Plasma Medical Science

Plasma Medical Science describes the progress that has been made in the field over the past five years, illustrating what readers must know to be successful. As non-thermal, atmospheric pressure plasma has been applied for a wide variety of medical fields, including wound healing, blood coagulation, and cancer therapy, this book is a timely resource on the topics discussed.

• Provides a dedicated reference for this emerging topic
• Discusses the state-of-the-art developments in plasma technology
• Introduces topics of plasma biophysics and biochemistry that are required to understand the application of the technology for plasma medicine
• Brings together diverse experience in this field in one reference text
• Provides a roadmap for future developments in the area

• Language: English
• Publisher: Academic Press
• Release date: Jul 6, 2018
• ISBN: 9780128150054

Book preview

Plasma Medical Science

Edited by

Shinya Toyokuni

Yuzuru Ikehara

Fumitaka Kikkawa

Masaru Hori

Table of Contents

Cover

Title page

Copyright

List of Contributors

Preface

Acknowledgments

Chapter 1: General Introduction

Abstract

Chapter 2: Physical and Chemical Basis of Nonthermal Plasma

Chapter 2.1: Introduction

Chapter 2.2: Atmospheric-Pressure Plasma Sources for Plasma Medicine

Chapter 2.3: Active Laser Spectroscopy

Chapter 2.4: Optical Diagnostics of Atmospheric Pressure Plasma

Chapter 2.5: Electrical Diagnostics

Chapter 2.6: Plasma Chemistry of Reactive Species in Gaseous Phase

Chapter 2.7: Production Control of Reactive Oxygen and Nitrogen Species in Liquid Water by Using a Nonthermal Plasma Jet

Chapter 2.8: Plasma-Liquid and Plasma-Biological Matter Interactions

Chapter 2.9: Simulation of Reactive Species: Kinetics in Aqueous Phase

Chapter 3: Plasma Biological Science in Various Species

Chapter 3.1: Introduction (Background, Aim of the Chapter)

Chapter 3.2: Modeling and Analysis of Interactions Between Plasma and Living Systems

Chapter 3.3: Effect of Plasma Irradiation on the In Vitro Growth of Babesia and Trypanosoma Parasites

Chapter 3.4: Intracellular Reactive Oxygen Species Generation and Gene Expression Changes—Characteristics of Physical Therapies

Chapter 3.5: Molecular Mechanism of Cellular Responses to Nonthermal Plasma

Chapter 3.6: Plasma Medical Science Through the Understanding of Biological Framework

Chapter 3.7: Synthetic Models to Monitor the Spatiotemporal Delivery of Plasma-Generated Reactive Oxygen and Nitrogen Species Into Tissue and Cells

Chapter 4: Regulation of Cell Membrane Transport by Plasma

Chapter 4.1: Introduction

Chapter 4.2: Cell Membrane Transport Enhanced by Plasma Activated Channel and Transporter

Chapter 4.3: Cell Membrane Transport Enhanced by Plasma-Activated Endocytosis

Chapter 4.4: Cell Membrane Transport Via Pore Formation Enhanced by Micro-Plasma Bubble

Chapter 4.5: Cell Membrane Transport Via Pore Formation Enhanced by Plasma Reactive Species

Chapter 4.6: Numerical Modeling of Cell Membrane Transport Enhanced by Plasma Irradiation

Chapter 4.7: Future Perspective of Plasma Gene Transfection

Chapter 5: Reactive Oxygen Species in Plasma Medical Science (PAM and Cancer Therapy)

Chapter 5.1: Introduction

Chapter 5.2: Plasma Activated Medium

Chapter 5.3: Pathology of Oxidative Stress

Chapter 5.4: The Translation Inhibitor Pdcd4-Mediated Mechanisms Inducing Apoptosis and Plasma-Stimulated Cell Death

Chapter 5.5: Plasma Medical Innovation for Cancer Therapy

Chapter 5.6: Gynecologic Cancers

Chapter 5.7: Plasma Medicine Innovations in Cancer Therapy: Glioblastoma

Chapter 5.8: Plasma Medical Innovation for Cancer Therapy: Melanoma

Chapter 5.9: Gastrointestinal Cancers

Chapter 5.10: Plasma Medical Innovation for Cancer Therapy: Cancer Initiating Cells

Chapter 5.11: Age-Related Macular Degeneration

Chapter 6: Application of Plasma to Humans (Blood Coagulation and Regenerative Medicine)

Chapter 6.1: Introduction

Chapter 6.2: Cutting-Edge Technologies of Bleeding Control Using Nonthermal Plasma—Mechanism of Blood Coagulation and Wound Healing

Chapter 6.3: Clinical Efficacy of Nonthermal Plasma Treatment in Minimally Invasive Gastrointestinal Surgery

Chapter 6.4: Molecular Morphological Analysis of The Effect of Plasma Irradiation on Cells, Tissue

Chapter 6.5: Evaluating the Invasiveness of Nonthermal Plasma Treatment Using Molecular Imaging Technique

Chapter 6.6: Molecular Dissection of Biological Effects for Mouse Embryonic Stem Cells Differentiation Treated by Low-Temperature Atmospheric-Pressure Plasma (APP)

Chapter 6.7: Cutting-Edge Studies on the Regeneration of Neural Tissue After Plasma Treatment

Chapter 6.8: Innovation in Wound Care Using Cold Atmospheric Plasma Technology

Chapter 6.9: Applying Plasma Technology Fornitric Oxide (NO) Generation in Clinical Practices

Chapter 6.10: Plasma Technologies for the Development of Innovative Orthopedic Materials

Chapter 7: Safety and Standardization Toward Clinical Applications

Chapter 7.1: Introduction

Chapter 7.2: General Concepts of Basic Safety on Plasma Treatment

Chapter 7.3: Application of Transgenic Mice to Analyze Genotoxic Effects Caused by Nonthermal Atmospheric Air Plasma

Chapter 7.4: International Standardization

Chapter 7.5: CE Marking for Medical Device

Chapter 8: Future Outlooks in Plasma Medical Science

Abstract

8.1. Introduction

8.2. Plasma Medical Innovation project as a driving force for creating a novel academic field of Plasma Medical Science

8.3. Emerging Plasma Medical Science and Medical Innovation

Index

Copyright

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List of Contributors

Tetsuo Adachi,     Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan

Yoshihiro Akimoto,     Department of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo, Japan

Vanni Antoni,     Consorzio RFX, Padua, Italy

Annemie Bogaerts,     Department of Chemistry, University of Antwerp, Antwerp, Belgium

Ko Eto,     Field of Biological Science, Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto, Japan

Osamu Goto,     Cancer Center, Keio University School of Medicine, Tokyo, Japan

Satoshi Hamaguchi,     Center for Atomic and Molecular Technologies, Graduate School of Engineering, Osaka University, Osaka, Japan

Takamichi Hirata,     Department of Medical Engineering, Tokyo City University, Tokyo, Japan

Masaru Hori,     Institute of Innovation for Future Society, Nagoya University, Nagoya, Japan

Masao Ichinose,     Faculty of Medicine, Teikyo University, Itabashi, Japan

Machiko Iida,     Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan

Jun-ichiro Ikeda,     Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Japan

Sanae Ikehara,     Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan

Yuzuru Ikehara

National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan

Department of Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan

Kazumasa Ikuse,     Center for Atomic and Molecular Technologies, Graduate School of Engineering, Osaka University, Osaka, Japan

Kenji Ishikawa,     Plasma Medical Science Global Innovation Center, Nagoya University, Nagoya, Japan

Paras Jawaid,     Department of Radiology, University of Toyama, Toyama, Japan

Masafumi Jinno,     Department of Electrical and Electronic Engineering, Ehime University, Matsuyama, Japan

Takehito Kajiwara,     Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan

Hiroaki Kajiyama,     Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Hiroki Kaneko,     Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Toshiro Kaneko,     Department of Electronic Engineering, Tohoku University, Sendai, Japan

Hiroyasu Kanetaka,     Graduate School of Dentistry, Tohoku University, Sendai, Japan

Makoto Kanzaki,     Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan

Yosky Kataoka

Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan

Multi-Modal Microstructure Analysis Unit, RIKEN-JEOL Collaboration Center, Kobe, Japan

Masashi Kato,     Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan

Hayato Kawakami,     Department of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo, Japan

Fumitaka Kikkawa,     Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Jaeho Kim,     National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan

Satoshi Kitazaki,     Electrical Engineering, Fukuoka Institute of Technology, Fukuoka, Japan

Satoru Kiyama,     National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan

Chihiro Kobayashi,     Department of Medical Engineering, Tokyo City University, Tokyo, Japan

Yasuhiro Kodera,     Nagoya University Graduate School of Medicine, Gastroenterological Surgery (Surgery II), Showa-ku, Nagoya, Japan

Kazunori Koga,     Department of Electronics, Kyushu University, Fukuoka, Japan

Takashi Kondo,     Department of Radiology, University of Toyama, Toyama, Japan

Michael G. Kong,     Department of Electrical and Computer Engineering, Old Dominion University, Norfolk, VA, United States

Kazuhiro Koshino,     National Cerebral and Cardiovascular Center Research Institute, Suita, Japan

Hirofumi Kurita,     Department of Environmental and Life Sciences, Toyohashi University of Technology, Toyohashi, Japan

Mounir Laroussi,     Plasma Engineering & Medicine Institute, Old Dominion University, Norfolk, VA, United States

Kenji Miyamoto,     Department of Physics, Graduate School of Engineering, Yokohama National University, Yokohama, Japan

Akira Mizuno,     Department of Environmental and Life Sciences, Toyohashi University of Technology, Toyohashi, Japan

Masaaki Mizuno,     Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan

Akira Mori,     Department of Medical Engineering, Tokyo City University, Tokyo, Japan

Hideki Motomura,     Department of Electrical and Electronic Engineering, Ehime University, Matsuyama, Japan

Kae Nakamura,     Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Maki Nakamura,     Nanomaterials Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan

Hayao Nakanishi,     Laboratory of Pathology and Clinical Research, Aichi Hospital, Aichi Cancer Center, Okazaki, Japan

Yoshimichi Nakatsu,     Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

Shoko Nishihara,     Department of Bioinformatics, Graduate School of Engineering, Soka University, Hachioji, Japan

Kyo Noguchi,     Department of Radiology, University of Toyama, Toyama, Japan

Mizuki Ohno,     Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

Yasuhiro Omata,     Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan

Ryo Ono,     Department of Advanced Energy, The University of Tokyo, Tokyo, Japan

Yasumasa Okazaki,     Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan

Ayako Oyane,     Nanomaterials Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan

Yang Peng,     Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Mati Ur Rehman,     Department of Radiology, University of Toyama, Toyama, Japan

Stephan Reuter,     Princeton University, Princeton, NJ, United States

Hajime Sakakita,     National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan

Shota Sasaki,     Department of Electronic Engineering, Tohoku University, Sendai, Japan

Awoi Sato,     Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan

Takehiko Sato,     Institute of Fluid Science, Tohoku University, Sendai, Japan

Susumu Satoh,     Department of Electrical and Electronic Engineering, Ehime University, Matsuyama, Japan

Yasuyuki Seto,     Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Yuichi Setsuhara,     Joining and Welding Research Institute, Osaka University, Osaka, Japan

Nobuyuki Shimizu

Surgery Department, Sanno Hospital, Tokyo, Japan

School of Medicine, International University of Health and Welfare, Narita, Japan

Tetsuji Shimizu

National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan

terraplasma GmbH, Garching, Germany

Masaharu Shiratani,     Department of Electronics, Kyushu University, Fukuoka, Japan

Robert D. Short,     Materials Science Institute and Department of Chemistry, The University of Lancaster, City of Lancaster, United Kingdom

Thillaiampalam Sivakumar,     National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan

Endre J. Szili,     Future Industries Institute, University of South Australia, Adelaide, SA, Australia

Yoshiaki Tabuchi,     Life Science Research Center, University of Toyama, Toyama, Japan

Masanori Tachikawa

Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan

Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

Noriko Takano,     Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

Kazunori Takashima,     Department of Environmental and Life Sciences, Toyohashi University of Technology, Toyohashi, Japan

Keisuke Takashima,     Department of Electronic Engineering, Tohoku University, Sendai, Japan

Keigo Takeda,     Department of Electrical and Electronic Engineering, Meijo University, Nagoya, Japan

Kosuke Takenaka,     Joining and Welding Research Institute, Osaka University, Osaka, Japan

Yasuhisa Tamura

Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan

Multi-Modal Microstructure Analysis Unit, RIKEN-JEOL Collaboration Center, Kobe, Japan

Akiyo Tanaka,     Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Hiromasa Tanaka

Institute of Innovation for Future Society, Nagoya University, Nagoya, Japan

Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan

Ryoko Tasaka,     Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan

Takashi Temma

National Cerebral and Cardiovascular Center Research Institute, Suita, Japan

Osaka University of Pharmaceutical Sciences, Takatsuki, Japan

Hiroko Terasaki,     Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Ryugo Tero,     Department of Environmental and Life Sciences, Toyohashi University of Technology, Toyohashi, Japan

Shinya Toyokuni,     Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan

Giichiro Uchida,     Joining and Welding Research Institute, Osaka University, Osaka, Japan

Satoshi Uchida,     Department of Electrical Engineering and Computer Science, Tokyo Metropolitan University, Hachioji, Japan

Hidefumi Uchiyama,     Tateyama Machine Co., Ltd., Toyama, Japan

Masashi Ueda,     Department of Biofunction Imaging Analysis, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

Takuya Urayama,     ADTEC EUROPE Ltd., Hounslow, United Kingdom

Fumi Utsumi,     Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Shunji Watanabe,     Nikon Corporation, Tokyo, Japan

Ichiro Yajima,     Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan

Hiromasa Yamada

National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan

University of Tsukuba, Tsukuba, Japan

Suguru Yamada,     Nagoya University Graduate School of Medicine, Gastroenterological Surgery (Surgery II), Showa-ku, Nagoya, Japan

Daiki Yamagami,     Department of Biofunction Imaging Analysis, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

Takashi Yamaguchi,     Molecular and Tumor Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan

Yoko Yamanishi,     Mechanical Engineering, Kyushu University, Fukuoka, Japana

Masanori Yamato

Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan

Multi-Modal Microstructure Analysis Unit, RIKEN-JEOL Collaboration Center, Kobe, Japan

Hachiro Yasuda,     Department of Environmental and Life Sciences, Toyohashi University of Technology, Toyohashi, Japan

Naoaki Yokoyama,     National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan

Mohammed Yousfi,     Laplace, CNRS, Université Paul Sabatier, Toulouse, France

Julia Zimmermann,     terraplasma GmbH, Garching, Germany

Preface

Although nonthermal atmospheric pressure plasmas have been applied to a wide variety of medical fields in the past two decades, trial and error approaches are still used in plasma medicine. To organize experimental results so far and/or to form a better understanding of this new filed, although several textbooks or technical books relating to plasma medicine have been already published, there is a need for a book focusing on the aspect of plasma medical science. Regarding wound healing, blood coagulation, cancer therapy and so on, new phenomena were found through treatments using plasma irradiation and plasma-activated liquid, which advanced the understanding of the academic aspect. On the basis of this scientific knowledge, attempts toward clinical study have already been performed. However, the mechanisms of biological effects by plasma treatments were not fully understood. I consider, There is no medical care where there is no science. So, what should be done for the establishment of plasma medical science?

On the basis of discussing this answer, among the Japanese community in particular, systematical research over the past 5 years has contributed to defining plasma medical science, which is an emerging multidisciplinary field that combines plasma science and medical science together through molecular biology. Herein, the progress in plasma medical science over the past 5 years is edited as a book to illustrate the scientific principles of plasma medicine.

In this book "Plasma Medical Science" which consists of 8 chapters, many scientific results on plasma medicine are organized so as to be able to understand and learn plasma medical science by bringing science to the fore. We hope that this book will stimulate the interest of researchers to pursue plasma medical science with rigorous scientific methodology.

In view of reality, however, it is fact that plasma medicine has not yet saved the life of even one person. Our aim is to realize plasma medical care as the future heath care. It would be wonderful if this book could help the dream of plasma saves human life come true.

Masaru Hori

as a Representative of all the editors

Acknowledgments

The authors greatly appreciate support of their plasma medical science research by a Grant-in-Aid for Scientific Research on Innovative Areas Plasma Medical Innovation (JSPS Kakenhi; JP24108001) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Chapter 1

General Introduction

Masaru Hori    Institute of Innovation for Future Society, Nagoya University, Nagoya, Japan

Abstract

Although the technologies used in plasma science were introduced in industrial manufacturing almost four decades ago, breakthroughs leading to multidisciplinary paradigm shifts have yet to occur, except in plasma medicine. Plasma is a partially ionized neutral gas consisting of active species of radicals, ions, electrons, and photons. Plasma has been described as the fourth state of matter. The development of atmospheric pressure nonequilibrium plasma technology has enabled the study of interactions between plasma and liquids, even within organisms, a previously unexplored scientific area. Biomedical applications of plasma have gained a great deal of recent attention because of potential medical applications in sterilization, wound healing, blood coagulation, gene transfection, and tissue regeneration, to name a few. The most exciting focus within this field, however, is on therapeutic uses of plasma in treating cancer. A major current trend in plasma science is the focus on systematic phenomena involving interactions of plasma with whole organisms, or plasma life sciences, which includes both medical and agricultural applications. A number of major breakthrough technologies have already been reported in these areas. Advances resulting from a number of fundamental studies will soon enable precise control of both the intracellular and extracellular redox balance, paving the way for the development of new plasma therapies. The development of plasma medicine as a new interdisciplinary science, however, will require that researchers keep abreast of the latest results, engage in robust exchange of ideas, and standardize their knowledge through a global network. The present volume will facilitate the development of networks between researchers and students, enabling them to rapidly and widely share systematic knowledge and cutting-edge results in the context of the fundamental theory of plasma medical science developed.

Keywords

blood coagulation

cancer treatment

gene transfection

nanosciences

plasma medical science

regeneration

Although the technologies used in plasma science were introduced in industrial manufacturing almost four decades ago, breakthroughs leading to multidisciplinary paradigm shifts have yet to occur, except in plasma medicine. Plasma is a partially ionized neutral gas consisting of active species of radicals, ions, electrons, and photons. Plasma has been described as the fourth state of matter. Over the past four decades, a type of low-temperature, so-called non-equilibrium plasma has begun to play ever more important roles in industry. This type of plasma has played roles in particularly important innovations in semiconductor manufacturing. It is not an exaggeration to state that there is no other plasma type that can match the industrial applications of nonequilibrium plasma.

Advances in nanosciences and plasma technology have enabled the integration of these technologies in processes on the nanometer scale. It is now possible to examine interactions between plasma and the surfaces and subsurfaces of particles on an atomic scale under vacuum in the study of physico-chemical reactions. Such cutting-edge plasma technology can overcome limits in the manufacturing of nanoscale materials.

The development of atmospheric pressure nonequilibrium plasma technology has enabled the study of interactions between plasma and liquids, even within organisms, a previously unexplored scientific area. Biomedical applications of plasma have gained a great deal of recent attention because of potential medical applications in sterilization, wound healing, blood coagulation, gene transfection, and tissue regeneration, to name a few. The most exciting focus within this field, however, is on therapeutic uses of plasma in treating cancer. A major current trend in plasma science is the focus on systematic phenomena involving interactions of plasma with whole organisms, or plasma life sciences, which includes both medical and agricultural applications. A number of major breakthrough technologies have already been reported in these areas.

The use of plasma for therapeutic applications will require that close attention be paid to patient safety. Potential applications must be evaluated in a strict scientific rather than trial-and-error manner. As such, phenomena must first be characterized quantitatively by measuring plasma component species in the gas phase, followed by systematic analyses of the interactions of these species with whole cells and tissues via a molecular biology approach (Fig. 1.1).

Figure 1.1   Plasma medical science requires seamless understanding of the processes leading to biological responses.

Atmospheric pressure plasma is generated by manipulating various external parameters, such as frequency, type of gas, power (supplied voltage and current), gas flow rate, and distance between the plasma and object of interest. When plasma comes in contact with the study object, a sheath (the boundary layer of shearing between the object and the plasma) is produced. The various species generated in the gas phase interact with the object through the sheath. In the case of plasma medicine, the object is usually a liquid and/or an organism (e.g., cells in culture medium). Short-lived reactive oxygen species (ROS) and reactive nitrogen species are generated at the surface of the liquid and organism, and these species interact and gradually change into more stable, long-lived compounds. In the presence of an electric field, these species can significantly impact cellular physiology, eliciting biological responses (particularly in the case of oxidative stress) that can lead to either cell death or proliferation.

Many diseases are associated with oxidative stress. It is hoped that cellular responses elicited by plasma can be exploited for therapeutic benefit in animals and humans. A greater understanding of the responses of cells to plasma at each step of the process shown in Fig. 1.1 has led to the establishment of a new field, plasma medical science. An overview of the expansive literature in plasma medicine research and development showed that many plasma sources are available, and many different parameters can be applied to the study of a variety of biological specimens under different atmospheric conditions.

First, it is important to define what plasma medical science is and what it entails. Although several volumes dealing with plasma medicine have been published to date, the present work focuses on the answers to these questions and proposes a new, systematic approach in plasma medicine research. Fig. 1.2 describes the approach from the preclinical level for multidisciplinary disease research involving plasma.

Figure 1.2   Approach to plasma medicine as proposed in Plasma Medical Science Innovation.

Fig. 1.2 shows the approach to plasma medicine proposed by the Japanese Project: Grant-in-Aid for Scientific Research on Innovative Areas Plasma Medical Science Innovation. The approach entails four so-called gears, which are (1) Source: Plasma source for medicine; (2) Diagnostics: Surface/interface reaction; (3) Clarification: Systematization based on molecular biology; and (4) Practice: Preclinical research and safety. The establishment of plasma medical science as a fusion of plasma science and medical science integrated with investigation of molecular biological dynamics is dependent on how the four gears rotate counterclockwise.

Initial areas of research within the Source and Diagnostics gears include establishing a method for the measurement of plasma species parameters, such as species type, density and energy in plasma, the electric field, and shock waves. Control of the internal parameters enables plasma irradiation of liquid and the organism(s) contained within it to provide insights into reaction phenomena at the atomic and molecular levels. These results can then be used to design plasmas suitable for use in medicine.

In the Diagnostics gear, research would focus on elucidating the fundamental characteristics of interactions between plasma and organisms on a molecular biological level for the purpose of developing a unified theory of plasma medicine. Based on the resulting theory, protocols can be developed for selectively promoting biological reactions via plasma for purposes such as inducing apoptosis of cancer cells or resuscitating dead or dying cells. The resulting information would then be fed into the Practice, Source, and Diagnostics gears.

The influence of plasma on living tissues is addressed in research within the Practice gear. Specific topics include selective killing of cancer cells via apoptosis induction as well as inducing hemostasis and tissue regeneration, for example. Other topics include examination of the use of plasma for treating pathologies surgically or for promoting health as well as characterizing possible side effects (toxicity) associated with the medical use of plasma. These academic pursuits are closely connected with evaluations of the medical safety of plasmas.

Several in vitro and in vivo studies have documented the efficacy of plasmas in medical treatments. In general, there are three modalities. The first modality involves direct interaction between the plasma and cells or tissues stimulated by plasma species and photons within an electric filed with and/or without liquid medium. Such direct plasma exposure is used for therapeutic induction of hemostasis, wound healing, and treatment of certain cancers (e.g., melanoma, a type of skin cancer). The second modality involves indirect treatment, in which plasma irradiation is used to activate liquid medium, which is then injected into cells or tissues. A particularly important new technology in this regard is plasma-activated medium (PAM), in which cell culture medium is irradiated with plasma. The resulting PAM can then be used for indirect treatment of various types of cancer by spreading the medium over or injecting it into affected organs, resulting in the selective killing of cancer cells. The third modality involves combined administration of plasma treatment and additional substances such as gold nanoparticles or anticancer drugs to elicit synergetic effects. Such approaches are highly versatile.

Plasma irradiation has a different effect on homeostasis compared with radiation and drugs. This enables the selective killing of cancer cells by inducing apoptosis without impacting homeostasis. However, this can result in side effects. For example, both indirect and direct plasma treatment can activate and enhance immune responses, leading to activation of macrophages and increases in cytokine release, thus posing challenges for plasma-assisted immunotherapy.

Advances resulting from a number of fundamental studies will soon enable precise control of both the intracellular and extracellular redox balance, paving the way for the development of new plasma therapies. The development of plasma medicine as a new interdisciplinary science, however, will require that researchers keep abreast of the latest results, engage in robust exchange of ideas, and standardize their knowledge through a global network. The present volume will facilitate the development of networks between researchers and students, enabling them to rapidly and widely share systematic knowledge and cutting-edge results in the context of the fundamental theory of plasma medical science developed through the four-gear approach illustrated in Fig. 1.2.

Chapter 2

Physical and Chemical Basis of Nonthermal Plasma

Outline

2.1Introduction

2.2 Atmospheric-Pressure Plasma Sources for Plasma Medicine

2.3 Active Laser Spectroscopy

2.4 Optical Diagnostics of Atmospheric Pressure Plasma

2.5 Electrical Diagnostics

2.6 Plasma Chemistry of Reactive Species in Gaseous Phase

2.7 Production Control of Reactive Oxygen and Nitrogen Species in Liquid Water by Using a Nonthermal Plasma Jet

2.8 Plasma-Liquid and Plasma-Biological Matter Interactions

2.9 Simulation of Reactive Species: Kinetics in Aqueous Phase

Chapter 2.1

Introduction

Kenji Ishikawa*

Masaru Hori**

*    Plasma Medical Science Global Innovation Center, Nagoya University, Nagoya, Japan

**    Institute of Innovation for Future Society, Nagoya University, Nagoya, Japan

Abstract

Plasma medical science deals with the complex interactions between electrically discharged plasmas and various biological systems, such as the skin and wounds, as well as eukaryotic, prokaryotic, and mammalian cells. Until the early 2010s, little was known of the interaction between nonthermal plasma (NTP) and biological materials and of the mechanism underlying this interaction. Since then, there has been enormous activity in this area, yet our understanding of how plasma interacts with biological materials remains minimal. Physicochemical diagnostics should provide insights into these complex systems because they would allow investigation of these interactions and mechanisms in molecular detail, ultimately leading to a universal model of plasma/biological material interactions.

Keywords

dark corona

electron velocity distribution function

nonthermal plasma (NTP)

photo-ionization

RONS

thermal equilibrium

2.1.1. Preface

Overwhelming beyond the old phenomenological approaches, the plasma diagnostics have been expected to provide more simply, reductionist-approached, essential answer to the complex questions. Until recently, biological responses have been much too complex to be understood comprehensively through simple mechanisms at the molecular level. Attempts have been made to understand interactions by analyzing biological states by parameterizing one variable. It may be possible to describe complex systems using holistic approaches; for example, systems biology attempts to provide a holistic interpretation. A new discipline, termed omics, encompasses staggering amounts of accumulated information. This approach may allow interpretation of biological complex responses resulting from the interaction of a biological material with an electrically discharged plasma. To this end, we have attempted to integrate various physicochemical parameters using numerous diagnostics to provide insights into medical applications of plasma.

The mechanism by which nonthermal plasma (NTP) induces changes in biological materials is clearly different from that of other physical methods. For example, DNA strand breaks are often studied in radiation chemistry. Studies of free radical chemistry and reactive oxygen species biology are based on understanding the biological functions occurring inside cells. In contrast, NTP may act to initiate oxygen stress. Indeed, NTP medicine draws a line between the induction of intracellular and extracellular physicochemical stress, as shown schematically in Fig. 2.1.1.

Figure 2.1.1   Schematic overview of the plasma-liquid interactions between nonthermal plasmas (NTP) and biological materials.

Compared with other physical treatments such as radiation therapy, NTP treatments generate large amounts of extracellular reactive species. In contrast, radiation chemistry generally generates large amounts of intracellular reactive species.

This chapter introduces the state of the art of physicochemical diagnostics using NTP for plasma medicine. We first describe the fundamentals of plasma sources used for plasma medical applications. Next, various methods for analyzing electrical discharge plasmas are explained, including electrical measurements of driving powers, optical diagnostics of plasma discharges, and physicochemical analyses of aqueous phases. In ) in the liquid phase. Both RONS and stimuli involving electric fields and electric currents play important roles in NTP medical science. The production of reactive species by the NTP source is under kinetic-control rather than thermal equilibrium. Thus, nonthermal effects are truly appeared with its characteristic link with homeostatic plasticity in biology. Lastly, in Chapter 2.9, K. Ikuse and S. Hamaguchi describes computational approaches to understanding a kinetic model of dominant reactions with reactive species. The aim of these eight chapters is to help readers understand the physicochemical basis of plasma medical science.

2.1.2. Physical Basis of NTP

Lightning generates natural plasmas and an aurora is a plasma. Artificial plasmas can be generated by flames or discharges. Here, we briefly explain the electric breakdown that occurs when a static electric field is applied. Electric breakdown results in an avalanche of ionized primary electrons under an accelerating static electrical force caused by applying high electric voltages. The break down of an electric charge causes transient sparks or arcing to form a filamentary discharge appearing trajectory in a space. Occasionally, primary electrons drift toward the anode, ionizing the background gas and causing avalanches. Positive ions strike the cathode and generate secondary electrons. This approach can be used if the electrode gap distance is small compared with the mean free path-length. As the distance increases, sparks, streamers or filaments are generated, forming a thin ionized channel as the streamer propagates between the electrodes. This mechanism allows ionization to occur at the head of the channel, where a strong electric field is built up by dipole formation due to the remaining positive ions in the tail of the channel. This is commonly called a primary streamer. Plasma emits high-energy photons, inducing photo-ionization, and another avalanche develops, surrounding the channel where there is a strong electric field due to dipole formation. Once the primary streamer is developed, the positive ions remain in the local channel to provide a conductive path, and secondary ionization forms additional avalanches.

For convenience, target positions with respect to the plasma are categorized as (1) electrode-target, (2) electrode-insulator and target, or (3) the plasma electrodes are placed independent of the target, as shown in Fig. 2.1.2. These geometries provide different ways of viewing electric charge phenomena. Case (1) yields an electric current flow in the target that acts as a counter electrode. Low electrical conductivity of the target results in a situation analogous to case (2). Here, if the polarity of the electric flow changes, only a charged current flows and a plasma discharge is ignited. In case (3), plasma is generated independent of and remote from the target. Reactive species transfer indirectly to the surface and often alter the effect of the plasma on the target.

Figure 2.1.2   Categories of configurations of plasma discharge with respect to the target position.

Electrodes are pins, planes, or ring shapes in cylindrical setups. (1) A counter electrode acts as the target, (2) an electrode is covered with insulator and the counter electrode acts as the target, and (3) the plasma is generated independent of and remote from the target. AC, alternating current; DC, direct current; MW, microwave; RF, radio-frequency.

The current-voltage characteristics change in relation with the plasma mode: dark corona, streamer, spark, filamentary, glow, and arc discharge, as shown in Fig. 2.1.3. If the electric current exceeds a certain limit, a conductive path is formed and an electric current flows, resulting in an arc discharge. The flow of a large electric current results in large secondary emissions at the cathode and ohmic (joule) heating in the discharge path. As a result, heating of the gas is dominant and simultaneous thermionic electron emissions sustain a high density of electrons. This is called a thermal plasma and has a temperature of 6000 K or higher.

Figure 2.1.3   (Top) Schematic images of plasma mode transition in the pin-to-plane geometry. (Bottom) Generalized current-voltage characteristics of DC discharges at low pressure (top) and at atmospheric pressure (bottom). Source: Modified from A. Schultz et al., IEEE Trans. Plasma Sci. 26 (1998) 1685 [1].

As the total discharge current increases, an arc transition (glow) for narrow gaps or a spark transition (cornea) for distant gaps occurs. At atmospheric pressure, electric breakdown is not stabilized. DC discharge always forms an arc transition, which produces streamers and no glow, as shown in Fig. 2.1.3. This prevents the thermalization of gas during discharge.

There are three major techniques for preventing thermalization: (i) dielectric-barrier discharges, (ii) current limit, and (iii) gas flow. Nonequilibrium conditions are defined as discharges that are spatially diffusive (space) or temporary short (time), as shown in Fig. 2.1.4. During an electrical discharge, the background gas is heated due to elastic collisions of electrons. This characteristic time is given by the inverse frequency of momentum transfers between masses of electrons "me and gases mg. Once the heated gas increases in temperature, it is cooled by diffusion with a diffusion coefficient Ds to the cooled ambient temperature or to the temperature of walls outside the discharge region. From this viewpoint, the characteristic cooling time is represented by the time required for diffusion to the wall. Also, excited electrons with a velocity distribution function g relax with a relaxation time t." When the balance of cooling exceeds the heating, nonequilibrium cold plasma conditions are maintained. The fundamental discharge phenomena and electrodynamics are similar when the gases have a temperature of 1000 K or lower.

Figure 2.1.4   Nonequilibrium conditions with spatially diffusive or temporary short discharges [2].

ξ is an election-kinetics term, nm is momentum transfer frequency, ni is collisional excitation of the i th level, p is pressure, l is characteristic length of the plasma volume, and k is a reaction coefficient for electron elastic collisions.

Electron collision-induced reactions produce reactive species. These species are different from those produced by radiation chemistry, which deals with the collisions of heavy particles with high energies above 100 eV. The plasma has properties that are clearly different from those of other physical treatments. In NTP processes, electron-related phenomena, including ionization, dissociation, and excitation, result in physically different processes, as shown in Fig. 2.1.5.

Figure 2.1.5   The ionization, dissociation, and excitation of molecules.

When an electron collides with a molecule (bonded A and B atoms), excitation of the molecule generates an excited state molecule (metastable) and subsequent de-excitation, accompanied by the emission of photons. Another process is dissociation, leading to rupture of the chemical bonds and the generation of A and B atoms. The ionization process generates an additional electron and the target molecule is ionized.

Although it is impossible to measure the exact energy, a mathematical description of how much energy these molecules have can be used to calculate the statistical probability of an event, that is, the probability of reaction. Once the probabilities are known, they can be used to calculate statistical averages (ensembles) for the entire target reaction. Therefore, these processes are statistically averaged, and interpretations based on quantum mechanics are valid for each collision. These statistics can be represented by cross-sectional data for inelastic electron collisions.

Statistical averages can be used to calculate and predict thermodynamic quantities such as temperature and pressure, and the amount of energy released or absorbed. These statistical averages, in turn, can be associated with specific parameters that can be measured. Rates or the speeds of processes such as biochemical reactions can be measured. Thermodynamics tells us whether or not a given process or reaction will occur. Kinetics is closely related to energetics and thermodynamics. The rate at which a process occurs is related to the energy pathway of a process. The paths through intermediate steps from the start to the end of a process will determine which intermediates are higher in energy.

In thermodynamics, heat is manifested as kinetic energy and the random motion of molecules. Electron density, ne, is an important characteristic of plasma. Randomness can be measured by the electron temperature, Te, or a velocity distribution function, electron velocity distribution function (eedf). Indeed, the reported values for ne are widely distributed, as tabulated in Table 2.1.1. The plasma density is determined primarily by the concentrations of the reactive species, that is, plasma chemistry is driven by the fundamental dynamics of electrons and the degree of nonequilibrium of the gases. The rate of the reaction can be estimated by multiplying the electron density, the cross-section available for a reaction to occur, and the eedf.

Table 2.1.1

APGD, Atmospheric pressure glow discharge; DBD, dielectric barrier discharge; HF, high frequency; CCP, capacitively coupled plasma; LIBS, Laser-induced breakdown; MW, microwave; NEAPP, nonequilibrium atmospheric pressure plasma; RF, radio frequency; ICP, inductively coupled plasma.

2.1.3. Background to the Hazards of Physical Stress

Hazard assessment of the acute and chronic effects of physical stress is being standardized by the World Health Organization (WHO). The WHO issued the guidelines of the International Commission on Nonionizing Radiation Protection (ICNIRP) and of the International Commission on Electromagnetic Safety (IEEE/ICES) [4]. These commissions reviewed the lethal effects of radiation and its biological effects on health. Dosimetry is the quantitative measure of the biological effect of radiation.

Biological effects of physical stress are typically the sum of thermal and nonthermal effects (Fig. 2.1.6). At high stress intensity, absorbed power is lost or dissipates due to loss of heat. Thus, high-intensity irradiation mainly results in thermal effects. In contrast, below a given threshold, nonthermal effects are dominant in lethal and biological effects.

Figure 2.1.6   Electromagnetic oscillation frequency for radiation effect on biological responses. (Top); An example of the physical stress response. As biological matters receive largely an energy of the physical stress, the thermal effect exceeds to the nonthermal effect. Blow a threshold of the thermalization, the nonthermal effect occurs to depend on the stress intensities. (Bottom).

A variety of physical stresses are assessed using a unit of dose defined as follows.

1. Ionizing radiation—Proton and X-ray irradiation of biological targets results in radiation power being absorbed by the target. The absorption dose is measured in grays, Gy (J/kg). Lethal and biological effects are evaluated by an equivalent dose in Sieverts, Sv. [4]

2. Ultraviolet—Intensity (W/cm²). Ultraviolet light spans the wavelengths 100–280 nm (UVC), 280–315 nm (UVB), and 315–400 nm (UVA). These bands correspond to nonionizing radiation. The depth of penetration of skin depends on the wavelength. Effective radiation, Eeff is defined as the summation, Eeff = ∑Eλ S(λ) ∆λ, where Eλ is light energy and S(λ) is wavelength-dependent absorption. The sun is the major source of UV, but all of the sun’s UVC and much of its UVB wavelengths are absorbed by the earth’s atmosphere. Consequently, at the earth’s surface, the highest proportion of UV is UVA (over 90%). However, exposure to UVB is biologically far more relevant than exposure to UVA [5].

3. Laser radiation—Intensity (W/cm²).

4. Electromagnetic radiation—Electromagnetic radiation with a frequency above 1 MHz has the specific absorption rate = σ|E|²/ρ, where σ is the conductivity (S/m), E is the electric field strength (V/m), and ρ is the density (kg/m³).

5. Induction current—Induction current (A/m²).

6. Ultrasound—Intensity (W/cm²) P²/ρc, where P is the effective acoustic pressure (Pa), ρ is the density of the medium (kg/m³), and c is the speed of sound (m/s). The temperature increase per unit time is proportional to the ultrasonic intensity I (W/cm²). Cavitation is bubble formation. Energy dissipates, the temperature inside the bubbles becomes very high, then the bubbles collapse. Ultrasound affects biological material via biophysical modes classified as thermal and nonthermal effects. Depending on the ultrasonic power, cavitational effects may be responsible for major effects above a certain threshold intensity [6].

7. Hyperthermia—Equivalent minutes (Thermal dose) Cumulative equivalent minutes at 43°C (CEM) = t R(43-T), where R is 1/2 (T > 43°C) and 1/4 (T < 43°C). [7]

In NTP processes, UV radiation and pH variations appear to be important [8]. UV radiation was measured in the range 200–400 nm in mW/cm² by optical emission spectroscopy. UV exposure in mJ/cm² was determined. The emission of VUV radiation was investigated using an apparatus used to determine the VUV radiation [9].

2.1.4. How to Measure the Strength of NTP Stress

First, the source receives an electric power input, P, which is the product of voltage and current, that is, P = I × V. This power is input into a plasma volume during the discharge period and thus plasma is measured in units of energy (Joule) divided by a unit volume and a unit time. This power is converted into energy for plasma generation, and plasma density and plasma temperature are roughly estimated from the input electric power. A thermalization process dissipates the energy to generate heat in the system, and the temperature of the gas in the system reaches an equilibrium state. It is possible to measure electron density, ne, volume, V, and an average time, ∆t, to provide the charge-particle dosage to the unit area of surface via the formula ne × V × ∆t. It is important to know the plasma density, listed in Table 2.1.1. Also, the plasma has additional effects, depending on the electric field and electric current. Moreover, the density of radicals (ROS and RNS) and of reactive reductants (RS) provides addition chemical effects. These effects act as a plasma-induced stress, which is represented by energy-dependent time-varying intensity. Integration of the stress intensity over time gives a dose. Also, temporal changes of dose, i.e., dose rates, are a notable parameter. The instantaneous stress intensity induces severe effects to targets. The effects are cumulative. Thus, either dose or dose-rate of plasma provides thermal and nonthermal effects (Fig. 2.1.6). Regardless of the dose or intensity, a thermal effect exists and increases with increasing of the NTP stress strengths. In between noneffective and lethal effects, the nonthermal stress effects are dominated owing to less thermal effect within a total effect. Accordingly this idea, plasma intensity is estimated by a summation of physical effects, Ef(ne, Te) and Ei(ne, Te), and chemical effects, nr × (ROS + RNS − RS), where Ef is the electric field factor, Ei is the electric current factor, as parameterized by the plasma density, ne, and the electron temperature, Te, and nr is a proportional factor of the radical density due to ROS, RNS, and RS. Briefly, the plasma intensity is a stress-intensity for the nonthermal effects on the biological responses.

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Chapter 2.2

Atmospheric-Pressure Plasma Sources for Plasma Medicine

Yuichi Setsuhara

Giichiro Uchida

Kosuke Takenaka    Joining and Welding Research Institute, Osaka University, Osaka, Japan

Abstract

In this section, fundamental overview of low-temperature atmospheric-pressure plasma generation has been provided focusing on low-temperature atmospheric plasma generation. Various sources for plasma medicine have been described in terms of operating conditions and plasma properties by categorizing the atmospheric-pressure plasma irradiation schemes as (a) DBD type, (b) plasma-jet type, and (c) plasma-effluent downstream type.

Keywords

atmospheric-pressure

low-temperature

plasma

plasma irradiation

plasma jet

2.2.1. Introduction

For sustaining plasmas in atmospheric pressure, application of high voltage is required for gas breakdown and the plasma tends to exhibit arcing and gas heating due to enhancement of collisions between electrons and gas molecules [1]. For avoiding arcing and lowering gas temperatures in atmospheric-pressure plasmas, thus for attaining low-temperature plasma sources, several discharge schemes have been developed in terms of electrode configurations and discharge-excitation voltage waveforms for limiting discharge duration [2].

For avoiding arching and gas heating it is effective to employ dielectric barrier discharge (DBD) [3,4] and pulsed voltage or high frequency (HF) voltage [5] for discharge excitation rather than direct current (DC) voltage. In the DBD configuration, discharge current enhancement causing considerable electrode heating (one of the major causes for arching generation) can be avoided by covering one or both of