## 1 Introduction
(photo-oxidative stress), which leads to severe damage to bacteria cell membranes and nucleic acids [10]. Various light sources have been mentioned for aPDT, including light-emitting diodes (LEDs), halogen lamps, and lasers [11]. Among these, diode lasers (DLs) are particularly favored due to their portability, ease of use, and lower cost. Additionally, the wavelength range emitted by DLs aligns well with the electronic absorption spectrum of the majority of available PS [12]. The wavelength for irradiating a PS is determined by its absorption coefficient. It has been specified that appropriate wavelengths are 620-700 nm for toluidine blue O (TBO) and methylene blue (MB), 600-805 nm for cyanine, 620-650 nm for hematoporphyrins, 300-500 nm (ultraviolet/blue light) for curcumin and its derivatives, and 660-700 nm for phthalocyanines [13]. Several aPDT protocols have been published for the disinfection of root canals in patients with endodontic infections; however, there is noticeably high variability in the parameters used among them. Despite this wide variation in parameters, aPDT has been shown to be effective in reducing the bacterial load within the root canal [14,15]. On the other hand, photobiomodulation therapy (PBMT) involves using non-thermal light at wavelengths ranging from 650 to 1350 nm to induce a biological response through photonic energy transfer. This non-ablative energy modulates the biological processes of the target tissue, directing its action mainly to tissue repair and pain reduction [16]. PBMT, also called low-level laser therapy (LLLT), operates through a photochemical effect, where the absorbed light triggers a chemical reaction known as photobiostimulation. This process influences the release of various growth factors, which are essential for the development of epithelial cells, fibroblasts, collagen, and vascular proliferation [17]. The effects generated can be described as anti-inflammatory, analgesic, and accelerated wound healing, while also stimulating the synthesis of enzymes that play roles in lysosomes and mitochondria [18]. Visible and infrared laser radiation produces photophysical effects that alter intracellular activities, impacting the respiratory chain by boosting ATP within the mitochondrial membrane (Figure 2A). Promising results have been reported for PBMT on human gingival fibroblast proliferation [19,20] or in bone tissue regeneration processes [21,22] (Figure 2B). It is believed that LLLLT reduces post-operative pain primarily by stimulating the production of endorphins, which, in turn, mitigates discomfort [23]. Figure 2: Schematic of the mechanisms of action and clinical effects of photobiomodulation: (**A**) Cytochrome C oxidase (CCO), the primary chromophore located in complex IV of the mitochondrial respiratory chain, plays a critical role in PBMT. When CCO absorbs light (particularly in the red and near-infrared wavelengths), it leads to the photodissociation of nitric oxide (NO). This process reduces oxidative stress and subsequently boosts the production of reactive oxygen species (ROS), ATP, and calcium ions (Ca\({}^{2+}\)). As a result of increased ATP and protein synthesis, the growth factor response within cells and tissue occurs. These changes promote the desired biological responses, including anti-inflammatory, analgesic, and healing effects, while also enhancing cellular processes such as differentiation, proliferation, and migration. For these effects to occur, light must be absorbed by chromophores, which are interrelated molecules (e.g., enzymes, cell membranes, and extracellular substances) that have the capacity to absorb light. (**B**) Extraoral application of laser (red/infrared) directed toward the apical area of the affected tooth. By irradiating this area as a supplement to the endodontic treatment, accelerated bone tissue regeneration can be achieved. As far as we are aware, there is limited information available regarding treatments that incorporate both aPDT and PBMT as adjunct therapies in in vivo studies.