Indian J Stomatol 2010;1(2):92-95

Photodynamic therapy and its role in periodontal therapy

1 2 3
Vadiraj S , Prashanth , Nagraj K

Abstract

Photodynamic therapy of periodontal diseases is based on the photosensitizing ability of dyes which, after administration, are
present in somewhat higher concentration in the bacteria than in normal surrounding tissue. After light activation of sensitizer,
singlet oxygen and probably oxygen free radicals are formed and consequently all kinds of cellular components are affected.
This review focuses on the cellular and biochemical aspects of photodynamic therapy.

Key Words: Photosensitizer, Photo activation, Photodynamic treatment.

Introduction photosensitizer that is activated by illumination in the

Light has been employed in the treatment of diseases since presence of oxygen. The exposure of the photosensitizer to
antiquity. In the latter part of the twentieth century it has light results in the formation of toxic oxygen species,
been used in many different forms, including phototherapy thereby causing localized photodamage and cell death.
for neonatal jaundice, the combination of psoralen Applications of the technique in dentistry may include
molecules and ultraviolet A light (PUVA) in dermatology, photodynamic diagnosis of malignant transformation of
photodynamic therapy (PDT) and photodetection (PD). oral lesions, treatment of premalignant and malignant oral
However, it is only relatively recently that it has been used lesions and photodynamic antibacterial chemotherapy
to any significant degree in dentistry. The concept of cell (PACT) of bacterial and fungal infections. Photodynamic
death being induced by the interaction of light and therapy already has shown potential in the treatment of oral
chemicals has been recognized for 100 years. This was first leukoplakia, oral lichen planus and squamous cell
reported by Oscar Raab, a medical student working with carcinoma of the tongue and lip.2
Professor Herman von Tappeiner in Munich. During the In photodynamic therapy, a photo sensitizer or its
course of his study on the effects of acridine on malaria metabolic precursor is administered to the patient. An
causing protozoa he discovered that the combination of overview of the photodynamic reaction is provided in
acridine red and light had a lethal effect on Infusoria, a Figure 1. Photodynamic therapy requires activation of the
species of Paramecium.1 He went on to demonstrate that photosensitizer via exposure to low-power visible light at a
this effect was greater than that of either acridine alone, specific wavelength. Human tissue transmits red light
light alone or acridine exposed to light and then added to efficiently, and the longer activation wavelength of the
the Paramecium. Raab had, therefore, discovered the photosensitizer results in deeper light penetration.
optical property of fluorescence and concluded that it was
not the light but rather some product of the fluorescence
that induced in vitro toxicity. He postulated that this effect
was caused by the transfer of energy from light to the
chemical, similar to that seen in plants after the absorption
of light by chlorophyll. The first report of parenteral
administration of photosensitizer in humans was in 1900
by Prime, a French neurologist, who used eosin orally in
the treatment of epilepsy. He discovered, however, that this
induced dermatitis in sun-exposed areas of skin.1 This
discovery then led to the first medical application of an
interaction between a fluorescent compound and light in
which von Tappeiner, together with a dermatologist named
Jesionek, used a combination of topical eosin and white
light to treat skin tumors. Together with Jodlbauer, von
Tappeiner went on to demonstrate the requirement of Figure 1: Overview Of The Photodynamic Reaction
oxygen in photosensitization reactions and in 1907 they
introduced the term “photodynamic action" to describe this Consequently, most photosensitizers are activated by light
phenomenon.1 between 630 and 700 nm, corresponding to a penetration
depth of 0.5 cm (at 630 nm) to 1.5 cm (at ~700 nm). The
Principles of photodynamic therapy total light dose, the dose rate and the depth of destruction
Photodynamic therapy (PDT) involves the use of a vary with each tissue that is treated and with each of the
1
Senior lecturer, Department of Periodontology, 1Senior lecturer, Department of Community Dentistry, H.K.D.E.T Dental College & Hospital,
Humnabad, 2Assoc. professor, Department of Periodontology, Department of Periodontology, P.M.N.M Dental College & Hospital, Bagalkot,
India. Correspondence : Dr Vaadiraj, email: vadi24@rediffmail.com

92

available photosensitizers.3
To go further, ground state sensitizer (0P) is excited by
absorption of light quanta to a higher excited singlet state
(1P), followed by intersystem crossing (ISC) to a triplet
3
state ( P). Two types of reactions occur after photo
activation of porphyrin dyes to triplet state (3P) ( Figure 2).
One reaction involves generation of free radicals (type 1
photochemical reaction) and in other singlet oxygen (1O2)
is generated (type II).4 Last, a Type III reaction is a unique
PS reaction because it is oxygen independent. These
reactions require either high concentration of the PS or a
deaerated system, in order to bypass the reaction with
oxygen. Under anaerobic systems radicals are generated
and these can subsequently react.5
ISC
0P 1P 3P
SUBSTRTE
1
O2
ROS (Singlet Oxygen)
Figure 2: Types Of Reactions Taking Place
After Photo Activation Of Porphyrin Dyes
Photosensitizers in PDT
Photo sensitizers should have following properties:
1. Chemically pure
2. Minimal dark toxicity
3. High tissue selectivity and less toxicity to other
tissues
4. Large absorption coefficient at high wavelength
5. High photochemical reactivity (long lived
excited triplet )
6. High ability to induce (indirect) tissue necrosis
Photo sensitizers are grouped into
1. Based on generations
2. Based on families:6
a) Tricyclic dyes: Acridine orange, Proflavine,
Riboflavin, Methylene blue, Fluorescein, Eosine,
Erythrosine, and Rose Bengal
b) Tetrapyrroles: Porphyrins and its derivatives,
Chlorophyll, Phylloerythrin and Phthalocyanines
c) Furocoumarins: Psoralen and its methoxy-deratives,
Xanthotoxin and Bergaptene
Only four photosensitizers are commercially available:
Photofrin, ALA, Visudyne (a Benzoporphyrin derivative,
Verteporfin) and Foscan. The FDA has approved the first
three, whereas all four are used in Europe. Two ALA
preparations, Metvix (PhotoCure ASA, Oslo, Norway)
and Levulan Kerastic (Dusa Pharmaceuticals, Wilmin-
gton, Mass.), have been approved by the European Agency
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Indian J Stomatol 2010;1(2):92-95
for the Evaluation of Medicinal Products and by the FDA,
respectively, for the treatment of nonhyperkeratotic actinic
keratoses of the face and scalp. PDT has not been approved
by the FDA for use in dentistry. In clinical trials, all patients
are treated in accordance with the FDA and local
Institutional Review Board approval. Foscan (temop-
orfin), the most potent second-generation photosensitizer,
has been found to be 100 times more active than Photofrin
in animal studies.7 ALA, a precursor of the fluorescent
photosensitizer protoporphyrin IX (PpIX), can be
administered systemically or applied topically to the oral
mucosa and the skin. For treatment of larger areas, various
noncoherent light sources such as tungsten filament,
quartz halogen, xenon arc, metal halide and phosphor-
coated sodium lamps are used. Recently, LEDs have been
applied in photodynamic therapy because they are small,
lightweight, highly flexible and less expensive than typical
light sources. Location and morphology of the lesion will
dictate the source of light to be used. But typically they are
fibre optic catheters terminated with cylindrical diffusers
or lenses for flat-field applications. Fibre tips can be made
into various shapes, allowing for diffusion in all directions
or for tighter focus. In order to improve PDT, the
knowledge of its effect on the tissues is at most important.
This was given by Henderson BW and Dougherty TJ in
1992.8
1. Vascular damage:
Vascular changes following PDT were observed by many
authors. Vasoconstriction and blood cell aggregation will
result in reduced blood oxygen pressure and anorexia in
the tissue resulting in tissue necrosis. Anticoagulation and
coagulation are maintained by endothelial cells which
produce prostacyclin and by platelets which produce
thromboxane A2. Interference in this equilibrium can play
a crucial role in the reduction of tissue blood flow. It was
observed that histamine and von Willibrand factor were
inducted after haematoporphyrin derivative (HPD)
photosensitization of human umbilical vein endothelial
cells.9 It was suggested that cyclooxygenase products
(thromboxanes, PGE2) were important factors in causing
vessel constriction and changes in permeability. These res-
ults indicate that the therapeutic response can be enhanced
by compounds that reduce blood flow and consequently
reduce blood oxygen pressure.
2. Membrane damage:
Three cell lines were studied in a systematic way, i.e
murine L929 fibroblasts, Chinese Hamster Ovary epith-
elial cells and T24 human bladder transitional carcinoma
cells with HPD as photosensitizer.8 Many plasma memb-
rane parameters could be excluded to be directly related to
the loss of clonogenicity and only a few plasma membrane
enzymes may be directly involved in photodynamic cell
killing of these three unrelated cell lines. Among the few
was the plasma membrane enzyme Na+-K+-ATPase, which
was very sensitive and which was not rapidly repaired.
Therefore it could not be excluded as a possible critical
target in L 929 fibroblasts as well as in T24 cells.
3. Mitochondrial damage:
Colony growth after photodynamic treatment reflects the

ability of the surviving cells to replicate. An increase in cell
number requires energy not only for replication but also for
repair processes. Cellular energy is available in the form of
high energy bonds in ATP, which is produced by anaerobic
glycolysis as well as by oxidative phosphorylation.
Persistent inhibition of these processes can ultimately lead
to ATP depletion and subsequently reproductive cell death.
The photosensitivity of mitochondrial enzymes increased
from intermembrane space enzymes such as adenylk-
inase10 via outer mitochondrial membrane enzymes like
monoamineoxidase to inner mitochondrial membrane enz-
ymes such as cytochrome c oxidase, succinate dehydroge-
nase and F0/F1- ATPase. Impaired mitochondrial funct-
ions may lead to ATP depletion. Indeed a decrease in ATP
levels immediately after light exposure has been observed
both in-vivo and in-vitro.11
4. Nuclear damage:
Poly (ADP-Ribose) transferase is a key enzyme in DNA
repair. Neutral Ca2+/Mg2+- dependent endonucleases are
maintained in a latent form by Poly (ADP-Ribose) trans-
ferase. It appears that, in photodynamically treated L929
cells, a small amount of DNA damage coincided with a
severe inhibition of Poly (ADP-Ribosyl)ation. As a conse-
quence, endonucleases are no longer inhibited and subse-
quently the DNA is broken down in random sized small
fragments. Boegheim et al.,12 have shown that DNA exci-
sion repair is severely inhibited at a stage beyond the
incision step when murine L929 fibroblasts were sensi-
tized with HPD. Therefore, both inhibitions of DNA
polymerase or DNA ligase activities were likely
candidates responsible for the reduced repair capacity after
HPD photosensitization.
PDT in periodontology
Two of the most common bacterial diseases afflicting
humans, dental caries and periodontal diseases result from
a build up of plaque biofilms on the teeth and soft tissues of
the mouth. The oral cavity is colonized by relatively
specific and highly interrelated micro organisms, inclu-
ding aerobic and anaerobic Gram positive and negative
bacteria, fungi, mycoplasma, protozoa and viruses. Dental
plaque is a complex aggregation of microorganisms found
on the tooth surface in the form of a biofilm; i.e., the
organisms are embedded in an extracellular polymeric
matrix. Biofilm-associated bacteria have increased
resistance to antibiotics, to environmental stresses and to
the immune defence mechanisms of their host. The limited
access of topical agents into the plaque and the
development of antibiotic resistance have stimulated the
search for new strategies to control plaque and to treat
caries, gingivitis and periodontal disease. PACT is equally
effective against antibiotic resistant and susceptible
bacteria, and repeated photosensitization has not induced
the selection of resistant strains. Since the antimicrobial
activity of photosensitizers is mediated by singlet oxygen,
PACT has a direct effect on extracellular molecules. The
polysaccharides of an extracellular polymeric matrix are
susceptible to photo damage. This dual activity, not displ-
ayed by antibiotics, represents a significant advantage of
PACT. The activity of PACT against homogeneous and
mixed Gram-positive and negative bacterial and fungal
Indian J Stomatol 2010;1(2):92-95
oral biofilms has been reported for a range of photo sensit-
izers. In addition to the treatment for periodontitis, PACT
for peri-implantitis, endodontic treatment and caries also
has come into focus. Electron microscopy revealed comp-
lete eradication of bacteria in biofilms of Actinobacillus
actinomycetemcomitans, Porphyromonas gingivalis or
Prevotella intermedia prepared on implant surfaces treated
with toluidine blue O and irradiated at 905 nm.
In addition to these, attempts were made by various authors
to study the adjunctive role of PDT along with ultrasonic
scaling, various flap surgeries and in treatment of
periodontal diseases in patients with systemic diseases like
diabetes. In a randomised clinical pilot trial designed to
evaluate photodynamic therapy for its bactericidal
potential and clinical effects in treatment of periodontitis it
has been found that application of a single cycle of PDT
was not effective as an adjunct to ultrasonic periodontal
treatment. There was no extra reduction in pocket depths
and bleeding on probing. With regard to eradicating
bacteria, however, there were no additional effects as
compared with conventional treatment alone.13
In an attempt to study the possible added benefits of
repeated adjunctive PDT to conventional treatment of
residual pockets in patients enrolled in periodontal
maintenance, authors came to conclusion that repeated
PDT adjunctive to debridement yielded improved clinical
outcomes in residual pockets in maintenance patients. The
effects were best documented after six months.14
A study conducted to know the short term effects of
photodynamic therapy on periodontal status and glycemic
control of patients with diabetes showed that PDT does not
benefit the conventional non-surgical periodontal therapy
in diabetic patients.15 Another study done to find the
capacity of PDT for microbial reduction in periodontal
pockets showed 81.24% reduction in numbers of bacteria
after scaling and 95.90% after PDT.16 Braun and co-
workers in their short term randomized clinical trial on
clinical effects of adjunctive antimicrobial photodynamic
therapy in periodontal treatment found that clinical
outcomes of conventional subgingival debridement can be
improved by adjunctive antimicrobial PDT.17
Based on the evidence available it can be concluded that
there is great need to develop an evidenced based approach
to the use of lasers for treatment of periodontitis. It would
be prudent to say that there is insufficient evidence to
suggest that PDT is superior to the traditional modalities of
periodontal therapy.
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Disclosures : The authors report no conflicts of interest.
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