Plasma medicine

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Plasma medicine is an emerging field that combines plasma physics, life sciences and clinical medicine. It is being studied in disinfection, healing, and cancer. [1] [2] Most of the research is in vitro and in animal models.

Contents

It uses ionized gas (physical plasma) for medical uses or dental applications. [3] Plasma, often called the fourth state of matter, is an ionized gas containing positive ions and negative ions or electrons, but is approximately charge neutral on the whole. The plasma sources used for plasma medicine are generally low temperature plasmas, and they generate ions, chemically reactive atoms and molecules, and UV-photons. These plasma-generated active species are useful for several bio-medical applications such as sterilization of implants and surgical instruments as well as modifying biomaterial surface properties. Sensitive applications of plasma, like subjecting human body or internal organs to plasma treatment for medical purposes, are also possible. This possibility is being heavily investigated by research groups worldwide under the highly-interdisciplinary research field called "plasma medicine".

Plasma sources

Plasma sources used in plasma medicine are typically "low temperature" plasma sources operated at atmospheric pressure. In this context, low temperature refers to temperatures similar to room temperature, usually slightly above. [4] There is a strict upper limit of 50 °C when treating tissue to avoid burns. The plasmas are only partially ionized, with less than 1 ppm of the gas being charged species, and the rest composed of neutral gas.

Dielectric-barrier discharges

Dielectric-barrier discharges are a type of plasma source that limits the current using a dielectric that covers one or both electrodes. The DBD was the plasma source used in the mid-1990s in the early groundbreaking work on the biomedical applications of cold plasma. [5] A conventional DBD device comprises two planar electrodes with at least one of them covered with a dielectric material and the electrodes are separated by a small gap which is called the discharge gap. Research has demonstrated that modifying the configuration of the embedded electrode and altering its distribution within the dielectric medium can significantly impact the effectiveness of dielectric barrier discharge (DBD) plasma actuators. [6] The performance characteristics of these actuators can be tuned and optimised by strategically manipulating the electrode's encapsulation and placement throughout the dielectric layer. [7] DBDs are usually driven by high AC voltages with frequencies in the kHz range. In order to use DC and 50/60 Hz power sources investigators developed the Resistive Barrier Discharge (RBD). [8] However, for medical application of DBD devices, the human body itself can serve as one of the two electrodes making it sufficient to devise plasma sources that consist of only one electrode covered with a dielectric such as alumina or quartz. DBD for medical applications [9] such as for the inactivation of bacteria, [10] for treatment of skin diseases and wounds, tumor treatment [11] and disinfection of skin surface are currently under investigation. The treatment usually takes place in the room air. They are generally powered by several kilovolt biases using either AC or pulsed power supplies.

Atmospheric pressure plasma jets

Atmospheric pressure plasma jets (APPJs) are a collection of plasma sources that use a gas flow to deliver the reactive species generated in the plasma to the tissue or sample. [12] The gas used is usually helium or argon, sometimes with a small amount (< 5%) of O2, H2O or N2 mixed in to increase the production of chemically reactive atoms and molecules. The use of a noble gas keeps temperatures low, and makes it simpler to produce a stable discharge. The gas flow also serves to generate a region where room air is in contact with and diffusing in to the noble gas, which is where much of the reactive species are produced. [13]

There is a large variety in jet designs used in experiments. [14] Many APPJs use a dielectric to limit current, just like in a DBD, but not all do. Those that use a dielectric to limit current usually consists of a tube made of quartz or alumina, with a high voltage electrode wrapped around the outside. There can also be a grounded electrode wrapped around the outside of the dielectric tube. Designs that do not use a dielectric to limit the current use a high voltage pin electrode at the center of the quartz tube. These devices all generate ionization waves that begin inside the jet and propagate out to mix with the ambient air. Even though the plasma may look continuous, it is actually a series of ionization waves or "plasma bullets". [14] This ionization wave may or may not treat the tissue being treated. Direct contact of the plasma with the tissue or sample can result in dramatically larger amounts of reactive species, charged species, and photons being delivered to the sample. [15]

One type of design that does not use a dielectric to limit the current is two planar electrodes with a gas flow running between them. In this case, the plasma does not exit the jet, and only the neutral atoms and molecules and photons reach the sample.

Most devices of this type produce thin (mm diameter) plasma jets, larger surfaces can be treated simultaneously by joining many such jets or by multielectrode systems. Significantly larger surfaces can be treated than with an individual jet. Further, the distance between the device and the skin is to a certain degree variable, as the skin is not needed as a plasma electrode, significantly simplifying use on the patient. Low temperature plasma jets have been used in various biomedical applications ranging from the inactivation of bacteria to the killing of cancer cells. [16]

Applications

Plasma medicine can be subdivided into five main fields:

  1. Non-thermal atmospheric-pressure direct plasma for medical therapy
  2. Plasma-assisted modification of bio-relevant surfaces
  3. Plasma-based bio-decontamination and sterilization
  4. Plasma-assisted modification of biomolecules, e.g., proteins, carbohydrates, lipids, and amino acids [17] [18] [19]
  5. Plasma-assisted prodrug activation [20] [21]

Non-thermal atmospheric-pressure plasma

One of challenges is the application of non-thermal plasmas directly on the surface of human body or on internal organs. Whereas for surface modification and biological decontamination both low-pressure and atmospheric pressure plasmas can be used, for direct therapeutic applications only atmospheric pressure plasma sources are applicable.

The high reactivity of plasma is a result of different plasma components: electromagnetic radiation (UV/VUV, visible light, IR, high-frequency electromagnetic fields, etc.) on the one hand and ions, electrons and reactive chemical species, primarily radicals, on the other. Besides surgical plasma application like argon plasma coagulation (APC), [22] which is based on high-intensity lethal plasma effects, first and sporadic non-thermal therapeutic plasma applications are documented in literature. [23] However, the basic understanding of mechanisms of plasma effects on different components of living systems is in the early beginning. Especially for the field of direct therapeutic plasma application, a fundamental knowledge of the mechanisms of plasma interaction with living cells and tissue is essential as a scientific basis.

Plasma Dermatology

The skin offers a convenient target for plasma applications, which partly explains the recent boom in plasma dermatology. [24] The first successes were achieved by German scientists using plasma treatment to heal chronic ulcers. [25] These studies resulted in the development of plasma devices now in clinical use in the European Union. [26]

In the United States, a collaborative group of academic scientists of the Nyheim Plasma Institute of Drexel University and dermatologist-researcher Dr. Peter C. Friedman pioneered the use of plasma to treat precancerous (actinic) keratosis [27] and warts. [28] [29] The same team was able to show promising results in the treatment of hair loss (androgenetic alopecia) with a modified protocol, called indirect plasma treatment. [30]

Successful plasma treatment of actinic keratosis was repeated by a different group in Germany using a different type of plasma device, [31] further demonstrating the value of this technology even when compared to established treatment methods such as topical diclofenac. [32]

There are ongoing clinical trials in dermatology for acne, rosacea, [33] hair loss, [34] and other conditions. The understanding gained from studying plasma treatment of skin diseases, may also help to develop new Plasma Medicine strategies to treat internal organs. [35]

Cold plasma is used to treat chronic wounds. Preliminary results indicate that cold plasma therapy can be more effective than the gold standard. [36]

Mechanisms

Though many positive results have been seen in the experiments, it is not clear what the dominant mechanism of action is for any applications in plasma medicine. The plasma treatment generates reactive oxygen and nitrogen species, which include free radicals. These species include O, O3, OH, H2O2, HO2, NO, ONOOH and many others. This increase the oxidative stress on cells, which may explain the selective killing of cancer cells, which are already oxidatively stressed. [37] Additionally, prokaryotic cells may be more sensitive to the oxidative stress than eukaryotic cells, allowing for selective killing of bacteria.

It is known that electric fields can influence cell membranes from studies on electroporation. Electric fields on the cells being treated by a plasma jet can be high enough to produce electroporation, which may directly influence the cell behavior, or may simply allow more reactive species to enter the cell. Both physical and chemical properties of plasma are known to induce uptake of nanomaterials in cells. For example, the uptake of 20 nm gold nanoparticles can be stimulated in cancer cells using non-lethal doses of cold plasma. Uptake mechanisms involve both energy dependent endocytosis and energy independent transport across cell membranes. [38] The primary route for accelerated endocytosis of nanoparticles after exposure to cold plasma is a clathrin-dependent membrane repair pathway caused by lipid peroxidation and cell membrane damage. [39]

The role of the immune system in plasma medicine has recently become very convincing. It is possible that the reactive species introduced by a plasma recruit a systemic immune response. [40]

Related Research Articles

<span class="mw-page-title-main">Corona treatment</span>

Corona treatment is a surface modification technique that uses a low temperature corona discharge plasma to impart changes in the properties of a surface. The corona plasma is generated by the application of high voltage to an electrode that has a sharp tip. The plasma forms at the tip. A linear array of electrodes is often used to create a curtain of corona plasma. Materials such as plastics, cloth, or paper may be passed through the corona plasma curtain in order to change the surface energy of the material. All materials have an inherent surface energy. Surface treatment systems are available for virtually any surface format including dimensional objects, sheets and roll goods that are handled in a web format. Corona treatment is a widely used surface treatment method in the plastic film, extrusion, and converting industries.

An atmospheric pressure discharge is an electrical discharge in air or another gas at atmospheric pressure.

<span class="mw-page-title-main">Plasma cleaning</span>

Plasma cleaning is the removal of impurities and contaminants from surfaces through the use of an energetic plasma or dielectric barrier discharge (DBD) plasma created from gaseous species. Gases such as argon and oxygen, as well as mixtures such as air and hydrogen/nitrogen are used. The plasma is created by using high frequency voltages to ionise the low pressure gas, although atmospheric pressure plasmas are now also common.

A nonthermal plasma, cold plasma or non-equilibrium plasma is a plasma which is not in thermodynamic equilibrium, because the electron temperature is much hotter than the temperature of heavy species. As only electrons are thermalized, their Maxwell-Boltzmann velocity distribution is very different from the ion velocity distribution. When one of the velocities of a species does not follow a Maxwell-Boltzmann distribution, the plasma is said to be non-Maxwellian.

Plasma activation is a method of surface modification employing plasma processing, which improves surface adhesion properties of many materials including metals, glass, ceramics, a broad range of polymers and textiles and even natural materials such as wood and seeds. Plasma functionalization also refers to the introduction of functional groups on the surface of exposed materials. It is widely used in industrial processes to prepare surfaces for bonding, gluing, coating and painting. Plasma processing achieves this effect through a combination of reduction of metal oxides, ultra-fine surface cleaning from organic contaminants, modification of the surface topography and deposition of functional chemical groups. Importantly, the plasma activation can be performed at atmospheric pressure using air or typical industrial gases including hydrogen, nitrogen and oxygen. Thus, the surface functionalization is achieved without expensive vacuum equipment or wet chemistry, which positively affects its costs, safety and environmental impact. Fast processing speeds further facilitate numerous industrial applications.

In mass spectrometry, direct analysis in real time (DART) is an ion source that produces electronically or vibronically excited-state species from gases such as helium, argon, or nitrogen that ionize atmospheric molecules or dopant molecules. The ions generated from atmospheric or dopant molecules undergo ion-molecule reactions with the sample molecules to produce analyte ions. Analytes with low ionization energy may be ionized directly. The DART ionization process can produce positive or negative ions depending on the potential applied to the exit electrode.

<span class="mw-page-title-main">Dielectric barrier discharge</span> Electrical discharge between two electrodes separated by an insulating dielectric barrier

Dielectric-barrier discharge (DBD) is the electrical discharge between two electrodes separated by an insulating dielectric barrier. Originally called silent (inaudible) discharge and also known as ozone production discharge or partial discharge, it was first reported by Ernst Werner von Siemens in 1857.

<span class="mw-page-title-main">Plasma pencil</span>

The plasma pencil is a dielectric tube where two disk-shaped electrodes of about the same diameter as the tube are inserted, and are separated by a small gap. Each of the two electrodes is made of a thin copper ring attached to the surface of a centrally perforated dielectric disk. The plasma is ignited when nanoseconds-wide high voltage pulses at kHz repetition rate are applied between the two electrodes and a gas mixture is flown through the holes of the electrodes. When a plasma is ignited in the gap between the electrodes, a plasma plume reaching lengths up to 12 cm is launched through the aperture of the outer electrode and into the surrounding room air. The cold plasma plume emitted by the plasma pencil can be used to kill bacteria without harming skin tissue.

A microplasma is a plasma of small dimensions, ranging from tens to thousands of micrometers. Microplasmas can be generated at a variety of temperatures and pressures, existing as either thermal or non-thermal plasmas. Non-thermal microplasmas that can maintain their state at standard temperatures and pressures are readily available and accessible to scientists as they can be easily sustained and manipulated under standard conditions. Therefore, they can be employed for commercial, industrial, and medical applications, giving rise to the evolving field of microplasmas.

<span class="mw-page-title-main">Wingless Electromagnetic Air Vehicle</span> Type of flight system

The Wingless Electromagnetic Air Vehicle (WEAV) is a heavier than air flight system developed at the University of Florida, funded by the Air Force Office of Scientific Research. The WEAV was invented in 2006 by Dr. Subrata Roy, plasma physicist, aerospace engineering professor at the University of Florida, and has been a subject of several patents. The WEAV employs no moving parts, and combines the aircraft structure, propulsion, energy production and storage, and control subsystems into one integrated system.

<span class="mw-page-title-main">Atmospheric-pressure plasma</span> Plasma in which the pressure equals that of the surrounding atmosphere

Atmospheric-pressure plasma is a plasma in which the pressure approximately matches that of the surrounding atmosphere – the so-called normal pressure.

<span class="mw-page-title-main">Plasma (physics)</span> State of matter

Plasma is one of four fundamental states of matter characterized by the presence of a significant portion of charged particles in any combination of ions or electrons. It is the most abundant form of ordinary matter in the universe, mostly in stars, but also dominating the rarefied intracluster medium and intergalactic medium. Plasma can be artificially generated, for example, by heating a neutral gas or subjecting it to a strong electromagnetic field.

<span class="mw-page-title-main">Plasma actuator</span> Type of actuator

Plasma actuators are a type of actuator currently being developed for active aerodynamic flow control. Plasma actuators impart force in a similar way to ionocraft. Plasma flow control has drawn considerable attention and been used in boundary layer acceleration, airfoil separation control, forebody separation control, turbine blade separation control, axial compressor stability extension, heat transfer and high-speed jet control.

<span class="mw-page-title-main">Mounir Laroussi</span> American physicist

Mounir Laroussi is a Tunisian-American scientist. He is known for his work in plasma science, especially low temperature plasmas and their biomedical applications.

Plasma-activated bonding is a derivative, directed to lower processing temperatures for direct bonding with hydrophilic surfaces. The main requirements for lowering temperatures of direct bonding are the use of materials melting at low temperatures and with different coefficients of thermal expansion (CTE).

<span class="mw-page-title-main">Streamer discharge</span> Type of transient electric discharge

In electromagnetism, a streamer discharge, also known as filamentary discharge, is a type of transient electric discharge which forms at the surface of a conductive electrode carrying a high voltage in an insulating medium such as air. Streamers are luminous writhing branching sparks, plasma channels composed of ionized air molecules, which repeatedly strike out from the electrode into the air.

An excimer lamp is a source of ultraviolet light based on spontaneous emission of excimer (exciplex) molecules.

The Drexel Plasma Institute, in Camden, New Jersey, is the largest university-based plasma research facility in the United States. Led by Drexel University, the members of the scientific team are from University of Illinois at Chicago, Argonne National Laboratory, Pacific Northwest National Laboratory and Kurchatov Institute of Atomic Energy. The primary fields of research are applications in medicine, Environmental Control, energy, and agricultural industries. The institute actively develops and researches specific types of plasma discharges such as gliding arc, dielectric barrier discharge, gliding arc tornado, reverse vortex flow, Pulsed Corona Discharge, and many more.

Piezoelectric direct discharge (PDD) plasma is a type of cold non-equilibrium plasma, generated by a direct gas discharge of a high voltage piezoelectric transformer. It can be ignited in air or other gases in a wide range of pressures, including atmospheric. Due to the compactness and the efficiency of the piezoelectric transformer, this method of plasma generation is particularly compact, efficient and cheap. It enables a wide spectrum of industrial, medical and consumer applications.

Soft Ionization by Chemical Reaction in Transfer (SICRIT) is an ambient, also known as 'open' ionization, specifically designed for ion generation in mass spectrometers (MS), where ionization occurs at atmospheric pressure.

References

  1. ↑ Gay-Mimbrera, J; García, MC; Isla-Tejera, B; Rodero-Serrano, A; García-Nieto, AV; Ruano, J (June 2016). "Clinical and Biological Principles of Cold Atmospheric Plasma Application in Skin Cancer". Advances in Therapy. 33 (6): 894–909. doi:10.1007/s12325-016-0338-1. PMC   4920838 . PMID   27142848.
  2. ↑ Erfani, Rasool (2022). "[https://e-space.mmu.ac.uk/629624/1/Erfani_et_al-2022-Scientific_Reports.pdf Nanosecond-pulsed DBD plasma treatment on human leukaemia Jurkat cells and monoblastic U937 cells in vitro]". Scientific Reports. 12 (1): 6270. doi:10.1038/s41598-022-10056-8. PMC   9012873 . PMID   35428374.{{cite journal}}: External link in |title= (help)
  3. ↑ Sladek, R.E.J. (2006). Plasma needle : non-thermal atmospheric plasmas in dentistry (Phd Thesis 1 (Research TU/e / Graduation TU/e)). Technische Universiteit Eindhoven. doi:10.6100/IR613009.
  4. ↑ Rasool Erfani, Zare-Behtash H.; Kontis, K. (2012). "Plasma actuator: Influence of dielectric surface temperature" (PDF). Experimental Thermal and Fluid Science. 42: 258–264. doi:10.1016/j.expthermflusci.2012.04.023.
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  6. ↑ Rasool Erfani, Zare-Behtash H.; Hale, C.; Kontis, K. (2015). "Development of DBD plasma actuators: The double encapsulated electrode" (PDF). Acta Astronautica. 109: 132–143. Bibcode:2015AcAau.109..132E. doi: 10.1016/j.actaastro.2014.12.016 .
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  11. ↑ Vandamme, Marc; Robert, Eric; Dozias, Sebastien; Sobilo, Julien; Lerondel, Stephanie; Le Pape, Alain; Pouvesle, Jean-Michel (2011). "Response of Human Glioma U87 Xenografted on Mice to Non Thermal Plasma Treatment" (PDF). Plasma Medicine. 1 (1): 27–43. doi:10.1615/PlasmaMed.v1.i1.30. ISSN   1947-5764.
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  14. 1 2 Lu, X (2012). "On atmospheric-pressure non-equilibrium plasma jets and plasma bullets". Plasma Sources Science and Technology. 21 (3): 034005. Bibcode:2012PSST...21c4005L. doi:10.1088/0963-0252/21/3/034005. S2CID   122874922.
  15. ↑ Norberg, Seth A.; Tian, Wei; Johnsen, Eric; Kushner, Mark J. (2014-01-01). "Atmospheric pressure plasma jets interacting with liquid covered tissue: touching and not-touching the liquid". Journal of Physics D: Applied Physics. 47 (47): 475203. Bibcode:2014JPhD...47U5203N. doi:10.1088/0022-3727/47/47/475203. ISSN   0022-3727. S2CID   15534702.
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  17. ↑ Ahmadi, Mohsen; Nasri, Zahra; von Woedtke, Thomas; Wende, Kristian (2022). "d-Glucose Oxidation by Cold Atmospheric Plasma-Induced Reactive Species". ACS Omega. 7 (36): 31983–31998. doi:10.1021/acsomega.2c02965. PMC   9475618 . PMID   36119990.
  18. ↑ Nasri, Zahra; Memari, Seyedali; Wenske, Sebastian; Clemen, Ramona; Martens, Ulrike; Delcea, Mihaela; Bekeschus, Sander; Weltmann, Klaus-Dieter; Woedtke, Thomas; Wende, Kristian (2021). "Singlet-Oxygen-Induced Phospholipase A2 Inhibition: A Major Role for Interfacial Tryptophan Dioxidation". Chemistry – A European Journal. 27 (59): 14702–14710. doi:10.1002/chem.202102306. PMC   8596696 . PMID   34375468.
  19. ↑ Wende, K.; Nasri, Z.; Striesow, J.; Ravandeh, M.; Weltmann, K.-D.; Bekeschus, S.; Woedtke, T. von (2022). "Is Biomolecule Oxidation by Plasma-Derived Reactive Species Restricted to the Gas-Liquid Interphase?". 2022 IEEE International Conference on Plasma Science (ICOPS). pp. 1–2. doi:10.1109/ICOPS45751.2022.9813129. ISBN   978-1-6654-7925-7. S2CID   250318321 . Retrieved 2022-07-01.
  20. ↑ He, Zhonglei; Charleton, Clara; Devine, Robert W.; Kelada, Mark; Walsh, John M.D.; Conway, Gillian E.; Gunes, Sebnem; Mondala, Julie Rose Mae; Tian, Furong; Tiwari, Brijesh; Kinsella, Gemma K.; Malone, Renee; O'Shea, Denis; Devereux, Michael; Wang, Wenxin; Cullen, Patrick J.; Stephens, John C.; Curtin, James F. (2021). "Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma". European Journal of Medicinal Chemistry. 224. doi: 10.1016/j.ejmech.2021.113736 . hdl: 11019/3088 . PMID   34384944.
  21. ↑ Ahmadi, Mohsen; Potlitz, Felix; Link, Andreas; von Woedtke, Thomas; Nasri, Zahra; Wende, Kristian (2022). "Flucytosine-based prodrug activation by cold physical plasma". Archiv der Pharmazie. 355 (9): e2200061. doi: 10.1002/ardp.202200061 . PMID   35621706. S2CID   249095233.
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  34. ↑ Friedman, Dr Peter C. (2020-08-09). "Using Indirect Cold Atmospheric Pressure Plasma (Plasma Activate Liquid) for the Treatment of Hair Loss". Dr. Peter C. Friedman.
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