Plasma is a partially ionized gas, in which a certain population of electrons are free rather than being bound to an atom or molecule. The ability of the positive and negative charges to move somewhat independently makes the plasma electrically conductive so that it responds strongly to electromagnetic fields. Plasma therefore has properties quite unlike those of solids, liquids or gases and is considered to be a distinct state of matter. Plasma typically takes the form of neutral gas-like clouds, as seen, for example, in the case of stars. Like gas, plasma does not have a definite shape or a definite volume unless enclosed in a container; unlike gas, in the influence of a magnetic field, it may form structures such as filaments, beams and double layers (1).
Plasma was first identified in a Crookes tube, and so described by Sir William Crookes in 1879 (he called it "radiant matter"). The nature of the Crookes tube "cathode ray" matter was subsequently identified by British physicist Sir J. J. Thomson in 1897, and dubbed "plasma" by Irving Langmuir in 1928, perhaps because it reminded him of a blood plasma (1).
Based on the relative temperatures of the electrons, ions and neutrals, plasmas are classified as "thermal" or "non-thermal". Thermal plasmas have electrons and ions at the same temperature and are said to be in thermal equilibrium. In other words electron temperature and gas temperature are in equilibrium with each other. Some examples of thermal plasmas are shown in Figure 1.
Figure 1. Thermal Plasmas (a) Sun, (b) Lightning and (c) Metal Spraying
Non-thermal plasmas on the other hand have the ions and neutrals at a much lower temperature (normally room temperature) whereas electrons are much "hotter". In other words electron temperature and gas temperature are not in equilibrium with each other. Non-Thermal plasmas are also known as non-equilibrium plasma. Some examples of non-thermal plasma are shown in Figure 2.
Figure 2. Non-Thermal Plasmas (a) Plasma Needle, (b) Plasma Jet and (c) Aurora Borealis
In my research towards the PhD degree, I primarily work with non-thermal non-equilibrium room temperature plasmas, specifically Non-Thermal atmospheric pressure Dielectric Barrier Discharge plasma and its applications in the clinical setting. I am currently developing DBD for various medical applications like blood coagulation, wound sterilization, wound healing, cancer treatment etc by trying to develop and understand the underlying mechanisms of interaction of non-thermal plasma with mammalian cells and tissue. The next section discusses the use of plasmas in medicine.
The term “plasma,” commonly employed in physical sciences for ionized medium, originally stems from the biological and medical fields1. Despite this historical connection, electrical plasma (e-plasma, electrical or gaseous discharge) is typically associated with high energy physics or low pressure processes employed in the semiconductor industry, while being rarely used in medical applications directly. The few known uses of e-plasma in medicine are based mainly on high temperature generated by conventional thermal discharges. One good example of this is the Argon Beam or Argon Plasma Coagulator (APC) developed mainly to cauterize wounds (2). This device generates e-plasma in flowing argon through ionization by high frequency (≥ 350 kHz) electrical discharge (3). The flow of argon takes e-plasma outside the ionization tube creating a jet that impinges onto the tissue. High temperature of the e-plasma (~ 10,000 K) leads to rapid cauterization and tissue desiccation. The procedure is painful and significant thermal tissue damage (up to 7 mm deep) results in prolonged healing (2-4). In general, today’s medical community is shifting the preference toward portable non-equilibrium room temperature discharges where thermal damage is minimized or eliminated and the plasma device is easy to use and does not require extensive and expensive equipment.
Initial steps in elimination of thermal damage by e-plasma have been made earlier. The most obvious is, of course, pouring saline over the arc to cool it off and prevent any significant tissue desiccation (3). A more refined e-plasma-based surgical tool that has recently been reported is the Pulsed Electron Avalanche Knife (PEAK). In this device, thermal damage to the tissue is reduced by keeping the current pulses short (microseconds) and the electrode thin (microns). Resulting streamers (micro-sparks) of e-plasma, forming under the micro-wire, deposit significant energy into the tissue rupturing it quickly without causing destruction of surrounding areas. Precision cutting has been demonstrated in this way (5, 6). Further advances in the non-thermal direction have been made by further size reduction of the needle tip and introduction of noble gases, where discharge power can be significantly lower. A discharge capable of a much gentler, non-thermal interaction with tissue, “plasma needle”, has been proposed (7). It involves a “glow” discharge igniting at the end of a sharp pin in flowing helium upon application of a radio frequency (13 MHz) electromagnetic excitation. This discharge operates at near room temperature, dissipating milli Watts in several cubic millimeters. Suggested applications include treatment of dental cavities and skin disorders. This e-plasma has been demonstrated to destroy cells and bacteria in a highly localized fashion without disturbing the nearby tissue (8). While the localized and non-thermal nature of a plasma needle can be beneficial, its power and temperature will be still high if the device is scaled up owing to the thermal nature of atmospheric pressure RF discharges.
To overcome the above mentioned challenges A. J. Drexel Plasma Institute developed a new non-thermal, room temperature e-plasma discharge operating in open air at atmospheric pressure which is safe for treatment of living animal or human tissue. This approach allows for novel treatment of biological and medical surfaces where no tissue damage is observed while some biological processes are initiated and/or catalyzed.
Non-thermal atmospheric pressure dielectric barrier discharge plasma has recently emerged as a novel tool in medicine. The principle of operation of the proposed e-plasma is similar to Dielectric Barrier Discharges (DBD) introduced by Siemens in the middle of 19th century (9, 10). It occurs at atmospheric pressure in air when sufficiently high voltage of continuous waveform or pulses of short duration are applied between two insulated electrodes. The presence of the insulator between the electrodes prevents the build-up of high current. As a result, the discharge creates e-plasma without substantial heating of the gas, thus offering no medium limitations (i.e. need for lower pressure or noble gases). We found that it is possible to replace one of the electrodes by an object with high capacity for charge storage—a “floating electrode” (FE). Living tissue of animal or human body with its high water content and a relatively high dielectric constant has the required high capacity for charge storage (11, 12) and, therefore, can easily be employed as the FE of the DBD e-plasma. In this case the FE-DBD e-plasma is created in the gap between the living tissue and the other insulated electrode. While the current in the gaseous discharge gap is mainly due to motion of charge carriers (electrons and ions), it continues mostly in the form of displacement current through the tissue. Moreover, most of the energy due to the e-plasma current is dissipated in the gap, just like in the case of a conventional DBD. Thus, in the FE-DBD we obtain non-thermal e-plasma that remains at room temperature throughout the operation of the system while active species, radicals, ultraviolet radiation, and sub-millimeter scale temperature fluctuations offer “synergetic” effect in tissue treatment. Moreover, the e-plasma generated in this way can be applied directly to a living human tissue (Figure 3.) without thermal or chemical damage (13–14). In addition to sterilization of tissue, we demonstrate that the FE-DBD e-plasma rapidly coagulates blood. Rather than a physical influence, we observe that e-plasma catalyses the natural blood coagulation processes.
Varying frequency and voltage power supply for generation of FE-DBD e-plasma was based on a system consisting of a wave-form generator, amplifier, and a transformer. A compact power supply was constructed in cooperation with Quinta, LTD (Moscow, Russia). Electric discharge generated by this power supply is sufficiently uniform (Figure. 5) for treatment of tissue and blood, where micro-patterns created by this and similar discharges are of no great importance (15).
E-plasma was generated between the insulated high voltage electrode and the sample (FE) undergoing treatment. One millimeter thick polished clear fused quartz (Technical Glass Products, Painesville, OH), was used as an insulating dielectric barrier. For power analysis of FE-DBD e-plasma in continuous or pulsed mode (Figure 6—signal output, Figure 7 - operating parameters) we measure current passing through e-plasma and the voltage drop in the gap. For current analysis we utilized a magnetic core current probe (1V/A +1/ − 0% Sensitivity, 10 ns usable rise time, 35MHz bandwidth, Model 4100 Pearson Current Monitor, Pearson Electronics, Palo Alto, CA). Voltage was measured using a wide bandwidth voltage probe (PVM-4 1000:1, North Start High Voltage, Marana, AZ). Signals were acquired and recorded by a Digital Phosphor Oscilloscope (500MHz bandwidth, TDS5052B, Tektronix, Inc, Richardson, TX) (Figure 6).
Non-thermal plasma can deactivate bacteria or induce apoptosis in malignant tissues (16-19). It can be applied in sub-lethal doses to elicit specific biological effects, including gene transfection (20-22), cell detachment (23-26), wound healing (17, 27-29), and blood coagulation (30). Non-thermal plasma can even have selective effects. In recent studies, non-thermal plasma initiated blood coagulation and deactivation of bacteria without inducing measurable toxicity in the surrounding living tissue. Non-thermal plasmas can be used in medicine for either direct plasma treatment (Figure 4) or indirect plasma treatment (16).
Plasma is composed of charged particles (electrons, ions), electronically excited atoms and molecules, radicals, and UV photons. Both direct and indirect plasma treatment expose cells or the tissue surface to active short and long lived neutral atoms and molecules, including ozone, NO, OH radicals, and singlet oxygen. However, direct plasma treatment allows a significant flux of charged particles, including both electrons and positive and negative ions like super oxide radicals , to reach the surface. Non-thermal plasma density, temperature, and composition can be changed to control plasma products.
2. Ginsberg GG, Barkun AN, et al (2002) Gastrointest Endosc 55(7):807–810
3. Vargo JJ (2004) Gastrointestinal Endoscopy 59(1):81–88
4. Watson JP, Jowett S, et al (1997) Gut 40:Th156–Th156
5. Priglinger SG, Haritoglou C, et al (2005) Arch Ophthalmol 123(10):1412–1418
6. Miller JM, Palanker DV, et al (2003) Arch Ophthalmol 121(6):871–877
7. Stoffels E, Flikweert AJ, et al (2002) Plasma Sources Sci Technol 11(4):383–388
8. Siemens CW (1862) J Franklin Inst 74(3):166–170.
9. Egli W, Kogelschatz U, Eliasson B (1994) Pure Appl Chem 66(6):1275–1286
10. Greason WD (2003) J Electrostat 59(3–4):285–300
11. Benjamin H, Bhansali S, et al (2005) Sensors Actuat B-Chem 111:430
12. Fridman G, Fridman A, Peddinghaus M, Balasubramanian M, Gutsol A, Friedman G (2005) From Plasma Biology to Plasma Medicine: Sterilization, Tissue Engineering, Treatment of Surface Wounds and Skin Diseases. in The 58th Annual Gaseous Electronics Conference (GEC). San Jose, CA, USA
13. Peddinghaus L, Fridman G, Vinovrski T, Jah A, Fridman A, Balasubramanian M, Gutsol A, Friedman G (2005) Use of Non-Thermal Atmospheric Pressure Plasma Discharge for Coagulation and Sterilization of Surface Wounds. in 32nd IEEE International Conference on Plasma Science, Monterey, CA, USA
14. Gutsol A, Fridman G, Friedman G, Balasubramanian M, Peddinghaus M, Fridman A (2005) Non-Thermal Plasma Blood Coagulation and Sterilization of SurfaceWounds. in 17th International Symposium on Plasma Chemistry. Toronto, Canada
15. Chirokov A, Gutsol A, et al (2005) IEEE Trans Plasma Sci 33(2):300
16. Fridman, G., Brooks, A. D., Balasubramanian, M., Fridman, A., Gutsol, A., Vasilets, V. N., Ayan, H., Friedman, G. 2006 Comparison of Direct and Indirect Effects of Non-Thermal Atmospheric Pressure Plasma on Bacteria, Plasma Process. Polym. 4: 370-375.
17. Fridman, G., Peddinghaus, M., Ayan, H., Balasubramanian, M., Gutsol, A., Brooks, A. D., Fridman, A., Friedman, G. 2006. Blood Coagulation and Living Tissue Sterilization by Floating-Electrode Dielectric Barrier Discharge in Air, Plasma Chem. and Plasma Proc. 26(4): 425-442
18. Fridman, G., A. Shereshevsky, M.M. Jost, A.D. Brooks, A. Fridman, A. Gutsol, V. Vasilets, G. Friedman. 2007. Floating Electrode Dielectric Barrier Discharge Plasma in Air Promoting Apoptotic Behavior in Melanoma Skin Cancer Cell Lines, Plasma Chemistry and Plasma Processing, 27(2): 163-176.
20. Coulombe, S., Léveillé, V., Yonson, S. and Leask, R. L., 2006. Miniature atmospheric pressure glow discharge torch (APGD-t) for local biomedical applications. Pure and Applied Chemistry, 78(6): p. 1147-1156.
21. Leveille, V. and S. Coulombe, 2005. Design and preliminary characterization of a miniature pulsed RF APGD torch with downstream injection of the source of reactive species. Plasma Sources Science and Technology, 14(3): p. 467(10).
24. Kieft, I.E., M. Kurdi, and E. Stoffels, 2006. Reattachment and Apoptosis after Plasma-Needle Treatment of Cultured Cells. Plasma Science, IEEE Transactions on, 34(4): 1331-1336.
25. 10. Stoffels, E., 2006. Gas plasmas in biology and medicine. Journal of Physics D: Applied Physics, 39(16).
26. Stoffels, E., Kieft, I. E., Sladek, R. E. J., Van den, L. J. M., 2006. Plasma needle for in vivo medical treatment: recent developments and perspectives. Plasma Sources Science and Technology, 15(4):S169.
27. G. Fridman, A. Shereshevsky, M. Peddinghaus, A. Gutsol, V. Vasilets, A. Brooks, M. Balasubramanian, G. Friedman, and A. Fridman, 2006. Bio-Medical Applications of Non-Thermal Atmospheric Pressure Plasma. In 37th AIAA Plasmadynamics and Lasers Conference. San Francisco, California.
28. Shekhter, A.B., et al., 2005. Beneficial effect of gaseous nitric oxide on the healing of skin wounds. Nitric Oxide-Biology and Chemistry, 12(4): 210-219.
29. Gostev, V. and D. Dobrynin. 2006. Medical microplasmatron. In 3rd International Workshop on Microplasmas (IWM-2006). Greifswald, Germany.
30. Kalghatgi, S. U., Fridman, G., Cooper, M., Nagaraj, G., Peddinghaus, G., Balasubramanian, M., Vasilets, V. N., Gutsol, A., Fridman, A., Friedman, G. 2007. Mechanism of Blood Coagulation by Non-Thermal Atmospheric Pressure Dielectric Barrier Discharge Plasma, IEEE Trans. Plasma Sci. 35(5): 1559-1566.
Relevant PublicationsDielectric Barrier Discharges
Chirokov A., Gutsol A., Fridman A., Sieber K. D., Grace J. M., and Robinson K. S., “Self-organization of microdischarges in dielectric barrier discharge plasma” IEEE Transactions on Plasma Science, April, 2005, V. 33, No. 2, P. 300-301.
Download full text (438 KB).
Chirokov A., Gutsol A., Fridman A., Sieber K. D., Grace J. M., and Robinson K. S., “A Study of Two-Dimensional Microdischarge Pattern Formation in Dielectric Barrier Discharge” Plasma Chemistry and Plasma Processing, Vol. 26, 2006, pp. 127-135.Download full text (358 KB).
Chirokov A., Gutsol A., Fridman A., Sieber K. D., Grace J. M., and Robinson K. S., “Analysis of two-dimensional microdischarge distribution in dielectric-barrier discharges” Plasma Sources Science and Technology, Vol.. 13, 2004, p. 623-635. Download full text (424KB)
A. Fridman, A. Chirokov and A. Gutsol, Topical Review “Non-thermal atmospheric pressure discharges”, J. Phys. D: Applied Physics, Vol. 38, Issue 2 (21 January 2005) R1-R24. Download full text (1,958KB)
A. Chirokov, A. Gutsol, and A. Fridman "Atmospheric pressure plasma of dielectric barrier discharges", Pure and Applied Chemistry, Vol. 77, No. 2 (2005), pp. 487-495. Download full text (415KB)
Biological and Medical Applications of Floating Electrode - Non-Thermal Dielectric Barrier Discharges Plasmas
Applied Plasma Medicine, G. Fridman, G. Friedman, A. Gutsol, A.B. Shekhter, V.N. Vasilets, A. Fridman, Plasma Process. Polym., Volume 5 Issue 6 (2008), Pages 503 – 533. FULL TXT (PDF)
Mechanism of Blood Coagulation by Non-Thermal Atmospheric Pressure Dielectric Barrier Discharge Plasma, S.U. Kalghatgi, G. Fridman, M. Cooper, G. Nagaraj, M. Peddinghaus, M. Balasubramanian, V.N. Vasilets, A. Gutsol, A. Fridman, G. Friedman, IEEE Transactions on Plasma Science, Volume 35, Issue 5, Part 2, Oct. 2007, pp. 1559-1566. FULL TXT(PDF).
Comparison of Direct and Indirect Effects of Non-Thermal Atmospheric Pressure Plasma on Bacteria, G. Fridman, A.D. Brooks, M. Balasubramanian, A. Fridman, A. Gutsol, V.N. Vasilets, H. Ayan, G. Friedman, Plasma Process. Polym., 2007, 4, 370-375. FULL TXT (PDF)
Floating Electrode Dielectric Barrier Discharge Plasma in Air Promoting Apoptotic Behavior in Melanoma Skin Cancer Cell Lines, G. Fridman, A. Shereshevsky, M.M. Jost, A.D. Brooks, A. Fridman, A. Gutsol, V. Vasilets, G. Friedman, Plasma Chemistry and Plasma Processing, 27, 2, 163-176 (2007). FULL TXT (PDF)
Blood Coagulation and Living Tissue Sterilization by Floating-Electrode Dielectric Barrier Discharge in Air, G. Fridman, M. Peddinghaus, H. Ayan, A. Fridman, M. Balasubramanian, A. Gutsol, A. Brooks, G. Friedman, Plasma Chemistry and Plasma Processing, 26, 425-442 (2006). FULL TXT (PDF)
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