# Advancing Dermatological Care: Potential of Gas Plasma Technology for Actinic Keratosis Treatment

L. Mckeever, L. Boeckmann, A. Bogaerts, S. Emmert, A. Privat-Maldonado, Eric Robert, D. Singer, E. Smits, A. Stancampiano, A. Sobota, et al.

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## To cite this version:

L. Mckeever, L. Boeckmann, A. Bogaerts, S. Emmert, A. Privat-Maldonado, et al. Advancing Dermatological Care: Potential of Gas Plasma Technology for Actinic Keratosis Treatment. IEEE Transactions on Radiation and Plasma Medical Sciences, inPress, 10.1109/TRPMS.2025.3639175. hal-05495969

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Submitted on 5 Feb 2026

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# Advancing Dermatological Care: Potential of Gas Plasma Technology for Actinic Keratosis Treatment

L. McKeever, L. Boeckmann, A. Bogaerts, S. Emmert, A. Privat-Maldonado, E. Robert, D. Singer, E. Smits, A.

Stancampiano, A. Sobota, T. von Woedtke, K.-D. Weltmann, K. Wende, S. Bekeschus

**Abstract**— Actinic keratosis is a precancerous skin condition, often necessitating effective treatment to prevent progression to invasive, potentially lethal skin cancer. Traditional methods, such as cryotherapy and other topical therapies, pose various challenges, including discomfort and the potential for scarring. In recent years, medical gas plasma technology has emerged as a potential additional therapeutic option, leveraging the unique properties of such partially ionized gases to offer a non-invasive and targeted approach. This review critically evaluates clinical evidence from CE-certified plasma devices, including the kINPen MED and PlasmaDerm VU-2010, which demonstrate the efficacy and safety of plasma treatment in accelerating healing, lesion burden reduction, and skin rejuvenation. Building on these clinical insights, the review also outlines the underlying mechanisms of plasma-induced oxidative stress, discusses advancements in device design that enhance treatment precision and patient comfort, and highlights existing challenges such as standardization and reproducibility. Together, these findings position medical gas plasma as a compelling addition to the dermatological treatment landscape and underscore the need for continued translational and clinical research to establish its place in standard AK therapy.

This work received funding from a Marie Sklodowska-Curie Action (MSCA) Doctoral Network (DN) by the European Commission (EC) under the Horizon Europe Research and Innovation Program, grant number 101118430. (Corresponding author: S. Bekeschus). L. McKeever is with Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany (lauren.mckeever@inp-greifswald.de). L. Boeckmann is with Department for Dermatology, Rostock University Medical Center, Strempelstr. 13, 18057 Rostock, Germany (lars.boeckmann@med.uni-rostock.de). A. Bogaerts is with PLASMANT, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen-Wilrijk, Belgium (annemie.bogaerts@uantwerpen.be). S. Emmert is with Department for Dermatology, Rostock University Medical Center, Strempelstr. 13, 18057 Rostock, Germany (steffen.emmert@med.uni-rostock.de). A. Privat-Maldonado is with

**Index Terms**—CAP; medical gas plasma; plasma medicine; reactive oxygen and nitrogen species; ROS; actinic keratosis; SCC; squamous cell carcinoma

## I. INTRODUCTION

THE widespread use of technology is the critical accelerator of improvements for human health and prosperity. Many of these success stories originated from critical innovations in physics and were further developed through interdisciplinary collaborations in engineering, chemistry, biology, and medicine. For example, physics-based research on X-rays motivated their diagnostic use for bone fractures and led to even more advanced techniques, such as computer tomography scans. Furthermore, ionizing radiation-boosted X-rays have become frontline treatments in oncology. Similarly, breakthroughs such as photodynamic therapy (PDT) [1] and pulsed electric field-driven electrochemotherapy (ECT) [2] have provided

PLASMANT, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen-Wilrijk, Belgium (angela.privatmaldonado@uantwerpen.be). E. Robert is with GREMI, Orléans University, 14 rue d'Issoudun, BP6744, 45067 Orléans Cedex 2, France (eric.robert@univ-orleans.fr). D. Singer is with ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany (debora.singer@inp-greifswald.de). E. Smits is with CORE, IPPON, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen-Wilrijk, Belgium (evelien.smits@uantwerpen.be). A. Stancampiano is with GREMI, Orléans University, 14 rue d'Issoudun, BP6744, 45067 Orléans Cedex 2, France (augusto.stancampiano@univ-orleans.fr). A. Sobota is with Department of Applied Physics, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands (a.sobota@tue.nl). T. von Woedtke is with ZIK plasmatis, Leibniz Institute for Plasma Science
and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany (thomas.woedtke@inp-greifswald.de). K.-D. Weltmann is with ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany (klaus-dieter.weltmann@inp-greifswald.de). K. Wende is with ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany (kristian.wende@inp-

substantial therapeutic benefits to many tumor patients. In this context of continual innovation, medical gas plasma technology emerges as a promising advancement in oncology and oncoimmunology [3]. Offering a non-invasive and targeted approach, it leverages the reactive properties of gas plasma to achieve tumor lesion reduction and regulation of inflammatory processes. Such advancements underscore the transformative potential of physics-based technologies in dermatology and beyond, marking a new frontier in the diagnosis and treatment of human diseases, particularly in treating the most prevalent human precancerous skin condition, actinic keratosis, which may progress to squamous cell carcinoma if left untreated [4]. Keratinocyte-associated cancers, particularly squamous cell carcinomas (SCCs), represent a significant challenge in oncology, with cutaneous and oral forms being the most prevalent [5, 6]. These cancers arise from keratinocytes, the predominant cell type in the epidermis and mucosal tissues [7], necessitating effective treatment strategies that minimize damage to surrounding healthy tissues.

## II. ACTINIC KERATOSIS – DISEASE AND TREATMENT

### *Disease*

The prevalent skin condition actinic keratosis (AK) is a common precancerous condition that arises

greifswald.de). S. Bekeschus is with ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany (sander.bekeschus@inp-greifswald.de) and Department for Dermatology, Rostock University Medical Center, Strempelstr. 13, 18057 Rostock, Germany (sander.bekeschus@med.uni-rostock.de). This work did not involve human subjects or animals in its research.

from chronic ultraviolet (UV) radiation exposure [8] and is considered a precursor to squamous cell carcinoma (SCC), an invasive and potentially deadly skin cancer. While AK is generally agreed to result from keratinocyte dysplasia in the epidermis, its exact classification remains a topic of debate due to its variable clinical and histological presentation and its position on the continuum between benign skin damage and invasive SCC [9]. AK often presents as scaly, rough lesions that are reddish or flesh-colored, with sizes ranging from small patches of a few millimeters to larger plaques formed by the consolidation of lesions [10, 11]. A subset of lesions exhibit unique features such as telangiectasias, small dilated blood vessels that appear near the surface of the skin or mucous membranes, within or surrounding the lesion, while others are often heavily pigmented [12]. The most commonly affected areas are the face, scalp, and other sun-exposed regions [11](Fig 1). Although many AK are asymptomatic, some may cause discomfort, including itching or tenderness [11]. Risk factors include lighter skin types (Fitzpatrick types I and II) and a history of significant sun exposure [13]. From a histopathological standpoint, AK is characterized by atypical keratinocytes, nuclear abnormalities, and increased cellular activity in the basal epidermis [12]. Features like solar elastosis and inflammatory infiltrates are common markers of UV-induced damage, although these characteristics vary widely between cases [12]. Advances in dermoscopy and non-invasive diagnostic tools have improved early
detection [14], but distinguishing AK from other conditions such as seborrheic keratosis or early SCC remains challenging.

Millions of Europeans have one or several AK lesions, and it is one of the most common diseases on our continent, with incidences rising with age and thus within the aging European societies [15]. As exposure to UV light-induced damage accumulates throughout life, the prevalence of AK in people >80 years exceeds 90% [16]. AK also has an immunological dimension, as in some cases, its development occurs in people exposed to ionizing radiation, suffering from acquired immune deficiency syndrome (AIDS), or taking immunosuppressive drugs, such as organ transplant recipients and cancer patients. Hence, the onset of invasive squamous cell cancer from AK involves two steps: an excess of UV light-generated mutations in skin cells and a decrease in the capacity of the immune system to recognize and inactivate these mutated cells. AK lesions may develop into invasive SCC if left untreated. Considering that most patients have multiple lesions and that 85% of SCC develops in or close to such lesions exemplifies the importance of therapeutically targeting AK lesions for preventing invasive skin cancer and its associated suffering, deaths, and therapeutic costs [8].

From a biological point of view, AK lesions exhibit features of dysplasia and are regarded as early-stage precancerous lesions with the potential to progress to SCC. In these lesions, the malignant keratinocytes span the entire or part of the epidermis without penetrating the basal membrane. There is considerable genetic heterogeneity in AK cancer cells. With increasing age and mutational load, these cells may invasively spread into the dermis and

metastasize into distant body regions, forming invasive SCC (Fig 2). Although this is a rare event, many AK lesions per patient and millions of AK patients across Europe lead to a considerable incidence and prevalence of invasive SCC. In Germany, for instance, 213,000 new cases of non-melanoma cancers are estimated per year, of which 22% are SCCs [17].

## Treatment

Current treatment options for this easy-to-access skin disease include topical approaches, such as curettage, CO₂ laser ablation, cryotherapy, cytotoxic ointments like 5-fluorouracil, and immunomodulatory creams, including Imiquimod and Tirbanibulin [18]. However, the best treatment option for AK is prevention. This can be achieved by reducing UV radiation exposure, whereby multiple studies have highlighted the effectiveness of the use of sunscreen, which has been shown to have a dose-dependent effect on decreasing the development of new AK, as well as increasing the remission rate of existing lesions [19, 20]. Other efforts of prevention that are presumed to be effective include advocating safe sun practices, reducing the use of indoor tanning beds, and wearing protective clothing [21]. Among the available treatments, photodynamic therapy (PDT) is widely regarded as one of the most effective options, offering high clearance rates and favorable cosmetic outcomes [22]. For PDT, a photosensitizer is applied as a cream that preferentially enters dedifferentiated keratinocytes. After three hours, the treated area is irradiated with visible red light, initiating a phototoxic reaction. Notably, the therapeutic effect of PDT is driven by the generation of reactive oxygen species (ROS), such as singlet oxygen, superoxide, and hydroxyl radicals, which
induce oxidative stress and cell death in dysplastic
cells [23]. These ROS are also found to be produced
during gas plasma treatment, suggesting overlapping
oxidative mechanisms between the two treatment
modalities.

Despite the availability of multiple treatment modalities, each conventional therapy presents limitations that can impact patient outcomes and adherence (Table I). Cryotherapy and CO2 laser ablation, while effective in lesion clearance, are often associated with pain, risk of scarring, and post-treatment erythema [24-26]. Topical cytotoxic agents such as 5-fluorouracil, and immunomodulatory creams including Imiquimod and Tiranibulin, require prolonged treatment schedules that may reduce patient adherence and increase local irritation [27-29]. PDT, although offering favorable cosmetic outcomes, can be uncomfortable and time-sensitive, and access to specialized equipment may be limited [25, 30-32]. In this context, medical gas plasma emerges as a promising alternative. Building on research from the late 2000s, medical gas plasma has increasingly been explored for treating various dermatological conditions [33, 34]. This innovative treatment modality utilizes gas plasma to selectively target abnormal keratinocytes, offering a non-invasive approach that minimizes damage to surrounding healthy tissue. As research continues to unveil its potential benefits, gas plasma therapy represents a significant advancement in the management of AK.

### III. MEDICAL GAS PLASMA TECHNOLOGY

#### *Mechanism of medical gas plasma production*

In medical applications, non-thermal atmospheric-pressure plasma is commonly used, as it

remains close to body temperature, which prevents thermal damage to tissues. This low temperature, combined with reactive oxygen and nitrogen species (RONS) production, makes non-thermal gas plasma (hereinafter referred to as *plasma*) a promising tool for treating skin diseases like AK. In current clinical settings, the two main configurations are plasma jets and dielectric barrier discharges (DBDs).

DBD-based devices generate plasma directly between two electrodes, one of which is typically in contact with or near the skin [36]. Depending on the electrode geometry, DBDs can be classified as surface DBDs, where plasma forms along the dielectric surface [37], or volume DBDs, where plasma occupies the gap between the electrodes [38]. Surface DBDs are particularly relevant in dermatological contexts, as they ensure homogenous exposure of larger treatment areas commonly using ambient air as the feed gas. In contrast, plasma jets operate by directing a plasma effluent, often sustained in noble gases such as helium, or argon toward the target tissue. This configuration allows for localized, contact-free treatment and controlled delivery of reactive species to the skin surface [35]. Both configurations produce therapeutic levels of RONS at body-safe temperatures, yet they differ in plasma chemistry, electric field exposure, and depth of interaction with biological tissue [3]. Understanding these distinctions is crucial for optimizing treatment parameters and comparing device outcomes across studies. Building on the fundamental principles of plasma generation, plasma multijet technology enhances the application by enabling precise and efficient coverage of larger areas, making it particularly suitable for medical treatments. Plasma multijet technology utilizes multiple, small plasma jets arranged in an array to
cover larger surface areas effectively and uniformly [39]. In the first option, each jet is powered by a controlled electric discharge, producing a stable and consistent plasma flow. In a second option, a primary jet powered by a controlled electric discharge is split into stable secondary jets [40, 41]. The first option consists of individual jets exiting from individual dielectric capillaries equipped with individual high-voltage electrodes inside. The second option generates multiple jets from a single dielectric assembly with multiple gas flow orifices and a single high-voltage electrode. This second option offers more flexibility than the first to generate multiple jets close together but is more unstable if jets are to be delivered on uneven surfaces. With both options, multijet devices can be tailored to optimize treatment for specific tissue types by adjusting parameters like voltage, frequency, and gas flow rate. This technology allows for precise targeting, minimizes heat generation, and enhances the delivery of RONS critical for cellular effects, such as promoting cell death in abnormal skin cells.

### Key reactive species

Reactive species are chemically reactive molecules, radicals, or ions that play a significant role in biological processes [42]. They include reactive oxygen species (ROS), such as hydrogen peroxide ($H_2O_2$) and superoxide ($O_2^-$), and reactive nitrogen species (RNS), like nitric oxide (NO) and peroxynitrite ($ONOO^-$). In controlled amounts, these species are essential for cellular signaling, immune responses, and homeostasis [43]. However, an imbalance in reactive species can lead to oxidative stress, which can damage cellular components such as DNA, proteins, and lipids [44]. When plasma is generated, various reactive species are produced

depending on the gas type, plasma source, and treatment conditions. In plasma treated with oxygen or air, ROS such as ozone ($O_3$), singlet oxygen ($^1O_2$), hydrogen peroxide ($H_2O_2$), and hydroxyl radicals (OH) are common. These ROS play a crucial role in initiating oxidative stress within cells, which can lead to apoptosis (programmed cell death) in abnormal or pre-cancerous cells [45, 46]. Additionally, RNS, including nitric oxide (NO), nitrogen dioxide ($NO_2$), and peroxynitrite ($ONOO^-$), are generated when nitrogen is present in the plasma environment. The combination of ROS and RNS forms a complex mixture of species that interact with each other and with cellular components, amplifying the oxidative effects. This cocktail of reactive species is particularly beneficial in plasma medicine as it allows for selective targeting and destruction of damaged cells, as non-malignant cells have been, in some instances, described to exhibit higher resilience to reactive species-enriched environments [47, 48] (Fig 3). While electrons are also produced, their biological relevance appears minimal. Findings indicate that plasma-generated electrons penetrate only 1-10 nm into the liquid phase [49], suggesting that direct electron-driven reactions are unlikely to contribute substantially to downstream biological effects, particularly given the much greater thickness of the skin barrier (31.2-596.6 µm) [50].

### CE-certified medical gas plasma devices used in dermatology

Gas plasma technology has shown promise in dermatology and wound healing due to its antimicrobial [51], immunomodulating [52], and regenerative properties [53]. Several CE-certified devices are available for clinical use in Europe, each with unique features and applications (Table II). The
kINPen MED, a Class IIb (according to medical device regulation guidelines of the European Union) CE-certified device, has been extensively validated through clinical trials, demonstrating accelerated healing of chronic wounds such as diabetic foot ulcers and venous leg ulcers [54-56], with significant reductions in bacterial load (e.g., *Pseudomonas aeruginosa*) and enhanced tissue regeneration through keratinocyte proliferation and angiogenesis. [54-56] The PlasmaDerm VU-2010 is approved for wound and skin treatment. It has shown efficacy in improving epithelialization rates in venous leg ulcers and reducing biofilm-forming bacteria, with its large treatment area particularly suited for dermatology applications [57, 58]. SteriPlas® is CE-certified for chronic wounds and dermatological applications, with clinical case series demonstrating its effectiveness in managing infected chronic ulcers resistant to conventional treatments, as well as promoting granulation tissue formation [51, 59]. Plasma Care®, a flexible, patch-based device, has shown potential for wound care in pilot trials, with consistent bacterial load reduction and promotion of fibroblast activity and collagen synthesis [60]. Additional CE-certified devices include PLASOMA® (plasmacure) and CPTcube/CPTpatch (Coldplasmatech) designed for the treatment of chronic wounds [61, 62]. PLASOMA® employs a flexible pad delivering plasma generated from ambient air directly over chronic wounds, and clinical studies have demonstrated that it can achieve wound closure in 60% of chronic wounds [61]. The CPTcube/CPTpatch system consists of an automated control unit and a specialized wound dressing, producing plasma within the space between the patch and the wound surface [62]. It has been shown to

effectively treat various chronic wounds, including diabetic foot ulcers, venous leg ulcers, and pressure ulcers [62]. Together, these devices offer a comprehensive suite of tools for addressing various dermatological conditions, with clinical evidence underscoring their safety and efficacy in promoting wound healing and infection control.

## IV. PLASMA IN KERATINOCYTE-ASSOCIATED CANCER TREATMENT

### Squamous cell carcinoma

One promising avenue of research is the application of medical gas plasma technology as an emerging therapeutic strategy for SCC, where it induces apoptosis through the generation of RONS [63, 64]. These species disrupt cellular functions, leading to oxidative stress that is particularly detrimental to malignant cells. Clinical and preclinical studies have demonstrated its efficacy in both cutaneous and oral SCC, highlighting its potential as a non-invasive treatment that preserves surrounding healthy tissue [65, 66]. In oral SCC, the ability of plasma to penetrate and treat lesions within the oral cavity has been explored, yielding promising results in reducing tumor viability and enhancing local immune responses [67]. Additionally, plasma can enhance the effectiveness of conventional therapies, such as chemotherapy and immunotherapy, by sensitizing cancer cells to these treatments and potentially mitigating resistance mechanisms [68, 69].

In addition to its antitumor effects, plasma application has been shown to modulate tissue oxygenation, blood flow, and microcirculation, processes that may help support tissue regeneration and improve cosmetic outcomes, and reduce itching, tenderness, and suffering [70-74]. In the context of
cosmetic studies, plasma delivery was also shown to result in transient and reversible skin barrier modulation [75, 76]. Following short plasma exposure, the penetration of cosmetic/therapeutic compounds with various molecular weights drastically speeds up and enhances. Safe and short-duration plasma exposure may be considered preliminary skin care before the topical application of cytotoxic ointments. Both lower doses and likely reduced side effects induction of such ointments or more efficient penetration of the active compounds can be targeted in combination with plasma care.

In vivo plasma treatment revealed that plasma action is also achieved in subcutaneous tumors in murine models [77-79], meaning through the skin. These demonstrations underscore the effectiveness of plasma in treating surface and deep tumors, potentially targeting invasive cells spread across the epidermis and those in invasive SCCs. Briefly, AK, as a skin disease, may be targeted through plasma exposure in many ways based via RONS delivery, transient skin barrier “opening”, invasive cancer cell targeting, and tissue physiological modulations. A comprehensive review of the potentialities of plasmas for various skin treatments has also been recently published [80]. Overall, the application of plasma in the treatment of keratinocyte-associated cancers, particularly cutaneous and oral SCC, represents a significant advancement in oncological therapeutics.

## Pre-cancerous lesions

Medical gas plasma has shown potential as a therapeutic modality for AK, primarily through the generation of RONS that induce oxidative stress in dysplastic keratinocytes [81-84]. In addition to its direct effects on abnormal cells, some studies

suggest that plasma can modulate local immune responses [3]. This is reminiscent of the mode of action of PDT and topical immunomodulators. However, specific evidence of this phenomenon in the context of AK plasma treatment is currently limited and warrants further investigation. The non-invasive nature of plasma treatment is an attractive feature, offering a potential alternative to traditional cryo or pharmacological therapies for AK. Ongoing studies are focused on optimizing treatment parameters, such as exposure time and frequency, to maximize therapeutic efficacy while minimizing adverse effects. While there is little preclinical research on animal models specific to AK or AK-like lesions [85, 86], findings from related studies on skin conditions provide a foundation for further exploration and eventual clinical translation.

## Case reports and clinical data

Although preclinical data, especially from animal models, remain scarce, clinical studies and case series have provided encouraging evidence supporting the efficacy and safety of medical gas plasma as a non-invasive therapy for AK (Table III). For instance, it was reported that plasma treatment led to significant reductions in lesion size and improvements in skin texture, with histological findings indicating reduced atypical keratinocytes and no severe adverse effects [87]. A U.S.-based study similarly described a complete resolution of AK lesions in a case series, showcasing plasma's potential as an effective alternative to conventional treatments [88]. Two Germany-centered reports emphasized plasma's success in managing hyperkeratotic AK lesions, reporting complete lesion clearance in some instances [89] and hypothesized selective cytotoxicity, effectively targeting
dysplastic cells while sparing healthy tissue [90].
Moreover, it was concluded that several plasma
device types can lead to AK lesion clearance and
improved histological outcomes with minimal side
effects [91]. An initial study also evaluated plasma
exposure for treating AK and skin field
cancerization, combining clinical and high-
frequency ultrasound assessments. Their findings
revealed substantial reductions in AK lesion count,
normalization of epidermal thickness, and improved
dermal echogenicity, demonstrating plasma's
capacity to restore skin integrity [92]. The patients
enrolled also reported high satisfaction due to the
treatment's non-invasive nature and absence of
significant discomfort. Collectively, these studies
underscore the potential of plasma to provide a safe
and effective therapeutic option for AK, leveraging
reactive species and potentially other plasma-derived
mediators to achieve cytotoxicity, reduce lesion
burden, and improve overall skin quality. Building
on the promising results of plasma in treating AK,
clinical studies in the treatment of head and neck
cancers further demonstrate the potential of plasma
as a versatile therapeutic tool. In oral SCC samples
exposed in the laboratory to plasma, apoptosis
induction was found only in cancer but not in non-
malignant skin tissue [93]. This finding was
paralleled by changes in inflammatory secretion
profiles of patient-derived oral SCC tumor tissues
after exposure to kINPen MED plasma ex vivo [66].
Clinical experience further supports the utility of
such plasma treatments, with patients experiencing
tumor size reduction, improved tissue healing, and
reduced inflammation [94] when plasma is used
alongside standard therapies. This growing body of
evidence underscores the broader potential of plasma
not only in inflammatory and infection-associated

skin conditions but also in managing more early and
advanced cancers, offering a non-invasive,
adjunctive treatment option that promotes healing
and enhances therapeutic efficacy.

V. EXPLORING THE BENEFITS OF GAS PLASMA THERAPY FOR ACTINIC KERATOSIS

Scientific rationale

AK represents a significant precancerous
condition that, if left untreated, can progress to
invasive and potentially lethal SCC. In this way,
medical gas plasma technology would be a tool for
cancer treatment and prevention of cancer
progression. From a molecular perspective, plasma
exerts its therapeutic effects primarily through
generating reactive species, while some reports also
suggest other effectors, such as electric fields, to be
effective [95, 96]. This oxidative stress oxidatively
modifies critical cellular components, including
lipids, proteins, and DNA, leading to apoptosis in
pre-cancerous cells [97, 98]. Reactive species also
influence key cellular signaling pathways, such as
p53, which act as tumor suppressors by halting
proliferation and promoting programmed cell death
[99]. Furthermore, plasma exposure can modulate
pathways like MAPK [100, 101] and NF-κB [102],
reducing pro-survival signaling and inflammation.
Emerging evidence also points to the role of plasma
in inducing epigenetic modifications [103, 104],
such as DNA methylation and histone changes,
which may reprogram dysplastic cells toward normal
differentiation or increase their susceptibility to
immune-mediated clearance. Together, these
molecular effects position plasma as a potent,
targeted approach to eliminating pre-cancerous
keratinocytes. Beyond its direct cytotoxic effects,
plasma was suggested to have immunomodulatory
capabilities [105, 106] that could enhance its therapeutic potential for AK. Plasma-induced apoptosis often triggers immunogenic cell death (ICD), a process marked by the release of danger-associated molecular patterns (DAMPs) such as calreticulin, adenosine triphosphate (ATP), and High-Mobility-Group-Protein B1 (HMGB1) [107, 108]. These molecules activate dendritic cells and promote antigen presentation, thereby initiating robust T-cell responses against tumor cells and potentially also against dysplastic and potentially malignant keratinocytes. Plasma treatment was found to modify the local cytokine milieu, including inflammatory mediators relevant to the tumor microenvironment (TME). This includes interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), as well as tumor-infiltrating leukocytes (TILs) in kINPen plasma-treated tumors [109, 110]. These immunological effects underscore the potential of plasma to not only treat existing lesions but also provide a durable anti-tumor immune response. The dual molecular and immunological effects of plasma make it a compelling option for treating AK. Its ability to selectively induce oxidative stress in pre-cancerous cells, reprogram cellular signaling and enhance anti-tumor immunity positions it as a novel therapeutic tool. This is also paralleled by oxidative processes in lipids, such as lipid peroxidation, and plasma-derived reactive species transport across membranes through, e.g., aquaporins [111, 112] (Fig 4).

## *Practical patient perspective*

From a practical patient perspective, the use of plasma in the treatment of AK presents several significant advantages that enhance the overall treatment experience. These benefits contribute not

only to patient satisfaction and comfort but also to improved compliance and outcomes. One of the primary advantages for patients is the non-invasive nature of plasma treatment. Unlike traditional therapies such as cryotherapy or curettage, plasma can be applied quickly and comfortably without the need for anesthesia to large skin areas [88-90, 92, 113]. This ease of application is particularly appealing for patients who may be anxious about more invasive procedures, making them more likely to seek treatment for their AK lesions. Moreover, the procedure typically involves minimal downtime, allowing patients to resume their daily activities almost immediately after treatment. Most patients experience only mild erythema or transient irritation at the treatment site, which can be easily managed with over-the-counter emollients. This low-impact recovery process is a stark contrast to more invasive therapies that may require significant healing time, leading to increased patient comfort and convenience. Patient satisfaction is further enhanced by the efficacy of plasma in achieving lesion clearance. Clinical studies have demonstrated high rates of complete clearance and improvement in AK lesions: Solaraze – 40% complete clearance, Tirbanibulin – 50% complete clearance, Imiquimod – 70% complete clearance, 2x PDT > 90% complete clearance [87-90], which can lead to increased patient confidence and a more positive perception of their skin health. Additionally, the potential for a lower recurrence rate compared to, e.g., cryotherapy provides patients with peace of mind, knowing that they are investing in a treatment that is more likely to provide lasting results.
Plasma source needs

From the perspective of plasma source
technology, the use of medical gas plasma in treating
AK offers distinct advantages that enhance treatment
efficacy and patient safety. The choice of the plasma
source, its covered area, and the (chemical) energy
being deposited can play a role in determining the
clinical outcomes and practical applications of this
innovative therapy. One significant advantage of
using atmospheric pressure plasma sources is their
ability to generate a diverse range of reactive species
that are essential for therapeutic action. These
sources produce reactive species at ambient
conditions, allowing for immediate interaction with
biological tissues. The non-thermal nature of these
plasma sources ensures that the surrounding healthy
tissues remain unharmed, thereby reducing the risk
of adverse effects commonly associated with other
treatment modalities. The versatility of plasma
sources is another key advantage. Different devices
can be adapted for various treatment protocols, such
as surface treatment for localized lesions or deeper
penetration for broader applications.

For instance, DBD devices typically generate
plasma over larger, planar areas, making them
advantageous for treating extended skin surfaces in a
single exposure [114]. Their configuration allows
uniform plasma exposure without requiring
mechanical movement of the device [114]. However,
DBDs can inadvertently affect surrounding healthy
tissue due to their broad treatment footprint and
limited control over the plasma-tissue interface. This
challenge becomes particularly relevant for AK,
where lesions are irregularly shaped and often
indistinct from surrounding tissue.

Plasma jets, on the other hand, provide
exceptional spatial precision [35]. Their pen-like
geometry enables localized delivery of reactive
oxygen and nitrogen species to target tissue while
sparing adjacent healthy areas [35]. The conductive
connection between the plasma jet and the tissue
surface allows for visually guided application and
more effective deposition of plasma-derived
effectors [115]. However, this precision comes at the
cost of limited coverage area [3]. Treating larger or
multifocal AK lesions using a single jet can be time-
consuming and less practical in clinical workflows.

Multijet systems represent a promising
technological evolution that bridges this gap. By
combining several small jets into a coordinated array,
they maintain the precision and controllability of
individual jets while significantly increasing the
treatment area. At first glance, the concept of
combining multiple plasma jets might appear to
challenge the intrinsic advantage of precision
associated with single-jet devices. However, multijet
configurations instead extend this precision to
clinically relevant lesion sizes, allowing efficient
coverage or larger or irregularly shaped areas while
maintaining controlled, localized plasma delivery.

From a translational standpoint, successful
implementation of plasma therapy for AK will
depend on harmonizing device design with
standardized diagnostic and operational parameters.
Quantitative plasma diagnostics, including
characterization of RONS flux, electron density, and
electric field strength at the plasma-liquid interface,
remain essential for comparing devices and
predicting biological outcomes. In particular,
diagnostics within the liquid phase will be crucial for
bridging physics-based characterization with
biological efficacy.

can be precisely controlled to target specific
areas of the skin, allowing for tailored treatment
strategies that can be optimized based on individual
patient needs and lesion characteristics. This
adaptability makes plasma a valuable option in a
clinical setting, as it can be potentially used for
multiple applications ranging from AK to other skin
lesions. Moreover, the ease of use and portability of
many plasma devices enhance their practicality in
clinical settings. Mobile units, such as hand-held
plasma pens, facilitate treatment in outpatient
environments, improving patient access and
convenience. This portability allows for immediate
application in dermatology clinics, thereby
streamlining the treatment process and minimizing
delays that can occur with traditional therapies.
Additionally, ongoing advancements in plasma
source technology promise to further enhance
treatment outcomes. In-depth studies on device
design and operational parameters can improve the
consistency and reproducibility of plasma treatments
[116], potentially leading to more reliable clinical
results. Plasma jets also have the advantage of
penetrating cavities and allowing for a homogenous
deposition of plasma-derived effectors onto the
target tissue. This is because of their non-flat
geometry, as opposed to the flat-shaped surface or
floating-potential dielectric barrier discharges
(DBDs) [36]. The pen-like or scalpel-like operation
of plasma jets also allows for a direct conductive
connection between the plasma and the target tissue
that can be controlled visually by the treating
physician and was shown to enhance the reactive
species deposition and anticancer activity
significantly. Such critical impact for RONS and

electric field delivery from plasma jets over various
targets having different electrical features,
mimicking biological tissue interaction, was reported
in detail and documented by plasma physics teams
[117, 118]. Recent studies have reported using
plasma jets as spot probes to distinguish tissues based
on plasma spectral emission or electrical features
dependent on the targeted sample. Machine learning
algorithms have been successfully implemented for
this purpose, analyzing the interaction of plasma jets
with biological targets [119]. Such noninvasive, AI-
driven approaches hold promise for controlled, safe,
and personalized skin treatment [120].

Safety and regulatory considerations

Ensuring patient safety and regulatory
compliance remains a key prerequisite for advancing
medical gas plasma therapy from clinical trials to
routine dermatological use. Although existing
clinical data indicate a favorable safety profile,
typically limited to mild erythema or transient
irritation [87-90, 92], the long-term safety of
repeated treatments and potential cumulative
oxidative effects require continued evaluation.
Particular attention should be given to parameters
such as local dose control, reactive species exposure,
and tissue temperature rise, which are crucial for
defining therapeutic windows and preventing
overtreatment.

From a regulatory perspective, plasma devices
occupy a unique position at the interface between
medical devices and active biological agents. Under
the European Medical Devices Regulation (MDR),
CE certification ensures conformity with safety and
performance standards [121]; however, current
assessment frameworks are primarily device-focused
and may not fully capture dynamic plasma-tissue
interactions or the biological activity of plasma-
derived effectors. In Germany, the introduction of
the original DIN SPEC 91315:2014-06 [122] laid
foundational guidelines for physical and biological
characterization of medical plasma sources. In July
2025, this was formally replaced by DIN SPEC
91315:2025-07 [123], which expands and
modernizes these requirements to account for
advances in plasma diagnostics and application-
specific standards.

Future regulatory progress will likely depend on
integrating plasma diagnostics with biological end-
point testing to develop validated reference
parameters. Coordinated efforts between engineers,
clinicians, and regulatory authorities will be essential
to expand frameworks like DIN SPEC into EU-wide
standards. Such efforts will support transparent
quality control, reliable efficacy assessment, and the
safe integration of plasma therapy into
dermatological practice for AK and other related skin
disorders.

Economic perspective

The rising incidence of AK, driven by an aging
population and increased sun exposure, necessitates
effective and cost-efficient treatment modalities.
Medical gas plasma technology presents a promising
economic advantage in the management of AK,
offering several key benefits that can reduce overall
healthcare costs while improving patient outcomes.
Firstly, plasma treatment is a non-invasive procedure
that often requires fewer clinical visits compared to
traditional therapies such as cryotherapy or topical
chemotherapeutics. This reduction in treatment
sessions translates to lower direct costs for both
healthcare providers and patients, minimizing the
financial burden associated with repeated visits and

associated procedures. Additionally, the quick
recovery time associated with plasma means that
patients can resume their daily activities sooner,
potentially decreasing lost productivity and
absenteeism from work. Secondly, the ability of
plasma to achieve high rates of lesion clearance with
minimal side effects can lead to improved patient
satisfaction and adherence to treatment protocols
[87-90, 92]. Higher treatment efficacy reduces the
likelihood of recurrence, a significant cost driver in
managing AK. Fewer recurrences benefit patients'
health and diminish the long-term costs associated
with managing complications and additional
treatments. This way, integrating plasma technology
into clinical practice may alleviate economic
pressure on healthcare systems. As an innovative
approach, medical gas plasma has the potential to
streamline treatment pathways and optimize resource
utilization, leading to better allocation of healthcare
resources. By reducing the need for more invasive
procedures and extensive follow-up care, healthcare
providers can focus their efforts on prevention and
early intervention strategies, ultimately leading to a
more sustainable healthcare model.

VI. LIMITATIONS AND CHALLENGES

Despite encouraging results, several challenges
impede the clinical translation of plasma therapy for
actinic keratosis. A key limitation lies in the lack of
standardized diagnostic and benchmark parameters
for comparing plasma sources. Variability in device
configuration, gas composition, treatment distance,
and operating parameters complicates
reproducibility and makes it difficult to correlate
plasma characteristics with biological outcomes.
Establishing reference parameters, such as reactive
species flux, electron density, or energy input at the
plasma-liquid interface, alongside harmonized reporting standards, would enable more meaningful cross-study comparisons and improve predictive power regarding therapeutic efficacy. Advancing plasma diagnostics in liquid phases, where most biologically relevant interactions occur, is especially critical to bridge the gap between plasma physics and biological responses.

Furthermore, the long-term safety and efficacy of plasma treatment remain insufficiently characterized. Most current investigations focus on short-term endpoints such as lesion clearance or wound healing, while longitudinal data on recurrence rates, cumulative oxidative stress, and potential genotoxicity are still limited. Addressing these gaps through standardized methodologies, extended follow-up studies, and collaborative efforts across clinical centers will be essential for establishing plasma therapy as a reliable and reproducible option in dermato-oncological care.

## VII. CONCLUSIONS AND OUTLOOK

Medical gas plasma technology represents a promising advancement in the treatment of AK, providing an effective and non-invasive alternative to traditional therapies. The unique ability of plasma to generate RONS allows for potentially selective targeting of abnormal cells while preserving healthy tissue, addressing a significant challenge in dermatological treatments. Clinical evidence supports the safety and efficacy of this approach, with patients experiencing minimal side effects and high lesion clearance rates. This reinforces the potential for plasma to become a preferred treatment modality for AK, especially for patients seeking less invasive options. The future of medical gas plasma technology in dermatology looks promising, with

ongoing technological advancements expected to further optimize treatment outcomes. Innovations in plasma source design and operational parameters will likely enhance the precision and reproducibility of treatments, making them more accessible and effective across diverse clinical settings. Continued research into the mechanisms of action and the development of plasma devices will expand the therapeutic applications of plasma. As regulatory frameworks evolve to accommodate this novel treatment modality, it is anticipated that more widespread adoption in clinical practice will follow. This will not only improve patient outcomes for AK but also pave the way for exploring its potential in other dermatological and oncological conditions.

## ACKNOWLEDGMENT

All authors declare that they have no known conflicts of interest in terms of competing financial interests or personal relationships that could have an influence or are relevant to the work reported in this paper.

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TABLES

<table><caption>**Table I.** Comparative overview of established and emerging therapeutic approaches for actinic keratosis.</caption><thead><tr><td>Therapy</td><td>Typical sessions</td><td>Recurrence rate</td><td>Pain / Discomfort</td><td>Cosmetic Outcome</td><td>Ref.</td></tr></thead><tbody><tr><td>Cryotherapy</td><td>1-2 sessions</td><td>20-40%</td><td>Moderate-severe</td><td>Variable: risk of hypopigmentation/ scarring</td><td>[24-26]</td></tr><tr><td>PDT</td><td>1-2 sessions</td><td>9-30%</td><td>Moderate-severe</td><td>Generally excellent</td><td>[25, 30-32]</td></tr><tr><td>5-FU (topical)</td><td>1-4 weeks</td><td>Up to 50%</td><td>Mild-moderate</td><td>Good after healing, but inflammatory reaction can be severe during treatment</td><td>[27]</td></tr><tr><td>Imiquimod (topical)</td><td>2-3x/week for 4-16 weeks</td><td>10-43%</td><td>Mild-moderate</td><td>Generally good, but transient inflammation common</td><td>[28, 29]</td></tr><tr><td>Plasma treatment</td><td>1-3 sessions</td><td>Not yet established; long-term data lacking</td><td>Generally mild</td><td>Early reports indicate good cosmetic outcomes and minimal scarring</td><td>[87, 88, 92]</td></tr></tbody></table>
<table><caption>**Table II.** Overview of CE-certified gas plasma devices approved for dermatology applications in Europe.</caption><thead><tr><td>Device</td><td>Plasma source gas</td><td>Key strength</td><td>Target condition</td><td>Clinical evidence highlights</td><td>Ref.</td></tr></thead><tbody><tr><td>kINPen MED</td><td>Argon</td><td>Precise application</td><td>Chronic ulcers, infections</td><td>Randomized control trials showing healing acceleration</td><td>[52, 124]</td></tr><tr><td>PlasmaDerm VU-2010</td><td>Ambient air</td><td>Large treatment area</td><td>Venous ulcers, wounds</td><td>Observational studies on epithelialization</td><td>[57]</td></tr><tr><td>SteriPlas</td><td>Argon</td><td>Hospital-grade use</td><td>Chronic infections, wounds</td><td>Case studies on microbial load reduction</td><td>[51, 59]</td></tr><tr><td>Plasma Care</td><td>Ambient air</td><td>Patch-based design</td><td>Wound care</td><td>Pilot trials on patient comfort</td><td>[60]</td></tr><tr><td>PLASOMA, Plasmacure</td><td>Ambient air</td><td>Large treatment area</td><td>Wound care</td><td>Randomized control trial showing healing acceleration</td><td>[61]</td></tr><tr><td>CPTcube/CPTpatch system, Coldplasmatech</td><td>Ambient air</td><td>Patch-based design</td><td>Wound care</td><td>Randomized control trial showing healing acceleration</td><td>[125]</td></tr></tbody></table>
<table><caption>**Table III.** Summary of case reports and clinical data in cancer patient therapy using gas plasma technology.</caption><thead><tr><td>Condition</td><td>Plasma source (gas)</td><td>No. pat.</td><td>Treatment protocol</td><td>Outcome</td><td>Key findings</td><td>Ref</td></tr></thead><tbody><tr><td>Actinic Keratosis</td><td>SteriPlas, argon</td><td>7</td><td>Twice weekly for 120-s for a total of 7 treatments</td><td>Lesion size reduction, improved skin texture</td><td>Histological improvements, reduced atypical keratinocytes, no severe side effects</td><td>[87]</td></tr><tr><td>Actinic Keratosis</td><td>Floating-electrode DBD (non-commercial), not stated</td><td>5</td><td>Single treatment of 60 - 120-s</td><td>Complete lesion resolution</td><td>Effective alternative to conventional treatments</td><td>[88]</td></tr><tr><td>Actinic Keratosis</td><td>SteriPlas, argon</td><td>60</td><td>Twice weekly for 180-s over 3 months</td><td>Complete lesion clearance</td><td>Success in managing hyperkeratotic</td><td>[89]</td></tr><tr><td>Actinic Keratosis</td><td>Maxium electrosurgery beamer, argon</td><td>1</td><td>Single treatment of 60-s</td><td>Selective cytotoxicity</td><td>Targets dysplastic cells, spares healthy</td><td>[90]</td></tr><tr><td>Actinic Keratosis</td><td>SteriPlas, argon</td><td>12</td><td>Twice weekly for 120-s until resolution or for a maximum of 7 weeks</td><td>Significant lesion reduction, improved skin integrity</td><td>High patient satisfaction, non-invasive treatment</td><td>[92]</td></tr><tr><td>Head and neck cancer</td><td>kINPen MED, argon</td><td>6</td><td>3 single treatments for 60-sec/cm² within 1 week</td><td>Tumor size reduction, improved healing</td><td>Reduced inflammation, improved tissue response</td><td>[94]</td></tr><tr><td>Head and neck cancer</td><td>kINPen MED, argon</td><td>12</td><td>3 single treatments for 60-sec/cm² within 1 week</td><td>Visible tumor response, induction of apoptosis</td><td>Significant tumor surface response observed with effective apoptotic cell death in treated lesions</td><td>[126]</td></tr><tr><td>Head and neck cancer</td><td>kINPen MED, argon</td><td>2</td><td>Single treatment of 60-s/cm²</td><td>Improved microcirculation, enhanced wound healing</td><td>Hyperspectral imaging revealed improved blood flow and tissue oxygenation; plasma promoted healing with no significant adverse effects</td><td>[127]</td></tr><tr><td>Head and neck cancer</td><td>kINPen MED, argon</td><td>20</td><td>3 single treatments for 60-sec/cm² within 1 week</td><td>Manageable side effects, reduction in tumor size</td><td>plasma treatment demonstrated a good safety profile with limited side effects, including minor inflammation</td><td>[128]</td></tr></tbody></table>
FIGURES

<figure><img src="image_3.png" /><figcaption>**Fig 1.** Representative clinical images of actinic keratosis lesions on sun-exposed skin. Lesions appear as erythematous, scaly plaques with irregular borders, commonly observed on the scalp, forehead, and cheeks. Images highlight morphological variation in AK presentations, including hyperkeratotic and pigmented forms.</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>**Fig 2.** Schematic overview of the initiation and progression of actinic keratosis lesions.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>**Fig 3.** Scheme of effectors potentially relevant in the treatment of actinic keratosis using gas plasma technology.</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>**Fig 4.** Potential mechanisms involved in gas plasma treatment of actinic keratosis.</figcaption></figure>