CN115671554A - Electric field frequency conversion method and device for TTF - Google Patents
Electric field frequency conversion method and device for TTF Download PDFInfo
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Abstract
The invention relates to an electric field frequency conversion method and a device for TTF, which are used for obtaining the uniform and integral adaptive frequency F of target tissue cells; acquiring a frequency conversion period delta T; the cell parameters C and F are corresponded, and corresponding adaptive frequency F is established; after a frequency conversion period delta T, the current frequency is changed into a new adaptive frequency F, and the frequency conversion of the electric field is stopped after the set TTF action time is reached. The invention is based on the node-change frequency conversion, approximately treats the cells of the target tissue as a uniform whole, applies the adaptation frequency to the uniform whole, only needs to apply one frequency at the same time, and changes the current frequency into the new adaptation frequency when the change reaches a certain amplitude so as to obtain better effect of inhibiting the growth of the tumor cells.
Description
Technical Field
The invention relates to the field of medical instruments, in particular to an electric field frequency conversion method and device for TTF.
Background
Current forms of radiotherapy or chemotherapy have limited effectiveness in treating tumors and tend to damage normal cells in the vicinity of the tumor. With the progress of medical science and technology, a new Tumor treatment method is proposed, namely Tumor electric field therapy (TTF), which realizes the treatment of Tumor cells by inhibiting the growth of Tumor cells through an alternating electric field.
TTF has frequency dependence on tumor killing according to different cell types, the frequency range is 50-500KHz, the electric field intensity is 0.5-10V/cm, and common parameters (clinical) are 1-3V/cm and 150-200KHz. However, recent researches show that the pulse electric field at low frequency (0-500 Hz) also has the effect of killing tumor cells, the common frequency range is 50-200Hz, the amplitude is 1-10V, the pulse width is 0-500 μm, the wave form is square wave or sine wave, and the common parameters are 50-150Hz,4V, 10V,90 μm pulse width or 450 μm pulse width. The main killing mechanism of the middle frequency range TTF is to inhibit the mitosis of tumor cells, while the main killing mechanism of the low frequency range TTF is to cause the death and apoptosis of tumor cells. The two killing means, combined with the chemotherapeutic drug, have better effect of inhibiting the growth of tumor cells than the single use (TTF or chemotherapeutic drug).
The structure of the cell membrane is not only a lipid bilayer, but also proteins embedded therein, some of which are so-called "ion channels", the presence of which allows transport of ions across the membrane, and physically speaking, the cell membrane capacitor is a "leaky capacitor" -which allows current to pass through the dielectric between the two plates, which leaky capacitor is represented by an ideal capacitor in parallel with a resistor-the leakage current passes through the capacitor via the resistor.
The total impedance of the plasma membrane at low frequencies is controlled primarily by the resistive portion; the total impedance of the plasma membrane at high frequencies is mainly controlled by the capacitive reactance. The intracellular electric field intensity is mainly determined by the relative values of the impedances of the plasma membrane, extracellular fluid and cytoplasm, and the higher the impedance of the plasma membrane is, the lower the intracellular electric field intensity is.
The killing effect of the medium-frequency electric field mainly comprises two aspects: dielectrophoretic force killing dependent on the later mitosis, and dipole force killing independent of the later mitosis. However, the cellular experiments with TTF found that the tumor cells became larger in volume over time as TTF treatment proceeded, and this effect was understood as a way for tumor cells to escape the TTF killing mechanism. That is, as TTF treatment progresses, the adaptation frequency of killing tumor cells changes and the probability of killing tumor cells becomes smaller, so that the current frequency-fixed treatment mode is not optimal.
Unlike insulated electrodes used in the middle band, TTF in the low band is mainly applied as a conductor electrode (metal electrode). The mechanism of killing at low frequency is less studied at present. From experimental data, it was observed that the killing effect below low frequency (1000 Hz) is mainly to cause the death and apoptosis of tumor cells, and to cause the increase of G0 phase cells (intermediate frequency causes the increase of G2/M phase cells). Since the G0 phase is a phase in which cells temporarily stop mitosis, it is thought that the low-frequency killing is such that cells do not enter the mitotic cycle, whereas the intermediate-frequency killing is such that cells do not normally complete mitosis.
The different killing mechanisms are summarized as follows, with intermediate frequency insulated electrodes: inhibiting mitosis, synchronizing cell cycle to G2/M phase, and inducing apoptosis; intermediate frequency conductor electrode: inducing cell death and apoptosis; low-frequency conductor electrode: inhibiting mitosis, synchronizing cell cycle to G0 phase, and inducing apoptosis.
Therefore, in the frequency band of TTF, among the currentless stimulation (insulated electrodes) of the intermediate frequency band, stimulation at a single frequency is not the most effective way; the low-frequency current stimulation and the medium-frequency current stimulation (conductor electrodes) can respectively exert the killing effect on the tumor cells through different mechanisms; moreover, the killing effect can be further improved by combining each killing effect with other therapies (such as radiotherapy and chemotherapy), and the killing effect is better than that of any single therapy.
Disclosure of Invention
The invention aims to provide an electric field frequency conversion method and device for TTF (TTF treatment), which are used for meeting the requirement of applying adaptive frequency of a TTF device in the using process and adjusting the adaptive frequency according to the parameter change of tumor cells so as to obtain better effect of inhibiting the growth of the tumor cells.
In order to achieve the above object, the present invention provides an electric field frequency conversion method for a TTF, the electric field frequency conversion method comprising the steps of:
step 101, acquiring uniform and integral adaptation frequency F of target tissue cells, and taking one of overall representative statistics of uniform and integral cell parameters C to obtain the adaptation frequency F from the cell parameters C;
102, acquiring a frequency conversion period DeltaT, wherein the frequency conversion period DeltaT is taken from natural time, or the frequency conversion period DeltaT is taken from time reaching the variation quantity DeltaC of a specified cell parameter C;
103, corresponding the cell parameters C and F, selecting one of the minimum value, the maximum value, or the value (such as arithmetic mean, geometric mean, blending mean, median, mode) that can statistically represent the whole of the interval to establish the corresponding adaptive frequency F, or selecting one of the other values of the cell parameters C to establish the corresponding adaptive frequency F;
and step 104, after a frequency conversion period DeltaT, changing the current frequency into a new adaptive frequency F, and stopping the frequency conversion of the electric field after the set TTF action time is reached.
Preferably, in step 102, when the frequency conversion period Δ T is taken from natural time, Δ T is taken from 1 hour, 2 hours, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days.
Preferably, in step 102, when the frequency conversion period Δ T is taken from the time when the variation Δ C of the specified cellular parameter C is reached, the variation Δ C is determined in an absolute value method or a relative value method according to the variation of the initial cellular parameter C0.
Preferably, when the variation Δ C is determined by an absolute value method, the specified cell parameter C is recorded as C1 after the variation of the specified cell parameter C from the initial cell parameter C0 exceeds a certain set value Δ C, and the frequency is changed to the corresponding F1 at T1 corresponding to C1; when the change value of C to C0 is smaller than a certain set value Δ C, the initial frequency F0 is still used.
Preferably, for cell size, approximately spherical cells at the beginning of mitosis are used as the measurement standard, Δ C is the radius or volume, the value of the radius is taken from 1 μm to 50 μm, and the value of the volume is taken from 1 μm 3 -10000μm 3 ；
Using end-mitotic double ellipsoid cells as a standard, and Δ C as a minor axis radius, a major axis radius, or a volume, said minor axis radius being taken from 0.5 μm to 50 μm, said major axis radius being taken from 1 μm to 50 μmμ m, values for volume taken from 1 μm 3 -10000μm 3 ；
Using spindle cells in non-dividing phase as standard, and Δ C as short axis length, long axis length or volume, wherein the short axis length is 0.5-50 μm, the long axis length is 1-100 μm, and the volume is 1 μm 3 -10000μm 3 ；
Using squamous cells of epithelial origin and astrocytes of nervous system origin as standard, and Δ C as radius or volume, the value of radius being taken from 0.5 μm to 50 μm, the value of volume being taken from 1 μm 3 -10000μm 3 ；
Using columnar cells of glandular origin as standard, and Δ C as column height, section radius or volume, the value of column height is taken from 0.5 μm to 50 μm, the value of section radius is taken from 0.5 μm to 100 μm, and the value of volume is taken from 1 μm 3 -10000μm 3 。
Preferably, when the variation Δ C is determined by using a relative value method, the variation of C to C0 exceeds a specified percentage of C0 and is recorded as C1, and the frequency should be changed to corresponding F1 at T1 corresponding to C1; the initial frequency F0 is still used when the C-to-C0 variation is less than a set value Δ C, where Δ C is taken from 10% -100% C0, where Δ C is an absolute value.
Preferably, in step 102, when the frequency conversion period Δ T is taken from the time of reaching the variation Δ C of the specified cell parameter C, the time of reaching Δ C is determined by taking C corresponding to the variation Δ F of the specified F as Δ C, where Δ F is 1KHz-150KHz.
Preferably, said Δ F is taken from 10KHz, 15KHz, 20KHz, 25KHz, 30KHz, 40KHz, 50KHz, 60KHz, 70KHz, 75KHz,80KHz, 90KHz or 100KHz.
Preferably, in step 104, if the natural time is Δ T, when T0 reaches T1 after Δ T, F0 is replaced by F1 corresponding to C1 at T1, and so on; if the time for reaching Δ C or Δ F is Δ T, when T0 reaches T1 through Δ T, the corresponding frequency F1 is replaced with F0, and so on.
Another object of the present invention is to provide an electric field frequency conversion apparatus for TTF, which performs frequency conversion control by using the electric field frequency conversion method.
Based on the technical scheme, the invention has the advantages that:
the electric field frequency conversion method and the electric field frequency conversion device for TTF are based on joint frequency conversion, approximately regard cells of a target tissue as a uniform whole, and apply adaptive frequency to the uniform whole, so that only one frequency is required to be applied. Since the parameters (size and/or electrical parameters) of this homogeneous ensemble vary with time, only one frequency needs to be applied at a time, and when this variation reaches a certain magnitude, the current frequency is changed to a new adaptation frequency to obtain a better effect of inhibiting the growth of tumor cells.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the invention without limiting the invention. In the drawings:
FIG. 1 is a schematic diagram of adaptation frequency versus cell size;
FIG. 2a is a diagram illustrating the relationship between cell types and adaptation frequencies;
FIG. 2b is a diagram showing the relationship between cell morphology and adaptation frequency;
FIG. 3 is a graph showing different frequencies versus corresponding suprathreshold areas for cells of different sizes;
fig. 4 is a diagram of the electric field frequency conversion method steps for TTF.
Detailed Description
The technical solution of the present invention is further described in detail by the accompanying drawings and embodiments.
The frequency conversion of the single stimulation mode refers to selecting one stimulation mode from three stimulation modes of medium-frequency current-free stimulation, low-frequency current stimulation and medium-frequency current stimulation, and changing parameters such as frequency, field intensity, duty ratio, direction conversion period and the like in the stimulation mode regularly to achieve better treatment effect.
Since the relationship between the frequency of the medium-frequency current-free stimulation and the killing effect of the cell type and the cell size has been studied clearly between the above-mentioned stimulation method and various stimulation parameters, the medium-frequency current-free stimulation frequency conversion method will be discussed first. The medium frequency current stimulation is similar to the medium frequency current-free stimulation in electric field efficiency, and only additional current effect is attached, so that the frequency conversion mode of medium frequency current-free stimulation can be applied during stimulation.
It should be noted that there is also a synergistic effect between the medium frequency no current stimulation, the low frequency current stimulation, and the medium frequency current stimulation. Therefore, the frequency conversion in the invention belongs to the broad frequency conversion concept, not only switches between different frequencies, but also switches between the three stimulation modes, and also belongs to the frequency conversion category of the invention, so as to play a stronger role in killing tumors.
The killing effect of TTF on tumor cells is frequency dependent. Without being limited to the size of the cell, the cellular multi-electrical parameters (mainly the conductivity and relative permittivity of the cell as a whole, and the conductivity and relative permittivity of the plasma membrane and cytosol, respectively) also affect the penetration of the electric field and thus the adaptation frequency. Therefore, the frequency conversion should be performed by reversely deducing the adaptive frequency according to different cell parameters, which mainly include cell size and electrical parameters.
In the technical scheme of the invention, the core is a frequency conversion method, and the correlation method of the cell parameters and the adaptive frequency is not the main content. But some associated methods are listed here to show their feasibility.
(1) Correlating cellular parameters and adaptation frequencies
The cell parameters include one or more of cell size (volume and/or diameter), cell conductivity, cell dielectric constant, cell cytoplasm conductivity, cell cytoplasm dielectric constant, cell impedance, cell membrane capacitance. In the following, the cell size is taken as an example, but in principle, the above parameters are all similar, and the previous variation relationship of each parameter is consistent, and the person skilled in the art can obtain the association with the adaptation frequency based on various cell parameters without any doubt based on the general knowledge in the art.
The relationship between cell size and mitotic killing is primarily a concern. Two things need to be defined here, namely establishing the relationship between cell size and adaptation frequency, and determining cell size. The actual application of frequency conversion is mainly divided into two types, one is that the frequency changes along with time (such as 200KHz in the first cycle and 150KHz in the second cycle), and the other is that a plurality of frequencies are applied simultaneously (such as 200KHz for 5s and 150KHz for 5 s). Therefore, in practice, the relationship among cell size, frequency and time is considered. Therefore, cell size and frequency relationships, and time and frequency relationships, respectively, need to be established to establish a complete frequency conversion scheme.
The fitting frequency in the present invention may be an optimum frequency, but in practical applications, the fitting frequency may be generally a value smaller than the optimum frequency for safety (the reference for judgment may include the physical condition of the subject, the type of tumor, the degree of malignancy of the cells in a sub-part, etc. according to the comprehensive judgment of the doctor).
Here, the process of confirming-optimizing is performed on the determined frequency conversion parameters. That is, treatment is performed with the frequency-varying parameters identified in the following manner, while feedback (mainly prognostic information of the patient) is collected, and the frequency-varying parameter-prognosis relationship is established, and then the frequency-varying is optimized according to the relationship by adding different weights (e.g., weighting each cell size) to the frequency-varying options described below, based on the prognostic relationship.
1) Hardware support
To collect data, existing TTF hardware is therefore upgraded, adding new functionality, as described below.
Data transmission: the data storage module and the Bluetooth module or the wireless network card are arranged in the equipment, and the hardware data are transmitted back to the database by using the Bluetooth or the wireless network, wherein the data mainly refer to the total use time (day), the daily use time, the frequency, the power (electricity consumption), the electrode heating and the frequency conversion mode of the patient equipment.
General files: when the doctor uses the system, a file can be established for the patient and associated with the patient (the patient can also establish the file by himself/herself), information such as name, sex, age, disease type, pathological stage, imaging information and the like can be archived, and data transmitted in the data transmission function can be classified into the file. In addition, the physician may enter the expected life of the patient.
Prognosis profile: during the follow-up visit of the patient, the files established in the file establishment function can be retrieved through the APP (program) in the mobile electronic device or the computer device, and the prognosis information (mainly including general conditions, tumor size, disease progression, disease remission and imaging information during the follow-up visit) of the patient is recorded in the files. And the disease progression (if any) is specifically marked.
And (3) integral file: the three types of data are classified into the file of the same patient as a whole file.
2) Establishment of cell size-integration frequency relationship
According to the rule that cell size influences the killing effect, the model is divided into a radius-integration frequency model and a volume-integration frequency model. The corresponding radius (or volume) change is selected according to the corresponding frequency change as the minimum characteristic frequency, namely the 'unit frequency' (such as 25 KHz), and the minimum unit is defined as the 'frequency conversion size' required for frequency conversion. The size range between two "conversion sizes" is defined as a "conversion interval". As shown in fig. 1, where the ordinate is the fitting frequency and the abscissa is the cell size, the fitting frequency decreases as the cell size increases. The target of frequency conversion is frequency, the minimum frequency conversion unit must be clearly defined, the too small frequency conversion unit is meaningless, and the too large frequency conversion unit can miss the adaptive frequency, so that it is proposed that the cell size 2 and the cell size 3 are both the "frequency conversion size", wherein a1 is the "frequency conversion interval" and the corresponding a2 is the "unit frequency". The unit frequency may range from 1 to 100Khz, but is preferably 10Khz, 20Khz, 25Khz, 50Khz, or 100Khz.
There are several ways to establish this relationship, such as using a formula calculation method or using a finite element simulation method. As shown in fig. 2a and 2b, the present invention provides a quantitative evaluation method, as follows:
suprathreshold stimulation quantification: relationship of cell size to temporal weight-suprathreshold stimulation calculation: we found that the TTF-mediated tumor killing effect is dependent on the internal electric field intensity E and the gradient change rate of the electric field intensity
(i.e., DEP force), thus adding E to
The relationship with tumor cell size, and mitotic phase, respectively, is plotted, where the abscissa is frequency and the ordinate is frequency
(i.e., DEP force).
Two pieces of information can thus be known: one is that for a single tumor cell, with a backward shift in the division phase (i.e., narrowing of the narrow bridge), E and E are present in the cell
Are all increased therewith; the second is the E sum of the same division period for different sizes of tumor cells
Is different. For cells, the effect of inhibiting mitosis depends on the dielectrophoretic force of organelles and microtubules in an alternating electric field, and the force of the electric field, which act separately from the other
And E (for the same cell structure).
Therefore, the present invention proposes
And E the concept of "field strength threshold", in this contextAn electric field below the threshold is considered to have a small influence on the cell, and an electric field above the threshold is considered to have a significant effect on the cell. The calculation method is as follows: for a certain organelle (e.g., mitochondria), it has a specific shape, volume, dielectric constant and conductivity. According to the data, the dielectrophoresis force F borne by the electric field can be calculated according to the dielectrophoresis force formula. Then, the moving speed v of the cytoplasm can be calculated according to the viscous resistance of the cytoplasm.
Since for a fixed cell size the field strength coverage D within the cell above the "field strength threshold" is also determined, the distance of movement S of the organelles is also determined according to v above. In order to exert the killing effect, the organelles need to move a certain distance, and S is more than or equal to D. Since both v and S are related to the "field strength threshold", we can know at what "field strength threshold" the intracellular organelles can achieve S ≧ D, as long as we specify a time T. T can be calculated from the relationship of v (i.e., S) to D. The upper limit of this T is the duration of the late mitosis. From this we have obtained a "field strength threshold" Ee.
Plotting the relationship of the curves above, marking Ee reveals that the horizontal axis is mitotic progression (which is time in units, whose biological meaning is the ratio of the width of the "narrow bridge" structure/initial width, or the distance separating two cells
Due to the fact that
Proportional to DEP (dielectrophoretic force) and S proportional to the square of time. The invention therefore proposes a concept of "suprathreshold area" which allows the effect of this frequency on the electric field force of the particle (organelle) to be quantitatively calculated, since "suprathreshold area" takes into account both time and velocity: (
DEP, i.e. velocity), can be used to characterize the mitotic inhibition (by dielectrophoresis) of a polarizable particle (organelle) in a TTF field.
It should be noted that "suprathreshold area" is an easily understood concept, and since time is squared with S, it is not a pure "suprathreshold area" where time has a square effect, as shown in fig. 3, the shaded portion is the suprathreshold area of pink line (radius R =30 μm cell), and it can be seen that cells of different sizes (corresponding to different lines) have different suprathreshold areas at the same frequency, while cells of the same size behave identically at different frequencies. Therefore, the problem of adapting frequency selection becomes the problem of calculating how to obtain the maximum suprathreshold area, and then different frequencies of cells of different sizes correspond to one suprathreshold area, and the frequency at which the maximum value can be obtained is the adapting frequency of the cell of the size.
The present invention gives the following equations relating the physical quantities in the above description for easy understanding:
first, the DEP formula of dielectrophoretic force of the polarizable particles (organelles) equivalent to spheres in the electric field, r is the equivalent radius of the particles, epsilon * The complex dielectric constant is, sigma is the conductivity, omega is the angular frequency of the electric field, subscripts p and m respectively represent the particle itself and the solution environment in which the particle is located, and the Hamiltonian represents the gradient of the square of the electric field. At a certain frequency,. Epsilon * σ, ω are fixed values, so Fp is related to the particle size and
in proportion to the amount of immobilized particles
Is in direct proportion.
First, the public of the particle (organelle) displacement SWherein F is the electric field force, F is the viscous resistance, F T The random force on the particle due to the thermal movement of the cell itself, S and F can be seen to be in direct proportion.
3) Establishment of cell size-time relationship
According to the above, the frequency-variable application mode is divided into the frequency variation with time (such as 200KHz in the first cycle and 150KHz in the second cycle), or the multiple frequencies are simultaneously applied (such as 200KHz for 5s and 150KHz for 5 s). Therefore, the relationship between cell size and time should be divided into two categories. Several ways of establishing the relationship are given below.
Cell size versus time-cell culture: patient tissue-derived cells (or tumor cell lines) were subjected to cell culture and time-radius (volume) curves were plotted for 30d. The method is more suitable for short-term relationship establishment.
Cell size versus time-animal culture: cells derived from patient tissue (or tumor cell lines) are inoculated into a model animal, and the tumor is cultured in the animal. The experimental animals are killed at a specific time point (e.g., every day or every 10 days) to remove the tumor, or a part of the tumor tissue in the body is removed by biopsy, and the cell size at that time node is counted. The method is suitable for short-term and long-term relationship establishment.
Cell size versus time-non-invasive examination: the shots are taken at each time interval (e.g., 15 days) by non-invasive imaging means (such as, but not limited to, verdit nuclear magnetism), and time-radius (volume) curves are plotted based on the cell size of each shot. The method is more suitable for long-term relationship establishment.
Cell size versus time-impedance examination: the size of the tumor cells in the area is reversely deduced by detecting the electrical impedance of the electrode coverage area according to the rule that the impedance of the tumor cells changes along with the volume. Time-radius (volume) curves were plotted for each cell size examined. The method is more suitable for long-term relationship establishment.
The electric field frequency conversion method and the electric field frequency conversion device for the TTF are based on section-variation frequency conversion, approximately regard cells of a target tissue as a uniform whole, and apply adaptive frequency to the uniform whole, so that only one frequency is needed to be applied. Since the parameters (size and/or electrical parameters) of this homogeneous ensemble vary with time, only one frequency needs to be applied at a time, and when this variation reaches a certain magnitude, the current frequency is changed to a new adaptation frequency to obtain a better effect of inhibiting the growth of tumor cells.
As shown in fig. 4, the electric field frequency conversion method includes the following steps:
step 101, acquiring uniform and integral adaptation frequency F of target tissue cells, and taking one of overall representative statistics of uniform and integral cell parameters C to obtain the adaptation frequency F from the cell parameters C;
102, acquiring a frequency conversion period DeltaT, wherein the frequency conversion period DeltaT is taken from natural time, or the frequency conversion period DeltaT is taken from time reaching the variation quantity DeltaC of a specified cell parameter C;
103, corresponding the cell parameters C and F, selecting one of the minimum value, the maximum value or the median of the interval to establish the corresponding adaptive frequency F, or selecting one of the other values of the cell parameters C to establish the corresponding adaptive frequency F;
and step 104, after a frequency conversion period delta T, changing the current frequency into a new adaptive frequency F, and stopping the frequency conversion of the electric field after the set TTF action time is reached.
Specifically, the electric field frequency conversion method comprises the following steps:
(1) Acquisition of the uniform overall adaptation frequency F:
first, the cells of the target tissue are regarded as a uniform whole, and thus, for the cell parameter C (size and/or electrical parameter) of the uniform whole, one of statistics having a whole representativeness is taken, and one of the average value, median and mode thereof may be taken. F can be deduced reversely from C.
(2) Obtaining a frequency conversion period delta T:
the first method comprises the following steps: the natural time is Δ T, and is, for example, 1 hour, 2 hours, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours (one week), 30 days, 45 days, 60 days (time interval between each double visit), 90 days (time interval between each double visit), and 120 days (time interval between each double visit).
The second method comprises the following steps: the time for reaching a certain C variation quantity deltaC is deltaT. Here again subdivided into two approaches. The first method is based on the variation of the initial cell parameter C0, which is divided into absolute value method and variation value method. Preferably, in step 102, when the frequency conversion period Δ T is taken from the time when the variation Δ C of the specified cellular parameter C is reached, the variation Δ C is determined in an absolute value method or a relative value method according to the variation of the initial cellular parameter C0.
Preferably, when the variation Δ C is determined by an absolute value method, the specified cell parameter C is recorded as C1 after the variation of the specified cell parameter C from the initial cell parameter C0 exceeds a certain set value Δ C, and the frequency is changed to a corresponding F1 at T1 corresponding to C1; when the change value of C to C0 is smaller than a set value DeltaC, the initial frequency F0 is still used.
For cell size, approximately spherical cells at the beginning of mitosis are used as the measurement standard, and Δ C is the radius or volume, the value of the radius is taken from 1 μm to 50 μm, and the value of the volume is taken from 1 μm 3 -10000μm 3 (ii) a Using end-stage mitotic double ellipsoid cells as a standard, and Δ C as a minor axis radius, a major axis radius, or a volume, said minor axis radius having a value from 0.5 μm to 50 μm, said major axis radius having a value from 1 μm to 50 μm, and said volume having a value from 1 μm 3 -10000μm 3 (ii) a Using spindle cells in non-dividing phase as standard, and Δ C as short axis length, long axis length or volume, wherein the short axis length is taken from 0.5 μm to 50 μm, the long axis length is taken from 1 μm to 100 μm, and the volume is taken from 1 μm 3 -10000μm 3 (ii) a Using squamous cells of epithelial origin and astrocytes of nervous system origin as standard, and Δ C as radius or volume, the value of radius being taken from 0.5 μm to 50 μm, and the value of volume being taken from 1 μm 3 -10000μm 3 (ii) a Taking columnar cells from glands as standard, and Δ C as column height, section radius or volumeThe column height is 0.5-50 μm, the section radius is 0.5-100 μm, and the volume is 1 μm 3 -10000μm 3 。
Preferably, when the variation Δ C is determined by using a relative value method, the variation of C to C0 exceeds a specified percentage of C0 and is recorded as C1, and the frequency should be changed to corresponding F1 at T1 corresponding to C1; the initial frequency F0 is still used when the C is less than C0 by a certain set value Δ C, where Δ C is taken from 10% -100% C0, Δ C is an absolute value, which may be positive or negative, since the parameters of the cells may be increased or decreased.
A third method is extended: when the frequency conversion period DeltaT is taken from the time of reaching the variation DeltaC of the specified cell parameter C, C corresponding to the variation DeltaF of the specified F is taken as DeltaC, and the time of reaching DeltaC is taken as T, wherein the DeltaF is 1KHz-150KHz. This method also has some benefit because the applied variation is in F when TTF is actually used, and the F variation that can be applied has its minimum gauge. Preferably, said Δ F is taken from 10KHz, 15KHz, 20KHz, 25KHz, 30KHz, 40KHz, 50KHz, 60KHz, 70KHz, 75KHz,80KHz, 90KHz or 100KHz.
(3) Correspondence of intervals and values
It should be noted that Δ C in the present invention is a range, and C is an interval, and different values in this interval have different F. Thus, one of the minimum/maximum values of the interval, or one of the values that statistically represent the whole (e.g., arithmetic mean, geometric mean, blending mean, median, mode), or one of the other values of C may be selected to establish the corresponding F.
(4) A section changing method comprises the following steps:
if the natural time is Δ T, when T0 reaches T1 through Δ T, F0 is replaced by F1 corresponding to C1 at T1, and so on.
If the time to reach Δ C or Δ F is Δ T, when T0 reaches T1 through Δ T, the corresponding frequency F1 is replaced with F0, and so on.
The invention also provides an electric field frequency conversion device for the TTF, and the electric field frequency conversion device adopts the electric field frequency conversion method to carry out frequency conversion control.
It should be noted that the electric field frequency conversion device for the TTF in the present invention is based on an electric field frequency conversion method. The electric field frequency conversion device for the TTF performs frequency conversion control by using the electric field frequency conversion method, and since a specific generation process of an electric signal for frequency conversion control is a known technical scheme, the present invention is not described herein again, and a person skilled in the art can completely obtain the electric field frequency conversion method based on the known technology in the art.
The electric field frequency conversion method and the electric field frequency conversion device for TTF are based on joint frequency conversion, approximately regard cells of a target tissue as a uniform whole, and apply adaptive frequency to the uniform whole, so that only one frequency is required to be applied. Since the parameters (size and/or electrical parameters) of this homogeneous ensemble vary with time, only one frequency needs to be applied at a time, and when this variation reaches a certain magnitude, the current frequency is changed to a new adaptation frequency to obtain a better effect of inhibiting the growth of tumor cells.
Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention and not to limit the same; although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that: modifications to the specific embodiments of the invention or equivalent substitutions for parts of the technical features may be made; without departing from the spirit of the present invention, it is intended to cover all aspects of the invention as defined by the appended claims.
Claims (10)
1. An electric field frequency conversion method for TTF is characterized in that: the electric field frequency conversion method comprises the following steps:
step 101, acquiring uniform and integral adaptation frequency F of target tissue cells, and taking one of overall representative statistics of uniform and integral cell parameters C to obtain the adaptation frequency F from the cell parameters C;
102, acquiring a frequency conversion period DeltaT, wherein the frequency conversion period DeltaT is taken from natural time, or the frequency conversion period DeltaT is taken from time reaching the variation quantity DeltaC of a specified cell parameter C;
103, corresponding the cell parameters C and F, and selecting one of the minimum value, the maximum value, the median value or the numerical value statistically representing the whole of the interval to establish the corresponding adaptive frequency F, or selecting one of the other values of the cell parameters C to establish the corresponding adaptive frequency F;
and step 104, after a frequency conversion period DeltaT, changing the current frequency into a new adaptive frequency F, and stopping the frequency conversion of the electric field after the set TTF action time is reached.
2. The method of claim 1, wherein: in step 102, Δ T is taken from 1 hour, 2 hours, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 30 days, 45 days, 60 days, 90 days or 120 days when the frequency conversion period Δ T is taken from natural time.
3. The method of claim 1, wherein: in step 102, when the frequency conversion period Δ T is taken from a time when the variation Δ C of the specified cell parameter C is reached, the variation Δ C is determined by an absolute value method or a relative value method according to the variation of the initial cell parameter C0.
4. The electric field frequency conversion method according to claim 3, characterized in that: when the variation quantity delta C is determined by adopting an absolute value method, the specified cell parameter C is recorded as C1 after the variation of the specified cell parameter C is more than a certain set value delta C than the initial cell parameter C0, and the frequency is changed into corresponding F1 when T1 corresponding to C1; when the change value of C to C0 is smaller than a set value DeltaC, the initial frequency F0 is still used.
5. The method of claim 4, wherein: for cell size, approximately spherical cells at the beginning of mitosis are used as the measurement standard, and Δ C is the radius or volume, the value of radius being taken from 1 μm to 50 μm, volumeIs taken from 1 μm 3 -10000μm 3 ；
Using end-mitotic double ellipsoid cells as a standard, Δ C as a minor axis radius, a major axis radius, or a volume, said minor axis radius being taken from 0.5 μm to 50 μm, said major axis radius being taken from 1 μm to 50 μm, and said volume being taken from 1 μm 3 -10000μm 3 ；
Using spindle cells in non-dividing phase as standard, and Δ C as short axis length, long axis length or volume, wherein the short axis length is 0.5-50 μm, the long axis length is 1-100 μm, and the volume is 1 μm 3 -10000μm 3 ；
Using squamous cells of epithelial origin and astrocytes of nervous system origin as standard, and Δ C as radius or volume, the value of radius being taken from 0.5 μm to 50 μm, and the value of volume being taken from 1 μm 3 -10000μm 3 ；
Using columnar cells of glandular origin as standard, and Δ C as column height, section radius or volume, the value of column height is taken from 0.5 μm to 50 μm, the value of section radius is taken from 0.5 μm to 100 μm, and the value of volume is taken from 1 μm 3 -10000μm 3 。
6. The electric field frequency conversion method according to claim 3, characterized in that: when the variation delta C is determined by adopting a relative value method, the variation of C to C0 exceeds the specified percentage of C0 and is marked as C1, and the frequency is changed into the corresponding F1 when the T1 corresponds to C1; the initial frequency F0 is still used when the C-to-C0 variation is less than a set value Δ C, where Δ C is taken from 10% -100% C0, where Δ C is an absolute value.
7. The method of claim 1, wherein: in step 102, when the frequency conversion period DeltaT is taken from the time of reaching the variation DeltaC of the specified cell parameter C, C corresponding to the variation DeltaF of reaching the specified F is taken as DeltaC, and the time of reaching the DeltaC is determined as T, wherein the DeltaF is 1KHz-150KHz.
8. The method of claim 7, wherein: the said Δ F is taken from 10KHz, 20KHz, 25KHz, 30KHz, 40KHz, 50KHz, 60KHz, 70KHz, 75KHz,80KHz, 90KHz or 100KHz.
9. The method of claim 1, wherein: in step 104, if the natural time is Δ T, when T0 reaches T1 after Δ T, F0 is replaced by F1 corresponding to C1 at T1, and so on;
if the time for reaching Δ C or Δ F is Δ T, when T0 reaches T1 through Δ T, F0 is replaced by the corresponding frequency F1, and so on.
10. An electric field frequency conversion device for TTF, characterized in that: the electric field frequency conversion device is subjected to frequency conversion control by using the electric field frequency conversion method as defined in any one of claims 1 to 9.
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| CN116196554A (en) * | 2023-03-23 | 2023-06-02 | 湖南安泰康成生物科技有限公司 | System for treating tumors by covering tumor cell sensitive frequency with multiple electric fields |
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| CN116196554A (en) * | 2023-03-23 | 2023-06-02 | 湖南安泰康成生物科技有限公司 | System for treating tumors by covering tumor cell sensitive frequency with multiple electric fields |
| CN116196554B (en) * | 2023-03-23 | 2024-03-12 | 湖南安泰康成生物科技有限公司 | System for treating tumors by covering tumor cell sensitive frequency with multiple electric fields |
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