Abstract:
A method for controlling an electroporation device configured for supplying an electrical power signal to a plurality of pairs of electrodes coupled to a portion of the human body, wherein the following steps are performed: detecting, in the course of an electroporation treatment, a condition of malfunctioning or fail for the pairs of electrodes for which at least one electrical parameter of the power signal supplied to the electrodes themselves has an anomalous value; storing an indicator of the pairs of electrodes in the fail condition; and selecting the pairs of electrodes in the fail condition and re-computing new parameters in order to implement a subsequent electroporation process.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This patent application is a U.S. National Phase Application under 35 U.S.C. §371 of International Application No. PCT/IB2012/052159, filed Apr. 30, 2012, entitled METHOD FOR CONTROLLING AN ELECTROPORATION DEVICE, which claims priority to Italian Patent Application No. TO2011A000374, filed Apr. 29, 2011. 
     TECHNICAL FIELD 
     The present invention relates to a method for controlling an electroporation device. 
     BACKGROUND ART 
     As is known, electroporation treatments are carried out using electronic devices designed to supply at output a pulsating a.c. signal to a plurality of electrodes applied to a tissue for creating currents induced in the tissue and modify the permeability of the cell membrane of the cells present in the tissue itself. The modification of the permeability of the cell membrane is normally used for carrying drugs, organic compounds, or generically molecules within the cell. 
     The parameters of the a.c. signal, for example the waveform, frequency, voltage, duty-cycle, and application time, are normally defined in an off-line mode, i.e., before starting the treatment, according to the effect that it is desired to obtain on the cells. Said definition includes the use of tables based upon experimental data, i.e., data that have been collected and refined by monitoring the results of a plurality of electroporation treatments performed previously. 
     Not always does the use of said experimental data enable execution of an electroporation treatment that obtains the desired effects. In the case of partial or total failure of the electroporation method, it is consequently difficult to determine what further actions to perform. 
     SUMMARY 
     The aim of the present invention is to provide a method for controlling an electroporation device that, in the case of failure, will enable automatic modification of the parameters of the treatment previously performed by computing and implementing new parameters. 
     The above aim is achieved by the present invention in so far as this relates to a method for controlling an electroporation device configured for supplying an electrical power signal to a plurality of pairs of electrodes coupled to a portion of the human body, the method comprising the steps of: detecting, in the course of an electroporation treatment, a condition of malfunctioning or fail for the pairs of electrodes for which at least one electrical parameter of the power signal supplied to the electrodes themselves has an anomalous value; storing an indicator of the pairs of electrodes in the fail condition; selecting the pairs of electrodes in the fail condition and re-computing for them new parameters for implementing a subsequent electroporation process. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The invention will now be described with reference to the attached drawings, which illustrate an example of embodiment thereof and in which: 
         FIG. 1  illustrates, in a schematic way, an electroporation device operating according to the method according to the present invention; and 
         FIG. 2  illustrates by means of a block diagram the method according to the present invention. 
     
    
    
     DETAILED DESCRIPTION 
     In  FIG. 1 , designated as a whole by  1  and illustrated schematically is an electroporation device which comprises a hardware structure of a known type, in which a signal generator  3  of an adjustable type produces at output a pulsating signal that is supplied at input to a power amplifier  4 , which in turn supplies a power signal to a set of electrodes  5  (for example, to a plurality of needle-shaped electrodes arranged according to an orderly array structure). 
     The electrodes  5  are designed to be applied to a portion of human body  7  for generating electrical fields designed to modify the permeability of the cell membrane of the cells comprised in the portion  7  and impinged upon by the electrical field. Typically, the power signal is supplied in sequence to different pairs of electrodes  5   a ,  5   b  so that the electrical field will impinge upon the entire portion  7  in which the electrodes  5  are arranged. 
     A control unit  10  of the signal generator  3  enables regulation of a plurality of parameters, amongst which:
         the waveform of the power signal (for example, square-wave, sawtooth, sinusoidal, triangular, exponential, etc.);   the frequency of the power signal;   the duty-cycle of the power signal;   the application time of the power signal;   the temporal spacing between groups of consecutive pulses; and   other electrical parameters of the power signal.       

     The device  1  is provided with a plurality of sensors that monitor continuously the electrical quantities of the electroporation process in progress; in particular, sensors  12 ,  13 ,  14  are provided, designed to measure the instantaneous value of the current le supplied to each pair of electrodes  5   a ,  5   b , the voltage value Ve applied to said pair of electrodes, and the impedance Z(ω) present between said pair of electrodes. 
     According to the present invention, the microprocessor unit of the control unit  10  implements a plurality of instructions that implement a control method, as described hereinafter with reference to  FIG. 2 . 
     In use, on the basis of the type of electroporation treatment to be carried out, by means of a calculation procedure of an off-line type, the distance between the electrodes  5  and their arrangement are set, and the characteristics of the power signal and the duration of the electroporation treatment are also defined. Typically, the setting is made with a set of maps (not illustrated) that take into account experimental data obtained from treatments performed previously. 
     The electroporation treatment starts. During said treatment the instantaneous values of the voltage Ve and of the current Ie are monitored continuously. 
     In the case where, for a given pair of electrodes, the value of current Ie departs from a range of acceptability (and, namely, is too high or too low) a situation of malfunctioning or fail is detected, for that pair of electrodes. 
     In the presence of an indication of fail the value of impedance Z(ω) present between the pair of electrodes considered is measured (said operation is indicated by block in  FIG. 2 ) and an indicator (tag) is stored, which identifies the pairs of electrodes  5  that have given rise to a fail. 
     The control method according to the present invention performs, for the pairs of electrodes for which a fail has been detected and a tag has been stored, a further analysis (said operations are indicated by the respective block  90  and  60  in  FIG. 2 ) described hereinafter with reference to  FIG. 2 . 
     With particular reference to  FIG. 2 , the method comprises a block  100  (subsequent to block  90 ), which, since parameters of the electroporation process have been detected outside an interval of acceptability for a pair of electrodes selected (block  90 —Identification of failed pairs), performs an analysis for defining the type of corrective action for said pair of electrodes. The pair of electrodes in question is again supplied with the power signal for verifying the value of the electrical quantities associated thereto. 
     In this connection, block  100  comprises a block  110  that verifies whether the current that has been supplied to the electrodes I E  is lower than a minimum threshold value I LOW ; if it is not (i.e., if the current I E  is higher than the threshold value I LOW ) the current is recognized as acceptable, and block  110  is followed by a block  120 ; otherwise (i.e., if the current I E  is lower than the threshold value I LOW ), an anomalous current is recognized, which is an index of an electroporation process that has not yet started, and from block  110  control passes to block  130 . 
     Block  130  computes (in a known way by applying Ohm&#39;s law once the impedance Z(ω) is known) the value of the voltage that can be applied to the electrodes necessary to obtain an increase of the current and bring the electroporation current to a target value (for example, at least 1.5 A). The calculation made in block  130  is possible in so far as the impedance of the tissue is known precisely. 
     Processing of block  130  continues until a current is calculated having a target value I TARGET  corresponding to which is a voltage V T  necessary to obtain said value of current. 
     Next, a check is made (block  140  subsequent to block  130 ) to verify whether the voltage V T  thus obtained is lower than (or equal to) the maximum voltage V Max  that can be supplied by the electroporation device  1 ; if so (i.e., in the case where the voltage calculated can be supplied by the device that implements the electroporation method, i.e., V T &lt;V Max ) block  140  is followed by a block  150  that stores the voltage equal to V T  to be applied for the pair of electrodes considered. The parameters of the electroporation process are thus redefined (block  225 ), and the verification process continues for each other pair of electrodes for which a fail condition has been detected (consequently control returns to block  90 ). 
     In the case where the voltage V T  thus obtained is higher than the maximum voltage V Max  that can be supplied, block  140  is followed by a block  160 , which detects said physical limit in the voltage that can be supplied to implement a series of solutions aimed at obtaining in any case electroporation of the tissue. In this connection, block  160  is followed by a block  170  that calculates the number of pulses per unit time (for example, the treatment time) necessary to obtain electroporation of the tissues having available the voltage V Max ; in particular, the number of pulses supplied per unit time is increased bringing the current number of pulses N PULSE  to a higher number K PULSE  (with K PULSE &gt;N PULSE ); the number of pulses per unit time is thus increased. The calculation of the number of pulses K PULSE  necessary is carried out by a block  175  on the basis of an algorithm. 
     The algorithm of block  175  envisages calculation of the equivalent dose EqD absorbed by the means, according to the formula
 
EqD=τ E   2   tk   −1/2 ρ −1   [1]
 
where τ is the conductivity of the tissue, E the electrical field supplied, t the time duration of each pulse, k the number of pulses supplied, and ρ the density of the material.
 
     Said equivalent dose is calculated first for the standard condition, i.e., the one that is determined by the protocol previously applied with parameters of the signal (for example, waveform, frequency, voltage, duty-cycle, application time) defined in an off-line mode and that has given rise to the fail condition. 
     In the present case, since the intensity E 2  of the electrical field is no longer modifiable (block  160 , the voltage reached is the limit voltage), it is alternatively possible to modify the number of pulses k −1/2  so as to maintain the equivalent dose EqD constant and equal to the one obtained in the calculation executed for the standard condition. 
     Consequently, the number k of the pulses is given by
 
EqD=τ E 2 tk− 1 / 2  ρ− 1  (1)
 
     For completeness, given that it is one and the same tissue, Equation 1 can be simplified as follows
 
 E   1   2   k   1   −1/2   =E   2   2   k   2   −1/2  
 
Since E=V/d, if we assume maintaining the same geometry of the electrodes, it can be further simplified as follows
 
 V   1   2   k   1   −1/2   =V   2   2   k   2   −1/2  
 
 k   PULSE =( V   2   /V   1 ) 4   k   1  
 
     In the case where the number of pulses necessary K PULSE  is lower than a threshold value X (said control is performed by a block  180  subsequent to block  170  that carries out the operation K PULSE &lt;X), stored as electroporation parameter is the value K PULSE  of pulses having a voltage equal to the maximum value that can be supplied by the machine (block  225 ), and the verification process continues for another pair of electrodes for which a fail condition has been detected. 
     In the case where the number of pulses necessary K PULSE  is higher than X, stored as electroporation parameter is the value X (block  182 ) of pulses having a voltage equal to the maximum value that can be supplied by the machine, and the verification process continues for another pair of electrodes for which a fail condition has been detected. 
     In the case where the maximum value of pulses X is detected, also a request for reversal of polarity of the power signal can be stored (block  183 ). Alternatively, the reversal of polarity can be carried out in any case irrespective of whether X is exceeded. 
     If necessary, other electro-sensitization techniques (block  184 ) can also be applied, i.e., techniques that increase the sensitivity of the tissues to the electroporation phenomenon, for example by dividing the number of pulses thus calculated into a number of applications separated by intervals in which no pulse is supplied (for example, 30 seconds-30 minutes). 
     All the parameters modified are stored, and the verification process continues for another pair of electrodes for which a fail condition has been detected. 
     Block  120  verifies whether the electroporation current I E  exceeds a maximum value I HIGH  beyond which the electroporation device cannot operate in safety conditions. 
     In the case where the current I E  exceeds the maximum value I HIGH , the process continues with a block  210  subsequent to block  120  that calculates a reduced voltage value V min  that enables a reduction in the current such that the value of current I E  drops below the maximum value I HIGH  according to Ohm&#39;s law given that the impedance of the tissue is known. 
     Block  210  is followed by a block  220  that calculates the increase in the numbers of pulses necessary per unit time (for example, treatment time) in order to compensate for the reduction in voltage performed in block  210 . 
     A value K COMP  of pulses is calculated with procedures (block  222 ) altogether similar to those of block  175  and consequently, for simplicity, not described in detail. 
     In the case where the number of pulses necessary K COMP  is lower than a threshold value X (said control is performed by a block  280  subsequent to block  270  that carries out the operation K PULSE &lt;X) stored as electroporation parameter is the value K PULSE  of pulses having a reduced voltage V min  equal to the one calculated by block  210 , and the verification process continues for another pair of electrodes for which a fail condition has been detected (block  225 ). 
     In the case where the necessary number of pulses K COMP  is higher than X, the maximum value X of pulses having a voltage corresponding to the reduced voltage V min  is stored (block  282 ) equal to the one calculated by block  210 , and the verification process continues for another pair of electrodes for which a fail condition has been detected after a series of corrective actions have been attempted. 
     In fact, in the case where the maximum value of pulses X is detected, it is possible to store also a request for reversal of polarity (block  283 ) of the power signal. Alternatively, the reversal of polarity can be carried out in any case irrespective of whether X has been exceeded. 
     If necessary, it is also possible to apply other electro-sensitization techniques (block  284 ), i.e., techniques that increase the sensitivity of the tissues to the electroporation phenomenon, for example by dividing the number of pulses thus calculated into a number of applications separated by intervals in which no pulse is supplied (for example, 30 seconds-30 minutes). 
     All the parameters modified are stored (block  225 ), and the verification process continues for another pair of electrodes for which a fail condition has been detected. 
     The condition whereby the current does not exceed the threshold (output NO from block  120 ) is considered a non-realizable condition in so far as—in the case of presence of a current that is in any case acceptable—the fail condition would not arise. 
     A different output from block  120  is only possible when the post-pulse analysis detects a condition of overcurrent due to short circuit between the electrodes of a pair and not to a low-impedance load (transition from block  120  to block  210 ). It is possible to establish a minimum impedance below which this condition arises. 
     In the above case of short circuit, it is possible to resort to identification (block  320  subsequent to block  120 ) of a pair of electrodes different from the short-circuited one. From block  320  control then passes to a block  330  where the parameters of the pair identified are modified to increase the coverage of the electrical field so as to compensate for the absence of the short-circuited pair. In the case where the activity of compensation is not effective, from block  330  control goes to a block  300 , which, in second instance, identifies all the pairs adjacent to the short-circuited one so as to modify the parameters of said pairs and increase the coverage of the electrical field in order to compensate for the absence of the short-circuited pair. 
     In the case where this procedure were to prove impracticable, a warning may be issued to signal the need to reposition the electrodes (block  310 ).