## 1 Introduction
Indeed, from a cellular point of view, the primary interaction with the photoacceptors, such as the cytochromes of the mitochondrial respiratory chain, the lipids, the nitrosothi compounds, and the bounded water and the modification of their energetic and vibrational state, supports the release of adenosine triphosphate (ATP), reactive oxygen species (ROS), nitric oxide, as well as calcium, which is liberated through voltage-dependent receptors or released from sequestered reserves of the organelles [16,17]. From a medical point of view, the energized cells and the activation of cellular pathways can resolve in improving inflammation, regeneration, and more generally, in the homeostasis recovery of metabolic dysfunction of the tissues [18]. Concerning the effect of photobiomodulation on AS, in our recent review [12], we concluded that \"photobiomodulation is a promising treatment modality. However, due to the heterogeneity of the literature's data, photobiomodulation needs further testing through well-designed, long-term, and randomized controlled trialstudies, allowing to evaluate it with diligent and impartial outcomes\". For instance, our screening of literature according to the PRISMA guideline through PubMed/MEDLINE and Google Scholar databases, using the keywords--Low-Level Laser Therapy OR Photo-biomodulation and aphtha OR aphthae OR aphthous (inclusion criteria: indexed papers written in the English language, peer review process, clinical studies, full research articles, description of therapy parameters following the criteria suggested by [PERSON] and [PERSON] [19]), found more than 900 papers, which was reduced to 76 and then 12 eligible works [20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31]; however, the articles were omitted if both the evaluation of irradiated energy by a power meter and the temperature measure before and after irradiation were requested for eligibility. Plus, many therapies were administered, starting from a non-indicated distance from the lesion with the operator slowly approaching the lesion, or in other cases, the distance from the affected area was kept \"quite constant\", but the fiber or handpiece was moved in a circular or \"painting-like\" fashion [21; 25]. Besides, the irradiation time indicated a lack of accuracy and it is described as being of only a \"few seconds\", or the therapy is administered with intervals of a few, but not a precise number of minutes between the two or more repeated irradiations; the actual irradiated parameter can therefore change from one operator to another, influencing the photobiomodulation therapy reliability and repeatability. To improve the clinical knowledge and the support of photobiomodulation in the treatment of aphtha healing and the standardization of the therapies, we thus set up a randomized double-blind controlled trial. In our previous works, we showed that a higher-power and -fluence laser therapy, such as 808-nm, 1 W, 1 W/cm\({}^{2}\), 60 J/cm\({}^{2}\), positively affects mitochondrial energetic metabolism [32; 33; 34], improving healing [35; 36; 37; 38] in in vitro and preclinical studies. Plus, we characterized a novel technology based on irradiation with a flat-top beam profile that can be supportive of the effectiveness and standardization of photobiomodulation therapy [32; 39] and Section 2.3 below. Therefore, the predictor variable of our research was the photobiomodulation through higher energy and power irradiated through the flat-top handpiece. The primary end point was the complete healing of the aphtha, defined as the time from the irradiation to the complete recovery. The secondary end point was pain relief, evaluated daily through the visual analogue scale (VAS), from the irradiation to 24 and 48 h after.