**1. Introduction**

In physical sciences, the term "plasma" often refers to the fourth state of matter consisting of electrons, ions and neutral particles; while in biology, it refers to the yellowish non-cellular liquid portion of the blood. The Nobel prize-winning American chemist Irving Langmuir first used the term plasma in 1927 to an ionized gas - an electrified fluid carrying electrons and ions, in analogy to the biological plasma carrying blood corpuscles, germs etc. Despite this historical connection, there had been no real correlation between the two plasmas until the emergence of the plasma medicine field recently [1].

Plasma can exist in a variety of forms and can be created in several ways. More than 99% of the visible universe is considered to be in the plasma state. The twinkling of stars, nebulas, auroras in the night sky are some examples of plasma that we observe away from us, and so is our Sun. On the other hand, flashes of lightning, fluorescent tubes, neon signs along our city streets are some other plasma examples that we encounter in our everyday life. Plasma can be classified in different ways based on thermodynamic equilibrium, ionization degree, density etc. Based on the thermal equilibrium between the electrons and the heavy particles, plasma can be categorized into thermal or high temperature plasma and nonthermal or cold plasma [2]. The distinction between thermal and nonthermal plasmas is very important in the context of this chapter. In all plasmas produced by applying an external electric field, the energy transfer to the electrons is much faster than that to the heavier ions. Due to their very high mobility, electrons have the opportunity to heat up to several thousands of degrees of Kelvin before the surrounding environment heats up or even without heating them at all. In thermal plasma, the electrons and heavy particles (neutrals and ions) reach a local thermodynamically equilibrium state, i.e., energy transfer from electrons to the heavy particles equilibrates the energy transfer from heavy particles to the environment, and all the species in the environment remain at almost the same temperature. Because of this, this type of plasma is also called equilibrium plasma. Thermal plasma can reach a temperature up to 108 K, as found in the solar core. On the other hand, in nonthermal plasma, cooling of heavier particles is more efficient than the energy transfer from electrons to them, and the gas temperature remains low. Therefore nonthermal plasma is also called non-equilibrium plasma or cold plasma.

With the advent of atmospheric pressure plasma discharges in the early 1990s, various industrial and environmental applications that do not require low pressure operating conditions became possible [3]. Among these, the use of low-temperature atmospheric pressure plasma for biomedical application took center stage. The ability of these cold atmospheric pressure (CAP) plasma discharges to produce enhanced gas phase chemistry at low gas temperature has led to their widespread application in fields that require low temperatures, such as biomedical applications and material processing [4]. In recent years, different devices have been designed to generate cold plasma in atmospheric pressure and have been investigated for their ability to use in biomedical applications [5]. It is demonstrated that CAP plasma could interact with organic substances without causing any electrical/thermal damage. The early results have indicated the great potential of these CAP plasma devices for biomedical applications. These devices can produce plasma at nearly room temperature (less than 40°C) at the contact zone, which is essential for direct application on the human or animal body as well as for sterilization of some medical devices [6]. **Figure 1** shows a typical photograph of a cold plasma jet extending out of a 7 mm quartz tube.

In the mid-1990s, a few researchers, for the very first time, demonstrated the efficient bactericidal property of the CAP plasma. This has opened up a new field of research in science and technology, combining plasma physics and biology called plasma medicine. Since then, CAP plasma devices have been successfully utilized in various applications ranging from sterilization to wound healing to killing cancer cells [3, 7]. From the very beginning, it was expected that the reactive species generated by the CAP plasma play a crucial role in the observed biological effects. Even if many details regarding the mechanism of interaction of plasma with biological matter are still not clear, some basic principles are known, and our depth of knowledge is growing very fast in this field. By the beginning of the second decade of the 2000s, clinical trials on patients started with some success [8]. Several applications have reached the clinical trial stage, and some of the CAP plasma devices have already been certified as medical devices. Woedkte et al. list three clinical trials

*Cold Atmospheric Pressure Plasma Technology for Biomedical Application DOI: http://dx.doi.org/10.5772/intechopen.98895*

**Figure 1.** *Photograph of a CAP plasma jet.*

using CAP plasma sources conducted in Germany, and two devices got CE marking as medical devices in 2013 [9]. Another device named SteriPlas (Adtec Ltd., London, UK) is the latest one to be certified for use as a medical device [10]. Several other devices have been tested under experimental and laboratory environments and are expecting possible clinical use certification. In 2019, the Food & Drug Administration (FDA) in the USA also approved for their first clinical trials of CAP plasma for cancer treatment [11].

It should be pointed out here that the early studies on plasma application in the biomedical field were concentrated on the thermal effects of plasma [12]. One such successful application was argon plasma coagulation (APC). It has been used to cut tissue in endoscopic applications. These devices operate by heating the tissue using electric current. Therefore their effects are mainly thermal. On the other hand, cold plasma transfers little heat, and its effects are primarily nonthermal.

These remarkable achievements of CAP plasma applications took only about 25 years from the initial discovery to the fundamental scientific investigation stage and finally to applications on actual patients.

In this chapter, we shall concentrate mainly on the nonthermal or cold plasmas produced at atmospheric pressure, their production methods, diagnostics, and their various applications in the biomedical field. After the introductory portion in Section 1, the fundamentals of nonthermal plasma is discussed in Section 2.

In Section 3, various CAP plasma generation methods will be discussed. These include dielectric barrier discharge (DBD), atmospheric pressure plasma jet (APPJ) and corona discharge. Then in Section 4, we shall discuss the diagnostics methods of CAP plasma. Due to the small size of the CAP plasma, generally passive, non-contact diagnostic methods are utilized for characterization. Optical emission spectroscopy (OES) is one such very popular non-invasive diagnostic tool for CAP plasma characterization. Then in Section 5, we shall discuss the interaction of CAP plasma with biomaterials and their biological effects. Section 6 discusses various significant biomedical applications of CAP plasma ranging from sterilization to wound healing to killing cancers. The final section then summarizes the application of CAP plasma technology in biomedical applications and their future outlook.
