DR.

GIANLUCA PLOTINO (Orcid ID : 0000-0003-3003-8029)

DR. MONTSE MERCADÉ (Orcid ID : 0000-0003-1303-3787)

Accepted Article
Article type : Review

Photodynamic therapy in endodontics

G Plotino1, NM Grande2, M Mercade3

1 2
Department of Endodontics, "Sapienza" - University of Rome, Rome, Italy; Catholic

University of Sacred Heart, Rome, Italy; 3Department of Dentistry, Universitat de Barcelona,

Barcelona, Spain. Researcher IDIBELL Institute, Barcelona, Spain

Running title: Photodynamic therapy

Keywords: antimicrobial, endodontics, root canal disinfection, photodynamic therapy.

Corresponding author information:

Dr Montse Mercade

Universitat de Barcelona, Department of Dentistry, C/Feixa Llarga s/n, 08907 Hospitalet de

Llobregat, Barcelona, Spain

Tel: +34617666747

e-mail: montsemercade@ub.edu

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/iej.13057
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 ABSTRACT
Accepted Article
Photodynamic therapy (PDT) is a treatment modality that was initiated in 1900; however, it

was not until the last decade that PDT regained attention again for its several favourable

features during the treatment of microbial infections in Endodontics. Recently, several

papers advocated its use for root canal treatment. The concept of photodynamic inactivation

requires microbial exposure to either exogenous or endogenous photosensitizer molecules,

followed by visible light energy, typically wavelengths in the red/near infrared region that

cause the excitation of the photosensitizers resulting in the production of singlet oxygen and

other reactive oxygen species that react with intracellular components and consequently

produce cell inactivation and death.

Recently, PDT was suggested as a promising effective adjunct to standard antimicrobial

intracanal cleaning and shaping for clinical treatment of periapical lesions. Current

publications tested PDT in terms of bacterial load reduction in vivo, in vitro and ex vivo,

showing promising results.

The purpose of this article is to review the existing literature on PDT in the endodontic field

regarding its mechanism of action, photosensitizers and light sources, limitations and clinical

procedures. Although positive results have been demonstrated in vitro, there are

considerably fewer in vivo investigations. In conclusion, more in vivo studies are needed on

the use of antimicrobial PDT in root canal treatment.

HISTORY

Photodynamic therapy (PDT) has been defined as “the light induced inactivation of cells,

microorganisms, or molecules” Gursoy et al. (2013). Since its introduction, several terms for

PDT have been suggested, such as antimicrobial photodynamic therapy (APD),

photodynamic antimicrobial chemotherapy (PACT) and photodynamic disinfection (PD)

(Wainwright 1998, Takasaki et al. 2009, Rossoni et al. 2010). Moreover, when the cells to be

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 killed are pathogenic microorganisms the procedure is termed photodynamic inactivation
Accepted Article (PDI) (O'Riordan et al. 2006), lethal photosensitization (Wilson 2004) or in the dental field,

photo-activated disinfection (PAD) and light-activated disinfection (LAD) (Bergmans et al.

2008).

The science of PDT follows the principles that a light is able to excite a non-toxic dye

(photosensitizer) at its target site with minimal photo-effects on the surrounding tissue

(Wainwright 1998). A photosensitizer (PS) is a dye with the capacity to absorb energy from a

light source and transfer this energy to another molecule (Plaetzer et al. 2009). The major

PSs used in modern clinical trials are the phenothiazine salts, namely toluidine blue O (TBO)

and methylene blue (MB), with wavelengths of absorption of 600–660 nm (Calzavara-Pinton

et al. 2012).

The combination of chemical substances and light is attributed to Oscar Raab in 1900.

(Ackroyd et al. 2001, Moan & Peng 2003, Baltazar et al. 2015); however, investigations on

the antimicrobial efficacy of the so-called ‘photodynamic therapy’ progressively decreased

with the advent of antibiotics in 1928 (Santezi et al. 2018). More recently, growing antibiotic

resistance has focused greater attention on clinical potential of PDT (Dobson & Wilson 1992,

Okamoto et al. 1992, Wilson & Pratten 1995, Bliss et al. 2004). PDT was a treatment

modality that has been developing rapidly within various medical specialties since the 1960s

(Dougherty et al. 1998, 2002, Soukos & Goodson 2011), because it is a selective, non-

invasive or, at least, minimally invasive modality of treatment for several types of diseases.

In fact, PDT was first developed as a therapy for several diseases such as tumours and pre-

malignant diseases and represents a highly promising alternative against bacteria, fungi and

viruses (Wainwright 1998) for the treatment of localized microbial infections (Wainwright

1998, Rossoni et al. 2010). In recent years, the indications for PDT have expanded, as it

represents a potential alternative to overcome bacterial resistance to antibiotics. The

development of resistance to PDT seems to be unlikely, since, in microbial cells, singlet

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 oxygen and free radicals interact with several cell structures and different metabolic
Accepted Article pathways (Wainwright & Crossley 2004). Moreover, regarding oral biofilms disruption, the

antimicrobial activity of PSs has a direct effect on extracellular molecules, because it is

mediated by single oxygen that has a high chemical reactivity. Thus, the polysaccharides

present in extracellular matrix of polymers (EMP) of a bacterial biofilm are also susceptible

to photo-damage. Such dual activity, not exhibited by antibiotics, represents a significant

advantage of PDT. Breaking down biofilms may inhibit plasmid exchange involved in the

transfer of antibiotic resistance and disrupt colonization (Konopka & Goslinski 2007).

MECHANISM OF ACTION OF PDT

PDT is a treatment performed in two stages that involves the application and retention of an

applied (PS) compound in target tissues (Sharwani et al. 2006) (first step), which is then

activated by exposure to visible light in an appropriate wavelength that is excitatory to this

compound and that is applied though a light device, which can be directly driven to the target

or can be directed to reach inner sites (second step). Upon irradiation, the PS undergoes

transition from singlet low-energy level “ground state” to a higher-energy “triplet state.”(Dai et

al. 2009).

There are two mechanisms by which in the presence of a substrate such as oxygen, the

activation of the sensitizer drug to the triple-state can get into chemical reactions with

biomolecules. Type I reactions lead to the formation of free radicals by hydrogen or

electrons transference. These reactive species, after the interaction with oxygen, might

produce highly reactive oxygen species, such as peroxide or superoxide anions, which

attack cellular targets (Foote 1991, Kalka et al. 2000). Type I reactions could cause direct

cellular damage by the action of free radicals (Lyon et al. 2011). In type II mechanisms, an

electronically excited and highly reactive state of oxygen is released, which is named singlet

oxygen. Since type II reactions are mediated through singlet oxygen species, this is

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 accepted as the major pathway in microbial cell destruction (De Rosa & Bentley 2000,
Accepted Article Konopka & Goslinski 2007). However, it is difficult to distinguish between the two reaction

mechanisms. A contribution from both Types I and II processes indicates that the

mechanism of damage is dependent on both oxygen tension and PS concentration

(Konopka & Goslinski 2007).

The presence of these molecules in the site to be treated causes an oxidative stress leading

to potential damage of target cells (Moreira & Pacheco-Soares 2008).

The bactericidal action of these cytotoxic species is attributed to 2 main pathways: damaging

of the cellular plasma membrane and/or damaging of the cell DNA. Both outcomes result in

cell death (Sharman et al. 1999, Lee et al. 2004a, Takasaki et al. 2009, Gursoy et al. 2013).

Injury to cells occurs only when the reactive oxygen cytotoxic species overwhelm the

biochemical defences of the cell (Moreira & Pacheco-Soares 2008), thus causing oxidation

of cellular constituents such as plasma membranes and DNA and resulting in cell death

(Konopka & Goslinski 2007). Clinically, this reaction is cytotoxic and vasculotoxic

(Wainwright 1998, Sharman et al. 1999, Maisch et al. 2004, Babilas et al. 2010). Another

type of damage caused by PDT is that caused to the cytoplasmic membrane of the bacteria

by cytotoxic species generated by PDT, leading to events such as inactivation of the

membrane transport system, inhibition of plasma membrane enzyme activities, lipid

peroxidation, and others (Takasaki et al. 2009). Microorganisms such as bacteria, fungi,

viruses, and protozoa can be killed by singlet oxygen species. Common herpes simplex

infections can be successfully treated with PDT (Takasaki et al. 2009).

Extensive laboratory studies have shown that an important aspect of this system is that the 2

components when used independently produce no effect on bacteria or on normal tissue. It

is only the combination of photo-sensitizer and light that produces the effect on the bacteria

(Burns et al. 1993, Williams et al. 2003, 2004). In fact, Xu et al. (2009), in an in vitro study,

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 assessed the presence of a therapeutic safe window by which PDT can inactivate cells
Accepted Article without affecting host cell viability on human gingival fibroblasts and osteoblasts.

PHOTOSENSITIZERS AND LIGHT SOURCES

Thousands of natural and synthetic photoactive compounds have photosensitizing potential.

However, to eradicate microorganisms, the most studied PSs belong to the groups

halogenated xanthenes, phenothiazines, acridines and conjugated chlorins (Wainwright

1998). Some features are desirable on an ideal PS: absence of toxicity and toxic by-

products, lack of mutagenic effect, selective accumulation on the target tissue, suitability for

topical administration, low cost (Allison et al. 2004), high absorption coefficient in the

spectral region of the excitation light, a triplet state of appropriate energy to allow for efficient

energy transfer to ground-state oxygen, high quantum yield of the triplet state and long

triplet-state lifetimes and high photo-stability (DeRosa 2002).

For PDT to be successful for antimicrobial purposes, it is essential to select an appropriate

and effective non-toxic PS capable of high absorption in the light length used (Meisel &

Kocher 2005). The role of PDT in endodontic therapy has been tested using different

combinations of PS and light sources and has shown divergent results (Bonsor et al. 2006a,

Fimple et al. 2008, Garcez et al. 2008, Garcez et al. 2010, Kishen et al. 2010, Pagonis et al.

2010, Souza et al. 2010, Nagayoshi et al. 2011, Ng et al. 2011, Nunes et al. 2011, Rios et al.

2011, Silva et al. 2012). Even when the same PS and light source were employed, the

diversity of irradiation protocols and variation of PS concentration, irradiation time and light

powers make comparison between studies difficult (Nagata et al. 2012). The major groups of

PS employed in PDT are hematoporphyrin derivatives (620–650 nm), phenothiazines (620–

700 nm), cyanine (600–805 nm), phytotherapic agents (550–700 nm), and phytalocyanines

(660–700 nm) and chlorines (Meisel & Kocher 2005, Sigusch et al. 2005, Pinheiro et al.

2009, Lyon et al. 2011).

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 The most studied and employed dyes in PDT are the phenothiazines (synthetic non-
Accepted Article porphyrin compounds) methylene blue (MB) and Toluidine blue O (TBO, tolonium chloride)

in several concentrations (Nagata et al. 2012). Curcumin, the major constituent of turmeric

powder that has been used for centuries in medicine, as food pigment and as a spice, has

also been used recently in dentistry as a PS for PDT (Neelakantan et al. 2015, Gomes-Filho

et al. 2016, Santezi et al. 2018).

Studies have shown that for MB the wavelength of maximum absorption is 660 nm (Ball et

al. 1998; Severino et al. 2003) while for TBO is 630 nm (Usacheva et al. 2003). MB and TBO

have similar bactericidal effects and are capable of inactivating both gram-positive and

gram-negative bacteria (Nagata et al. 2012), for example E. faecalis (Foschi et al. 2007,

Bergmans et al. 2008, Fonseca et al. 2008, Pagonis et al. 2010, Nagayoshi et al. 2011,

Poggio et al. 2011, Vaziri et al. 2012, Bago et al. 2013). In some studies. In general, the

dyes may either have a more hydrophilic or hydrophobic character or may be amphiphilic.

Considering that endodontic infections are of mixed gram-positive and gram-negative

bacteria, amphiphilic PS such as MB and TBO (both hydrophobic and hydrophilic) seems to

be the most appropriate for PDT in endodontics (Usacheva et al. 2001, Giusti et al. 2008,

Wainwright et al. 1997, Usacheva et al. 2001, Wilson et al. 1993).

The choice of PSs used in dentistry is also dependent on the light source used. The basic

requirement for PDT light sources is that they match the activation spectrum (electronic

absorption spectrum) of the PS (usually the longest wavelength peak) and generate

adequate light potency at this wavelength (Wilson & Patterson 2008).

Currently, light sources of a specific wavelength (between 630 and 800 nanometers) mostly

applied in PDT are helium–neon lasers (633 nm), gallium–aluminum–arsenide diode lasers

(630–690, 830, or 906 nm), and argon lasers (488–514 nm). The wavelengths of these

sources range from visible light to the blue of argon lasers or from the red of helium–neon

and gallium–aluminium–arsenide lasers to the infrared area of some diode lasers (Klotz et

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 al. 1999). Although low power lasers are the most used for PDT, Nagai et al. (Nagai et al.
Accepted Article 2018) proposed the combination of a high power laser (an GaAlAs/InGaAsP diode laser with

a wavelength of 940 nm) with a new PS, the azulenocyanine (Azc).

The literature describes three main classes of clinical PDT light sources: LASER, light-

emitting diodes (LED) and halogen lamps (Kübler 2005, Nagata et al. 2012). Among them,

diode lasers (Jerjes et al. 2007), which are easy to handle, cheaper and more portable, have

become the preferred light source in PDT. The laser light used in PDT has several

advantages, namely, it can be directed through a fibre optic to deliver the proper amount of

light, mono-chromaticity, high efficiency, high potency and interstitial light delivery devices;

however, they do have a high cost (Nagata et al. 2012).

Non-lasers sources such as LED are recently used in PDT particularly for irradiation of

easily accessible tissue surfaces (Juzeniene & Moan 2007, Gursoy et al. 2013).

Filtered halogen lamps have the advantage that they can be spectrally filtered to match any

PS; however, they cannot be efficiently coupled into optical fibre bundles or liquid light

guides and cause heating. With broadband sources, their effective output potency is

reduced (Nagata et al. 2012).

From the point of view of bacteria and PS interaction, the effectiveness of PDT is mostly

related to three main aspects: (a) PS capability of interacting with the bacterial membrane;

(b) PS ability of penetration and action inside the cell and (c) reactive singlet oxygen

formation around the bacterial cell by illumination of the PS. The resistance of gram-negative

bacteria against efficient killing by anti-bacterial PDT is due to the various outer membrane

structures of gram-positive and gram-negative bacteria (Maisch et al. 2004) and hydrophobic

and charge effects of the PSs. In fact, the photosensitivity of bacteria appears to be related

to the charge of the sensitizer (Konopka & Goslinski 2007). The cationic PSs, such as MB

and TBO are capable of inactivating both gram-positive and gram-negative bacteria

(Usacheva et al. 2001, Junqueira et al. 2002, Severino et al. 2003, Wainwright M 2003).

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 In general, gram-negative species are significantly resistant to some commonly used PS in
Accepted Article PDT (Perussi 2007), while effective PDT results were obtained against gram-positive

species, which are more susceptible, because the relatively porous layer of peptidoglycan

and lipoteichoic acid outside the cytoplasmic membrane of gram-positive species allows the

PS to diffuse into sensitive sites (Usacheva et al. 2001, Schaechter et al. 2002, Konopka &

Goslinski 2007).

In general, the choice of an appropriate PS should consider the species of the target

bacterium. If it is gram-positive, both cationic and anionic dyes may be utilized, if it is gram-

negative, cationic dyes are more effective (Nagata et al. 2012).

Besides the PS capacity to bind to the bacterial membrane and penetrate bacteria, there are

reports of inactivation of bacteria, in which the PS does not have to penetrate or even to

encounter the cells to be effective. According to some authors, if sufficient quantities of

singlet oxygen can be generated near the outer membrane of the bacteria, it will be able to

inflict damage on vital structures (Dahl et al. 1987). Therefore, if the PS cannot interact with

the target bacteria, but the reactive products of therapy (such as singlet oxygen) are

generated near the cell, its viability will depend on the distance to the bacteria. Therefore,

reaching the most inaccessible intracanal area should be also important because success

may be achieved even without direct contact between the PS and the bacteria. In any case,

despite all above considerations, the main PDT treatment is considered a Type II

mechanism, via singlet oxygen as a reactive specie that induces biological cellular damage

(Dhami 1996, Ryter & Tyrrell 1998).

PRE-IRRADIATION TIME AND IRRADIATION DOSES

The time elapsed between the delivery of the PS into the root canal system and the actual

photo-activation is called ‘pre-irradiation time’(Trindade et al. 2015). The pre-irradiation time

is a key factor in PDT, as it permits the PS to penetrate through the dentine and to exert its

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 antibacterial effect and it helps to keep the PS inside the bacteria, allowing more light
Accepted Article absorption (Usacheva et al. 2001; Figueiredo et al. 2014). Research is controversial

regarding the pre-irradiation time and available data show pre-irradiation times ranging from

5 to 15 min (Seal et al. 2002, Fimple et al. 2008, Pagonis et al. 2010, Fumes et al. 2018,

Nagai et al. 2018). According to Williams et al. (2003), the energy dose and irradiation time

of light are the most important factors in killing the microorganisms using PDT.

Pourhajibagher & Bahador (2018b) study used an output power of 220mW at 635 nm

wavelength for 60s. The results revealed that the microbial diversity and count significantly

decreased (P < 0.05), except for P. gingivalis that was not inhibited in this short exposure to

laser irradiation. Furthermore, the authors stated that the inappropriate PS concentration

may also be a reason for the survival of P. gingivalis against TBO-PAD. Moreover, the

reduced susceptibility of P. gingivalis to PDT was attributed to the low TBO penetration.

Soares et al. (2018) reported that overall, the efficacy of PDT varied in a statistically

significant scale according to the energy dose increase, the reduction of volume of the

bacterial suspension and mainly when the output power was deposited in the form of cycles.

According to Wainwright (1998), a PS that is slowly uptaken by the microorganism may

cause only cell wall photo-damage at first, whereas nucleic acid strand breakage, for

example, will be apparent after longer incubation times.

APPLICATIONS IN DENTISTRY

In Oral Surgery and Periodontics, antimicrobial PDT, with its use of a PS in combination with

low-intensity laser light enabling singlet oxygen molecules to destroy bacteria, also

represents a treatment alternative for alveolar osteitis, post-extraction pain, peri-implantitis

(Hayek et al. 2005, Neugebauer 2005) and localized microbial periodontal infections. (Sarkar

& Wilson 1993, Wilson et al. 1993, Soukos et al. 1998, Komerik et al. 2003, Williams et al.

2003, Sigusch et al. 2005, Zanin et al. 2005, Metcalf et al. 2006, Wood et al. 2006, Zanin et

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 al. 2006, Fontana et al. 2009, Schneider et al. 2012). PDT resulted in a significant bacterial
Accepted Article reduction, although complete elimination of bacteria was not achieved (Dortbudak et al.

2001, Shibli et al. 2003)

In recent decades, PDT and the use of lasers or LEDs of different wavelengths, in

association with various photosensitizing dyes, has been studied as an alternative treatment

to remove dental plaque (Wilson 1994, Shibli et al. 2003, Bevilacqua et al. 2007) and against

the aetiological factors of dental caries (Nagata et al. 2012).

Photodynamic approach has also been used to kill microorganisms in root canals in vitro

and in vivo (Fimple et al. 2008). These studies suggested the potential of PDT adjunctive to

standard endodontic antimicrobial treatment.

APPLICATIONS IN ENDODONTICS

Endodontic failure may occur in cases of persistent bacteria in the root canal system as a

consequence of poor disinfection and debridement of the endodontic space, untreated

canals, inadequate filling or coronal leakage (Siqueira 2001). Mechanical instrumentation

alone is not able to obtain a complete cleaning of the root canal system (Peters et al. 2001).

To assist in the cleaning and debridement of the canal, a wide range of irrigating and

disinfecting solutions have been used (Zehnder 2006).

Recently, new systems and substances have been proposed to improve root canal

disinfection either by replacing conventional chemo-mechanical procedures or by

supplementing their effects (Siqueira & Roças 2011). PDT was suggested as a promising

effective adjunct to standard antimicrobial intracanal cleaning and shaping for clinical

treatment of periapical lesions (Nagayoshi et al. 2011, Garcez et al. 2015), in particular for

teeth undergoing one-session endodontic treatment or retreatment (Siqueira & Roças 2011,

Silva et al. 2012, Asnaashari et al. 2017, Pourhajibagher et al. 2017b, Rabello et al. 2017),

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 because photodynamic effects in experimentally infected root canals of extracted teeth led
Accepted Article up to 99 % reduction of colony-forming unit counts when PDT parameters were optimized

(Fimple et al. 2008, Tennert et al. 2015).

Currently, the use of PDT in endodontic therapy has been tested in terms of bacterial load

reduction in vivo (Bonsor et al. 2006a, Garcez et al. 2008, 2010, Rabello et al. 2017) as well

as in vitro (Foschi et al. 2007, Fimple et al. 2008, Asnaashari et al. 2016, Soares et al. 2016)

and ex vivo (Ng et al. 2011) and has shown promising results.

In vitro studies

Antimicrobial

Antibiofilm (mono-species)

E. faecalis, a gram-positive facultative anaerobic coccoid, is one of the major aetiological

factors that plays a role in persistent infections and post-treatment endodontic disease (Love

2001, Lee et al. 2004b, Roças et al. 2004). A recent systematic review of PDT against E.

faecalis provided a direct comparison of these studies (Siddiqui et al. 2013), confirming that

its use in vitro has revealed a promising bactericidal potential as stated by others (Soukos et

al. 2006, Foschi et al. 2007, Bergmans et al. 2008, Fonseca et al. 2008, Garcez et al. 2010,

Kishen et al. 2010, Pagonis et al. 2010, Schlafer et al. 2010, Nagayoshi et al. 2011, Nunes

et al. 2011, Poggio et al. 2011, Rios et al. 2011, Vaziri et al. 2012, Bago et al. 2013,

Chiniforush et al. 2016b, Pourhajibagher et al. 2016a, 2016c, Pourhajibagher & Bahador

2018a, Soares et al. 2018). In fact, it was concluded that PDT was effective in the attempt to

decrease the numbers of E. faecalis colonies from infected root canals of extracted human

teeth (Neugebauer 2005, Tennert et al. 2014, Asnaashari et al. 2016, Susila et al. 2016)

compared to traditional endodontic instrumentation/irrigation treatment protocols (Soukos et

al. 2006, Foschi et al. 2007, Bergmans et al. 2008, Fonseca et al. 2008, Garcez et al. 2010,

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 Pagonis et al. 2010, Schlafer et al. 2010, Nagayoshi et al. 2011, Nunes et al. 2011, Poggio
Accepted Article et al. 2011, Rios et al. 2011, Vaziri et al. 2012, Bago et al. 2013, Hoedke et al. 2018). The

synergism of light and methylene blue loaded nanoparticles resulted in approximately 2 and

1 log10 reduction of E. faecalis colony-forming units in planktonic phase and root canals,

respectively (Pagonis et al. 2010). Borba et al.(2017) reported 100% efficacy of PDT with

erythrosine and LED in the eradication E. faecalis in planktonic suspension. The efficacy of

PDT on P gingivalis (Pourhajibagher et al. 2017a) or E faecalis (Chiniforush et al. 2016a,

Afkhami et al. 2017, Akbari et al. 2017, Beltes et al. 2017) biofilm has been demonstrated

using indocyanine green as the PS. Some studies reported that PDT at high doses revealed

antimetabolic and antibiofilm potential activity against E. faecalis (Pourhajibagher et al.

2016a) and P. gingivalis (Pourhajibagher et al. 2016b) biofilms up to 42.8% when using

indocyanine green as the PS, and also with MB and TBO at a lesser extent. These authors

also evaluated the use of PDT for treatment of endo-perio lesions showing a reduction of

biofilm formation (Pourhajibagher et al. 2016a).

Antibiofilm (Multi-species)

Hoedke et al. (2018) analyzed several irrigation protocols as well as the application of PDT

on a multispecies biofilm model of endodontic infection simulating a one-visit root canal

treatment of retreatment cases. The irrigation protocols affected bacterial reduction

immediately after treatment and after 5 days of further incubation for planktonic and

adherent bacteria. Moreover, a significant effect of adjunctive PDT on bacterial reduction

could be demonstrated after 5 days of additional incubation and chemo-mechanical

debridement using 1% NaOCl and 2% CHX. Although significant bacterial reduction was

detected after PDT, the amount of remaining bacteria was still high and clinically

unsatisfactory. This is in correspondence with previous studies (Souza et al. 2010,

Muhammad et al. 2014, Shrestha & Kishen 2014, Tennert et al. 2014, 2015, Chiniforush et

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 al. 2016b, Rosa et al. 2017), suggesting that PDT might be an effective adjunctive method in
Accepted Article root canal disinfection, but not a stand-alone treatment. When PDT was used with 5%

NaOCl a 99.99% reduction of the count of viable microorganisms in CFU/mL from the first

(S1) to the second (S2) microbial sampling in the root canals infected with E. faecalis, P.

aeruginosa, S. aureus and C. albicans was observed (de Oliveira et al. 2015).

However, methodologic differences in the in vitro studies that employed PDT for targeting

root canal microorganisms make comparisons difficult. The in vitro studies have used

different PS, such as toluidine blue O, azulene and chlorin e6, as well as different light

parameters and light-delivery techniques (Soukos & Goodson 2011).

In vivo studies

In vivo results (Bonsor et al. 2006a, b, Garcez et al. 2008, 2010, da Silva et al. 2018,

Pourhajibagher & Bahador 2018b, Pourhajibagher et al. 2018) reported endodontic bacteria

(including E. faecalis) to significantly reduce following endodontic therapy with adjunct PDT

compared to when endodontic therapy is used alone for intracanal disinfection. However,

controversial results have also been reported (Souza et al. 2010, Cheng et al. 2012, Hecker

et al. 2013, Miranda et al. 2013). Four ex vivo studies (Souza et al. 2010, Nunes et al. 2011,

Cheng et al. 2012, Hecker et al. 2013) reported conventional endodontic treatment regimens

(such as mechanical debridement and copious NaOCl irrigation) to be significantly more

effective in eliminating intracanal bacteria compared to PDT. Two studies (Souza et al. 2010,

Miranda et al. 2013) reported that PDT does not have a significant additional effect to the

chemo-mechanical preparation using 2.5% NaOCl as an irrigant in the reduction of E.

faecalis counts (Souza et al. 2010). An explanation in this regard may be the presence of

low concentration of available oxygen in the canals, particularly in irregularities and in

dentinal tubules. Under such circumstances, formation of cytotoxic oxygen derivatives may

be either be blocked or minimized. In clinical scenarios, the PS may be unable to diffuse well

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 into irregular canals and dentinal tubules or even through possible bacterial biofilms
Accepted Article persisting on untouched canal walls. These factors may compromise the outcome of PDT in

infected root canals.

Further studies also favoured the use of PDT for the elimination of biofilms and residual and

drug-resistant microorganisms (Williams et al. 2006, Garcez et al. 2010, Kishen et al. 2010,

Ng et al. 2011, Nunes et al. 2011). Studies concluded that PDT application enhances

disinfection during root canal treatment (Bonsor et al. 2006a, Garcez et al. 2008, 2010,

Asnaashari et al. 2017) and that mature biofilms seem to be more challenging (Bonsor et al.

2006a, Lim et al. 2009). Garcez et al. (2008, 2010) used PDT in combination with

conventional chemo-mechanical debridement. They presented promising results of

adjunctive PDT application. When they evaluated their protocol in teeth with necrotic pulps

undergoing initial root canal treatment, they found that a significantly greater reduction in the

bacterial count occurred after the additional application of PDT. If they allowed for weekly

treatment with Ca(OH)2 as an intracanal medicament and performed a second session of

chemo-mechanical debridement followed by PDT, a near-complete bacterial elimination

(99.9%) was noted. Pourhajibagher & Bahador (2018b) published the first in vivo study that

investigated the effects of PAD in the treatment of primary endodontic infections. This study

revealed a significant decrease in the microbial diversity and count of the infected root canal

after PDT with toluidine blue.

The use of PDT as the main disinfection protocol has been also evaluated. Bonsor et al.

(2006a) found that the use of PDT in lieu of NaOCl was equally effective as 2.25% NaOCl

combined with 20% citric acid irrigation after crown-down instrumentation.

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 Clinical procedures
Accepted Article
PDT is based on the combination of a photo-sensitizer and a powerful light. The photo-

sensitizer attaches to the membranes of microorganisms and binds itself to their surface,

absorbs energy from the light and then releases this energy to oxygen (O2), which is

transformed into highly reactive oxygen species (ROS), such as oxygen ions and radicals.

The ROS reacts strongly and destroys the microorganisms instantly and effectively. The

results of a study by Bouillaguet et al. (2010) support the use of blue- or red-light-absorbing

photo-sensitizers as candidates to produce ROS for clinical applications.

The PDT principle is not only effective against bacteria, but also against other micro-

organisms including viruses, fungi and protozoa (Hamblin & Hasan 2004, Jori 2006,

Konopka & Goslinski 2007). The applied PS have far less affinity to mammalian cells; thus,

no negative side effects in the treatment have been reported by toxicological tests (Komerik

et al. 2002).

Clinically, after completion of canal preparation, the canal is inoculated with the PS solution,

which is left in situ for a fixed period of time (60 seconds) to permit the solution to come into

contact with the bacteria and diffuse through any biofilm structures. The emitter is then

placed in the root canal and irradiation carried out for 30 seconds in each canal. This has

been demonstrated in the laboratory to kill high concentrations of bacteria generally found in

root canals (Williams et al. 2006, Pourhajibagher & Bahador 2018b). Care must be taken to

ensure maximum wetting, as it is important that the solution contacts the bacteria, otherwise

the photosensitization process will not occur (Bonsor et al. 2006b). It has been reported that

the PDT technique was successful in eliminating all the cultivable bacteria when the PS

reached the bacteria (Bonsor et al. 2006b). Furthermore, it highlighted the need for caution

in the use of the emitter to ensure that it is not bent too tightly or trapped in the canal

(Bonsor et al. 2006b). Kosarieh et al. (2016) reported that 2-minute irrigation with 17% EDTA

improve the penetration of PS inside the dentinal tubules, so it could be assumed that the

This article is protected by copyright. All rights reserved.

 PS could reach the bacteria localized in deeper parts of the root canal wall. The PDT
Accepted Article principle appears to be not only effective against bacteria, but also against biofilms (George

& Kishen 2007b). Advanced non-invasive PDT using a PS formulation containing oxidizer

and oxygen carrier has been demonstrated to disrupt the biofilm matrix and to facilitate

comprehensive inactivation and disinfection of matured endodontic biofilm (George & Kishen

2008a).

Nunes et al. (2011) also showed in vitro that PDT can be effective with or without the use of

an intracanal fibre, meaning that light delivery may not drastically affect its antimicrobial

action. Additionally, Pinheiro et al. (2016) reported that the penetration depth of the fibre was

not a significant factor because they found similar values when using PDT before and after

instrumentation. It is important to highlight that when the fibre optic probe did not penetrate

the entire length of the canal, the extrusion of apical microbial pathogens is prevented.

Firmino et al. (2016) reported that the use of PDT with MB accelerated the healing of a

periapical lesion, probably because laser light in the red spectrum increases bone repair in

the presence of periapical disease in permanent teeth (Yoshida 2009).

LIMITATIONS OF PDT

Even though the application of PDT has significant advantages, potential adverse events

have been reported. Tooth staining and discoloration may be an adverse effect that follows

the use of PDT in root canal treatment when methylene blue (MB) is used as the

photosensitizer (PS) (Carvalho Edos et al. 2011, Ramalho et al. 2017). According to

Figueiredo et al. (2014) the pre-irradiation time of 10 min promoted more severe

discoloration of the tooth structure when compared with a pre-irradiation time of 5 min. The

longer time likely allowed the PSs to penetrate deeper into the dentine and closer to the

dentine–enamel interface, making the discoloration more noticeable. There have been some

attempts to overcome this disadvantage by evaluating the efficacy of several chemical

This article is protected by copyright. All rights reserved.

 compounds. It has been concluded that 2.5% NaOCl used during cleaning and shaping of
Accepted Article the root canals, was effective in preventing tooth staining related to the application of MB

during PDT (Carvalho Edos et al. 2011). In addition, Zanin et al. (2005), and George &

Kishen (2007b), have reported that MB when used in concentrations of 100μg/mL minimizes

the chances of dental discoloration, while safeguarding its photo-bactericidal properties

studies. According to the results of Figueiredo et al. (2014) and Carvalho et al. (2011) Endo-

PTC cream (10% urea peroxide, 15% Tween 80, and 75% carbowax, pharmaceutical

compound) associated with 2.5% NaOCl effectively removes this dye.

Another disadvantage is that a PS is a viscous substance that impregnates the dentine

surface in a significant way. A chemical smear layer may form, promoting the obliteration of

dentinal tubules, which can lead to microleakage and a decrease in the bond strength of the

filling materials to root canal dentine (Shahravan et al. 2007). In this way, a final irrigant

should be used to promote the effective removal of the PS from root canal walls after

PDT. Souza et al. (2017) reported that the use of ultrasonics improved the ability of 17%

EDTA and QMix to remove the PS from the cervical, middle and apical regions of the root

canal walls after PDT.

Several limitations have been associated with PDT and its antimicrobial efficacy. The

species of bacteria in the root canal system and their growth mode were found to influence

their susceptibility to PDT in a dose-dependent manner (Upadya & Kishen 2010).

Furthermore, dentine, dentine matrix, pulp tissue, bacterial lipopolysaccharides and bovine

serum albumin were found to significantly decrease PDT antimicrobial efficacy (Shrestha &

Kishen 2012). An effort to enhance the photodynamic effect by encapsulating and delivering

MB in polymeric nanoparticles appears promising (Pagonis et al. 2010). Other strategies

include the use of a PS solvent (George & Kishen 2008b), efflux pump inhibitors (Upadya &

Kishen 2010) or photo-activated functionalized chitosan nanoparticles for disinfection and

stabilization of the dentine matrix (Shrestha et al. 2014).

This article is protected by copyright. All rights reserved.

 Another area of concern is the potential cytotoxicity of PDT. In vitro and ex vivo studies have
Accepted Article been performed that aimed to investigate the safety profile of PDT for potential in vivo

applications (George & Kishen 2007a, Xu et al. 2009). The authors concluded that under a

therapeutic window PDT is safe (Xu et al. 2009). Other studies reported that PDT

cytotoxicity was significantly less compared with NaOCl when used for root canal

disinfection (George & Kishen 2007a, Gomes-Filho et al. 2016). Gomes-Filho et al. (2016)

reported that PDT with curcumin was not cytotoxic and did not inhibit fibroblast viability.

Since the toxicity of the PS, both light-activated and not light-activated, is similar to common

endodontic irrigants, it has been recommended to be used clinically with precautions of use

similar to those usually recommended for the irrigating solutions (Gambarini et al. 2011).

Related to the dose of energy, the highest potency observed refers to LASER sources

(Burns et al. 1993, Zanin et al. 2005), probably because this light concentrates great energy

in a small area (Takasaki et al. 2009). These aspects should be carefully analysed when

used in teeth, since temperature increases may induce trauma to surrounding tissues

through thermal injury and cause irreversible changes. The use of LED may be suggested,

considering its capacity of not changing the temperature allied to its high dose energy supply

(Nagata et al. 2012). One of the advantages of PDT with high clinical relevance when using

light is the absence of thermal-side effects in the periradicular tissues (Soukos et al. 2006).

The lethal action of PDT is based on photochemical events and not thermal effects, as

opposed to many laser therapy techniques (Walsh 1997, Amyra et al. 2000). The absence of

a thermal effect of PDT makes it potent in eradicating microorganisms such as bacteria

(Soukos et al. 2006), fungi (Bliss et al. 2004) and viruses (Ceballos-Salobrena et al. 2000)

without causing overheating of the adjacent tissues (Soukos et al. 2006).

This article is protected by copyright. All rights reserved.

 PDT appears to be effective against antibiotic-sensitive and antibiotic-resistant
Accepted Article microorganisms. In addition, there is no evidence of resistance development in the target

bacteria after PDT (Wilson 2002, Komerik & MacRobert 2006), even after repeated

applications treatment (Wainwright & Crossley 2004, Konopka & Goslinski 2007, Rossoni et

al. 2010).

OPTIMIZATION OF PDT EFFICACY

Recently, in order to improve the uptake of PS by microorganisms using the PDT approach,

these molecules have been loaded, linked or encapsulated in a drug delivery system for

widely different purposes (Ding et al. 2016, Junqueira et al. 2016).

Current research is also focused on increasing the anti-biofilm efficacy of PDT by combining

the photodynamic effects with bioactive micro and nanoparticles (Pagonis et al. 2010,

Shrestha & Kishen 2012, Afkhami et al. 2017) Shrestha & Kishen (2014) tested a newly

developed rose bengal–functionalized chitosan nanoparticles (CSRBnps) for their

interaction/uptake with monospecies bacteria/biofilm and assess their anti-biofilm efficacy on

a multispecies biofilm model in vitro. Their results reported an increased affinity to bacterial

cell membrane, greater penetration into biofilm structure and an enhanced ability to

eliminate clinically relevant multispecies bacterial biofilm. Afkhami et al. (2017) reported

enhanced efficacy of the combination of PDT with a diode laser with silver nanoparticles and

indocyanine green than that of PDT alone.

CONCLUDING REMARKS

Despite technological and scientific advances in endodontics, there are many cases that

result in failure due to microbial factors. One challenge that has motivated many researchers

in recent years is to develop new technologies to eliminate these persistent microorganisms.

This article is protected by copyright. All rights reserved.

 PDT is a minimally invasive approach that has been demonstrated to be an adjunct to
Accepted Article conventional root canal treatment in eliminating microorganisms that remain viable in the

root canal system (Silva et al. 2012). Although there is limited information and sometimes

conflicting data pertaining to the use of antimicrobial PDT in endodontic treatment,

preclinical data suggest that this treatment option is a promising adjunctive supplement after

conventional chemo-mechanical debridement for further reduction of persistent bacteria (Ng

et al. 2011, Gursoy et al. 2013). Further in vivo clinical trials are necessary to make more

reliable conclusions regarding the use of PDT in endodontics (Gursoy et al. 2013), and to

determine the appropriate parameters for the PS concentration, design of different PS

formulations, energy dosage used and the irradiation optimal time (Xu et al. 2009, de

Oliveira et al. 2014, Pourhajibagher & Bahador 2018b).

Conflict of Interest statement

The authors have stated explicitly that there are no conflicts of interest in connection with

this article.

This article is protected by copyright. All rights reserved.

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 Journal 34, 221-30.
Accepted Article
Pinheiro SL, Azenha GR, Democh YM et al. (2016) Antimicrobial Activity of Photodynamic

Therapy Against Enterococcus faecalis Before and After Reciprocating Instrumentation in

Permanent Molars. Photomedicine and Laser Surgery 34, 646-51.

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Photodynamic therapy in endodontic treatment of deciduous teeth. Lasers in Medical

Science 24, 521-6.

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24, 259-68.

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Organs 34, 889-97.

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Photodynamic Therapy 22,140-6.

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after the photo-activated disinfection in primary endodontic infections: traditional phenotypic

and molecular approaches. Photodiagnosis and Photodynamic Therapy 22,19-25.

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This article is protected by copyright. All rights reserved.

 (2016a) Effects of sub-lethal doses of photo-activated disinfection against Porphyromonas
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and Photodynamic Therapy 16, 50-3.

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5.

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lethal doses of photodynamic therapy affect biofilm formation ability and metabolic activity of

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 Rios A, He J, Glickman GN, Spears R, Schneiderman ED, Honeyman AL (2011) Evaluation
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extracted human teeth. Journal of Endodontics 37, 856-9.

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 antimicrobial photodynamic therapy in an artificial biofilm model. Lasers in Medical Science
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 chitosan nanoparticles and photodynamic therapy. Journal of Endodontics 38, 1275-8.
Accepted Article
Shrestha A, Kishen A (2014) Antibiofilm efficacy of photosensitizer-functionalized bioactive

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This article is protected by copyright. All rights reserved.

 Soukos NS, Goodson JM (2011) Photodynamic therapy in the control of oral biofilms.
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 endodontics: a literature review. Photomedicine and Laser Surgery 33, 175-82.
Accepted Article
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 applications. Australian Dental Journal 42, 247-54.
Accepted Article
Williams JA, Pearson GJ, Colles MJ (2006) Antibacterial action of photoactivated

disinfection {PAD} used on endodontic bacteria in planktonic suspension and in artificial and

human root canals. Journal of Dentistry 34, 363-71.

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 for the photodynamic therapy of oral plaque biofilms. Journal of Antimicrobial Chemotherapy
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