Development of photodynamic therapy in treating oral diseases
Introduction Millions of individuals worldwide are affected by oral disorders, including gingivitis, caries, endodontic-periodontal diseases, and oral cancer, negatively impacting life quality and placing a massive financial burden on society. Besides affecting daily activities, poor oral health greatly increases several systemic disease risks, including diabetes and cardiovascular disease; therefore, developing more effective therapies to preserve oral and overall health is crucial. Pathogenic cells, including bacteria, fungal, viral and cancer cells, are the leading causes of oral disorders. Accordingly, oral therapies aim to eliminate these cells instantly. For example, treatments for microbial infectious diseases rely primarily on antibiotic therapy. However, antimicrobial agents abuse has increased the concerns about bacterial drug resistance. Although surgery is the most frequent treatment for resectable tumors, incomplete or ineffective resection of lesions could result in local recurrence and a poor prognosis ( ). Radiotherapy and chemotherapy can potentially result in serious systemic adverse effects and permanent damage to normal tissue due to toxicity ( ). Photodynamic therapy (PDT) is a non-invasive and secure therapeutic alternative for treating cancer and many other non-oncological diseases. Oscar Raab, who discovered that paramecia cultured with fluorescent dyes was killed upon exposure to light, first proposed the PDT idea in 1898 ( ). The PDT has demonstrated beneficial application in various medical specialties, including dermatology, cancer, gynecology, and urology ( , ). Using PDT in dentistry for conditions including oral cancer, potentially malignant disorders, periodontitis, dental caries, peri-implant disorders, and bacterial and fungal infections during root canal therapy is expanding rapidly ( , ). The PDT offers better patient compliance than conventional surgery or drug therapy since it is non-invasive, safe, practical, and drug-resistant. Furthermore, PDT might be easily controlled by changing the parameters as needed to provide an accurate and personalized treatment. This review seeks to present a comprehensive overview of the applications of photodynamic therapy in the treatment of various oral diseases, including oral cancer, potentially malignant disorders, periodontitis, dental caries, peri-implant diseases, endodontic infections, and oral fungal infections ( ). 

Basic principles of photodynamic therapy 2.1 Mechanism of photodynamic therapy PDT mechanism consists of three crucial elements: photosensitizer (PS), specified wavelength light source, and oxygen dissolved in the cells ( ), which exclusively generates the desired outcomes through mutual interactions within pathological tissues. shows that the photodynamic reaction has two basic mechanisms, wholly dependent on oxygen molecules inside cells. Upon exposure to light, the photosensitizer transitions from a singlet basic energy level (S 0 ) to an excited singlet state (S 1 ). The excited singlet state could then transition to a triplet state (T 1 ) or revert to the ground state with fluorescence emission. Reactive oxygen species (ROS) are created when the PS in the triplet state directly interacts with nearby biomolecules through hydrogen or electron transfer (Type I reaction); when this occurs, molecular oxygen is converted by the PS to highly reactive singlet oxygen ( 1 O 2 ) (Type II reaction) ( ). Free radicals, including superoxide, hydroxyl, and lipid-derived radicals, are released due to type I reaction and attack cellular targets, resulting in direct cellular damage ( ). Singlet excited-state oxygen is released in a type II reaction, which oxidizes lipids, proteins, and nucleic acids to cause cytotoxicity ( ). Unsaturated lipids, comprising most cell and nuclear membranes, could react with the singlet oxygen. Consequently, these reaction byproducts may impede cell growth, trigger apoptosis in oral carcinoma cells, and significantly harm microorganisms. 2.2 Photosensitizers PS development has progressed in recent decades of PDT research; a desirable PS should possess numerous important characteristics, including nontoxicity to surrounding tissues, hydrophilicity, high affinity and selectivity to target cells or microbes, and high quantum yield of photodynamic reaction (PDR). The first-generation typical photosensitizers, the hematoporphyrin derivative (HpD), and photofrin could be absorbed into the body for a long time but penetrate only into the tissue to a limited depth (<0.5 cm) ( ). Porfifimer sodium, marketed under photofrin, was authorized for treating Barrett's esophagus in 2003 and early-stage lung cancer in 1998. The absorbance spectrum, tissue selectivity, and ROS production efficiency of the second-generation PSs have been enhanced. A naturally occurring pro-photosensitizer and a precursor to hemoglobin manufacture is 5-aminolaevulinic acid (ALA). A surplus of ALA leads tumor cells to absorb ALA rapidly but slowly degrade protoporphyrin IX (PpIX), causing PpIX photosensitizer to accumulate. Numerous second-generation photosensitizers are available, including phthalocyanines, verteporfin (VP), meta-tetrahydroxyphenylchlorin (m-THPC), and palladium bacteriopheophorbide. A light bleaching capability, antibody conjugates, or a protein/receptor system were added to photosensitizers in the third generation, improving the ability of a photosensitizer to target tumor tissues more effectively. The antibody affinity for tumor cells increases when conjugates to photosensitizers, decreasing healthy cell location. Furtherer more, toluidine blue (TB), methylene blue (MB), and erythrosine have been widely used for antimicrobial photodynamic therapy ( , ). Besides photosensitizers, certain inorganic salts (such as potassium iodide and potassium bromide) the inhibition or deterioration of target cells and effectively inhibited or eradicated bacterial and fungal biofilms ( – ). The selection of an appropriate photosensitizer for PDT is a crucial decision influenced by several factors, including the specific type of oral disease being addressed (whether antitumor or antimicrobial), the chemical properties of the photosensitizer, its capacity to generate reactive oxygen species, as well as its toxicity, selectivity, and availability. In addition to these intrinsic properties, the formulation and delivery method of the photosensitizer can significantly impact its therapeutic performance. Utilizing a molecular carrier, including a liposome nano species, is an alternative strategy. To maintain a high concentration in the targeted tissues, these modified photosensitizers with poor solubility in aqueous solutions are prevented from being delivered into the bloodstream. 2.3 Light source Lamps, light-emitting diodes (LEDs), and lasers are the main light sources in PDT that are chosen based on the target tissue location, photosensitizer type, and administration dose. Lasers produce a coherent, focused, monochromatic light intensity, widely used to perform superficial and interstitial PDT; its limited clinical applicability is the monochromatic nature and high cost. The LED is becoming increasingly popular for PDT as a viable alternative to lasers because of their low cost, easy manipulation, and access to tissue surfaces. The LED semiconductor device uses electron-hole recombination to produce light: large beam divergence and wide spectral breadth enable LEDs to excite numerous PSs in their emission spectrum simultaneously. Lamps were the first artificial light sources utilized in PDT studies ( ). Theoretically, lamps could couple to light guides to concentrate the light on particular therapy lesions; however, the coupling losses are substantial. Consequently, lamps are better suited to treating superficial malignancies such as skin or oral cavities. Compared with lasers or LEDs, the lamps (300–1,200 nm) with appropriate optical filtering could match any photosensitizer, but they have poor monochromaticity, insufficient intensity, and low energy. The properties of the light source, whether it is a laser or a LED, play a pivotal role in the effectiveness of PDT. Primarily, each photosensitizer requires activation by light at a wavelength that aligns with its specific absorption characteristics. For example, certain photosensitizers, such as mTHPC, porfimer sodium, and ALA, are activated by red light, which typically spans a wavelength range of 600–700 nm. This wavelength range is advantageous for deeper tissue penetration, rendering it suitable for the treatment of oral cavity cancers. Another critical attribute is the intensity of the light source. The light must possess sufficient intensity to activate the photosensitizer while avoiding thermal damage to adjacent tissues. Low-power light sources are often favored as they reduce the risk of heat-induced damage while still effectively activating the photosensitizer. Additionally, the coherence and collimation of the light are important considerations. Lasers, which emit coherent and collimated light, are frequently employed in PDT due to their ability to deliver light precisely to the target area, thereby enabling controlled activation of the photosensitizer. LEDs, which emit non-coherent light, are increasingly utilized due to their cost-effectiveness and ease of use. LEDs are advantageous for treating larger surface areas as they provide a broader area of illumination. Critical parameters in this context include the duration of exposure and the total energy delivered, known as fluence. The light source must deliver an adequate dose of energy to effectively activate the photosensitizer. The optimal fluence is contingent upon the specific application and the photosensitizer employed. In conclusion, the ideal light source for PDT should possess a wavelength that aligns with the absorption spectrum of the photosensitizer, sufficient intensity to activate the photosensitizer without inducing thermal damage, and the capability to deliver the appropriate fluence to the target tissue. 

Mechanism of photodynamic therapy PDT mechanism consists of three crucial elements: photosensitizer (PS), specified wavelength light source, and oxygen dissolved in the cells ( ), which exclusively generates the desired outcomes through mutual interactions within pathological tissues. shows that the photodynamic reaction has two basic mechanisms, wholly dependent on oxygen molecules inside cells. Upon exposure to light, the photosensitizer transitions from a singlet basic energy level (S 0 ) to an excited singlet state (S 1 ). The excited singlet state could then transition to a triplet state (T 1 ) or revert to the ground state with fluorescence emission. Reactive oxygen species (ROS) are created when the PS in the triplet state directly interacts with nearby biomolecules through hydrogen or electron transfer (Type I reaction); when this occurs, molecular oxygen is converted by the PS to highly reactive singlet oxygen ( 1 O 2 ) (Type II reaction) ( ). Free radicals, including superoxide, hydroxyl, and lipid-derived radicals, are released due to type I reaction and attack cellular targets, resulting in direct cellular damage ( ). Singlet excited-state oxygen is released in a type II reaction, which oxidizes lipids, proteins, and nucleic acids to cause cytotoxicity ( ). Unsaturated lipids, comprising most cell and nuclear membranes, could react with the singlet oxygen. Consequently, these reaction byproducts may impede cell growth, trigger apoptosis in oral carcinoma cells, and significantly harm microorganisms. 

Photosensitizers PS development has progressed in recent decades of PDT research; a desirable PS should possess numerous important characteristics, including nontoxicity to surrounding tissues, hydrophilicity, high affinity and selectivity to target cells or microbes, and high quantum yield of photodynamic reaction (PDR). The first-generation typical photosensitizers, the hematoporphyrin derivative (HpD), and photofrin could be absorbed into the body for a long time but penetrate only into the tissue to a limited depth (<0.5 cm) ( ). Porfifimer sodium, marketed under photofrin, was authorized for treating Barrett's esophagus in 2003 and early-stage lung cancer in 1998. The absorbance spectrum, tissue selectivity, and ROS production efficiency of the second-generation PSs have been enhanced. A naturally occurring pro-photosensitizer and a precursor to hemoglobin manufacture is 5-aminolaevulinic acid (ALA). A surplus of ALA leads tumor cells to absorb ALA rapidly but slowly degrade protoporphyrin IX (PpIX), causing PpIX photosensitizer to accumulate. Numerous second-generation photosensitizers are available, including phthalocyanines, verteporfin (VP), meta-tetrahydroxyphenylchlorin (m-THPC), and palladium bacteriopheophorbide. A light bleaching capability, antibody conjugates, or a protein/receptor system were added to photosensitizers in the third generation, improving the ability of a photosensitizer to target tumor tissues more effectively. The antibody affinity for tumor cells increases when conjugates to photosensitizers, decreasing healthy cell location. Furtherer more, toluidine blue (TB), methylene blue (MB), and erythrosine have been widely used for antimicrobial photodynamic therapy ( , ). Besides photosensitizers, certain inorganic salts (such as potassium iodide and potassium bromide) the inhibition or deterioration of target cells and effectively inhibited or eradicated bacterial and fungal biofilms ( – ). The selection of an appropriate photosensitizer for PDT is a crucial decision influenced by several factors, including the specific type of oral disease being addressed (whether antitumor or antimicrobial), the chemical properties of the photosensitizer, its capacity to generate reactive oxygen species, as well as its toxicity, selectivity, and availability. In addition to these intrinsic properties, the formulation and delivery method of the photosensitizer can significantly impact its therapeutic performance. Utilizing a molecular carrier, including a liposome nano species, is an alternative strategy. To maintain a high concentration in the targeted tissues, these modified photosensitizers with poor solubility in aqueous solutions are prevented from being delivered into the bloodstream. 

Light source Lamps, light-emitting diodes (LEDs), and lasers are the main light sources in PDT that are chosen based on the target tissue location, photosensitizer type, and administration dose. Lasers produce a coherent, focused, monochromatic light intensity, widely used to perform superficial and interstitial PDT; its limited clinical applicability is the monochromatic nature and high cost. The LED is becoming increasingly popular for PDT as a viable alternative to lasers because of their low cost, easy manipulation, and access to tissue surfaces. The LED semiconductor device uses electron-hole recombination to produce light: large beam divergence and wide spectral breadth enable LEDs to excite numerous PSs in their emission spectrum simultaneously. Lamps were the first artificial light sources utilized in PDT studies ( ). Theoretically, lamps could couple to light guides to concentrate the light on particular therapy lesions; however, the coupling losses are substantial. Consequently, lamps are better suited to treating superficial malignancies such as skin or oral cavities. Compared with lasers or LEDs, the lamps (300–1,200 nm) with appropriate optical filtering could match any photosensitizer, but they have poor monochromaticity, insufficient intensity, and low energy. The properties of the light source, whether it is a laser or a LED, play a pivotal role in the effectiveness of PDT. Primarily, each photosensitizer requires activation by light at a wavelength that aligns with its specific absorption characteristics. For example, certain photosensitizers, such as mTHPC, porfimer sodium, and ALA, are activated by red light, which typically spans a wavelength range of 600–700 nm. This wavelength range is advantageous for deeper tissue penetration, rendering it suitable for the treatment of oral cavity cancers. Another critical attribute is the intensity of the light source. The light must possess sufficient intensity to activate the photosensitizer while avoiding thermal damage to adjacent tissues. Low-power light sources are often favored as they reduce the risk of heat-induced damage while still effectively activating the photosensitizer. Additionally, the coherence and collimation of the light are important considerations. Lasers, which emit coherent and collimated light, are frequently employed in PDT due to their ability to deliver light precisely to the target area, thereby enabling controlled activation of the photosensitizer. LEDs, which emit non-coherent light, are increasingly utilized due to their cost-effectiveness and ease of use. LEDs are advantageous for treating larger surface areas as they provide a broader area of illumination. Critical parameters in this context include the duration of exposure and the total energy delivered, known as fluence. The light source must deliver an adequate dose of energy to effectively activate the photosensitizer. The optimal fluence is contingent upon the specific application and the photosensitizer employed. In conclusion, the ideal light source for PDT should possess a wavelength that aligns with the absorption spectrum of the photosensitizer, sufficient intensity to activate the photosensitizer without inducing thermal damage, and the capability to deliver the appropriate fluence to the target tissue. 

Oral cavity cancers and potentially malignant disorders Oral cavity cancers are prevalent globally, accounting for nearly 202,000 new cases yearly ( ). Additionally, oral squamous cell carcinoma (OSCC) accounts for nearly 90% of oral cavity malignancies, with a global incidence anticipated at 377,713 new cases and 177,757 deaths in 2020 ( ). Oral cancer oncogenesis is influenced by several variables and developmental stages. The malignant development of oral potentially malignant disorders (OPMDs) including actinic cheilitis (AC), oral leukoplakia (OL), oral lichen planus (OLP), oral erythroleukoplakia (OEL), oral erythroplakia (OE), oral submucosal fibrosis, proliferative verrucous leukoplakia (PVL), and epithelial dysplasia can be viewed through oral carcinogenesis studies. Recently, it has become widely accepted. Patients with OPMDs have a 5–100 fold higher risk of developing malignant transformation than the general population ( ); OL, OE, and PVL exhibited a 15%–90% malignant transformation rate ( ). The most popular forms of oral cancer treatment include surgery, chemotherapy, and radiation therapy, all of which have clear drawbacks. Oral cancer surgery could alter the facial appearance, and radiation therapy, chemotherapy, and surgery all have severe functional side effects that can affect the ability of a patient to chew, speak, swallow, and taste ( ). PDT may be appropriate for patients with significant lesions in areas with high cosmetic value or who refuse standard invasive surgery. Hopper et al. ( ) conducted a study that was open-label and multicenter in nature. The purpose of the study was to investigate the effectiveness of administering 0.15 mg/kg of mTHPC through intravenous injection in conjunction with a 20 J/cm 2 red laser (652 nm) for the treatment of early-stage OSCC at stages Tis, T1, or T2, N0M0. The results indicated that 85% of the patients who followed the treatment (97 out of 114) experienced full tumor responses. The response rate remained constant at 85% (95% CI: 77%–93%) after one year and 77% (95% CI: 66%–87%) after two years. The actuarial survival rates at one and two years were 89% (95% CI: 83%–95%) and 75% (95% CI: 66%–84%), respectively. Researchers also recorded remarkable aesthetic and functional outcomes, with no significant adverse effects on tissue integrity, speech, or swallowing ability. A study conducted by Han et al. showcased the therapeutic effectiveness of ALA-PDT in the treatment of oral leukoplakia in Chinese patients ( ). The therapy consisted of applying a 20% ALA gel and exposing the area to a 632 nm laser with an intensity of 500 mW/cm 2 and a 90–180 J/cm 2 dose. The overall response rate was 86.2%, with 55.2% of participants achieving complete remission. In a separate investigation, Yao et al. ( ) conducted a comparison between the impacts of ablative fractional laser-assisted photodynamic treatment (AFL-PDT) and ablative fractional laser (AFL) alone for oral leukoplakia. The findings revealed a notably greater percentage of successful treatment in the AFL-PDT group (100%) than in the AFL group (80.9%), with a difference of 19.1% (95% CI: 0.7%–40.0%). In addition, the AFL-PDT group demonstrated decreased recurrence rates at 6 and 12 months after therapy. Neither group experienced any serious adverse events or systemic effects. Schuch et al. ( ) extensively examined the effects of PDT on treating OPMD and OSCC. Fourteen different types of photosensitizing agents (ALA, chlorine-e6, foscan, and so on) with a light source irradiation at 417–670 nm, 10–500 mW/cm 2 , 1.5–200 J/cm 2 , and 0.5–143 min was used. The analysis included 9,245 people with OPMD ( n = 7,487) or OSCC ( n = 1,758). OEL (93%; 100 cases) and AC (67.6%; 448 cases) had the highest complete response rates among the informed cases; conversely, OLP had a 42.9% complete response rate. Eight studies were conducted to investigate the OL, OE, OEL, or both, revealing that OL responded less strongly than OE and OEL. Less than half of OL cases receive a complete answer, compared with over 90% of instances for OE and OEL. Four investigations ( n = 411) on OSCC demonstrated complete resolution in 83.4% of the cases and nonresolution in 16.6% of instances; a follow-up of 28.4 months showed a 12% recurrence rate. PDT is commonly used to treat OPMD or early-stage oral cavity cancers without nodal metastases (Cis, T1, T2), either as the main treatment or as an alternate option ( , ). The greatest positive reactions are seen in surface tumors that fall within the light source's permeability region, which is between 5 and 10 mm ( ). Although PDT provides favorable cosmetic results and preserves functionality with low invasiveness and no toxicity ( ), it is crucial to acknowledge that its efficacy is restricted to treating superficial early-stage lesions and does not affect lymph nodes. Moreover, PDT can serve as an adjunctive therapy for treating remaining margins following surgical procedures or in conjunction with other therapies. 

Periodontitis Periodontitis is a chronic multi-factorial inflammatory disease brought on by bacteria and is characterized by the loss of alveolar bone and loosening of the teeth ( , ); it is related to the formation of the dental plaque biofilm. Mechanical debridement (MD) and antibiotic treatment are frequently utilized in clinics. However, mechanical debridement frequently leaves dental plaque in periodontal pockets, furcations, and uneven root surface areas, ultimately leading to treatment failure. Porphyromonas gingivalis ( P. gingivalis ) and Aggregatibacter actinomycetemcomitans ( A. actinomycetemcomitans ) are primarily responsible for periodontitis ( ). The effectiveness of many systemic antimicrobials is constrained because they cannot continuously suppress P. gingivalis and A. actinomycetemcomitans . Antimicrobial resistance, dysbacteriosis, and gastrointestinal disorders are increasingly common due to antibiotic abuse, resulting in antibiotic failures; therefore, a more effective method for treating periodontitis is needed. PDT may be helpful in hard-to-reach places like periodontal pockets or furcation sites for microbial reduction without bacterial resistance, demonstrating its potential as an adjuvant treatment for periodontitis ( ). Besides having a bactericidal effect on the periodontal tissues, PDT has an anti-inflammatory effect by lowering inflammatory mediator levels, creating a more favorable healing environment, and re-establishing the cellular biological balance ( ). In order to evaluate the clinical and radiographic outcomes of periodontitis patients treated with conventional mechanical debridement along with those treated with methylene blue-mediated adjunctive photodynamic treatment (MB-PDT), Alasqah et al. ( ) conducted a meta-analysis of randomized controlled trials. The findings showed that when MB-PDT was used in conjunction with MD, as opposed to only MD, periodontal plaque index (PI), probing depth (PD), as well as bleeding on probing (BOP) scores exhibited significant improvements. Nevertheless, there was no statistically significant disparity in clinical attachment level (CAL) values seen between the control group (treated with MD alone) and the experimental group (treated with supplementary MB-PDT). The long-term effects of PDT and antibiotic therapy (amoxicillin 500 mg and metronidazole 400 mg for seven days) combined with traditional nonsurgical therapy in individuals with advanced periodontitis were compared in another investigation ( ), proving that PDT and antibiotic therapy significantly improve clinical parameters (PD, CAL, and BOP) three months after treatment, and that stays also decreased six, nine, and twelve months later. Ivanaga et al. ( ) compared the clinical effectiveness of PDT with 100 mg/L curcumin (CUR) solution and LED irradiation (465–485 nm, 100 mW/cm 2 , 60 s) in treating residual pockets in type 2 diabetics, indicating that PDT group (SRP, irrigation with CUR solution and LED irradiation) showed a notable CAL gain at three months in comparison to baseline data compared with SRP group, CUR group (SRP and irrigation with CUR solution), and LED group (SRP and LED irradiation). All treatment groups showed reductions in PD and BOP in the intragroup comparison at three and six months. The result showed that the addition of PDT to SRP may yield short-term benefits in CAL gain among the type 2 diabetics with residual pockets. In vitro experiments, Al-Ahmad et al. ( ) tested the antimicrobial effects of PDT against a variety of periodontal pathogens, including subgingival dental biofilm and Eikenella corrodens, Actinomyces odontolyticus, A. actinomycetemcomitans, Fusobacterium nucleatum, P. gingivalis, Atopobium rimae, Slackia exigua and Parvimonas micra . It is showed that all tested periodontal pathogens and the PDT-treated subgingival biofilm were eliminated over the ranges of 3.43–8.34 and 3.91–4.28 log 10 colony forming units (CFU), respectively. 

Dental caries Tooth caries is a multi-factorial, non-transmissible, biofilm-mediated disease that affects sensitive tooth hard tissues and is characterized by a phasic demineralization and remineralization phase. Dental caries is mostly caused by Lactobacilli and Streptococcus mutans , which produce acidity from carbohydrate metabolism, leading to an acidic pH and enamel demineralization ( ). Dental caries has historically been frequently treated with fillings, eliminating carious tissue and cariogenic germs. However, insufficient clearance leads to a significant recurrence risk (secondary caries). PDT prevents cariogenic bacterial biofilm growth by damaging bacterial structure and decreasing acid production. Therefore, PDT is regarded as a successful adjuvant therapy for dental caries. PDT can prevent dental caries by reducing microbial colonization and removing biofilm from the enamel surface. Alsaif et al. ( ) studied the effects of erythrosine-PDT on in vivo -formed dental plaque biofilms using dental plaque samples from 18 healthy adult participants wearing intraoral appliances, showing that 220 M erythrosine-B (2 min or 15 min incubation times) with green light source (500–550 nm, 22.7 mW/cm 2 , 15 min continuous light or the fractionated light with 30 s light pulses ×5) reduced total bacterial counts (93%–95%) of in vivo -formed biofilms. Faria et al. ( ) conducted a randomized controlled experiment to assess the effectiveness of composite restorations after selective caries removal (SCR) coupled with PDT. Following 12 months of observation, the group that had PDT treatment demonstrated a notably superior level of marginal adaption of the restoration in comparison to the control group. Nie et al. ( ) demonstrated that photodynamic inactivation based on Ce6 or methylene blue could be useful for preventing caries by controlling biofilms. Additionally, Ce6-mediated PDT produces more bactericidal activity (with an excess of 3 log 10 ) than MB-PDT at the same PS concentration and light dose. Furthermore, PDT could impact the virulence characteristics of Streptococcus mutans as well ( ); however, applying PDT to caries has only been studied in limited clinical trials, necessitating further in vivo proof to be considered valid ( ). 

Peri-implant diseases Dental implants are crucial components of oral rehabilitation to restore missing teeth and enhance the quality of life of those with such therapeutic needs. Depending on the degree of the peri-implant tissue inflammatory pathological state, peri-implantitis can be subdivided into peri-implant mucositis and peri-implantitis. While peri-implantitis is an inflammatory condition resulting in cracked and absorbed alveolar bone, loosening of implants, and other risks, peri-implant mucositis is an inflammation of the mucous membrane around the implant ( ). This element is a significant contributor to implant failure. The etiopathogenesis of peri-implant inflammatory disorders is related to A. Actinomycetemcomitans and Treponema denticola ( T. denticola ) ( ). These microorganisms increase probing depth, plaque index, and gingival index (GI) surrounding implants, promoting crestal bone loss (CBL) as well as soft tissue inflammation ( , ). The primary objective of peri-implantitis treatment is to eradicate the deleterious constituents of bacterial plaque in the vicinity of the implant. In most cases, peri-implantitis is treated with mechanical debridement using ultrasonic scalers, air-powered abrasives, and polishing brushes. However, these techniques have not entirely eradicated or effective inactivated peri-implant infections. This is primarily attributed to the complex nature of implant surfaces, which possess rough and microporous characteristics on macro- and microscopic scales ( ). PDT has demonstrated successful infection cures from Staphylococcus aureus , Pseudomonas aeruginosa , P. gingivalis , and multidrug-resistant bacteria ( ). And PDT, used with surgery, is more effective while preventing medication resistance and harm to nearby tissues ( ). For nonsurgical peri-implantitis treatment, adjunctive use of PDT has been investigated in four randomized controlled studies ( – ), and all studies have shown significant improvements for PD, BOP, and CBL. As for bacteria count measurement, Labban et al. ( ) found that PDT application significantly reduced peri-implant pathogens than mechanical debridement. Oral yeasts are also related to the etiopathogeneses of peri-implant disorders besides bacteria ( ). In patients with peri-implant mucositis, Shetty et al. ( ) investigated the effectiveness of 0.005% methylene-blue with 660 nm diode laser at the energy density of 16.8 J/cm 2 in lowering subgingival oral yeast colonization (OYC). After a 3-month follow-up, the modified plaque index (mPI), modified bleeding index (mBI), PD, and OYC scores in the PDT group were lower than those in the control group. The in vitro investigation proved that T. Forsythia and P. gingivalis grown on titanium specimens subjected to PDT mediated by 312 µM methylene blue for 1 min under a 685 nm diode laser with a dosage of 7.9 J/cm 2 could significantly lower T. forsythia and P. gingivalis biofilm compared with neodymium-doped yttrium aluminum garnet (Nd: YAG) laser, H 2 O 2 , and chlorhexidine groups ( ). The study also revealed that surface roughness remained constant while the contact angle decreased in the PDT group. In another vitro investigation, Anil et al. ( ) discovered that methylene blue-PDT significantly reduced P. gingivalis and T. Forsythia viability over Zirconia specimens in comparison with other disinfection groups (the hydrogen peroxide group, the Nd: YAG laser, and the chlorhexidine group). The PDT approach decreased contact angles from zirconia specimens, suggesting increased hydrophilicity. PDT had the highest surface free energy (SFE) score (41.68) across all decontamination methods, followed by chlorhexidine (39.83), Nd: YAG (34.52), and H 2 O 2 (29.88). 

Endodontic root canal infections Pulpitis and periapical periodontitis are prevalent oral disorders mostly attributed to anaerobic bacteria, including P. gingivalis and Enterococcus faecalis (E. faecalis) . E. faecalis is a frequent species of re-infection after root canal therapy, owing to factors such as antibiotic resistance, microbial biofilm formation, and dentinal penetration, whose eradication poses significant challenges ( ). Although the main treatment for pulpitis and periapical periodontitis is root canal therapy, the complexity of the root canal system (communicating branches, lateral branches, and an apical bifurcation) and the multispecies biofilm communities have made the microbial biofilm complete removal more challenging. Clinical studies on this topic recommend that PDT could be a promising technique to eliminate root canal bacteria after standard chemo mechanical debridement ( ). Alves-Silva et al. ( ) evaluated the effectiveness of PDT as an additional treatment for improving bacterial clearance and reducing lipopolysaccharide (LPS) and lipoteichoic acid (LTA) levels. The study involved two groups: one group received endodontic therapy with chemo-mechanical preparation (CMP) alone, while the other group received PDT (using a 9 J/cm 2 660 nm red laser with 0.005% methylene blue for 3 min) following CMP. The results revealed that root canals had samples with pulp necrosis and periapical lesions. Additionally, LPS and LTA levels were significantly reduced in the PDT group, with a higher reduction in the CMP group. Pourhajibagher et al. performed a comprehensive study and synthesis of existing studies to examine the effectiveness of combining PDT with standard chemo-mechanical debridement in treating infected root canal systems in endodontic diseases ( ). Their research revealed a substantial decrease in the amount of microorganisms when PDT was used in addition to other treatments. 

Oral fungal infections Candida species are the most common fungi indigenous to human mucosal surfaces, which is mainly caused by Candida albicans ( C. albicans ). Although C. albicans is a commensal organism in healthy individuals, it could convert into a pathogenic one following changes in the host environment. Oral candidiasis (OC) is the most commonly encountered oral manifestation, which is mainly caused by C. albicans infection ( ). Traditional antifungal treatment applied in OC include amphotericin B, nystatin, clotrimazole and ketoconazole ( , ). However, the limitation of antifungal drugs, high resistance and host defense mechanisms made antifungal treatment difficult. Hence, alternative strategies such as PDT against the emergence of drug-resistant C. albicans are being considered ( ). Ma et al. ( ) conducted investigations on the impact of curcumin on biofilms of C. albicans . The researchers carried out experimental analyses on a standard strain as well as two clinical isolates obtained from individuals with HIV and oral lichen planus. The findings of their study indicated that a 20 min pre-irradiation of 60 µM curcumin and a 6 min exposure to LED with a dosage of 7.92 J/cm 2 resulted in a reduction of C. albicans biofilms. Furthermore, expression of efg1, ume6, hgc1, and ece1 genes expression of C. albicans was decreased after PDT treatment. Additionally, ALA–PDT (using a 635 nm red laser at 300 J/cm 2 ) showed potent inhibition of the metabolic activity of C. albicans ( ). Pereira et al. ( ) evaluated potential effects of 200 µM erythrosine plus a 532 ± 10 nm green LED (237 mW/cm 2 , 42.63 J/cm 2 ) in planktonic culture, biofilms and virulence factors of Candida strains. The results indicated that the addition of PDT could significantly reduce Candida species growth as well as lower the virulence and pathogenicity of certain Candida species, however, there was a greater resistance to PDT in biofilm structures compared to planktonic cultures. Hu et al. ( ) conducted a meta-analysis of 11 trials to assess the impact of PDT as a supplementary or substitute treatment for oral candidiasis compared to conventional antifungal medications such as nystatin, fluconazole, and miconazole. The results demonstrated that PDT outperformed nystatin in reducing the number of oral candida colonies in the palates of patients. However, no statistically significant difference was observed in the denture location. Fluconazole and PDT had similar efficiency in the treatment of oral candidiasis. However, miconazole was shown to be more effective than PDT. However, the use of PDT in conjunction with nystatin has been found to be a more effective treatment for oral candidiasis, with improved effectiveness and a lower chance of the condition recurrence. 

Perspectives and future directions 9.1 Recent clinical advances in PDT PDT development direction mainly focuses on development of photosensitizer and laser development and utilization to enhance its targeting and light penetration ability. Combining functionalized nano-materials, radiosensitizers, and hyperthermia with PDT can enhance the synergistic effect of photosensitizers and increase the curative effect on deep tissues. Numerous functional nano-materials have been created due to the quick development of nanotechnology for better medication delivery and anticancer and antibacterial effects. Many different nanoparticles have been created, including 5-ALA-loaded chitosan-tripolyphosphate nanoparticles (CS-TPP NPs) ( ), MPP (Polymers) combined with Ce6 ( ), and rose bengal (RB) in silver nanoclusters (AgNCs) ( ), among others ( ). Sonodynamic therapy employs ultrasonic waves to activate photosensitizers, inducing singlet oxygen production. This mechanism serves as a compensatory strategy for the limited tissue penetration capabilities of light-based therapies ( ). Photochemical internalization (PCI) is a new method wherein photosensitizers and cytotoxic substances (including bleomycin) are injected into tissues. Subsequently, the cytotoxic molecules exert their effects on the cytoplasm through light internalization. Two-photon absorption PDT uses two wavelengths of photons to reach the photosensitizer simultaneously to increase the absorption power and intensity to act on cells. This brings a new research direction for PDT, makes up for the shortcomings of traditional PDT, and hopefully becomes a new method widely used in clinical treatment. Aiming at increasing the therapeutic efficiency, combination regimens through multiple photosensitizers with multiple certain wavelengths of light sources either sequentially or simultaneously, is needed in the future. 9.2 Limitations PDT is ROS-dependent, non-invading and convenient. However, all three crucial elements for PDT (PS, light, and oxygen) could contribute to the limitation of ROS generation. Poor tissue penetration occurs with short wavelength lights. Due to the hypoxic tumor environment caused by extensive areas of tumoral necrosis and local hypoxia, which results in a poor response to PDT, the absolute demand for oxygen may be insufficient. The severe limitations of conventional PS, including poor solubility, low stability, and inadequate tissue penetration, continue to be a barrier to PDT, requiring innovative solutions to improve PDT clinical results. 9.3 Current controversies in PDT Before PDT becomes widely used in therapeutic settings, various questions about its utilization must be cleared up; PDT toxicity, oral ecosystem balance, and impact of complicated infection should be investigated in vitro and in vivo research. Photosensitizers, including MB, toluidine blue O (TBO), or malachite green, can alter tooth structure shade. More PS molecules can permeate the internal composition of the tooth with the increased PS incubation time. 

Recent clinical advances in PDT PDT development direction mainly focuses on development of photosensitizer and laser development and utilization to enhance its targeting and light penetration ability. Combining functionalized nano-materials, radiosensitizers, and hyperthermia with PDT can enhance the synergistic effect of photosensitizers and increase the curative effect on deep tissues. Numerous functional nano-materials have been created due to the quick development of nanotechnology for better medication delivery and anticancer and antibacterial effects. Many different nanoparticles have been created, including 5-ALA-loaded chitosan-tripolyphosphate nanoparticles (CS-TPP NPs) ( ), MPP (Polymers) combined with Ce6 ( ), and rose bengal (RB) in silver nanoclusters (AgNCs) ( ), among others ( ). Sonodynamic therapy employs ultrasonic waves to activate photosensitizers, inducing singlet oxygen production. This mechanism serves as a compensatory strategy for the limited tissue penetration capabilities of light-based therapies ( ). Photochemical internalization (PCI) is a new method wherein photosensitizers and cytotoxic substances (including bleomycin) are injected into tissues. Subsequently, the cytotoxic molecules exert their effects on the cytoplasm through light internalization. Two-photon absorption PDT uses two wavelengths of photons to reach the photosensitizer simultaneously to increase the absorption power and intensity to act on cells. This brings a new research direction for PDT, makes up for the shortcomings of traditional PDT, and hopefully becomes a new method widely used in clinical treatment. Aiming at increasing the therapeutic efficiency, combination regimens through multiple photosensitizers with multiple certain wavelengths of light sources either sequentially or simultaneously, is needed in the future. 

Limitations PDT is ROS-dependent, non-invading and convenient. However, all three crucial elements for PDT (PS, light, and oxygen) could contribute to the limitation of ROS generation. Poor tissue penetration occurs with short wavelength lights. Due to the hypoxic tumor environment caused by extensive areas of tumoral necrosis and local hypoxia, which results in a poor response to PDT, the absolute demand for oxygen may be insufficient. The severe limitations of conventional PS, including poor solubility, low stability, and inadequate tissue penetration, continue to be a barrier to PDT, requiring innovative solutions to improve PDT clinical results. 

Current controversies in PDT Before PDT becomes widely used in therapeutic settings, various questions about its utilization must be cleared up; PDT toxicity, oral ecosystem balance, and impact of complicated infection should be investigated in vitro and in vivo research. Photosensitizers, including MB, toluidine blue O (TBO), or malachite green, can alter tooth structure shade. More PS molecules can permeate the internal composition of the tooth with the increased PS incubation time. 

Conclusions Although PDT has demonstrated much promise and usefulness in dentistry, it is important to acknowledge several limitations. These factors encompass the restricted capacity of the PS to deeply enter dentinal tubules, difficulties in the transmission of light, and the lack of oxygen in deep periodontal pockets. Moreover, there is a lack of consensus about the most effective treatment strategy for oral problems. Therefore, further thorough and carefully controlled study is necessary to determine the most efficient PS, the suitable irradiation protocols, and the optimal wavelengths for activating the PS. This will enable healthcare practitioners to achieve the intended outcomes. 

