Measuring device for detecting biological and / or physical parameters with the aid of an applicator

Abstract

The invention describes a measuring device for detecting biological and / or physical parameters with the aid of an applicator. The measuring device comprises the applicator, which is configured to apply electromagnetic waves generated by a signal source to a biological material. The measuring device also comprises a detection unit, which is configured to detect the electromagnetic waves and electromagnetic waves returning to the applicator as a result of reflection at the biological material. The measuring device also comprises a processing unit, which is configured to determine the biological and / or physical parameters from at least one of the electromagnetic waves and the returning electromagnetic waves.

Description

Description Title: MEASURING DEVICE FOR THE DETECTION OF BIOLOGICAL AND / OR PHYSICAL PARAMETERS USING AN APPLICATOR Cross-reference to related applications

[0001] This application claims priority from German patent application No. 10 2022 134 363.4, filed on December 21, 2022. Technical field of the invention

[0002] The invention relates to a measuring device and a method for detecting biological and / or physical parameters with the aid of an applicator, as well as to a therapy system for exposing a biological material of a mammal to electromagnetic waves and to a therapy method for treating tumors. Background of the invention

[0003] In addition to the known thermal effects of high-frequency electromagnetic fields (EMF), electromagnetic waves, or electromagnetic radiation, it has been suspected for decades that EMFs can also trigger biological effects in biological material that are not caused by an increase in temperature in the respective biological material. Decades of research have been devoted to these so-called non-temperature-induced effects. A non-temperature-induced effect is considered proven if, under otherwise identical conditions, EMFs cause a greater cytotoxic effect on cells than water bath hyperthermia at the same or higher temperature. Constant and homogeneous temperatures in the biological material are essential for the experimental verification of non-temperature-induced effects. Temperature inhomogeneities such as local temperature peaks, so-called hot spots, must be experimentally excluded.

[0004] Meanwhile, experimental evidence of the existence of non-temperature-induced effects at temperatures of 40-42°C on cell suspensions and experimental tumors using the commercial system LabEHY-200 A novel applicator allowed separate adjustment of the EMF level and temperature of the biological material using all-round water flow cooling.

[0005] The studies showed that a harmonic radiofrequency or EMF carrier frequency of 13.56 MHz can achieve greater cytotoxicity in several tumor cell lines, including the biological endpoints of clonogenicity or apoptosis. Physical measurements suggested that this higher biological efficacy is associated with a 20% higher energy absorption in the cells compared to the medium alone.

[0006] The additional application of EMF amplitude modulation further demonstrated increased cytotoxic effects. More detailed studies using constant amplitude modulation parameters showed a significant increase in apoptosis in one type of tumor cell, whereas no increased cytotoxic effects were observed in other tumor cell types. It is suspected that by altering the amplitude modulation parameters, increased apoptosis rates can also be achieved in other tumor cells. This suggests that, depending on the type of tumor cell, increased cytotoxic effects can be achieved with different EMF amplitude modulation parameters.

[0007] Furthermore, differences in cell membrane stiffness and Young's modulus have been demonstrated between tumor cells and healthy cells (Wust, P.; Veltsista, PD; Oberacker, E.; Yavvari, P.; Walther, W.; Bengtsson, O.; Sterner-Kock, A.; Weinhart, M.; Heyd, F.; Grabowski, P.; Stintzing, S.; Heinrich, W.; Stein, U.; Ghadjar, P. Radiofrequency Electromagnetic Fields Cause Non-Temperature-Induced Physical and Biological Effects in Cancer Cells. Cancers 2022, 14, 5349.). This leads to different mechanical resonance frequencies of the tumor cell walls. Depending on the resonance frequency of the cell walls, a suitable modulation frequency or frequency for the amplitude modulation of the EMF results, with which increased cytotoxic effects can be achieved.

[0008] The EMF carrier frequency most suitable for increasing cytotoxic effects is currently unknown. The carrier frequency of 13.56 MHz is an approved frequency chosen primarily for practical reasons. The experimentally confirmed non-temperature-induced effects were explained by processes in ion channels and protein interactions (delta dispersion). Dispersion leads to an increase in the dielectric constant s r to several hundred compared to the clinically used EMF frequencies in hyperthermia of 70-100 MHz (so-called Annul ar-Phased-Array technique). Here, s r about 80 and corresponds to the s rof the extracellular space. Interactions with cell components presumably no longer occur in the frequency range above 70 MHz. It is rather unlikely that the carrier frequency of 13.56 MHz leads to the highest non-temperature-induced effects. A further reduction of the carrier frequency down to the MHz range would lead to r of several thousand, which increases interactions with the cell membrane.

[0009] In general, the cell membranes of tumor cells exhibit a lower Young's modulus than normal tissue cells. Furthermore, the Young's modulus of tumor cell membranes appears to be lower the more aggressive they are. Furthermore, a correlation is observed between the Young's modulus of tumor cells and their temperature. The Young's modulus, especially in tumor cells, exhibits an unusually high dependence on temperature, dropping to just a few hundred Pa at 41°C.

[0010] The detection of non-temperature-induced effects enhanced by EMF amplitude modulation raises fundamental questions about the influence of the EMF carrier frequency, the temperature, and the amplitude modulation parameters on the severity of the non-temperature-induced effects.

[0011] The previously described study results suggest that the most suitable frequency of amplitude modulation for achieving an additive (non-temperature-induced) cytotoxic effect differs for different tumor cell types and tumors. However, the temperature of the biological material appears to be an important covariate, as suggested by the strong temperature dependence of the Young's modulus of cell membranes. It is therefore assumed that, for different tumor cells, increased cytotoxic effects can be achieved with a suitable combination of EMF carrier frequency, EMF power, and EMF amplitude modulation parameters. The set or achieved temperature of the biological material appears to be another important variable.

[0012] Investigations in this four-dimensional parameter space (carrier frequency, power, parameters of amplitude modulation (modulation frequency and modulation index), temperature of the biological material) to determine the Determining parameters suitable for specific tumor cells, possibly with subsequent treatment of patients using the determined appropriate parameters, is not possible with the available technology. The current technical limitations regarding variation of these parameters are significant and, even in the limited ranges, time-consuming.

[0013] German patent application DE 10 2006 043984 A1 describes a detachable electrode coupled to an electric field for energy transfer and its use with a hyperthermia device having an electric field. The detachable electrode enables simple and effective connection and detachment of the electrode from a hyperthermia device having an electric field.

[0014] The publication Wust, P.; Veltsista, PD; Oberacker, E.; Yavvari, P.; Walther, W.; Bengtsson, O.; Sterner-Kock, A.; Weinhart, M.; Heyd, F.; Grabowski, P.; Stintzing, S.; Heinrich, W.; Stein, LT.; Ghadjar, P. "Radiofrequency Electromagnetic Fields Cause Non-Temperature-Induced Physical and Biological Effects in Cancer Cells." Cancers 2022, 14, 5349 describes non-temperature-induced effects in cancer cells when treated with electromagnetic fields. These non-temperature-induced effects can be enhanced by amplitude modulation.

[0015] The publications Wust P., Stein LT., Ghadjar P., "Non-thermal membrane effects of electromagnetic fields and therapeutic applications in oncology." Int J Hyperthermia 2021, 38(1), 715-731, and Wust P., Kortüm B., Strauss U., et al., "Non-thermal effects of radiofrequency electromagnetic fields." Scientific Rep 2020, 10: 13488, describe membrane effects of EMF on cell membranes / ion channels, which are differentially expressed in cancer cells and healthy cells (channelome). Non-temperature-induced effects are described, and an explanatory model based on ion channels in the cell membrane is developed. Healthy cells and cancer cells have different ion channel expressions (channelome). This also leads to a different resting membrane potential. Based on this and the previously described differences in the Young's modulus, the assumption is that the proposed therapy according to the present invention has the potential to treat cancer cells in a "cancer cell-specific" manner.

[0016] The European patent application EP 0 430 340 A2 describes a non-invasive oximeter arrangement with a clamp-like sensor for, for example, a finger, a Self-calibrating control unit for detecting and processing two electromagnetic waves of a predetermined wavelength and an intermediate transmission path for use in strongly electromagnetically influenced environments, while simultaneously eliminating sources of interference and errors, such as movement errors, coupling factors of the sensor on the finger, etc. The control unit also has a transmitter (LED), a receiver, and a computing unit for determining the oxygen content of the blood from the relative magnitude of the pulse-dependent modulation degree of the electromagnetic waves reflected from the finger, which have previously been differently coded and correspond to the spectral windows of the transmission path. A first electromagnetic wave of 660 nm and a second wavelength of approximately 780 nm to approximately 850 nm are used.The two electromagnetic waves received by the receiver are each electromagnetic waves reflected by the finger, each of which was emitted separately by the transmitter. Summary of the invention

[0017] The electromagnetic fields (EMF) or electromagnetic waves or electromagnetic radiation are generated by means of an electrical oscillating circuit or LC oscillating circuit or resonant circuit, which, in addition to at least one inductance such as a coil, also includes one or more capacitances such as capacitors. In an electrical oscillating circuit, a periodic exchange of energy takes place between a magnetic field of the inductance and an electric field of the capacitance. This results in alternating high currents or high voltages. The carrier frequency of the electromagnetic waves corresponds to the resonant frequency of the electrical oscillating circuit, which is characterized or described, among other things, by the capacitance of the capacitor(s), the inductance of the coil(s) and a loss resistance in the electrical oscillating circuit. During exposure or treatment of the biological material (e.g.When a biological material (such as tumor cells) is exposed to electromagnetic waves of a desired carrier frequency, power absorption occurs. This power absorption represents a further, variable loss resistance in the electrical resonant circuit. Changing the power absorption can adjust the tuning of the electrical resonant circuit to the desired frequency. The desired carrier frequency can be ensured by changing the capacitance of the capacitor(s) and / or the inductance of the coil(s).

[0018] A statistically significant change in power absorption was observed, particularly when amplitude modulation of the electromagnetic waves was added, as well as when the treated biological material was changed. This requires retuning the electrical oscillating circuit by adjusting the capacitance of the capacitor(s). An increased change in power absorption when amplitude modulation is added indicates greater biological efficacy, i.e., increased cytotoxic effects in the treated biological material. The increased power absorption in this case requires a greater adjustment of the capacitance of the capacitor(s).

[0019] Changes in re-tuning parameters of the electrical oscillating circuit as an indicator of impedance differences as an indicator of the biological effectiveness of exposure to electromagnetic waves depending on the type of biological material (e.g. type of tumor cells) could be shown.

[0020] It is assumed that the reasonable variation of the amplitude modulation parameters (frequency and modulation index) amplifies the non-temperature-induced effects and thus also leads to stronger changes in impedance.

[0021] In comparison to prior art applications of impedance measurement, such as bioelectrical impedance measurement, the present invention involves targeted changes in the four-dimensional parameter space. Changing the parameters leads to increased non-temperature-induced effects that are intended to be exploited in therapy.

[0022] The basis is the presumed “mode of action” with demodulation at the cell membrane, impact on ion channels (channelome) and resonance effects at the cell membrane (Young’s modulus).

[0023] The changes in the impedance of the electrical resonant circuit are represented by the capacitance changes of the capacitor(s) of the electrical resonant circuit necessary to ensure the desired carrier frequency of the electromagnetic waves.

[0024] The invention is based on the technical problem of measuring the impedance and other biological and / or physical parameters of the biological material at to enable treatment with electromagnetic waves by varying parameters such as the carrier frequency and power of the electromagnetic waves, the amplitude modulation parameters, and the temperature of the biological material. The parameters are varied in short temporal sequences, with the impedance monitored either in real time or retrospectively. This is intended to identify suitable parameter combinations that maximize non-temperature-induced effects and thus biological effectiveness and thus cytotoxic effects in the biological material. The identified parameter combinations can then be used therapeutically.It is assumed that a changed temporal sequence of the parameters such as the carrier frequency and power of the electromagnetic waves as well as the parameters of the amplitude modulation, for example by means of a pulsed carrier wave of the electromagnetic waves, can further increase the non-temperature-induced effects or the effectiveness.

[0025] This technical problem is solved by a measuring device and a method for detecting biological and / or physical parameters with the aid of an applicator as well as a therapy system for exposing a biological material of a mammal to electromagnetic waves and a therapy method for treating oncological tumors according to the present invention.

[0026] The measuring device for detecting biological and / or physical parameters with the aid of an applicator comprises the applicator, which is configured to apply electromagnetic waves generated by a signal source to a biological material. The measuring device further comprises a detection unit configured to detect the electromagnetic waves generated by the signal source as well as electromagnetic waves returning to the applicator due to reflection from the biological material, and a processing unit configured to determine the biological and / or physical parameters from at least one of the electromagnetic waves and the returning electromagnetic waves.

[0027] The measuring device may further comprise the signal source for generating the electromagnetic waves.

[0028] The applicator can be arranged in an electrical oscillating circuit with the signal source and the applicator can be replaceable.

[0029] The measuring device may further comprise a control unit, wherein the control unit is arranged with the applicator and the signal source in an electrical oscillating circuit.

[0030] The applicator may comprise an electrode and a counter electrode, or the applicator may comprise an electrode that serves as a counter electrode to an electrode integrated in a treatment table.

[0031] The detection unit may comprise at least one of a network analyzer, oscilloscope and analog-to-digital converter.

[0032] The measuring device may further comprise a dual-directional or two bidirectional or two directional couplers arranged in series, which is / are arranged to transmit the electromagnetic waves from the signal source proportionally to the applicator and the detection unit.

[0033] The coupler may be further configured to transmit the returning electromagnetic waves to the detection unit.

[0034] The electromagnetic waves may have an adjustable power, an adjustable carrier frequency and / or an adjustable amplitude modulation, and the amplitude modulation may have a frequency and a modulation index.

[0035] The detection unit may be further configured together with the processing unit to determine an impedance.

[0036] The measuring device may further comprise a temperature unit configured to determine a temperature of the biological material.

[0037] The temperature unit may be configured to operate in a control loop with a temperature system for controlling the temperature of the biological material.

[0038] Furthermore, the therapy system for exposing a mammal's biological material to electromagnetic waves is described. The therapy system comprises a signal source for generating the electromagnetic waves, a measuring device according to the present invention, and the treatment table with the integrated electrode suitable for the treatment of humans and / or animals. The signal source, the applicator of the measuring device, and the integrated electrode are arranged in an electrical oscillating circuit.

[0039] The measuring device can interchangeably operate as an applicator at least one of different applicators for preclinical in vitro and in vivo treatment as well as clinical treatment of patients.

[0040] Furthermore, the measurement method for detecting biological and / or physical parameters with the aid of an applicator is described. The measurement method comprises the steps of generating electromagnetic waves with a signal source, wherein the electromagnetic waves have a carrier frequency and amplitude modulation, and applying the generated electromagnetic waves to a biological material with the applicator. The method further comprises the steps of detecting the electromagnetic waves reflected by the biological material with the detection unit and determining the biological and / or physical parameters with the processing unit, wherein the determination is carried out from at least one of the generated electromagnetic waves and the reflected electromagnetic waves.

[0041] The use of the measuring device according to the present invention and / or the measuring method for detecting biological and / or physical parameters of a biological material according to the present invention is further described, wherein the use is exclusively for diagnostic purposes.

[0042] Furthermore, the therapy method for treating oncological tumors using a measuring device, a therapy system and / or a measuring method according to the present invention is described. Description of the characters

[0043] Fig. 1 shows a block diagram of a measuring device according to the present invention.

[0044] Fig. 2 shows a block diagram of a first aspect of the measuring device according to the present invention.

[0045] Fig. 3 shows a block diagram of a second aspect of the measuring device and a therapy system according to the present invention.

[0046] Fig. 4 shows a process flow diagram of a measuring method according to the present invention. Detailed description of the invention

[0047] The invention will now be described based on the drawings. It is understood that the embodiments and aspects of the invention described herein are only examples and do not limit the scope of the claims in any way. The invention is defined by the claims and their equivalents. It is understood that features of one aspect or embodiment of the invention may be combined with a feature of another aspect or other aspects and / or embodiments of the invention.

[0048] Fig. 1 shows a block diagram of a measuring device 10 according to the present invention. The measuring device 10 comprises an applicator 20, by means of which electromagnetic waves EM can be applied to a biological material 30. The biological material 30 can be, for example, tissue such as mammalian tissue and tumor cells. The biological material 30 has biological and physical parameters 15. Examples of the biophysical parameters are ion channel expression (channelome), the expression of proteins / lipids in the cell membrane, and cell membrane elasticity (Young's modulus), although other biophysical parameters are also possible. The applicator 20 can have different designs, two of which are described in Fig. 2 and Fig. 3.

[0049] The electromagnetic waves EM emitted by the applicator 20 strike the biological material 30 and are reflected by it as returning electromagnetic waves EM'. The applicator 20 and the biological material 30 can be aligned with each other such that the biological material 30 is exposed to the electromagnetic waves EM emitted by the applicator 20, and the returning electromagnetic waves EM' reflected by the biological material 30 in turn strike the applicator 20, so that the applicator 20 can absorb the returning electromagnetic waves EM'.

[0050] The applicator 20 is arranged with a signal source 35 in an electrical oscillating circuit, LC oscillating circuit, or resonant circuit. The signal source 35 can be designed separately from the measuring device 10 and connected to the measuring device 10. Alternatively, the signal source 35 can be integrated into the measuring device 10. The applicator 20 represents a capacitance in the electrical oscillating circuit. The capacitance of the Applicator 20 is determined by the design of the applicator as well as by the biological Material 30 is influenced (this is described in more detail in Fig. 2 and Fig. 3).

[0051] The signal source 35 comprises an inductance, such as a coil, which is necessary for the realization of the electrical resonant circuit. The inductance can be designed to be adjustable. The signal source 35 further comprises at least one further adjustable capacitance, such as a capacitor with adjustable capacitance, as well as a function generator, such as an arbitrary waveform generator, for generating any periodic electrical signals. The inductance, the adjustable capacitance, and the function generator of the signal source 35 are electrically connected to the applicator 20 in such a way that they form the electrical resonant circuit.

[0052] Alternatively, the adjustable capacitance and inductance may not be included in the signal source 35, but may be provided separately in the measuring device 10. For example, the adjustable capacitance and inductance may be provided in a separate control unit 37. In this case, the measuring device 10 also includes the control unit 37. The control unit 37 is connected to the signal source 35 and the applicator 20 to form the electrical resonant circuit and may also include more than one adjustable capacitance and one adjustable inductance. Alternatively, the control unit 37 may also be provided separately from the measuring device 10 and the signal source 35 and connected to the measuring device 10 and the signal source 35 to form the electrical resonant circuit.

[0053] The adjustable capacitance and inductance, as well as the applicator, are connected in series, making the electrical resonant circuit a series resonant circuit. Alternatively, the measuring device 10 can also be implemented with a parallel resonant circuit.

[0054] Individual or multiple previously described components of the signal source 35 may alternatively also be integrated into the measuring device, as long as the said components are connected to the electrical oscillating circuit.

[0055] The electrical resonant circuit has a resonant frequency at which a periodic exchange of energy takes place between a magnetic field of the inductors and an electric field of the capacitances. The resonant frequency results from the inductances and capacitances contained within. Due to damping caused by losses (such as ohmic losses in the components and cables used), the amplitude of the oscillation of the electrical resonant circuit would decrease over time. This can be achieved by regularly supplying energy to the electrical oscillating circuit can be prevented.

[0056] The function generator excites the electrical oscillating circuit by regularly supplying energy. This allows the electrical oscillating circuit to oscillate continuously at its resonant frequency. As described below, a variable adjustment of the resonant frequency of the electrical oscillating circuit is desirable. The function generator can therefore excite the electrical oscillating circuit at the desired resonant frequency. Furthermore, the power P of the electromagnetic waves EM can be varied using the function generator.

[0057] A carrier frequency RF of the electromagnetic waves EM, which are applied to the biological material 30 by means of the applicator 20, corresponds to the resonant frequency of the electrical resonant circuit. In order to vary the carrier frequency RF during the exposure of the biological material 30, a variation of the resonant frequency of the electrical resonant circuit is necessary. For this purpose, all components connected to the electrical resonant circuit must be coordinated with one another. The (adjustable) inductance(s) and the (adjustable) capacitance(s) of the signal source 35 or the measuring device 10 or the control unit 37, as well as the capacitance of the applicator 20, must be coordinated so that the resonant frequency of the resonant circuit corresponds to the desired carrier frequency RF. The relationship RF = (1 / 2TT) (LC)' 1 / 2 be fulfilled, where L is the inductance(s) and C is the capacitance (of the signal source 35 and the applicator 20).

[0058] The resonant frequency of the electrical resonant circuit can thus be adjusted by deliberately varying the capacitance(s) and inductance(s) of the components connected to the electrical resonant circuit. For this purpose, the inductance and / or the capacitance can be designed to be adjustable. The inductance can, for example, be designed as a coil with a ferromagnetic core, whereby the ferromagnetic core can be inserted into the coil with a variable length. This allows the inductance of the coil to be adjusted. The capacitance can be designed to be adjustable, for example, by using a capacitor with a variable PI distance or a capacitor with a variable proportion of the opposing surfaces.

[0059] By detecting the electromagnetic waves EM and the returning electromagnetic waves EM' and determining their difference, the Capacitance(s) and inductance(s) can be readjusted to control the resonant frequency of the electrical oscillating circuit to a desired value. This control can be performed by the separate control unit 37, which includes the adjustable capacitance(s) and inductance(s). Alternatively, this control can also be performed by the signal source 35, provided the signal source 35 includes the adjustable capacitance(s) and inductance(s).

[0060] The function generator can also modulate the amplitude of the oscillation of the electrical resonant circuit with a variable frequency and modulation index, thus implementing AM amplitude modulation. Examples of possible parameter ranges for AM amplitude modulation that can be set with the function generator are 1 Hz - 1 MHz for the frequency and 10 - 100% for the modulation index. The output power of the function generator is variable and selected to be sufficiently high to achieve a sufficiently high level in the applicator 20.

[0061] The adjustability of the capacitance(s) of the signal source 35 also serves to maintain the desired resonant frequency in the event of increased loss resistance of the electrical resonant circuit, since the resonant frequency of a real resonant circuit is also influenced by the loss resistance. Increased loss resistance occurs when the power absorption by the biological material 30 changes. Increased power absorption by the biological material 30, and thus a change in power absorption, can be observed, particularly when amplitude modulation AM is switched on. By adjusting the adjustable capacitance(s) of the signal source 35, the resonant frequency of the electrical resonant circuit can be kept stable at the desired value even when the power absorption by the biological material 30 changes.

[0062] The measuring device 10 further comprises a dual-directional or two bidirectional or two directional coupler 40. The coupler 40 is configured to transmit the electromagnetic waves EM from the electrical oscillating circuit proportionally to the applicator 20 and to a detection unit 45 of the measuring device 10. The transmission ratio of the electromagnetic waves EM transmitted to the applicator 20 and to the detection unit 45 is variable. The coupler 40 also transmits the returning electromagnetic waves EM' reflected from the biological material 30 and the applicator 20 to the detection unit 45.

[0063] The measuring device 10 further comprises the detection unit 45. The detection unit 45 detects the electromagnetic waves EM as well as the returning electromagnetic waves EM', which are fed to the detection unit 45 via the coupler 40. The detection unit 45 and the signal source can alternatively be implemented as a single unit.

[0064] The measuring device 10 further comprises a processing unit 50, such as a network analyzer. The processing unit 50 analyzes the electromagnetic waves EM and the returning electromagnetic waves EM' detected by the detection unit 45. The processing unit 50 determines, for example, the impedance Z of the electrical resonant circuit in phase 0 and amplitude |Z| as Z = |Z| exp(+j0).

[0065] The signal source 35, the coupler 40, the detection unit 45 and / or the processing unit 50 can alternatively also be designed individually or in any combination as separate components from the measuring device 10 and can be connected to the measuring device.

[0066] The temperature of the biological material 30 can be determined using a temperature unit 55. The temperature unit 55 can be configured, for example, as a temperature sensor that can be arranged in or on the biological material 30. The temperature unit 55 is connected to a temperature system 58. The temperature system 58 can maintain the temperature of the biological material 30 within a desired temperature range, even with increased energy input into the biological material 30 by applying electromagnetic waves EM to the biological material 30. The temperature system 58 uses the temperature of the biological material 30 determined by the temperature unit 55 for temperature control.

[0067] The temperature system 58 can increase and / or reduce the temperature of the biological material. The temperature system 58 is used in particular with the applicator 20 according to the first aspect, which is suitable for in vitro examinations. In the case of the applicator 20 according to the second aspect, which is suitable for in vivo examinations or treatments, the temperature of the biological material can be controlled by the living being itself. Alternatively, the temperature of the biological material 30 of the living being in in vivo examinations or treatments can also be achieved by other means, such as fans and / or cooling / heating pads.

[0068] The temperature system 58 can be configured, for example, as a flow-through temperature system. A heat transfer medium, such as a coolant, flows around the biological material on all sides, which serves to transfer or transfer thermal energy to or from the biological material 30.

[0069] The measuring device 10 allows for user-friendly testing of the parameters carrier frequency RF, frequency, and modulation index of the amplitude modulation AM, as well as the temperature of the biological material 30 (as a covariate) with regard to non-temperature-induced cytotoxic effects in the biological material. For preclinical use, the biological endpoints (apoptosis, clonogenicity, etc.) can be freely selected. In each case, a comparison with (conventional) water bath hyperthermia at the selected temperature (e.g., 37-42 °C) under otherwise identical conditions is required.

[0070] The measuring device 10 also consists of standard high-frequency components such as an amplifier with sufficient bandwidth and a matching network and selectable amplitude modulation, thermometry, a water flow system, a network analyzer system with passive high-frequency components (in the desired frequency range up to 120 MHz), and applicators (capacitive electrodes). Due to the relatively low frequency range (<120 MHz) for high-frequency applications, the costs of the standard components can be kept low.

[0071] Fig. 2 shows a block diagram of a first aspect of the measuring device 10 according to the present invention. Components designated by the same reference numerals as in Fig. 1 will not be described again. The applicator 20 according to the first aspect consists of an electrode 22 and a counter electrode 24, which form a capacitor with a capacitance that is part of the previously described electrical oscillating circuit. The electrode 22 and the counter electrode 24 are arranged such that the biological material 30 can be placed between the electrode 22 and the counter electrode 24.

[0072] The applicator 20 allows the use of commercially available standard laboratory components. The electrode 22 and the counter electrode 24 are arranged in such a way that the biological material 30 in a Petri dish (for example, with a diameter of 35 mm and a height of 10 mm) can be inserted between the electrode 22 and the counter electrode 24. The biological material 30 inserted between the electrode 22 and the counter electrode 24 can thus be exposed to the electromagnetic waves EM. The applicator 20 according to the first aspect of the invention is thus suitable for in vitro studies on cells.

[0073] In addition, the biological material 30 can be surrounded on all sides by the coolant of the temperature system 58 in order to ensure the desired temperature in the biological material 30.

[0074] The use of a single Petri dish is just one example. For rapid testing of potentially multiple cell lines simultaneously, microtiter plates (also standard laboratory equipment) can also be inserted between electrode 22 and counter electrode 24.

[0075] As previously described, the capacitance of the applicator 20 influences the resonant frequency of the electrical oscillating circuit. The capacitance of the applicator 20 is influenced by the design and arrangement of the electrode 22 and the counter electrode 24, as well as by the biological material 30 and the coolant of the temperature system 58. The size, shape, volume, and material of a vessel containing the biological material 30, such as a Petri dish or microtiter plates, also influence the capacitance of the applicator 20.

[0076] An exemplary embodiment of the previously described components is described below. The applicator 20 for in vitro cell testing using Petri dishes with a diameter of 35 mm and a height of 10 mm and using water flow cooling can have a capacitance of 33 pF. For a desired resonance frequency and thus carrier frequency RF of 13.56 MHz, an inductance of the signal source 35 of 4.2 pH should be selected. If the carrier frequency RF is to be variable in the range from 1 MHz to 100 MHz, the inductance of the signal source 35 must be variable in a range from 770 pH to 0.077 pH. Inductors in this range are commercially available and allow the carrier frequency to be varied in steps.

[0077] Investigations suggest that low carrier frequencies (RF) in the range of a few MHz are particularly effective. Therefore, this RF range should be able to be checked particularly carefully with the measuring device 10. For this purpose, high inductances of the Signal source 35 of up to 1000 pH is required. Another interesting range is high frequencies of 70–100 MHz, which are used for hyperthermia using the complex annular phased array technique.

[0078] Fig. 3 shows a block diagram of a second aspect of the measuring device 10 and a therapy system 100 according to the present invention. Components designated by the same reference numerals as in Fig. 1 and Fig. 2 will not be described again. The applicator 20 according to the second aspect comprises only one electrode 22 and no counter electrode. The electrode 22 is designed such that it can be positioned relative to an electrode 62 integrated in a treatment table 60 such that biological material 30 can be placed between the electrode 22 of the applicator 20 and the integrated electrode 62 of the treatment table 60.

[0079] The electrode 22 and the integrated electrode 62 thus form a capacitor with a capacitance, which is part of the previously described electrical oscillating circuit. In this case, the electrical oscillating circuit consists of the signal source 35, the applicator 20, and the integrated electrode 62 of the treatment table 60. With this configuration of the applicator 20, the biological material 30 is not limited to cell samples, so that the applicator 20 according to the second aspect of the invention is suitable for in vivo studies on living beings, such as mammals.

[0080] The therapy system 100 includes the measuring device 10, the signal source 35, and the treatment table 60 with the integrated electrode 62. The treatment table 60 is designed for the treatment of a human patient. The signal source 35, the measuring device 10, and the treatment table 60 are electrically connected to one another such that the electrode 22 of the applicator 20 of the measuring device 10, the integrated electrode 62 of the treatment table 60, the adjustable capacitance(s) and inductance(s), and the function generator of the signal source 35 form the electrical oscillating circuit.

[0081] The therapy system 100 can be used to determine the appropriate parameters such as carrier frequency RF, frequency and modulation index of the amplitude modulation AM, as well as the temperature for the treatment of the patient with the electromagnetic waves EM. This allows a personalized therapy with optimal therapy parameters to be determined for the respective patient. Furthermore, the therapy system 100 can be used for this very treatment. For the treatment of a patient, a higher power of the electromagnetic waves is required than for the determination of the optimal parameters. The required power can, for example, be in the range of 100 to 400 W, or in another aspect, in the range of 100 to 200 W. For this purpose, the high-frequency components used in the measuring device 10 and the signal source 35 must be dimensioned for the higher required power.

[0082] The optimal therapy parameters for a personalized therapy can alternatively be determined with the measuring device 10 of the therapy system 100, for example, in vitro with cultured tumor cells using the applicator 20 according to the first aspect of the invention. The patient can then be treated with the determined optimal therapy parameters using the applicator 20 according to the second aspect of the invention. In this case, the therapy system 100 can comprise both the applicator 20 according to the first aspect and the applicator 20 according to the second aspect.

[0083] The therapy system 100 can also be used for veterinary tumors if its components are dimensioned accordingly.

[0084] For the treatment of a patient using the previously determined optimal therapy parameters, already available systems for oncological applications (e.g. EHY-2030) can alternatively be used after prior adaptation.

[0085] The described therapy system 100 enables personalized locoregional oncology therapy. This can improve current standard therapy in oncology. Examples include liver metastases or brain metastases in conjunction with systemic and / or radiotherapy for numerous tumor entities (gastrointestinal tumors, breast carcinomas, bronchial carcinomas, glioblastomas, etc.).

[0086] Fig. 4 shows a process flow diagram of a measurement method 200 according to the present invention. In a step S100, electromagnetic waves EM are generated by means of a signal source 35. The signal source 35 is arranged in an electrical oscillating circuit with an applicator 20 of a measuring device 10. The electromagnetic waves EM have adjustable parameters such as a carrier frequency RF as well as a frequency and modulation index of a switchable amplitude modulation AM.

[0087] In a step S110, the electromagnetic waves EM are applied to a biological material 30 by means of the applicator 20. The The returning electromagnetic waves EM' reflected from the material are detected by a detection unit 45 in a step S120. In a step S130, a processing unit 50 determines biological and / or physical parameters 15 of the biological material 30 from at least one of the electromagnetic waves EM and the returning electromagnetic waves EM'. The physical parameters can be, for example, the impedance Z and the specific absorption rate. List of reference symbols 10 Measuring device 15 Biological and / or physical parameters 20 Applicator 22 Electrode 24 Counter electrode 30 Biological material 35 Signal source 37 control unit 40 couplers 45 Detection unit 50 processing units 55 temperature unit 58 Temperature system 60 treatment table 62 Integrated electrode 100 Therapy System 200 measuring methods 300 therapy procedures AM amplitude modulation EM Electromagnetic Waves EM' Returning electromagnetic waves P Performance RF carrier frequency Z Impedance S 100 Generation of electromagnetic waves S 110 Application of electromagnetic waves S120 Detection of reflected electromagnetic waves S130 Determination of biological and / or physical parameters

Claims

Claims 1. A measuring device (10) for detecting biological and / or physical parameters (15) with the aid of an applicator (20), the measuring device (10) comprising: the applicator (20), configured to apply electromagnetic waves (EM) generated by a signal source (35) to a biological material (30); a detection unit (45) configured to detect the electromagnetic waves (EM) as well as electromagnetic waves (EM') returning to the applicator (20) by reflection from the biological material (30); and a processing unit (50) configured to determine the biological and / or physical parameters (15) from at least one of the electromagnetic waves (EM) and the returning electromagnetic waves (EM').

2. Measuring device (10) according to claim 1, further comprising the signal source (35) for generating the electromagnetic waves (EM).

3. Measuring device (10) according to claim 1 or 2, wherein the applicator (20) is arranged with the signal source (35) in an electrical oscillating circuit.

4. Measuring device (10) according to one of claims 1 to 3, further comprising a control unit (37), wherein the control unit (37) is arranged with the applicator (20) and the signal source (35) in an electrical oscillating circuit.

5. Measuring device (10) according to one of claims 1 to 4, wherein the applicator (20) is replaceable.

6. Measuring device according to one of claims 1 to 5, wherein the applicator (20) comprises an electrode (22) and a counter electrode (24).

7. Measuring device according to one of claims 1 to 5, wherein the applicator (20) comprises an electrode (22) which serves as a counter electrode to an electrode (62) integrated in a treatment table (60).

8. Measuring device (10) according to one of claims 1 to 7, wherein the detection unit (45) comprises at least one of a network analyzer, oscilloscope and analog-to-digital converter.

9. Measuring device (10) according to one of claims 1 to 8, further comprising: a coupler (40) arranged to transmit the electromagnetic waves (EM) from the signal source (35) proportionally to the applicator (20) and the detection unit (45).

10. Measuring device (10) according to claim 9, wherein the coupler (40) is further configured to transmit the returning electromagnetic waves (EM') to the detection unit (45).

11. Measuring device (10) according to one of claims 1 to 10, wherein: the electromagnetic waves (EM) have an adjustable power (P), an adjustable carrier frequency (RF) and / or an adjustable amplitude modulation (AM).

12. Measuring device (10) according to claim 11, wherein the adjustable amplitude modulation (AM) has a frequency and a modulation index.

13. Measuring device (10) according to one of claims 1 to 12, wherein: the detection unit (45) together with the processing unit (50) is further configured to determine an impedance (Z).

14. Measuring device (10) according to one of claims 1 to 13, further comprising: a temperature unit (55) configured to determine a temperature of the biological material (30).

15. Measuring device (10) according to claim 14, wherein the temperature unit (55) is arranged to be operated in a control circuit with a temperature system (58) for controlling the temperature of the biological material (30).

16. A therapy system (100) for exposing a biological material (30) of a mammal to electromagnetic waves (EM), the therapy system (100) comprising: a signal source (35) for generating the electromagnetic waves (EM); a measuring device (10) according to one of claims 6 to 14; and a treatment table (60) suitable for the treatment of humans and / or animals, said treatment table having an integrated electrode (62), wherein the signal source (35), the applicator (20) of the measuring device (10) and the integrated electrode (62) are arranged in an electrical oscillating circuit.

17. Therapy system (100) according to claim 16, wherein the measuring device (10) as an applicator (20) can interchangeably operate at least one of different applicators for preclinical in vitro and in vivo treatment as well as clinical treatment of patients.

18. A measuring method (200) for detecting biological and / or physical parameters (15) using an applicator (20), the measuring method (200) comprising: Generating (S100) electromagnetic waves (EM) with a signal source (35), wherein the electromagnetic waves (EM) have a carrier frequency (RF) and an amplitude modulation (AM); Applying (S110) the generated electromagnetic waves (EM) to a biological material (30) with the applicator (20); Detecting (S120) the electromagnetic waves (EM') reflected by the biological material (30) with the detection unit (45); Determining (S130) the biological and / or physical parameters (15) with the processing unit (50), wherein the determining (S130) is carried out from at least one of the generated electromagnetic waves (EM) and the reflected electromagnetic waves (EM').

19. Use of a measuring device (10) according to one of claims 1 to 15 and / or a measuring method (200) according to claim 17 for the detection of biological and / or physical parameters (15) of a biological material (30), wherein the use is exclusively for diagnostic purposes.

20. Therapy method (300) for treating oncological tumors using a measuring device (10) according to one of claims 1 to 15, a therapy system (100) according to claim 15 or 16 and / or a measuring method (200) according to claim 18.

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