Cold Atmospheric Plasma: The Revolutionary Fourth State of Matter Fighting Skin Cancer
How a physics phenomenon is transforming oncology with precise, selective cancer cell destruction
A Spark of Genius in Cancer Treatment
Imagine a technology that can selectively target cancer cells while leaving healthy tissue unharmed, that operates at room temperature, and uses a unique form of matter most of us rarely encounter outside of lightning strikes or neon signs.
This isn't science fiction—it's the emerging reality of cold atmospheric plasma (CAP) in skin cancer treatment. In the ongoing battle against cancer, researchers have constantly sought more precise, effective, and less harmful treatments.
Traditional approaches like chemotherapy and radiation often cause significant collateral damage to healthy cells, leading to debilitating side effects. Enter cold atmospheric plasma: an innovative approach that's generating excitement in medical laboratories worldwide.
What Exactly is Cold Atmospheric Plasma?
The fourth state of matter transitions from physics phenomenon to medical breakthrough
The Fourth State of Matter
We're all familiar with the three traditional states of matter: solid, liquid, and gas. Plasma is often called the fourth state of matter, and it's actually the most abundant form of ordinary matter in the universe, found in stars like our sun and in lightning bolts.
Simply put, plasma is an ionized gas—a gas that has been energized enough that some of its electrons break free from their atoms, creating a mixture of positively charged ions, electrons, photons, and various neutral species 1 .
While we might associate plasma with extremely high temperatures (like those found in the sun), technological advances have enabled the creation of "cold" plasmas that can be safely applied to living tissue.
Cold atmospheric plasma devices generate a safe, low-temperature plasma suitable for medical applications.
From Physics to Medicine
The journey of plasma from physics laboratories to medical applications represents a fascinating story of scientific innovation. Plasma-based devices have actually been used in medicine for decades in the form of electrosurgical tools for cutting and coagulating tissue 1 .
The real breakthrough came with the development of genuine cold atmospheric plasma sources that operate at temperatures below 40°C (104°F), making them safe for direct application on skin and other tissues 1 . This temperature control, combined with the complex mixture of reactive species produced by CAP, opened up entirely new therapeutic possibilities beyond simple tissue destruction.
Types of Cold Atmospheric Plasma Sources Used in Medicine
| Type | Description | Examples | Key Features |
|---|---|---|---|
| Direct Plasma Sources | Use the human body as an electrode | PlasmaDerm® | Current passes through tissue |
| Indirect Plasma Sources | Plasma created between two electrodes, then transported to treatment area | kINPen® MED, MicroPlaSter® | Current-free application to tissue |
| Hybrid Plasma Sources | Combine features of direct and indirect sources | MiniFlatPlaSter | Enhanced safety profile |
How CAP Fights Skin Cancer: A Cellular Perspective
Precision medicine at the cellular level through reactive species and selective toxicity
The Reactive Cocktail
When cold atmospheric plasma interacts with ambient air, it generates a rich mixture of reactive oxygen and nitrogen species (RONS) 1 . This includes molecules like hydrogen peroxide (H₂O₂), ozone (O₃), nitric oxide (NO), and various free radicals.
Cancer cells are already under higher oxidative stress than normal cells due to their accelerated metabolism . CAP treatment delivers an additional oxidative challenge that pushes cancer cells beyond their capacity to cope.
Selective Toxicity
The concept of selective toxicity—harming cancer cells while sparing healthy ones—represents the holy grail of cancer treatment. CAP appears to achieve this selectivity through several mechanisms.
Research has demonstrated that the cytotoxic effects of CAP are significantly more pronounced in various skin cancer cell lines compared to normal skin cells 9 . This differential sensitivity has been observed across multiple studies.
Multiple Death Pathways
Unlike many targeted therapies that focus on a single pathway, CAP appears to activate multiple cell death mechanisms simultaneously, making it more difficult for cancer cells to develop resistance.
These include apoptosis (programmed cell death) 1 , ferroptosis (iron-dependent cell death) 7 , and immunogenic cell death (activating the immune system) 2 .
Cell Death Mechanisms Triggered by Cold Atmospheric Plasma
| Mechanism | Process | Key Features |
|---|---|---|
| Apoptosis | Programmed cell death | Controlled process; no inflammation |
| Ferroptosis | Iron-dependent cell death | Lipid peroxidation; distinct from apoptosis |
| Immunogenic Cell Death | Death that activates immune response | Presents cancer antigens to immune system |
A Closer Look at A Key Experiment: Transferred CAP for Melanoma
How researchers demonstrated selective toxicity against melanoma cells
The Experimental Setup
A compelling 2021 study published in Applied Sciences provides an excellent example of how researchers are exploring CAP's potential against one of the most dangerous forms of skin cancer: melanoma 9 .
The research team developed an innovative transferred CAP system using a silicone tube to deliver argon-based plasma. This approach allowed the plasma to cool to near-room temperature as it traveled through the tube, addressing safety concerns while maintaining therapeutic efficacy.
The system was characterized using electrical measurements and optical emission spectroscopy to identify the reactive species being generated.
Methodology Step-by-Step
Cell Preparation
Researchers cultured two types of cells: B16F10 mouse melanoma cells (cancerous) and L929 mouse fibroblasts (non-malignant) in standard laboratory conditions 9 .
Plasma Treatment
The team removed culture medium from the cells and treated them with the transferred CAP for 30 seconds 9 .
Viability Assessment
After treatment, they used MTT assay—a standard laboratory test that measures cellular metabolic activity as an indicator of cell viability and proliferation 9 .
Catalase Application
In some experiments, they applied the enzyme catalase to neutralize hydrogen peroxide, testing whether this would reduce CAP's effects 9 .
Results and Analysis
The findings from this experiment were particularly revealing. The transferred CAP system successfully generated various reactive oxygen and nitrogen species while maintaining a biocompatible temperature near room temperature.
When applied to cells, the CAP treatment demonstrated selective toxicity—effectively killing melanoma cancer cells while causing significantly less damage to non-malignant cells 9 . This selectivity is crucial for any potential cancer treatment, as it suggests the possibility of effective therapy with minimal side effects.
Furthermore, when researchers added catalase enzyme (which neutralizes hydrogen peroxide) to the cells, the toxic effects of CAP were reduced 9 . This important observation suggests that hydrogen peroxide and similar reactive species play a central role in CAP's mechanism of action against cancer cells.
Key Findings from the Transferred CAP Experiment on Melanoma Cells
| Parameter | Melanoma (B16F10) Cells | Non-Malignant (L929) Cells |
|---|---|---|
| Viability after 30s CAP | Significantly reduced | Less affected |
| Cell Morphology | Evidence of cell death | Relatively normal |
| Response with Catalase | Reduced CAP toxicity | Further protection |
The Scientist's Toolkit: Essential Tools for CAP Cancer Research
Specialized equipment and reagents driving plasma medicine forward
Dielectric Barrier Discharge Devices
These direct plasma sources use the human body as an electrode and are valuable for treating larger surface areas 1 .
Plasma Jet Systems
These indirect plasma sources generate a precise plume of plasma that can be directed at specific lesions (e.g., kINPen® MED) 2 .
Mass Flow Controllers
These devices precisely regulate the flow of gases (such as argon or helium) through plasma systems, ensuring consistent treatment conditions 9 .
Optical Emission Spectroscopy
This analytical technique allows researchers to identify and quantify the reactive species generated by plasma by analyzing the light emitted 9 .
Cell Viability Assays
These laboratory tests measure cellular metabolic activity as an indicator of cell health and proliferation after plasma treatment (e.g., MTT assay) 9 .
Catalase Enzyme
This enzyme is used experimentally to neutralize hydrogen peroxide, helping researchers understand the specific roles of different reactive species 9 .
The Future of Plasma Cancer Therapy: Where Do We Go From Here?
Clinical applications, combination therapies, and the path forward
Combination Therapies
Perhaps the most promising direction for CAP in oncology lies in combination therapies. Recent research has demonstrated that CAP can synergistically enhance the effectiveness of conventional chemotherapy drugs.
A 2025 meta-analysis published in Scientific Reports examined 41 studies on the combination of CAP and doxorubicin (a common chemotherapy drug) for melanoma treatment 4 . The pooled analysis found that the combination had a significant synergistic effect on reducing cell viability and increasing cytotoxicity in melanoma cells—more than either treatment alone 4 .
This suggests that CAP could potentially allow for lower doses of toxic chemotherapy drugs while maintaining or even enhancing effectiveness.
Clinical Applications and Approval Status
The translation of CAP technology from laboratory research to clinical practice is already underway. Since 2013, certain CAP devices have received clinical approval for treating acute and chronic wounds, ulcers, and pathogen-related skin diseases in Europe 2 5 .
This established safety profile for non-cancer conditions provides a foundation for expanding applications into oncology. For skin cancer specifically, researchers are exploring various application strategies:
- Direct tumor ablation for superficial skin cancers
- Adjuvant therapy during surgery to eliminate remaining cancer cells
- Field cancerization treatment for areas with widespread sun damage
- Enhanced drug delivery by increasing skin permeability to topical chemotherapies 5
Challenges and Future Directions
Despite the promising results, several challenges remain before CAP becomes a standard cancer treatment. There is currently no standardized protocol for plasma treatment in oncology, with different devices, gases, treatment times, and power settings being used across studies .
Additionally, while numerous in vitro and animal studies have shown efficacy, large-scale human clinical trials for skin cancer applications are still needed. Future research will need to focus on optimizing treatment parameters, understanding long-term effects, and developing standardized protocols that can be applied consistently across medical centers.
The Growing Promise of Plasma Medicine
Cold atmospheric plasma represents a fascinating convergence of physics and medicine, offering a novel approach to one of medicine's most persistent challenges.
The ability to selectively target cancer cells while sparing healthy tissue, combined with the potential for synergistic effects with existing treatments, positions CAP as a potentially transformative technology in dermatologic oncology.
While questions remain and further research is needed, the current evidence suggests that this "fourth state of matter" may soon claim its place as a valuable tool in our fight against skin cancer.
As research continues to unravel the mechanisms behind CAP's selective toxicity and optimize its application parameters, we move closer to a future where cancer treatment can be both effective and gentle. The path from laboratory curiosity to clinical reality is often long and complex, but cold atmospheric plasma appears to be steadily advancing along this journey, sparking excitement among researchers and hope among patients.