An inflammatory condition that affects the periodontium, cementum, and alveolar bone of the tooth is known as periodontitis. The global prevalence of periodontitis is estimated at 20%–50% (Garg et al., 2015). The primary cause of this disease is microorganisms that can be exacerbated by smoking and underlying disorders (diabetes and obesity) (Russo et al., 2016). In periodontitis, the attachments between the tooth-supporting tissue (periodontal tissue) and the tooth are destroyed, and this provides the basis for the emergence of periodontal pockets in which a wide range of periodontal pathogens can survive (Nazir et al., 2020). Chronic periodontitis (CP) refers to a long-term inflammatory status that is induced by a range of periodontal pathogens, such as Porphyromonas gingivalis (P. gingivalis), A. actinomycetemcomitans (Aggregatibacter actinomycetemcomitans), and Fusobacterium nucleatum (f. nucleatum), etc., due to their virulence factors including enzymes, lipopolysaccharide (LPS), toxins, and heat shock proteins (HSPs), as well as biofilm formation. These virulence factors enable pathogens to destroy periodontal tissue and alveolar bone (Bassir et al., 2013; Meimandi et al., 2017). The highest incidence of CP is in older patients (82%), followed by adults (73%) and adolescents (59%) (Tadjoedin et al., 2017), and it seems that the severity of the disease increases with age (Meimandi et al., 2017). Periodontal pathogens can indirectly induce systemic disorders, such as diabetes and cardiovascular disease, by spreading directly from the damaged tissue and dental plaque in the oral cavity through the blood stream to other tissues and organs. Hence, the early treatment of this disease is very important (Nazir, 2017). Periodontal therapy involves scaling and root planing (mechanical debridement) and administration of antimicrobial agents, including antibiotics and mouthwashes (chemical therapy). Dental scaling refers to removing dental plaques (teeth tartar or dental calculus), which is sometimes combined with root planing, a process of smoothing root surfaces (Garg et al., 2015). Antibiotic resistance and lack of accessibility into the deeper areas of the periodontal pocket complicate treatment (Mahdizade-Ari et al., 2019; Amaral et al., 2020). While scaling and root planing (SRP) is still the gold standard of periodontal therapy (Jia et al., 2020), several new strategies have been developed to inhibit biofilm formation on the tooth surface.

One of the new therapeutic strategies is photodynamic therapy (PDT) (Meimandi et al., 2017), which is a non-invasive chemical method that first originated in 1990 for cancer therapy. PDT has the potential to treat various types of diseases, including microbial infections, by destroying abnormal cells (Garg et al., 2015). A light source and a photosensitizer (PS) are the two main components of PDT. Following the insertion of the photosensitizer at the site of infection, light is emitted at a specific wavelength, leading to the excitation of the photosensitizer from the ground state to the triplet state. The excited photosensitizer will produce two types of toxic reactive oxygen metabolites after an interaction with organic molecules: Type-Ⅰ (hydrogen peroxide, superoxide, and free hydroxyl radicals) and Type-Ⅱ (singlet-oxygen). This can lead to selective abnormal cell or microbial death (Kwiatkowski et al., 2018). The significant effects of photodynamic therapy on cellular and microbial populations have made it a popular treatment for periodontal diseases in recent years (Bassir et al., 2012; Campos et al., 2013; Kashef et al., 2016; Raut et al., 2018; Pooja and Mannava, 2020b; Joshi et al., 2020). The reduction of bacteria following the application of different photosensitizers in the treatment of chronic periodontitis was shown by both in vitro and in vivo studies. In comparison to SRP, photodynamic therapy is faster, less expensive, and has a stronger bactericidal effect (Jia et al., 2020). Moreover, due to the very low half-life of the singlet-oxygen, the antibacterial effect of PDT remains localized and limited to the treated sites (Joshi et al., 2020).

The latest update published by the American Academy of Periodontology and the European Federation of Periodontology recognized four stages (Ⅰ–Ⅳ) of periodontitis classified according to tooth loss and severity and include slight, moderate, chronic, and advanced (necrotizing) periodontitis (Kapoor et al., 2022). Slight and moderate chronic periodontitis is still affected by mechanical therapy through the removal of microbial plaques, but the chronic and advanced stage needs new treatment to penetrate deep into the periodontal pockets (Swedish Council on Health Technology Assessment SBU, 2004). Chronic periodontitis was chosen in the present study because it is more common among the population, and it is important to diagnose and treat it in order to suppress its progression to advanced periodontitis. Therefore, the aim of this systematic review was to investigate more than 10 years of clinical trials (2008–2023) to determine the effectiveness of PDT in adjunct to the scaling method as a simple method for the treatment of chronic periodontitis.

1. Population: Patients diagnosed with chronic periodontitis

In the current study, 53 clinical trials during 2008–2023 were reviewed. Risk factors such as smoking, diabetes, and obesity not only increase the chances of developing periodontal disease but can also influence the outcome of the treatment process. Therefore, studies with such a situation were excluded from the present systematic review in order to examine the exact effect of photodynamic therapy on the treatment process by considering the conditions of normal patients with periodontitis.

The overall results of the present systematic review showed that PDT treatment could improve several periodontal parameters, including BOP, CAL, PI, GI, and PPD, change the profile of inflammatory and anti-inflammatory cytokines in favor of patient recovery, and significantly reduce the red complex (usually P. gingivalis, T. denticola, and T. forsythia) and blue complex of periodonto-pathogens (Actinomyces species) (Mongardini et al., 2014). Evaluation of periodontal parameters, blood cell count (PMN and RBC, especially leukocytes), and bacterial and cytokine profiles will give helpful guidance about the status of periodontal disease (Giannelli et al., 2012). Therefore, any change in these parameters can relate to changes in the severity of periodontal inflammation and bleeding in the oral cavity. Moreover, because leukocytes are considered sources of toxic products such as reactive oxygen species (ROS), inflammatory mediators, and matrix-degrading enzymes, which aggravate inflammation, it seems that reduction of leukocyte levels can help to repair the damaged periodontal tissues (Giannelli et al., 2012; Giannelli et al., 2015).

PDT is a chemical process that produces exogenous ROS in the presence of oxygen when PS is placed in the target area. ROS are the main factor in the effectiveness of the PDT mode of action by destroying abnormal cancer cells (Zheng et al., 2023) and pathogenic bacteria (Ghorbani et al., 2018) that are specifically targeted to be destroyed. On the other hand, under normal conditions, 90% of the ROS in the body are produced by the mitochondrial electron chain in response to hypoxia, ischemia, aging, etc. The presence of endogenous ROS is harmful to the body; thus, 90% of them are reduced to water by cytochrome oxidase. Endogenous ROS are under the control and regulation of mitochondrial membrane potential (MMP) (Sarniak et al., 2016). The question of whether the ROS formed by PDT aggravate inflammation may arise. PDT has the ability to intensify endogenous ROS by affecting MMP, but in general, this ability of exogenous ROS is not impressive, and few studies have addressed this issue (Zhang et al., 2020). More studies are needed. Moreover, the very low half-life of ROS, which is approximately 0.01–0.04 μs in a diffusion distance range of 0.01–0.02 μm (Gunaydin et al., 2021), is very short to trigger an inflammatory response. Therefore, ROS disappear quickly. For this reason, photodynamic therapy is very specific.

Mineralized residual deposits and dental plaques on the root surfaces are believed to be the main cause of bacterial attachment in periodontal lesions by acting as a reservoir for the recurrence of the disease and progression of periodontitis and tooth loss (Bassir et al., 2012; Campos et al., 2013; Raut et al., 2018; Vohra et al., 2018; de Melo Soares et al., 2019). Restoring the compromised periodontal tissues and providing suitable and durable conditions are the primary aims of periodontal therapy (Kotsilkov and Popova, 2010; Russo et al., 2016). Conventional methods such as SRP and antibiotic therapy are currently used for periodontal therapy. Although SRP is still the gold standard for periodontal therapy and pocket reduction therapy, Choi et al. believed that SRP may help bacteria penetrate deeper into the sub-epithelial spaces (Choi et al., 2014). Furthermore, the frequent need for using SRP, the amount of treatment time required (Russo et al., 2016), and the lack of accessibility of SRP into the deep periodontal pockets (≥5 mm) to remove bacterial deposits and toxins (Malgikar et al., 2016) have led to a search for novel strategies to control biofilm formation (Grzech-Leśniak et al., 2018; Gandhi et al., 2019). The success of a periodontal treatment depends on the complete removal of the subgingival biofilm and the eradication of bacteria from the root surfaces (Grzech-Lesniak et al., 2019). Limitations associated with the use of antibiotics in periodontal therapy are reported as allergic reactions, poor accessibility of antibiotics to sub-gingival plaque, antibiotic-resistant bacterial emergence, discoloration of teeth, and gastrointestinal disorders (Socransky and Haffajee, 2000; Bassir et al., 2012; Raut et al., 2018). Studies have shown that the administration of only doxycycline or minocycline did not show any improvements in PPD reduction and CAL gain (Tomasi et al., 2008; Kolbe et al., 2014).

The main side effects of PDT in the oral cavity were reported as burning, pain, and edema (Sharma et al., 2022). The results of the present review showed no emergence of strains resistant to toxic reactive oxygen mediators of PDT (Raut et al., 2018), no cytotoxicity for host cells (Srikanth et al., 2015), and patients undergoing PDT (with or without anesthesia) rarely experience discomfort, which reflects the safety and tolerability of PDT (Giannelli et al., 2012).

In addition to the antimicrobial effects of PDT, a concern about their effect on periodontal tissue and oral microbiota must be clarified. High-level lasers cause thermal damage to periodontal tissue and lead to excessive ablation, root, pulp, and tooth necrosis (Takasaki et al., 2009). Studies have shown that PDT as a low-level laser not only selectively destroys pathogens without affecting the periodontal tissue (Andersen et al., 2007; Christodoulides et al., 2008; Qin et al., 2008; Takasaki et al., 2009) but also improves the blood flow of the gum tissue and increases oxygen delivery to the tissue in inflammatory conditions (Raghavendra et al., 2009). The diode wavelength of recent lasers and their short radiation time do not interact with the periodontal tissue, except in the case of longer radiation duration, which may cause thermal damage to the pulp and teeth due to radiation. Due to the toxicity potential of PS for periodontal tissue, it is recommended to aspirate all the dye from the periodontal pocket after a PDT procedure (Takasaki et al., 2009). According to Hamblin et al., PDF does not have any side effects on the normal and beneficial microflora in other parts of the mouth (Hamblin and Hasan, 2004; Jori et al., 2006). This adds to the superiority and credibility of PDT over antimicrobial agents such as antibiotics because antibiotics destroy all beneficial and pathogenic bacteria without distinguishing between the microbial population in the oral cavity, but PDT targets only the target area due to local radiation and the short half-life of ROS (Gilaberte et al., 2021).

According to the Theodor et al. study, a combination of PDT with antibiotics (metronidazole + amoxicillin) in adjunct to SRP can reduce PPD markers more effectively than SRP alone or antibiotics alone (Pooja and Mannava, 2020b). Therefore, PDT cannot be replaced by antibiotic therapy, but caution is required regarding the development of resistant strains during this treatment method (Bundidpun et al., 2018).

PDT is able to reduce BOP levels, leading to a reduction in inflammation and healing of local periodontal wounds (Campos et al., 2013; Barbosa et al., 2016). Therefore, the absence or reduction of BOP can be directly associated with periodontal stability, and the presence of BOP can be related to the disease progression. PPD and CAL are indicators of periodontal tissue damage and the effectiveness of treatment (Vohra et al., 2018). Because PPD changes can occur in response to any factor, analyzing the clinical attachment level by measuring the distance from the point under examination to the bottom of the periodontal pocket is the gold standard of an appropriate indicator. As dental plaque is the major contributing factor in periodontitis, control of supra-gingival biofilm and PI values is important in improving PPD (Bassir et al., 2012; Gandhi et al., 2019).

Although the anti-cancer effects of PDT have been studied, a few studies evaluated the effect of PDT on the immune system in oral infection. PDT leads to the enhancement of apoptosis, improvement of the function of damaged tissue, and establishment of homeostasis between inflammatory and anti-inflammatory cytokines (Falk-Mahapatra and Gollnick, 2020; Mosaddad et al., 2023). Periodontal pathogens can escape from the host immune system and inactivation mediated-antibiotics by penetrating into the epithelial cells and dental pockets, which helps them to re-grow and cause chronic disease (Giannelli et al., 2015). Salvadora persica is an herbal gel with silica, sodium bicarbonate, and tannic acid compounds used to decrease dental plaque on root surfaces, bleeding, and inflammatory mediators, as well as to maintain a normal pH in the mouth. This herbal medication can also reduce periodontal pathogens such as A. actinomycetemcomitans, P. gingivalis, and S. mutans (Niazi et al., 2020). LPS released from the Gram-negative bacteria enables bacterial attachment to root surfaces and their survival even after SRP, leading to chronic inflammation (Giannelli et al., 2012). In this context, TBO has stronger bactericidal properties than MB due to the stronger binding of TBO to the bacterial LPS. This also makes Gram-negative bacteria more sensitive to inactivation by PDT (Raut et al., 2018). Moreover, the significant decrease in PMNs of the oral cavity, usually seen after PDT, could be related to the radiation-induced inactivation of LPS.

Chronic periodontitis patients show an increase in the TNF-α, IL-6, IL-1B, and RANK-L levels and a decrease in OPG. RANK-L and OPG are two important factors in the regulation of osteoclastogenesis that can reflect the patient’s condition. PDT is proved to have the potential to suppress inflammation (Huang et al., 2019; Phutim-Mangkhalthon et al., 2020; Deng et al., 2023), pro-inflammatory cytokines and RANK-L (Segarra‐Vidal et al., 2017). IL-6 and TNF-α are pro-inflammatory cytokines that stimulate bone decomposition. PDT decreases these pro-inflammatory cytokines by reducing T-lymphocyte stimulation and interfering with APC stimulatory function (Kolbe et al., 2014; Niazi et al., 2020). IL-1 and MMP-8 are two main immunological factors involved in the tissue destruction of periodontitis. High levels of MMP-8, following SRP, indicate further loss of periodontal tissue, while PDT proved to have the potential to improve it (Queiroz et al., 2013).

The potential reasons for discrepancies or contradictory results among different trials that evaluated the impact of PDT on the treatment of periodontitis may be related to the lack of a standard protocol for PDT, variations in the type and concentration of the photosensitizer, differences in the penetration mode of the photosensitizer, duration of its placement at the site of infection (Segarra‐Vidal et al., 2017), laser-related characteristics (laser device type, output power, wavelength, and irradiation time), type of the studied teeth, frequency and combination using of PDT, and the presence of any medical condition among patients, age, gender, hormonal changes, etc. (Alwaeli et al., 2013; Campos et al., 2013; Bundidpun et al., 2018; Hill et al., 2019). These are potential reasons for any discrepancies or contradictory results observed across different trials.

It is important to use a proper type of photosensitizer to reach desirable outcomes in PDT. Differences in the cell walls of Gram-positive and Gram-negative bacteria (the thickness of peptidoglycan, presence/absence of lipoteichoic acid (LTA), outer membrane, and LPS) influence the permeability rate of photosensitizers and application of PDT in removing these bacteria (Grzech-Leśniak et al., 2018). In this regard, Gram-positive bacteria are eliminated by both types of positive- and negative-charged photosensitizers, while only positive-charged photosensitizers have antibacterial effects on Gram-negative bacteria.

PDT has great anti-biofilm effects on single-rooted teeth; thus, the type of the studied teeth in different trials can also affect the efficacy of the PDT treatment (Alwaeli et al., 2013). Periodontal pockets in multiple-rooted teeth show less response to SRP + PDT treatment than non-molar teeth (Bassir et al., 2012). This is consistent with the Campos et al. study that showed a positive effect of PDT on single-rooted teeth of patients with chronic periodontitis (Campos et al., 2013). Thus, it is recommended that studies performed on multiple-root teeth not be compared with those performed on single-rooted teeth (Dos Santos et al., 2016). No significant difference in microbiological analysis was attributed to the translocation of pathogenic bacteria (Karmakar et al., 2021) and insufficient removal of the biofilm in the root surface by the PDT protocol (Birang et al., 2015).

Single or multiple applications of PDT are another important issue that can result in discrepancies in outcomes. However, some evidence showed the frequency of PDT administration may result in no significant difference between the intervention and control groups. It is suggested that if PDT is repeated in the first week of the intervention, the effect of PDT will be strengthened (Christodoulides et al., 2008). Other RCTs reported that repeated use of PDT, which is also known as the dose effect (Gandhi et al., 2019), along with the SRP can show better outcomes (Barbosa et al., 2016; AlAhmari et al., 2019; Hill et al., 2019; Mirza et al., 2019; Joshi et al., 2020). This is proved by Alwaeli et al. (2013), Campos et al. (2013), Grzech-Leśniak et al. (2018), and Pooja and Mannava (2020b). Furthermore, halitosis, which is characterized by the release of volatile sulfur compounds and bad breath (De Geest et al., 2016), will be significantly improved after several episodes of PDT (Betsy et al., 2014). In contrast to single PDT or single SRP, a combination therapy of PDT with SRP makes significant improvements in the treatment outcome. This claim is supported by studies that show that the use of PDT + SRP causes a larger decrease in the number of plaques ≥5 mm, BOP, and risk of progression to destructive periodontitis and tooth loss than monotherapy with SRP alone (Alwaeli et al., 2013; Campos et al., 2013; Kolbe et al., 2014). Another factor affecting the treatment outcomes is menstruation, which is associated with increased expression of inflammatory cytokines and inflammation in periodontal tissues. Hormonal changes may affect the outcome of SRP + PDT periodontal therapy in trials carried out on women.

There is wide heterogeneity among RCTs due to a lack of standard clinical protocol for photodynamic therapy and small sample sizes, which limits the comparison of RCTs and makes claims about the reliability of PDT for the treatment of oral diseases difficult to quantify. We could have considered the effect of PDT on patients with underlying diseases or special conditions like diabetes, obesity, smokers, etc., but due to the large amount of content that may be beyond the reader’s interest, we excluded them from the present study and will examine those studies in a future review. In addition to superficial localized infection and cancer, the present study showed that PDT is effective on oral diseases like periodontitis, but more trial studies on a larger scale, development of more standardized protocols, novel and various photosensitizers, and efficient delivery strategies are needed.

The evidence from RCTs has shown that photodynamic therapy was as effective as conventional therapy like SRP in ameliorating clinical symptoms such as PPD and CAL and reducing pathogens and periodontal pockets, especially when used with conventional therapy. Although photodynamic therapy is able to overcome the limitations of the SRP, more large-scale clinical trials are needed. Photodynamic therapy is a promising, adjunctive, and low-cost therapeutic method that is effective in tissue repair, reducing chronic periodontitis, reducing inflammation, and well-tolerated by patients. For these reasons, photodynamic therapy can be used as a potential complementary method to conventional therapy. Moreover, photodynamic therapy, along with SRP, appears to mediate the conditions for periodontal recovery in the long term.