**3.6 Dermograph**

The use of dermographs has also been investigated to improve drug delivery. A dermograph is a device currently used in esthetic procedures, which works similarly to a tattoo machine, with simpler handling [44]. The device is composed of a handpiece that couples to different types of needles which oscillate vertically. Usually, both frequency and depth can be adjusted in those devices, according to the application. The holes performed into the skin allow for greater skin penetration of liquids by capillarity [45, 46].

A more homogeneous PpIX distribution and a greater penetration in the tissue were observed for animal model using dermographs compared to the topical application of the cream only [46]. A pilot clinical trial was also performed in nodular BCC lesions using a dermograph for intradermal delivery in PDT, and no recurrence was observed after 28 months of follow-up [46].

### **3.7 Temperature**

Temperature is a parameter with a strong influence on PpIX formation. The increase of the skin temperature (especially in areas that naturally present lower temperatures such as the extremities of the body) during the DLI can improve PDT effectiveness. There are four hypotheses regarding the PpIX formation with the increase of local temperature: increase of ALA penetration in the skin; increase of the conversion rate of ALA to PpIX; increased ALA uptake in the cells due to disruption of the cell membrane, and increase of the amount of skin oxygen due to vasodilation [13, 47].

However, the temperature must be well controlled in order to obtain the desired effect and prevent damage to surrounding tissues [48]. Stringasci *et al.* demonstrated that the most efficient way to increase the production of PpIX and its penetration in the tissue by temperature is to increase the local temperature before applying the cream. This same study reported that the prolonged increase of temperature (during 3 hours) promoted a smaller amount of PpIX accumulation in the skin, unlike other abovementioned hypotheses. That happens because, after increasing the temperature for longer times, cellular metabolism is accelerated which promotes faster elimination of PpIX within the cells [47]. In a clinical study, Willey *et al.* reported the results after PDT treatment of AK on the extremities (head, fingers, and toes) in 18 patients. Skin warming was performed during DLI and was well tolerated, did not promote side effects, and improved PDT efficacy with a clearance rate of 90% after a 1-year follow-up [49].
