Abstract: The rapid advances in the field of cold plasma research led to the development of many plasma jets for various purposes. The COST plasma jet was created to set a comparison standard between different groups in Europe and the world. Its physical and chemical properties are well studied, and diagnostics procedures are developed and benchmarked using this jet. In recent years, it has been used for various research purposes. Here, we present a brief overview of the reported applications of the COST plasma jet. Additionally, we discuss the chemistry of the plasma-liquid systems with this plasma jet, and the properties that make it an indispensable system for plasma research.

Abstract: Cold atmospheric plasma and nanomedicine originally emerged as individual domains, but are increasingly applied in combination with each other. Most research is performed in the context of cancer treatment, with only little focus yet on the possible synergies. Many questions remain on the potential of this promising hybrid technology, particularly regarding regenerative medicine and tissue engineering. In this perspective article, we therefore start from the fundamental mechanisms in the individual technologies, in order to envision possible synergies for wound healing and tissue recovery, as well as research strategies to discover and optimize them. Among these strategies, we demonstrate how cold plasmas and nanomaterials can enhance each other’s strengths and overcome each other’s limitations. The parallels with cancer research, biotechnology and plasma surface modification further serve as inspiration for the envisioned synergies in tissue regeneration. The discovery and optimization of synergies may also be realized based on a profound understanding of the underlying redox- and field-related biological processes. Finally, we emphasize the toxicity concerns in plasma and nanomedicine, which may be partly remediated by their combination, but also partly amplified. A widespread use of standardized protocols and materials is therefore strongly recommended, to ensure both a fast and safe clinical implementation.

Abstract: Plasma-liquid systems have attracted increasing attention in recent years, owing to their high potential in material processing and nanoscience, environmental remediation, sterilization, biomedicine, and food applications. Due to the multidisciplinary character of this scientific field and due to its broad range of established and promising applications, an updated overview is required, addressing the various applications of plasma-liquid systems till now. In the present review, after a brief historical introduction on this important research field, the authors aimed to bring together a wide range of applications of plasma-liquid systems, including nanomaterial processing, water analytical chemistry, water purification, plasma sterilization, plasma medicine, food preservation and agricultural processing, power transformers for high voltage switching, and polymer solution treatment. Although the general understanding of plasma-liquid interactions and their applications has grown significantly in recent decades, it is aimed here to give an updated overview on the possible applications of plasma-liquid systems. This review can be used as a guide for researchers from different fields to gain insight in the history and state-of-the-art of plasma-liquid interactions and to obtain an overview on the acquired knowledge in this field up to now.

Abstract: Cold atmospheric plasma (CAP) and plasma-treated liquids (PTLs) have recently become a promising option for cancer treatment, but the underlying mechanisms of the anti-cancer effect are still to a large extent unknown. Although hydrogen peroxide () has been recognized as the major anti-cancer agent of PTL and may enable selectivity in a certain concentration regime, the co-existence of nitrite can create a synergistic effect. We develop a mathematical model to describe the key species and features of the cellular response toward PTL. From the numerical solutions, we define a number of dependent variables, which represent feasible measures to quantify cell susceptibility in terms of the membrane diffusion rate constant and the intracellular catalase concentration. For each of these dependent variables, we investigate the regimes of selective versus non-selective, and of synergistic versus non-synergistic effect to evaluate their potential role as a measure of cell susceptibility. Our results suggest that the maximal intracellular concentration, which in the selective regime is almost four times greater for the most susceptible cells compared to the most resistant cells, could be used to quantify the cell susceptibility toward exogenous . We believe our theoretical approach brings novelty to the field of plasma oncology, and more broadly, to the field of redox biology, by proposing new ways to quantify the selective and synergistic anti-cancer effect of PTL in terms of inherent cell features.

Abstract: Cold atmospheric plasma (CAP) is a promising new agent for (selective) cancer treatment, but the underlying cause of the anti-cancer effect of CAP is not well understood yet. Among different theories and observations, one theory in particular has been postulated in great detail and consists of a very complex network of reactions that are claimed to account for the anti-cancer effect of CAP. Here, the key concept is a reactivation of two specific apoptotic cell signaling pathways through catalase inactivation caused by CAP. Thus, it is postulated that the anti-cancer effect of CAP is due to its ability to inactivate catalase, either directly or indirectly. A theoretical investigation of the proposed theory, especially the role of catalase inactivation, can contribute to the understanding of the underlying cause of the anti-cancer effect of CAP. In the present study, we develop a mathematical model to analyze the proposed catalase-dependent anti-cancer effect of CAP. Our results show that a catalase-dependent reactivation of the two apoptotic pathways of interest is unlikely to contribute to the observed anti-cancer effect of CAP. Thus, we believe that other theories of the underlying cause should be considered and evaluated to gain knowledge about the principles of CAP-induced cancer cell death.

Abstract: Targeting the redox balance of malignant cells via the delivery of high oxidative stress unlocks a potential therapeutic strategy against glioblastoma (GBM). We investigated a novel reactive oxygen species (ROS)-inducing combination treatment strategy, by increasing exogenous ROS via cold atmospheric plasma and inhibiting the endogenous protective antioxidant system via auranofin (AF), a thioredoxin reductase 1 (TrxR) inhibitor. The sequential combination treatment of AF and cold atmospheric plasma-treated PBS (pPBS), or AF and direct plasma application, resulted in a synergistic response in 2D and 3D GBM cell cultures, respectively. Differences in the baseline protein levels related to the antioxidant systems explained the cell-line-dependent sensitivity towards the combination treatment. The highest decrease of TrxR activity and GSH levels was observed after combination treatment of AF and pPBS when compared to AF and pPBS monotherapies. This combination also led to the highest accumulation of intracellular ROS. We confirmed a ROS-mediated response to the combination of AF and pPBS, which was able to induce distinct cell death mechanisms. On the one hand, an increase in caspase-3/7 activity, with an increase in the proportion of annexin V positive cells, indicates the induction of apoptosis in the GBM cells. On the other hand, lipid peroxidation and inhibition of cell death through an iron chelator suggest the involvement of ferroptosis in the GBM cell lines. Both cell death mechanisms induced by the combination of AF and pPBS resulted in a significant increase in danger signals (ecto-calreticulin, ATP and HMGB1) and dendritic cell maturation, indicating a potential increase in immunogenicity, although the phagocytotic capacity of dendritic cells was inhibited by AF. In vivo, sequential combination treatment of AF and cold atmospheric plasma both reduced tumor growth kinetics and prolonged survival in GBM-bearing mice. Thus, our study provides a novel therapeutic strategy for GBM to enhance the efficacy of oxidative stress-inducing therapy through a combination of AF and cold atmospheric plasma.

Abstract: Plasma catalysis is gaining increasing interest for various gas conversion applications, such as CO2 conversion into value-added chemicals and fuels, N2 fixation for the synthesis of NH3 or NOx, and CH4 conversion into higher hydrocarbons or oxygenates [...]

Abstract: We investigated the mode transition from volume to surface discharge in a packed bed dielectric barrier discharge reactor by a two-dimensional particle-in-cell/Monte Carlo collision method. The calculations are performed at atmospheric pressure for various driving voltages and for gas mixtures with different N2 and O2 compositions. Our results reveal that both a change of the driving voltage and gas mixture can induce mode transition. Upon increasing voltage, a mode transition from hybrid (volume+surface) discharge to pure surface discharge occurs, because the charged species can escape much more easily to the beads and charge the bead surface due to the strong electric field at high driving voltage. This significant surface charging will further enhance the tangential component of the electric field along the dielectric bead surface, yielding surface ionization waves (SIWs). The SIWs will give rise to a high concentration of reactive species on the surface, and thus possibly enhance the surface activity of the beads, which might be of interest for plasma catalysis. Indeed, electron impact excitation and ionization mainly take place near the bead surface. In addition, the propagation speed of SIWs becomes faster with increasing N2 content in the gas mixture, and slower with increasing O2 content, due to the loss of electrons by attachment to O2
molecules. Indeed, the negative O-2 ion density produced by electron impact attachment is much higher than the electron and positive O+2 ion density. The different ionization rates between N2 and O2 gases will create different amounts of electrons and ions on the dielectric bead surface, which might also have effects in plasma catalysis.

Abstract: N2 fixation into NH3 is one of the main processes in the chemical industry. Plasma catalysis is among the environmentally friendly alternatives to the industrial energy-intensive Haber-Bosch process. However, many questions remain open, such as the applicability of the conventional catalytic knowledge to plasma. In this work, we studied the performance of Al2O3-supported Fe, Ru, Co and Cu catalysts in plasma-catalytic NH3 synthesis in a DBD reactor. We investigated the effects of different active metals, and different ratios of the feed gas components, on the concentration and production rate of NH3, and the energy consumption of the plasma system. The results show that the trend of the metal activity (common for thermal catalysis) does not appear in the case of plasma catalysis: here, all metals exhibited similar performance. These findings are in good agreement with our recently published microkinetic model. This highlights the virtual independence of NH3 production on the metal catalyst material, thus validating the model and indicating the potential contribution of radical adsorption and Eley-Rideal reactions to the plasma-catalytic mechanism of NH3 synthesis.

Abstract: This work proposes to use core-shell structured spheres to evaluate whether it allows to individually optimize bulk and surface effects of a packing material, in order to optimize conversion and energy efficiency. Different core-shell materials have been prepared by spray coating, using dense spheres (as core) and powders (as shell) of SiO2, Al2O3, and BaTiO3. The materials are investigated for their performance in CO2 dissociation and compared against a benchmark consisting of a packed-bed reactor with the pure dense spheres, as well as an empty reactor. The results in terms of CO2 conversion and energy efficiency show various interactions between the core and shell material, depending on their combination. Al2O3 was found as the best core material under the applied conditions here, followed by BaTiO3 and SiO2, in agreement with their behaviour for the pure spheres. Applying a thin shell layer on the cores showed equal performance between the different shell materials. Increasing the layer thickness shifts this behaviour, and strong combination effects were observed depending on the specific material. Therefore, this method of core-shell spheres has the potential to allow tuning of the packing properties more closely to the application by designing an optimal combination of core and shell.

Abstract: Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells’ uncontrolled growth. The major barrier in treating MM is the occurrence of primary and acquired therapy resistance to anticancer drugs. Often, this therapy resistance is associated with constitutive hyperactivation of tyrosine kinase signaling. Novel covalent kinase inhibitors, such as the clinically approved BTK inhibitor ibrutinib (IBR) and the preclinical phytochemical withaferin A (WA), have, therefore, gained pharmaceutical interest. Remarkably, WA is more effective than IBR in killing BTK-overexpressing glucocorticoid (GC)-resistant MM1R cells. To further characterize the kinase inhibitor profiles of WA and IBR in GC-resistant MM cells, we applied phosphopeptidome- and transcriptome-specific tyrosine kinome profiling. In contrast to IBR, WA was found to reverse BTK overexpression in GC-resistant MM1R cells. Furthermore, WA-induced cell death involves covalent cysteine targeting of Hinge-6 domain type tyrosine kinases of the kinase cysteinome classification, including inhibition of the hyperactivated BTK. Covalent interaction between WA and BTK could further be confirmed by biotin-based affinity purification and confocal microscopy. Similarly, molecular modeling suggests WA preferably targets conserved cysteines in the Hinge-6 region of the kinase cysteinome classification, favoring inhibition of multiple B-cell receptors (BCR) family kinases. Altogether, we show that WA’s promiscuous inhibition of multiple BTK family tyrosine kinases represents a highly effective strategy to overcome GC-therapy resistance in MM.

Abstract: Skin cancers have the highest prevalence of all human cancers, with the most lethal forms being squamous cell carcinoma and malignant melanoma. Besides the conventional local treatment approaches like surgery and radiotherapy, cold physical plasmas are emerging anticancer tools. Plasma technology is used as a therapeutic agent by generating reactive oxygen species (ROS). Evidence shows that inflammation and adaptive immunity are involved in cancer-reducing effects of plasma treatment, but the role of innate immune cells is still unclear. Natural killer (NK)-cells interact with target cells via activating and inhibiting surface receptors and kill in case of dominating activating signals. In this study, we investigated the effect of cold physical plasma (kINPen) on two skin cancer cell lines (A375 and A431), with non-malignant HaCaT keratinocytes as control, and identified a plasma treatment time-dependent toxicity that was more pronounced in the cancer cells. Plasma treatment also modulated the expression of activating and inhibiting receptors more profoundly in skin cancer cells compared to HaCaT cells, leading to significantly higher NK-cell killing rates in the tumor cells. Together with increased pro-inflammatory mediators such as IL-6 and IL-8, we conclude that plasma treatment spurs stress responses in skin cancer cells, eventually augmenting NK-cell activity.

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with low five-year survival rates of 8% by conventional treatment methods, e.g., chemotherapy, radiotherapy, and surgery. PDAC shows high resistance towards chemo- and radiotherapy and only 15–20% of all patients can have surgery. This disease is predicted to become the third global leading cause of cancer death due to its significant rise in incidence. Therefore, the development of an alternative or combinational method is necessary to improve current approaches. Cold atmospheric plasma (CAP) treatments could offer multiple advantages to this emerging situation. The plasma-derived reactive species can induce oxidative damage and a cascade of intracellular signaling pathways, which could lead to cell death. Previous reports have shown that CAP treatment also influences cells in the tumor microenvironment, such as the pancreatic stellate cells (PSCs). These PSCs, when activated, play a crucial role in the propagation, growth and survival of PDAC tumors. However, the effect of CAP on PSCs is not yet fully understood. This review focuses on the application of CAP for PDAC treatment and the importance of PSCs in the response to treatment.

Abstract: Tumours are complex systems formed by cellular (malignant, immune, and endothelial cells, fibroblasts) and acellular components (extracellular matrix (ECM) constituents and secreted factors). A close interplay between these factors, collectively called the tumour microenvironment, is required to respond appropriately to external cues and to determine the treatment outcome. Cold plasma (here referred as ‘plasma’) is an emerging anticancer technology that generates a unique cocktail of reactive oxygen and nitrogen species to eliminate cancerous cells via multiple mechanisms of action. While plasma is currently regarded as a local therapy, it can also modulate the mechanisms of cell-to-cell and cell-to-ECM communication, which could facilitate the propagation of its effect in tissue and distant sites. However, it is still largely unknown how the physical interactions occurring between cells and/or the ECM in the tumour microenvironment affect the plasma therapy outcome. In this review, we discuss the effect of plasma on cell-to-cell and cell-to-ECM communication in the context of the tumour microenvironment and suggest new avenues of research to advance our knowledge in the field. Furthermore, we revise the relevant state-of-the-art in three-dimensional in vitro models that could be used to analyse cell-to-cell and cell-to-ECM communication and further strengthen our understanding of the effect of plasma in solid tumours.

Abstract: Increasing the selectivity of cancer treatments is attractive, as it has the potential to reduce side-effects of therapy. Cold atmospheric plasma (CAP) is a novel cancer treatment that disrupts the intracellular oxidative balance. Several reports claim CAP treatment to be selective, but retrospective analysis of these studies revealed discrepancies in several biological factors and culturing methods. Before CAP can be conclusively stated as a selective cancer treatment, the importance of these factors must be investigated. In this study, we evaluated the influence of the cell type, cancer type, and cell culture medium on direct and indirect CAP treatment. Comparison of cancerous cells with their non-cancerous counterparts was performed under standardized conditions to determine selectivity of treatment. Analysis of seven human cell lines (cancerous: A549, U87, A375, and Malme-3M; non-cancerous: BEAS-2B, HA, and HEMa) and five different cell culture media (DMEM, RPMI1640, AM, BEGM, and DCBM) revealed that the tested parameters strongly influence indirect CAP treatment, while direct treatment was less affected. Taken together, the results of our study demonstrate that cell type, cancer type, and culturing medium must be taken into account before selectivity of CAP treatment can be claimed and overlooking these parameters can easily result in inaccurate conclusions of selectivity.