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- ItemMurine Macrophages Modulate Their Inflammatory Profile in Response to Gas Plasma-Inactivated Pancreatic Cancer Cells(Basel : MDPI, 2021) Khabipov, Aydar; Freund, Eric; Liedtke, Kim Rouven; Käding, Andre; Riese, Janik; van der Linde, Julia; Kersting, Stephan; Partecke, Lars-Ivo; Bekeschus, SanderMacrophages and immuno-modulation play a dominant role in the pathology of pancreatic cancer. Gas plasma is a technology recently suggested to demonstrate anticancer efficacy. To this end, two murine cell lines were employed to analyze the inflammatory consequences of plasma-treated pancreatic cancer cells (PDA) on macrophages using the kINPen plasma jet. Plasma treatment decreased the metabolic activity, viability, and migratory activity in an ROS- and treatment time-dependent manner in PDA cells in vitro. These results were confirmed in pancreatic tumors grown on chicken embryos in the TUM-CAM model (in ovo). PDA cells promote tumor-supporting M2 macrophage polarization and cluster formation. Plasma treatment of PDA cells abrogated this cluster formation with a mixed M1/M2 phenotype observed in such co-cultured macrophages. Multiplex chemokine and cytokine quantification showed a marked decrease of the neutrophil chemoattractant CXCL1, IL6, and the tumor growth supporting TGFβ and VEGF in plasma-treated compared to untreated co-culture settings. At the same time, macrophage-attractant CCL4 and MCP1 release were profoundly enhanced. These cellular and secretome data suggest that the plasma-inactivated PDA6606 cells modulate the inflammatory profile of murine RAW 264.7 macrophages favorably, which may support plasma cancer therapy.
- ItemGas Flow Shaping via Novel Modular Nozzle System (MoNoS) Augments kINPen-Mediated Toxicity and Immunogenicity in Tumor Organoids(Basel : MDPI, 2023) Berner, Julia; Miebach, Lea; Herold, Luise; Höft, Hans; Gerling, Torsten; Mattern, Philipp; Bekeschus, SanderMedical gas plasma is an experimental technology for anticancer therapy. Here, partial gas ionization yielded reactive oxygen and nitrogen species, placing the technique at the heart of applied redox biomedicine. Especially with the gas plasma jet kINPen, anti-tumor efficacy was demonstrated. This study aimed to examine the potential of using passive flow shaping to enhance the medical benefits of atmospheric plasma jets (APPJ). We used an in-house developed, proprietary Modular Nozzle System (MoNoS; patent-pending) to modify the flow properties of a kINPen. MoNoS increased the nominal plasma jet-derived reactive species deposition area and stabilized the air-plasma ratio within the active plasma zone while shielding it from external flow disturbances or gas impurities. At modest flow rates, dynamic pressure reduction (DPR) adapters did not augment reactive species deposition in liquids or tumor cell killing. However, MoNoS operated at kINPen standard argon fluxes significantly improved cancer organoid growth reduction and increased tumor immunogenicity, as seen by elevated calreticulin and heat-shock protein expression, along with a significantly spurred cytokine secretion profile. Moreover, the safe application of MoNoS gas plasma jet adapters was confirmed by their similar-to-superior safety profiles assessed in the hen’s egg chorioallantoic membrane (HET-CAM) coagulation and scar formation irritation assay.
- ItemCold Atmospheric Plasma in the Treatment of Osteosarcoma(Basel : Molecular Diversity Preservation International, 2017-9-19) Gümbel, Denis; Bekeschus, Sander; Gelbrich, Nadine; Napp, Matthias; Ekkernkamp, Axel; Kramer, Axel; Stope, Matthias B.Human osteosarcoma (OS) is the most common primary malignant bone tumor occurring most commonly in adolescents and young adults. Major improvements in disease-free survival have been achieved by implementing a combination therapy consisting of radical surgical resection of the tumor and systemic multi-agent chemotherapy. However, long-term survival remains poor, so novel targeted therapies to improve outcomes for patients with osteosarcoma remains an area of active research. This includes immunotherapy, photodynamic therapy, or treatment with nanoparticles. Cold atmospheric plasma (CAP), a highly reactive (partially) ionized physical state, has been shown to inherit a significant anticancer capacity, leading to a new field in medicine called “plasma oncology.” The current article summarizes the potential of CAP in the treatment of human OS and reviews the underlying molecular mode of action.
- ItemArgon 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, RamonaCold 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.
- ItemAntitumor Effects in Gas Plasma-Treated Patient-Derived Microtissues—An Adjuvant Therapy for Ulcerating Breast Cancer?(Basel : MDPI, 2021) Akbari, Zahra; Saadati, Fariba; Mahdikia, Hamed; Freund, Eric; Abbasvandi, Fereshteh; Shokri, Babak; Zali, Hakimeh; Bekeschus, SanderDespite global research and continuous improvement in therapy, cancer remains a challenging disease globally, substantiating the need for new treatment avenues. Medical gas plasma technology has emerged as a promising approach in oncology in the last years. Several investigations have provided evidence of an antitumor action in vitro and in vivo, including our recent work on plasma-mediated reduction of breast cancer in mice. However, studies of gas plasma exposure on patient-derived tumors with their distinct microenvironment (TME) are scarce. To this end, we here investigated patient-derived breast cancer tissue after gas plasma-treated ex vivo. The tissues were disjoint to pieces smaller than 100 µm, embedded in collagen, and incubated for several days. The viability of the breast cancer tissue clusters and their outgrowth into their gel microenvironment declined with plasma treatment. This was associated with caspase 3-dependent apoptotic cell death, paralleled by an increased expression of the anti-metastatic adhesion molecule epithelial (E)-cadherin. Multiplex chemokine/cytokine analysis revealed a marked decline in the release of the interleukins 6 and 8 (IL-6, IL-8) and monocyte-chemoattractant-protein 1 (MCP) known to promote a cancer-promoting milieu in the TME. In summary, we provide here, for the first time, evidence of a beneficial activity of gas plasma exposure on human patient-derived breast cancer tissue.
- ItemCold Atmospheric Pressure Plasma Jet Operated in Ar and He: From Basic Plasma Properties to Vacuum Ultraviolet, Electric Field and Safety Thresholds Measurements in Plasma Medicine(Basel : MDPI, 2022) Nastuta, Andrei Vasile; Gerling, TorstenApplication desired functionality as well as operation expenses of cold atmospheric pressure plasma (CAP) devices scale with properties like gas selection. The present contribution provides a comparative investigation for a CAP system operated in argon or helium at different operation voltages and distance to the surface. Comparison of power dissipation, electrical field strength and optical emission spectroscopy from vacuum ultraviolet over visible up to near infrared ((V)UV-VIS-NIR) spectral range is carried out. This study is extended to safety relevant investigation of patient leakage current, induced surface temperature and species density for ozone (O3) and nitrogen oxides (NOx). It is found that in identical operation conditions (applied voltage, distance to surface and gas flow rate) the dissipated plasma power is about equal (up to 10 W), but the electrical field strength differs, having peak values of 320 kV/m for Ar and up to 300 kV/m for He. However, only for Ar CAP could we measure O3 up to 2 ppm and NOx up to 7 ppm. The surface temperature and leakage values of both systems showed different slopes, with the biggest surprise being a constant leakage current over distance for argon. These findings may open a new direction in the plasma source development for Plasma Medicine.
- ItemFirst insights on plasma orthodontics - Application of cold atmospheric pressure plasma to enhance the bond strength of orthodontic brackets(Amsterdam [u.a.] : Elsevier, 2016) Metelmann, Philine H.; Quooß, Alexandra; Woedtke, Thomas von; Krey, Karl-FriedrichObjective: The development of an ideal adhesive system has long been subject of research. Recent studies show that treatment with cold atmospheric pressure plasma (CAP) positively affects the bonding properties of enamel. Conditioning with CAP could therefore improve the mechanical and physical properties of bracket adhesives, e.g. Glass ionomer cement (GIC). Material and methods: Laser-structured brackets (Dentaurum, Ispringen) were bonded onto 60 bovine mandibular incisors using different orthodontic adhesives. For 20 specimens FujiOrthoLC (GC America Corp, Alsip, USA) was used according to manufacturer's instructions. Another 20 specimens received a 60 s CAP-treatment (kINPen med, Neoplas tool, Greifswald, Germany) before bracket bonding, of which 10 were re-moistened before applying FujiOrthoLC and 10 remained dry. Onto 20 specimens, brackets were bonded with the Composite Transbond XT (3M/Unitek, St. Paul, USA) following manufacturer's instructions. The shear bond strength of brackets on the teeth was determined with the universal testing machine Zwick BZ050/TH3A (Zwick, Ulm, Germany). Results: Brackets bonded with FujiOrthoLC in standard method, showed average shear bond strength of 5.58±0.46 MPa. Specimens treated with plasma showed clinically unacceptable adhesion values (re-moistened group: 2.79±0.38 MPa, dry group: 1.01±0.2 MPa). Bonding onto dried out teeth also led to spontaneous bracket losses (4 of 10 specimens). The composite group (Transbond XT) showed clinically acceptable adhesion values (7.9±1.03 MPa). Conclusions: Despite promising potential, surface conditioning with CAP could not improve the adhesive properties of GIC. By contrast, a decrease in shear bond strength was noticed after CAP treatment. Further investigations have to show whether it is possible to increase the retention values of other orthodontic adhesives by CAP application and thus take advantage of positive characteristics and reduce side effects.
- ItemCold physical plasma-induced oxidation of cysteine yields reactive sulfur species (RSS)(Amsterdam [u.a.] : Elsevier, 2019) Bruno, Giuliana; Heusler, Thea; Lackmann, Jan-Wilm; Woedtke, Thomas von; Weltmann, Klaus-Dieter; Wende, KristianPurpose: Studying plasma liquid chemistry can reveal insights into their biomedical effects, i.e. to understand the direct and indirect processes triggered by the treatment in a model or clinical application. Due to the reactivity of the sulfur atom, thiols are potential targets for plasma- derived reactive species. Being crucial for protein function and redox signaling pathways, their controllable modification would allow expanding the application range. Additionally, models to control and standardize CAP sources are desired tools for plasma source design. Methods: Cysteine, a ubiquitous amino acid, was used as a tracer compound to scavenge the reactive species produced by an argon plasma jet (kINPen). The resulting product pattern was identified via high-resolution mass spectrometry. The Ellman´s assay was used to screen CAP derived thiol consumption, and long-lived species deposition (hydrogen peroxide, nitrite, nitrate) was monitored in relation to the presence of cysteine. Results: The intensity of cysteine oxidation increased with treatment time and availability of oxygen in the feed gas. A range of products from cysteine was identified, in part indicative for certain treatment conditions. Several non-stable products occur transiently during the plasma treatment. Bioactive reactive sulfur species (RSS) have been found for mild treatment conditions, such as cysteine sulfoxides and cysteine-S-sulfonate. Considering the number of cysteine molecules in the boundary layer and the achieved oxidation state, short-lived species dominate in cysteine conversion. In addition, a boundary layer depletion of the tracer was observed. Conclusion: Translating these data into the in-vivo application, strong direct oxidation of protein thiol groups with subsequent changes in protein biochemistry must be considered. Plasma-derived RSS may in part contribute to the observed biomedical effects of CAP. Care must be taken to control the discharge parameter tightly as chemical dynamics at or in the liquid are subject to change easily. © 2019