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Cold atmospheric plasma (CAP) treatment induces cancer cell death through the generation of reactive oxygen and nitrogen species (RONS). However, the efficacy of RONS delivery into cells remains limited by membrane permeability. Here, we investigated whether combining CAP with pulsed electric fields (PEFs) could enhance cancer cell death through increased intracellular RONS uptake. HeLa cells were treated with argon atmospheric pressure plasma jet (Ar-APPJ), PEF, or their combination. The combined treatment showed significantly enhanced cell death compared to single treatments. While PEF treatment alone induced membrane permeabilization, the combination with Ar-APPJ resulted in more pronounced and sustained membrane disruption, as evidenced by increased calcein leakage. This enhanced effect was attributed to Ar-APPJ-induced lipid peroxidation interfering with membrane resealing after PEF-induced electroporation. We also demonstrated that PEF-induced membrane electroporation facilitates the intracellular uptake of CAP-generated RONS. These findings provide mechanistic insights into the synergistic effects of combined CAP and PEF treatments, suggesting enhanced cell death via multiple pathways. [ABSTRACT FROM AUTHOR]

Non-invasive physical plasma (NIPP) has been used effectively for wound healing in human medicine for over two decades. The advantages are that NIPP has few side effects, is painless and gentle on the tissue. The therapeutic effect is mediated by reactive oxygen species (ROS). Based on the biomedical effects known to date, it can be assumed that NIPP can also be used for wound treatment in non-human mammals. In this prospective, non-randomized monocentric clinical trial, 43 European hedgehogs with cut and bite wounds were treated with conventional wound management (CWM: 21 patients) and compared with 22 patients with CWM plus NIPP treatment (CWM + NIPP). Under NIPP treatment, patients showed no signs of pain, stress or discomfort, even after several applications. In 76% of CWM + NIPP patients, three or four NIPP applications were sufficient. In patients in the CWM + NIPP group, wound treatment was completed statistically significantly 6 d earlier (CWM: 19.0 d versus CWM + NIPP: 13.2 d; p = 0.0008). This wildlife clinical trial demonstrates that NIPP can be used to improve wound healing in wild European hedgehogs. It is conceivable that NIPP therapy could also lead to positive effects in other injured wild animals, domestic animals or livestock. [ABSTRACT FROM AUTHOR]

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Plasma jets, crucial atmospheric pressure sources in biomedical applications, generate reactive species in liquids, with electrical fields playing a significant role, as variations in pulse rise times and durations in dielectric barrier discharges yield diverse effects. This study presents a novel nanosecond pulse plasma jet. Here, investigations with phosphate‐buffered saline and Ringer's saline elucidate critical parameters influencing species generation, such as treatment time and gas flow rate. Results showed increasing concentrations of H2O2 and NO2− over time, with NO2− degrading faster in Ringer's saline due to acidification. The nanosecond pulse jet exhibits superior energy efficiency than conventional jets, laying the groundwork for optimizing species generation and studying electrical field effects in future biological works. [ABSTRACT FROM AUTHOR]

Cold atmospheric plasma (CAP) has been shown to be beneficial in various medical fields such as wound healing, oncology or dentistry. A prominent effect induced by CAP is the boost of microcirculation in human skin tissue. Being a complex cocktail of physical and chemically reactive components, the mechanisms by which CAP enhances microcirculation still remain unclear. Thus, this study aims to identify relevant CAP components involved in stimulation of dermal microcirculation. In a comparative approach, the application of the same CAP source was modified in such a way that three different treatment modalities could be realized, each with a characteristic composition of electrical current flow and concentration of reactive species. Microcirculation parameters oxygen saturation (StO2), tissue hemoglobin index, near-infrared perfusion index and tissue water index were recorded before and after each treatment on the lateral proximal left arm of 10 healthy volunteers by means of hyperspectral imaging. The maximum microcirculatory response to CAP was observed when all components were allowed to interact with skin tissue (standard treatment). In contrast, no upregulation was found as soon as electric currents and fields had been removed from the effective component spectrum. Application of the CAP source at reduced concentrations of reactive species compared to standard treatment led to significant but less pronounced enhancement of dermal microcirculation. The findings of this study indicate that a synergistic interplay of all CAP components promotes microcirculation in dermal tissue most effectively. Moreover, the findings support the hypothesis that electric currents and fields play a key role in enabling microcirculation boost whereas availability of reactive species in the gas phase is associated with the intensity of the tissue response to CAP treatment. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests the role of reactive oxygen and nitrogen species (RONS) in regulating antitumor immune effects and immunosuppression. RONS modify biomolecules and induce oxidative post‐translational modifications (oxPTM) on proteins that can alarm phagocytes. However, it is unclear if and how protein oxidation by technical means could be a strategy to foster antitumor immunity and therapy. To this end, cold gas plasma technology producing various RONS simultaneously to oxidize the two melanoma‐associated antigens MART and PMEL is utilized. Cold plasma‐oxidized MART (oxMART) and PMEL (oxPMEL) are heavily decorated with oxPTMs as determined by mass spectrometry. Immunization with oxidized MART or PMEL vaccines prior to challenge with viable melanoma cells correlated with significant changes in cytokine secretion and altered T‐cell differentiation of tumor‐infiltrated leukocytes (TILs). oxMART promoted the activity of cytotoxic central memory T‐cells, while oxPMEL led to increased proliferation of cytotoxic effector T‐cells. Similar T‐cell results are observed after incubating splenocytes of tumor‐bearing mice with B16F10 melanoma cells. This study, for the first time, provides evidence of the importance of oxidative modifications of two melanoma‐associated antigens in eliciting anticancer immunity. [ABSTRACT FROM AUTHOR]

Cold physical plasma, a partially ionized gas, has been shown to be effective in treating chronic wounds and cancer. However, there is limited research on plasma exposure of leukemia cell lines, such as chronic lymphocytic leukemia (CLL) and cytotoxic CD8+ T cells. To investigate the potential proimmunogenic effects of plasma‐derived reactive oxygen species, cytotoxic T cells were isolated from CLL patients and healthy volunteers. Extensive cold plasma treatment reduced T‐cell metabolic activity and viability in both diseased and healthy groups. Plasma treatment of cocultures, but not CD8+ T‐cell monocultures, spurred cytotoxic T‐cell proliferation, possibly due to plasma‐enhanced CLL antigen display and plasma‐mediated modulation of immunoregulatory surface molecules. Further studies are needed to understand the mechanisms and clinical relevance of these findings. [ABSTRACT FROM AUTHOR]

This work focuses on the antimycotic effects of the plasma gun as a potential tool for the treatment of superficial infections. Candida glabrata was chosen as a model microorganism. The preliminary tests have been done on the agar plates to establish the basic plasma parameters. To render this research more appropriate to the real application, more complex inoculation substrates, pork skin and 3D‐printed models of the dog ear canal have been used. The results of this work confirm the high efficiency of cold plasma in the inhibition of yeasts on different surfaces and will lead to further experiments. [ABSTRACT FROM AUTHOR]

In this transformative study, machine learning (ML) and t‐distributed stochastic neighbor embedding (t‐SNE) are employed to interpret intricate patterns in colorimetric images of cold atmospheric plasma (CAP)‐treated water. The focus is on CAP's therapeutic potential, particularly its ability to generate reactive oxygen and nitrogen species (RONS) that play a crucial role in antimicrobial activity. RGB, HSV, LAB, YCrCb, and grayscale color spaces are extracted from the colorimetric expression of oxidative stress induced by RONS, and these features are used for unsupervised ML, employing density‐based spatial clustering of applications with noise (DBSCAN). The DBSCAN model's performance is evaluated using homogeneity, completeness, and adjusted rand index with a predictive data distribution graph. The best results are achieved with 3,3′,5,5′‐tetramethylbenzidine–potassium iodide colorimetric assay solution immediately after plasma treatment, with values of 0.894, 0.996, and 0.826. t‐SNE is further conducted for the best‐case scenario to evaluate the clustering efficacy and find the best combination of features to better present the results. Correspondingly, t‐SNE enhances clustering efficacy and adeptly handles challenging points. The approach pioneers dynamic and comprehensive solutions, showcasing ML's precision and t‐SNE's transformative visualization. Through this innovative fusion, complex relationships are unraveled, marking a paradigm shift in biomedical analytical methodologies. [ABSTRACT FROM AUTHOR]

AimThe intricate structure of the tooth root canals has a role in the colonization and biofilm formation in hidden areas that are hardly reached by standard endodontic treatments. This review aims at summarizing data from in vitro and ex vivo studies for a better understanding of the application of cold atmospheric plasma (CAP) for the disinfection of dental root canals.MethodsPubMed, Scopus, and Web of Science databases were screened. Characteristics of the included studies were extracted, and a meta-analysis on ex vivo studies was carried out to evaluate the effect of CAP on colony forming unit assay of Enterococcus faecalis (E. faecalis). The study was performed following the PRISMA 2020 guidelines.ResultsA total of 31 studies fulfilled the selection criteria. Only 2 investigations reported an indirect plasma treatment, 28 trials used direct CAP administration, while 1 study applied both methods. Most of the studies were conducted on E. faecalis using as carrier gas Helium or Argon alone or in combination with Oxygen as well air. A considerable heterogeneity among studies was found regarding treatments which varied for source type, settings, and protocols of application. Despite this, CAP showed effectiveness in reducing E. faecalis colony forming unit with a standardized mean difference of 4.51, 95% C.I. = 2.55–6.48, p-value

Cold atmospheric plasma (CAP) has emerged as an innovative tool with broad medical applications, including ovarian cancer (OC) treatment. By bringing CAP in close proximity to liquids such as water or cell culture media, solutions containing reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated, called plasma-activated media (PAM). In this systematic review, we conduct an in-depth analysis of studies focusing on PAM interactions with biological substrates. We elucidate the diverse mechanisms involved in the activation of different media and the complex network of chemical reactions underlying the generation and consumption of the prominent reactive species. Furthermore, we highlight the promises of PAM in advancing biomedical applications, such as its stability for extended periods under appropriate storage conditions. We also examine the application of PAM as an anti-cancer and anti-metastatic treatment for OC, with a particular emphasis on its ability to induce apoptosis via distinct signaling pathways, inhibit cell growth, suppress cell motility, and enhance the therapeutic effects of chemotherapy. Finally, the future outlook of PAM therapy in biomedical applications is speculated, with emphasis on the safety issues relevant to clinical translation. [ABSTRACT FROM AUTHOR]

Plasma treatment is necessary to optimize the performance of biomaterial surfaces. It enhances and regulates the performance of biomaterial surfaces, creating an effective interface with the human body. Plasma treatments have the ability to modify the chemical composition and physical structure of a surface while leaving its properties unaffected. They possess the ability to modify material surfaces, eliminate contaminants, conduct investigations on cancer therapy, and facilitate wound healing. The subject of study in question involves the integration of plasma science and technology with biology and medicine. Using a helium plasma jet source, applying up to 18 kV, with an average power of 10 W, polymer foils were treated for 60 s. Plasma treatment has the ability to alter the chemical composition and physical structure of a surface while maintaining its quality. This investigation involved the application of helium plasma at atmospheric pressure to polyamide 6 and polyethylene terephthalate sheets. The inquiry involves monitoring and assessing the plasma source and polymer materials, as well as analyzing the impacts of plasma therapy. Calculating the mean power of the discharge aids in assessing the economic efficacy of the plasma source. Electric discharge in helium at atmospheric pressure has beneficial effects in technology, where it increases the surface free energy of polymer materials. In biomedicine, it is used to investigate cytotoxicity and cell survival, particularly in direct blood exposure situations that can expedite coagulation. Comprehending the specific parameters that influence the plasma source in the desired manner for the intended application is of utmost importance. [ABSTRACT FROM AUTHOR]

The bactericidal components of air plasma jets generated by a direct-current glow discharge and a dielectric barrier discharge were studied using IR and UV absorption spectroscopy. The mole fractions of bactericidal components with an absorption spectrum band structure were determined by selecting a mole fraction value in the calculated spectrum that ensured correlation with the experimental spectrum. The spectra were calculated using the HITRAN spectral database and the Specair 3.0 program. The error in the mole fractions due to violation of the Bouguer–Lambert–Beer law when using absorption coefficients convoluted with the instrument function was determined. The mole fractions of bactericidal components with a continuous absorption spectrum were calculated using the Bouguer–Lambert–Beer law in a standard way. IR and UV absorption spectroscopy were shown to enable determination of the mole fractions for the full set of bactericidal components in air plasma jets of glow and barrier discharges. [ABSTRACT FROM AUTHOR]

Plasma medicine has attracted tremendous interest in a variety of medical conditions, ranging from wound healing to antimicrobial applications, even in cancer treatment, through the interactions of cold atmospheric plasma (CAP) and various biological tissues directly or indirectly. The underlying mechanisms of CAP treatment are still poorly understood although the oxidative effects of CAP with amino acids, peptides, and proteins have been explored experimentally. In this study, machine learning (ML) technology is introduced to efficiently unveil the interaction mechanisms of amino acids and reactive oxygen species (ROS) in seconds based on the data obtained from the reactive molecular dynamics (MD) simulations, which are performed to probe the interaction of five types of amino acids with various ROS on the timescale of hundreds of picoseconds but with the huge computational load of several days. The oxidative reactions typically start with H‐abstraction, and the details of the breaking and formation of chemical bonds are revealed; the modification types, such as nitrosylation, hydroxylation, and carbonylation, can be observed. The dose effects of ROS are also investigated by varying the number of ROS in the simulation box, indicating agreement with the experimental observation. To overcome the limits of timescales and the size of molecular systems in reactive MD simulations, a deep neural network (DNN) with five hidden layers is constructed according to the reaction data and employed to predict the type of oxidative modification and the probability of occurrence only in seconds as the dose of ROS varies. The well‐trained DNN can effectively and accurately predict the oxidative processes and productions, which greatly improves the computational efficiency by almost ten orders of magnitude compared with the reactive MD simulation. This study shows the great potential of ML technology to efficiently unveil the underpinning mechanisms in plasma medicine based on the data from reactive MD simulations or experimental measurements. [ABSTRACT FROM AUTHOR]

In this transformative study, machine learning (ML) and t‐distributed stochastic neighbor embedding (t‐SNE) are employed to interpret intricate patterns in colorimetric images of cold atmospheric plasma (CAP)‐treated water. The focus is on CAP's therapeutic potential, particularly its ability to generate reactive oxygen and nitrogen species (RONS) that play a crucial role in antimicrobial activity. RGB, HSV, LAB, YCrCb, and grayscale color spaces are extracted from the colorimetric expression of oxidative stress induced by RONS, and these features are used for unsupervised ML, employing density‐based spatial clustering of applications with noise (DBSCAN). The DBSCAN model's performance is evaluated using homogeneity, completeness, and adjusted rand index with a predictive data distribution graph. The best results are achieved with 3,3′,5,5′‐tetramethylbenzidine–potassium iodide colorimetric assay solution immediately after plasma treatment, with values of 0.894, 0.996, and 0.826. t‐SNE is further conducted for the best‐case scenario to evaluate the clustering efficacy and find the best combination of features to better present the results. Correspondingly, t‐SNE enhances clustering efficacy and adeptly handles challenging points. The approach pioneers dynamic and comprehensive solutions, showcasing ML's precision and t‐SNE's transformative visualization. Through this innovative fusion, complex relationships are unraveled, marking a paradigm shift in biomedical analytical methodologies.

This paper presents and explains the principle behind anelectrochemical method to enhance the antimicrobial action of plasma‐activated hydrogel therapy (PAHT) in the context of wound decontamination. The process involves grounding and hydratingpoly(vinyl alcohol) (PVA) hydrogel films during treatment with a helium (He) plasma jet. This electrochemically enhances production of hydrogen peroxide (H2O2), which is amajor antibacterial agent produced in the PVA hydrogel. Production of H2O2 is shownto be electrically enhanced through electron dissociation reactions, and through reactions associated with excited state species, metastables and ultra‐violet (UV) photolysis. H2O2 production is chemically enhanced through the He flow of the plasma jet dehydrating the PVA hydrogel, which fuels the electrochemical dependent reactions associated with H2O2 production. The electrochemical process produces an unprecedented 3.4 mM of H2O2 in the PVA hydrogel. Production of other molecules such as reactive nitrogen species (RNS) are also enhanced by the same method. The electrochemically enhanced PAHT is highly effective ateradicating common wound pathogens Escherichia coli and Pseudomonas aeruginosa and mildly effective against Staphylococcus aureus. Overall, this study shows that the new PAHT dressing offers a promising alternative to antibiotics and silver‐based dressings for controlling infection and stimulating healing in wounds. [ABSTRACT FROM AUTHOR]

Epidermal melanin synthesis determines an individual's skin color. In humans, melanin is formed by melanocytes within the epidermis. The process of melanin synthesis strongly depends on a range of cellular factors, including the fine-tuned interplay with reactive oxygen species (ROS). In this context, a role of cold atmospheric plasma (CAP) on melanin synthesis was proposed due to its tunable ROS generation. Herein, the argon-driven plasma jet kINPen® MED was employed, and its impact on melanin synthesis was evaluated by comparison with known stimulants such as the phosphodiesterase inhibitor IBMX and UV radiation. Different available model systems were employed, and the melanin content of both cultured human melanocytes (in vitro) and full-thickness human skin biopsies (in situ) were analyzed. A histochemical method detected melanin in skin tissue. Cellular melanin was measured by NIR autofluorescence using flow cytometry, and a highly sensitive HPLC-MS method was applied, which enabled the differentiation of eu- and pheomelanin by their degradation products. The melanin content in full-thickness human skin biopsies increased after repeated CAP exposure, while there were only minor effects in cultured melanocytes compared to UV radiation and IBMX treatment. Based on these findings, CAP does not appear to be a useful option for treating skin pigmentation disorders. On the other hand, the risk of hyperpigmentation as an adverse effect of CAP application for wound healing or other dermatological diseases seems to be neglectable. [ABSTRACT FROM AUTHOR]

During the development of new therapeutic devices, comprehensive experimental investigations are necessary in all phases of the process. This requires the provision of device prototypes with reproducible and comparable operating parameters. In the current study, such miniature neon plasma jet prototypes designated for medical applications have been manufactured, characterized, and compared. The multi-parametric characterization included measurements of energy, power, temperature, leakage current, effluent length, and relative as well as absolute radiation. The dissipated electrical power and the optical emission in the UV range were identified as parameters indicating definable tolerances to sort out a device with inadequate species output. A liquid phase model was used to investigate reactive species deposition into simple matrices. Based on these investigations, a quality control procedure for manufacturing new device series is proposed. In conclusion, our findings suggest a test concept of achieving reproducible and comparable plasma device characterization as a putative quality control measure for lab-scale plasma source production. [ABSTRACT FROM AUTHOR]

Dielectric barrier discharge (DBD) plasma has several applications in different fields. One of these fundamental applications is medical usages, where various methods are employed to improve the plasma treatment process. The combination of different gases is one of the important strategies to improve the performance of plasma in treatment. In this paper, the optimized plasma parameters for one-dimensional radiofrequency discharge produced at low pressures in a helium gas combination is studied. In this research, the optimal combination of H2O and He is identified to attain the highest amount of reactive oxygen species (ROS). Considered mixture are 5, 10, 15 and 20 precent of H2O for one dimensional helium gas discharge. The results show that the parameters of the output plasma are highly dependent on the composition of the input gases. It is found that the greatest concentrations of H+, H+, Hes (excited helium), and OH densities are observed when the H2O percentage was at 10%. Moreover, the density distributions of various species and the temperatures of electrons are numerically calculated during the electrical discharge process. These findings provide useful knowledge on how to optimize plasma parameters for biomedical applications, which may lead to improved treatment results in several therapeutic areas. [ABSTRACT FROM AUTHOR]

This comprehensive review explores decade-long research conducted on the applications of Cold Atmospheric Plasma (CAP) and Plasma Activated Liquids (PAL), including Plasma Activated Water (PAW), in the fields of Medicine and Dentistry. CAPs, operating at atmospheric pressure, offer unique advantages over conventional medical devices, generating Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) that interact with substances, enabling diverse applications. The review examined CAP and PAL efficacy against infectious diseases using in vitro, ex vivo, in vivo, and direct application methods. Significant strides were observed in wound healing, cancer treatment, and dental care. However, ensuring patient safety through rigorous plasma source standards remains crucial. The study underscores CAPs and PALs' potential to transform medical and dental therapies, urging further research and development in these groundbreaking technologies. These findings highlight the transformative impact of CAPs and PALs, offering promising avenues for innovative medical and dental treatments. [ABSTRACT FROM AUTHOR]

Cold atmospheric plasma (CAP) is a source of cell‐damaging oxidant molecules that may be used as low‐cost cancer treatment with minimal side effects. Liquids treated with cold plasma and enriched with oxidants are a modality for non‐invasive treatment of internal tumors with cold plasma via injection. However, liquids are easily diluted with body fluids which impedes high and localized delivery of oxidants to the target. As an alternative, plasma‐treated hydrogels (PTH) emerge as vehicles for the precise delivery of oxidants. This study reports an optimal protocol for the preparation of injectable alginate PTH that ensures the preservation of plasma‐generated oxidants. The generation, storage, and release of oxidants from the PTH are assessed. The efficacy of the alginate PTH in cancer treatment is demonstrated in the context of cancer cell cytotoxicity and immunogenicity–release of danger signals and phagocytosis by immature dendritic cells, up to now unexplored for PTH. These are shown in osteosarcoma, a hard‐to‐treat cancer. The study aims to consolidate PTH as a novel cold plasma treatment modality for non‐invasive or postoperative tumor treatment. The results offer a rationale for further exploration of alginate‐based PTHs as a versatile platform in biomedical engineering. [ABSTRACT FROM AUTHOR]

As carbon monoxide has a broad spectrum of biological activities, its production by plasma is a significant advantage in medicine. This paper presents a comparative study of the CO production of two plasma jets: a MHz‐jet and a kHz‐jet. Both were fed with a helium gas with CO2 ${\text{CO}}_{2}$ admixture (0%–1%). CO was produced by CO2 ${\text{CO}}_{2}$ dissociation and its maximal concentration was hundreds of parts per million, which is safe for clinical applications. For the same specific energy input, the CO production was more efficient for the kHz‐jet than the MHz‐jet. Both had antibacterial properties on Escherichia coli, and the addition of CO2 ${\text{CO}}_{2}$ improved them for the MHz‐jet, while it reduced them for the kHz‐jet. [ABSTRACT FROM AUTHOR]

Cold atmospheric plasma has become a widespread tool in bacterial decontamination, harnessing reactive oxygen and nitrogen species to neutralize bacteria on surfaces and in the air. This technology is often employed in healthcare, food processing, water treatment, etc. One of the most energy-efficient and universal methods for creating cold atmospheric plasma is the initiation of a piezoelectric direct discharge. The article presents a study of the bactericidal effect of piezoelectric direct discharge plasma generated using the multifunctional source "CAPKO". This device allows for the modification of the method of plasma generation "on the fly" by replacing a unit (cap) on the working device. The results of the generation of reactive oxygen and nitrogen species in a buffer solution in the modes of direct discharge in air and a plasma jet with an argon flow are presented. The bactericidal effect of these types of plasma against the bacteria E. coli BL21 (DE3) was studied. The issues of scaling the treatment technique are considered. [ABSTRACT FROM AUTHOR]

Plasma, the fourth fundamental state of matter, comprises charged species and electrons, and it is a fascinating medium that is spread over the entire visible universe. In addition to that, plasma can be generated artificially under appropriate laboratory techniques. Artificially generated thermal or hot plasma has applications in heavy and electronic industries; however, the non-thermal (cold atmospheric or low temperature) plasma finds its applications mainly in biomedicals and therapeutics. One of the important characteristics of LTP is that the constituent particles in the plasma stream can often maintain an overall temperature of nearly room temperature, even though the thermal parameters of the free electrons go up to 1 to 10 keV. The presence of reactive chemical species at ambient temperature and atmospheric pressure makes LTP a bio-tolerant tool in biomedical applications with many advantages over conventional techniques. This review presents some of the important biomedical applications of cold-atmospheric plasma (CAP) or low-temperature plasma (LTP) in modern medicine, showcasing its effect in antimicrobial therapy, cancer treatment, drug/gene delivery, tissue engineering, implant modifications, interaction with biomolecules, etc., and overviews some present challenges in the field of plasma medicine. [ABSTRACT FROM AUTHOR]

Diabetes can disrupt physiological wound healing, caused by decreased levels or impaired activity of angiogenic factors. This can contribute to chronic inflammation, poor formation of new blood vessels, and delayed re-epithelialization. The present study describes the preclinical application of medical gas plasma to treat a dermal, full-thickness ear wound in streptozotocin (STZ)-induced diabetic mice. Gas plasma-mediated effects occurred in both sexes but with gender-specific differences. Hyperspectral imaging demonstrated gas plasma therapy changing microcirculatory parameters, particularly oxygen saturation levels during wound healing, presumably due to the gas plasma's tissue delivery of reactive species and other bioactive components. In addition, gas plasma treatment significantly affected cell adhesion by regulating focal adhesion kinase and vinculin, which is important in maintaining skin barrier function by regulating syndecan expression and increasing re-epithelialization. An anticipated stimulation of blood vessel formation was detected via transcriptional and translational increase of angiogenic factors in gas plasma-exposed wound tissue. Moreover, gas plasma treatment significantly affected inflammation by modulating systemic growth factors and cytokine levels. The presented findings may help explain the mode of action of successful clinical plasma therapy of wounds of diabetic patients. [ABSTRACT FROM AUTHOR]

The current trends that incorporate artificial intelligence (AI) and medicine have created new opportunities for improvement in both early diagnosis and treatment of diseases. In this framework, AI might also have the potential to significantly revolutionize the way we approach the field of plasma medicine, an area that is quickly growing and uses cold atmospheric plasma (CAP) to address a variety of medical conditions. Plasma medicine offers promising therapeutic alternatives for conditions widely ranging from cancer treatment to wound healing and antimicrobial applications, but the complexity of the plasma sources and the huge number of parameters may be overwhelming for the determination of underlying mechanisms and for understanding the effect of the source. This is where AI steps in, to provide strong tools for modeling, evaluating, and controlling CAPs. By harnessing the power of AI, researchers in the plasma medicine area, are now able to evaluate massive volumes of data, enhance their treatment protocols, and predict treatment results with a level of precision never possible before. Hereby, we emphasized the potential and further utilization of AI in plasma medicine in light of the fascinating and recent developments in this cooperation. New opportunities are encouraging, but potential limitations, ethical issues, model transparency, and generalizability should be considered. Regardless, the possibilities are endless, and the future of plasma medicine is looking brighter than ever with the implementation of AI. [ABSTRACT FROM AUTHOR]

This study investigates the efficacy of cold atmospheric plasma (CAP) in treating squamous cell carcinoma (SCC), a highly metastatic cancer. To assess the anticancer activity, two CAP treatment methods—direct treatment and indirect treatment (plasma‐treated N‐acetyl cysteine solution)—were used. Results indicate that both methods selectively target SCC cells, inducing oxidative and nitrosative stress, leading to decreased metabolic activity and increased apoptosis. Furthermore, a critical feature of cancer cells, metastatic behavior is also inhibited by CAP treatment. Coculture experiments demonstrate the effectiveness of CAP treatment in selectively inactivating SCC cells while leaving healthy cells unaffected. These findings suggest the potential use of CAP as a selective and effective treatment for SCC. [ABSTRACT FROM AUTHOR]

In this study, Plasma-Activated Water (PAW) was synthesized using a coaxial Dielectric Barrier Discharge (DBD) reactor, benefiting from the elevated capacity of air-flow-assisted DBD discharges to enhance nitrogen-based species concentration. By manipulating operational parameters, including gas flow rate, activation time, and DI water volume, we achieved significant concentrations of reactive oxygen and nitrogen species (RONS). As a result, the PAW obtained displayed pronounced physicochemical attributes: a pH of 2.06, an ORP of 275 mV, conductivity of 3 mS/cm, and TDS of 1200 mg/L. A pivotal aspect of this research was the evaluation of the reactor's efficiency, as indicated by metrics like the specific input energy and ozone efficiency yield. The antimicrobial potential of the PAW was also assessed against pathogenic microbes, with remarkable reductions in viability for both Staphylococcus aureus and Escherichia coli (99.99%) and a more moderate decrease for Candida albicans (37%). These findings underscore the capability of coaxial DBD reactors in crafting high-quality PAW with significant antimicrobial properties, necessitating further studies to validate its broad-spectrum and safe applications. [ABSTRACT FROM AUTHOR]

Cold physical plasma (CPP) technology is of high promise for various medical applications. The interplay of specific components of physical plasma with living cells, tissues and organs on a structural and functional level is of paramount interest with the aim to induce therapeutic effects in a controlled and replicable fashion. In contrast to other medical disciplines such as dermatology and oromaxillofacial surgery, research reports on CPP application in orthopaedics are scarce. The present implementation of CPP in orthopaedics involves surface modifications of orthopaedic materials and biomaterials to optimize osseointegration. In addition, the influence of CPP on musculoskeletal cells and tissues is a focus of research, including possible adverse reactions and side effects. Its bactericidal aspects make CPP an attractive supplement to current treatment regimens in case of microbial inflammations such as periprosthetic joint infections. Attributed anticancerogenic and pro-apoptotic effects underline the clinical relevance of CPP as an additive in treating malignant bone lesions. The present review outlines ongoing research in orthopaedics involving CPP; it distinguishes considerations for safe application and the need for more evidence-based research to facilitate robust clinical implementation.

Cold atmospheric-pressure plasma (CAP) has emerged as a potential alternative or adjuvant to conventional antibiotics for the treatment of bacterial infections, including those caused by antibiotic-resistant pathogens. The potential of sub-lethal CAP exposures to synergise conventional antimicrobials for the eradication of Pseudomonas aeruginosa biofilms is investigated in this study. The efficacy of antimicrobials following or in the absence of sub-lethal CAP pre-treatment in P. aeruginosa biofilms was assessed. CAP pre-treatment resulted in an increase in both planktonic and biofilm antimicrobial sensitivity for all three strains tested (PAO1, PA14, and PA10548), with both minimum inhibitory concentrations (MICs) and minimum biofilm eradication concentrations (MBECs) of individual antimicrobials, being significantly reduced following CAP pre-treatment of the biofilm (512-fold reduction with ciprofloxacin/gentamicin; and a 256-fold reduction with tobramycin). At all concentrations of antimicrobial used, the combination of sub-lethal CAP exposure and antimicrobials was effective at increasing time-to-peak metabolism, as measured by isothermal microcalorimetry, again indicating enhanced susceptibility. CAP is known to damage bacterial cell membranes and DNA by causing oxidative stress through the in situ generation of reactive oxygen and nitrogen species (RONS). While the exact mechanism is not clear, oxidative stress on outer membrane proteins is thought to damage/perturb cell membranes, confirmed by ATP and LDH leakage, allowing antimicrobials to penetrate the bacterial cell more effectively, thus increasing bacterial susceptibility. Transcriptomic analysis, reveals that cold-plasma mediated oxidative stress caused upregulation of P. aeruginosa superoxide dismutase, cbb3 oxidases, catalases, and peroxidases, and upregulation in denitrification genes, suggesting that P. aeruginosa uses these enzymes to degrade RONS and mitigate the effects of cold plasma mediated oxidative stress. CAP treatment also led to an increased production of the signalling molecule ppGpp in P. aeruginosa, indicative of a stringent response being established. Although we did not directly measure persister cell formation, this stringent response may potentially be associated with the formation of persister cells in biofilm cultures. The production of ppGpp and polyphosphate may be associated with protein synthesis inhibition and increase efflux pump activity, factors which can result in antimicrobial tolerance. The transcriptomic analysis also showed that by 6 h post-treatment, there was downregulation in ribosome modulation factor, which is involved in the formation of persister cells, suggesting that the cells had begun to resuscitate/recover. In addition, CAP treatment at 4 h post-exposure caused downregulation of the virulence factors pyoverdine and pyocyanin; by 6 h post-exposure, virulence factor production was increasing. Transcriptomic analysis provides valuable insights into the mechanisms by which P. aeruginosa biofilms exhibits enhanced susceptibility to antimicrobials. Overall, these findings suggest, for the first time, that short CAP sub-lethal pre-treatment can be an effective strategy for enhancing the susceptibility of P. aeruginosa biofilms to antimicrobials and provides important mechanistic insights into cold plasma-antimicrobial synergy. Transcriptomic analysis of the response to, and recovery from, sub-lethal cold plasma exposures in P. aeruginosa biofilms improves our current understanding of cold plasma biofilm interactions.

In the past decade, the applications of dielectric barrier discharge (DBD) plasma technologies have been expanding, and one of the most exciting and rapidly growing applications is in biology and medicine. Most biomedical studies with DBD plasma systems are performed in vitro, which include cells grown on the surface of plastic well plates, or in vivo, which include animal research models (e.g. mice, pigs). Since many DBD systems use the biological target as the secondary electrode for direct plasma generation and treatment, they are sensitive to the surface properties of the target, and thus can be altered based on the in vitro or in vivo system used. This could consequently affect biological response from plasma treatment. Therefore, in this study, we investigated the DBD plasma behavior both in vitro (i.e. 96-well flat bottom plates, 96-well U-bottom plates, and 24-well flat bottom plates), and in vivo (i.e. mouse skin). Intensified charge coupled device (ICCD) imaging was performed and the plasma discharges were visually distinguishable between the different systems. The geometry of the wells did not affect DBD plasma generation for low application distances (≤ 2 mm), but differentially affected plasma uniformity on the bottom of the well at greater distances. Since DBD plasma treatment in vitro is rarely performed in dry wells for plasma medicine experiments, the effect of well wetness was also investigated. In all in vitro cases, the uniformity of the DBD plasma was affected when comparing wet versus dry wells, with the plasma in the wide-bottom wells appearing the most similar to plasma generated on mouse skin. Interestingly, based on quantification of ICCD images, the DBD plasma intensity per surface area demonstrated an exponential one-phase decay with increasing application distance, regardless of the in vitro or in vivo system. This trend is similar to that of the energy per pulse of plasma, which is used to determine the total plasma treatment energy for biological systems. Optical emission spectroscopy performed on the plasma revealed similar trends in radical species generation between the plastic well plates and mouse skin. Therefore, taken together, DBD plasma intensity per surface area may be a valuable parameter to be used as a simple method for in situ monitoring during biological treatment and active plasma treatment control, which can be applied for in vitro and in vivo systems. [ABSTRACT FROM AUTHOR]

An update to the article "Dielectric-barrier Discharges: Their History, Discharge Physics, and Industrial Applications" by Ulrich Kogelschatz from 2003 is given. The research and applications of barrier discharges of the last decades are summarized. In particular, the latest developments in ozone generation, radiation sources, environmental applications and surface treatment are discussed. Topics, which appeared with growing attention after 2003, such as plasma medicine, carbon dioxide chemistry, liquid treatment and airflow control, are also summarized to provide an outlook into the coming years. It can be stated, that this type of gas discharge is still of high scientific and technological relevance. Its wide range of applications made the research more inter- and cross-disciplinary while modern diagnostic and modeling enabled deeper insights in the complex physical and chemical processes. In this sense, the contribution of Ulrich Kogelschatz, who introduced and inspired several generations of researchers in the field, cannot be overstated. [ABSTRACT FROM AUTHOR]

Plasma medicine, or the biomedical application of cold atmospheric plasma (CAP), is an expanding field within plasma research. CAP has demonstrated remarkable versatility in diverse biological applications, including cancer treatment, wound healing, microorganism inactivation, and skin disease therapy. However, the precise mechanisms underlying the effects of CAP remain incompletely understood. The therapeutic effects of CAP are largely attributed to the generation of reactive oxygen and nitrogen species (RONS), which play a crucial role in the biological responses induced by CAP. Specifically, RONS produced during CAP treatment have the ability to chemically modify cell membranes and membrane proteins, causing nitro-oxidative stress, thereby leading to changes in membrane permeability and disruption of cellular processes. To gain atomic-level insights into these interactions, non-reactive molecular dynamics (MD) simulations have emerged as a valuable tool. These simulations facilitate the examination of larger-scale system dynamics, including protein-protein and protein-membrane interactions. In this comprehensive review, we focus on the applications of non-reactive MD simulations in studying the effects of CAP on cellular components and interactions at the atomic level, providing a detailed overview of the potential of CAP in medicine. We also review the results of other MD studies that are not related to plasma medicine but explore the effects of nitro-oxidative stress on cellular components and are therefore important for a broader understanding of the underlying processes. [ABSTRACT FROM AUTHOR]

Fundamental and applied research on plasma‐treated liquids for biomedical applications was boosted in the last few years, dictated by their advantages with respect to direct treatments. However, often, the lack of consistent analysis at a molecular level of these liquids, and of the processes used to produce them, have raised doubts of their usefulness in the clinic. The aim of this article is to critically discuss some basic aspects related to the use of plasma‐treated liquids in medicine, with a focus on their chemical composition. We analyze the main liquids used in the field, how they are affected by non‐thermal plasmas, and the possibility to replicate them without plasma treatment. [ABSTRACT FROM AUTHOR]

The field of "plasma medicine" is expanding. It is based on advances in plasma physics and chemistry; a better knowledge of the species produced, a better control in the creation of gaseous plasmas, enable different plasma processes with potential different clinical applications. In the medical field, progress is being made towards predictive, preventive, personalized, participatory, and populational medicine. In particular, three‐dimensional printing is useful in the challenge of customized oral healthcare. For example, plasma technology offers many options to optimize the use of custom‐made prothesis, particularly in the area of oral medicine and oral surgery. [ABSTRACT FROM AUTHOR]

Objective: Cold atmospheric plasma (CAP) is a promising new option for the treatment of hard-to-heal (chronic) wounds. The aim of this study was to observe the effect of CAP on wound pH, as a correlation between the pH of a wound and its healing tendency has been established in the literature. Method: Patients with hard-to-heal wounds were treated with CAP in addition to standard treatment. Treatment was performed with the aid of a small, mobile plasma device, which was used for one minute at a time during dressing changes. The pH value, wound size, and other parameters, such as exudate and signs of infection, were recorded for each treatment. Results: A total of 10 patients took part in the study. During the observation period, there was a significant reduction in pH from a markedly alkaline pH of 9.6 to a neutral pH of 7. This was accompanied by a marked reduction in wound size by an average of 76% with seven applications of CAP within 28 days. The evaluation of tissue granulation, exudate and signs of infection showed a positive trend. Conclusion: The number of patients in the present study is not sufficient to prove the relationship between the pH value of the wound and the treatment with CAP. However, there are clear indications that the positive effects of CAP on wound healing, which are recognised in several publications, are also due to its influence on wound pH value. [ABSTRACT FROM AUTHOR]

In musculoskeletal surgery, the treatment of large bone defects is challenging and can require the use of bone graft substitutes to restore mechanical stability and promote host-mediated regeneration. The use of bone allografts is well-established in many bone regenerative procedures, but is associated with low rates of ingrowth due to pre-therapeutic graft processing. Cold physical plasma (CPP), a partially ionized gas that simultaneously generates reactive oxygen (O2) and nitrogen (N2) species, is suggested to be advantageous in biomedical implant processing. CPP is a promising tool in allograft processing for improving surface characteristics of bone allografts towards enhanced cellularization and osteoconduction. However, a preclinical assessment regarding the feasibility of pre-therapeutic processing of allogeneic bone grafts with CPP has not yet been performed. Thus, this pilot study aimed to analyze the bone morphology of CPP processed allografts using synchrotron radiation-based microcomputed tomography (SR-µCT) and to analyze the effects of CPP processing on human bone cell viability and function. The analyzes, including co-registration of pre- and post-treatment SR-µCT scans, revealed that the main bone morphological properties (total volume, mineralized volume, surface area, and porosity) remained unaffected by CPP treatment if compared to allografts not treated with CPP. Varying effects on cellular metabolic activity and alkaline phosphatase activity were found in response to different gas mixtures and treatment durations employed for CPP application. It was found that 3 min CPP treatment using a He + 0.1% N2 gas mixture led to the most favourable outcome regarding a significant increase in bone cell viability and alkaline phosphatase activity. This study highlights the promising potential of pre-therapeuthic bone allograft processing by CPP prior to intraoperative application and emphasizes the need for gas source and treatment time optimization for specific applications.

Introduction: Rosacea is a common, facial, chronic inflammatory skin disease. Due to its complex pathogenesis, adequate therapy of rosacea can be challenging. An innovative recent therapeutic tool is cold atmospheric plasma (CAP), which is already established in the treatment of chronic wounds and promising in different other skin diseases. Methods: In a split-face pilot study we investigated dielectric-barrier-discharged CAP in erythemato-telangiectatic (ETR) and/or papulopustular rosacea (PPR). CAP treatment was applied on lesional skin of a randomized side once daily (90 s/area) for 6 weeks. The other untreated side served as control. Co-primary endpoints were ≥1 improvement of the Investigator Global Assessment (IGA) score on the treated side compared to control and a decline of the Dermatology Life Quality Index (DLQI) after 6 weeks. Secondary endpoints included inflammatory lesion count (papules and pustules), skin redness intensity and erythema size. Adverse events (AEs) were recorded constantly. Additionally, participants were weekly assessed for symptoms, skin condition, trigger factors, skin care, treatment success, and local tolerance parameters. All p values were calculated using the Wilcoxon signed-rank test. Results: Twelve subjects (ETR, n = 3; ETR and PPR, n = 9) completed the study. DLQI was significantly improved after 6 weeks (p = 0.007). On the CAP-treated side, lesions (p = 0.007) and erythema size (p = 0.041) were significantly reduced compared to the control. IGA (p = 0.2) and skin redness intensity (p = 0.5) did not differ significantly between control and CAP-treated side. No serious AEs occurred and treatment was well tolerated. Conclusion: CAP is a promising new treatment of rosacea, especially for PPR. [ABSTRACT FROM AUTHOR]

Recently, the cold atmospheric plasma (CAP) has demonstrated a satisfactory ability to inactivate severe acute respiratory syndrome CoV‐2 (SARS‐CoV‐2), but the microscopic inactivation mechanism is still unclear. This paper takes the interaction process between O atoms generated by plasma and the spike protein of coronavirus as the research object. It uses the reaction molecular dynamics simulation method to study the reaction mechanism of different numbers of O atoms and the spike protein molecules. The results show that the O atom triggers a chain reaction by taking away hydrogen atoms in the spike protein molecule, destroying the molecular structure of the spike protein and making it inactive. The severity of the reaction and the destruction of the spike protein molecule also increases with increasing O atom numbers. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) and oral squamous cell carcinoma (OSCC) are among the most common types of cancer, but current clinical outcomes remain unsatisfactory. Available therapies have limitations in terms of efficacy and may also cause severe side effects. Cold physical plasma is a promising approach for selectively eliminating cancer cells while avoiding genotoxic effects on non-malignant cells. In this study, we investigated the potential of cold physical plasma as a therapeutic intervention for BC and OSCC through in vitro and ex vivo studies on toxicity. For the in vitro study, T-47 BC cells and SCC-4 and SCC-9 OSCC cell lines were used, and we found cold plasma to be toxic in a treatment time-dependent manner. Moreover, we investigated the safety of physical plasma therapy and found no genotoxic potential in plasma-treated human keratinocytes in vitro. Finally, for the first time, 20 BC and OSCC patient-derived tumor tissues were punch biopsied and ex vivo-exposed to cold physical plasmas to study responses in the tumor microenvironment TME). Cold physical plasma caused significant apoptosis in patient-derived BC and OSCC tumor tissues, and decreased the number of CD163+ cells (e.g., tumor-associated macrophages, TAM) in BC tissue plasma-treated ex vivo. Collectively, our findings motivate the investigation of cold physical plasma as a potential adjuvant treatment in oncology. [ABSTRACT FROM AUTHOR]

Despite continuous therapeutic progress, cancer remains an often fatal disease. In the early 2010s, first evidence in rodent models suggested promising antitumor action of gas plasma technology. Medical gas plasma is a partially ionized gas depositing multiple physico-chemical effectors onto tissues, especially reactive oxygen and nitrogen species (ROS/RNS). Today, an evergrowing body of experimental evidence suggests multifaceted roles of medical gas plasma-derived therapeutic ROS/RNS in targeting cancer alone or in combination with oncological treatment schemes such as ionizing radiation, chemotherapy, and immunotherapy. Intriguingly, gas plasma technology was recently unraveled to have an immunological dimension by inducing immunogenic cell death, which could ultimately promote existing cancer immunotherapies via in situ or autologous tumor vaccine schemes. Together with first clinical evidence reporting beneficial effects in cancer patients following gas plasma therapy, it is time to summarize the main concepts along with the chances and limitations of medical gas plasma onco-therapy from a biological, immunological, clinical, and technological point of view.

Hydroxyl radicals (OH) play a crucial role in plasma-bio applications. As pulsed plasma operation is preferred, and even expanded to the nanosecond range, it is essential to study the relationship between OH radical production and pulse characteristics. In this study, we use optical emission spectroscopy to investigate OH radical production with nanosecond pulse characteristics. The experimental results reveal that longer pulses generate more OH radicals. To confirm the effect of pulse properties on OH radical generation, we conduct computational chemical simulations, focusing on two types of pulse properties: pulse instant power and pulse width. The simulation results show that, similar to the experimental results, longer pulses generate more OH radicals. In the nanosecond range, reaction time is critical for OH radical generation. In terms of chemical aspects, N2 metastable species mainly contribute to OH radical generation. It is a unique behavior observed in nanosecond range pulsed operation. Furthermore, humidity can turn over the tendency of OH radical production in nanosecond pulses. In a humid condition, shorter pulses are advantageous for generating OH radicals. Electrons play key roles in this condition and high instant power contributes to them. [ABSTRACT FROM AUTHOR]

Reactive oxygen and nitrogen species (RONS) can be generated in liquids by different cold plasma processes. These species can influence cell biology and pathological states, and trigger wound healing, disinfection, and cancer treatments. The optimization of plasma sources' configurations and experimental conditions is fundamental to dose‐produced RONS in liquids. This research is a case study comparing RONS generation (H2O2 and NO2−) in water, after exposure to two different atmospheric pressure cold dielectric barrier discharge (DBD) plasma sources: a plasma jet‐DBD and a planar‐DBD operating in contact with the liquid and in remote, respectively. The data demonstrate that the reactor geometry and the treatment modality strongly impact the generation of the active species in water. [ABSTRACT FROM AUTHOR]

Cold atmospheric plasmas are a known source of reactive species enabling various treatments, from the healing of chronic wounds to the treatment of surface cancers. Therapeutic endoscopic procedures require developing specific flexible tools that can be used through or alongside endoscopes. Plasma devices for endoscopy have aroused significant research interest over the past few decades, but their electrical behaviour is not yet fully understood and predictable. There is thus a clear need for a robust model that provides a way to understand and optimize future devices. In this work, for the first time, an electrical equivalent model of a long plasma source (comprising plasma generation, transport and target interaction) was designed, implemented, and validated. System parameters were estimated based on the system geometry and independent measurements. The model reliably reproduces the double ignition (in the quartz chamber and at the treatment site) observed experimentally. Simulations globally agree with measurements taken for various gas gap distances and input voltages. Internal parameters that are difficult to measure, such as the electrical charge at the gas gaps, were inferred. The model can predict leakage current in the body and current at the target site. This work provides a new understanding of endoscopic plasma systems that could be used in the future to ensure patient and operator safety. [ABSTRACT FROM AUTHOR]

The SARS‐CoV‐2 pandemic reemphasized the importance of and need for efficient hygiene and disinfection measures. The coronavirus' efficient spread capitalizes on its airborne transmission routes via virus aerosol release from human oral and nasopharyngeal cavities. Besides the upper respiratory tract, efficient viral replication has been described in the epithelium of these two body cavities. To this end, the idea emerged to employ plasma technology to locally reduce mucosal viral loads as an additional measure to reduce patient infectivity. We here outline conceptual ideas of such treatment concepts within what is known in the antiviral actions of plasma treatment so far. [ABSTRACT FROM AUTHOR]

In this study, a self‐enhanced plasma brush based on a single dielectric barrier discharge was developed by optimizing the load position for treatment in dermatology. The electrical, optical, and temperature characteristics of the fabricated reactor were investigated. Results show that the length and the width of the plasma brush could reach 20 and 15 mm, respectively. The electric field and the resulting discharge between the reactor and the human impedance model were enhanced and the discharging resistance decreased when introducing a human load. The plume temperature is around 24°C and the current flowing through the human model is lower than the threshold of perception current, which is friendly for human contact. The sterilization effects are verified by killing Escherichia coli. [ABSTRACT FROM AUTHOR]