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Non-healing wounds pose a major burden to patients and health care systems alike. These wounds are chronically stuck in the inflammatory phase of the healing process without transitioning to the proliferative phase. They are also characterized by the excessive presence of leukocytes which are assumed to provoke the persistent inflammation observed in pathological wound healing. Recent studies suggested a beneficial role of cold physical plasma in the treatment of chronic wounds. Hence, it was the central question, whether exposure to cold physical plasma would affect the viability and/or function of human leukocytes. Cold plasma displays various properties of which the generation of reactive molecules, such as reactive oxygen and nitrogen species (ROS/RNS), where found to be central in mediating redox changes in leukocytes. Oxidative stress was present especially in lymphocytes that readily underwent apoptosis after exposure to plasma. This was largely a direct consequence of plasma-generated hydrogen peroxide but not superoxide or RNS. Amount of apoptosis was comparable among several lymphocyte subpopulations, with the wound healing-relevant γδ T cells being least affected. Lymphocyte apoptosis was accompanied by mitochondrial membrane depolarization, caspase 3 activation, DNA fragmentation, and phosphatidylserine exposure. These results are in line with previous characterizations of the intrinsic apoptotic pathway in redox biology, and suggest that plasma-induced apoptosis was not mediated by alternative molecular mechanisms. An important immune response mechanism, the proliferation of lymphocytes, was not interrupted in plasma-treated but non-apoptotic cells. In wounds, a central role of leukocytes is to orchestrate the healing response via the release of small communication molecules called cytokines. Non-healing wounds are associated with elevated amounts of pro-inflammatory IL-1β, IL-6, and TNFα, and plasma-treatment of leukocytes strongly decreased their concentrations. At the same time, the expression of anti inflammatory cytokines (IL-10, TGFβ) was markedly increased. The pro inflammatory chemokine IL-8 was the only molecule to be significantly increased in supernatants of plasma-treated cells. IL-8 is the major chemo-attractant for neutrophil granulocytes. Neutrophils are frequently associated with non-healing wounds. These professional phagocytes are the first to migrate to the site of injury where they inactivate invading pathogens by various mechanisms. Importantly, highly relevant effector functions remained mostly unaffected by plasma treatment: the phagocytosis of bacteria, the oxidative burst, and the intracellular killing of microbes. Of note, plasma induced a strong induction of neutrophil extracellular traps (NETs). Decorated with antimicrobial proteins, NETs are web-like chromatin extrusions that entrap pathogens. These results have several implications for wound healing. Plasma-treated neutrophils were still capable of eradicating bacteria, which are frequently associated with non-healing wounds. In addition, plasma-induced NETs could aid in wound healing by providing an antibacterial scaffold to safeguard against further dissemination of microorganisms. Chronic wounds display a state of sustained inflammation and plasma induced apoptosis but not necrosis in lymphocytes. This was an important finding as necrosis, the involuntary cell death, is associated with the release of intracellular content, enhancing inflammation. By contrast, apoptosis dampens it as dead cells are cleared by macrophages inducing anti inflammatory responses. Further, the cytokine signature of plasma-treated leukocytes was largely non inflammatory, which could further decrease inflammation in wounds. Altogether, this work provided first insight with regard to effects and mechanisms of cold physical plasma treatment of wound-relevant leukocytes. Generally, these cells were affected by a plasma mediated modulation of their redox state. Future studies should include the possibility of redox modulation into their experimental approach to further elucidate the role of ROS/RNS in inflammation and possibly to improve existing wound healing therapies.
The first Therapeutic ROS and Immunity in Cancer (TRIC) meeting was organized by the excellence research center ZIK plasmatis (with its previous Frontiers in Redox Biochemistry and Medicine (FiRBaM) and Young Professionals’ Workshop in Plasma Medicine (YPWPM) workshop series in Northern Germany) and the excellence research program ONKOTHER-H (Rostock/Greifswald, Germany). The meeting showcased cutting-edge research and liberated discussions on the application of therapeutic ROS and immunology in cancer treatment, primarily focusing on gas plasma technology. The 2-day hybrid meeting took place in Greifswald and online from 15–16 July 2021, facilitating a wide range of participants totaling 66 scientists from 12 countries and 5 continents. The meeting aimed at bringing together researchers from a variety of disciplines, including chemists, biochemists, biologists, engineers, immunologists, physicists, and physicians for interdisciplinary discussions on using therapeutic ROS and medical gas plasma technology in cancer therapy with the four main sessions: “Plasma, Cancer, Immunity”, “Plasma combination therapies”, “Plasma risk assessment and patients studies”, and “Plasma mechanisms and treated liquids in cancer”. This conference report outlines the abstracts of attending scientists submitted to this meeting.
Gas Plasma Exposure of Glioblastoma Is Cytotoxic and Immunomodulatory in Patient-Derived GBM Tissue
(2022)
Simple Summary
Despite treatment advances, glioblastoma multiforme (GBM) remains an often-fatal disease, motivating novel therapeutic avenues. Gas plasma is a technology that has been recently employed in preclinical oncology research and acts primarily via reactive oxygen-species-induced cell death. In addition, the modulation of immune processes and inflammation have been ascribed to gas plasma exposure. This is the first study that extends those observations from in vitro investigations to a set of 16 patient-derived GBM tumor biopsies analyzed after gas plasma treatment ex vivo. Besides cell culture results showing cell cycle arrest and apoptosis induction, an immunomodulatory potential was identified for gas plasma exposure in vitro and cultured GBM tissues. The proapoptotic action shown in this study might be an important step forward to the first clinical observational studies on the future discovery of gas plasma technology’s potential in neurosurgery and neuro-oncology.
Abstract
Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor. Therapeutic options for glioblastoma are maximal surgical resection, chemotherapy, and radiotherapy. Therapy resistance and tumor recurrence demand, however, new strategies. Several experimental studies have suggested gas plasma technology, a partially ionized gas that generates a potent mixture of reactive oxygen species (ROS), as a future complement to the existing treatment arsenal. However, aspects such as immunomodulation, inflammatory consequences, and feasibility studies using GBM tissue have not been addressed so far. In vitro, gas plasma generated ROS that oxidized cells and led to a treatment time-dependent metabolic activity decline and G2 cell cycle arrest. In addition, peripheral blood-derived monocytes were co-cultured with glioblastoma cells, and immunomodulatory surface expression markers and cytokine release were screened. Gas plasma treatment of either cell type, for instance, decreased the expression of the M2-macrophage marker CD163 and the tolerogenic molecule SIGLEC1 (CD169). In patient-derived GBM tissue samples exposed to the plasma jet kINPen ex vivo, apoptosis was significantly increased. Quantitative chemokine/cytokine release screening revealed gas plasma exposure to significantly decrease 5 out of 11 tested chemokines and cytokines, namely IL-6, TGF-β, sTREM-2, b-NGF, and TNF-α involved in GBM apoptosis and immunomodulation. In summary, the immuno-modulatory and proapoptotic action shown in this study might be an important step forward to first clinical observational studies on the future discovery of gas plasma technology’s potential in neurosurgery and neuro-oncology especially in putative adjuvant or combinatory GBM treatment settings.
The loss of skin integrity is inevitable in life. Wound healing is a necessary sequence of events to reconstitute the body’s integrity against potentially harmful environmental agents and restore homeostasis. Attempts to improve cutaneous wound healing are therefore as old as humanity itself. Furthermore, nowadays, targeting defective wound healing is of utmost importance in an aging society with underlying diseases such as diabetes and vascular insufficiencies being on the rise. Because chronic wounds’ etiology and specific traits differ, there is widespread polypragmasia in targeting non-healing conditions. Reactive oxygen and nitrogen species (ROS/RNS) are an overarching theme accompanying wound healing and its biological stages. ROS are signaling agents generated by phagocytes to inactivate pathogens. Although ROS/RNS’s central role in the biology of wound healing has long been appreciated, it was only until the recent decade that these agents were explicitly used to target defective wound healing using gas plasma technology. Gas plasma is a physical state of matter and is a partially ionized gas operated at body temperature which generates a plethora of ROS/RNS simultaneously in a spatiotemporally controlled manner. Animal models of wound healing have been vital in driving the development of these wound healing-promoting technologies, and this review summarizes the current knowledge and identifies open ends derived from in vivo wound models under gas plasma therapy. While gas plasma-assisted wound healing in humans has become well established in Europe, veterinary medicine is an emerging field with great potential to improve the lives of suffering animals.
on-healing wounds continue to be a clinical challenge for patients and medical staff.
These wounds have a heterogeneous etiology, including diabetes and surgical trauma wounds. It is
therefore important to decipher molecular signatures that reflect the macroscopic process of wound
healing. To this end, we collected wound sponge dressings routinely used in vacuum assisted therapy
after surgical trauma to generate wound-derived protein profiles via global mass spectrometry.
We confidently identified 311 proteins in exudates. Among them were expected targets belonging to
the immunoglobulin superfamily, complement, and skin-derived proteins, such as keratins. Next to
several S100 proteins, chaperones, heat shock proteins, and immune modulators, the exudates
presented a number of redox proteins as well as a discrete neutrophil proteomic signature, including
for example cathepsin G, elastase, myeloperoxidase, CD66c, and lipocalin 2. We mapped over 200
post-translational modifications (PTMs; cysteine/methionine oxidation, tyrosine nitration, cysteine
trioxidation) to the proteomic profile, for example, in peroxiredoxin 1. Investigating manually
collected exudates, we confirmed presence of neutrophils and their products, such as microparticles
and fragments containing myeloperoxidase and DNA. These data confirmed known and identified
less known wound proteins and their PTMs, which may serve as resource for future studies on
human wound healing
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.
Gas plasma is an approved technology that generates a plethora of reactive oxygen species, which are actively applied for chronic wound healing. Its particular antimicrobial action has spurred interest in other medical fields, such as periodontitis in dentistry. Recent work has indicated the possibility of performing gas plasma-mediated biofilm removal on teeth. Teeth frequently contain restoration materials for filling cavities, e.g., resin-based composites. However, it is unknown if such materials are altered upon gas plasma exposure. To this end, we generated a new in-house workflow for three commonly used resin-based composites following gas plasma treatment and incubated the material with human HaCaT keratinocytes in vitro. Cytotoxicity was investigated by metabolic activity analysis, flow cytometry, and quantitative high-content fluorescence imaging. The inflammatory consequences were assessed using quantitative analysis of 13 different chemokines and cytokines in the culture supernatants. Hydrogen peroxide served as the control condition. A modest but significant cytotoxic effect was observed in the metabolic activity and viability after plasma treatment for all three composites. This was only partially treatment time-dependent and the composites alone affected the cells to some extent, as evident by differential secretion profiles of VEGF, for example. Gas plasma composite modification markedly elevated the secretion of IL6, IL8, IL18, and CCL2, with the latter showing the highest correlation with treatment time (Pearson’s r > 0.95). Cell culture media incubated with gas plasma-treated composite chips and added to cells thereafter could not replicate the effects, pointing to the potential that surface modifications elicited the findings. In conclusion, our data suggest that gas plasma treatment modifies composite material surfaces to a certain extent, leading to measurable but overall modest biological effects.