Concise review of non‐invasive physical plasma as a promising treatment option for radiation injuries of the skin

Radiation injury has a complex pathophysiology and can result in long‐term impediment of the dermal barrier function. Historically, its treatment has been no different to that of thermal burns and it is not always possible to prevent an unpredictable and uncontrolled extension of the radiation‐induced reactions. Non‐invasive physical plasma (NIPP), a highly energised gas encompassing a combination of various reactive species, positively affects the key players involved in wound healing and proves to be a promising treatment option for chronic wounds and inflammatory skin disorders. Recent clinical evidence also suggests preliminary efficacy in radiation injury following therapeutic irradiation as a part of cancer therapy. Further research is warranted to also investigate the clinical value of NIPP in the context of unplanned or accidental radiation exposure, either as a topical treatment or possibly as an intraoperative procedure, to potentially improve the dermatological outcome and reduce symptoms in radiation victims.

Recent clinical evidence also suggests preliminary efficacy in radiation injury following therapeutic irradiation as a part of cancer therapy. Further research is warranted to also investigate the clinical value of NIPP in the context of unplanned or accidental radiation exposure, either as a topical treatment or possibly as an intraoperative procedure, to potentially improve the dermatological outcome and reduce symptoms in radiation victims.

K E Y W O R D S
cold atmospheric plasma, cold atmospheric pressure plasma, non-invasive, physical plasma, physical plasma, radiation burn, radiation dermatitis, radiation skin injury, radiation therapy, tissue tolerable plasma Due to its complex composition of various maturing and proliferating cell types, the human skin is extremely susceptible to ionising radiation. Radiation injuries of the skin lead to the disruption of highly radiosensitive cells, especially keratinocytes, melanocytes and hair follicle stem cells and are accompanied by inflammatory processes and damage to cell structure elements and DNA. 1-3 As a result, radiation disables the high turnover and self-renewing capacity of the epidermis, losing its barrier function and making the underlying tissues more vulnerable.
Radiation skin injuries are classified into either acute or late injuries. Acute injury includes dryness, itching, erythema, depilation, pigment changes, oedema, dry or moist desquamation and necrosis/ ulceration and occurs within hours to weeks after radiation exposure.
Late radiation skin injury occurs months to years after radiation exposure and involves necrosis/ulceration, fibrosis, atrophy, dyspigmentation and telangiectasia. In cases of severe radiation skin injury, a complete loss of the epidermis may occur. Re-epithelialisation is initiated within 2 weeks after the initial radiation exposure, depending on the microbial colonisation of the wound. Several months after radiation exposure, the skin is subsequentially damageable and also susceptible toward infection and trauma. 1,2 For a long time, the medical treatment of radiation skin injury has been no different to that of thermal burns. The significant differences in the pathophysiology and clinical aspects of radiation and thermal Leonard Christopher Schmeel and Matthias Bernhard Stope contributed equally to this study. burns were thus being ignored. Radiation-induced skin injury is dosedependent and oftentimes associated with opiate-resistant chronic pain. 3,4 In addition, and this is of particular importance in the management of radiation injury, successive and uncontrolled inflammatory waves might occur weeks to years after the initial radiation exposure. 5 In the phase of erythema or desquamation, the skin should be washed gently and treated with hydrophilic preparations, hydrogels and emollients, which act as mild lubricants and protect dry lesions.
Erosions and ulcers should be covered with dressings, to support wound healing and protect the area from external contamination and subsequent infection. In the case of a suspected or proven infection, local antibacterial agents and topical and/or systemic antibiotics should be considered. 1,2,6 The application of local antibiotics must be viewed critically, however, as their effectiveness is often limited due to resistance. To modulate the inflammatory immune response and its subsequent symptoms, topical corticosteroids can be applied. These can, however, also lead to side effects such as skin atrophy and increased susceptibility to infections, limiting their widespread use. 1,2,6,7 In severe wounds, (repeated) enzymatic and/or mechanical debridement, excision, reconstruction with skin grafts or rotation flaps, and sometimes even amputation surgery might be necessary. 1,6 Surgical treatment, however, unfortunately often fails to prevent the unpredictable and uncontrolled extension of the radiation-induced necrosis. 4,5 Non-invasive physical plasma (NIPP) is a promising treatment regimen for chronic wounds and other inflammatory dermatological disorders. [8][9][10] Therefore, it might also possibly be used to address radiation injury. NIPP is a highly energised gas that encompasses a  Figure 1). Further advantages of NIPP treatment are its non-invasive and virtually painless application, the absence of any relevant side effects, and the penetration of structures that are otherwise difficult to access due to its gaseous state. [8][9][10][11][12][13][14] Collateral radiation damage frequently occurs following the therapeutic use of ionising radiation as a part of cancer therapy. This socalled radiation dermatitis is the most common acute side effect of radiation treatment and majorly impacts the quality of life in many patients undergoing cancer treatment. Recent evidence from a firstin-human feasibility study established the role of NIPP for preventing and treating radiation dermatitis in breast cancer irradiation, confirming preclinical data in mice. 15,16 As is the case for conventional radiation injury therapy, potent preventative and therapeutic options are infamously lacking, resulting in a significant physical and psychological impact among a large proportion of cancer patients. Using clinicianand patient-reported outcomes, radiation dermatitis was less frequent and milder in comparison with standard skin care. The tolerability was excellent, and neither NIPP-related adverse events nor side effects were reported. Since reactive species also play a crucial role in tissue damage induced by ionising radiation, it was imperative to first assess F I G U R E 1 Proposed pathophysiology of non-invasive physical plasma (NIPP) and its effects on the key players involved in tissue recovery and wound healing following radiation injury to the skin (created with BioRender.com).
the safety of NIPP combined with radiation treatment. Although promising, these initial results of course prompt the need for further (already ongoing) research in the form of a randomised double-blind placebo-controlled trial to establish the exact clinical value of NIPP in this unexplored clinical scenario.
In contrast to such therapeutic radiation exposure in the context of oncological therapy, there are also patients with unplanned and usually significantly higher radiation exposures. These events, for example, occur in accidents in radioactive facilities or, much less frequently, in criminal or terrorist uses of radioactive material. In these cases, there are no means of administering protective agents before the unplanned radiation exposure. The expected clinical course and choice of the corresponding and most suitable therapy option strongly depend on the type of irradiation and its respective energy and dose. These parameters, however, are generally unknown in the case of accidental radiation exposure, complicating adequate and timely treatment.
Due to the positive and especially wound healing properties of NIPP, as well as the first preliminary clinical efficacy data in the context of therapeutic radiation, a prompt and repeated treatment may therefore appear as a suitable additional therapeutic option following accidental or unplanned skin radiation exposure (e.g., in the context of nuclear incidents or warfare). The application of NIPP, potentially also as an intraoperative procedure, may significantly improve prognosis and dermatological outcome and reduce symptoms in radiation victims by successfully expanding the limited armamentarium.