Photodiagnosis and Photodynamic Therapy 31 (2020) 101756

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Photodiagnosis and Photodynamic Therapy

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

Comparison between Antimicrobial Photodynamic Therapy and Low-level T

laser therapy on non-surgical periodontal treatment: A Clinical Study
Alice Engel Naves Freire1, Thaisa Macedo Iunes Carrera1,
Guilherme José Pimentel Lopes de Oliveira2, Suzane Cristina Pigossi1,*, Noé Vital Ribeiro Júnior1
1
Department of Clinics and Surgery, School of Dentistry, Alfenas Federal University, Gabriel Monteiro St, 700, Center, 37130-001, Alfenas, MG, Brazil
2
Department of Periodontology, School of Dentistry, Uberlandia Federal University (UFU), Uberlandia, Minas Gerais, Brazil

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

Keywords: Background: Alternative antibacterial therapeutic modalities, such as antimicrobial photodynamic therapy
Periodontitis (aPDT) and low-level laser therapy (LLLT), have been proposed to improve the effectiveness of periodontal
Photodynamic therapy treatment. However, clinical studies evaluating the efficiency of these treatments have been inconclusive, partly
Low-level light therapy due to contradictory results regarding their clinical and microbiological effects. The aim of this study was to
evaluate the clinical effects of aPDT and LLLT after a one-stage full-mouth disinfection (OSFMD) protocol during
periodontitis treatment.
Methods: A split-mouth clinical trial was conducted in 20 patients presenting at least two contralateral teeth
with a probing pocket depth (PD) ≥ 5 mm and bleeding on probing (BOP) on both sides of the mouth. All
patients were submitted to an OSFMD protocol. The selected sites randomly received either (1) aPDT (methylene
blue as a photosensitizer activated by red and infrared diode laser) or (2) LLLT (red and infrared diode laser).
Clinical parameters were assessed at baseline and at 4 and 12 weeks post-treatment.
Results: Both treatment protocols promoted significant reductions in PD, number of deep pockets and BOP and
an increase in clinical attachment level (CAL) after 4 and 12 weeks, but there were no differences between the
two groups. There was no change in the gingival level (GL) of either group for all periods of analysis. A decrease
in the number of moderate pockets (4–5 mm) was found in the LLLT group (5.15 ± 4.20) when compared to the
aPDT group (7.10 ± 5.24), but only after 4 weeks.
Conclusions: In conclusion, both the aPDT and LLLT therapies promoted improvements in periodontal clinical
parameters after the OSFMD protocol; however, in general, there were no distinct differences between the two
treatment modalities evaluated in this study.

1. Introduction
Periodontitis is a chronic, multifactorial and polymicrobial in-
flammatory disease which is characterized by periodontal ligament and
alveolar bone destruction, associated with gingival inflammation,
pocket formation and/or gingival recession (1). The main etiological
factor underlying periodontitis is the presence of anaerobic Gram-ne-
gative bacilli residing in the biofilm adhered to the tooth surface (2).
The presence of periodontopathogenic bacteria, such as Aggregatibacter
actinomycetemcomitans (A. actinomycetemcomitans), Porphyromonas gin-
givalis (P. gingivalis), Treponema denticola (T. denticola) and Tannerella
forsythia (T. forsythia), leads to disrupted hemostasis and destructive
immunological host responses that result in periodontal breakdown
and, eventually, tooth loss (3). In addition, various host risk factors can
influence the initiation, progression and extension of periodontitis, in-
cluding age, cigarette smoking, systemic diseases, immune system dis-
orders and hormonal changes (4).
Treatment for periodontitis is focused on the reduction or elimina-
tion of the supragingival and subgingival microbial biofilm, as well as
eliminating the factors that favor its deposition in order to prevent
disease progression (5). A reduction in the subgingival biofilm can be
achieved by scaling and root planing (SRP), where the root surface is
debrided with hand instruments, allowing sufficient cleaning of the
periodontal pockets and facilitating periodontal reattachment (6).
However, the effectiveness of SRP can be compromised by the presence
of deep pockets, furcation involvement and the presence of root

⁎
Corresponding author at: Dra. Suzane Cristina Pigossi, Alfenas Federal University (Unifal-MG), Department of Clinics and Surgery – Gabriel Monteiro da Silvia St,
700 Center, CEP 37130-001, Alfenas, Minas Gerais, Brazil.
E-mail address: supigossi@ymail.com (S.C. Pigossi).

https://doi.org/10.1016/j.pdpdt.2020.101756
Received 23 December 2019; Received in revised form 11 February 2020; Accepted 20 March 2020
Available online 15 April 2020
1572-1000/ © 2020 Elsevier B.V. All rights reserved.
A. Engel Naves Freire, et al.
curvatures and invaginations that are challenging for instruments to
access, making it more difficult to completely remove the biofilm and
calculus deposit from the root surface (7). In addition, periodontal
pathogens are able to invade the surrounding soft tissues and cannot be
eliminated by mechanical instrumentation (8). In this way, even with
therapy, some patients still have attachment loss, which is probably
associated with the persistence of pathogens at the periodontal site (9).
Several treatment options are available to support the efficacy of
SRP, including the use of systemic antibiotics; however, given the
prevalence of antibiotic-resistant strains, the adjunct use of antibiotics
is controversial and should be saved for cases of severe periodontitis
(10,11). Therefore, alternative antibacterial therapeutic modalities,
such as antimicrobial photodynamic therapy (aPDT), have been sug-
gested to improve the effectiveness of periodontal treatment. The me-
chanism of aPDT involves the use of a photosensitizer (e.g., toluidine
blue O, methylene blue or malachite green) that directly target both
Gram-negative and Gram-positive bacteria without affecting the host
cells (12). This photosensitizer is activated by light of a specific wa-
velength and reacts with oxygen, producing a highly reactive state of
oxygen known as singlet oxygen, which is cytotoxic to microorganisms
(13). In this way, aPDT ensures a reduction in microbial challenge,
which remains even after SRP in difficult to access sites. Moreover,
aPDT has other advantages including easy application, absence of a
collateral effect and no selection of resistant bacteria upon repeated
application (8). Some clinical studies have shown a reduction in the
percentage of bleeding on probing (BOP) and probing pocket depth
(PD) in sites treated with aPDT (5,8,14), whereas other studies have
shown no clinical advantages with the use of aPDT (15–17).
The isolated use of low-level laser therapy (LLLT) as an adjunct to
the mechanical approach in periodontal therapy has also been proposed
(18,19). Different types of infrared lasers, including neodymium:yt-
trium-aluminum-garnet (Nd:YAG), erbium:yttrium-aluminum-garnet
(Er:YAG), carbon dioxide (CO2) and diode lasers have been used in the
treatment of periodontal diseases (20). The use of infrared lasers ad-
junct to SRP is recommended based on its pain-reducing, anti-in-
flammatory and wound healing promoter effects (18). The infrared
laser can accelerate wound healing by stimulating collagen synthesis,
angiogenesis and the release of growth factors (21,22). It has been
suggested that infrared lasers accelerate periodontal wound healing and
regeneration by promoting the debridement and decontamination of
diseased periodontal tissues (23). Additionally, the bactericidal and
detoxifying effects of the diode laser during non-surgical periodontal
treatment have also been documented (24,25).
Given the relevance of this topic and the existence of conflicting
results in the literature, the aim of the present study was to evaluate the
clinical effects of the adjunctive use of aPDT or LLLT in a one-stage full-
mouth disinfection (OSFMD) protocol in patients with periodontitis.
2. Materials and methods
2.1. Study population
The present study was a single-center, blinded, randomized clinical
trial lasting 12 weeks which used a split-mouth design. This study was
approved by the Ethical Committee of Alfenas Federal University
(CAAE 77385417.0.0000.51442) and was performed in accordance
with the requirements of the World Medical Association’s Declaration
of Helsinki (26). All patients received a detailed description of the
proposed treatment and signed a consent form prior to their inclusion in
the study. Twenty patients (11 females and 9 males) diagnosed with
periodontitis were included in this study, which was conducted over a
period of 1 year (February 2018 to February 2019) at the outpatient
unit of the Department of Clinic and Surgery, Alfenas Federal Uni-
versity, Minas Gerais, Brazil. The patients were recruited after a
screening examination that included a full medical and dental history,
intraoral examination, full-mouth periodontal probing and radiographs.
2
Photodiagnosis and Photodynamic Therapy 31 (2020) 101756
For the sample size calculation, the clinical attachment level (CAL)
was considered the primary variable of this study. We used the CAL
data provided in the study by Gündoğar et al. (27), which evaluated the
effect of LLLT on the treatment of chronic periodontitis in healthy pa-
tients, to perform the sample size calculation. Considering a difference
in CAL of 1 mm between the groups as clinically relevant, and knowing
that the expected standard deviation for this type of analysis will be
approximately 0.45, a sample size of 18 patients was determined suf-
ficient to obtain a β power of 0.90 and α power of 0.05. Two additional
patients were added to the sample, as we expected some drop-outs
during follow-up.
The inclusion criteria were subjects with untreated periodontitis
(according to the criteria of the 2018 international classification (28))
with at least two contralateral teeth with PD ≥ 5 mm, CAL ≥ 3 mm,
BOP and radiographic signs of bone loss. Exclusion criteria were
pregnancy, current smoking and history of smoking in the past 10 years,
use of mouth rinses containing antimicrobials in the preceding 2
months, orthodontic appliances, systemic conditions that could affect
the progression of periodontitis, and the long-term administration of
anti-inflammatory and immunosuppressive medications.
2.2. Treatment protocol
All the patients included in the study received information about the
etiology of periodontal disease and instructions for maintaining ade-
quate biofilm control, including interdental cleaning with dental floss
and interdental toothbrushes. The patients were treated using the
OSFMD protocol (29), wherein SRP was completed in one session as-
sociated with antiseptics. SRP was performed under local anesthesia
using low-speed diamond tips (Periodont; KG Sorensen, São Paulo,
Brazil; Fig. 1A–D) and periodontal hand instruments (Gracey curettes;
Hu-Friedy, Chicago, IL, USA). In addition to SRP, tongue brushing with
1% chlorhexidine gel for 1 min, mouth rinsing with 0.2% chlorhexidine
solution for 2 min and subgingival irrigation of all pockets (three times
for 10 min) with 1% chlorhexidine gel (Fig. 1E) were performed in all
included patients.
After these procedures, at least two teeth in different quadrants with
PD ≥ 5 mm, according to the inclusion criteria, were randomly as-
signed by coin toss to receive aPDT + SRP (test group) or LLLT + SRP
(control group). In the test group, the included periodontal sites were
irrigated with 1 ml of the photosensitizer liquid (0.005% methylene
blue dye) using a blunt needle, starting from the apical end of the
pocket and moving coronally to avoid entrapment of air bubbles (30)
(Fig. 1F). Three minutes later, all pockets were thoroughly rinsed with
sterile saline to remove any excess photosensitizer liquid (31). Im-
mediately after rinsing, diode laser (Therapy – Plus, DMC®, São Carlos,
Brazil) red (wavelength of 660 nm, power 100 mW, spot size 600 μm
and energy density of 60 J/cm²) and infrared (wavelength of 808 nm,
power 2500 mW, spot size 600 μm and energy density of 140 J/cm²)
were simultaneously applied inside the periodontal pocket. The laser
was equipped with a probe tip that was placed at the pocket depth and
moved circumferentially around the tooth for 1 min (six sites per tooth
for 10 s: mesio-facial, mid-facial, disto-facial, mesiolingual, mid-lingual,
and disto-lingual; Fig. 1G) (31). In the control group, only the diode
laser (Therapy – Plus, DMC®, São Carlos, Brazil) red (wavelength of 660
nm, power 100 mW, spot size 600 μm and energy density of 60 J/cm²)
and infrared (wavelength of 808 nm, power 2500 mW, spot size 600 μm
and energy density of 140 J/cm²) were simultaneously applied inside
the periodontal pocket after the OSFMD protocol. After the procedure,
patients were instructed to rinse twice daily with 0.12% chlorhexidine
for 15 days. Seven days after the procedure, subgingival irrigation of all
pockets (three times for 10 min) with 1% chlorhexidine gel was re-
peated (Fig. 1H).
A. Engel Naves Freire, et al. Photodiagnosis and Photodynamic Therapy 31 (2020) 101756

Fig. 1. Therapy sequence in the test group. (A) Initial probing depth at the mesial site of tooth 21. (B–D) Scaling and root planing using low-speed diamond tips. (E)
Subgingival irrigation with 1% chlorhexidine gel. (F) Photosensitizer liquid (0.005% methylene blue dye) application in the pocket using a blunt needle. (G) Diode
laser application in the depth of the pocket using a probe tip. (H) Clinical aspect 7 days after the procedure.

2.3. Clinical measurements 2.4. Statistical analysis

Clinical findings were taken on six sites (mesio-facial, mid-facial,
disto-facial, mesiolingual, mid-lingual and disto-lingual) of each tooth
included in the analysis at the baseline visit (immediately before the
therapies) and again at 4 and 12 weeks after the therapies. All mea-
surements were performed by an experienced masked periodontist
(AENF) who was not involved in the treatment phase. All parameters
were measured using a University of North Carolina periodontal probe
(UNC-15, Hu-Friedy, Chicago, IL, USA) by one calibrated examiner.
Interexaminer correlation analysis was performed using the Pearson
test, and the result was 0.91. The following clinical parameters were
evaluated: gingival level (GL; measured from the cementoenamel
junction to the free gingival margin), PD (measured from the free gin-
gival margin to the bottom of the periodontal pocket), CAL (measured
from the bottom of the periodontal pocket to the cementoenamel
junction) and BOP. BOP was defined as the presence (+) or absence (-)
of bleeding within 15 s after probe insertion into the pocket.
The data for periodontal clinical parameters, including BOP-positive
sites, PD, number of sites with PD between 4–5 mm and PD ≥ 6 mm,
CAL and GL were submitted to the Kolgomorov-Smirnov normality test,
which confirmed that the data conformed to a normal distribution for
all clinical parameters analyzed. Comparison between the groups was
performed using paired t-test, while comparison within each group over
the different experimental periods was performed using the ANOVA
parametric test for repeated samples, supplemented by Tukey’s post hoc
test. GraphPad Prism 6 software (San Diego, CA, USA) was used for all
statistical analyses, and all statistical tests were applied at a significance
level of 5%.
3. Results
No patients were excluded from the study. The sample was com-
posed of 14 females and 9 males, totaling 20 patients with a mean age

3
A. Engel Naves Freire, et al. Photodiagnosis and Photodynamic Therapy 31 (2020) 101756

Fig. 2. Flowchart of the study design.

Table 1
Periodontal parameters at different time intervals for the two groups, presented as the mean and standard deviation.
Variables/Period Baseline 4 weeks 12 weeks

Test Control Test Control Test Control

b b a a a
PD 3.04 ± 0.71 3.01 ± 0.66 2.39 ± 0.61 2.28 ± 0.57 2.36 ± 0.55 2.23 ± 0.57a
PD 4-5 mm 14.37 ± 8.30b 12.62 ± 8.61b 7.10 ± 5.24a 5.15 ± 4.20a* 6.31 ± 3.56a 4.94 ± 4.66a
PD > 6mm 5.21 ± 4.89b 4.52 ± 3.65b 2.42 ± 2.81a 2.57 ± 2.83a 2.26 ± 3.03a 1.78 ± 1.98a
GL 1.14 ± 0.67 1.15 ± 0.65 1.35 ± 0.60 1.34 ± 0.67 1.15 ± 0.67 1.20 ± 0.65
CAL 4.19 ± 1.14b 4.16 ± 1.21b 3.74 ± 0.94a,b 3.62 ± 0.93a,b 3.51 ± 0.94a 3.44 ± 0.96a
BOP 27.37 ± 15.98b 26.16 ± 15.78b 11.00 ± 14.84a 8.89 ± 9.29a 5.89 ± 5.61a 5.05 ± 5.58a

Table 1 Mean (standard deviation) of the periodontal variables at different time intervals for both groups.
PD (probing depth pocket); GL (Gingival level); CAL (clinical attachment level); BOP (bleeding on probing). Different letters represent a statistical significance
(lowercase letters compare times; ANOVA in split plot design/Tukey); *p < 0.05 in comparison to test group (t-paired test).

of 52.30 ( ± 9.43) years. Fig. 2 presents the study flowchart. The
baseline data indicated that both groups were similar with regard to
clinical parameters (Table 1). No differences between groups were
observed for PD, number of deep pockets (PD > 6 mm), CAL and BOP
at the different time periods (Table 1). A greater decrease in the number
of moderate pockets (4–5 mm) was observed in the control (LLLT)
group (5.15 ± 4.20) in comparison to the test group (aPDT)
(7.10 ± 5.24), but only after 4 weeks (Table 1).
Comparing the different experimental periods, both treatment pro-
tocols resulted in reductions in PD, number of moderate and deep
pockets and BOP after 4 and 12 weeks (Table 1). A reduction in CAL
was observed only after 12 weeks in comparison to baseline for both
groups. No differences in GL were found for either group in all periods
of analysis (Table 1).
4. Discussion
To the best of our knowledge, no published study has evaluated the
use of aPDT or LLLT associated with an OSFMD protocol using a split-
mouth design. The split-mouth design used in this study was chosen to
eliminate interpatient variance, which is challenging in parallel study
designs, even with perfect matching (32). In addition, a smaller sample
size is required to achieve an equal test power in the split-mouth design,
facilitating its execution (33). The OSFMD was first proposed by
Quirynen et al. (34), aimed at suppressing periopathogens from all
oropharyngeal habitats (mucous membranes, tongue, tonsils and saliva)
in a very short time span. In this protocol, it is recommended that all
debridement be completed within a short time frame, together with the
use of a strong antiseptic. In this way, the OSFMD helps to prevent
cross-contamination of the treated periodontal pockets by bacteria from
untreated habitats. A systematic review and meta-analysis by Fang et al.
(35) showed that the OSFMD provides modest additional clinical ben-
efits over scaling and root planing in PS reduction and CAL gain.
Moreover, less time is required to complete treatment in the OSFMD
protocol, increasing patient acceptance of this non-surgical periodontal
treatment. Based on these advantages, the OSFMD protocol, which in-
cludes the application of chlorhexidine to all oral habitats, was used in
this study as the non-surgical periodontal treatment.
The results of the present study show that both treatments promoted
significant reductions in PD, the number of deep pockets and BOP after
4 and 12 weeks, but there were no differences between the aPDT and
LLLT groups. Moreover, an increase in CAL was observed after 12 weeks
for both groups. The use of photosensitizer liquid (0.005% methylene
blue dye) did not seem to promote additional gains in clinical period-
ontal parameters compared to LLLT use alone. Similarly, a split-mouth
clinical trial by Katsikanis et al. (36) also demonstrated that both LLLT
and aPDT associated with SRP led to statistically significant improve-
ments in the evaluated clinical parameters (PD, CAL and BOP) at 3 and
6 months compared to baseline, but with no differences between them.
The results presented by Teymouri et al. (37) also support the findings

4
A. Engel Naves Freire, et al.
of our study, showing an improvement in the aPDT and LLLT groups in
PD, CAL and BOP clinical parameters without any statistically sig-
nificant differences in intergroup analysis. Additionally, various clinical
studies (8,15,30,38) did not find any statistically significant improve-
ments in PD and CAL, favoring the group submitted to SRP with aPDT
in comparison to SRP alone.
On the other hand, studies that evaluated the efficiency of aPDT as
an adjuvant to SRP in periodontitis treatment showed greater PD re-
ductions and significant improvements in clinical insertion compared to
SRP alone (5,39,40). In fact, a study by Campos et al. (39) involving the
treatment of residual pockets in single-rooted teeth using a diode laser
with 660 nm wavelength, 60 mW power and 129 J/cm2 energy density,
together with methylene blue as a photosensitizer (10 mg/ml), showed
greater PD depth reductions and CAL gains in the aPDT plus SRP group
at 3 months when compared to SRP alone. Furthermore, sites treated
with the combined approach showed a significant reduction in the
number of sites with PD > 5 mm and BOP after 3 months compared to
sites treated with SRP alone. In a similar approach, Correa et al. (40)
showed greater PD depth reduction and CAL gain in the aPDT plus SRP
group, associated with a statistically significant reduction in A. actino-
mycetemcomitans levels on day 3 and 7 after therapy in comparison to
SRP alone. Berakdar et al. (5) compared aPDT (using a diode laser at a
wavelength of 670 nm and maximum power of 150 mW, with 0.005%
methylene blue) to SRP alone in initial periodontal treatment and re-
ported a statistically significant reduction in PD with a combination of
SRP and aPDT after 6 months.
The beneficial effects of aPDT as an adjunct to SRP probably result
from the photodestructive effects of oxygen-reactive species associated
with the modulation action of LLLT (1). These cytotoxic species can
damage plasma membranes and DNA, resulting in cell death (8). Me-
thylene blue, commonly used as a photosensitizer, has a pronounced
cationic charge that helps it bind to the membranes of Gram-negative
bacteria, giving it a high degree of selectivity for killing microorganisms
(41). In vitro studies have shown the complete removal of anaerobic
bacteria and reductions in lipopolysaccharide and protease activities
after aPDT (42,43). Furthermore, clinical studies have shown a reduc-
tion in periodontopathogens after aPDT therapy (15,44). Therefore, the
aPDT approach has been indicated for deeper sites that are less acces-
sible for mechanical debridement, as these sites contain more anaerobic
microorganisms compared to shallow pockets (8). However, the use of
methylene blue in association with red and infrared lasers in a single
application did not promote additional periodontal gains in the present
study. It is suggested that the short time of exposure to light could
explain the lack of effect of aPDT in the present study, as some authors
have suggested that multiple aPDT treatments are more effective than a
single treatment (1,45,46).
In this study, the simultaneous application of red and infrared laser
during aPDT was chosen to not only activate the photosensitizer,
achieved using the red laser, but also increase tissue repair through the
action of the infrared laser. Curettage with an infrared laser guarantees
complete removal of the pocket epithelium without tissue necrosis (47).
Moreover, LLLT can promote wound healing by accelerating collagen
synthesis and increasing the levels of anti-inflammatory cytokines, ATP
synthesis and fibroblast proliferation (48). In the present study, a
greater decrease in the number of moderate pockets (4–5 mm) was
found in the LLLT group (5.15 ± 4.20) in comparison to the aPDT
group (7.10 ± 5.24) after 4 weeks. A split-mouth study by Birang et al.
(49) also showed a statistically significant reduction in PD in pockets
treated with LLLT (diode laser, 810 nm wavelength and 0.5 W/cm2
power density) in comparison to aPDT and SRP alone. However, in this
study, laser irradiation was conducted in three sessions, the first 48 h
after SRP, and the second and third at 7 and 14 days, respectively.
Gündoğar et al. (27) tested multiple LLLT therapy (980 nm wavelength,
7.64 J/cm2) in premolar teeth with deep pockets, and also showed
significant decreases in CAL, PD and GI in the SRP plus LLLT group
compared to the SRP group at 3 and 6 months. However, other studies
5
Photodiagnosis and Photodynamic Therapy 31 (2020) 101756
found no advantages in the use of LLLT associated with SRP (50,51). A
recent meta-analysis concluded that LLLT-mediated SRP demonstrated
significant short-term benefits over SRP monotherapy in improving PD
and the level of interleukin-1β in the gingival crevicular fluid. Never-
theless, LLLT failed to show significant additional intermediate-term (3
and 6 months) effects in terms of clinical parameters and alveolar bone
density (32).
The present study has some methodological limitations. The con-
flicting data reported in different clinical trials involving aPDT and
LLLT may be associated with differences in laser parameters, resulting
in a different level of energy density and, consequently, different de-
grees of change in the target tissue (51). Due to the lack of adequate
studies, there is no agreement regarding the optimal treatment para-
meters for laser therapy. Therefore, in the present study, we tested the
simultaneous application of red and infrared laser to evaluate its effi-
ciency. Moreover, the absence of an SRP-alone group and the short
follow-up period (90 days) are also considered limitations of the present
study.
Within the limitations of this study, it can be concluded that aPDT
and LLLT therapies promote improvements in periodontal clinical
parameters after an OSFMD protocol; however, no distinct differences
between the treatment modalities were found regarding increases in
clinical attachment, control of inflammation and the elimination of
residual periodontal pockets.
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