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ISSN : 1225-1577(Print)
ISSN : 2384-0900(Online)
The Korean Journal of Oral and Maxillofacial Pathology Vol.44 No.3 pp.59-75
DOI : https://doi.org/10.17779/KAOMP.2020.44.3.001

Literature Review: Photodynamic Therapy in Oral Diseases

Yuzhu He1), Ok-su Kim2), Ok-joon Kim1)*
1)Department of Oral Pathology, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea
2)Department of Periodontology, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea
#

The authors contributed equally to this work.


*Correspondence: Ok Joon Kim, Department of Oral Pathology, School of Dentistry, Chonnam National University, Buk-Gu, Gwangju, 61186, Korea Tel: +82-62-530-4832, Fax: +82-62-530-4839 E-mail: js3894@jnu.ac.kr
May 18, 2020 May 29, 2020 June 5, 2020

Abstract


Photodynamic therapy (PDT) has been widely used in clinical fields and done by three components: photosensitizers (PSs), light and oxygen. Under the action of PS as an energy transforming media, the light energy is converted to chemical energy to make effects on target. In the process of PDT, its effect is determined a lot by the parameter of light and the characteristics of PSs. With the development of light source and photosensitizer, the application of PDT has been investigated in oral diseases. This review mainly focused on the effect of PDT on non-tumor diseases of oral cavity, including endodontic, periodontal and mucosal problem. Compared with the normal therapy, the combination therapy with PDT could obtain better efficacy. It was suggested that PDT showed great advantages as an adjuvant therapy in the above oral diseases. Through a further improvement, PDT is expected to play an increasingly important role on the oral disease treatment in the future.


Photodynamic therapy , Oral disease , Photosensitizer

구강질환의 광역학 치료에 대한 문헌고찰

허 옥주1), 김 옥수2), 김 옥준1)*
1)전남대학교 치의학대학원 구강병리학교실
2)전남대학교 치의학대학원 치주학교실

초록

    National Research Foundation of Korea
    2019R1F1A1059492

    Ⅰ. What is Photodynamic Therapy ?

    1. The development of photodynamic therapy

    Photodynamic therapy (PDT) includes at least following three sections: a photosensitizer (PSs), light and oxygen1). The concept of PDT should be dated back to over 100 years ago. Oscar Raab reported that apoptosis in some microorganism was induced by certain dyes under light irradiation with the interaction of light and chemicals2). PDT was carried out in skin cancer patient using eosin and white light for the first time by Appaeiner and H. Jesionek in 19043). Since 1960, porphyrin derivatives as photosensitizer were used in PDT. The modern stage of PDT was begun with hematoporphyrin derivative (HPD) emitting fluorescence in neoplasm during the surgery by Lipson and Schwartz4,5). Since then PDT has emerged as an established alternative for several medical indications6). Up to now, PDT was applied in various clinical fields, such as bacterial infection7), neoplasm8,9), dermatological diseases10), other non-oncologic diseases11) or used as an adjuvant therapy12). The photodynamic therapy used in anti- bacterial fields is also named as photodynamic antibacterial therapy (PDAT)13).

    It is worth mentioned that PDT should be distinguished from photodynamic diagnosis (PDD). PDD usually is used to locate the distribution of tumor and confirm the intensity of PSs in tumor through the fluorescence of photosensitizer under certain light before PDT. Although the PDD is belonged to a part of PDT process, the used wavelength of light in PDD and PDT are different14). The PSs in PDD just emit fluorescence, not induce oxidative stress, so it will not destroy the tissue15). And ‘Photodynamic therapy’ means a photochemical reactions which should be distinguished from ‘photodynamic action’ which just means a photosensitized reaction in biology.

    2. The history of light therapy

    Before PDT, light has been used to treat diseases for over thousands of years. Date back to 3500 years ago, the ancient time, sunlight was used to treat vitiligo by Eyptians16). The light treatment is also called phototherapy. Smallpox was successfully treated by Niels Finsen with red light in 189317). And in 1896, he reported his research of light treatment on the lupus vulgaris patient which drove him to award the Nobel Prize in medicine in 190318). Nowadays, light therapy has been used in various conditions, unconjugated hyperbilirubinaemia in neonates, psoriasis, alopecia areata, childhood dermatoses, ophthalmologic disorders, vililigo and etc.19). There are also reports about phototherapy on dental problem. In the research of Lui20), periodontitis was much reduced by scaling and root planning with diode laser 940 nm (SRP-PDT) than SRP. And the value of gingival crevicular fluid (GCF) and bleeding on probing (BOP) was also obviously reduced in short term. Similarly, the 24 periodontitis patients (smoking and non- smoking) were treated with twice SRP or SRP-PDT (diode laser 808 nm) by Aykol21). The combined therapy of SRP with PDT performed better than only SRP therapy for both smokers and nonsmokers periodontitis patients. However, compared to light therapy, the combined action of light with photosensitizer in PDT was more effective.

    The major light sources of PDT include light emitting diodes (LEDs), lasers and lamps. The first man-made light sources used for PDT studies were lamps with the wavelength of 300 to 1,200 nm that is are more suitable for superficial tumors, skin or oral cavity 22). Laser with output wavelengths from 415 to 690 nm are widely used for superficial and interstitial PDT23). Light with any visible wavelength can be emitted by LEDs with a wider spectral width compared with diode lasers what lead to a lower absorption efficiency by the photosensitizer. Therefore, it would be beneficial to use LED for superficial tumors in clinical PDT. The wavelength range between 600 to 800 nm was called “therapeutic window” because the energy in this range was high enough to activate photo- sensitizer and low enough to penetrate into tissue24). Light source selection is dependent on the target location, the photo- sensitizer, and the dose to be delivered.

    3. The classification of Photosensitizer

    The functional difference of PDT mainly depends on the properties of photosensitizer. A photosensitizer is an agent that produces a chemical developing to another molecule in a photochemical process. Photosensitizing drugs have been known and applied in medicine before about 1900. The application of PDT was limited by the development of photosensitizers which react to special wavelength light. Through decades of development, a variety of photosensitizers have been officially recognized and used clinically in the field of anticancer, such as Lutrin®, Lutex®, Foscan®, Hexvix®, Metvix®, Levulan®, NPe6, Tookad® and etc.25). According to their structure and origin, photosensitizers were classified into synthetic dyes, tetra-pyrrole structures, natural PSs and nano-structures [13]. Some researchers classified them into porphyrin-based photosensitizer, chlor ophyll-based photosensitizer and dye [11]. Based on the application areas, photosensitizers were divided into research application and clinical application [15]. In some reviews, the photosensitizers were also introduced through the application mode, such as non-self-quenching PSs, conjugated polymer–based PSs, nano-PSs26). Each photo- sensitizer reacts to a certain wavelength light, and different wavelength would act the different function of photosensitizer. For example, the excitation wavelength of porphyrin for S. aureus is about 446 nm27); the excitation wavelength of hypericin for S. aureus is 593 nm28); and the excitation wavelength of chlorine for anti-S. aureus is 660 nm29), for anti-E.coli is 532 nm30). In this study, some common photosensitizers are listed in the following table:

    4. The mechanism of PDT

    PS is a media of energy transforming, which converts light energy to chemical energy during photodynamic therapy. Under irradiation with a certain wavelength, the PS is promoted from the ground state to an excited state. After PSs were activated light, there are two photodynamic processes; type Ⅰ and II related electron transfer (Fig. 1).

    In the type Ⅰ process, activated PSs by light interact with oxygen in molecular level leading to the production of reactive oxygen species (ROS), such as -O2, -OH and H2O2. It has been proven that amino acids are predisposed to oxidative destruction which would lead to modifications of DNA, RNA, lipids, and proteins. These modifications produce aggregates accumulating in the cell finally disrupting its functions [26]. In the type Ⅱ process, PSs produce singlet oxygen that interact with various molecules in the cells to generate oxidized products. It is noticed that oxidation product would break DNA via reacting with nucleobases, especially with guanine. Another target of singlet oxygen is cell membrane leading to the leakage of metabolites. Moreover, membrane disruption also causes problems in ATP formation7).

    Ⅱ. PDT in Dentistry

    1. PDT in endodontic infection

    The dental caries are caused by the acidogenic plaque containing high levels of Streptococci, Lactobacillus and Actinomyces groups31). The low PH induced by these bacterial plaques would cause demineralization and decomposition of the tooth. When the progressive destruction of the tooth propagates to the pulp, it would cause the endodontic infection. The main goal of endodontic treatment is to clear microbial infection. At present, to clear the microbial pulp in root canal, a combination of mechanical instrumentation and chemical irrigation is widely used in clinic 32). However, this therapy cannot remove bacteria completely from root canals. The cultivable bacteria has been found in 40 to 60 % of instrumented canals with NaOCl irrigation 33). As the complexities of the canal system, like isthmi, lateral canals, fins, ramifications and anatomical structures, bacteria were also found in these inaccessible space with mechanical instrumentation34). To achieve efficient intracanal disinfection, PDT as a kind of adjunctive strategies was proposed35). The application of PDT in endodontic infection was focus on its property on anti-bacteria. Enterococcus feacalis, Pseudomonas, Staphylococci and Streptococci were thought to be related to the failed treatment36). So these kinds of bacteria were generally used as evaluating indicator of treatment. In the study of Araujo37), the multi-species biofilm of S. mutans and L. acidophilus was treated with curcumin under the LED irradiation (5.7 J/cm2). The results suggested to be potential of curcumin as a photosensitizer on antibacterial under the action of light37). Schneider38) used phenotiazinium chloride as a photosensitizer combined with a laser light (660 nm, 100 mW) on S. mutans biofilm. The decrease of PS treated bacteria was only caused by exposing to the laser which indicated the role of irradiation in PDT38). Bulit showed the inhibition of curcumin, eosin Y and/or rose Bengal on E. faecalis biofilm irradiated with blue light39). Methylene blue as photosensitizer was used to against P. aeruginosa and E. faecalis under the low level laser (660 nm, 9 J) by Oliveira in 2014 [40]. The sterilizing rate was 72.41 % and 96.44 % for P. aeruginosa and E. faecalis respectively 40). Furthermore, the case report by Oliveira was related to the right mandibular canine in 201841). He gave an aqueous solution of 0.01 % methylene blue in surgical cavity which continued to be irradiated with a diode laser for three minutes (660 nm, 100 mW)41). Similarly, 25 mg/ml methylene blue was also used as a PS on reducing the percentage of E. faecalis by Bumb42). The 96.7 % reduction PDT group (910 nm, 1 W) suggested its potential on the treatment of endodontics. Toluidine blue was also used as a PS on the dose of 13-15 mg/ml by Tennert and PDT treatment (635 nm, 100mW) showed a significant reduction of E. faecalis in root canals36). In the study of Xhevdet, the result of 2.5 % NaOCl for 5 min was similar to irradication with 10 mg/ml chloride as a PS for 5 min which suggested that the efficiency of longer irradiation was higher than short irradiation43). According to the study of Yildirim, however, PDT therapy was compared to 5% NaOCl and the treatment of PDT showed no significant benefit to NaOCl [44]. And PDT (660 nm, 100mW) with 0.1 mg/ml toluidine blue indicated insignificant differences with H2O2 and other chemical substances45). Methylene blue and 665 nm light were used to increase the effectiveness of conventional chemomechanical preparation in the failed endodontically treated apical periodontitis34). Different doses (50, 100, 150, and 300 μM) of methylene blue were tested by Aguinaldo and Micheal using a 660 nm diode laser. According to their study, 50 μM methylene blue was combined with pre-treatment for 1 min with H2O2 and achieved a better reduction of E. faecalis than only PDT46). In the study of Vaziri, 100 % reduction of bacteria was observed with the combination of PDT (625 nm, 200 mW, 15 μg/ml toluidine blue) and 2.5 % NaOCl47). On the basis of the above evidence, PDT showed great potential on endodontic treatment and retreatment.

    Generally speaking, the most common and effective PS in endodontic therapy was methylene blue, and toluidine blue was the second. In the present studies, the PDT had been used in endodontic therapy in clinic, but most of them were performed in vitro with bacterial biofilm models. According to the results of these studies, the efficiency of PDT was decided by the property of PS and the parameter of light. Some results suggested that PDT could be used as a single therapy of endodontic treatment. However, it would be better that the combination of PDT and other chemical substance, like H2O2 and NaClO. Conversely, there were also some study indicated the PDT therapy could not contribute to the treatment of endodontitis. In summary, the PDT therapy could be a good probable choice for the endodontic treatment, but it was not a completely effective therapy.

    2. PDT in periodontal infection

    1) Periodontitis

    Periodontitis is an inflammatory disease caused by complex microorganisms, such as F. nucleatum, P. gingivalis and Aggregatibacter actinomycetemcomitans and etc.48,49). The conventional treatments for periodontitis is non-surgical antibacterial treatment, like Minocycline Hydrochloride Ointment, Amoxicillin trihydrate, 0.05 % Sepidinolamine gargle, Iodine Glycerol and so on. Patients with periodontal disease should be treated with compeletly periodontal scaling and root planning (SRP) before drug administration50). However, the long term use of antibiotics in the process of managing periodontal disease would result in antibiotics resistance. As the shortage in conventional treatment for periodontal infection, PDT was mentioned as an adjunctive therapy to achieve better effect51). Some people also used PSs to enhance the effect of PDT. In the study of Voos, safranine O was used as a PS to against F. nucleatum, P. gingivalis and Aggregatibacter actinomycetemcomitans in a biofilm model. The results suggested that oral pathogens in planktonic suspension was significantly decreased by PDT with safranin O compared to 0.2 % CHX52). Tuluidine blue O with 650 nm LED irradiation were used to remove F. nucleatum and P. gingivalis by Danbi Park to investigate the effect of PDT in periodontitis. The conclusion was confirmed that TBO-mediated PDT using LED irradiation has potential as a safe adjunctive procedure for periodontitis53). There were also reports about PDT used in aggressive periodontitis with Methylene blue, toluidine blue or phenothiazinium chloride as PSs and diode lasers at wavelengths ranging from 660 to 690 nm as a light source54,55). Ayaka used protoporphyrin IX (PpIX) and a blue light irradiation on P. gingivalis to detect the effect of PDT on periodontal diseases and multiple drug resistant bacteria treatment56). PDT with methylene blue and a diode laser was used in residual periodontal pockets as an adjunct treatment after ultrasonic debridement. The research suggested that PDT destruction on the biofilm avoid the hard tissue being damaged by repeated mechanical instrumentation57). According to the above researches, PDT has not been used as the main therapy for the periodontitis, but as an adjunct. And it may give a lot benefit.

    2) Orthodontic related diseases

    The occlusal disharmony in orthodontic patient is liable to cause periodontal diseases and these conditions may worsen the use of fixed corrective orthodontic appliances58). The existence of orthodontic brackets increases the difficulty of biofilm accumulation and oral hygiene cleaning, inducing periodontal health problem59). Usually orthodontic patients show different stages of gingivitis during treatment. As a function of PDT on inhibiting normal periodontitis, there was hypothesis that PDAT could contribute to the microbial management in orthodontic patients. Soares used photosensitizer solution (MB+TB) under a red light (640 nm) on the biofilm around the brackets right mandibular anterior teeth in orthodontic patient. As a result, they found that PDAT was able to significantly reduce the number of colony- forming units (CFU) in orthodontic patients58). Panho´ ca irradiated the retentive area around orthodontic appliances under blue light (450±10 nm) with/without curcumin solution in 24 orthodontic patients. According to the CFU of non-stimulated saliva, they suggested that the PDAT could be used as an adjutant and a convenient agent to promote the oral decontamination in clinical practice60). Rosa Abellan used 0.005 % (w/v) methylene blue as photosensitizer in oral for 3 minutes operating at a wavelength of 670 nm61). PDT could therefore be consolidated as a new safe therapeutic alternative for supportive periodontal maintenance routines in patients treated with orthodontic fixed appliances 61). Clara Gómez used PDT in periodontal pocket of 20 patients under orthodontic treatment with methylene blue photoactivated by 670 nm light for no longer than 60s per tooth. They found that PDT improved in clinical outcomes and microbiological counts during the orthodontic treatment in adolescents with fixed devices62).

    In fact, orthodontic-related oral disease is a special case of periodontal diseases. Therefore, the essence of PDT for (orthodontic related) periodontitis is a kind of antibacterial treatment. Although the bacteria could be inhibited by PDT, the PDT cannot replace the traditional therapy. It would be reasonable to treat periodontitis with a combined therapy, in which PDT was used as an adjuvant therapy.

    3. PDT in oral mucosal diseases

    1) Oral Candidiasis

    Candida albicans (C. albicans) which is thought to be related to oral precancerous lesions causes opportunistic fungal infections63). If the patients get a suppressed immune system, this C. albicans comprised microorganism would penetrate into the underlying tissues or blood vessels causing life-threatening systemic infections64). The resistance in C. albicans would be developed by a widespread use of topical and systemic antifungal agents as conventional treatment for oral candidiasis65). It is necessary to develop alternative therapies for the treatment of oral candidiasis. A promising modality is PDT, which has been demonstrated against oral species but not promote damage to host cells and tissues66).

    Giuseppe isolated a strain of C. albicans from plaques on the oral mucus membrane of an infected patient and treated with 5 % 5-aminolevulinic acid (5-ALA) under a wavelength of 630 nm light. It was come to conclusion that 5 % 5-ALATPt was effective in inhibiting the growth of C. albicans, in vitro, on both biofilm and inoculum67). Ewerton used PDT on tongue candidiasis of murine model with hematoporphyrin derivative with red light (630 nm). The results of this study demonstrated that PDT promoted significant reduction in the viability of C. albicans biofilm without harming the tongue tissue68). Franak compared the effect of photodynamic therapy with curcumin and methylene blue on colonies of C. albicans under the light of 460 and 660 nm wavelengths. And he showed that a 460 nm / 25 mW laser irradiated for 30s in combination with curcumin had the maximum antifungal efficiency against C. albicans69).

    2) Oral mucositis

    Defined as an inflammatory, painful and debilitating condition, oral mucositis (OM) affects the oral tissues of patients undergoing peri-implant, chemotherapy, enture restoration and so on70). It may make them difficult to eat, swallow, speak and perform oral hygiene, in addition to serving as the port of entry for mycoplasma, virus or bacteria71). Up to now, there has been no consensus about the level of evidence presented by these studies, or any agreement about the best therapeutic option. Among the possible interventions suggested are the use of oral care protocols; mouth washes72); morphine73); glutamin74); photobiomodulation75) and the use of keratinocyte growth factors76). As mucositis lesions are frequently associated with infections, it is necessary to disinfect the area to achieve adequate healing. PDT is believed to be a safe, cast benefit, non- invasive and painless treatment for OM with antimicrobial activities77), which can eliminate infections with adverse interaction with tissue repair. Silva treated oral mucositis of patients submitted to chemotherapy with 0.01 % methylene Blue and red laser (660 nm with 3 J per point). PDT could be used for treatment of oral mucositis in children/young patients which achieved satisfactory results in reducing pain associated with the lesion 71). Meanwhile, Lavaee used 0.05 mg/ml methylene blue and a 660 nm diode laser (19.23 J/cm2) on chemotherapy patients. The results suggested that PDT could improve the oral mucositis induced by chemotherapy78).

    3) Other mucosal disease

    Oral leukoplakia (OL) is a pre-malignant lesion which is the most frequent precancerous disorder of the oral mucosa [79]. Several local treatments have been used, such as conventional surgery, retinoids and steroids, cryotherapy, and laser therapy, but none of these performed perfectly80). Topical application of 5 % 5-ALA-mediated PDT with a laser at a wavelength of 630 nm caused an immediate deleterious effect on the vascular network, to avoid OL resistance and recurrence after treatment. 5-ALA-mediated PDT was applied on the OL of ventral and dorsal tongue mucosa with a laser at a wavelength of 630 nm by Flávia81). Aleksandra compared cryotherapy and photodynamic therapy (ALA, 630 to 635 nm) in treatment of oral leukoplakia. PDT group obtained 72.9 % complete response and 27.1 % recurrences observed; meanwhile, cryotherapy group obtained 89.2 % complete response and 24.3 % recurrence was observed. The advantages of PDT are connected with minimally invasive and localized character of the treatment and without damage of collagenous tissue structures. It is more convenient for patients, less painful, and more esthetic82). Maloth treated 13 patients (24 OL lesions) with topical 5-ALA and LED irradiation. 16.6 % of cases showed complete response, 66.6 % partial response, 16.6 % no response of the lesions to the treatment83).

    Oral Lichen planus (OLP) as a chronic immune-mediated disorder, is estimated to impact 0.5 to 2 % of the population. Topical corticosteroids dominate treatment for symptomatic OLP always brings some negative effects, like candidiasis, dysgeusia, nausea, dry mouth, swollen lips or sore throat. Meanwhile, the other therapies, such as surgery, cryotherapy and laser treatment are limited by the extent of lesions. A notable current method of OLP treatment is PDT and its major advantages are insignificant invasiveness and minor side effects84). Sana Mirza made PDT perform on OLP of the tongue or buccal mucosa with topical application of 1 mg/ml toluidine blue and treated by laser irradiation (630nm) for 10 min. PDT was proven effective in the treatment of erosive- atrophic forms of OLP in 45 adult patients 85). Maloth treated 8 patients (20 OLP lesions) with topical 5-ALA and LED irradiation. 80 % and 20 % of the lesions showed partial and no response respectively83). Magdalena used 5-ALA and a high-power LED emitting light at 630 nm in treatment of reticular oral lichen planus in 50 patients with 124 OLP lesions. The results proved that PDT was effective and as such it can be used as an optional treatment for symptomatic OLP86). Sigrid treated OLP with PDT using topical methyl 5-aminolevulinate (MAL) induced photoactive porphyrins (PpIX) and red light in the region 600 to 660 nm. The results suggested that OLP treated with MAL-PDT showed lasting improvement after a single treatment87).

    Oral verrucous hyperplasia (OVH) as a pre-malignant lesion has the risk to transform into a verrucous carcinoma or a squamous cell carcinoma. Traditional treatment for OVH is total surgical excision that always leads to scar formation. Yu successfully treated OVH lesions using photodynamic therapy with a topical 5-aminolevulinic acid (topical ALA-PDT) protocol under a 635 nm light-emitting diode light [88]. The PDT treatment efficiency for OVH was influenced by the outer appearance, surface keratin thickness, size, color and epithelial dysplasia of the lesion [88]. Chen treated eight OVH lesions with topical ALA-PDT once a week. The results showed that OVH lesions can be achieved by less than six treatments89).

    PDT is a therapeutic modality for oral microbial infections, oral candidiasis and infection-induced OM. Clinical and laboratory studies show that PDT can effectively treat infection on oral mucosa. PDT is not harmful for the surrounding healthy tissue because the photosensitizer accumulates in cancerous and inflammatory cells selectively. On the other hand, PDT is also beneficial to other mucosal problem, like OL, OLP and OVH. All of studies were on clinical patients, so the mechanism was not very clear. But there was reported suggested that 5-ALA-mediated PDT could increase vessel permeability and reduce vessel density, which contributed to avoid resistance and recurrence after treatment. The intracellular cytotoxic ROS produced by PDT would result in oxidative damage to pre-malignant and malignant cells90). 5-ALA is a second generation photosensitizer approved by FDA83). As shown above, the most widely used photosensitizer in the clinical treatment of oral diseases is ALA. As a non-surgical treatment, PDT seems to be a useful therapeutic strategy in the management of oral mucosal diseases.

    Ⅲ. The Conclusion and Future

    1. The challenge

    Although PDT has been investigated for over one hundred years and used as an anticancer treatment and adjuvant therapy for various diseases in clinic as well, there are also a lot of problem left. The applicability of PDT is limited by the light penetration in tissue. In addition to the parameters of the light source, the properties of the photosensitizer will also impact the effect of PDT. Most of the current PSs usually showed low water solubility or hard to disperse in water, both of which reduce the utilization of photosensitizers91). Furthermore, the selectivity of PSs is unsatisfactory that lead to the overtreatment risks on normal tissue92). Another reason of overtreatment was due to the uncontrolled damage induced by ROS during PDT. In summary, how to overcome the short penetration depth of light, choose correct photosensitizer and accurately control target cell damage will be the key point in the future of PDT application.

    2. The future

    Based on the current situation and limitation of three components (light, photosensitizer and oxygen reaction), there are some expectation for PDT.

    1) Light source: Cheaper, Smaller and Stronger

    The man-made light source used for PDT studies has gone through three stages: lamps, lasers, laser diode and LEDs. But they can’t replace each other completely due to their advantages and disadvantages in economic price, output power, light devices in size, light wavelength and etc. According to the action mode of light source, the PDT light delivery can be divided into: non-contact, contact and interstitial 23). Limited by the thickness of the tissue that can be penetrated by the light source, the anti-bacterial and anti- cancer effects of PDT were mostly used on superficial tissue, like skin or oral cavity. Some detection on X-ray irradiation, near-infrared light and self-luminescent particles/agents are investigated for the application of PDT on deep-seated targets93). Future light sources should become smaller, cheaper and more efficient94), especially in root canals and periodontal pocket. High output power is not the final aim, the light source should incorporate the private condition of each patient and the mechanism of photosensitizer.

    2) Photosensitizer: Multifunction, Higher selectivity and Application of nanoparticles

    In addition to light source, the development of photosensitizers and photosensitizer delivery systems could enhance the function of PDT. A good photosensitizer always includes following characteristics: easily to get and low cost; good hydrophilic; excellent photo stability; oxygen reaction under irradiation; easy delivery; without cytotoxicity; high selectively into microorganism and (pre-) malignant cells26). In recent decades, the development of nanotechnology made a great influence on PDT95). Nanoparticle-based photosensitizers were more satisfactory than normal ones, through embedded or bound with nanoparticles to avoid hydrophobic nature of some PS, following to improve the delivery in tissue. And the distribution of nanoparticle-based photosensitizers showed locally accumulation in target part, compared to free PSs96). For the process of treatment, the photosensitizer should keep at the affected areas for at least several hours and then quickly be metabolized, thus minimizing the negative effects of PDT97). Under irradiation of certain light, the PSs were activated to form oxidant stress in cells, which finally achieve the purpose of treatment.

    3) Oxygen reaction: Real-time oxygen monitoring and controlling

    Although the application is limited by the characteristics of light and photosensitizers, the therapeutic efficiency of PDT is determined by the level of oxygen produced by the reaction of light and photosensitizers. Thus, the real-time oxygen monitoring and controlling is necessary. The future clinical protocols for PDT will include real-time oxygen monitoring to prevent hypoxia and to take advantage of the predictive value of PDT-induced changes in blood flow and hemoglobin oxygen saturation98). In the future, we should confirm a series of PDT protocols for common photosensitizers through monitoring and controlling the produce of oxygen in vivo and in vitro researches, on the basis of the treatment results.

    3. Conclusion

    Although the application of PDT has shown advantages in oral disease, most are used as adjuvant therapy. PDT still needs to be further improved, and most applications are still in the exploration stage. We believe that PDT will be used more commonly in clinic with the development of new PSs and optical technologies and it would achieve more social and economic values in the future.

    ACKNOWLEDGEMENT

    This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT) (No. 2019R1F1A1059492)

    Figure

    KAOMP-44-3-59_F1.gif

    The mechanism of action of PDT in cells. The light-activated photosensitizers produce free radicals and singlet oxygen via electron and energy transfer.

    Table

    Commonly used photosensitizers

    The application of PDT in endodontic

    The application of PDT in periodontitis

    The application of PDT in mucosal diseases

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