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- ItemCombining Biocompatible and Biodegradable Scaffolds and Cold Atmospheric Plasma for Chronic Wound Regeneration(Basel : Molecular Diversity Preservation International (MDPI), 2021) Emmert, Steffen; Pantermehl, Sven; Foth, Aenne; Waletzko-Hellwig, Janine; Hellwig, Georg; Bader, Rainer; Illner, Sabine; Grabow, Niels; Bekeschus, Sander; Weltmann, Klaus-Dieter; Jung, Ole; Boeckmann, LarsSkin regeneration is a quite complex process. Epidermal differentiation alone takes about 30 days and is highly regulated. Wounds, especially chronic wounds, affect 2% to 3% of the elderly population and comprise a heterogeneous group of diseases. The prevailing reasons to develop skin wounds include venous and/or arterial circulatory disorders, diabetes, or constant pressure to the skin (decubitus). The hallmarks of modern wound treatment include debridement of dead tissue, disinfection, wound dressings that keep the wound moist but still allow air exchange, and compression bandages. Despite all these efforts there is still a huge treatment resistance and wounds will not heal. This calls for new and more efficient treatment options in combination with novel biocompatible skin scaffolds. Cold atmospheric pressure plasma (CAP) is such an innovative addition to the treatment armamentarium. In one CAP application, antimicrobial effects, wound acidification, enhanced microcirculations and cell stimulation can be achieved. It is evident that CAP treatment, in combination with novel bioengineered, biocompatible and biodegradable electrospun scaffolds, has the potential of fostering wound healing by promoting remodeling and epithelialization along such temporarily applied skin replacement scaffolds.
- ItemNon-thermal plasma treatment induces MAPK signaling in human monocytes(Berlin : de Gruyter, 2014) Bundscherer, Lena; Nagel, Stefanie; Hasse, Sybille; Tresp, Helena; Wende, Kristian; Walther, Reinhard; Reuter, Stephan; Weltmann, Klaus-Dieter; Masur, Kai; Lindequist, UlrikeThe application of non-thermal atmospheric pressure plasma raises a hope for the new wound healing strategies. Next to its antibacterial effect it is known to stimulate skin cells. However, monocytes are also needed for the complex process of a wound healing. This study investigates the impact of plasma on the intracellular signaling events in the primary human monocytes. The proliferative MEK-ERK (MAPK/ERK kinase-extracellular signal-regulated kinase) pathway was activated by short plasma treatment times. In contrast, an induction of the apoptotic JNK (c-Jun N-terminal kinase) cascade as well as activation of caspase 3 were observed after long plasma exposure. These findings indicate that monocytes can be differentially stimulated by plasma treatment and may contribute to the proper wound recovery.
- ItemA Comparison of Floating-Electrode DBD and kINPen Jet: Plasma Parameters to Achieve Similar Growth Reduction in Colon Cancer Cells Under Standardized Conditions(Dordrecht : Springer Science + Business Media B.V., 2017-9-6) Bekeschus, Sander; Lin, Abraham; Fridman, Alexander; Wende, Kristian; Weltmann, Klaus-Dieter; Miller, VandanaA comparative study of two plasma sources (floating-electrode dielectric barrier discharge, DBD, Drexel University; atmospheric pressure argon plasma jet, kINPen, INP Greifswald) on cancer cell toxicity was performed. Cell culture protocols, cytotoxicity assays, and procedures for assessment of hydrogen peroxide (H2O2) were standardized between both labs. The inhibitory concentration 50 (IC50) and its corresponding H2O2 deposition was determined for both devices. For the DBD, IC50 and H2O2 generation were largely dependent on the total energy input but not pulsing frequency, treatment time, or total number of cells. DBD cytotoxicity could not be replicated by addition of H2O2 alone and was inhibited by larger amounts of liquid present during the treatment. Jet plasma toxicity depended on peroxide generation as well as total cell number and amount of liquid. Thus, the amount of liquid present during plasma treatment in vitro is key in attenuating short-lived species or other physical effects from plasmas. These in vitro results suggest a role of liquids in or on tissues during plasma treatment in a clinical setting. Additionally, we provide a platform for correlation between different plasma sources for a predefined cellular response.
- ItemxCT (SLC7A11) expression confers intrinsic resistance to physical plasma treatment in tumor cells(Amsterdam [u.a.] : Elsevier, 2020) Bekeschus, Sander; Eisenmann, Sebastian; Sagwal, Sanjeev Kumar; Bodnar, Yana; Moritz, Juliane; Poschkamp, Broder; Stoffels, Ingo; Emmert, Steffen; Madesh, Muniswamy; Weltmann, Klaus-Dieter; von Woedtke, Thomas; Gandhirajan, Rajesh KumarCold physical plasma is a partially ionized gas investigated as a new anticancer tool in selectively targeting cancer cells in monotherapy or in combination with therapeutic agents. Here, we investigated the intrinsic resistance mechanisms of tumor cells towards physical plasma treatment. When analyzing the dose-response relationship to cold plasma-derived oxidants in 11 human cancer cell lines, we identified four 'resistant' and seven 'sensitive' cell lines. We observed stable intracellular glutathione levels following plasma treatment only in the 'resistant' cell lines indicative of altered antioxidant mechanisms. Assessment of proteins involved in GSH metabolism revealed cystine-glutamate antiporter xCT (SLC7A11) to be significantly more abundant in the 'resistant' cell lines as compared to 'sensitive' cell lines. This decisive role of xCT was confirmed by pharmacological and genetic inhibition, followed by cold physical plasma treatment. Finally, microscopy analysis of ex vivo plasma-treated human melanoma punch biopsies suggested a correlation between apoptosis and basal xCT protein abundance. Taken together, our results demonstrate that xCT holds the potential as a biomarker predicting the sensitivity of tumor cells towards plasma treatment.
- ItemBiocompatible Gas Plasma Treatment Affects Secretion Profiles but Not Osteogenic Differentiation in Patient-Derived Mesenchymal Stromal Cells(Basel : Molecular Diversity Preservation International (MDPI), 2022) Fischer, Maximilian; Schoon, Janosch; Freund, Eric; Miebach, Lea; Weltmann, Klaus-Dieter; Bekeschus, Sander; Wassilew, Georgi I.Cold physical plasma (CPP), a partially ionized gas that simultaneously generates reactive oxygen and nitrogen species, is suggested to provide advantages in regenerative medicine. Intraoperative CPP therapy targeting pathologies related to diminished bone quality could be promising in orthopedic surgery. Assessment of a clinically approved plasma jet regarding cellular effects on primary bone marrow mesenchymal stromal cells (hBM-MSCs) from relevant arthroplasty patient cohorts is needed to establish CPP-based therapeutic approaches for bone regeneration. Thus, the aim of this study was to derive biocompatible doses of CPP and subsequent evaluation of human primary hBM-MSCs’ osteogenic and immunomodulatory potential. Metabolic activity and cell proliferation were affected in a treatment-time-dependent manner. Morphometric high content imaging analyses revealed a decline in mitochondria and nuclei content and increased cytoskeletal compactness following CPP exposure. Employing a nontoxic exposure regime, investigation on osteogenic differentiation did not enhance osteogenic capacity of hBM-MSCs. Multiplex analysis of major hBM-MSC cytokines, chemokines and growth factors revealed an anti-inflammatory, promatrix-assembling and osteoclast-regulating secretion profile following CPP treatment and osteogenic stimulus. This study can be noted as the first in vitro study addressing the influence of CPP on hBM-MSCs from individual donors of an arthroplasty clientele.
- ItemPlasma treatment limits cutaneous squamous cell carcinoma development in vitro and in vivo(Basel : MDPI AG, 2020) Pasqual-Melo, Gabriella; Nascimento, Thiago; Sanches, Larissa Juliani; Blegniski, Fernanda Paschoal; Bianchi, Julya Karen; Sagwal, Sanjeev Kumar; Berner, Julia; Schmidt, Anke; Emmert, Steffen; Weltmann, Klaus-Dieter; Woedtke, Thomas von; Gandhirajan, Rajesh Kumar; Cecchini, Alessandra Lourenço; Bekeschus, SanderCutaneous squamous cell carcinoma (SCC) is the most prevalent cancer worldwide, increasing the cost of healthcare services and with a high rate of morbidity. Its etiology is linked to chronic ultraviolet (UV) exposure that leads to malignant transformation of keratinocytes. Invasive growth and metastasis are severe consequences of this process. Therapy-resistant and highly aggressive SCC is frequently fatal, exemplifying the need for novel treatment strategies. Cold physical plasma is a partially ionized gas, expelling therapeutic doses of reactive oxygen and nitrogen species that were investigated for their anticancer capacity against SCC in vitro and SCC-like lesions in vivo. Using the kINPen argon plasma jet, a selective growth-reducing action of plasma treatment was identified in two SCC cell lines in 2D and 3D cultures. In vivo, plasma treatment limited the progression of UVB-induced SSC-like skin lesions and dermal degeneration without compromising lesional or non-lesional skin. In lesional tissue, this was associated with a decrease in cell proliferation and the antioxidant transcription factor Nrf2 following plasma treatment, while catalase expression was increased. Analysis of skin adjacent to the lesions and determination of global antioxidant parameters confirmed the local but not systemic action of the plasma anticancer therapy in vivo. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- ItemCombination treatment with cold physical plasma and pulsed electric fields augments ros production and cytotoxicity in lymphoma(Basel : MDPI AG, 2020) Wolff, Christina M.; Kolb, Juergen F.; Weltmann, Klaus-Dieter; Woedtke, Thomas von; Bekeschus, SanderNew approaches in oncotherapy rely on the combination of different treatments to enhance the efficacy of established monotherapies. Pulsed electric fields (PEFs) are an established method (electrochemotherapy) for enhancing cellular drug uptake while cold physical plasma is an emerging and promising anticancer technology. This study aimed to combine both technologies to elucidate their cytotoxic potential as well as the underlying mechanisms of the effects observed. An electric field generator (0.9–1.0 kV/cm and 100-μs pulse duration) and an atmospheric pressure argon plasma jet were employed for the treatment of lymphoma cell lines as a model system. PEF but not plasma treatment induced cell membrane permeabilization. Additive cytotoxicity was observed for the metabolic activity and viability of the cells while the sequence of treatment in the combination played only a minor role. Intriguingly, a parallel combination was more effective compared to a 15-min pause between both treatment regimens. A combination effect was also found for lipid peroxidation; however, none could be observed in the cytosolic and mitochondrial reactive oxygen species (ROS) production. The supplementation with either antioxidant, a pan-caspase-inhibitor or a ferroptosis inhibitor, all partially rescued lymphoma cells from terminal cell death, which contributes to the mechanistic understanding of this combination treatment. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- ItemActivation of murine immune cells upon co-culture with plasma-treated B16F10 melanoma cells(Basel : MDPI, 2019) Rödder, Katrin; Moritz, Juliane; Miller, Vandana; Weltmann, Klaus-Dieter; Metelmann, Hans-Robert; Gandhirajan, Rajesh; Bekeschus, SanderRecent advances in melanoma therapy increased median survival in patients. However, death rates are still high, motivating the need of novel avenues in melanoma treatment. Cold physical plasma expels a cocktail of reactive species that have been suggested for cancer treatment. High species concentrations can be used to exploit apoptotic redox signaling pathways in tumor cells. Moreover, an immune-stimulatory role of plasma treatment, as well as plasma-killed tumor cells, was recently proposed, but studies using primary immune cells are scarce. To this end, we investigated the role of plasma-treated murine B16F10 melanoma cells in modulating murine immune cells' activation and marker profile. Melanoma cells exposed to plasma showed reduced metabolic and migratory activity, and an increased release of danger signals (ATP, CXCL1). This led to an altered cytokine profile with interleukin-1β (IL-1β) and CCL4 being significantly increased in plasma-treated mono- and co-cultures with immune cells. In T cells, plasma-treated melanoma cells induced extracellular signal-regulated Kinase (ERK) phosphorylation and increased CD28 expression, suggesting their activation. In monocytes, CD115 expression was elevated as a marker for activation. In summary, here we provide proof of concept that plasma-killed tumor cells are recognized immunologically, and that plasma exerts stimulating effects on immune cells alone. © 2019 by the authors.
- ItemEx Vivo Exposure of Human Melanoma Tissue to Cold Physical Plasma Elicits Apoptosis and Modulates Inflammation(Basel : MDPI, 2020) Bekeschus, Sander; Moritz, Juliane; Helfrich, Iris; Boeckmann, Lars; Weltmann, Klaus-Dieter; Emmert, Steffen; Metelmann, Hans-Robert; Stoffels, Ingo; von Woedtke, ThomasCutaneous melanoma is the most aggressive type of skin cancer with a not-sufficient clinical outcome. High tumor mutation rates often hamper a remedial treatment, creating the need for palliative care in many patients. To reduce pain and burden, local palliation often includes cryo-ablation, immunotherapy via injection of IL2, or electrochemotherapy. Yet, a fraction of patients and lesions do not respond to those therapies. To reach even these resistances in a redox-mediated way, we treated skin biopsies from human melanoma ex vivo with cold physical plasma (kINPen MED plasma jet). This partially ionized gas generates a potent mixture of reactive oxygen species (ROS). Physical plasmas have been shown to be potent antitumor agents in preclinical melanoma and clinical head and neck cancer research. The innovation of this technology lies in its ease-of-use without anesthesia, as the “cold” plasma temperature of the kINPen MED does not exceed 37 °C. In metastatic melanoma skin biopsies from six patients, we identified a marked increase of apoptosis with plasma treatment ex vivo. This had an impact on the chemokine/cytokine profile of the cultured biopsies, e.g., three of six patient-derived biopsy supernatants showed an apparent decrease in VEGF compared to non-plasma treated specimens. Moreover, the baseline release levels of 24 chemokines/cytokines investigated may serve as a useful tool for future research on melanoma skin biopsy treatments. Our findings suggest a clinically useful role of cold physical plasma therapy in palliation of cutaneous melanoma lesions, possibly in a combinatory setting with other immune therapies.