In dermatology, the use of non-ablative and ablative fractional lasers has become the gold standard treatment for a number of indications. Among ablative dermatological laser systems, the carbon dioxide (CO
2) laser (wavelength 10,600 nm) and the erbium yttrium aluminium garnet (Er:YAG) laser (wavelength 2940 nm) are the most frequently used [
1]. While the wavelength of the CO
2 laser is absorbed by intracellular water, leading to tissue heating and vaporization, the Er:YAG laser causes only a minimal thermal reaction in the skin [
2]. Non-ablative laser systems such as the Er:glass laser (wavelength 1540 nm) also cause collagen heating and dermal remodelling, but due to the cooling of the epidermis there is no injury and no tissue vaporization, reducing the risk of side effects [
2]. Although non-ablative and ablative fractional lasers are widely used in the treatment of a variety of indications, the molecular effects of these laser treatments on human skin cells are not yet completely understood. However, the knowledge of the underlying biological properties of a laser system is essential in order to optimize its application and to evaluate its safety aspects. Each of the individual laser types is advantageous for different types of indications due to its respective properties, but new technologies open up new fields of application for individual laser systems. In this context, the VSP (variable square pulse) technology has broadened the scope of use of the Er:YAG laser by enabling a non-ablative mode [
3]. The mechanism of action is the production of low fluence pulses inside an overall super-long pulse that is absorbed at the tissue surface and cause transient heat increase of the collagen, inducing tissue shrinkage and remodelling, but also microvascularization and new vessel formation [
4,
5]. Using the non-ablative mode, the Er:YAG laser is nowadays an important tool for various minimally invasive, non-surgical procedures on mucosa, e.g., in gynecology [
4] or oral tissue thermotherapy to reduce snoring [
6]. Although many clinical studies have confirmed the efficacy of Er:YAG laser therapy with non-ablative mode [
5,
7‐
13], the underlying molecular effects on gene regulation are scarcely known. …
