|Year : 2010 | Volume
| Issue : 2 | Page : 285-291
|Photodynamic therapy - A strategic review
Rajvir Malik, Anish Manocha, DK Suresh
Department of Periodontics and Oral Implantology, M.M. College of Dental Sciences and Research, M.M. University, Mullana, Ambala, Haryana - 133 203, India
Click here for correspondence address and email
|Date of Submission||19-Sep-2009|
|Date of Decision||12-Nov-2009|
|Date of Acceptance||06-Feb-2010|
|Date of Web Publication||22-Jul-2010|
| Abstract|| |
Mechanical removal of the biofilm and adjunctive use of antibacterial disinfectants or various antibiotics have been conventional methods of the periodontitis therapy. There has been an upsurge of bacterial strains becoming resistant due to the injudicious use of antibiotics, recently. As a result there is pronounced interest and keenness in the development of alternate antimicrobial concepts. As the scientific community seeks alternatives to antibiotic treatment, periodontal researchers have found that photodynamic therapy (PDT) is advantageous to suppress anaerobic bacteria. Hence, PDT could be an alternative to conventional periodontal therapeutic methods. This review elucidates the evolution and use of photo dynamic therapy. The application of photosensitizing dyes and their excitation by visible light enables effective killing of periodontopathogens. Even though PDT is still in the experimental stages of development and testing, the method may be an adjunct to conventional antibacterial measures in periodontology. PDT application has an adjunctive benefit besides mechanical treatment at sites with difficult access. Necessity for flap operations may be reduced, patient comfort may increase and treatment time decrease. Clinical follow-up studies are needed to confirm the efficacy of the procedure.
Keywords: Flap surgery, microbial resistance, photodynamic therapy, photosensitizers, systemic antibiotics
|How to cite this article:|
Malik R, Manocha A, Suresh D K. Photodynamic therapy - A strategic review. Indian J Dent Res 2010;21:285-91
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. , The 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 becoming resistant particularly due to the frequent use of antibiotics. ,, As a result there is pronounced interest and keenness in the development of alternatives to antimicrobial therapies.
As the scientific community is seeking alternatives to antibiotic treatment, periodontal researchers found that photodynamic therapy (PDT) is advantageous for suppressing anaerobic bacteria that lead to periodontal diseases.  Michael P. Rethman the president of the American Academy of Periodontology in 2003 had said "Antibiotics may be used as an adjunctive therapy for periodontal diseases. Although the studies are still in their early phase, with the recent number of reports about bacterial strains becoming resistant to frequent doses of antibiotics, so there is a pronounced interest in the development of alternative antimicrobial concepts. PDT could be an alternative to conventional periodontal therapeutic methods".
This literature aims to discuss the PDT from a periodontal perspective.
| 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, greenhouse fertilization or household chemicals is blamed as contributing to resistance development. , In general, use of antibiotic drugs has advantages and disadvantages and this is also true with respect to resistance issues of periodontal bacteria. , Amoxicillin resistance was occasionally observed in periodontal reservoirs due to the production of β-lactamases. Preferably, this was detected in Prevotella sp. and Fusobacteria and not so in A. actinomycetemcomitans.  In various studies during the last 20 years, 0-2% of subgingival anaerobes were reported to be insensitive to metronidazole,  2-3% of bacteria were resistant to penicillin G and 0.5% to amoxicillin. , Methicillin-resistant strains of Staphylococcus aureus (MRSA) may develop cross resistance to triclosan, an antiseptic used in toothpaste and mouth rinses. 
Insufficient drug concentration within the sulcus fluid or biofilm may also be responsible for lacking efficacy. Occasionally this was observed with amoxicillin, roxithromycin, metronidazole, and doxycycline; alternatively the gyrase inhibitor moxifloxacin is recommended against A. actinomycetemcomitans.  Sulcus concentrations of antibiotic drugs may remain below the MIC of the target organisms. Systemic administration of drugs may cause adverse effects, mostly as gastrointestinal disturbances. Further unwanted side effects are: allergies caused by penicillins, uptake of tetracyclines into bones and teeth, arthropathies induced by quinolones, headache, dizziness, metallic taste or alcohol intolerance with metronidazole etc.
However, in future, difficulties with antibiotic therapy can emerge because of
- increased resistance to most antibiotics used in periodontics
- 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, also known as photo radiation therapy, phototherapy or photo chemotherapy earlier, was established as early as 1900 by Raab  who realized that the interaction between acridine (a dye) and visible light in the presence of oxygen killed paramecia. The PDT was introduced in the medical therapy in 1904, as the light induced inactivation of the cells, microorganisms or molecules.  The German physician Friedrich Meyer-Betz performed the pioneering study which was at first called photo radiation therapy (PRT) with porphyrins in 1913. He tested the effects of hematoporphyrin-PRT on his own skin. 
It was John Toth, as product manager for Cooper Medical Devices Corp/Cooper Lasersonics, who acknowledged the "photodynamic chemical effect" of the therapy with early clinical argon dye lasers and wrote the first "white paper" renaming the therapy as "Photodynamic Therapy" (PDT). This was done to support efforts in setting up 10 clinical sites in Japan where the term "radiation" had negative connotations. PDT received even greater interest because of Thomas Dougherty who helped in expanding clinical trials and forming the International Photodynamic Association, in 1986. PDT was first approved by the Food and Drug Administration in 1999 to treat pre-cancerous skin lesions of the face or scalp. PDT has extensively been used to treat cancers and certain other diseases. , PDT has emerged in recent years as a new non-invasive therapeutic modality for the treatment of various infections by bacteria, fungi, and viruses. 
| Principles Behind Photodynamic Therapy|| |
The knowledge of the preferred uptake and accumulation of some dyes (mostly porphyrins) into tumor tissues stimulated the introduction of PDT into clinical practice. 
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. ,
By irradiation with light in the visible range of the spectrum the dye (photosensitizer) is excited to its triplet state, the energy of which is transferred to molecular oxygen. The product formed is the highly reactive singlet oxygen capable of reacting with biological systems and destroying them. Only the first excited state with energy of 94 kJ/mol (22 kcal/mol) above the ground state is important, the second excited state does not react.
| Mechanism of Action|| |
Briefly, upon illumination, the photosensitizer is excited from the ground state to the triplet state. The longer life time of the triplet state enables the interaction of the excited photosensitizer with the surrounding molecules, and it is generally accepted that the generation of the cytotoxic species takes place during PDT while in this state only.  The cytotoxic product, usually 1 O 2 cannot migrate >0.02 mm after its formation, thus making it ideal for the local application of PDT without endangering distant molecules, cells, or organs. 
PDT involves two stages. In the first stage, a light-sensitive drug is applied. The second stage involves shining a light or laser directly on the area treated with the drug. When the light is combined with the drug, phototoxic reactions are induced which destroy bacterial cells.
Wilson  proved the effect of a cyanide photosensitizer on Gram-positive and Gram-negative species. On the other hand, Nitzan et al. and Bertolini et al. have reported a limited activity of porphyrin-containing photosensitizers toward Gram-negative bacteria. Meanwhile, attempts are being made to increase the permeability of the Gram-negative bacterial membrane to photosensitizers by using membrane active substances or by synthesizing special, positively charged photosensitizers that bind more easily to the bacterial membrane. 
| Photosensitizers|| |
More than 400 compounds are known with photosensitizing properties including dyes, drugs, cosmetics, chemicals and many natural substances.  Most of the sensitizers used for medical purposes belong to the following basic structures:
- Tricyclic dyes with different meso-atoms. Acridine orange, proflavine, riboflavin, methylene blue, fluorescein, eosine, erythrosin, rose bengal
- Tetrapyrroles. Porphyrins and derivatives, chlorophyll, phylloerythrin, phthalocyanines
- Furocoumarins. Psoralen and its methoxy-derivatives xanthotoxin, bergaptene
Porphyrins known for cancer PDT are also used to kill bacteria. 
The porphyrin derivative (HpD) is the first generation sensitizer followed by the second generation: sulphonated metallo-phthalocyanines, chlorine e6, and lysine-conjugated chlorine p6, and tetrahydroxy-phthalocyanine. The chlorine as well as the green pigment bonellin intensively absorb light at 650 nm.  Phthalocyanines absorb light in the long wave range of the visible spectrum, especially with silicon or aluminum as central atoms.  Encapsulated viruses may be a target of these compounds.  Bactericidal effects were reported on Streptococcus sanguinis ofilms and on MRSA. ,
Methylene blue (MB), toluidine blue (TB), and acridine orange are potent photosensitizers. Riboflavin (vitamin B2) is a potent photosensitizer absorbing at wavelength 450 nm. Degradation products formed upon illumination are lumichrome and lumiflavin, both with photosensitizing properties. Riboflavin was suggested for antibacterial and antiviral decontamination of blood conserves and plasma or cell concentrates. Activity and function of the blood conserves remain largely unaffected during this treatment. , Chlorophyll is a photosensitizer absorbing light maximally at 683 nm. Tetracyclines used as antibiotics in periodontal diseases are effective photosensitizers producing singlet oxygen. 
| Applications of PDT in Dentistry|| |
Non-surgical treatment of aggressive periodontitis
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 scaling and root planning (SRP) with hand instruments;  to compare the CAL at baseline and three months after treatment with an automated periodontal probe, concludes that PDT and SRP show 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 seconds), 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.
An adjunct in non surgical periodontal treatment
Twenty-four subjects with chronic periodontitis were randomly treated with scaling and root planning followed by a single episode of PDT (test) and scaling and root planing alone (control). Gingival recession, and clinical attachment level (CAL) were measured at baseline and three, six months after therapy and it was concluded that the additional application of a single episode of PDT to scaling and root planing failed to result in an additional improvement in terms of pocket depth reduction and CAL gain, but it resulted in a significantly higher reduction in bleeding scores compared to scaling and root planning alone.
When interpreting the clinical and microbiologic effect so obtained with PDT, the possible effects due to the application of the photosensitizer itself should be considered. The frequency of the PDT application is another possible explanation for the absence of clinical or microbiologic differences between the groups. The manufacturer suggests that PDT treatment should be performed repeatedly during the first weeks of healing to enhance the antimicrobial effect. However, in this study, a single episode of PDT was performed to avoid an additional confounding factor (i.e., frequency of applied treatment), which could influence the clinical outcome. Thus, with the help of further studies, conclusions can be drawn about the possible clinical benefit of PDT used in conjunction with non-surgical therapy and to what extent multiple applications of PDT might enhance the outcome of therapy. 
Destruction of periodontopathogenic bacteria
To evaluate a new approach to kill periodontopathogenic bacteria using PDT, it was concluded that PDT with chlorine e6 and BLC 1010 is advantageous for suppressing periodontopathogenic bacteria. 
Various studies have shown that Gram-positive bacteria are most susceptible to PDT. , Photo-killing of Gram-negative bacteria is also possible. However, experiments were published showing PDT resistant Gram-negative bacteria. This resistance can be overcome by cell wall modification or by the selection of appropriate sensitizing dyes. Special interest is concentrated on PDT effects in bacteria resistant to antimicrobial drugs. Reliable killing of strains important in hospital infections such as Pseudomonas aeruginosa MRSA has been attained by PDT. This also holds true for Gram-negative strains with antibiotic resistance. Cases of failing PDT, i.e., resistance to the light action, are mostly the consequence of poor cellular uptake of the sensitizer. Main efforts to introduce PDT into the periodontal arsenal came from Wilson. Experiments in rat have shown that lethal photosensitization of Porphyromonas gingivalis ossible in vivo and that this results in decreased bone loss. Thus, it was suggested that PDT may be useful as an alternative approach for the antimicrobial treatment of periodontitis.
| 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 control of 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 micro flora disturbance in other sites of the oral cavity. PDT is also beneficial during the maintenance of periodontal therapy because it may act on the biofilm and eliminate the need for the removal of additional root substance by mechanical retreatment. Thus, the patient may experience less dentinal hypersensitivity. This therapy also serves as an adjunct to mechanical therapy in sites with difficult access.
| Prerequisites and Further Demands and Scope for the Future|| |
Optimizing the efficacy
The improvement of phototherapeutic effects was enabled mostly by chemical derivatization of the dyes allowing better cellular uptake. This was shown by the introduction of side chains into the dye molecules with methylene blue  and porphyrins.  Improved dye uptake into Gram-negative bacteria is achieved by conjugation of chlorine dyes with polylysine. Cellular uptake in Gram-positive bacteria is even achieved with small molecules.  Specific targeting is also possible by coupling the dyes with antibodies specific for cell-wall constituents as reported for P. gingivalis or S. aureus; d-Amino levulinic acid (ALA) is a precursor of endogenous porphyrins circumventing the rate-limiting step in biosynthesis.  Therefore, administration of ALA increases the intracellular sensitizer concentration of bacteria possessing this metabolic pathway. There may be a selectivity obstacle as human cells are also able to synthesize porphyrins from ALA.  Dyes absorbing at long wavelengths (so-called infrared sensitizers) have the advantage that the absorbed light penetrates into deeper layers of tissue. Mostly they were synthesized from chlorine dyes and absorb above 700 nm.  Indocyanine green is a dye which is longer known. It generates singlet oxygen when irradiated at 805 nm. 
In ALA-PDT treatment of various forms of skin cancer it has been found that the methylated form of ALA (m-ALA) shows better results compared to ALA due to a more efficient transport through the stratum corneum of the skin. ,
In a study conducted by Ramsted et al. it was observed that elevating the skin temperature during ALA application could be a factor in improving ALA-based PDT. The amount of PDT-relevant porphyrins formed in P. acnes in vitro was increased by approx. 100% (ALA) and 33% (m-ALA), respectively, when the incubation temperature was raised from 37 to 42°C. Thus, it would be favorable to heat the skin (e.g. up to 42°C) during the topical ALA or ALA ester application.
It was also found that the initial cultivation temperature of the bacteria (25, 30 or 37°C) did not influence the amount of PDT-relevant porphyrins induced after incubation with ALA or m-ALA at incubation temperatures between 10 and 37°C. This is an advantage from a clinical point of view as it means that topical application of ALA or m-ALA will induce porphyrins independent of the skin temperature that the patient has had prior to the clinic visit.
| Plaque-Related Issues|| |
Bacteria growing in biofilms are less accessible to antibiotics due to the protection within the polymer plaque matrix as well as by the bacterial adhesion to teeth or epithelia.  Reported minimal inhibiting concentrations (MIC50) are not applicable to the situation within the plaque.  Thus, there is a type of apparent resistance or impaired drug availability which may be eliminated by PDT.  Uptake of photosensitizers into the plaque is impeded in the same way as that of antibiotics. Ultrasonic devices or photomechanical waves may improve the drug uptake and, as a consequence the efficacy.  With such measures, it was shown that methylene blue penetrates deeper into the plaque and the killing rate of A. viscosus is considerably increased. Photodynamic treatment also influences the structure of the biofilm with thinning of the layer and loss of biomass.
| Irradiation|| |
Determinants of the phototherapeutic efficacy are a high absorption coefficient of the dye, the concentration at the target and the energy flow from the incident light. Today, diode lasers are cheap and powered by normal main voltage. With Light Emitting Diodes (LED) it is possible to vary spectrum, irradiance and the ratio of visible to infrared radiation. Further advantages of the LED technology include-longer irradiation time as well as cheaper and easier operation than with lasers.  Patents are pending for different devices designated to irradiate the gingiva.
| Adverse Effects|| |
Photodynamic action has the potential of phototoxic or photo allergic 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. , It usually occurs in the early part of light exposure, peaking within minutes, then leveling out during the remainder of exposure, and probably reflects nerve stimulation and ⁄ or tissue damage by reactive oxygen species.
A clinically obvious scar is rarely observed. The histological evidence of scarring is evident.  Hyper pigmentation or hypo pigmentation can occasionally be seen in treated areas and usually resolves within six months. Permanent hair loss has been observed following ALA-PDT.
| Carcinogenicity|| |
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.  ALA-PDT has a low frequency of severe adverse effects, achieves a good cosmetic outcome, and has a low risk of carcinogenicity.
| Summary|| |
While many articles on PDT begin by stating that PDT is new or experimental treatment for cancer and many other diseases, the fact is that it has rapidly matured over the past 15 years both in clinical application and basic mechanistic understanding to the point where PDT can be considered acceptable standard treatment for several conditions and has been approved for use by the U.S Food and Drug administration (FDA) and numerous other health agencies throughout the world. These conditions include various cancers (for example, esophageal and lung cancers) as well as various non-cancerous ones such as age related macular degeneration (AMD) and actinic keratosis. 
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 as compared to the classical methods or only efficacy in therapy - resistant cases. Established methods of mechanical scaling and root planing 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; 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 procedure (although very less). On the other hand, unequivocal evidence is present which shows 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.
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Department of Periodontics and Oral Implantology, M.M. College of Dental Sciences and Research, M.M. University, Mullana, Ambala, Haryana - 133 203
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