RU2827538C2 - Plasma generation system - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: system for generating plasma used for prevention, treatment of intraepithelial new growths and / or treatment of invasive carcinomas accessible through epithelium, contains: medical instrument for exposure to plasma on patient’s tissue, a high-frequency device configured to supply the instrument with alternating voltage, a neutral electrode placed on the patient's body to close the electric circuit, a gas supply device for supplying the instrument with gas, a device for controlling the output power of the high-frequency device.

EFFECT: creation of warm plasma having a sparing and uniform effect on tissue, in particular sensitive tissue, such as mucous membranes.

15 cl, 8 dwg, 1 tbl

Description

The invention relates to a system for creating (generating) plasma used for preventing, treating intraepithelial neoplasms and/or treating invasive carcinomas accessible through the epithelium. In addition, the invention relates to corresponding physical plasmas, media, chemical compounds, and a method for treating diseases.

The concept of plasma medicine unites numerous methods of treating diseases using physical plasma.

The articles "Cold atmospheric plasma, a novel promising anti-cancer treatment modality" by YAN et al., Oncotarget, 2017, Vol. 8, (No. 9), pp.: 15977-15995, and "Use of cold atmospheric plasma in oncology: a concise systematic review" by Dubuc et al., Ther Adv Med Oncol, 2018, Vol. 10: 1-12 describe studies on the use of cold atmospheric plasma (CAP) in cancer treatment.

The article "Virucide properties of cold atmo-spheric plasma for future clinical applications" by Weiss et al., Journal of Medical Virology 89: 952–959 (2017) describes the inactivation of viruses using cold plasma at atmospheric pressure.

The article "Physical plasma: a new treatment option in gynecological oncology" by Weiss et al., Archives of gynecology and obstetrics, September 2018, briefly describes the use of cold physical plasma at atmospheric pressure for the treatment and prevention of gynecological cancers.

The article "Cold atmospheric plasma (CAP) for anti-cancer applications: Epigenetic effects on DNA integrity and functionality of cervical cancer cells" describes the effects of cold atmospheric plasma on cervical cancer cells.

The article "Modified Argon Plasma Coagulation Methods and First Clinical Experiences with Unicentric Tumors in Gastroenterological Endoscopy" (Frank et al., Endo heute 2006; 19: 15-22) describes the use of argon plasma coagulation methods in the treatment of tumors and lesions.

The article "Clinical investigation of the safety and efficacy of a cervical intraepithelial neoplasia treatment using a hyperthermia device that uses heat induced by alternating magnetic fields" by Koizumi et al., Molecular And Clinical Oncology, 5: 310–316, 2016, describes the treatment of patients with grade III cervical intraepithelial neoplasia (CIN III) using heated treatment needles.

WO 02/11634 A1 describes a high-frequency generator for high-frequency surgery with adjustable power limitation. The generator provides for regulation of the pulse duration of the modulating signal and/or the duration of the pause between modulating signals in such a way that the limiting value of the high-frequency output voltage or the intensity of the electric volt arc can be maintained constant.

The poster presentation "Cold atmospheric plasma (CAP) for anti-cancer applications: Epigenetic effects on DNA integrity and functionality of cervical cancer cells" by Weiss et al., for the 62nd DGGG Congress, Berlin, 31.10. - 03.11.2018 illustrates the cell growth-inhibiting effect of CAP application on cervical SiHa cells (a cervical carcinoma cell line).

In the article "Molecular Effects and Tissue Penetration Depth of Physical Plasma in Human Mucosa Analyzed by Contact-and Marker-Independent Raman Microspectroscopy" by Wenzel et al., published October 28, 2019 in ACS Appl. Mater. Interfaces, noninvasive treatment with SAR is identified as a promising therapeutic option for precancerous lesions and neoplastic diseases of the human mucosa, such as cervical neoplasms. The article describes the results of a study to investigate the use of Raman microspectroscopy to characterize the effects of plasma parameters on human tissue, when examined in cervical tissue samples in vitro. As described in the SAR effect study, inhibition of cell proliferation in a cell culture with a cervical cancer cell line was confirmed. SAR treatment of both cervical tissue samples and the cell line was performed using an argon plasma jet instrument. In the study, the instrument was dynamically moved over the samples to avoid thermal tissue damage.

Web page

https://clinicaltrials.gov/ct2/show/NCT03218436?term=argon+plasma&cond=CiN&rank=l describes a study of low-temperature physical plasma treatment of cervical intraepithelial neoplasm. Histologically confirmed grades I/II CIN were specified as criteria for plasma treatment.

Given these premises, there is a need for plasma with improved characteristics for the treatment of diseases, as well as for systems and methods for creating such plasma.

To achieve this goal, a system is proposed for the creation of plasma used for the prevention, treatment of intraepithelial neoplasms and/or treatment of epithelial accessible invasive carcinomas, containing:

- a medical instrument for plasma exposure to patient tissue, having at least one electrode located at the distal end of the instrument with the possibility of galvanic contact with the plasma,

- a high-frequency device designed to supply the instrument with alternating voltage having a high frequency of at least 100 kHz and modulated by pulses of medium frequency ranging from 5 kHz inclusive to 100 kHz inclusive and by pulses of low frequency ranging from 0.5 Hz inclusive to 200 Hz inclusive,

- a neutral electrode placed on the patient's body to close the electrical circuit passing from the high-frequency device through the instrument electrode, the plasma and the patient's body, wherein the instrument is designed with the possibility of igniting the plasma between the electrode and the patient's tissue,

- a gas supply device, which is designed to supply the tool with gas, and

- a device for regulating the output power of a high-frequency device to the required value.

The generated plasma can be used for preventing intraepithelial neoplasms, in particular by means of antiviral therapy, for example by means of plasma-based inactivation of the human papilloma virus, for treating intraepithelial neoplasms of all degrees of severity, for example carcinoma at the lesion site, and/or for treating invasive carcinomas accessible through the epithelium. The plasma is preferably an argon plasma, otherwise, for example, a helium plasma. As stated above, the system for generating plasma comprises a medical instrument with at least one electrode, a high-frequency device for providing alternating voltage for supplying the instrument with electrical power, and a gas supply device, which is designed to supply the instrument with gas, in particular argon. At least one electrode of the system preferably has a galvanic contact with the plasma. The system preferably generates plasma in the form of a conductive plasma.

The system according to the invention can also be used to obtain plasma-activated media. The term "activated" means that therapeutically effective chemical compounds, especially radicals, are created in the medium by means of plasma and/or therapeutically effective chemical compounds, especially radicals, are placed in the medium. Media can be, for example, liquids, especially suspensions, emulsions, especially tissue fluid, human or animal tissue, especially neoplastic tissue, or, for example, a pasty or solid material. Media, especially materials, can be used to treat intraepithelial neoplasms. An activated medium that contains the endogenous tissue of a patient to be treated, or an activated endogenous medium on the endogenous tissue to be treated, for example a biological fluid, can also be referred to as an activated target medium. An activated foreign medium, such as a liquid, in particular a solution, suspension or emulsion, gel or paste, which is applied to or into the tissue of a patient for treatment, or which is supplied to the patient in another way, is to be understood as a medicament for the prevention or treatment of the diseases mentioned. If the plasma created in accordance with the invention is used to produce an activated endogenous or foreign medium, the plasma can, in this sense, be indirectly used to treat, in particular, one or more of the diseases mentioned above. Radicals may be, for example, reactive oxygen species (ROS) and/or reactive nitrogen species (RNS). The totality of all reactive oxygen species and all reactive nitrogen species is designated RONS.

The system proposed in the invention can also be used to create chemical compounds by means of plasma, especially chemical compounds placed in the above-mentioned environment, and/or to create chemical compounds, especially radicals, in the above-mentioned environment.

The system can be set in embodiments by selecting predetermined system settings, such as, for example, high-frequency voltage, high-frequency power, high-frequency modulation, gas flow rate, and the like, to create plasma and thereby prevent and/or treat the said diseases.

At least one electrode of the system can have a galvanic contact with the plasma by means of the fact that the electrically conductive, in particular metallic, surface of the electrode has contact with the plasma. By conductive plasma is meant a plasma with such a contact with the electrode that electrons pass from the electrode into the plasma. In contrast to a barrier discharge through a dielectric layer on the electrode, such that the plasma has no contact with the electrode, in preferred embodiments of the system according to the invention for the treatment, for example by preventing, of the said diseases, the electrons enter the plasma from the electrode. Preferred embodiments of the system according to the invention provide the possibility of carrying out a discharge in the vicinity of the treated site, which leads to a high density of neutral and charged, however short-lived chemical compounds, and/or reactive chemical compounds of nitrogen, to which, in particular, radicals in the plasma at the site on the tissue and/or at the site on the tissue to be treated may belong.

The system in its embodiments provides the ability to create a warm plasma, which allows for athermal plasma delivery by moving over the area being treated; however, when stopping over one area, thermal effects may occur, primarily damage to the functional tissue structure, primarily as a result of protein denaturation. The warm plasma can have, for example, a temperature, in particular an ion temperature, of more than 45°C, more than 55°C or even more than 65°C. In particular, at a location adjacent to which the tip of the instrument is held without moving it relative to the tissue, the temperature on the surface of the location on the tissue can rise to at least 45°C, at least 55°C or even at least 65°C. The plasma can have, for example, a temperature such that only at an application rate including or exceeding a limit value, for example 10 mm/sec, with which the tissue is covered, the tissue temperature at the location on the tissue of the human or animal patient to be treated remains less than the limit temperature or equal to it, for example 40°C, particularly preferably less than or equal to 37°C. Preferably, in order to be able to work with a manually achievable and controlled application rate, preferably a maximum of 50 mm/sec or less, such that the tissue temperature at the location on the tissue, which is covered by the plasma, can be maintained at a temperature lower than or equal to a limiting temperature, for example 40°C, particularly preferably lower than or equal to 37°C, or in such a way that thermal damage to the tissue, especially coagulation as a result of the plasma treatment, can be prevented, the plasma preferably having a temperature lower than or equal to a limiting temperature, wherein the limiting temperature can be, for example, 150°C or 120°C.

The system proposed in the invention allows to implement a method comprising the use of plasma, for example the above-described plasma, for the prevention of intraepithelial neoplasms, especially by means of antiviral therapy, for example against the human papilloma virus, for the treatment of intraepithelial neoplasms of all degrees of severity, for example carcinomas at the site of injury, or for the treatment of invasive carcinomas accessible through the epithelium. Equivalent to the use of the plasma described above and, therefore, also belonging to the invention, is the use of a medium (for example, the creation of a medium), chemical compounds or a system for one or some of the specified types of treatment.

Such a method comprises, in particular, the athermal application of a warm plasma, for example, embodiments of the plasma created according to the invention. For this purpose, an instrument, for example an instrument of the system according to the invention, as explained above by way of example, and thus the plasma, preferably in a continuous manner, are directed over the tissue to be treated without touching it, such that the temperature of the locations on the tissue covered by the plasma remains below a limit temperature, preferably 37°C or 40°C, such that thermal damage to the tissue is reliably excluded.

Due to the absence of tissue destruction during athermal application of plasma, the usual dangers and complications of laser treatment (bleeding, infection) and conization (bleeding, infection, decrease in creatine kinase, 10-fold increase in risks during pregnancy, complications during childbirth, etc.) are prevented. Athermal treatment is painless or only slightly painful, and therefore can be performed on an outpatient basis, as well as without general sedation and without local anesthesia, in the situation of general consultation hours. In many cases, a treatment with a treatment time of 10 seconds to 10 minutes may be sufficient. Only one person (medical specialist personnel or a doctor) is required for the treatment. Sports, sexual intercourse, bathing, swimming, and work are possible again immediately after the treatment.

The system proposed in the invention for creating plasma, in particular conductive plasma, preferably argon plasma, comprises, as stated above, a medical instrument with at least one electrode and a high-frequency device for providing alternating voltage for supplying the instrument with electric power. The electrode preferably has a galvanic contact with the plasma. The system preferably has a gas supply device, which is designed to supply the instrument for creating plasma with gas, especially argon. The system comprises a device for regulating the output power, for example the output useful power or the output apparent power or the average value of the output instantaneous power of the high-frequency device according to the required value. Preferably, the system is intended for use, which can be achieved in embodiments by selecting predetermined system settings such as, for example, voltage, power, high-frequency modulation, gas flow rate, etc., in at least one of the following types of therapy: prevention of intraepithelial neoplasms, especially by means of antiviral therapy, for example against the human papilloma virus, treatment of intraepithelial neoplasms of all degrees of severity, for example carcinoma at the site of injury, and/or treatment of invasive carcinomas accessible through the epithelium.

The plasma generated by the system can be used for application in the prevention of intraepithelial neoplasms, in particular by means of antiviral therapy, for example against the human papilloma virus, the treatment of intraepithelial neoplasms of all degrees of severity, for example carcinoma at the lesion site, and/or the treatment of invasive carcinomas accessible through the epithelium. The plasma generated by the system can also be used to activate the medium for the said types of therapeutic treatment. In addition, the plasma generated by the system can also be used to produce chemical compounds. The plasma generated by the system can also be used to implement a method for the prevention of intraepithelial neoplasms, in particular by means of antiviral therapy, for example against the human papilloma virus, the treatment of intraepithelial neoplasms of all degrees of severity, for example carcinoma at the lesion site, and/or the treatment of invasive carcinomas accessible through the epithelium using the system according to the invention, the plasma generated by it, the production of the aforementioned medium and/or the aforementioned chemical compounds. The embodiments of the above-mentioned method relate primarily to the athermal use of plasma. Thus, in the embodiments, the use of the system proposed in the invention, the media obtained with its help, as well as chemical compounds, is equivalent and belongs to the invention.

The features of the plasma, system, medium, chemical compounds or method according to the first to fifth aspects of the invention presented in this document can be advantageously represented by optional features of the plasma, system, medium, chemical compounds or method according to the sixth to tenth aspects of the invention and vice versa. The embodiments of the system according to the sixth aspect, the plasma according to the seventh aspect, the medium according to the eighth aspect and the chemical compounds according to the ninth aspect correspond to the plasma, system, medium or chemical compounds according to the first to fourth aspects of the invention, so that the description of the first to fifth aspects can be used to describe, first of all, these embodiments.

Other advantageous embodiments and features of the plasma, media, chemical compounds, system and method according to the invention, according to aspects from the first to the tenth, can be obtained from the following description. Also in the case where in the following presentation the plasma, medium, system, method are indicated in the singular, the optional features and advantages of all aspects, from the first aspect to the tenth aspect of the invention, are always involved, except for cases where something else follows from the relationship.

Using the plasma according to the invention, it is possible to treat, in particular, intraepithelial neoplasms of at least one of the following organ systems of mammals: the cervix, the internal os of the uterus, the esophagus, the stomach, the colon, the rectum and the peritoneum.

Plasma can be used primarily for the treatment of intraepithelial neoplasms, especially cervical intraepithelial neoplasms of grades I or II, in humans.

Despite the decreasing incidence in this country due to greater efforts in prevention and early radical therapy, more than 500,000 women develop invasive cervical cancer (CC) worldwide each year. Approximately 270,000 patients die from the disease each year, and the majority of patients struggle throughout their lives with the often severe physical and mental consequences of the disease and treatment.

Cervical carcinoma without invasion (CIS) and CC arise from preexisting lesions that, in most cases, persist for several years. Among others, the main risk factor for the development of these cervical intraepithelial neoplasms (CIN) is local infection with highly infectious variants of the human papillomavirus (HPV).

The initial therapy for CIN is laser vaporization (thermal obliteration) or conization (tissue removal). These procedures are usually performed under general anesthesia and are associated with a relatively high invasiveness as well as high clinical and financial costs. The high incidence of CIN each year of approximately 4.2 new cases per 1000 people ultimately results in the need for a large number of expensive surgical facilities. In addition, these surgical interventions for the treatment of CIN are associated under certain circumstances with severe bleeding, decreased fertility and a multiple increase in the risk of pregnancy complications. Finding an optimal balance between overtreatment and the concern about the manifestation of invasive SS is an economic and health issue. In view of the insufficient quotas for HPV vaccinations and other risk factors in Germany and worldwide, CIN is still a problem that deserves serious consideration. Effective and minimally invasive methods of treatment without the use of anesthesia, primarily for CIN, but also for other precancerous conditions of the mucous membranes, are urgently needed in clinical practice and are currently largely lacking.

In this case, the invention is useful because the proposed plasma types, systems, media, chemical compounds and methods provide for the creation of a particularly gentle, but effective therapy, especially CIN. Preferred are the plasma types, systems, media, chemical compounds for athermal treatment of tissue surfaces, up to penetration into the tissue. This means that at the treated location on the tissue, the temperature is especially preferably always below the critical temperature for thermal damage to the tissue, for example less than or equal to 40 °C or less than or equal to 37 °C.

The gas flow rate (plasma-forming gas), for example argon, serves to create a suitable, if possible, specified mixed atmosphere between the distal tip of the instrument and the tissue in such a way that the ignition of the plasma becomes possible. If the gas flow rate is too low, too little plasma-forming gas is between the electrode and the tissue. The minimum gas flow rate is the smallest gas flow rate flowing through the instrument that ensures the ignition of the plasma. If the gas flow rate is too high, excessive admixture of air or other gases or media from the environment occurs due to turbulence. The maximum gas flow rate is the largest gas flow rate flowing through the instrument that ensures the ignition of the plasma. An atmosphere consisting exclusively of plasma-forming gas can presumably hinder the formation of therapeutically effective chemical compounds. Therefore, the selected gas flow rate (plasma-forming gas), for example argon, for creating the plasma is preferably located in the range between the minimum gas flow rate and the maximum gas flow rate. The selected gas flow rate through the instrument may be as high, for example at least as the minimum gas flow rate, but may be lower than the maximum gas flow rate. The gas flow rate of the plasma-forming gas is preferably selected in the range from the minimum gas flow rate inclusive up to and including a gas flow rate that exceeds, for example, three times the minimum gas flow rate. The minimum gas flow rate as well as the maximum gas flow rate may depend on several parameters and/or settings. The minimum gas flow rate may depend, in particular, on the required treatment distance between the instrument tip and the tissue surface. For treatment, for example, a treatment distance between the instrument tip and the tissue surface may be specified (for example, 7 mm), and on the basis of the specified treatment distance, a gas flow rate appropriate to the flow through the instrument may be selected. With an internal diameter of the gas channel at the distal end of 2.4 mm, the gas flow rate can be, for example, preferably in the range from 1 l/min inclusive to 3 l/min inclusive, particularly preferably from 1.3 l/min inclusive to 2.5 l/min inclusive, for example 1.6 l/min.±20%. The indications apply, as do the subsequent indications regarding gas flow rates in this application, to normal conditions. Normal conditions correspond to a temperature of 0°C and an atmospheric pressure of 1 atmosphere. With a smaller internal diameter, a lower gas flow rate may be advantageous, with the same other parameters and settings, and with a larger internal diameter, with the same other parameters and settings, a higher gas flow rate. The internal diameter of the gas line (e.g. gas channel) of the instrument at its distal end can be, for example, from 0.5 mm inclusive to 10 mm inclusive, preferably from 0.8 mm inclusive to 3 mm inclusive, in particular 2.4 mm.

In embodiments, it may be advantageous to have a gas flow rate, for example argon or another plasma-forming gas, of preferably less than 3 l/min, particularly preferably less than or equal to 2 l/min, which, on the one hand, ensures reliable ignition of the plasma even at low voltage and, on the other hand, ensures a mixing of argon and air between the electrode and the tissue in such a way that, with the assistance of the plasma, a high density of reactive chemical compounds can be formed, in particular reactive chemical compounds of oxygen and/or reactive chemical compounds of nitrogen, which are carried with the gas jet to the tissue and/or carried into the tissue.

To obtain effective plasma, instruments in which the direction of propagation of electric current coincides with the direction of plasma flow to the tissue are preferable.

A particularly effective plasma can be obtained by means of a system that has a neutral electrode, wherein the neutral electrode is placed on the patient's body to close the electric circuit of the high-frequency device by means of the electrode through the plasma and the patient's body. The plasma can be ignited between the electrode at the distal end of the instrument and the patient's tissue. If the system is to be used to obtain an activated medium from outside or separately from the patient's body by means of plasma, the medium can be placed on a carrier or in a container that serves as a neutral electrode. For example, the neutral electrode module of the system can be electrically connected to a conductive carrier or container for the medium.

A particularly gentle treatment is possible when the high-frequency device is designed to deliver an electrical output useful power limited to a maximum of 3.5 W, particularly preferably a maximum of 2.5 W, most preferably a maximum of 2 W, and even more preferably a maximum of 1 W or less. When the output useful power is limited to a maximum value, the actual power can take a maximum value, such as 2 W, or a lower value, such as 1 W.

In preferred embodiments, the high-frequency device is designed to supply the electrode with an alternating voltage that has a high frequency (HF) from 200 kHz inclusive to 16 MHz inclusive, preferably from 300 kHz to 500 kHz, such as 350 kHz. The high frequency may also be designated as a carrier frequency.

The average frequency used for modulating the high-frequency alternating voltage may preferably be from 10 kHz inclusive to 50 kHz inclusive, for example 20 kHz. The pulse length of each of the average frequency pulses preferably comprises one or more high-frequency periods. When pulsating with an average frequency, the power of the high-frequency device can be reduced compared to the continuous generation mode (continuous oscillations) without the risk of reducing the peak voltage to a level critical for ignition.

Furthermore, the constant or variable low frequency used for modulating the alternating high-frequency voltage may preferably be from 20 Hz inclusive to 150 Hz inclusive, in particular 100 Hz. The pulse length of each of the low-frequency pulses preferably constitutes at least one period of the medium frequency, preferably from one inclusive to 50 periods of the medium frequency, for example 20 periods of the medium frequency. If the pulse length of the low-frequency pulse contains more than one pulse of the medium frequency, it may also be a low-frequency pulse packet. The low-frequency pulsation, additionally or alternatively with the medium-frequency pulsation, leads to a reduction in the useful output power compared to the continuous generation mode of the high-frequency device. The high-frequency device may or may not allow the continuous generation mode. However, the low-frequency pulsation additionally leads to the extinction of the plasma in the interpulse pauses between the low-frequency pulses and, consequently, to the detachment of the plasma from the tissue surface. In this way, the plasma can be directed over the tissue surface without its adhesion to the tissue surface. This facilitates the achievement of a particularly uniform treatment result. In this way, it is also easier to prevent the occurrence of hot spots on the tissue, i.e. tissue spots with a treatment-induced temperature above a critical temperature, such as 37°C or 40°C, as a result of the plasma "adhesion" to the site, while simultaneously intensively treating the tissue spots.

The system can be designed to increase the peak output voltage of the high-frequency device at the beginning of a low-frequency pulse, which can be represented in particular by a packet of several medium-frequency pulses, until either the upper limit is reached or the plasma is ignited. The upper limit is, for example, from 2 kW inclusive to 6 kV inclusive, preferably from 4 kV to 5 kV, for example 4.7 kV. In addition, the system is preferably designed to reduce, upon ignition recognized by the system, the voltage of the power supply unit of the high-frequency device. This achieves a reduction in the peak output voltage of the high-frequency device in such a way that at the beginning of the next low-frequency pulse, the peak voltage is less significant than at the moment of plasma ignition in the preceding low-frequency pulse packet. This can prevent the creation of an excessively intense plasma, which can lead to an excessively strong thermal effect, in particular to thermal damage to tissue.

Preferably, the system comprises a device for regulating the output power, such as the output useful power or the output apparent power of the high-frequency device, to a desired value, wherein the plasma according to the invention is preferably created with the output power regulation activated.

The device for regulating the output power can be designed, for example, to correct the voltage amplitude in such a way that the required value of the output power of the high-frequency device can be achieved.

In the case of medium frequency and low frequency modulation, the low frequency pulse train preferably has one or more medium frequency pulses followed by interpulse pauses. The medium frequency pulse train preferably has one or more high frequency oscillation periods followed by pauses. In particular, at low and medium output powers, the low frequency pulse trains are so short that power regulation by known control strategies (voltage regulation) is not possible. Without taking corrective measures, the power supplied to the tissue in this case depends on the voltage at which the plasma is ignited. This ignition voltage depends on external conditions, such as the distance from the tissue, the properties of the electrode or the plasma-forming gas used (e.g. helium or argon). For many applications, the effect of this coupling does not necessarily lead to a clinically noticeable difference in the effects on the tissue. However, a distance-independent effect on the tissue should be particularly advantageous, especially in the treatment of CIN lesions. Preferably, therefore, alternatively or additionally to the correction of the peak voltage, a correction is applied by pulsation (modulation) of the output voltage. The output power can be changed, for example, by influencing the modulation of the middle frequency and/or low frequency for regulating the output power and/or by changing the length of the low frequency pulse packets.

Therefore, the device can be designed to control the output power during plasma generation by either peak voltage correction or modulation correction, or both.

The modulation change, as is preferably provided by the invention instead of the correction of the peak voltage for the correction of the output power, may affect the low frequency and/or the middle frequency. The output power may be subject to registration continuously or at regular or irregular intervals. Advantageously, it is registered at the end of the low frequency pulse packet and compared with the desired value. Depending on the deviation from the desired value, the pulse length and/or the period of the middle frequency and/or the low frequency may be changed in such a way that the output power approaches the desired value.

The desired value of the average useful output power of the high-frequency device can be, for example, a maximum of 3.5 W, particularly preferably a maximum of 2.5 W, most preferably a maximum of 2 W, even more preferably 1 W or less. If the desired value of the average useful output power is, for example, a maximum of 2 W, the desired value actually selected can be, for example, 2 W or less, for example 1 W. The power data can relate, for example, to an averaging over a period of low frequency. Alternatively, the power data can relate, for example, to an averaging over the duration of a low frequency pulse. Or the power data can relate, for example, to an averaging over at least one or more pulses or periods of the average frequency. The desired value is preferably smaller than the maximum high-frequency useful output power that can be supplied by the high-frequency device.

Other advantages and features of the plasma according to the invention, the systems according to the invention, the media, the chemical compounds and the method can be obtained from the following description, as well as the drawings. Also, when in the following presentation the plasma, the medium, the system, the method are indicated in the singular, the optional features and advantages of all aspects, from the first aspect to the tenth aspect of the invention, are always included, except for cases where something else follows from the relationship. Shown in:

Fig. 1A - schematic view of the system with a monopolar instrument and a neutral electrode,

Fig. 1B is an alternative system with a plasma generating tool according to the invention in accordance with the jet principle,

Fig. 2 - spin densities achieved by treatment with a system with a monopolar instrument with a neutral electrode or with a system with an instrument operating according to the jet principle,

Fig. 3, 4 are schematic representations of the use of plasma created by means of the system according to the invention,

Fig. 5 - surface temperature of the hydrogel sample tissue during the introduction of argon plasma at atmospheric pressure with different introduction rates,

Fig. 6 - average absolute cell counts after 24, 72 and 120 hours of athermal application of argon plasma at atmospheric pressure to cervical cancer cell lines in a test tube with different dosages from 0 seconds to 120 seconds,

Fig. 7 is a schematic representation for illustrating high-frequency generators of systems according to the invention, for example for the system according to Fig. 1A or Fig. 1B, preferably with a device for regulating the output power of the high-frequency generator,

Fig. 8A, Fig. 8B schematic representation of the sequence of pulses of the high-frequency output voltage of the high-frequency generator according to Fig. 7.

Fig. 1A shows an example of an embodiment of a system 10 according to the invention. The system 10 has a high-frequency device 11, a neutral electrode 12, a gas supply device 13 and a medical instrument 14 with an electrode 15, in particular a metal electrode. The electrode 15 can consist, for example, of stainless steel, tungsten or another electrically conductive material. Embodiments are possible in which the electrode 15 has at least one metal surface on a non-metallic core. The electrode 15 can have, in particular, the form of a wire, a plate or a spatula. The distal end 17a of the electrode 15 can be designed, for example, rounded, in the form of a cylinder or can be provided with a tip. The electrode can be represented, in particular, by a stainless steel plate with a tip at the distal end. The electrode 15 of the instrument 14 is preferably free of a dielectric coating. In any case, however, the distal end 17a of the electrode 15 is free of a dielectric coating. Furthermore, preferably, the distal end 17a of the electrode 15, as well as the electrode shank 17b connected thereto, at least the section of the electrode shank 17b adjacent to the electrode 15 at the distal end 17a, are free of a dielectric coating. Preferably, not only the distal end 17a of the electrode 15, but also the section of the electrode shank 17b connected thereto are free of a dielectric sheath. The system 10 does not operate according to the dielectric barrier discharge (DBD) principle. The high-frequency device 11 is connected to the tool 14 for supplying the electrode 15 with electrical power. The instrument 14 has a gas channel 16 along which an electrode 15 extends. The distal end 17a of the electrode 15 can be positioned within the gas channel 16 (as shown), the electrode 15 can be closed by the gas channel 16 or the electrode 15 can protrude from the gas channel 16. The inner diameter of the distal end of the gas channel 16 is preferably from 0.5 mm inclusive to 10 mm inclusive, particularly preferably from 0.8 mm to 3 mm, for example 2.4 mm. The gas supply device 13 is fluidly connected to the gas channel 16 for supplying the gas channel 16 with a gas, preferably an inert gas, particularly preferably a noble gas, for example argon. The system 10 includes a flat neutral electrode 12, which is electrically conductively connected over a large area to the body 18 of the patient, which is shown in this case in a highly simplified form. The instrument 14 can be represented by such an instrument 14, which can also be used for argon plasma coagulation.

By loading the instrument 14 with a high-frequency voltage using the high-frequency device 11, a physical plasma 19 is ignited between the electrode 15 and the body 18 of the patient. The surface of the electrode 15 has a galvanic contact with the plasma 19. The electric circuit from the electrode 15 is closed back by means of the neutral electrode 12 to the high-frequency device 11 through the plasma 19 and through the body 18 of the patient. In this case, electrons from the electrode 15 in the instrument 14 exit into the conductive plasma 19 and vice versa. The plasma 19 has a galvanic contact with the body 18 of the patient. Therefore, the conductive body 18 of the patient can be understood as the second electrode of the system 10, which has a galvanic contact with the plasma 19 at the treated location 21 on the tissue. In the system 10 according to Fig. 1A, respectively, in use, two electrodes 15, 21 have galvanic contact with the plasma. The distance from the first electrode 15 to the tissue 21 is, without additional measures, variable and depends on the direction of the instrument 14 by the user. The plasma 19 serves as a "line section" for the electric current from the electrode 15 to the body 18 of the patient. The body 18 of the patient is another line section for the electric current between the plasma 19 and the neutral electrode 12. A gas jet 20 supplied by means of a gas supply device 13, which is at least partially converted to a plasma state, at least partially displaces air or another atmosphere-forming gas (for example, pure nitrogen) or a gas mixture from the location between the electrode 15 and the location on the tissue. The system 10 according to Fig. 1A is an example of a system 10 in which the direction of passage of the electric current coincides with the direction of flow of the plasma to the tissue 21.

Fig. 1B shows an example of another embodiment of the system 10 according to the invention. This embodiment of the system 10 does not operate on the principle of a dielectric discharge either. The system 10 operates in accordance with the jet principle. The system 10 has a high-frequency device 11, a gas supply device 13, a medical instrument 14 with a first electrode 15 and with a ring-shaped second electrode 22. The high-frequency device 11 is connected to the instrument 14 for supplying the first electrode 15 with electric voltage. The instrument 14 has a capillary 23 made of an electrically insulating material, along which the first electrode 15 extends. The second electrode 22 covers the end of the capillary 23. The tip 17a of the electrode of the first electrode 15 is located within the capillary 23. The first electrode 15 and the second electrode 22 are located at a constant distance from each other. The first electrode 15 and the second electrode 22 are not located directly opposite each other, but between the first electrode 15 and the second electrode 22 an insulating material of the capillary 23 is placed. The gas supply device 13 is flow-connected to the capillary 23 for feeding the capillary 23 with a gas, preferably an inert gas, particularly preferably a noble gas, for example argon. In the embodiment of the system 10 according to Fig. 1B, the neutral electrode 12 is not provided. On the contrary, when the plasma 19 is ignited, the electric circuit between the first electrode 15 and the second electrode 22 is closed through the plasma 19. Due to the galvanic contact between the first electrode 15 and the plasma 19, electrons from the first electrode 15 can enter the plasma 19 and vice versa. Due to the electrically insulating capillary 23 between the first electrode 15 and the second electrode 22, the second electrode 22 does not have a galvanic contact with the plasma 19. The plasma 19 can be blown out by a gas jet 20 continuously supplied through the capillary from the capillary 23 to the treated location 21 on the tissue. In addition, the gas jet or the plasma jet displaces, at least partially, air or another atmosphere-forming gas (for example, pure nitrogen) or a gas mixture from the place between the electrode and the location on the tissue.

With the help of the plasma 19 created by the system 10 according to the first embodiment (Fig. 1A) and with the help of the plasma 19 created by the system 10 according to the second embodiment (Fig. 1B), therapeutically effective chemical compounds 25 (atoms, molecules, ions), in particular neutral or charged radicals, are produced at the location 21 on the tissue and/or they are introduced into the location 21 on the tissue. In particular, the plasma 19 created by the system 10 according to the first embodiment (Fig. 1A) ensures a particularly high density of neutral and charged chemical compounds 25, for example reactive chemical compounds of oxygen and/or reactive chemical compounds of nitrogen in the plasma 19 and/or in the treated location 21 on the tissue. The location 21 on the tissue activated in this way forms an environment activated by the plasma, whereby the activation leads to the death of, for example, neoplasms.

The embodiments of the instruments 14 described in connection with Fig. 1 and 2 can have a more slender design compared to instruments 14 that operate according to the dielectric barrier discharge principle. This is true above all for the embodiment described in connection with Fig. 1A, since for it only one electrode 15 on the instrument 14 has to be provided. Also, the instruments 14, as described in connection with Fig. 1 and 2, can be directed over the tissue 21 with a large distance to the distal end 28 of the instrument, which makes it easier to manipulate them. The embodiments explained in connection with Fig. 1A differ from the embodiments explained in connection with Fig. 1B in that in at least one plasma channel 19 between the first electrode 15 and the location 21 on the tissue of the body connected to the neutral electrode 12, new radicals are constantly formed in the vicinity of the tissue. This makes it possible for particularly short-lived radical chemical compounds to also reach the tissue 21. In the instruments 15, as explained in connection with Fig. 1B, the generation of plasma, on the contrary, takes place further away from the location 21 on the tissue, and the plasma 19 only has to be blown out of the instrument 15. As an advantage of the plasma 19 created by means of the system 10 according to the embodiments as described in connection with Fig. 1A, in the treatment of the diseases described in the present document or in the production of activated media for the treatment of the diseases described in the present document, compared to the systems 10 according to the embodiments as described in connection with Fig. 1B, it should be noted the higher number of radicals formed after the same duration of action of the plasma 19 on human or animal tissue, in particular epithelium, or another endogenous or foreign environment. The increased number of radicals formed with the same duration of action of the plasma 19 and the same distance between the distal end 28 of the instrument and the surface 21 to be treated can be confirmed, for example, by detecting the spin density in the treated samples of the same volume by measuring the electron paramagnetic resonance (ESR), by means of which a measure for the number of radicals in the samples can be obtained. As samples, samples of human or animal tissue or solutions with materials known as spin traps can be considered, for example. The solution can be formed, for example, from 0.1 mol of DMPO (5,5-dimethyl-1-pyrrolidine-M-oxide), as an example of a spin trap, in degassed DPBS (composition see below). The tissue samples and/or the solution can be placed during the treatment with the monopolar instrument 14 of the embodiment of the system 10 according to Fig. 1, for example, on the neutral electrode 12, or the neutral electrode 12 can be electrically conductively connected to the container or carrier for the samples. Fig. 2 shows the spin densities in the tissue samples detected after the treatment of preputial tissue samples for 10 seconds (flat dark stripes) and 30 seconds (stripes of horizontal lines placed one above the other) of the treatment duration when using the device parameter "preciseAPC" (pulse mode with a pulse repetition rate of 10 ms, respectively, 100 Hz low frequency and 20 kHz medium frequency), at an exposure level of 1, 1.6 l/min of argon. Exposure level 1 means that when loading a nominal resistance of 1000 ohms by connecting it to the potential of the electrode 15 of the instrument and to the potential of the neutral electrode 12, the average effective power is a maximum of 2 W. With a longer treatment duration (compare a treatment duration of 30 sec with a treatment duration of 10 sec), the achieved spin density decreases again. The error bar shows the standard deviation. The APC3/VIO3 system used is an example of an embodiment of the system 10 explained in connection with Fig. 1A. The kINPen MED system used is an example of an embodiment of the system 10 explained in connection with Fig. 1B. The functional diagram of the plasma generation in this device is represented by a quartz capillary with an internal diameter of 1.6 mm in the inner part of the hand-held device, in which a radiofrequency electrode in the form of a pin with an external diameter of 1 mm is centrally placed and to which a high-frequency voltage (1.1 MHz, 2-6 kV voltage peak-to-peak) is constantly applied, which ionizes the flowing gas, with a gas flow rate of 4.1 l/min used for the comparative test. The distance to the test medium is constantly 7 mm. As shown in Fig. 2, a higher spin density can be recorded in a tissue sample after treatment with the APC3/VIO3 system than after treatment of a comparable tissue sample with the kINPen MED system. The effectiveness of plasma 19 in treating one or more of the diseases described herein is based on the radical chemical compounds created in or introduced into the tissue by the plasma.

Fig. 3 illustrates the use of the plasma 19 according to the invention for the prevention of cervical intraepithelial neoplasms, in particular by means of antiviral therapy, for example against the human papilloma virus, the treatment of intraepithelial neoplasms of all degrees of severity, for example carcinoma at the lesion site, and/or the treatment of invasive epithelial-accessible carcinomas in humans using the plasma 19 generated by the system 10 according to the first embodiment or the system 10 according to the second embodiment (Figs. 1, 2). The neutral electrode 12 (not shown in Fig. 3) must have a large-area contact with the body 18 of the patient in a suitable place during treatment using the system according to Fig. 1A. The instrument 14 is inserted through the vagina 26 to the cervix 27 or into it, and the plasma 19 is ignited. As illustrated in Fig. 4, the plasma 19 covers the treated location 21 on the tissue by, for example, manually created movements (indicated by means of an arrow 29) of the tip 28 of the instrument (the distal end of the instrument), preferably with a minimum insertion speed, for example 10 mm/sec. The insertion speed is a component of the speed of the tip 28 of the instrument parallel to the surface of the location 21 on the tissue. Despite the production of warm plasma, preferably, no thermal damage to the surface of the location 21 on the tissue, especially its coagulation, occurs due to the movement. Therefore, the preferred use of the plasma 19 is referred to as athermal insertion. In order to be able to operate with a manually achievable and controlled application speed, preferably a maximum of 50 mm/sec or less, in such a way that the temperature of the tissue at the location 21 on the tissue which is covered by the plasma can be maintained lower than or equal to a limit temperature, for example 40°C, particularly preferably lower than or equal to 37°C, or in such a way that thermal damage to the tissue, especially coagulation as a result of the plasma treatment, can be prevented, the plasma 19a preferably has a temperature lower than or equal to a limit temperature, wherein the limit temperature can be, for example, 150°C or 120°C.

The gas flow rate (plasma-forming gas), for example argon, serves to create a suitable, if possible, specified mixed atmosphere between the distal tip of the instrument and the tissue in such a way that the ignition of the plasma 19 becomes possible. If the gas flow rate is too low, too little plasma-forming gas is located between the electrode 15 and the tissue 21. The minimum gas flow rate is the smallest gas flow rate flowing through the instrument 14 that ensures the ignition of the plasma 19. If the gas flow rate is too high, due to turbulence, excessive admixture of air or other gases or media from the environment occurs, making the ignition of the plasma 19 impossible. The maximum gas flow rate is the largest gas flow rate flowing through the instrument 14 that ensures the ignition of the plasma 19. An atmosphere consisting exclusively of plasma-forming gas can presumably hinder the formation of therapeutically effective chemical compounds. Therefore, the selected gas flow rate (plasma-forming gas), for example argon, for creating the plasma 19 is preferably located in the range between the minimum gas flow rate and the maximum gas flow rate. The selected gas flow rate flowing through the instrument 14 can be as large, for example at least as the minimum gas flow rate, but can be smaller than the maximum gas flow rate. The gas flow rate of the plasma-forming gas is preferably selected in the range from and including the minimum gas flow rate up to and including a gas flow rate that exceeds, for example, three times the minimum gas flow rate. The minimum gas flow rate as well as the maximum gas flow rate can depend on several parameters and/or settings. The minimum gas flow rate can depend above all on the required treatment distance between the instrument tip and the tissue surface. For treatment, for example, a treatment distance between the instrument tip and the tissue surface can be specified (for example 7 mm), and on the basis of the specified treatment distance, the gas flow rate appropriate for flowing through the instrument can be selected. With an internal diameter of the gas channel at the distal end of 2.4 mm, the gas flow rate can be, for example, preferably in the range from 1 l/min inclusive to 3 l/min inclusive, particularly preferably from 1.3 l/min inclusive to 2.5 l/min inclusive, for example 1.6 l/min.±20%. With a smaller internal diameter, it can be advantageous, with the same other parameters and settings, to have a lower gas flow rate, with a larger internal diameter, with the same other parameters and settings, to have a higher gas flow rate.

The invention is illustrated in Fig. 3 using the example of treating a cervical intraepithelial neoplasm of a patient by a transvaginal method. In general, for treating intraepithelial neoplasms of various organ systems of mammals, the introduction can be carried out by transvaginal, oral, parenteral, laparoscopic, intranasal, intrabronchial and rectal methods or by means of media or materials (medicines) activated by means of plasma 19 according to the invention. When plasma 19 is used to obtain an activated foreign or endogenous medium 21, plasma 19 can thus be indirectly used to treat, in particular, one or more of the diseases indicated in this description. When obtaining, in particular, an activated foreign medium, the neutral electrode 12 can be formed by a carrier or container (not shown) of the medium, when the obtaining is created by means of the system 10 according to the embodiments, as they are explained by means of Fig. 1A. Athermal introduction of argon plasma 19 at atmospheric pressure is suitable for the treatment of cervical intraepithelial neoplasms of various pathogenesis and for the prevention of invasive carcinomas. Intraepithelial neoplasms include, but are not limited to, intraepithelial neoplasms of various organ systems of mammals, such as, for example, the cervix, internal os of the uterus, esophagus, stomach, colon, rectum and peritoneum. The spectrum of application of plasma 19 according to the invention also includes preventive measures for the prevention of cervical and other intraepithelial neoplasms, carcinomas at the site of injury (CIS) and invasive carcinomas of various pathogenesis in mammals predisposed to the corresponding diseases. The treatment includes alleviation of the disease, arrest or delay of its development, induction of remission of cervical and other intraepithelial neoplasms, CIS lesions and invasive carcinomas of various pathogenesis in mammals predisposed to the corresponding diseases. Combinations with other methods are possible and are useful for the prevention or treatment of cervical and other intraepithelial neoplasms, CIS lesions and invasive carcinomas of various pathogenesis.

The proof of the effect of athermal introduction of plasma 19 at atmospheric pressure, especially argon plasma for the treatment of intraepithelial neoplasms, is based on standardized and controlled studies outside the body, in vitro and in a living organism, the implementation of which and the results achieved are described in the following presentation. For the athermal introduction of argon plasma 19 at atmospheric pressure, a VIO3/APC3 generator (ERBE Elektromedizin, Tübingen), a high-frequency device model 11 and a gas supply device 13 were used respectively. The high-frequency device 11 generates an alternating voltage with a frequency of 350 kHz. A FiAPC probe (ERBE Elektromedizin, Tübingen) with an outer diameter of 3.2 mm and an inner diameter of the distal end of the gas channel 16 of 2.4 mm was used as a sample instrument 14. The probe has a stainless steel plate with a tip at the distal end as an electrode. The following parameters were used: preciseAPC (pulse mode with a pulse repetition rate of 10 ms, respectively, 100 Hz low frequency and 20 kHz medium frequency), exposure level 1, 1.6 l/min argon. Exposure level 1 means that when loading a nominal resistance of 1000 ohms by connecting it to the potential of the electrode 15 of the instrument and to the potential of the neutral electrode 12, the average effective power is a maximum of 2 W.

The nature of the temperature change upon introduction of argon plasma 19 at atmospheric pressure was tested in vitro. The effect on neoplastic cells based on cervical carcinoma cell lines was tested in vitro. The effect on cervical intraepithelial neoplasms of grades I and II was tested in vivo.

The possibility of athermal introduction of argon plasma 19 at atmospheric pressure is based on studies of tissues outside the body using standard infrared thermography. In this case, hydrogel samples were subjected to treatment with argon plasma at atmospheric pressure at different introduction rates. At introduction rates of more than 10 mm/sec, on average stable and non-critical tissue temperatures of less than 37°C were obtained. Fig. 5 shows the surface temperature of the hydrogel tissue during the introduction of argon plasma 19 at atmospheric pressure at different introduction rates outside the body. The results are presented as individual measurement points (small dark dots) and the average absolute temperature (large light dots). A distance of 7 mm between the tip of the instrument and the surface of the tissue sample was maintained constant. The tip of the instrument was directed perpendicular to the surface of the hydrogel samples during the measurements. In order to be able to perform representative thermographic test measurements for the treatment on the surface of human or animal tissue, hydrogel specimens were prepared from 12.5% stock solution of gelatin type B and Dulbecco's phosphate-buffered saline (DPBS ⁺ ). DPBS ⁺ is a water-based saline solution. It is isotonic in that its ion concentration corresponds to that of the human body. This solution has a pH value between 7.0 and 7.3. To prepare the hydrogel specimens, the stock solution was chemically cured with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and placed in a polylactide mold (70×20×5mm) in a shaker at 37°C and 100 rpm for 2 hours. After a washing process with pure DPBS ^+, the hydrogel specimens were provided for use in the test measurements.

The results of standard infrared thermography show the possibility of athermal introduction of argon plasma 19 at atmospheric pressure according to the invention with a tissue temperature of <37°C when using the described devices and installations with an introduction rate of ≥10 mm/sec.

The efficacy of the athermal application of argon plasma 19 at atmospheric pressure according to the invention on the cervical carcinoma cell line (SiHa) was investigated in vitro. By means of standard cell counts using a CASY cell counter and analyzer (Roche), the results were obtained after the athermal application of argon plasma 19 at atmospheric pressure according to the invention at application rates of ≥10 mm/sec and at different dosages from 0 seconds to 120 seconds and after several incubation periods from 24 hours to 120 hours. Plasma treatment was performed in standard Dulbecco's modified Eagle's medium (DMEM) with 10% fetal calf serum and 1% penicillin/streptomycin. Incubation was performed in a humidified atmosphere (37°C, 5% CO ₂ , pH 7.4).

Fig. 6 shows the results of athermal application of argon plasma 19 at atmospheric pressure to cervical carcinoma cell lines in vitro. The mean absolute cell counts of N=6 independently performed measurements at 24, 72 and 120 hours are presented. Error bars show +/- standard deviation.

The results of in vitro standard cell counts using a CASY cell counter and analyzer (Roche) after athermal introduction of argon plasma 19 at atmospheric pressure according to the invention at introduction rates of ≥10 mm/sec and at different dosages from 0 seconds to 120 seconds showed a dose-dependent and dose-proportional suppression of the proliferation of cervical carcinoma cell lines (SiHa cells) within incubation periods from 24 hours to 120 hours.

The effectiveness of the athermal application of argon plasma 19 at atmospheric pressure according to the invention on CIN grades I and II was examined in a living organism. The ability of the athermal application of argon plasma 19 at atmospheric pressure according to the invention in histologically confirmed CIN grade I/grade II to bring about remission was analyzed by means of standard cytological examinations (Pap cytology) after 2 weeks, 3 months and 6 months, as well as histological examinations (interpretation of external results by the Institute of Pathology, Tübingen) after 3 and 6 months. The method is briefly described below. Patients with histologically confirmed CIN grade I or grade II were subjected to a clinical colposcopic examination with an acetic iodine test to visualize the lesion before the athermal treatment with argon plasma 19 at atmospheric pressure according to the invention. Then, under colposcopic observation, a single athermal application of argon plasma 19 was performed at atmospheric pressure with application rates of ≥10 mm/sec and, depending on the extent of the lesion, with a minimum dosage of ≥4 immediately following application cycles lasting 30 seconds, respectively. The following parameters were selected as the device settings: preciseAPC, exposure level 1, 1.6 l/min argon. No local or general sedation or analgesia was used.

Patients >18 years of age with confirmed CIN grade I or grade II who were initially informed about the condition and possible therapeutic strategies were enrolled at the University Gynecological Clinic in Tübingen. The patients were recruited prospectively and non-randomized. The inclusion criteria for plasma treatment were: age >18 years, histologically confirmed CIN grade I or grade II, reliably assessable transformation zones of the vaginal part of the cervix and lesion margins, written informed consent for participation in the study. The exclusion criteria for plasma treatment were: histologically confirmed CIN grade III, incompletely visible transformation zone, evidence of invasive disease, missing expected consent of the patient or inability of the patient to understand the meaning and purpose of the clinical trial, serious cardiovascular diseases, preference for a classical therapeutic option, missing consent of the patient. The primary endpoint was histological complete remission of CIN grade I or grade II. The secondary endpoint was histological partial remission of CIN grade I or grade II, reduction in HPV viral load, pain reduction and improvement in quality of life, tissue tolerance and tolerability of plasma treatment.

The following table shows the histological results obtained.

These results show that athermal application of argon plasma 19 at atmospheric pressure with application rates of ≥10 mm/sec and with dosages of ≥4 consecutive application cycles of 30 sec duration, respectively, is associated with a remission rate of 82% for CIN I and II grade lesions within 3 months. After 6 months, 93% of the treated lesions are stable and subsequently histologically undetectable. For example, average spontaneous remission rates of 40 to 50% have been described in the literature for CIN II. In comparison, the remission rates after athermal application of argon plasma 19 at atmospheric pressure are significantly higher.

The following table shows the virological results that were achieved using the system and the settings indicated.

These results show that athermal application of argon plasma 19 at atmospheric pressure with application rates ≥10 mm/sec and with doses ≥4 consecutive application cycles of 30 sec duration, respectively, is associated with a remission rate for a positive test result for risky HPV of about 60% within 6 months.

Results from standard in vitro and in vivo studies indicate that athermal application of argon plasma 19 at atmospheric pressure is a useful treatment modality, primarily for CIN lesions.

Fig. 7 illustrates a high-frequency device 11 that can be used in a system 10 according to the invention, for example according to Figs. 1A and 1B. The high-frequency device 11 has a high-frequency generator 30, a control device 31, a modulation device 32 and a network power supply unit 33. The system 10 can have a first detection device 34 for detecting a voltage, a second detection device 35 for detecting a current, a signal evaluation device 36 and a comparing device 37. In addition, a total load resistance 38 is illustrated, which, in the case of the system 10 according to Fig. 1A, includes the impedance of the plasma 19 and the body 18 between the plasma 19 and the neutral electrode 12, and in the case of the system 10 according to Fig. 1B, the impedance of the plasma 19.

The high-frequency generator 30 is designed to generate a high-frequency voltage, which may have a high frequency, for example at least 100 kHz, preferably from 200 kHz inclusive to 16 MHz inclusive, particularly preferably from 300 kHz to 500 kHz, for example 350 kHz.

Fig. 8A schematically and as an example shows the modulated alternating output voltage U of high frequency from the high frequency generator 30 during the process in time. Fig. 8B shows a fragment from Fig. 8A.

The alternating voltage U is modulated by means of the modulation device 32, preferably with a medium frequency (MF) and/or with a low frequency (NF). The medium frequency can be, for example, from 5 kHz inclusive to 100 kHz inclusive, particularly preferably from 10 kHz inclusive to 50 kHz inclusive, for example 20 kHz. The pulse length TPulsMF of the medium frequency pulses 40 preferably comprises at least one or more high frequency periods.

The low frequency is, for example, from 0.5 Hz inclusive to 200 Hz inclusive, preferably from 20 Hz inclusive to 150 Hz inclusive, in particular 100 Hz. The pulse length TPulsNF of the pulse packets 41 of the low frequency is preferably at least one period MFP of the medium frequency. Preferably from one period of the medium frequency inclusive to 50 periods of the medium frequency, for example 20 periods of the medium frequency.

Modulation with a medium frequency and/or with a low frequency can be used, for example, with a predetermined minimum peak voltage, to reduce the output power compared to a non-pulsating alternating voltage. Modulation or pulsation with a low frequency leads to the extinction of the plasma 19 in the interpulse pauses of the low frequency PPNF and, thus, to the detachment of the plasma 19 from the location 21 on the tissue. Thus, the plasma 19, despite the longitudinal movement of the tip 28 of the instrument 14 parallel to the location 21 on the tissue at a distance from it, does not adhere to the location 21 on the tissue. On the contrary, the location 21 on the tissue to be treated can be uniformly covered (covered) by the plasma 19.

In the above-mentioned preciseAPC mode of the action level 1 of the high-frequency device APC3/VIO3 (example for the system according to Fig. 1A), which, for example, can be used for treating female patients, the middle frequency MF and the low frequency NF are pre-assigned constant (MF=20 kHz and NF=100 Hz) in such a way that, when operating with a constant nominal resistance without a plasma section, the intended average power can be obtained for the corresponding action level. The selection of the action level (from 1 to 10) in this case affects the constant length TPulsNF of each of the low-frequency pulses. When the user holds the tip 28 of the instrument adjacent to the location 21 on the tissue and activates the plasma generation, the high-frequency device 11, regardless of the action level, selects the initial voltage in such a way that the plasma 19 can be ignited. In the mentioned preciseAPC mode, for example with the action level 1 of the VIO3 system as an example for the system 10, it can be designed to increase at the beginning of the low-frequency pulse, which pulse can be represented in particular by a packet of several medium-frequency pulses, the peak output voltage of the high-frequency device 11 until either the upper limit is reached or the plasma is ignited. The upper limit is, for example, from 2 kW inclusive to 6 kV inclusive, preferably from 4 kV to 5 kV, for example 4.7 kV, for a system with VIO3, for example 4.7 kV. In addition, the system 10 is designed to reduce, upon ignition recognized by the system 10, the voltage of the network power supply unit 33 of the high-frequency device 11. In particular, the output voltage of the network power supply unit 33 can be set to a desired value, which is lower than the value required for ignition. This achieves a reduction in the peak output voltage of the high-frequency generator 30 in such a way that at the beginning of the next low-frequency pulse the peak voltage is less significant than at the moment of plasma ignition in the preceding low-frequency pulse packet. In this way, for the VI03 system, the creation of an excessively intense plasma can be prevented, which can lead to an excessively strong thermal effect, especially thermal damage to tissue.

However, the ignition voltage depends on the distance to the tissue 21 and, in addition, for example, on the properties of the electrode 15 (for example, its geometry and/or material), the gas used, the properties of the tissue and the environment. The dependence on the distance means that the average output power of the high-frequency device 11 at the same action level 1 depends on the distance from the tip 17a of the electrode to the tissue 21. For example, the average useful output power of the high-frequency device 11 can be for a given action level, for example action level 1, at a distance of 3 mm approximately 1.5 W, at a distance of 12 mm approximately 5 W. This places particularly high demands, in order to achieve a uniform action on the tissue, on the direction by the user of the tip 28 of the instrument over the tissue 21, if possible always at the same distance and at a constant speed. In this case, when moving over tissue 21, as a result of low-frequency modulation, re-ignition occurs at the beginning of each packet 41 of low-frequency pulses at potentially different distances from the tip 17a of the electrode to tissue 21.

Therefore, a system 10 according to the invention is proposed (it is also illustrated by means of Fig. 7), which comprises a device 42 for regulating the output power, for example the output useful power or the output apparent power of a high-frequency device. The system 10 can have a control device for reducing the peak output voltage, as presented above in connection with the commentary on the VIO3 system.

For this purpose, the device 42 has a device for detecting the output useful power. For example, the device can be designed to detect the output power of the network power supply unit 33 and, by means of a known efficiency of the high-frequency generator 30, to detect the output useful power of the high-frequency generator 30. Alternatively or additionally, the device 42, as illustrated in Fig. 7, can be designed to detect the output voltage of the high-frequency generator 30 by means of a first detection device 34 and to detect the output current of the high-frequency generator 30 by means of a second detection device 35. The device 42 can be designed to detect the output power of the high-frequency generator 30 based on the measured values of the first detection device 34 and the second detection device 35 by means of a signal evaluation device 36.

The detection of the output power and the correction of the modulation can be carried out both continuously and in regular or irregular time intervals. The output power can be detected, for example, by averaging the product of the phase-dependent voltage and current over one or more periods, for example one or more periods of the medium frequency and/or periods of the low frequency. The detection of the output power in this case is preferably carried out in the subsequent interpulse pause, in particular the interpulse pause PPNF of the low frequency or the interpulse pause PPMF of the medium frequency. The detection can be carried out, for example, as a rule, in the interpulse pauses PPNF of the low frequency. In particular, the output power over one or more periods of the medium frequency can be averaged until the end of the pulse packet of the low frequency, and in this way the average value of the output power can be detected as the actual value of the output power after the end of the pulse packet of the low frequency.

The device 42 can be designed to compare, using the comparing device 37, the detected output power (actual value), for example the output useful power, with the required value of the output power, for example the output useful power, and, if the actual value deviates from the required value, can be designed to implement, using the control device 31, one or more changes to bring the actual value closer to the required value.

Additionally or alternatively, in principle, it is possible for the purposes of regulation to change the limit value of the output voltage of the high-frequency generator 30 depending on the detected deviation of the actual value from the required value. However, this requires, in the case of very short pulse packets 41 of low frequency, a high, difficult to achieve regulation speed. In addition, a decrease in the peak voltage can lead to a significant deterioration in the ignition characteristics. Therefore, it is preferable for regulation to refrain from changing the limit value of the output voltage, and instead, to use a high-frequency modulation depending on the deviation of the actual value from the required value of the output power, in particular the output useful power. In principle, an alternative regulation is possible, in which both the limit value of the output voltage is changed in such a way that it is maintained above the lowest value, and, additionally or alternatively, the modulation is changed.

When regulating the power by means of modulation correction, in embodiments, the capture of the actual value of the output power in a packet of low frequency pulses and the correction of the modulation are so fast that it is possible to achieve the desired value of the output power within the same packet of pulses or within the first subsequent packet of low frequency pulses or at the beginning thereof. The change in modulation may include, first of all, low frequency modulation and/or middle frequency modulation. For example, the pulse duty cycle of the packets of low frequency pulses 41 may be changed by changing the pulse length TPulsNF, changing the pause length TPauseNF and/or changing the period of the low frequency. Alternatively or additionally, the pulse duty cycle of the pulses 40 middle frequency may be changed by changing the pulse length TPulsMF, changing the pause length TPauseMF and/or changing the period of the middle frequency.

By means of the system 10 with the device 42 for regulating the output power, for example the output useful power, the plasma 19 can be formed at a constant output power of the high-frequency generator, regardless of the ignition conditions, in particular the distance to the tissue 21, which significantly simplifies the guidance of the instrument 14 for effective athermal treatment, as shown, for example, in Figs. 3 and 4. The system 10 with the device 42 for regulating the output power or the plasma 19 created by them can advantageously be used, in particular, for the treatment of one or more of the above-mentioned diseases. In general, the system 10 with the power regulation described in connection with the device 42 can advantageously be used universally in cases where a reproducible effect on the tissue, regardless of the distance, is desired. By means of the power regulation, the effect on the tissue can be adjusted in a particularly fine manner. The field of application can be represented, for example, by athermic treatment of wounds, where thermal damage to the injured tissue must be prevented.

According to the invention, in particular, the plasma 19 can be created for the prevention of intraepithelial neoplasms, in particular by means of antiviral therapy, for example against the human papilloma virus, for the treatment of intraepithelial neoplasms of all degrees of severity, for example carcinoma at the site of injury, and/or for the treatment of invasive carcinomas accessible through the epithelium, wherein the plasma can be created using a system 10 for creating plasma 19, preferably argon plasma, having a medical instrument 14 with at least one electrode 15 with galvanic contact with the plasma 19, a high-frequency device 11 for providing alternating voltage for powering the instrument 14 with electrical power, and a gas supply device 13, which is designed to power the instrument 14 with gas, in particular argon.

List of reference designations:

10 system

11 high frequency device

12 neutral electrode

13 gas supply device

14 medical instrument

15 electrode, first electrode

16 gas channel

17a distal end of the electrode

17b electrode shank

18 body

19 plasma

20 gas flow

21 locations on fabric/environment

22 second electrode

23 capillary

25 chemical compounds

26 vagina

27 cervix

28 tool tip

29 arrow

30 high frequency generator

31 control device

32 modulation device

33 network power supply

34 first detection device

35 second detection device

36 signal evaluation device

37 Comparison Device

38 total load resistance

40 medium frequency pulse

41 low frequency pulse packets

42 device

TPulsMF medium frequency pulse length

TPulsNF low frequency pulse length

MFP medium frequency period

PPNF low frequency interpulse pause

PPMF interpulse pause of medium frequency

TPauseNF duration of low frequency pauses

TPauseMF duration of mid-frequency pauses

Claims (20)

1. A system (10) for creating a plasma (19) used for the prevention, treatment of intraepithelial neoplasms and/or treatment of epithelial accessible invasive carcinomas, comprising: - a medical instrument (14) for plasma exposure to patient tissue, having at least one electrode (15) located at the distal end of the instrument (14) with the possibility of galvanic contact with the plasma (19), - a high-frequency device (11) designed to supply the instrument (14) with alternating voltage having a high frequency of at least 100 kHz and modulated by pulses of medium frequency (MF) ranging from 5 kHz inclusive to 100 kHz inclusive, and by pulses of low frequency (NF) ranging from 0.5 Hz inclusive to 200 Hz inclusive, - a neutral electrode (12) placed on the patient's body (18) to close an electrical circuit passing from the high-frequency device (11) through the electrode (15) of the instrument (14), the plasma (19) and the patient's body (18), wherein the instrument (14) is designed with the possibility of igniting the plasma (19) between the electrode (15) and the patient's tissue (21), - a gas supply device (13), which is designed to supply the tool (14) with gas, - a device (42) for regulating the output power of the high-frequency device (11) to the required value. 2. The system (10) according to claim 1, intended for creating plasma (19) used for treating intraepithelial neoplasms of at least one of the following mammalian organ systems: the cervix, the internal os of the uterus, the esophagus, the stomach, the colon, the rectum, and the peritoneum. 3. The system (10) according to claim 1 or 2, intended for creating plasma (19) used for treating cervical intraepithelial neoplasms of grade I to III, for example grade I to II, especially grade II. 4. The system (10) according to one of the preceding claims, wherein the high frequency of the alternating voltage is from 200 kHz inclusive to 16 MHz inclusive, in particular from 300 to 500 kHz, for example 350 kHz. 5. A system (10) according to one of the preceding claims, wherein the mid-frequency (MF) is from 10 kHz inclusive to 50 kHz inclusive, for example 20 kHz. 6. The system (10) according to claim 5, wherein the length (TPulsMF) of the pulses (40) of the medium frequency (MF) is equal to at least one period of the high frequency. 7. The system (10) according to one of the preceding claims, wherein the low frequency (NF) is from 20 Hz inclusive to 150 Hz inclusive, in particular 100 Hz. 8. The system (10) according to claim 6 or 7, wherein the length (TPulsNF) of the low frequency pulses (NF) is equal to at least one period (MFP) of the average frequency, in particular it is from one inclusive to 50 inclusive periods (MFP) of the average frequency, for example 20 periods (MFP) of the average frequency. 9. The system (10) according to one of the preceding claims, wherein the gas supply device (13) is designed to supply the tool (14) with gas at a flow rate in the range from the minimum gas flow rate inclusively up to and including a gas flow rate that is three times greater than the minimum gas flow rate. 10. A system (10) according to one of the preceding paragraphs, intended for creating a conductive argon plasma (19), wherein the gas supply device (13) is designed to supply the tool (14) with argon, and the device (42) is designed to regulate the output useful power of the high-frequency device (11) to the required value. 11. The system (10) according to claim 10, wherein the device (42) is designed to regulate the output useful power by correcting the modulation at a medium frequency and/or at a low frequency. 12. The system (10) according to claim 10 or 11, wherein the required value of the output useful power of the high-frequency device is a maximum of 3.5 W, in particular a maximum of 2.5 W, preferably a maximum of 2 W, most preferably a maximum of 1 W. 13. A system (10) according to one of the preceding claims, intended to create a plasma (19) having a temperature greater than or equal to 45°C. 14. The system (10) according to one of the preceding claims, intended for the creation of plasma (19) used for the prevention of intraepithelial neoplasms by means of antiviral therapy, in particular against the human papillomavirus. 15. The system (10) according to one of the preceding claims, intended for the creation of plasma (19) used for the treatment of intraepithelial neoplasms of all degrees of severity, in particular carcinoma at the site of injury.