Photodiagnosis and Photodynamic Therapy 31 (2020) 101818

Contents lists available at ScienceDirect

Photodiagnosis and Photodynamic Therapy

journal homepage: www.elsevier.com/locate/pdpdt

Antimicrobial Photodynamic Therapy with Diode laser and Methylene blue T

as an adjunct to scaling and root planning: A clinical trial
Nahid Derikvanda, Seyedeh Sara Ghasemib, Hannaneh Safiaghdamc, Hassan Piriaeid,
Nasim Chiniforushe,*
a
Department of periodontics faculty of dentisty, Borujerd Branch, Islamic Azad University, Borujerd, Iran
b
Dentist, Private practice, Khorramabad, Iran
c
Student research committee, Dental school, Shahid Beheshti University of Medical Sciences, Tehran, Iran
d
Department of Mathematics, Borujerd Branch, Islamic Azad University, Borujerd, Iran
e
Dental Implant Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran

A R T I C LE I N FO A B S T R A C T

Keywords: Introduction: Chronic periodontitis, the most common periodontal disease, is the destruction of tooth supporting
Antimicrobial photodynamic therapy structures and alveolar bone which may result in teeth exfoliation. Conventionally, treatment aims at decreasing
Chronic periodontitis bacterial load by mechanical debridement and systemic or local delivery of antibiotics. Antimicrobial photo-
Scaling and root planing dynamic therapy (aPDT) is a safe alternative adjunct therapy for elimination of pathogenic bacteria in period-
Clinical trial
ontal pocket. The aim of this study was to evaluate the effect of aPDT with 660 nm diode laser and methylene
Methylene blue
blue as an adjunct to scaling and root planning (SRP) on clinical periodontal parameters.
.
Materials and Methods: In this clinical trial, we assessed aPDT as an adjunct to scaling and root planning (SRP) in
chronic periodontitis treatment. A total of 50 subjected were enrolled. The case group received SRP and aPDT
with methylene blue solution as photosensitizer and diode laser (wavelength= 660 nm, power = 150 mW)
irradiation. The control group received only SRP. The effect on clinical parameters, namely Plaque index (PI),
Gingival index (GI), and probing depth (PD) was recorded at baseline, 6 weeks, 3 months and 6 months.
Results: There were no significant differences between participants for clinical parameters at baseline. PI, GI and
PD significantly improved compared to baseline (P < 0.05).
Conclusion: It can be concluded that aPDT can be considered a safe and efficient technique in addition to SRP for
reducing the pocket depth in chronic periodontitis patients.

1. Introduction
Chronic periodontitis is a prevalent inflammatory condition invol-
ving destruction of tooth-supporting structures and alveolar bone loss.
When left untreated, in susceptible patients, periodontitis is one of the
major causes of adult tooth loss [1]. The primary etiology for this dis-
ease is oral bacteria, forming a biofilm or plaque, on root surfaces and
periodontal pocket linings [2]. Clinicians mainly aim to eliminate or
reduce this bacterial load by removing plaque and calcified deposits in
the management of periodontitis. The standard periodontal treatment
ranges from mechanical debridement (scaling and root planning or
SRP) with or without adjunctive antibiotics to surgical approaches [3].
The highly demanding procedure of mechanical removal of plaque and
calculus has shown clinically improved conditions but is not feasible in
all situations, such as in deep pockets or furcation areas. The bacterial
residue, thus, will hinder the healing process after treatment [4]. Local
or systemic delivery of antibiotic agents have shown promising results
[5,6]. However, a growing resistance of oral microbiota to therapeutic
concentrations of antibiotics commonly used in clinical periodontal
practice has been shown in studies [7]. Also, the development of allergy
towards antibiotics in some patients and failing to achieve the desired
concentration in pockets are among its disadvantages [8]. Anti-
microbial photodynamic therapy (aPDT) has been proposed as an al-
ternative method in the recent years utilizing photosensitizers such as
Methylene blue and Toluidine blue and an appropriate wavelength of
laser beam to selectively annihilate periodontal pathogens [9,10].
These photosensitizers once stimulated by an appropriate wavelength
(between 650-900 nm), can release free radicals of oxygen in a radius of
0.20 μm which are cytotoxic [9]. The effect of these radicals are limited
to the area of photosensitizer accumulation and thus does not harm host

⁎
Corresponding author: Dentistry Research Institute, Tehran University of Medical Sciences, Qouds Ave, Tehran, Postal code: 1441987566, IR Iran.
E-mail address: n-chiniforush@farabi.tums.ac.ir (N. Chiniforush).

https://doi.org/10.1016/j.pdpdt.2020.101818
Received 5 December 2018; Received in revised form 17 April 2020; Accepted 4 May 2020
Available online 13 May 2020
1572-1000/ © 2020 Elsevier B.V. All rights reserved.
N. Derikvand, et al. Photodiagnosis and Photodynamic Therapy 31 (2020) 101818

Table 1
The criteria for scoring PI.
Scores Criteria

0 No plaque
1 A film of plaque adhering to the free gingival margin and adjacent area of the tooth. The plaque may be seen in situ only after application of disclosing solution or by
using the probe on the tooth surface.
2 Moderate accumulation of soft deposit s within the gingival pocket, or the tooth and gingival margin which can be seen with the naked eye.
3 Abundance of soft matter within the gingival pocket and/or on the tooth and gingival margin.

Table 2
The criteria for scoring GI.
Scores Criteria

0 Normal gingiva
1 Mild inflammation; slight change in colour and little change in texture. No bleeding on probing
2 Moderate inflammation; moderate glazing, redness, oedema and hypertrophy; bleeding on sensing
3 Severe inflammation; marked redness and oedema; tendency to spontaneous bleeding; ulceration

Fig. 1. Linear plot of Mean ± Standard deviation plaque score at baseline, 6 weeks, 3 months and 6 months follow up between case and control groups.

Table 3 cells or other tissues [11]. The rationale for the application of aPDT as
Comparing the plaque score at baseline, 6 weeks, 3 months and 6 months an adjunct to SRP is that, it is a safe non-invasive treatment with minute
follow-up using Independent Samples T-Test between case and control groups. side effects which can promote clinical outcomes and is more accep-
Group Plaque Index Mean ± SD P value table to the patient compared to surgical treatments [10]. Several stu-
dies have shown improved pocket depth (PD), clinical attachment loss
Control Baseline 6.96 ± 0.73 0.135 (CAL), and bleeding on probing (BOP) with the use of aPDT in addition
Case Baseline 6.48 ± 1.39
to SRP [12,13]. While others have failed to find a significant difference
Control 6 Weeks 4.68 ± 1.11 0.571
Case 6 Weeks 4.48 ± 1.36 between aPDT + SRP, and SRP alone [14,15]. These conflicts can be
Control 3 Months 3.72 ± 1.04 0.747 attributed to different treatment protocols such as different wavelength,
Case 3 Months 3.84 ± 1.56 power, irradiation time, energy density, etc. Balata et al, in 2013, de-
Control 6 Months 3.00 ± 1.00 0.791 monstrated that the application of aPDT with 0.005% methylene blue
Case 6 Months 2.92 ± 1.12
activated by 660 nm diode laser in the treatment of severe chronic
periodontits patients did not provide any added advantage compared to
ultrasonic debridement used alone [16]. In another study by Bundidpun
et al, in 2018, aPDT with phenothiazine chloride and red light resulted
in improvement of all clinical parameters including PD, GI and BOP in
treatment of chronic periodontitis [17]. Clinically, photoablation fol-
lowed by multiple photodynamic cycles with diode laser (λ = 810 nm
and λ = 635 nm respectively) and 0.3% methylene blue yielded a
significant reduction in PD, CAL, BOP [18]. In this study we aimed to
assess the effect of aPDT with diode laser (λ =660 nm) and methylene
blue as an adjunct to SRP on clinical periodontal parameters. We hope
to further clarify the efficacy of this treatment and help clinician make
an evidence-based decision.

Fig. 2. Linear plot of Mean ± Standard deviation Probing Depths at baseline, 6

2. Methods and materials
weeks, 3 months and 6 months follow up between case and control groups.

This controlled clinical trial was conducted in a full-mouth design

with a duration of six months. The study protocol was designed in

2
N. Derikvand, et al. Photodiagnosis and Photodynamic Therapy 31 (2020) 101818

Table 4 compromising systemic condition (systemic diseases, previous or cur-

Comparing the Probing Depths at baseline, 6 weeks, 3 months and 6 months rent radiation or immunosuppressive therapies) were excluded as well
follow- up using Independent Samples T-Test between case and control groups. as those who had received any local or systemic antibiotic treatment
Group Probing Depths Mean ± SD P value during the past 6 months. Pregnant or lactating women, patients with
history of periodontal surgery and smokers were also excluded. Written
Control Baseline 6.92 ± 0.40 0.676 consent was obtained from all patients after detailed explanation of the
Case Baseline 7.04 ± 1.37
treatment procedure was given. Patients were randomly allocated into
Control 6 Weeks 5.00 ± 0.58 0.081
Case 6 Weeks 5.40 ± 0.95 two groups using urn randomization method. The case group (n = 25)
Control 3 Months 3.88 ± 1.01 0.008* received SRP and aPDT while the control group (n = 25) received SRP
Case 3 Months 3.08 ± 0.81 and a placebo aPDT with a serum solution as dye and turned-off laser
Control 6 Months 3.20 ± 0.87 0.019*
device. The patients were not cognizant of the group they belonged to.
Case 6 Months 2.64 ± 0.75
All the patients were examined at the baseline. The examiners were
* Statistically Significant Difference (P < 0.05). calibrated in a previous training session, on five patients not related to
the study, examining them by 48 -h intervals. The acceptable agree-
ment percentage was set at 90%. The examiners were not aware of the
treatment protocol. The following clinical parameters were recorded:
PI, defined by Löe and Silness (Table. 1). PD, defined as the distance in
millimeters between gingival margin and base of periodontal pocket. GI
or gingival index, defined by Löe and Silness [19] for assessing the
severity of gingivitis (Table. 2). Four sites (buccal, mesial, distal, and
lingual) were evaluated for gingival index and each site is given a score
from 0 to 3 for and the total score was reported. Also for plaque index,
the same method was used. Six sites (mesiobuccal, mid buccal, dis-
tobuccal, mesiolingual,midlingual, distolingual) were evaluated for
probing and the deepest one was reported. These recordings were made
using a periodontal probe (Hu Friedy, IL., Chicago, IL) at baseline, 6
weeks, 3 months, and 6 months after. Later, a thorough mechanical
Fig. 3. Linear plot of Mean ± Standard deviation Probing Depths at baseline, 6 debridement was carried out with manual and ultrasonic devices
weeks, 3 months and 6 months follow up between case and control groups. (woodpecker, China) and oral hygiene instructions were given by an
experienced clinician who was not aware of treatment assignment.
Table 5 After three days, in case group, the pockets were treated with photo-
Comparing the Gingival Index at baseline, 6 weeks, 3 months and 6 months dynamic therapy using a Diode laser (DX61, Konftec, Taiwan) at wa-
follow- up using Independent Samples T-Test between case and control groups. velength of 660 nm, power of 150 mW, and methylene blue solution
Group Gingival Index Mean ± SD P value (Blue+M, Novateb Pars Co, Iran). The solution at concentration of 100
μg/mL was applied inside the pockets and gingival sulci using a 1 mm
Control Baseline 6.92 ± 1.12 0.672 syringe. After 5 min, irradiation was done by laser light with photo-
Case Baseline 6.76 ± 1.52
dynamic tip for 60 sec in each pocket moving apico-coronally both
Control 6 Weeks 5.04 ± 1.28 0.203
Case 6 Weeks 4.56 ± 1.36 buccal and lingual part of tooth.Gingival sulcus was washed with
Control 3 Months 4.00 ± 0.88 0.291 physiological saline after the laser irradiation. All procedures were
Case 3 Months 3.64 ± 1.44 carried out according to manufacturer’s protocol. One trained operator
Control 6 Months 3.04 ± 0.92 0.614
blinded to the clinical examinations and data collection carried out the
Case 6 Months 2.88 ± 1.28
photodynamic therapy. Special safety glasses were provided to the
patients, operator and dental assistant. In control group, patients re-
compliance with the consolidated standards of reporting trials ceived the physiologic serum in the gingival sulcus but with placebo
(CONSORT) statement and according to the guidelines of the laser irradiation.
Declaration of Helsinki, as amended in Edinburgh, 2008. The ethical
committee of Lorestan University of Medical Sciences, Lorestan, Iran 3. Statistical analysis
reviewed and approved the protocol (Code: IR.LUMS.REC.1397.034).
Patients attending periodontics department of Lorestan University of Collected data were analyzed with SPSS version 18 (Chicago, IL,
medical sciences were assessed for eligibility between 2017-2018. USA) statistical software. normal distribution of data was validated
Subjects were included if they were diagnosed with chronic period- with the Kolmogorov–Smirnov test. Repeated measure ANOVA test was
ontitis, had a good oral hygiene (a plaque index < 20% after SRP), were applied to compare the mean values of the parameters (6 weeks, 3 and
aged above 35 and had at least three teeth with pockets deeper than 5 6 months). Statistical significance was defined at P < 0.05.
millimeters accompanied by bleeding on probing. Patients who had any Independent Samples T-Test between case and control groups were
used to compare the clinical parameters in baseline and different follow

Table 6
Overall comparison using Repeated Measurement ANOVA test of within subject effect in case group.a
Baseline 6 Weeks 3 Months 6 Months Time Effect

F P value

Plaque Index 6.48 ± 1.39 4.48 ± 1.36 3.84 ± 1.56 2.92 ± 1.12 472.131 < 0.000*
Gingival Index 6.76 ± 1.52 4.56 ± 1.36 3.64 ± 1.44 2.88 ± 1.28 434.695 < 0.000*
Probing Depths 7.04 ± 1.37 5.40 ± 0.95 3.08 ± 0.81 2.64 ± 0.75 2626 < 0.000*

a
* Statistically Significant Difference (P < 0.05).

3
N. Derikvand, et al.
Table 7
Overall comparison using Repeated Measurement ANOVA test of within subject effect in control group.a
Baseline 6 Weeks
Plaque Index 6.96 ± 0.73 4.68 ± 1.11
Gingival Index 6.92 ± 1.12 5.04 ± 1.28
Probing Depths 6.92 ± 0.40 5.00 ± 0.58
a
* Statistically Significant Difference (P < 0.05).
up sessions.
4. Results
All enrolled patients completed the study, 28 males (56%) and 22
women (44%) aged between 35-50. There was no significant difference
between case and control at the baseline in any of the parameters. The
healing was uneventful and no adverse reactions were observed.
PI was significantly reduced at all-time points compared to baseline
in both case and control group (P < 0.001) (Fig. 1). There was no
significant difference for PI in case and control group at 6 weeks, 3
months and 6 months after treatment (p > 0.05) (Table. 3).
PD also showed a decreasing pattern in both groups when compared
to baseline (P < 0.001) (Fig. 2). This was indicative of a positive
treatment result with the course of time. PD was more significantly
reduced in aPDT group at 3 and 6 months after treatment compared to
control group (P < 0.01) (Table 4) .
Gingival inflammation was also observed to decrease as GI was
lower at all follow-ups compared to baseline (P < 0.001) (Fig. 3) but no
significant difference was observed between case and control group
(Table 5).
The clinical parameters were significantly improved in both case
and control group at 6 weeks, 3 months and 6 months after treatment
(P < 0.001) (Tables 6 and 7).
5. Discussion
The present single-center clinical study evaluated the effect of
adding antimicrobial photodynamic therapy to conventional mechan-
ical debridement in treating chronic periodontitis. Our analysis of data
indicated that irradiation with diode laser (wavelength=660 nm) and
methylene blue as a photosensitizer significantly improved the clinical
parameters, namely PI, GI and PD. Photodynamic therapy has been
explored in medicine over a century and its application in periodontics
has gained more attention in the recent years. Our findings were in line
with studies which have demonstrated a benefit in additional use of
aPDT with SRP. Monzavi et al., in 2016, compared adjunctive in-
docyanine green aPDT with Diode laser (810 nm) to SRP alone in 50
patients (25 in each group) and concluded that BOP, PD and full mouth
bleeding score was enhanced in the test group while no significant
difference in clinical attachment level (CAL), PI or full mouth plaque
index was observed between groups after 3 months [20]. The authors
argued that PI is more in correlation with patient compliance and thus
its similar value in groups can be explained. In a split-mouth study by
Goh et al., in 2017, IL-1β, IL-6, IL-8, TNF-α and MMP-8 levels in gin-
gival crevicular fluid as well as PD and CAL were measured and com-
pared between test sites (PDT + SRP) and control sites (SRP) in 27
patients after 3 and 6 months. They found a more rapid reduction in
CAL and PD in test sites but no significant difference was observed
between groups after 6 months or in gingival crevicular fluid (GCF)
cytokines [21]. Other studies have argued however, against the clinical
advantage of using lasers in photochemical non-surgical periodontal
therapy. In a systematic review and meta-analysis by Xue et al., in
2017, it was concluded that adjunctive photodynamic therapy has a
short-term effect on clinical variables but no significant benefit was
Photodiagnosis and Photodynamic Therapy 31 (2020) 101818
3 Months 6 Months Time Effect
F P value
3.72 ± 1.04 3.00 ± 1.00 937.402 < 0.000*
4.00 ± 0.88 3.04 ± 0.92 1032 < 0.000*
3.88 ± 1.01 3.20 ± 0.87 2109 < 0.000*
seen in terms of CAL gain at 6 months [22]. This was confirmed by
another systematic review by Akram et al., in the same year, which
compared aPDT versus antibiotic therapy as an adjunct to SRP and
declared that None of the studies showed additional benefits of aPDT at
follow up [23]. American Academy of Periodontology (AAP) best evi-
dence consensus statement on the efficacy of laser therapy used alone
or as an adjunct to non‐surgical treatment of periodontitis, in 2018,
reported a modest additional benefit (< 1 mm) of aPDT in PD and CAL
compared with conventional SRP in treatment of moderate to severe
chronic and aggressive forms of periodontitis. This statement, also
deems the current evidence insufficient and suggests further standar-
dized, large scale controlled trials to further clarify the effect of aPDT
and justify its use an adjunct in chronic periodontitis treatment protocol
[24]. The statement also emphasized the research into development of
photosensitizers. Methylene blue, a molecule with a peak absorption at
664 nm, has been identified as a photosensitizer agent in photodynamic
therapy and is used in chronic periodontitis aPDT treatment [25]. In
2012, Noro Filho et al. investigated 12 patients with HIV and chronic
periodontitis in a split-mouth clinical trial. They randomly divided
them into 2 groups: (1) treatment with SRP and (2) treatment with SRP
and PDT (diode laser 660 nm, and photosensitizer methylene blue). Six
months later they have observed improvements in PD and CAL clinical
parameters in the second group [26]. Another split-mouth clinical trial
in 2012, compared SRP + PDT (laser 670 nm, 150 mW and photo
sensitizer 0.005% methylene blue) to SRP alone in 22 chronic period-
ontitis patients. They observed improvement in PD, CAL and BOP in
both groups but the amount of PD improvement was significant in the
test group [27]. In this study we used methylene blue solution with 660
nm Diode laser in order to eliminate periodontal pathogens and ob-
tained similar results. Katsikanis F et al. in assessing aPDT (670 nm) and
diode laser (940 nm) as an adjunctive method in treatment of chronic
periodontal disease indicated that all clinical parameters were im-
proved compared to baseline but the both approach aPDT and diode
laser have not shown any additional benefits to the conventional peri-
odontal treatment [28]. Giannelli M et al. used a laser and light-emit-
ting diode (LED) procedure adjunctive to scaling and root planning for
treatment of severe periodontitis. They applied toluidine blue as pho-
tosensitizer activated by 635 nm laser. They concluded that SRP ac-
companied by phototherapy and aPDT was more effective for im-
provement of clinical parameters compared to SRP alone [29]. In
interpreting the results of this study, limitations such as small sample
size, being single-centered (one dental school) should be considered.
Achieving to best results in aPDT depends on many factors including
concentration of photosensitizer, incubation time, laser parameters
(power, time, dose, tip diameter, diffusivity of tip), etc. Within the
limitations of this study, it can be concluded that adjunctive use of
photodynamic therapy with diode 660 nm laser and methylene blue
photosensitizer can be beneficial in reducing PD, PI and GI. Further
large scale studies comparing aPDT to other treatment measures and
evaluating not only the clinical parameters but specific bacterial species
are suggested. Moreover, a standardized protocol in the application of
lasers in photodynamic therapy regarding wavelength, energy and de-
livery method would help draw more accurate conclusions.
4
N. Derikvand, et al.
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clinical trial investigating its efficacy and patient-reported outcomes at 1 year,
Laser. Med. Sci. 33 (2018) 991–1002.