|Year : 2014 | Volume
| Issue : 1 | Page : 48-55
Photodynamic therapy: Truly a marriage between a drug and a light
Harveen Singh1, Heena Khurana2, Harshneet Singh3, Manmohit Singh4
1 Department of Periodontics, Genesis Institute of Dental Sciences and Research, Ferozepur, Punjab, India
2 Department of Pedodontics, Faculty of Dental Sciences, King George's University, Lucknow, Uttar Pradesh, India
3 Department of Prosthodontics, Surendera Dental College, Sri Ganganagar, Rajasthan, India
4 Department of Prosthodontics, Genesis Institute of Dental Sciences and Research, Ferozepur, Punjab, India
|Date of Web Publication||15-Mar-2014|
13, New Jawahar Nagar, Jalandhar - 144 001, Punjab
Source of Support: None, Conflict of Interest: None
Microbial biofilms in the oral cavity are involved in the etiology of various oral conditions, including caries, periodontal and endodontic diseases, oral malodor, denture stomatitis, candidiasis and dental implant failures. It is generally recognized that the growth of bacteria in biofilms imparts a substantial decrease in susceptibility to antimicrobial agents compared with cultures grown in suspension. It is therefore not surprising that bacteria growing in dental plaque, a naturally occurring biofilm, show increased resistance to antimicrobial agents. As result there is pronounced interest and keenness in the development of alternate antimicrobial concepts. Therefore, the application of alternative method to eradicate bacteria from periodontal pockets is desirable. One such approach is photodynamic therapy (PDT). The purpose of this review was to evaluate the effectiveness of PDT for periodontitis as an adjunct to non-surgical treatment of scaling and root planning. This review provides an overview of PDT with emphasis on its current status as an antimicrobial therapy to control oral bacteria. Finally, new frontiers of antimicrobial PDT research will be introduced, including targeting strategies that may open new opportunities for the maintenance of bacterial homeostasis in dental plaque, thereby providing the opportunity for more effective disease prevention and control. Thus, the available knowledge of PDT should encourage a more clinically oriented application of this technique.
Keywords: Bacterial resistance, photodynamic therapy, photosensitizers, systemic antibiotics
|How to cite this article:|
Singh H, Khurana H, Singh H, Singh M. Photodynamic therapy: Truly a marriage between a drug and a light. Muller J Med Sci Res 2014;5:48-55
|How to cite this URL:|
Singh H, Khurana H, Singh H, Singh M. Photodynamic therapy: Truly a marriage between a drug and a light. Muller J Med Sci Res [serial online] 2014 [cited 2019 Nov 22];5:48-55. Available from: http://www.mjmsr.net/text.asp?2014/5/1/48/128946
| Introduction|| |
Periodontitis is a multifactorial disease associated with loss of supporting tissues of the tooth caused by certain periodontopathogenic species of bacteria and/or extracellular macromolecules as well. , It is generally recognized that the growth of bacteria in biofilms imparts a substantial decrease in susceptibility to antimicrobial agents compared with cultures grown in suspension. Current treatment techniques involve either periodic mechanical disruption of oral microbial biofilms or maintaining therapeutic concentrations of antimicrobials in the oral cavity, both of which are fraught with limitations.  Mechanical removal of the bio-film and adjunctive use of antibacterial disinfectants or various antibiotics have been conventional methods of the periodontal therapy. Recently, there have been a number of reports about the bacterial strains become resistant particularly due to the frequent use of antibiotics. ,,
The application of alternative method to eradicate bacteria from periodontal pockets is desirable. One such approach is photodynamic therapy (PDT).  Henceforth, the main aim of this literature review is to discuss the role of antimicrobial PDT in the field of periodontics.
| Drawbacks of Antibacterial Drug Treatment in Periodontal Disease|| |
In this Era of scientific explosion, there is increasing awareness, about microbial resistance-related phenomena. Resistance development may be the consequence of injudicious use of antibiotics in common bacterial or viral infections. Moreover, excessive use of antibiotics in meat production, in greenhouse fertilization or in household chemicals is blamed as contributing to resistance development. , Insufficient drug concentrations within the sulcus fluid or biofilm may also be responsible for lacking efficacy. Sulcus concentrations of antibiotic drugs may remain below the minimum inhibitory concentration of the target organisms.
However, in future difficulties with antibiotic therapy can emerge because of
- An increased resistance to most antibiotics used in periodontics,
- An increase in the number of immune-suppressed patients  and
- Periodontal infections are caused by many diverse pathogens requiring different antibiotics with different risks of adverse reactions. 
| Historical Perspective of PDT|| |
The term PDT was established as early as 1900 and noted the interaction between acridine, a dye and visible light in the presence of oxygen killed paramecia. Recently, PDT also has been used to eliminate tumor cells. 
In 1904, the photodynamic inactivation of bacteria by an exogenously applied photosensitizer was demonstrated.  In 1978, authors successfully applied this novel technique for the treatment of different cancers. It was thought that a common feature between tumor cells and micro-organisms was high proliferation and an active metabolism. PDT, as a novel approach in medicine, was first approved by the US Food and Drug Administration (FDA) in 1999 to treat pre-cancerous skin lesions of the face or scalp. 
The Principles Behind PDT
PDT is based on the principle that a photoactivatable substance, the photosensitizer, binds to the target cell and can be activated by light of a suitable wavelength.  During this process, free radicals are formed (among them singlet oxygen), which then produce an effect that is toxic to the cell. To have a specific toxic effect on bacterial cells, the respective photosensitizer needs to have selectivity for prokaryotic cells. Although several authors have reported the possibility of a lethal photosensitization of bacteria in vivo and in vitro, ,,, others have pointed out that Gram-negative bacterial species, due to their special cell wall, are largely resistant to PDT. ,
Components of PDT
PDT involves the combination of visible light, usually through the use of a diode laser and a photosensitizer. 
Light Source-diode Laser
A diode laser or visible light source [Figure 1] is used to activate the photosensitizer. Subsequently, diode laser systems that were easy to handle, portable and cost-effective are used. According to Aoki et al., the diode laser is a solid-state semiconductor laser that typically uses a combination of gallium, arsenide and other elements such as aluminum and indium to change electrical energy into light energy. 
|Figure 1: Visible light, which covers the range of 400-700 nm of all electromagnetic radiation, is most relevant to photodynamic therapy (PDT). The range of light used in PDT is generally >600 nm. This is because endogenous molecules, such as hemoglobin, absorb light strongly at wavelengths of <600 nm and therefore capture most of the incoming photons|
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The wavelength range is about 800-980 nm.  Adam and Pang stated that the diode laser wavelength is delivered in a continuous wave or gate pulse in a contact mode. The ability to use this instrument in a continuous wave or pulsed mode greatly increases its usefulness in soft-tissue surgery. FDA approved oral soft-tissue surgery in 1995 and sulcular debridement in 1998 by means of a diode laser (GaAlAs 810 nm) as safe for the surgery. 
It can be delivered through a flexible quartz fiber optic handpiece. This energy level is absorbed by pigmentation in the soft-tissues and makes the diode laser an excellent hemostatic agent. It is used for soft-tissue removal in a contact mode, giving a tactile sensation similar to electrocautery. The power output for dental use is generally around 2-10 W and can be either pulsed or continuous mode.  The optic fiber needs to be cleaved and prepared before initial use and during the procedure to ensure the efficient operation. Some clinicians prefer to initiate the end of the fiber with a small amount of carbon pigment and refer to this as a "hot tip".
These lasers are relatively poorly absorbed by tooth structure so that soft-tissue surgery can be safely performed in close proximity to enamel, dentin and cementum. The continuous wave emission mode of the diode laser can cause a rapid temperature rise in the target tissue. The chief advantage of the diode laser is one of a smaller size, portable instrument.  The diode laser is expected to have a disinfecting thermal effect on bacteria that is basically limited to the root surface. Most of the diode laser radiation is absorbed by superficial layers, thus having a better effect on sites affected by periodontal disease. 
The advantages of diode lasers are:
- The smaller size of the units as well as the lower financial costs.
- Proven to be successful with soft-tissue incision and ablation.
- Gingival troughing.
- Esthetic recontouring of gingiva.
- Treatment of oral ulcers.
- Frenectomy and gingivectomy.
- Laser curettage with diode appears to be neither scientifically nor ethically justified.  Convissar stated that diode lasers are able to deliver laser energy efficiently and effectively to the periodontal pockets for non-surgical periodontal therapy. 
Chemically, many photosensitizers belong to dyes and porphyrin-chlorine groups. A variety of photosensitizers include:
- Dyes: Tricyclic dyes with different meso-atoms - methylene blue, toluidine blue O and acridine orange; and phthalocyanines - aluminum disulfonated phthalocyanine and cationic Zn (II) - phthalocyanine.
- Chlorines: Chlorine e6, stannous (IV) chlorine e6, chlorine e6-2.5 N-methyl-d-glucamine, polylysine and polyethyleneimine conjugates of chlorine e6.
- Porphyrins: Hematoporphyrin HCl, photofrin and 5 aminolevulinic acid (ALA), benzoporphyrin derivative.
- Xanthenes: Erythrosine.
- Monoterpene: Azulene.
Photosensitizers can also be activated by low power visible light at a specific wavelength. Activation of the photosensitizer is dependent on the total light dose, the dose rates, the depth of light penetration and the localization of target area.
Optimal Properties of a Photosensitizer
- Highly selective.
- Low toxicity and fast elimination from skin and epithelium.
- Absorption peaks in the low-loss transmission window of biological tissues.
- Optimum ratio of the fluorescence quantum yield to the interconversion quantum yield.
- High quantum yield of singlet oxygen production in vivo.
- High solubility in water, injection solutions and blood substitutes.
- Storage and application light stability.
| The Mechanism of Action|| |
PDT involves three components: Photosensitizer, light and oxygen. When a photosensitizer is irradiated with light of specific wavelength it undergoes a transition from a low-energy ground state to an excited singlet state. Subsequently, the photosensitizer may decay back to its ground state, with emission of fluorescence, or may undergo a transition to a higher-energy triplet state. The triplet state can react with endogenous oxygen to produce singlet oxygen and other radical species, causing a rapid and selective destruction of the target tissue. This utilization of oxygen in the production of reactive oxygen species is known as photochemical oxygen consumption. The triplet state photosensitizer reacts with biomolecules by two mechanisms. The Type I reaction involves electron/hydrogen transfer directly from the photosensitizer, producing ions or electron/hydrogen removal from a substance molecules to form free radicals. These radicals react rapidly with oxygen resulting in the production of highly reactive oxygen species (superoxide, hydroxyl radicals, hydrogen peroxide). The Type II reaction produces electronically excited and singlet oxygen [Figure 2]. These two reactions indicate the mechanisms of tissue/cell damage, which is dependent on both oxygen tension and photosensitizer concentration. PDT produces cytotoxic effects on subcellular organelles and molecules. Its effects are targeted on mitochondria, lysosomes, cell membranes and nuclei of tumor cells. Photosensitizer induces apoptosis in mitochondria and necrosis in lysosomes and cell membranes.
| How PDT Operates in Periodontitis|| |
Biofilm in oral cavity causes two of the most common diseases, dental caries and periodontal diseases. An effective approach of periodontal therapy is to change the local environment to suppress the growth of periodontal pathogens. Micro-organisms in gelatinous matrix (glycocalyx) are less accessible to antibiotics. Using antimicrobial agents to treat periodontitis without disruption of the biofilm ultimately results in treatment failures. It is difficult to maintain therapeutic concentrations at the target sites and target organisms can develop resistance to drugs. This resistance is minimized by using PDT. Polysaccharides present in extracellular matrix of oral biofilm are highly sensitive to singlet oxygen and susceptible to photo damage. Breaking the biofilm may inhibit plasmid exchange involved in transfer of antibiotic resistance and disrupt colonization. PDT is even effective against antibiotic resistant bacteria. Antioxidant enzymes produced by bacteria may protect against some oxygen radicals, but not against singlet oxygen. Photodynamic antimicrobial chemotherapy could be an ideal complement to conventional scaling and root planing (SRP). It is used during initial and maintenance therapy for the treatment of periodontitis. The activity of PDT against periodontopathic bacteria has been reported in vitro and in vivo for a range of photosensitizers. During inflammation there is venous stagnation and reduced oxygen consumption by tissues. This decrease in oxygen level and change in pH may enhance the growth of anaerobic species. In such cases, PDT may improve tissue blood flow in the microcirculatory system and reduce venous congestion in gingival tissues. Furthermore, PDT may increase oxygenation of gingival tissues by 21-47% respectively. This in turn decreases the time and speed of oxygen delivery and utilization, thus normalizing oxygen metabolism in periodontal tissues.
| Molecular Basis of Mechanism of Action|| |
There are two basic mechanisms that have been proposed to account for the lethal damage caused to bacteria by PDT:
- Deoxyribonucleic acid (DNA) damage.
- Damage to the cytoplasmic membrane, allowing leakage of cellular contents or inactivation of membrane transport systems and enzymes.
Breaks in both single- and double stranded DNA and the disappearance of the plasmid supercoiled fraction have been detected in both Gram-positive and Gram-negative species after PDT with a wide range of photosensitizer structural types. It has been hypothesized that photosensitizers that operate chiefly via Type I mechanisms penetrate the outer membrane of Gram-negative bacteria, whereas the Type II photosensitizers penetrate the outer membrane of Gram-positive bacteria more efficiently.
| Advantages of PDT in Periodontal Treatment|| |
- Development of resistance to the PDT is less as singlet oxygen and other free reactive oxygen species interact with several cell structures different metabolic pathway.
- As PDT is non-invasive local therapy, following application of a sensitizer, a light source delivered into the target area precisely via a fiberoptic cable, so disturbances of the microflora at other sites would not occur and damage to the adjacent host tissues can be avoided.
- PDT offers thorough irrigation and elimination of pathogens in inaccessible areas of periodontal pocket within short span of time, thus beneficial to both operator and the patient.
- The risk of bacteremia after periodontal debridement can be minimized.
- There is no need to prescribe antibiotics therefore the possibility of side effects is avoided.
- There is no need to anaesthetize the area and destruction of bacteria is achieved in a very short period (<60 s). 
| Applications of PDT in Dentistry|| |
PDT as an Adjunct in Non-surgical Periodontal Treatment
A short-term clinical trial was to evaluate the effects of a combination of PDT with low-level laser therapy as an adjunct to non-surgical treatment of chronic periodontitis. The test teeth achieved significant reductions in the percentage of sites with bleeding on probing, mean probing depth gingival crevicular fluid volume interleukin-1b levels in gingival crevicular fluid. Thus, it was concluded that a combined course of PDT with low-level laser therapy could be a beneficial adjunct to non-surgical treatment of chronic periodontitis on a short-term basis [Figure 3], [Figure 4] and [Figure 5]. 
|Figure 3: Photodynamic therapy of periodontitis. Following application of the photosensitizer to the periodontal pocket, light could be applied to the region via an optical fiber|
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|Figure 4: Clinical presentation: Application of photosensitizer in the periodontal pocket|
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PDT in Non-surgical Treatment of Aggressive Periodontitis
In a study on 10 patients with aggressive periodontitis in a split-mouth design to compare PDT using a laser source with a wavelength of 690 nm associated with a phenothiazine photosensitizer or SRP with hand instruments  to compare the CAL at baseline and 3 months after treatment with an automated periodontal probe, it was concluded that PDT and SRP showed similar clinical results in the non-surgical treatment of aggressive periodontitis.
PDT has advantages such as reducing the treatment time, no need for anesthesia, destruction of bacteria in a very short period of time (<60 s), unlikely development of resistance by the target bacteria and avoidable damage to the adjacent host tissues. Further studies using larger sample sizes are warranted to confirm these results.
Effect of PDT on Dental Plaque
This review provided an overview of PDT with emphasis on its current status as an antimicrobial therapy to control oral bacteria and the applications of PDT for targeting biofilm-associated oral infections. Thus, new frontiers of antimicrobial PDT including targeting strategies that may open new opportunities for the maintenance of bacterial homeostasis in dental plaque and providing the opportunity for more effective disease prevention and control has been discussed. 
Killing of Periodontopathogenic Bacteria by PDT
A systematic review to evaluate the disadvantages of using antibiotics after periodontal therapy was done and other antimicrobial approaches to combat those disadvantages. A novel approach, PDT, could be one of such approaches. Lethal photosensitization of many bacteria, both Gram-positive and Gram-negative was found and concluded by estimating the advantages of this new approach which includes rapid bacterial elimination, minimal chance of resistance development and safety of adjacent host tissue and normal microflora. 
| Effect of PDT on Periodontal Bone Loss in Dental Furcations|| |
A study to evaluate the influence of PDT on bone loss in furcation areas in rats with experimentally induced periodontal disease was conducted and it was concluded that within the parameters used in this study, PDT may be an effective alternative for controlling bone loss in furcation areas in periodontitis. 
The use of PDT in furcation involvement in induced periodontitis shows some advantages over the use of conventional antimicrobials, such as the reduced need for flap procedures and shorter treatment time; as local therapy, with lack of microflora disturbance in other sites of the oral cavity.
Photodynamic action has the potential of phototoxic or photoallergic unwanted side effects.  There can be impairment of benign oral flora which may lead to an overgrowth of a single resistant species.  In order to avoid phototoxic reactions, it is most important to stain selectively the target leaving out gingiva, mucosa or tongue.
Pain or discomfort, often described as burning, stinging or prickling restricted to the illuminated area is commonly experienced during ALA-PDT. ,
Initially, hematoporphyrin derivatives and porfimer sodium were the photosensitizers used in cutaneous malignancy, but systemic administration and the consequent prolonged generalized photosensitivity, which can last 6-10 weeks, limited their use. Systemic photosensitizers with a shorter duration of action are currently under exploration in dermatology. 
A clinically obvious scar is rarely observed. The histological evidence of scarring is evident.  Hyperpigmentation or hypopigmentation can occasionally be seen in treated areas and usually resolves within 6 months. Permanent hair loss has been observed following ALA-PDT.
PDT has the potential of promoting genotoxic effects, including induction of DNA strand breaks, chromosomal aberrations and alkylation of DNA. ,,, However, porphyrin molecules also possess antimutagenic properties, with ALA-PDT delaying photocarcinogenesis in mice. 
| Discussion|| |
It has been clearly demonstrated that periodontitis is an infectious disease and a current concept for treating periodontitis is based on eliminating the infection. As stated by de Oliveira et al.  mechanical therapy of the root surface is the basic prerequisite for eliminating infection and long-term treatment success.
Non-surgical periodontal therapy has shown to be an effective and predictable treatment approach. Mechanical debridement can significantly decreases the population of bacteria associated with chronic periodontitis, including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, prevotella intermedia, Tannerella forsythia and Treponema denticola. The impact of specific bacteria on periodontal conditions has made the clinicians to incorporate the antimicrobials as a part of periodontal therapy.
However, the frequent use of antimicrobials may lead to antimicrobial resistance, development of opportunistic infections, such as candidiasis and unwanted systemic effects, such as hypersensitivity and gastrointestinal reactions, which limits their clinical usage.
As it is easy to access the periodontal pocket, periodontitis would be very amenable to treatment by PDT. Hence, the photosensitizer could be placed directly in the pocket which could then be irradiated either through the thin gingival tissues or via an optical fiber placed directly into the pocket.
Antimicrobial PDT is mediated by singlet oxygen, which has a direct effect on extracellular molecules. Thus, the polysaccharides present in the extracellular matrix of polymers of a bacterial biofilm are also susceptible to photo damage. Such dual activity is not exhibited by antibiotics and may represent a significant advantage of aPDT.
Moreover, a development of resistance to the cytotoxic action of singlet oxygen or free radicals seems to be unlikely. As stated by Braun et al.  antimicrobial PDT is equally effective against antibiotic-resistant and antibiotic-susceptible bacteria and repeated photosensitization has not induced the selection of resistant strains.
According to Chan and Lai  selection of an effective photosensitizer is essential for the success of the technique. As well as being non-toxic to humans, the ideal photosensitizer needs to absorb a laser beam at the compatible wavelength and has to produce high excitation efficiency. Methylene blue, which belongs to the phenothiazinium family of dyes (which includes toluidine blue O), is a well-known photosensitizer.
Clinical studies combining PDT with non-surgical periodontal therapy have reported mixed outcomes. In a study by Lui et al.  showed that PDT in combination with scaling and root debridement led to a significant improvement in clinical as well as microbiological parameters compared with scaling and root debridement alone.
Even after such a detailed knowledge and published data there is no routine application of PDT in periodontal diseases as well as in general practice. Due to some of the unsolved questions there is a hesitant attitude to conduct controlled studies to prove the superior efficacy of PDT when compared to the classical methods or only efficacy in therapy- resistant cases. Established methods of mechanical SRP and/or adjuvant administration of antibiotics are successful in most cases to resolve inflammation and to establish periodontal health. However, there are definite possible benefits of PDT as explained earlier.
PDT application has an adjunctive benefit besides mechanical treatment at sites with difficult access (e.g., furcations, deep invaginations, concavities). Necessity for flap operations may be reduced, patient comfort may increase and treatment time decrease. PDT removes the biofilm in residual deep pockets during maintenance phase; no more root substance is removed by mechanical retreatment. Thus the patient may experience less dentinal hypersensitivity. PDT may decrease the risk of bacteremia which routinely occurs after periodontal treatment procedures (although very less) and, on the other hand, unequivocal evidence is present showing a periodontal risk of systemic diseases such as cardiovascular diseases and diabetes.  If the resistance against antibiotics may become worse, PDT may be a valuable alternative for most indications in which hitherto antibiotic drugs were administered. If the number of immunosuppressed patients bring new challenges for treatment strategies. The concept of PDT is plausible and could foster new therapy concepts for periodontal disease. The available knowledge should enable and encourage steps forward into more clinical oriented research and development.
New Frontiers in Oral Antimicrobial PDT
The role of PDT as a local treatment of oral infection, either in combination with traditional methods of oral care, or alone, arises as a simple, non-toxic and inexpensive modality with little risk of microbial resistance. Evolving therapeutic strategies for biofilm-related infections include the use of substances designed to target the biofilm matrix, non-growing bacteria (persister cells) within biofilms and/or quorum sensing.  The use of bacteriophages  and naturally occurring or synthetic antimicrobial peptides  may offer the possibility of bacterial targeting without the emergence of resistance. Recently, the advantages of targeted therapy become more apparent and the use of light alone, antibody - photosensitizer and bacteriophage - photosensitizer conjugates or non-antibody based targeting moieties, such as nanoparticles, are gaining increasing attention.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
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