Gas plasma-spurred wound healing is accompanied by regulation of focal adhesion, matrix remodeling, and tissue oxygenation

Abstract

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.

Multimodal Imaging Techniques to Evaluate the Anticancer Effect of Cold Atmospheric Pressure Plasma

“…By detecting ROS, the present study confirmed that ROS resulting from CAP treatment overcomes tissue barriers and can be used for tumour control. This is in line with findings showing that ROS and RNS could penetrate a 1 mm thick gelatine film in vitro [29], while in vivo it was shown that CAP-derived ROS and RNS oxidize and pass the stratum corneum to subsequently elicit intracutaneous responses [30,31]. To confirm that ROS and RNS mediate the anticancer effect of CAP, it was shown that treatment of MM with CAP in the presence of glycerol and sodium bicarbonate gel, used as scavenger for reactive species, radicals, and ions, inhibits the ability of plasma to ablate the tumour, which vice versa leads to tumour reoccurrence [32].…”

Gas Plasma-Augmented Wound Healing in Animal Models and Veterinary Medicine

“…Mechanistically, these findings correlated with increased expression and activation of Nrf2 (nuclear factor erythroid 2–related factor 2) and modulation of inflammation and granulation [ 40 ]. The healing responses were guided by changes in focal adhesion complexes and junction protein expression, along with epithelial to mesenchymal and fibroblast to myofibroblast transitions (EMT, FMT) [ 41 ]. Notably, a one-year follow-up study in those mice, which translated to a 60 year equivalent time span for humans, did not find any side effects or risks associated with carcinogenesis or defective healing [ 42 ].…”

Combining Nanotechnology and Gas Plasma as an Emerging Platform for Cancer Therapy: Mechanism and Therapeutic Implication

“…Although it has been reported that gas plasma triggers tissues effects in cm ranges, it has to be kept in mind, however, that the penetration depth of the most reactive species is about a few micrometers only, which is not enough to penetrate the tissue and seems appropriate for superficial skin lesions treatment. Notwithstanding, the signaling function of these gas plasma-derived ROS/RNS seems to transport information deep into tissues, as demonstrated using hyperspectral imaging of murine gas plasma-treated skin and wounds [ 106 – 108 ]. Hence, the current model is that superficial layers are being oxidized by the gas plasma-generated ROS/RNS, subsequently leading to PTMs and oxPTMs (oxidative post-translational modifications) on biomolecules, ultimately being sensed by cells and translated into differential signaling responses [ 109 ].…”