Diabetes mellitus (DM) is one of the most prevalent non-communicable chronic diseases worldwide [1]. As of 2021, the global prevalence of diabetes was estimated to be 537 million adults (9.3 % of the global population aged 20–79 years), according to the International Diabetes Federation. This number is projected to rise to 643 million by 2030 and 783 million by 2045 if current trends continue [2]. Type 2 diabetes mellitus (DM2) accounts for >90 % of all diabetes cases and is largely driven by obesity, sedentary lifestyles, and aging populations [1]. Periodontitis, a chronic multifactorial inflammatory disease, is associated with biofilm dysbiosis and characterized by the progressive destruction of the supporting periodontium [3]. The interplay between microbial pathogenicity and the host immune response plays a pivotal role in the progression of periodontitis, driving extensive periodontal destruction. Periodontal pathogens trigger a dysregulated immune response, resulting in chronic inflammation and excessive production of proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and IL-6 [4]. This sustained inflammatory state leads to the breakdown of the periodontal ligament, alveolar bone resorption, and connective tissue degradation. Additionally, microbial virulence factors, such as lipopolysaccharides, proteases, and fimbriae, enhance immune evasion and disrupt host tissue homeostasis. As the disease progresses, an imbalance between tissue destruction and repair mechanisms impairs periodontal support structures, culminating in increased tooth mobility and eventual tooth loss [5].
The management of DM2 is multifaceted and aims to achieve optimal glycemic control, reduce complications, and improve overall quality of life. Initial therapy focuses on lifestyle modifications, including dietary changes, increased physical activity, and weight loss, which have been shown to significantly improve insulin sensitivity and metabolic parameters [[6], [7], [8]]. When lifestyle interventions are insufficient, pharmacologic therapy is introduced, typically starting with metformin due to its proven efficacy, safety profile, and cardiovascular benefits [[6], [7], [8]]. As the disease progresses, additional agents such as sulfonylureas, or thiazolidinedione may be added based on individual patient characteristics, including the presence of cardiovascular or renal comorbidities. Insulin therapy remains an essential option for patients with severe hyperglycemia or progressive beta-cell failure [[6], [7], [8]]. Continuous monitoring of glycemic status through HbA1c measurements and, when appropriate, self-monitoring or continuous glucose monitoring devices is critical for ongoing management [1]. Additionally, patient education and structured diabetes self-management programs are integral to supporting adherence and empowering individuals to effectively manage their condition. Overall, the treatment of DM2 requires a personalized, dynamic approach that adapts to the evolving clinical needs of the patient [9].
Epidemiological evidence strongly indicates that poorly controlled DM2 serves as a significant modifying factor in both the onset and progression of periodontitis. Chronic hyperglycemia in individuals with DM2 exacerbates systemic and local inflammatory responses, leading to increased periodontal tissue destruction, impaired wound healing, and greater susceptibility to infection [10]. Studies have consistently shown that uncontrolled DM2 patients exhibit higher prevalence and severity of periodontitis, characterized by deeper periodontal pockets, increased clinical attachment level (CAL), and elevated bleeding on probing (BOP) [11,12]. Moreover, the bidirectional relationship between DM2 and periodontitis suggests that periodontal inflammation can further contribute to systemic insulin resistance, complicating diabetes management [13]. A complex, bidirectional relationship between DM and periodontal disease has been well documented in the literature. As a result, periodontal treatment may provide direct benefits for patients with poorly controlled DM2 [[14], [15], [16]].
Periodontal treatment aims to manage bacterial biofilm and inflammation to prevent disease progression and preserve periodontal structures. This process begins with supragingival biofilm control, which relies on patient education, behavioral modifications, and the reduction of systemic and local risk factors such as smoking, poor glycemic control, and inadequate oral hygiene (step one of therapy) [17]. Effective patient motivation is critical, as adherence to oral hygiene practices significantly influences treatment outcomes [18]. Following initial biofilm control, subgingival instrumentation (SI) is performed to mechanically remove bacterial deposits and disrupt the subgingival biofilm (step two of therapy). While this approach is often effective in reducing inflammation and improving periodontal health, some patients exhibit persistent periodontal pockets after initial therapy [17]. These pockets, characterized by probing pocket depth (PPD) of ≥ 4 mm with BOP indicate the need for further intervention, which can be performed in the second or third phase of therapy [17]. In such cases, re-intervention may be required, either through surgical periodontal therapy or SI associated with adjunctive treatments such as antimicrobial photodynamic therapy (aPDT), locally delivered antimicrobials [19], and host-modulating therapies to enhance treatment response [17,20,21]. Notably, patients with poorly controlled DM2 often show a diminished response to non-surgical periodontal therapy compared to non-diabetic individuals or those with well-controlled diabetes [22,23]. This reduced treatment response frequently compromises the effectiveness of periodontal therapy, making adjunctive treatments necessary to achieve better disease management. aPDT has emerged as an encouraging adjunct to conventional mechanical debridement for periodontal treatment, particularly in patients with DM [24]. aPDT is a non-invasive therapeutic approach that combines a photosensitizing agent such as methylene blue or toluidine blue, with a specific wavelength of light, typically from a laser or LED source spectrum [25,26]. When activated, the photosensitizer generates reactive oxygen species (ROS), leading to targeted destruction of periodontal pathogens while minimizing damage to surrounding host tissues [18,22,24,[27], [28], [29], [30], [31]]. Several clinical studies [[27], [28], [29],32] have evaluated the combination of aPDT with SI in systemically healthy individuals, reporting improvements in CAL reductions in PPD and BOP [[27], [28], [29]]. However, some studies have not observed significant improvements in clinical periodontal parameters with the addition of aPDT to SI [32,33]. Furthermore, limited research has investigated the effect of aPDT on HbA1c levels in diabetic patients [18,24,30,34,35], with conflicting results - some studies report improvements [34], while others find no additional benefits [18,24,30,35].
In vitro studies have demonstrated promising outcomes with the novel photosensitizer butyl toluidine blue (BuTB) compared to other phenothiazine-based photosensitizers, such as toluidine blue and methylene blue [36]. A previous study using an experimental periodontitis model in rats highlighted the beneficial effects of BuTB in aPDT, particularly at a concentration of 0.5 mg/mL followed by irradiation with 660 nm diode laser. This treatment promoted bone formation after 30 days, mediated by upregulation of osteocalcin [37]. The superior performance of BuTB is attributed to its increased molecular asymmetry, achieved by the inclusion of a bulky tertiary‑butyl group, which reduces molecular aggregation [37,38]. This structural modification enhances long-wavelength absorption and improves tissue penetration, thereby increasing the photodynamic effect in infected areas, such as periodontal pockets. The absorption peak of BuTB occurs at 650 nm, which is close to that of methylene blue [38]. Consequently, BuTB activated by a 660 nm diode laser may effectively reduce both gram-negative and gram-positive bacterial colonization.
Although aPDT has emerged as a promising adjunctive approach in the management of periodontitis due to its ability to selectively target and eliminate pathogenic bacteria, the persistence and re-growth of periodontal pathogens remain a significant clinical challenge [39]. Despite its immediate antimicrobial effects, studies have reported that the subgingival microbial community may gradually recover following treatment, with pathogenic species such as Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola repopulating the periodontal pockets [40,41]. Factors contributing to this re-growth include the complexity of the biofilm architecture, limited penetration of the photosensitizer and light into deep periodontal pockets, and the resilience of certain microbial niches that serve as reservoirs for recolonization [[40], [41], [42]]. Moreover, patient-related factors such as inadequate oral hygiene practices and systemic conditions can further facilitate the re-establishment of a pathogenic microbiota. Therefore, while aPDT offers significant initial reductions in bacterial load and inflammation, its long-term effectiveness may depend on repeated applications, combination with conventional mechanical debridement, and the implementation of strict supportive periodontal therapy protocols aimed at maintaining a healthy microbial balance.
While the EFP S3 Level Clinical Practice Guideline [17] does not currently endorse aPDT as a standard adjunct to SI in the general management of periodontitis, it is important to recognize that clinical guidelines often reflect the average outcomes in heterogeneous populations and may not fully capture the therapeutic needs of medically complex patients. Our study provides critical and timely evidence by targeting a particularly vulnerable population, individuals with DM2, who frequently experience impaired wound healing and persistent periodontal inflammation. By investigating a novel photosensitizer and applying aPDT adjunctively to mechanical debridement, our research explores an innovative strategy aimed at enhancing periodontal healing in a setting where conventional therapy alone may be suboptimal. Therefore, our findings not only address a significant clinical gap but also pave the way for reconsideration of the role of aPDT in personalized, risk-based periodontal therapy, particularly in patients with systemic conditions that compromise periodontal health.
Therefore, this study hypothesized that butyl toluidine blue (BuTB) at a concentration of 0.5 mg/mL would exert a beneficial photodynamic effect in periodontal pockets resistant to treatment steps 1 and 2, as outlined in the EFP S3 clinical practice guideline [17], leading to improvements in both periodontal clinical parameters and the immunoinflammatory response in poorly controlled DM2 patients. Considering the current lack of studies evaluating the effects of aPDT on residual periodontal pockets in this population, this randomized controlled clinical trial aimed to investigate the effectiveness of a novel aPDT protocol using BuTB as an adjunct to non-surgical periodontal therapy.
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