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    Medical gas plasma-stimulated wound healing: Evidence and mechanisms
    (Amsterdam [u.a.] : Elsevier, 2021) Bekeschus, Sander; von Woedtke, Thomas; Emmert, Steffen; Schmidt, Anke
    Defective wound healing poses a significant burden on patients and healthcare systems. In recent years, a novel reactive oxygen and nitrogen species (ROS/RNS) based therapy has received considerable attention among dermatologists for targeting chronic wounds. The multifaceted ROS/RNS are generated using gas plasma technology, a partially ionized gas operated at body temperature. This review integrates preclinical and clinical evidence into a set of working hypotheses mainly based on redox processes aiding in elucidating the mechanisms of action and optimizing gas plasmas for therapeutic purposes. These hypotheses include increased wound tissue oxygenation and vascularization, amplified apoptosis of senescent cells, redox signaling, and augmented microbial inactivation. Instead of a dominant role of a single effector, it is proposed that all mechanisms act in concert in gas plasma-stimulated healing, rationalizing the use of this technology in therapy-resistant wounds. Finally, addressable current challenges and future concepts are outlined, which may further promote the clinical utilization, efficacy, and safety of gas plasma technology in wound care in the future.
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    Argon Plasma Exposure Augments Costimulatory Ligands and Cytokine Release in Human Monocyte-Derived Dendritic Cells
    (Basel : Molecular Diversity Preservation International (MDPI), 2021) Bekeschus, Sander; Meyer, Dorothee; Arlt, Kevin; von Woedtke, Thomas; Miebach, Lea; Freund, Eric; Clemen, Ramona
    Cold physical plasma is a partially ionized gas expelling many reactive oxygen and nitrogen species (ROS/RNS). Several plasma devices have been licensed for medical use in dermatology, and recent experimental studies suggest their putative role in cancer treatment. In cancer therapies with an immunological dimension, successful antigen presentation and inflammation modulation is a key hallmark to elicit antitumor immunity. Dendritic cells (DCs) are critical for this task. However, the inflammatory consequences of DCs following plasma exposure are unknown. To this end, human monocyte-derived DCs (moDCs) were expanded from isolated human primary monocytes; exposed to plasma; and their metabolic activity, surface marker expression, and cytokine profiles were analyzed. As controls, hydrogen peroxide, hypochlorous acid, and peroxynitrite were used. Among all types of ROS/RNS-mediated treatments, plasma exposure exerted the most notable increase of activation markers at 24 h such as CD25, CD40, and CD83 known to be crucial for T cell costimulation. Moreover, the treatments increased interleukin (IL)-1α, IL-6, and IL-23. Altogether, this study suggests plasma treatment augmenting costimulatory ligand and cytokine expression in human moDCs, which might exert beneficial effects in the tumor microenvironment.
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    Gas plasma-spurred wound healing is accompanied by regulation of focal adhesion, matrix remodeling, and tissue oxygenation
    (Amsterdam [u.a.] : Elsevier, 2021) Schmidt, Anke; Liebelt, Grit; Nießner, Felix; von Woedtke, Thomas; Bekeschus, Sander
    In response to injury, efficient migration of skin cells to rapidly close the wound and restore barrier function requires a range of coordinated processes in cell spreading and migration. Gas plasma technology produces therapeutic reactive species that promote skin regeneration by driving proliferation and angiogenesis. However, the underlying molecular mechanisms regulating gas plasma-aided cell adhesion and matrix remodeling essential for wound closure remain elusive. Here, we combined in vitro analyses in primary dermal fibroblasts isolated from murine skin with in vivo studies in a murine wound model to demonstrate that gas plasma treatment changed phosphorylation of signaling molecules such as focal adhesion kinase and paxillin α in adhesion-associated complexes. In addition to cell spreading and migration, gas plasma exposure affected cell surface adhesion receptors (e.g., integrinα5β1, syndecan 4), structural proteins (e.g., vinculin, talin, actin), and transcription of genes associated with differentiation markers of fibroblasts-to-myofibroblasts and epithelial-to-mesenchymal transition, cellular protrusions, fibronectin fibrillogenesis, matrix metabolism, and matrix metalloproteinase activity. Finally, we documented that gas plasma exposure increased tissue oxygenation and skin perfusion during ROS-driven wound healing. Altogether, these results provide critical insights into the molecular machinery of gas plasma-assisted wound healing mechanisms.