## 4 Discussion  
In this first controlled clinical trial with a split face design, CAP (8\(-\)10 treatments within four to six weeks) was shown to be a safe and effective method for treating moderate facial acne in adults. The treated side of the face showed a significant and continuous decrease in inflammatory acne lesions from baseline to the last treatment (\(-\)30%) as well as to the two-week follow-up (\(-\)44%) and the four-week follow-up (\(-\)52%). No significant reduction was found for non-inflammatory lesions on the treated side and for inflammatory and non-inflammatory lesions on the untreated side. The mean absolute change in acne lesions did not significantly differ between the treated and the untreated side from baseline to the last treatment and the two- and four-week follow-ups, although the treated side showed a clear trend for an increased reduction in lesions. Indeed, significant differences between the treated and the untreated side were found in the subgroup of patients who had received 10 instead of 8 CAP treatments. After 10 treatments, the reduction in inflammatory acne lesions was significantly higher on the treated side than on the untreated side at the time of treatment completion as well as at the two- and four-week follow-ups. In general, inflammatory acne lesions responded better to CAP treatment than non-inflammatory lesions. Significant differences were also found for the subjective aesthetic change as measured by means of the GAIS. The percentage of patients reporting improved aesthetics was higher for the treated side than for the untreated side at the last treatment (79% vs. 45%) and at two-week (72% vs. 45%) and four-week follow-ups (79% vs. 52%). The physicians' ratings of aesthetics (GAIS) and the physicians' acne severity ratings (IGA) however, did not yield significant differences between the treated and the untreated side after therapy. The major pathogenetic factors in the development of acne are increased sebum production by hyperplastic sebaceous glands, follicular hyperkeratinisation, bacterial hypercolonisation of the follicle and immune reactions triggering inflammation [28]. _Cutibacterium acnes_ contributes to the formation of micro-comedones and inflammatory lesions, triggering the secretion of proinflammatory cytokines, such as interleukin (IL)-1\(\alpha\), IL-8 and tumour necrosis factor (TNF)-\(\alpha\) through activation of toll-like receptors (TLR) [29; 30; 31]. The rationale for using CAP to treat acne was the assumption that CAP may target some of these causative factors. CAP has been shown to inactivate _Cutibacterium acnes_ grown on culture media in planktonic and even in biofilm state in a time-dependent manner [32]. In addition, CAP uses hair as a conductor that transports the plasma deep into the hair follicles, thus enabling local antisepsis of the follicular reservoir [27]. In an in vivo animal model, CAP induced energy-dependent microscopic changes in the follicular epithelium and the sebaceous glands [33]. The authors suggest that sebaceous glands can be selectively modified or damaged by selecting the proper gaseous sources for generating CAP with regulated energy settings. Furthermore, CAP modulates the induction of several cytokines and growth factors in wound healing (e.g., IL-1, IL-6, IL-8, TNF-\(\alpha\), 8-defensins and matrix metalloproteinases), which also play a pathogenetic role in acne [34; 35; 36; 37]. Thus, it can be hypothesised that CAP effects on acne result from inactivation of _Cutibacterium acnes_, alteration of the follicular milieu and reduced sebum production as well as from immunomodulatory and anti-inflammatory effects. Cold plasma has been studied with regard to its use for the treatment of several dermatological conditions, but controlled clinical studies on acne are still lacking. In an uncontrolled study conducted in Thailand, a Direct Barrier Discharge air plasma contact skin-type electrode (called BioPlasma device) was used for acne treatment.