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Decreased inflammatory profile in oral leukoplakia tissue exposed to cold physical plasma ex vivo
(2023)
Background
Oral leukoplakia (OL) is an unfavorable oral disease often resistant to therapy. To this end, cold physical plasma technology was explored as a novel therapeutic agent in an experimental setup.
Methods
Biopsies with a diameter of 3 mm were obtained from non-diseased and OL tissues. Subsequently, cold atmospheric pressure plasma (CAP) exposure was performed ex vivo in the laboratory. After 20 h of incubation, biopsies were cryo-conserved, and tissue sections were quantified for lymphocyte infiltrates, discriminating between naïve and memory cytotoxic and T-helper cells. In addition, the secretion pattern related to inflammation was investigated in the tissue culture supernatants by quantifying 10 chemokines and cytokines.
Results
In CAP-treated OL tissue, significantly decreased overall lymphocyte numbers were observed. In addition, reduced levels were observed when discriminating for the T-cell subpopulations but did not reach statistical significance. Moreover, CAP treatment significantly reduced levels of C-X-C motif chemokine 10 (CXCL10) and granulocyte-macrophage colony-stimulating factor in the OL biopsies' supernatants. In idiopathically inflamed tissues, ex vivo CAP exposure reduced T-cells and CXCL10 as well but also led to markedly increased interleukin-1β secretion.
Conclusion
Our findings suggest CAP to have immuno-modulatory properties, which could be of therapeutic significance in the therapy of OL. Future studies should investigate the efficacy of CAP therapy in vivo in a larger cohort.
Cerebral cavernous malformations (CCM) are low-flow vascular lesions prone to cause severe hemorrhage-associated neurological complications. Pathogenic germline variants in CCM1, CCM2, or CCM3 can be identified in nearly 100% of CCM patients with a positive family history. In line with the concept that tumor-like mechanisms are involved in CCM formation and growth, we here demonstrate an abnormally increased proliferation rate of CCM3-deficient endothelial cells in co-culture with wild-type cells and in mosaic human iPSC-derived vascular organoids. The observation that NSC59984, an anticancer drug, blocked the abnormal proliferation of mutant endothelial cells further supports this intriguing concept. Fluorescence-activated cell sorting and RNA sequencing revealed that co-culture induces upregulation of proangiogenic chemokine genes in wild-type endothelial cells. Furthermore, genes known to be significantly downregulated in CCM3−/− endothelial cell mono-cultures were upregulated back to normal levels in co-culture with wild-type cells. These results support the hypothesis that wild-type ECs facilitate the formation of a niche that promotes abnormal proliferation of mutant ECs. Thus, targeting the cancer-like features of CCMs is a promising new direction for drug development.
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.
Cerebral cavernous malformation (CCM) is a neurovascular disease that can lead to seizures and stroke-like symptoms. The familial form is caused by a heterozygous germline mutation in either the CCM1, CCM2, or CCM3 gene. While the importance of a second-hit mechanism in CCM development is well established, it is still unclear whether it immediately triggers CCM development or whether additional external factors are required. We here used RNA sequencing to study differential gene expression in CCM1 knockout induced pluripotent stem cells (CCM1−/− iPSCs), early mesoderm progenitor cells (eMPCs), and endothelial-like cells (ECs). Notably, CRISPR/Cas9-mediated inactivation of CCM1 led to hardly any gene expression differences in iPSCs and eMPCs. However, after differentiation into ECs, we found the significant deregulation of signaling pathways well known to be involved in CCM pathogenesis. These data suggest that a microenvironment of proangiogenic cytokines and growth factors can trigger the establishment of a characteristic gene expression signature upon CCM1 inactivation. Consequently, CCM1−/− precursor cells may exist that remain silent until entering the endothelial lineage. Collectively, not only downstream consequences of CCM1 ablation but also supporting factors must be addressed in CCM therapy development.
Pancreatic cancer is known for its tumor microenvironment (TME), which is rich in stromal and immune cells supporting cancer growth and therapy resistance. In particular, tumor-associated macrophages (TAMs) are known for their angiogenesis- and metastasis-promoting properties, which lead to the failure of conventional therapies for pancreatic cancer. Hence, treatment options targeting TAMs are needed. The C-C chemokine receptor type 4 (CCR4) is critical for immune cell recruitment into the TME, and in this paper we explore the effects of its genetic or immunotherapeutic blockade in pancreatic-cancer-bearing mice. Murine PDA6606 pancreatic cancer cells and murine peritoneal macrophages were used for in vitro migration assays. In vivo, a syngeneic, orthotropic pancreatic cancer model was established. Tumor growth and survival were monitored under prophylactic and therapeutic application of a CCR4 antagonist (AF-399/420/18025) in wildtype (CCR4wt) and CCR4-knockout (CCR4−/−) mice. Immune infiltration was monitored in tumor tissue sections and via flow cytometry of lysed tumors. PDA6606 cells induced less migration in CCR4−/− than in CCR4wt macrophages in vitro. Pancreatic TAM infiltration was higher, and survival was reduced in CCR4wt mice compared to CCR4−/− mice. Antagonizing CCR4 in wildtype mice revealed similar results as in CCR4−/− mice without antagonization. Prophylactic CCR4 antagonist application in wildtype mice was more efficient than therapeutic antagonization. CCR4 seems to be critically involved in TAM generation and tumor progression in pancreatic cancer. CCR4 blockade may help prolong the relapse-free period after curative surgery in pancreatic cancer and improve prognosis.
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.
Introduction
Medical gas plasma therapy has been successfully applied to several types of cancer in preclinical models. First palliative tumor patients suffering from advanced head and neck cancer benefited from this novel therapeutic modality. The gas plasma-induced biological effects of reactive oxygen and nitrogen species (ROS/RNS) generated in the plasma gas phase result in oxidation-induced lethal damage to tumor cells.
Objectives
This study aimed to verify these anti-tumor effects of gas plasma exposure on urinary bladder cancer.
Methods
2D cell culture models, 3D tumor spheroids, 3D vascularized tumors grown on the chicken chorion-allantois-membrane (CAM) in ovo, and patient-derived primary cancer tissue gas plasma-treated ex vivo were used.
Results
Gas plasma treatment led to oxidation, growth retardation, motility inhibition, and cell death in 2D and 3D tumor models. A marked decline in tumor growth was also observed in the tumors grown in ovo. In addition, results of gas plasma treatment on primary urothelial carcinoma tissues ex vivo highlighted the selective tumor-toxic effects as non-malignant tissue exposed to gas plasma was less affected. Whole-transcriptome gene expression analysis revealed downregulation of tumor-promoting fibroblast growth factor receptor 3 (FGFR3) accompanied by upregulation of apoptosis-inducing factor 2 (AIFm2), which plays a central role in caspase-independent cell death signaling.
Conclusion
Gas plasma treatment induced cytotoxicity in patient-derived cancer tissue and slowed tumor growth in an organoid model of urinary bladder carcinoma, along with less severe effects in non-malignant tissues. Studies on the potential clinical benefits of this local and safe ROS therapy are awaited.
on-healing wounds continue to be a clinical challenge for patients and medical staff.
These wounds have a heterogeneous etiology, including diabetes and surgical trauma wounds. It is
therefore important to decipher molecular signatures that reflect the macroscopic process of wound
healing. To this end, we collected wound sponge dressings routinely used in vacuum assisted therapy
after surgical trauma to generate wound-derived protein profiles via global mass spectrometry.
We confidently identified 311 proteins in exudates. Among them were expected targets belonging to
the immunoglobulin superfamily, complement, and skin-derived proteins, such as keratins. Next to
several S100 proteins, chaperones, heat shock proteins, and immune modulators, the exudates
presented a number of redox proteins as well as a discrete neutrophil proteomic signature, including
for example cathepsin G, elastase, myeloperoxidase, CD66c, and lipocalin 2. We mapped over 200
post-translational modifications (PTMs; cysteine/methionine oxidation, tyrosine nitration, cysteine
trioxidation) to the proteomic profile, for example, in peroxiredoxin 1. Investigating manually
collected exudates, we confirmed presence of neutrophils and their products, such as microparticles
and fragments containing myeloperoxidase and DNA. These data confirmed known and identified
less known wound proteins and their PTMs, which may serve as resource for future studies on
human wound healing
: 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.
Multiple evidence in animal models and in humans suggest a beneficial role of cold physical
plasma in wound treatment. Yet, risk assessment studies are important to further foster therapeutic
advancement and acceptance of cold plasma in clinics. Accordingly, we investigated the long-term
side effects of repetitive plasma treatment over 14 consecutive days in a rodent full-thickness ear
wound model. Subsequently, animals were housed for 350 days and sacrificed thereafter. In blood,
systemic changes of the pro-inflammatory cytokines interleukin 1β and tumor necrosis factor α
were absent. Similarly, tumor marker levels of α-fetoprotein and calcitonin remained unchanged.
Using quantitative PCR, the expression levels of several cytokines and tumor markers in liver,
lung, and skin were found to be similar in the control and treatment group as well. Likewise,
histological and immunohistochemical analysis failed to detect abnormal morphological changes
and the presence of tumor markers such as carcinoembryonic antigen, α-fetoprotein, or the neighbor
of Punc 11. Absence of neoplastic lesions was confirmed by non-invasive imaging methods such as
anatomical magnetic resonance imaging and positron emission tomography-computed tomography.
Our results suggest that the beneficial effects of cold plasma in wound healing come without apparent
side effects including tumor formation or chronic inflammation.
Chondrosarcoma is the second most common malign bone tumor in adults. Surgical
resection of the tumor is recommended because of its resistance to clinical treatment such as
chemotherapy and radiation therapy. Thus, the prognosis for patients mainly depends on sufficient
surgical resection. Due to this, research on alternative therapies is needed. Cold atmospheric plasma
(CAP) is an ionized gas that contains various reactive species. Previous studies have shown an
anti-oncogenic potential of CAP on different cancer cell types. The current study examined the effects
of treatment with CAP on two chondrosarcoma cell lines (CAL-78, SW1353). Through proliferation
assay, the cell growth after CAP-treatment was determined. A strong antiproliferative effect for
both cell lines was detected. By fluorescein diacetate (FDA) assay and ATP release assay, alterations
in the cell membrane and associated translocation of low molecular weight particles through the
cytoplasmic membrane were observed. In supernatant, the non-membrane-permeable FDA and
endogenously synthesized ATP detected suggest an increased membrane permeability after CAP
treatment. Similar results were shown by the dextran-uptake assay. Furthermore, fluorescence
microscopic G-/F-actin assay was performed. G- and F-actin were selectively dyed, and the ratio
was measured. The presented results indicate CAP-induced changes in cell membrane function and
possible alterations in actin-cytoskeleton, which may contribute to the antiproliferative effects of CAP.
Despite continuous advances in therapy, malignant melanoma is still among the deadliest
types of cancer. At the same time, owing to its high plasticity and immunogenicity, melanoma is
regarded as a model tumor entity when testing new treatment approaches. Cold physical plasma is a
novel anticancer tool that utilizes a plethora of reactive oxygen species (ROS) being deposited on the
target cells and tissues. To test whether plasma treatment would enhance the toxicity of an established
antitumor therapy, ionizing radiation, we combined both physical treatment modalities targeting
B16F10 murine melanoma cell in vitro. Repeated rather than single radiotherapy, in combination
with gas plasma-introduced ROS, induced apoptosis and cell cycle arrest in an additive fashion. In
tendency, gas plasma treatment sensitized the cells to subsequent radiotherapy rather than the other
way around. This was concomitant with increased levels of TNFα, IL6, and GM-CSF in supernatants.
Murine JAWS dendritic cells cultured in these supernatants showed an increased expression of cell
surface activation markers, such as MHCII and CD83. For PD-L1 and PD-L2, increased expression
was observed. Our results are the first to suggest an additive therapeutic effect of gas plasma and
radiotherapy, and translational tumor models are needed to develop this concept further.
Background: Cold atmospheric plasma (CAP) is increasingly used in the field of oncology.
Many of the mechanisms of action of CAP, such as inhibiting proliferation, DNA breakage, or the
destruction of cell membrane integrity, have been investigated in many different types of tumors.
In this regard, data are available from both in vivo and in vitro studies. Not only the direct treatment
of a tumor but also the influence on its blood supply play a decisive role in the success of the therapy
and the patient’s further prognosis. Whether the CAP influences this process is unknown, and the
first indications in this regard are addressed in this study. Methods: Two different devices, kINPen
and MiniJet, were used as CAP sources. Human endothelial cell line HDMEC were treated directly
and indirectly with CAP, and growth kinetics were performed. To indicate apoptotic processes,
caspase-3/7 assay and TUNEL assay were used. The influence of CAP on cellular metabolism
was examined using the MTT and glucose assay. After CAP exposure, tube formation assay was
performed to examine the capillary tube formation abilities of HDMEC and their migration was
messured in separate assays. To investigate in a possible mutagenic effect of CAP treatment,
a hypoxanthine-guanine-phosphoribosyl-transferase assay with non malignant cell (CCL-93) line was
performed. Results: The direct CAP treatment of the HDMEC showed a robust growth-inhibiting
effect, but the indirect one did not. The MMT assay showed an apparent reduction in cell metabolism
in the first 24 h after CAP treatment, which appeared to normalize 48 h and 72 h after CAP application.
These results were also confirmed by the glucose assay. The caspase 3/7 assay and TUNEL assay
showed a significant increase in apoptotic processes in the HDMEC after CAP treatment. These results
were independent of the CAP device. Both the migration and tube formation of HDMEC were
significant inhibited after CAP-treatment. No malignant effects could be demonstrated by the CAP
treatment on a non-malignant cell line.
Cold physical plasma is a partially ionized gas expelling many reactive oxygen and nitrogen
species (ROS/RNS). Several plasma devices have been licensed for medical use in dermatology, and
recent experimental studies suggest their putative role in cancer treatment. In cancer therapies with
an immunological dimension, successful antigen presentation and inflammation modulation is a
key hallmark to elicit antitumor immunity. Dendritic cells (DCs) are critical for this task. However,
the inflammatory consequences of DCs following plasma exposure are unknown. To this end,
human monocyte-derived DCs (moDCs) were expanded from isolated human primary monocytes;
exposed to plasma; and their metabolic activity, surface marker expression, and cytokine profiles
were analyzed. As controls, hydrogen peroxide, hypochlorous acid, and peroxynitrite were used.
Among all types of ROS/RNS-mediated treatments, plasma exposure exerted the most notable
increase of activation markers at 24 h such as CD25, CD40, and CD83 known to be crucial for T cell
costimulation. Moreover, the treatments increased interleukin (IL)-1α, IL-6, and IL-23. Altogether,
this study suggests plasma treatment augmenting costimulatory ligand and cytokine expression in
human moDCs, which might exert beneficial effects in the tumor microenvironment.
Reactive oxygen species (ROS) have been subject of increasing interest in the pathophysiology and therapy of cancers in recent years. In skin cancer, ROS are involved in UV-induced tumorigenesis and its targeted treatment via, e.g., photodynamic therapy. Another recent technology for topical ROS generation is cold physical plasma, a partially ionized gas expelling dozens of reactive species onto its treatment target. Gas plasma technology is accredited for its wound-healing abilities in Europe, and current clinical evidence suggests that it may have beneficial effects against actinic keratosis. Since the concept of hormesis dictates that low ROS levels perform signaling functions, while high ROS levels cause damage, we investigated herein the antitumor activity of gas plasma in non-melanoma skin cancer. In vitro, gas plasma exposure diminished the metabolic activity, preferentially in squamous cell carcinoma cell (SCC) lines compared to non-malignant HaCaT cells. In patient-derived basal cell carcinoma (BCC) and SCC samples treated with gas plasma ex vivo, increased apoptosis was found in both cancer types. Moreover, the immunomodulatory actions of gas plasma treatment were found affecting, e.g., the expression of CD86 and the number of regulatory T-cells. The supernatants of these ex vivo cultured tumors were quantitatively screened for cytokines, chemokines, and growth factors, identifying CCL5 and GM-CSF, molecules associated with skin cancer metastasis, to be markedly decreased. These findings suggest gas plasma treatment to be an interesting future technology for non-melanoma skin cancer topical therapy.
Medical gas plasmas are of emerging interest in pre-clinical oncological research. Similar to an array of first-line chemotherapeutics and physics-based therapies already approved for clinical application, plasmas target the tumor redox state by generating a variety of highly reactive species eligible for local tumor treatments. Considering internal tumors with limited accessibility, medical gas plasmas help to enrich liquids with stable, low-dose oxidants ideal for intratumoral injection and lavage. Pre-clinical investigation of such liquids in numerous tumor entities and models in vitro and in vivo provided evidence of their clinical relevance, broadening the range of patients that could benefit from medical gas plasma therapy in the future. Likewise, the application of such liquids might be promising for recurrent BRAF(V600E) papillary thyroid carcinomas, resistant to adjuvant administration of radioiodine. From a redox biology point of view, studying redox-based approaches in thyroid carcinomas is particularly interesting, as they evolve in a highly oxidative environment requiring the capability to cope with large amounts of ROS/RNS. Knowledge on their behavior under different redox conditions is scarce. The present study aimed to clarify resistance, proliferative activity, and the oxidative stress response of human papillary thyroid cancer cells K1 after exposure to plasma-oxidized DMEM (oxDMEM). Cellular responses were also evaluated when treated with different dosages of hydrogen peroxide and the RNS donor sodium nitroprusside (SNP). Our findings outline plasma-oxidized liquids as a promising approach targeting BRAF(V600E) papillary thyroid carcinomas and extend current knowledge on the susceptibility of cells to undergo ROS/RNS-induced cell death.
Reactive species generated by medical gas plasma technology can be enriched in liquids for use in oncology targeting disseminated malignancies, such as metastatic colorectal cancer. Notwithstanding, reactive species quantities depend on the treatment mode, and we recently showed gas plasma exposure in conductive modes to be superior for cancer tissue treatment. However, evidence is lacking that such a conductive mode also equips gas plasma-treated liquids to confer augmented intraperitoneal anticancer activity. To this end, employing atmospheric pressure argon plasma jet kINPen-treated Ringer’s lactate (oxRilac) in a CT26-model of colorectal peritoneal carcinomatosis, we tested repeated intraabdominal injection of such remotely or conductively oxidized liquid for antitumor control and immunomodulation. Enhanced reactive species formation in conductive mode correlated with reduced tumor burden in vivo, emphasizing the advantage of conduction over the free mode for plasma-conditioned liquids. Interestingly, the infiltration of lymphocytes into the tumors was equally enhanced by both treatments. However, significantly lower levels of interleukin (IL)4 and IL13 and increased levels of IL2 argue for a shift in intratumoral T-helper cell subpopulations correlating with disease control. In conclusion, our data argue for using conductively over remotely prepared plasma-treated liquids for anticancer treatment.
Gas plasma is an approved technology that generates a plethora of reactive oxygen species, which are actively applied for chronic wound healing. Its particular antimicrobial action has spurred interest in other medical fields, such as periodontitis in dentistry. Recent work has indicated the possibility of performing gas plasma-mediated biofilm removal on teeth. Teeth frequently contain restoration materials for filling cavities, e.g., resin-based composites. However, it is unknown if such materials are altered upon gas plasma exposure. To this end, we generated a new in-house workflow for three commonly used resin-based composites following gas plasma treatment and incubated the material with human HaCaT keratinocytes in vitro. Cytotoxicity was investigated by metabolic activity analysis, flow cytometry, and quantitative high-content fluorescence imaging. The inflammatory consequences were assessed using quantitative analysis of 13 different chemokines and cytokines in the culture supernatants. Hydrogen peroxide served as the control condition. A modest but significant cytotoxic effect was observed in the metabolic activity and viability after plasma treatment for all three composites. This was only partially treatment time-dependent and the composites alone affected the cells to some extent, as evident by differential secretion profiles of VEGF, for example. Gas plasma composite modification markedly elevated the secretion of IL6, IL8, IL18, and CCL2, with the latter showing the highest correlation with treatment time (Pearson’s r > 0.95). Cell culture media incubated with gas plasma-treated composite chips and added to cells thereafter could not replicate the effects, pointing to the potential that surface modifications elicited the findings. In conclusion, our data suggest that gas plasma treatment modifies composite material surfaces to a certain extent, leading to measurable but overall modest biological effects.
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.
Cold medical gas plasmas are under pre-clinical investigation concerning their hemostatic activity and could be applied for intra-operative bleeding control in the future. The technological leap innovation was their generation at body temperature, thereby causing no thermal harm to the tissue and ensuring tissue integrity. This directly contrasts with current techniques such as electrocautery, which induces hemostasis by carbonizing the tissue using a heated electrode. However, the necrotized tissue is prone to fall, raising the risk of post-operative complications such as secondary bleedings or infection. In recent years, various studies have reported on the ability of medical gas plasmas to induce blood coagulation, including several suggestions concerning their mode of action. As non-invasive and gentle hemostatic agents, medical gas plasmas could be particularly eligible for vulnerable tissues, e.g., colorectal surgery and neurosurgery. Further, their usage could be beneficial regarding the prevention of post-operative bleedings due to the absence or sloughing of eschar. However, no clinical trials or individual healing attempts for medical gas plasmas have been reported to pave the way for clinical approvement until now, despite promising results in experimental animal models. In this light, the present mini-review aims to emphasize the potential of medical gas plasmas to serve as a hemostatic agent in clinical procedures. Providing a detailed overview of the current state of knowledge, feasible application fields are discussed, and possible obstacles are addressed.