
interferon-gamma (IFN-γ) level and total antioxidant capacity at baseline, 1 month, and 3 months. Results: All
clinical variables improved after treatment in both groups, with signicant improvement in Group II, which was
higher than that in Group I at different intervals. The GCF total antioxidant level revealed a signicant rise,
while the IFN-γ level showed a signicant decrease throughout the study within both groups, with no signicant
difference between the 2 groups. Conclusion: Quercetin nano-emulgel showed promising results in improving
clinical and biochemical parameters in treating periodontitis When used in conjunction with scaling and root
planing. This encourages using quercetin nano-emulgel in clinical practice as an adjunctive treatment for stage
I and II periodontitis.
KEYWORDS
Drug Delivery System; Emulgel; Nanomedicine; Periodontitis; Quercetin.
RESUMO
Objetivo: O objetivo foi avaliar o impacto do nanoemulgel de quercetina nos marcadores clínicos e bioquímicos
de pacientes com periodontite estágio I e II como adjuvante à raspagem e alisamento radicular (RAR). Material e
Métodos: Vinte sítios de pacientes com periodontite estágio I e II foram aleatoriamente distribuídos em dois grupos:
Grupo I, no qual 10 sítios foram tratados com RAR, e Grupo II, no qual 10 sítios receberam RAR em associação
com o nanoemulgel de quercetina. Os parâmetros clínicos foram registrados no início, após 1 mês e 3 meses,
incluindo índice de placa (IP), índice gengival (IG), profundidade de sondagem (PS) e nível de inserção clínica
(NIC). Avaliações bioquímicas foram realizadas para medir os níveis de interferon-gama (IFN-γ) e a capacidade
antioxidante total no uido gengival crevicular (FGC) nos mesmos períodos. Resultados: Todas as variáveis clínicas
apresentaram melhora após o tratamento em ambos os grupos, com uma melhora signicativamente maior no
Grupo II em comparação ao Grupo I em diferentes momentos da avaliação. Os níveis de capacidade antioxidante
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Mohammed KA et al.
Efficacy of quercetin nano-emulgel as adjuvant local delivery drug in non-surgical treatment of periodontitis
Mohammed KA et al. Efficacy of quercetin nano-emulgel as adjuvant local delivery
drug in non-surgical treatment of periodontitis
INTRODUCTION
Periodontitis is a multifactorial inammatory
condition affecting the teeth’s supporting tissues
that causes progressive deterioration of the
periodontal ligament and alveolar bones, resulting
in irreparable tooth loss if left untreated. It is
dened as a complex disease in which the biolm
interacts with the host’s immunoinammatory
response, resulting in changes in bone and
connective tissue homeostasis. Numerous studies
indicate that both the host’s immune system and
the commensal oral microbiota that colonizes
the biofilm are responsible for the initiation
and progression of this periodontal disease [1].
Furthermore, immune cells’ reactive oxygen
species (ROS) further aggravate gingival tissue
injury [2].
Mechanical debridement, scaling and root
planing (SRP), is the mainstay of periodontal
treatment. To allow periodontal tissues to
adhere to the treated root surface in the future,
it aims to remove supragingival and subgingival
biolms and restore the biological compatibility
of periodontally diseased root surfaces.
Nevertheless, not all pathogenic microorganisms
in the subgingival region can be eradicated by
instrumentation [3]. Adjunctive pharmacological
drugs can increase the effectiveness of mechanical
therapy. However, systemic drugs have limitations
due to their systemic effects, leading to ineffective
medication concentrations at the site of action,
which negatively impacts patient outcomes.
Therefore, it was essential to design other localized
delivery methods [4]. This necessity prompted
researchers to investigate alternative localized
drug delivery systems. Various in situ localized
drug delivery systems have been evaluated
with favorable outcomes for periodontitis [5].
However, in certain clinical circumstances, such
as localized deep pockets or during supportive
periodontal therapy, commercially available
local antimicrobials might be useful. However,
because of an unclear cost-benet ratio, their
clinical usefulness is limited [6].
In this context, the academic community
began concentrating on adjuvants to conventional
periodontal therapy which are less likely to
induce side effects and lack antibiotic resistance.
Recent research has proven phytochemicals to
be useful in the treatment of periodontitis [7,8].
Among the organic phenolic chemicals found
in fruits and vegetables are avonoids, which
possess anti-inflammatory, antibacterial, and
antioxidant qualities [9].
Quercetin is an example of these crucial
flavonoids. It has been proven that quercetin
possesses signicant pharmacological characteristics
as an antioxidant [10], anti-inammatory [11],
antimicrobial [12], antineoplastic [13], and
antiallergic [14].
Due to its potent antibacterial action against
periodontal microorganisms, quercetin can be
used as an adjuvant local delivery medication in
the non-surgical treatment of periodontitis [15].
Quercetin may impact mature plaque biolm’s
morphology and metabolic activity [16]. Due to
its anti-inammatory properties, quercetin may
reduce inammation caused by lipopolysaccharide
(LPS) by interfering with the nuclear factor
kappa-B (NF-κB) signaling pathway and inhibiting
the production of inammatory cytokines such as
IL-12, IFN-γ, IFN-α, IL-6, IL-8, cyclooxygenase-2,
and prostaglandin E2 [17]. Quercetin inhibits
the release of reactive oxygen species (ROS) by
increasing the expression of antioxidant enzyme-
related genes such as catalase (CAT), glutathione
peroxidase 3 (GPx3), quinone oxidoreductase
1 (NQO-1), and heme oxygenase-1 (HO-1), as
well as enhancing superoxide dismutase (SOD)
activity [18]. Quercetin has the ability to increase
collagen expression, enhance wound healing,
and restore periodontal soft tissue integrity [19].
total no FGC aumentaram signicativamente, enquanto os níveis de IFN-γ diminuíram ao longo do estudo em
ambos os grupos, com mudanças mais expressivas no Grupo II em relação ao Grupo I. Conclusão: O nanoemulgel
de quercetina demonstrou resultados promissores na melhoria dos parâmetros clínicos e bioquímicos no tratamento
da periodontite quando utilizado em conjunto com a raspagem e alisamento radicular. Esses achados incentivam
o uso do nanoemulgel de quercetina na prática clínica como tratamento adjuvante para periodontite estágio I e II.
PALAVRAS-CHAVE
Sistema de Liberação de Fármacos; Emulgel; Nanomedicina; Periodontite; Quercetina.
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Mohammed KA et al.
Efficacy of quercetin nano-emulgel as adjuvant local delivery drug in non-surgical treatment of periodontitis
Mohammed KA et al. Efficacy of quercetin nano-emulgel as adjuvant local delivery
drug in non-surgical treatment of periodontitis
Furthermore, quercetin has a strong effect on
promoting osteogenesis [20].
Even though quercetin has been shown in
numerous studies to be a potential phytochemical
for maintaining the integrity of periodontal
tissue, its limited bioavailability, low water
solubility, low absorption, high metabolic rate,
and quick elimination from the body limit its
practical application. As a result, scientists have
focused on developing local delivery systems
that avoid biopharmaceutical challenges and
minimize systemic clearance, thus improving
its therapeutic and prophylactic potential using
various techniques [21,22].
The incorporation of oils and emulsiers
improves quercetin absorption. Therefore, nano-
emulsion may be an appropriate drug delivery
medium for loading quercetin [23]. That can be
combined with the polymer solution to create
an in-situ nano-emulgel that facilitates easy
administration and sustained/controlled drug
delivery, increasing patient compliance [24].
The key research question for this study was,
“Does quercetin nano-emulgel, as an adjuvant
local delivery drug in the phase I (non-surgical)
treatment of periodontitis, improve clinical and
biochemical parameters?”
MATERIAL AND METHODS
Study design and population
This randomized, controlled clinical
and biochemical study was conducted from
August 23, 2023, to February 2024. It involved
23 patients with stage I to stage II periodontitis,
comprising 13 females and 10 males aged 20 to
45 years. Patients were chosen from individuals
attending the Oral Medicine and Periodontology
Departments’ outpatient clinics at the Faculty
of Dental Medicine, Al-Azhar University, Assiut
Branch, and the Faculty of Dentistry, Assiut
University. The diagnosis was made based on
recording case history and conducting extraoral
and intraoral clinical examinations, and patients
selected for the study met the inclusion criteria.
Ethical considerations
This randomized controlled trial followed
the ethical guidelines established in the Helsinki
Declaration for medical research and was
approved by the ethical committee of the
Faculty of Dental Medicine, Al-Azhar University
(Approval number: AUAREC202200001-6).
The clinical trial was registered under the
number NCT05928546 on ClinicalTrials.gov [25].
Before participation, all patients were
provided with comprehensive information
regarding the nature of the trial, potential
hazards, and benets. They were fully informed
and subsequently signed their informed consent
forms.
Inclusion criteria
The inclusion criteria for this study were as
follows:
- Patients in stages I and II of periodontitis
(Stage I has no tooth loss, a clinical
attachment level (CAL) of 1 to 2 mm, and
a probing depth of ≤4 mm; Stage II has no
tooth loss, a CAL of 3 to 4 mm, and a probing
depth ≤ 5mm [26] (Figure 1a).
- Patients possessing more than 20 natural teeth
with mesial and distal neighboring teeth.
- Patients who do not exhibit any systemic
diseases that could impact their periodontal
condition, as determined by the Cornell
Medical Index and its modications.
Figure 1 - (a) probing depth and attachment level measurement using a UNC15 periodontal probe; (b) quercetin nano-emulgel application; (c)
GCF sample taking.
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Mohammed KA et al.
Efficacy of quercetin nano-emulgel as adjuvant local delivery drug in non-surgical treatment of periodontitis
Mohammed KA et al. Efficacy of quercetin nano-emulgel as adjuvant local delivery
drug in non-surgical treatment of periodontitis
Exclusion criteria
The exclusion criteria for this study included:
- long-term use of medicines including
antibiotics and non-steroidal anti-
inammatory drugs that may have an effect
on the condition or rate at which periodontal
tissues heal.
- Expectant and nursing mothers.
- Individuals with a history of traumatic
occlusion.
- Patients who have undergone mechanical
debridement or periodontal surgery within
the last three and six months, respectively,
and those with teeth having both endo-perio
lesions.
Sample size calculation
The sample size for this study was determined
with α = 0.05 and 95% power. A 1 mm value
was used, with clinical attachment level (CAL)
change as the primary outcome variable. Using
the G*Power statistical power analysis program
(version 3.1.9.4) and Sonar et al. [27] as a basis, a
sample size of 10 (ve per Group) was found to be
sufcient to nd a notable effect size (d) of 2.98,
with an actual power (1-β error) of 0.95 (95%)
and a signicance level (α error) of 0.05 (5%) for
the two-sided hypothesis test.
The sample size was increased by 100%
to account for potential dropout, resulting in a
total sample size of 20 (n = 10 in each Group).
23 patients received the treatment but 3 patients
were lost in the follow up. Making the final
sample size 20 (Figure 2).
Patient grouping and randomization
Using online software [28], patients were
randomly assigned to two groups, with numbers
concealed in locked envelopes.
The periodontally affected sites selected in
this study were classied into two groups:
- Group I: Sites received non-surgical
periodontal therapy (scaling and root
planing).
- Group II: Sites received the same treatment
followed by applying quercetin nano-
emulgel local delivery.
The allocation ratio was 1:1 for both groups.
Allocation concealment mechanism
Allocation concealment was achieved
by assigning sequential numbers to opaque
sealed envelopes containing the interventions
to be administered to the recruited individuals
following the randomized numbers in the
randomization list. After scaling and root
planning, patients were allotted to either Group
I or Group II. At this stage, a person other than
the operator selected the number and opened the
sealed envelope with the treatment assignment.
Blinding
Blinding was implemented for participants,
the outcome assessor, and the biostatistician;
however, blinding the operator was not feasible.
Preparation of quercetin nano-emulgel
For 30 minutes, 4 mg of quercetin
(purchased from Loba India) was dissolved in
1.25 g of cinnamon oil, 9 g of surfactant (tween
80) (purchased from Loba India), and 2.5 g
cosurfactant (ethylene glycol) (purchased from
Loba India). Additionally, 10 g of aqueous phase
poloxamer was dissolved in 37.5 g of distilled
water. The samples were stored for 72 hours
at 37 °C in a water bath shaker [24]. The total
concentration of quercetin is 6.64% w/w.
The particle size (mean size) and polydispersity
index (PDI) of the generated cinnamon oil nano-
emulsion were analyzed using dynamic light
scattering after proper dilution with distilled water
(Malvern Instruments, Malvern, Worcestershire,
UK; Zetasizer, Nanoseries, Nano-zs). Standard
operating procedures were employed to regulate
every measurement and analysis conguration.
The preparation was conducted by NanoGate
(25 Ibrahim Abou Elnaga St., Ext. of Abbas El
Akkad, Nasr city, 11765, Cairo, Egypt).
Zeta potential measurement:
After proper dilution of the samples with
distilled water, charges on the produced Q@
cinnamon oil nano-emulsion were examined,
and their zeta potential values were obtained
using a Zeta-sizer under standard operating
circumstances.
Size & shape:
A JEOL JEM-2100 high-resolution
transmission electron microscope operating at
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Mohammed KA et al.
Efficacy of quercetin nano-emulgel as adjuvant local delivery drug in non-surgical treatment of periodontitis
Mohammed KA et al. Efficacy of quercetin nano-emulgel as adjuvant local delivery
drug in non-surgical treatment of periodontitis
an accelerating voltage of 200 kV was used to
perform transmission electron microscopy (TEM),
respectively (Figure 3).
Periodontal intervention
Phase I periodontal treatment was
administered to each patient, involving non-
surgical mechanical periodontal debridement
(full-mouth scaling and root planing). This
procedure was conducted without the use of
adjunct disinfectants.
Intra-pocket application of quercetin nano-emulgel:
A cotton roll was used to isolate application
sites after standard periodontal treatment.
The gel was carefully applied sub-gingivally
(about 2 to 4 ml depending on pocket depth)
until it appeared from the gingival margin, using
a needle inserted into the base of the periodontal
pocket (Figure 1b).
Patients were asked not to eat, spit, or
drink for one hour following the application.
Figure 2 - Flow diagram.
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Mohammed KA et al.
Efficacy of quercetin nano-emulgel as adjuvant local delivery drug in non-surgical treatment of periodontitis
Mohammed KA et al. Efficacy of quercetin nano-emulgel as adjuvant local delivery
drug in non-surgical treatment of periodontitis
Additionally, brushing and flossing were
prohibited for four hours post-application.
Patients were instructed on a plaque control
regimen. The application was repeated after
2 weeks, resulting in the gel being applied twice,
once on the day of non-surgical periodontal
treatment and again after 2 weeks.
Periodontal assessment
Clinical assessment
All patients’ periodontal condition was
clinically evaluated at baseline, one month,
and three months after treatment using the
following parameters: modified plaque index
(PI) [29], gingival index (GI) [30], probing
depth (PD) [31], and clinical attachment level
(CAL) [32].
Biochemical assessment
Gingival crevicular uid samples collection
Before GCF collection, sample sites
were carefully dried and isolated from
saliva contamination using cotton rolls.
The supragingival plaque was removed without
touching the marginal gingiva. Samples of GCF
were collected from the site with the greatest
probing depth (range 4-5mm) and CAL less than
5 mm. Sterilized paper point size #30 was used
for GCF collection. This can be accomplished
by carefully placing the paper point into the
periodontal pocket until little resistance was
noticed and holding it there for 30 seconds
(Figure 1c). Any paper points stained with blood
were discarded.
Following GCF collection, the samples
were promptly placed in Eppendorf tubes lled
with phosphate-buffered saline (PBS containing
137 mm NaCl, 10 mm Na2HPO4, and 2.7 mm
KCl; pH 7.3). The tubes were then frozen at
-80 °C [33]. Interferon-gamma (IFN-γ) and
total antioxidant capacity concentrations were
assessed using enzyme-linked immunosorbent
assay (ELISA).
IFN-γ analysis
The laboratory procedure was conducted
using the ELISA method. An ELISA kit from
SinoGeneClon Biotech was utilized to detect the
level of IFN-γ in pg/ml in the sample of GCF,
following the manufacturer’s directions.
Total antioxidant capacity analysis
The samples were assayed using the
Bio-Diagnostic total antioxidant capacity kit
(http://bio-diagnostic.com) to evaluate the
antioxidant impact of quercetin. The instructions
provided by the manufacturer were followed for
utilizing the kit.
Figure 3 - TEM images of the prepared Q@cinnamon oil nano-emulsion.
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Mohammed KA et al.
Efficacy of quercetin nano-emulgel as adjuvant local delivery drug in non-surgical treatment of periodontitis
Mohammed KA et al. Efficacy of quercetin nano-emulgel as adjuvant local delivery
drug in non-surgical treatment of periodontitis
Outcomes
The primary outcome considered in this
study was the CAL, while the PI, GI, PD, IFN-
γ, and total antioxidant capacity analysis were
dened as secondary outcomes.
Statistical analysis
The mean and standard deviation values
were calculated for each Group in each test.
The data’s normality was assessed using the
Kolmogorov-Smirnov and Shapiro-Wilk tests,
which revealed a non-parametric (non-normal)
distribution. Continuous data were expressed
as minimum and maximum, mean ± standard
deviation (SD), or median (interquartile range).
The Mann-Whitney test was utilized to
compare unrelated sample results between two
groups. To compare more than two groups in
related samples, the Friedman test was used,
whereas the Wilcoxon signed-rank test was
used to compare two groups in related samples.
The Pearson test was employed to nd correlation
coefcients.
The significance level was set at
p < 0.05 indicated by “*”, with a very signicance
level set at p < 0.01 indicated by “**” and highly
significant at p < 0.001 indicated by “***”.
Statistical analysis was performed using IBM®
SPSS® statistics version 26 for Windows.
RESULTS
The mean gingival index (GI) score in Group
I was 2 ± 0 at baseline, which significantly
reduced to 1.4 ± 0.52 and 1.5 ± 0.71 after
1 month and 3 months of treatment, respectively
(p < 0.05). In Group II, the mean GI score was
2 ± 0 at baseline, signicantly reduced to 0.8 ±
0.42 and 0.6 ± 0.52 at 1 month and 3 months
after treatment, respectively (p < 0.01).
There is a statistically signicant difference
between the two groups at 1 month (p < 0.05)
and a very statistically signicant difference at
3 months (p < 0.01) (Table I).
The mean plaque index (PI) score in
Group I was 2.7 ± 0.67 at baseline, which very
signicantly reduced to 1.1 ± 0.57 after 1 month
and significantly reduced to 1.2 ± 1.03 after
3 months of treatment (p < 0.05). In Group II,
the mean plaque index score was 2.4 ± 0.52 at
baseline, which very significantly reduced to
0.7 ± 0.48 and 0.4 ± 0.52 at 1 month and
3 months after treatment, respectively (p < 0.01).
Table I - Distribution of gingival index scores among the studied groups over time
Gingival index (GI)
Group I (without gel) Group II (with gel)
p-value
n=10 n=10
Baseline
Min. - Max. 2 - 2 2 - 2
Mean ± SD 2 ± 0 2 ± 0
Median (Q1-Q3) 2(2-2) 2(2-2) 1.000
1 month
Min. - Max. 1 - 2 0 - 1
Mean ± SD 1.4 ± 0.52 0.8 ± 0.42
Median (Q1-Q3) 1(1-2) 1(0.75-1) 0.015*
3 months
Min. - Max. 0 - 2 0 - 1
Mean ± SD 1.5 ± 0.71 0.6 ± 0.52
Median (Q1-Q3) 2(1-2) 1(0-1) 0.007**
p-value2
0.016* <0.001**
p1
0.014* 0.003**
p2 0.059
0.004**
p3 0.564 0.317
p-value: calculated by the Mann-Whitney test between the two groups for each period. p-value2: calculated by the Friedman test between
baseline, 1 month, and 3 months for each Group. p1: calculated by the Wilcoxon test between baseline & and 1 month for each Group. p2:
calculated by the Wilcoxon test between baseline & and 3 months for each Group. p3: calculated by the Wilcoxon test between 1 month &
and 3 months for each Group.
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Mohammed KA et al.
Efficacy of quercetin nano-emulgel as adjuvant local delivery drug in non-surgical treatment of periodontitis
Mohammed KA et al. Efficacy of quercetin nano-emulgel as adjuvant local delivery
drug in non-surgical treatment of periodontitis
Non-statistically signicant differences were
found when the comparison was carried out
between groups (Table II).
The mean probing depth (PD) in Group I
was 5 ± 0.82 at baseline, which very signicantly
lowered to 4 ± 0.94 after 1 month and signicantly
Table II - Distribution of plaque index among the studied groups over time
Plaque index (PI)
Group I (without gel) Group II (with gel)
p-value
n=10 n=10
Baseline
Min. - Max. 1 - 3 2 - 3
Mean ± SD 2.7 ± 0.67 2.4 ± 0.52
Median (Q1-Q3) 3(2.75-3) 2(2-3) 0.136
1 month
Min. - Max. 0 - 2 0 - 1
Mean ± SD 1.1 ± 0.57 0.7 ± 0.48
Median (Q1-Q3) 1(1-1.25) 1(0-1) 0.111
3 months
Min. - Max. 0 - 3 0 - 1
Mean ± SD 1.2 ± 1.03 0.4 ± 0.52
Median (Q1-Q3) 1(0-2) 0(0-1) 0.062
p-value2 0.001** <0.001**
p1 0.004** 0.004**
p2 0.011* 0.004**
p3
0.705 0.257
p-value: calculated by the Mann-Whitney test between the two groups for each period. p-value2: calculated by the Friedman test between
baseline, 1 month, and 3 months for each Group. p1: calculated by the Wilcoxon test between baseline & and 1 month for each Group. p2:
calculated by the Wilcoxon test between baseline & and 3 months for each Group. p3: calculated by the Wilcoxon test between 1 month &
and 3 months for each Group.
Table III - Distribution of probing depth among the studied groups over time
Probing depth (PD)
Group I (without gel) Group II (with gel)
p-value
n=10 n=10
Baseline
Min. - Max. 4 - 6 3 - 6
Mean ± SD 5 ± 0.82 4.8 ± 0.92
Median (Q1-Q3) 5(4-6) 5(4-5.25) 0.687
1 month
Min. - Max. 3 - 5 2 - 4
Mean ± SD 4 ± 0.94 3.2 ± 0.92
Median (Q1-Q3) 4(3-5) 3.5(2-4) 0.098
3 months
Min. - Max. 3 - 7 1 - 4
Mean ± SD 4.3 ± 1.25 2.9 ± 0.74
Median (Q1-Q3) 4(3-5) 3(3-3) 0.005**
p-value2 0.002** <0.001**
p1 0.004** 0.004**
p2 0.035* 0.004**
p3
0.257 0.257
p-value: calculated by the Mann-Whitney test between the two groups for each period. p-value2: calculated by the Friedman test between
baseline, 1 month, and 3 months for each Group. p1: calculated by the Wilcoxon test between baseline & and 1 month for each Group. p2:
calculated by the Wilcoxon test between baseline & and 3 months for each Group. p3: calculated by the Wilcoxon test between 1 month &
and 3 months for each Group.
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Mohammed KA et al.
Efficacy of quercetin nano-emulgel as adjuvant local delivery drug in non-surgical treatment of periodontitis
Mohammed KA et al. Efficacy of quercetin nano-emulgel as adjuvant local delivery
drug in non-surgical treatment of periodontitis
reduced to 4.3 ± 1.25 after 3 months of treatment
(p < 0.05). In Group II, the mean probing depth
was 4.8 ± 0.92 at baseline, which signicantly
lowered to 3.2 ± 0.92 and 2.9 ± 0.74 at 1 month
and 3 months following treatment, respectively
(p < 0.01) (Table III).
When comparing between groups, very
statistically signicant differences were found
at 3 months (p < 0.01). The reduction in PD
between baseline and after 3 months was 14.0%
in Group I and 39.6% in Group II (Table IV).
The mean clinical attachment level (CAL)
in Group I was 2.7 ± 1.06 at baseline, which
signicantly reduced to 2.1 ± 0.88 at 1 month
(p < 0.05) and very signicantly reduced to 1.6 ±
1.07 after 3 months of treatment (p < 0.01).
In Group II, the mean CAL was 2.5 ± 0.85 at
baseline, which signicantly reduced to 1.9 ±
0.99 at 1 month (p < 0.05) and very signicantly
reduced to 0.85 ± 1 at 3 months after treatment
(p < 0.01) (Table V).
There were non-statistically significant
differences between the two groups in CAL at
baseline, 1 month, and 3 months. However, the
reduction percentage between baseline and after
3 months was 40.7% in Group I and 66% in Group
II, indicating that the amount of gain in clinical
attachment after 3 months was 1.1 mm in Group
I and 1.65 mm in Group II (Tables VI and VII).
Table IV - Reduction between baseline and after 3 months for each group according to probing depth (PD)
Probing depth (PD)
Group I Group II
Mean Mean
Baseline 5 4.8
3 months 4.3 2.9
Reduction
(Between baseline and after 3 months follow up in each group) 14.0% 39.6%
Table V - Distribution of clinical attachment loss among the studied groups over time
Clinical attachment loss (CAL)
Group I (without gel) Group II (with gel)
p-value
n=10 n=10
Baseline
Min. - Max. 1 - 4 1 - 4
Mean ± SD 2.7 ± 1.06 2.5 ± 0.85
Median (Q1-Q3) 2.5(2-3) 2.5(2-3) 0.691
1 month
Min. - Max. 1 - 3 1 - 4
Mean ± SD 2.1 ± 0.88 1.9 ± 0.99
Median (Q1-Q3) 2(1-3) 2(1-2.25) 0.524
3 months
Min. - Max. 0 - 3 0 - 3
Mean ± SD 1.6 ± 1.07 0.85 ± 1
Median (Q1-Q3) 1(1-3) 0.75(0-1.25) 0.089
p-value2
<0.001** <0.001**
p1
0.014* 0.014*
p2
0.002** 0.007**
p3
0.025* 0.005**
p-value: calculated by the Mann-Whitney test between the two groups for each period. p-value2: calculated by the Friedman test between
baseline, 1 month, and 3 months for each Group. p1: calculated by the Wilcoxon test between baseline & and 1 month for each Group. p2:
calculated by the Wilcoxon test between baseline & and 3 months for each Group. p3: calculated by the Wilcoxon test between 1 month &
and 3 months for each Group.
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Efficacy of quercetin nano-emulgel as adjuvant local delivery drug in non-surgical treatment of periodontitis
Mohammed KA et al. Efficacy of quercetin nano-emulgel as adjuvant local delivery
drug in non-surgical treatment of periodontitis
The mean IFN-γ level in Group I was
216.64 ± 164.73 at baseline, which signicantly
reduced to 92.6 ± 60.06 and 99.81 ± 57.56 after
1 month and 3 months of treatment, respectively
(p < 0.05). In Group II, the mean IFN-γ level was
353.33 ± 175.71 at baseline, which signicantly
decreased to 109.64 ± 81.08 and 121.7 ±
99.11 after 1 month and 3 months of treatment,
Table VI - Reduction between baseline and after 3 months for each group according to clinical attachment loss (CAL)
Clinical attachment loss (CAL)
Group I Group II
Mean Mean
Baseline 2.7 2.5
3 months 1.6 0.85
Reduction
(Between baseline and after 3 months follow up in each Group) 40.7% 66%
Table VII - The gain in clinical attachment (CA) between baseline, after 1 month and after 3 months for each group
Clinical attachment loss (CAL)
Group I Group II
Mean Mean
Baseline 2.7 2.5
1 month 2.1 1.9
3 months 1.6 0.85
CAL gain in 1 month
(Mean of baseline – Mean of 1 month follow up) 0.6 0.6
CAL gain in 3 months
(Mean of baseline – Mean of 3 months follow up) 1.1 1.65
Table VIII - Distribution of interferon gamma among the studied groups over time
Inter feron gamma
Group I (without gel) Group II (with gel)
p-value
n=10 n=10
Baseline
Min. - Max. 33.69 - 521.85 80.26 - 606.46
Mean ± SD 216.64 ± 164.73 353.33 ± 175.71
Median (Q1-Q3) 202.517(43.949-375.879) 340.179(244.819-536.526) 0.112
1 month
Min. - Max. 23.42 - 186.38 19.62 - 245.06
Mean ± SD 92.6 ± 60.06 109.64 ± 81.08
Median (Q1-Q3) 90.936(35.146-147.257) 76.289(50.795-186.134) 0.821
3 months
Min. - Max. 27.33 - 217.19 9.84 - 257.29
Mean ± SD 99.81 ± 57.56 121.7 ± 99.11
Median (Q1-Q3) 96.397(53.241-132.586) 113.758(26.868-218.777) 0.821
p-value2
0.025* 0.001**
p1
0.022* 0.005**
p2 0.047*
0.005**
p3 1.000 0.575
p-value: calculated by the Mann-Whitney test between the two groups for each period. p-value2: calculated by the Friedman test between
baseline, 1 month, and 3 months for each Group. p1: calculated by the Wilcoxon test between baseline & and 1 month for each Group. p2:
calculated by the Wilcoxon test between baseline & and 3 months for each Group. p3: calculated by the Wilcoxon test between 1 month &
and 3 months for each Group.
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Efficacy of quercetin nano-emulgel as adjuvant local delivery drug in non-surgical treatment of periodontitis
Mohammed KA et al. Efficacy of quercetin nano-emulgel as adjuvant local delivery
drug in non-surgical treatment of periodontitis
respectively (p < 0.01). Non-statistically
significant differences were found when the
comparison was carried out between groups
(Table VIII).
The mean total antioxidant capacity in
Group I was 0.61 ± 0.64 at baseline, signicantly
increasing to 0.97 ± 0.39 after 1 month (p < 0.05)
and 0.78 ± 0.53 after 3 months of treatment.
In Group II, the mean total antioxidant capacity was
0.65 ± 0.41 at baseline, which very signicantly
increased to 1.04 ± 0.27 and 0.98 ± 0.48 after
1 month and 3 months of treatment, respectively
(p < 0.01) (Table IX). When a comparison was
conducted between groups, non-statistically
signicant differences were found. No harm or
side effects were observed in this study.
DISCUSSION
From a pathological perspective, periodontitis
can be described as the presence of inammation
associated with connective tissue attachment
loss that leads to tooth-supporting tissue
destruction [34]. It involves complex, dynamic
interactions between specic bacterial pathogens,
harmful host immune responses, and external
factors such as smoking [35]. Periodontitis is
primarily caused by bacterial biolm on tooth
surfaces, with factors like calculus, plaque,
genetics, environmental, health, lifestyle choices,
and social determinants also influencing its
progression [36].
Improving the patient’s gingival health and
maintaining the residual periodontal tissues are
the primary goals of periodontal therapy [37].
Eradication or inhibition of periodontopathic
bacteria in the subgingival microbiota is crucial for
periodontal repair [38]. Non-surgical periodontal
therapy, including scaling and root planing,
is foundational [35], but may not effectively
remove plaque and calculus from inaccessible
areas, including deep pockets and furcation
areas, leading to high treatment failure rates.
Additionally, it is impossible to eliminate all
pathogenic bacteria through instrumentation
within the subgingival region [39]. Medications
can promote tissue regeneration by reducing
inammation and microbial burden. Effective
pharmaceutical distribution can be achieved
through systemic and local delivery, though
systemic dosing can cause various adverse
effects [40].
The pocket’s anatomy makes it an ideal
target for local delivery systems. Although
Table IX - Distribution of total antioxidants among the studied groups over time
Total antioxidant
Group I (without gel) Group II (with gel)
p-value
n=10 n=10
Baseline
Min. - Max. -0.77 - 1.3 -0.06 - 1.22
Mean ± SD 0.61 ± 0.64 0.65 ± 0.41
Median (Q1-Q3) 0.63(0.194-1.219) 0.813(0.354-0.919) 0.821
1 month
Min. - Max. 0.39 - 1.31 0.5 - 1.4
Mean ± SD 0.97 ± 0.39 1.04 ± 0.27
Median (Q1-Q3) 1.189(0.44-1.233) 1.083(0.836-1.233) 0.940
3 months
Min. - Max. 0.06 - 1.4 0.14 - 1.4
Mean ± SD 0.78 ± 0.53 0.98 ± 0.48
Median (Q1-Q3) 0.889(0.241-1.262) 1.154(0.457-1.387) 0.406
p-value2
0.045* 0.002**
p1
0.022* 0.005**
p2 0.241
0.009**
p3 0.093 0.878
p-value: calculated by the Mann-Whitney test between the two groups for each period. p-value2: calculated by the Friedman test between
baseline, 1 month, and 3 months for each Group. p1: calculated by the Wilcoxon test between baseline & and 1 month for each Group. p2:
calculated by the Wilcoxon test between baseline & and 3 months for each Group. p3: calculated by the Wilcoxon test between 1 month &
and 3 months for each Group.
12
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Mohammed KA et al.
Efficacy of quercetin nano-emulgel as adjuvant local delivery drug in non-surgical treatment of periodontitis
Mohammed KA et al. Efficacy of quercetin nano-emulgel as adjuvant local delivery
drug in non-surgical treatment of periodontitis
released in small amounts, gingival uid aids
in drug distribution in the pocket’s limited
locations [41]. Local drug delivery improves
pharmaceutical outcomes by delivering drugs to
targeted areas in higher concentrations, lowering
side effects, and providing advantages such as
solubility, action duration, and targeting, all
while promoting tissue regeneration [40].
Quercetin, known for its antimicrobial
properties, reduces inammation, lowers ROS
levels, and decreases bone loss [42]. Unfortunately,
its low aqueous solubility and instability in
physiological media hinder its bioavailability,
permeability and absorption [43]. Scientists have
attempted to improve quercetin bioavailability
by various means [21]. Nanotechnological drug
delivery systems have the advantage of making
good contact with the mucosal areas of the
periodontium, staying in the targeted tissue for a
long time, and increasing epithelial transport of
poorly absorbed drugs [44]. Nano-emulgel allows
for convenient administration and sustained/
controlled drug delivery [24]. The nano-emulgel
is a colloidal system as the emulsion part protects
pharmaceuticals from enzymatic destruction
and hydrolysis, while the gel part enhances
their viscosity, spreadability, retention time, and
thermodynamic stability [45].
This study attempts to explore the efcacy
of quercetin nano-emulgel as an adjuvant
local delivery drug in the Phase I treatment
of periodontitis. Between baseline and three
months, the clinical evaluation revealed a
significant decrease in plaque index in both
groups. These findings may be attributed to
all patients maintaining and reinforcing oral
hygiene during the study’s observation period.
However, Group II showed better results at 1 and
3 months, possibly due to quercetin’s anti-biolm
properties [16,46].
The study found a signicant decrease in
gingival index in both groups, with statistically
signicant differences between the two groups at
one month and three months. These results are
consistent with prior studies that have reported
quercetin’s capacity to inhibit the activation of
NF-κB and induce molecules that extensively
recruit leukocytes resulting in improved clinical
parameters [27,47].
The study reported a signicant lessen in
probing pocket depth in both groups, with no
signicant differences at baseline or 1 month.
However, Group II showed a very significant
difference at 3 months. Quercetin’s anti-
inammatory properties can reduce inammation
caused by lipopolysaccharide (LPS) by hindering
the synthesis of inflammatory cytokines for
instance prostaglandin E, IL-12, INF-α, IL-6,
and IL-8 [17]. Moreover, quercetin improves
wound healing, increases collagen expression,
and preserves the integrity of periodontal soft
tissues [19].
The study discovered significant CAL
reductions at various intervals in both groups.
Despite no significant differences between
the groups during the trial period, Group II
showed greater gains at the 3-month follow-up
than Group I. This is attributable to quercetin’s
strong osteogenesis-promoting effects. Quercetin
downregulates osteoclasts and reduces stimulating
cytokines such as IL-1, TNF-α, and IL-17 [48].
Biochemically, the study found a signicant
drop in IFN-γ levels in both groups at baseline,
1 month, and 3 months. However, the two groups
had no signicant differences at these time points.
The results for Group I are consistent
with previous research indicating that SRP
improved periodontal health by significantly
lowering IFN-γ levels [49-53]. In contrast,
several investigations found that GCF IFN-γ levels
remained unaltered after treatment. The low
frequency and concentration of this cytokine’s
sensitivity to the immunoassay may contribute
to this observation [54-57].
IFN-γ levels drop dramatically in Group II
after 1 and 3 months of treatment with quercetin.
In addition to SRP, quercetin suppresses
IFN-γ production following T-cell receptor
stimulation [58,59]. However, some studies
suggest quercetin increases gene expression
and Th-1-derived interferon-γ production while
decreasing Th-2-derived interleukin-4 (IL-4)
in normal peripheral blood mononuclear cells
(PBMCs) [60,61]. Conversely, Rogerio et al.
found that quercetin does not signicantly affect
IFN-γ levels [62]. The differences in quercetin
concentrations utilized in various studies could
explain this discrepancy [63].
The study revealed a signicant increase
in total antioxidant capacity in both groups at
different intervals, consistent with previous
studies indicating similar improvements [64-67].
Group II showed better results, though without
13
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Mohammed KA et al.
Efficacy of quercetin nano-emulgel as adjuvant local delivery drug in non-surgical treatment of periodontitis
Mohammed KA et al. Efficacy of quercetin nano-emulgel as adjuvant local delivery
drug in non-surgical treatment of periodontitis
statistical signicance, compared to Group I at the
1- and 3-month follow-up. This could be due to
the antioxidant effect of quercetin [18].
The relatively small sample size and patient
diversity in maintaining oral hygiene during the
clinical trial are signicant limitations of this
study. Another limitation is that the control group
did not receive a placebo.
CONCLUSION
This study’s use of quercetin nano-emulgel as
an adjunct to scaling and root planing for treating
periodontitis stages I and II showed improvement
in reducing clinical and biochemical parameters,
particularly in gingival index and probing depth.
This treatment approach holds promise for
widespread use as an adjunct.
Acknowledgments
All co-authors have reviewed and approved
the article’s contents, and there is no nancial
interest to disclose.
Author’s Contributions
KAM: Conceptualization, Writing – Original
Draft Preparation, Project administration,
Writing – Review & Editing. AAA: Methodology,
Validation, Formal Analysis. AIARA: Investigation,
Resources, Data Curation. HFH: Formal analysis,
Investigation. IMM: Visualization, Supervision.
Conict of Interest
The authors have no proprietary, nancial,
or other personal interest in any product, service,
and/or company presented in this article.
Funding
This study received no specic grants from
funding sources in the public, commercial, or
not-for-prot sectors.
Regulatory Statement
This study was conducted following the
Helsinki Declaration’s ethical principles for
medical research and was approved by the
Faculty of Dental Medicine, Al-Azhar University’s
ethical committee (AUAREC202200001-6).
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Khoshoe Al-mokhtar Mohammed
(Corresponding address)
Assiut University, Faculty of Dentistry, Assiut, Egypt.
Email: KhoshoeAl-Mokhtar@dent.aun.edu.eg
Date submitted: 2024 June 23
Accept submission: 2024 Dec 19
