Reducing electrosensation whilst treating subject using alternating electric fields by pairing transducer arrays together

Abstract

To provide a method for treating a tumor in a target area and delivering substance beyond a biological barrier in the target area.SOLUTION: When treating a subject using alternating electric field (e.g., using TT Field to treat a tumor, or using alternating electric fields to increase permeability of a blood brain barrier), some subjects experience an unpleasant electrosensation effect. This electrosensation can be reduced or eliminated by increasing an area of transducer arrays that is active during certain times in the treatment. In some embodiments, this is accomplished by applying an AC signal between two pairs of transducer arrays at certain times (as opposed to the prior art approach applying an AC signal between two individual transducer arrays).SELECTED DRAWING: Figure 4

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Application No. 63 / 325,438, filed March 30, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Tumor treating electric fields, or TT fields, are alternating electric fields in the mid-frequency range (e.g., 100-500 kHz) that inhibit cancer cell growth. This non-invasive treatment targets solid tumors and is described in U.S. Patent No. 7,565,205, which is incorporated herein by reference in its entirety. 200 kHz TT fields are FDA-approved for the treatment of glioblastoma (GBM) and can be delivered, for example, via a conventional Optune® system, shown schematically in FIG. 1. TT fields are delivered to the patient via four transducer arrays 10 (i.e., electrode arrays) placed on the patient's skin adjacent to the tumor. Each transducer array 10 includes multiple (e.g., 9-20) capacitively coupled electrode elements, each of which has a conductive substrate with a dielectric layer disposed thereon.

[0003] Alternating current electric fields with frequencies between 50 kHz and 1 MHz can also be used to treat conditions other than tumors. For example, as described in U.S. Patent No. 10,967,167 (incorporated herein by reference in its entirety), alternating current electric fields, for example, between 50 and 200 kHz, increase the permeability of the blood-brain barrier (BBB), allowing, for example, chemotherapy drugs to reach the brain. Also, as described in U.S. Patent No. 11,103,698 (incorporated herein by reference in its entirety), alternating current electric fields, for example, between 50 and 500 kHz, increase the permeability of cell membranes, allowing large molecules to pass through them.

[0004] When Optune® is used to treat glioblastoma, one pair of arrays (10L, 10R) is placed on the left and right sides of the tumor, and another pair of arrays (10A, 10P) is placed in front and behind the tumor. The Optune® signal generator 95 (a) applies an AC voltage between arrays 10L and 10R for one second to induce an electric field in one direction through the tumor. Then, (b) applies an AC voltage between arrays 10A and 10P for one second to induce an electric field in the other direction through the tumor. This two-step sequence (a) and (b) is then repeated throughout the treatment period. Summary of the Invention [Means for solving the problem]

[0005] One aspect of the present application relates to a first method for treating a tumor in a target area and delivering a substance across a biological barrier within the target, the first method including applying an alternating current voltage at a first frequency between a first set of one or more electrode elements disposed on a first side of the target area and a second set of one or more electrode elements disposed on a second side of the target area, the first side and the second side being on opposite sides of the target area, and applying an alternating current voltage at a second frequency between a third set of one or more electrode elements disposed on a third side of the target area and a fourth set of one or more electrode elements disposed on a fourth side of the target area, the third side and the fourth side being on opposite sides of the target area, the third side being circumferentially disposed between the first side and the second side, and the fourth side being circumferentially disposed between the first side and the second side. The first method also includes applying an AC voltage at a third frequency between (i) both the first and third sets of one or more electrode elements and (ii) both the second and fourth sets of one or more electrode elements, the third frequency being lower than the first frequency and the third frequency being lower than the second frequency, wherein the AC voltage at the first frequency, the AC voltage at the second frequency, and the AC voltage at the third frequency are each applied for a different time interval.

[0006] Some examples of the first method further include the steps of positioning a first set of one or more electrode elements on a first side of the target area, a second set of one or more electrode elements on a second side of the target area, a third set of one or more electrode elements on a third side of the target area, and a fourth set of one or more electrode elements on a fourth side of the target area.

[0007] In some examples of the first method, the first frequency is selected so that an electric field induced in the target region by applying an alternating voltage at the first frequency between a first set of one or more electrode elements and a second set of one or more electrode elements has an antimitotic effect. The second frequency is selected so that an electric field induced in the target region by applying an alternating voltage at the second frequency between a third set of one or more electrode elements and a fourth set of one or more electrode elements has an antimitotic effect. Also, the third frequency is selected so that an electric field induced in the target region by applying an alternating voltage at the third frequency between (a) both the first and third sets of one or more electrode elements and (b) both the second and fourth sets of one or more electrode elements increases the permeability of a biological barrier in the target region. Optionally, in these examples, the first frequency and the second frequency may be the same.

[0008] In some examples of the first method, the first frequency and the second frequency are each between 50 kHz and 1 MHz, and the third frequency is between 50 kHz and 300 kHz. In some examples of the first method, the AC voltage at the third frequency is applied for at least 24 hours.

[0009] In some examples of the first method, the steps of (a) applying an alternating voltage at a first frequency between a first set of one or more electrode elements and a second set of one or more electrode elements, and (b) applying an alternating voltage at a second frequency between a third set of one or more electrode elements and a fourth set of one or more electrode elements are alternately repeated at least 10,000 times.

[0010] Another aspect of the present application relates to a first device for treating a tumor in a target region and facilitating delivery of a substance across a biological barrier in the target region. The first device includes at least one signal generator, a switch bank, and a controller. The at least one signal generator is configured to generate an AC voltage at a first frequency and generate an AC voltage at a second frequency, the second frequency being lower than the first frequency. The switch bank has at least one control input, a first output terminal, a second output terminal, a third output terminal, and a fourth output terminal. The switch bank receives the AC voltage at the first frequency and receives the AC voltage at the second frequency. The switch bank is configured to route the AC voltage at the first frequency between the first output terminal and the second output terminal in response to a first state of the at least one control input. The switch bank is further configured to route the AC voltage at the first frequency between the third output terminal and the fourth output terminal in response to a second state of the at least one control input. The switch bank is further configured to route the AC voltage at the second frequency such that the AC voltage at the second frequency appears (a) between both the first and third output terminals and (b) between both the second and fourth output terminals in response to a third state of the at least one control input. The controller is programmed to (i) set the at least one control input to the first state, (ii) set the at least one control input to the second state, and (iii) set the at least one control input to the third state at different time intervals.

[0011] In some embodiments of the first device, the first frequency is selected to provide an antimitotic effect, and the second frequency is selected to increase the permeability of a biological barrier. In some embodiments of the first device, the first frequency is between 50 kHz and 1 MHz, and the second frequency is between 50 kHz and 300 kHz. In some embodiments of the first device, the controller is programmed to alternately repeat (i) setting at least one control input to a first state and (ii) setting at least one control input to a second state at least 10,000 times. In some embodiments of the first device, the controller is programmed to, after repeating (i) and (ii) at least 10,000 times, set at least one control input to a third state, and then leave the at least one control input in the third state for at least 12 hours.

[0012] Another aspect of the present application relates to a second method for applying an AC electric field to a target region of a subject's body using a first set of one or more electrode elements disposed on a first side of the target region, a second set of one or more electrode elements disposed on a second side of the target region, a third set of one or more electrode elements disposed on a third side of the target region, and a fourth set of one or more electrode elements disposed on a fourth side of the target region. The second method includes the steps of (a) applying an AC voltage at a first frequency between both the first and third sets of one or more electrode elements and (ii) between both the second and fourth sets of one or more electrode elements, and (b) applying an AC voltage at a second frequency between both the first and fourth sets of one or more electrode elements and (ii) between both the second and third sets of one or more electrode elements. The first and second sides are on opposite sides of the target region. The third and fourth sides are on opposite sides of the target region. The third side is circumferentially disposed between the first and second sides. The fourth side is circumferentially disposed between the first side and the second side. Steps (a) and (b) are alternately repeated at least 10 times.

[0013] Some examples of the second method further include placing a first set of one or more electrode elements on or within the subject's body, a second set of one or more electrode elements on or within the subject's body, a third set of one or more electrode elements on or within the subject's body, and a fourth set of one or more electrode elements on or within the subject's body.

[0014] In some examples of the second method, the first frequency and the second frequency are each between 50 kHz and 1 MHz. In some examples of the second method, the first frequency and the second frequency are the same.

[0015] Another aspect of the present application relates to a second device for applying signals to a set of electrodes. The second device includes at least one signal generator, a switch bank, and a controller. The at least one signal generator is configured to generate an AC voltage. The switch bank has at least one control input, a first output terminal, a second output terminal, a third output terminal, and a fourth output terminal, and the switch bank receives the AC voltage at a first frequency. The switch bank is configured to route the AC voltage in response to a first state of the at least one control input such that the AC voltage appears (a) between both the first output terminal and the third output terminal, and (b) between both the second output terminal and the fourth output terminal. The switch bank is also configured to route the AC voltage in response to a second state of the at least one control input such that the AC voltage appears (a) between both the first output terminal and the fourth output terminal, and (b) between both the second output terminal and the third output terminal. The controller is also programmed to alternately repeat at least 10 times: (i) setting at least one control input to a first state; and (ii) setting at least one control input to a second state.

[0016] In some embodiments of the second device, the frequency of the AC voltage is between 50 kHz and 1 MHz.

[0017] Another aspect of the present application relates to a third method for applying an alternating current electric field to a body part of a subject, the body part having a longitudinal axis. The third method includes applying an alternating current voltage between a first side or a first set of one or more electrode elements disposed on the first side of the body part and a second side or a second set of one or more electrode elements disposed on the second side of the body part. The first side and the second side are on opposite sides of the longitudinal axis. The first set of one or more electrode elements subtend a first azimuthal angle of at least 120° with respect to the longitudinal axis, within which the electrode elements provide at least one-third coverage. The second set of one or more electrode elements subtend a second azimuthal angle of at least 120° with respect to the longitudinal axis, within which the electrode elements provide at least one-third coverage.

[0018] In some examples of the third method, the first set of one or more electrode elements is a set of capacitively coupled electrode elements, and the second set of one or more electrode elements is a set of capacitively coupled electrode elements.

[0019] In some examples of the third method, the frequency of the AC voltage is less than 1 MHz. In some examples of the third method, the frequency of the AC voltage is less than 190 KHz. In some examples of the third method, the AC voltage is applied for at least 24 hours. In some examples of the third method, the first azimuthal angle is at least 135° and the second azimuthal angle is at least 135°.

[0020] In some examples of the third method, the coverage by the electrode elements within the first azimuthal angle is at least half, and the coverage by the electrode elements within the second azimuthal angle is at least half.

[0021] In some examples of the third method, the body part is the head and the first set of one or more electrode elements has a total area of ​​at least 40 cm 2 and the second set of one or more electrode elements has a total area of ​​at least 40 cm 2 is.

[0022] Another aspect of the present application relates to a fourth method of applying an alternating current electric field to a subject's head having a longitudinal axis and a circumference. The fourth method includes applying an alternating current voltage between a first set of one or more electrode elements disposed on a first side of the subject's head and a second set of one or more electrode elements disposed on a second side of the subject's head. The first and second sides are on opposite sides of the longitudinal axis. The first set of one or more electrode elements extend along the circumference over a first length of at least 15 cm, with at least one-third of the circumference covered by the electrode elements. The second set of one or more electrode elements extend along the circumference over a second length of at least 15 cm, with at least one-third of the circumference covered by the electrode elements.

[0023] In some examples of the fourth method, the first set of one or more electrode elements is a set of capacitively coupled electrode elements, and the second set of one or more electrode elements is a set of capacitively coupled electrode elements.

[0024] In some examples of the fourth method, the frequency of the AC voltage is less than 1 MHz. In some examples of the fourth method, the frequency of the AC voltage is less than 190 kHz. In some examples of the fourth method, the AC voltage is applied for at least 24 hours.

[0025] In some examples of the fourth method, the coverage by the electrode elements within the first length is at least half, and the coverage by the electrode elements within the second length is at least half.

[0026] In some examples of the fourth method, the total area of ​​the first set of one or more electrode elements is at least 40 cm 2 and the second set of one or more electrode elements has a total area of ​​at least 40 cm 2 is. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 is a schematic diagram of a conventional Optune® system. [Figure 2A]1 shows a set of transducer arrays used to deliver alternating electric field therapy to a subject's head. [Figure 2B] 1 shows a set of transducer arrays used to deliver alternating electric field therapy to a subject's head. [Figure 2C] 1 shows a set of transducer arrays used to deliver alternating electric field therapy to a subject's head. [Figure 2D] 1 shows a set of transducer arrays used to deliver alternating electric field therapy to a subject's head. [Figure 3A] FIG. 1 is a schematic diagram of the electric field induced when an AC voltage is applied between the left and right transducer arrays. [Figure 3B] FIG. 1 is a schematic diagram of the electric field induced when an AC voltage is applied between the front and rear transducer arrays. [Figure 4] FIG. 1 is a block diagram of an embodiment in which one phase of an AC signal is applied simultaneously to two transducer arrays and the other phase of the AC signal is applied simultaneously to the other two transducer arrays. [Figure 5A] Schematic of the electric field induced when an AC voltage is applied between two transducer arrays (front + left) and the remaining two transducer arrays. [Figure 5B] Schematic of the electric field induced when an AC voltage is applied between two transducer arrays (front + right) and the remaining two transducer arrays. [Figure 6] FIG. 5B is a timing diagram of commands for inducing an electric field in the direction of FIG. 5A and the direction of FIG. 5B at different times. [Figure 7] FIG. 10 is a block diagram of another embodiment in which one phase of an AC signal is applied simultaneously to two transducer arrays and the other phase of the AC signal is applied simultaneously to the other two transducer arrays. [Figure 8A] FIG. 5B is a timing diagram of commands for inducing electric fields in the directions of FIG. 3A, FIG. 3B, and FIG. 5A at different times. [Figure 8B]FIG. 5B is a timing diagram of commands for inducing electric fields in the directions of FIGS. 3A, 3B, and 5B at different times. DETAILED DESCRIPTION OF THE INVENTION

[0028] Various embodiments will now be described in detail with reference to the accompanying drawings, in which like reference numerals represent like elements, and in which:

[0029] When treating a subject with an AC electric field, the greater the amplitude, the greater the therapeutic effect. However, as the amplitude of the AC electric field increases and / or the frequency of the AC electric field decreases (e.g., up to approximately 100 kHz), some subjects may experience an electrosensory effect when the AC field switches direction. This electrosensation may be, for example, a vibratory sensation, paresthesia, and / or a muscle fiber twitching or contraction sensation. The electrosensation is thought to arise from the interaction of AC electric fields placed near or adjacent to the transducer array with nerve cells (i.e., neurons). These sensations may also deter some subjects from continuing treatment with AC electric fields.

[0030] This application describes various approaches to reducing or eliminating electrical sensations while a subject is being treated with an alternating current electric field. These approaches rely on increasing the area of ​​the transducer array that is active at specific times during treatment. In some embodiments, this is achieved by applying an alternating current signal between two pairs of transducer arrays at specific times (as opposed to the traditional approach of applying an alternating current signal between two separate transducer arrays).

[0031] Suppose an alternating current of a particular frequency is coupled into a subject's body through a pair of electrodes placed on the subject's skin. If the current density (i.e., the current through any electrode divided by the area of ​​that electrode) is below a threshold (which may vary from person to person), no electrical sensation occurs. However, if the current density exceeds that threshold, an electrical sensation begins to occur, and as the current density increases further, the electrical sensation becomes more noticeable.

[0032] A numerical example is helpful to illustrate this point. Assume that a conventional Optune® system, shown in Figure 1, is being used to treat a glioblastoma in a subject's head using a 200 kHz TT field. Figures 2A-2D show the Optune® transducer arrays used to deliver treatment to the subject's head. Each of these transducer arrays contains nine circular electrode elements, each 2 cm in diameter (1 cm radius). Therefore, the total area of ​​all electrode elements in any transducer array is 9 × 3.14 × 1 2 =28cm 2 is.

[0033] Further, assume that the output current of the conventional Optune system is 2 A. As explained above, during one time interval, an AC voltage is applied only between arrays 10L and 10R, inducing an electric field in the subject's head. The electric field lines run, on average, from left to right (i.e., in the direction of the dashed line in Figure 3A). During another time interval, an AC voltage is applied only between arrays 10A and 10P, inducing an electric field in the subject's head. The electric field lines run, on average, from front to back (i.e., in the direction of the dashed line in Figure 3B). During the former interval, the current density in each of transducer arrays 10L and 10R is 2 A ÷ 28 cm. 2 =71mA / cm 2 At the latter spacing, the current density in each of the transducer arrays 10L and 10R is 2 A ÷ 28 cm 2 =71mA / cm 2 (Note that in reality, the electric field lines are not straight; however, in Figures 3A / B and 5A / B, straight dashed lines are used to represent the general direction of the magnetic field lines.)

[0034] Here, for a specific subject (hereinafter referred to as "subject #1"), the threshold at which electrical sensation begins to occur at a specific frequency is 60 mA / cm 2 In this example, the current density in each transducer array is assumed to be 71 mA / cm 2 (i.e., higher than subject #1's threshold), subject #1 experiences an electric sensation. One approach to remedy this situation is to reduce the current to, for example, 1.5 A. This reduces the current density to 1.5 A ÷ 28 cm 2 =54mA / cm 2 , below the electrosensory threshold of subject #1. However, this approach is suboptimal as lower currents typically result in less effective treatment.

[0035] 4 is a block diagram of an embodiment that uses a different approach to reduce the current density in each transducer array without reducing the overall current. The transducer arrays 10 in this embodiment are themselves similar to the transducer arrays 10 described above. However, the AC voltages are applied to these transducer arrays 10 in a different pattern, as described below.

[0036] In this embodiment of FIG. 4 , an AC signal generator 20 generates an AC output signal having two phases, each of which is input to a switch bank 25. Various approaches for implementing the switch bank 25 will be apparent to those skilled in the art (including, but not limited to, wiring four SPST solid-state relays between a first phase input and each of the four outputs, and wiring four more SPST solid-state relays between a second phase input and each of the four outputs). The path of the AC output signal through the switch bank 25 is controlled by signals originating from a controller 30. The switch bank 25 (operating in response to commands from the controller 30) is configured to simultaneously route one phase of the AC output signal to two transducer arrays 10 and simultaneously route the other phase of the AC output signal to the other two transducer arrays 10.

[0037] For example, the switch bank 25 can be instructed to route one phase of the AC output signal to both the front and left transducer arrays 10A, 10L, and the other phase of the AC signal to both the rear and right arrays 10P, 10R. When the switch bank 25 is configured in this manner, these voltages induce an electric field in the subject's head whose electric field lines run, on average, diagonally (i.e., in the direction of the dashed lines in FIG. 5A). The switch bank 25 can also be instructed to route one phase of the AC output signal to both the rear and left transducer arrays 10P, 10L, and the other phase of the AC signal to both the front and right arrays 10A, 10R. When the switch bank 25 is configured in this manner, these voltages induce an electric field in the subject's head whose electric field lines run, on average, diagonally (i.e., in the direction of the dashed lines in FIG. 5B).

[0038] Next, using the embodiment of Figure 4, we will energize the transducer arrays on subject #1's head using the same output current as in the original example (i.e., 2 A) and analyze what happens when each phase of the AC output signal is simultaneously routed to two transducer arrays 10. As explained above, the total area of ​​all electrode elements in any transducer array is 28 cm 2 However, since each phase of the AC output signal is routed to two transducer arrays 10 simultaneously, the same 2 A current is applied to a 2 × 28 cm 2 =56cm 2 Therefore, the current density of each transducer array 10 is 2A ÷ 56cm 2 =36mA / cm 2 This corresponds to the electrical sensation threshold of subject #1 of 60 mA / cm 2 In fact, in this embodiment, the current could be increased to above 3 A before reaching subject #1's electrical sensation threshold.

[0039] As explained above, when each phase of the AC output signal is simultaneously routed to two transducer arrays 10, the current in the AC output signal is spread over a significantly wider area. Meanwhile, the extent of the electrode elements in active use at any instant, whether measured in area (see above) or in other units such as azimuth or circumference (see below), is significantly wider than the extent of the electrode elements active at any instant in a conventional Optune® system.

[0040] 5A and 5B are plan views of a subject's head being treated with an AC electric field using four transducer arrays 10A, 10P, 10L, and 10R positioned on the front, back, left, and right sides of the subject's head, respectively. The dashed lines in FIG. 5A show a very rough approximation of the electric field lines when one phase of the AC output signal is routed to both the front and left transducer arrays 10A and 10L, and the other phase of the AC signal is routed to both the back and right arrays 10P and 10R. In this situation, the front and left transducer arrays collectively act as a first set of electrode elements, and the back and right transducer arrays collectively act as a second set of electrode elements.

[0041] In this situation, an alternating current electric field is applied to the subject's head by applying an alternating current voltage between (a) a first set of one or more electrode elements 10A, 10L disposed on a first side of the head and (b) a second set of one or more electrode elements 10P, 10R disposed on or in a second side of the head, the first and second sides being on opposite sides of the longitudinal axis of the head.

[0042] In particular, a first set of one or more electrode elements collectively define a first azimuthal angle φ(L+A) relative to the longitudinal axis, and a second set of one or more electrode elements collectively define a second azimuthal angle φ(R+P) relative to the longitudinal axis (note that the azimuthal angles referred to herein are measured in polar coordinates in a plane perpendicular to the longitudinal axis of the head).

[0043] The first azimuthal angle φ(L+A) and the second azimuthal angle φ(R+P) in FIG. 5A are each at least 120°, and in some embodiments, these angles are each at least 135°. These angles are significantly larger than the azimuthal angles collectively defined by the electrode elements active at any given time in a conventional Optune® system (i.e., φ(L) and φ(R) in FIG. 3A (the instant when an AC voltage is applied between the left transducer array 10L and the right transducer array 10R), or φ(A) and φ(P) in FIG. 3B (the instant when an AC voltage is applied between the front transducer array 10A and the rear transducer array 10P).

[0044] A similar situation exists when considering the circumference of the head spanned by the electrode elements in each of the first and second sets of electrode elements. More specifically, the one or more first set of electrode elements collectively span more than 15 cm around the head, and the one or more second set of electrode elements collectively span more than 15 cm around the head. These distances are significantly greater than the circumference spanned collectively by the active electrode elements in left and right transducer arrays 10L and 10R of a conventional Optune® system at the moment an AC voltage is applied between these arrays, as shown in FIG. 3A . In some embodiments, these distances are even greater, with each of the one or more first and second sets of electrode elements collectively spanning more than 18, 20, or 25 cm around the head.

[0045] Regardless of whether the span of the electrode elements active at any instant is measured in azimuth or centimeters along the circumference, the electrode elements cover at least one-third of the span from the beginning to the end of the arc φ(L+A), and the electrode elements cover at least one-third of the span from the beginning to the end of the arc φ(R+P) (this means that the open space between the electrode elements covers less than two-thirds of the span). In some embodiments, the electrode elements cover at least half of the span from the beginning to the end of the arc φ(L+A), and the electrode elements cover at least half of the span from the beginning to the end of the arc φ(R+P) (this means that the open space between the electrode elements covers less than half of the span). The coverage within these spans can be even higher (e.g., >65%, >80%, or 100%).

[0046] The situation shown in Figure 5B is similar to that described above in connection with Figure 5A, except that the dashed lines in Figure 5B show a very rough approximation of the electric field lines when one phase of the AC output signal is routed to both the front and right transducer arrays 10A, 10R, and the other phase of the AC signal is routed to both the rear and left arrays 10P, 10L. In this situation, the front and right transducer arrays collectively act as a first set of electrode elements, and the rear and left transducer arrays collectively act as a second set of electrode elements.

[0047] In some situations, it may be advantageous to repeatedly switch the direction of the AC electric field between the directions shown in Figure 5A and 5B. One example is when the AC electric field is a TTField being used to treat a tumor (because tumor sensitivity to the electric field is directional). Another example is when repeatedly shifting the direction of the AC electric field increases the range of application of the field within the head based on the shape of the transducer array relative to the head. The hardware shown in Figure 4 can implement this alternation between the directions of Figure 5A and 5B, as described below.

[0048] Figure 6 shows the commands issued by the controller 30 to implement this alternating operation. First, between t0 and t1, the controller 30 issues a command to the switch bank 25 to route one phase of the AC output signal to both the front and left transducer arrays 10A and 10L and the other phase of the AC signal to both the rear and right arrays 10P and 10R. This induces an electric field in the direction shown in Figure 5A. Next, between t1 and t2, the controller 30 issues a command to the switch bank 25 to route one phase of the AC output signal to both the rear and left transducer arrays 10P and 10L and the other phase of the AC signal to both the front and right arrays 10AP and 10R. This induces an electric field in the direction shown in Figure 5B. These two steps are then alternately repeated at least 10 times. The duration of each step in the sequence ranges from 10 milliseconds to 12 seconds. In some embodiments, the duration of each step in the sequence is between 100 milliseconds and 1000 seconds, or between 200 milliseconds and 5 seconds (eg, 1 second).

[0049] 4 can be used to practice a method of applying an AC electric field to a target area of ​​a subject using a first set of one or more electrode elements 10A disposed on a first side of the target area of ​​the subject, a second set of one or more electrode elements 10P disposed on a second side of the target area, a third set of one or more electrode elements 10L disposed on a third side of the target area, and a fourth set of one or more electrode elements 10R disposed on a fourth side of the target area. The method includes steps (a) of applying an AC voltage at a first frequency between both the first set 10A and the third set 10L of one or more electrode elements, and (ii) between both the second set 10P and the fourth set 10R of one or more electrode elements, and (b) of applying an AC voltage at a second frequency between both the first set 10A and the fourth set 10R of one or more electrode elements, and (ii) between both the second set 10P and the third set 10L of one or more electrode elements. In this method, (1) the first side and the second side are on opposite sides of the target area, (2) the third side and the fourth side are on opposite sides of the target area, (3) the third side is circumferentially disposed between the first side and the second side, (4) the fourth side is circumferentially disposed between the first side and the second side, and (5) steps (a) and (b) are alternately repeated at least 10 times.

[0050] At some point prior to performing the method, the first, second, third, and fourth sets of one or more electrode elements 10 are all positioned on or within the subject's body. Optionally, the first and second frequencies may each be between 50 kHz and 1 MHz, e.g., between 100 kHz and 500 kHz, or between 100 kHz and 300 kHz. In some embodiments, the first and second frequencies may be the same.

[0051] This method can be used to apply an alternating electric field to a variety of body regions, including, but not limited to, the chest, abdomen, and head. When the body region is the head, the total area of ​​the first set of one or more electrode elements is at least 40 cm. 2 and the second set of one or more electrode elements has a total area of ​​at least 40 cm2 is.

[0052] As explained above, alternating current electric fields of certain frequencies (e.g., 100-500 kHz) can be used to treat tumors, while lower-frequency electric fields (e.g., 50-200 kHz) can increase the permeability of the blood-brain barrier (BBB), allowing, for example, chemotherapy drugs to reach the brain. Therefore, combining an alternating current electric field of the former frequency with chemotherapy enhanced by an alternating current electric field of the latter frequency can be an effective approach to treating brain tumors. See, for example, U.S. Patent No. 10,967,167, which is incorporated herein by reference in its entirety.

[0053] The presence and intensity of electrical sensations are intensity-dependent effects, with unpleasant electrical sensations typically worsening with increasing field strength. The presence and intensity of electrical sensations are also frequency-dependent effects. More specifically, all other things being equal, unpleasant electrical sensations associated with AC electric fields are typically worse at lower frequencies (e.g., 100 kHz) that are effective in increasing BBB permeability compared to frequencies most effective in treating tumors (e.g., 200 kHz for glioblastoma).

[0054] Suppose we encounter a patient with glioblastoma and wish to treat him or her with 200 kHz TTFields. By placing four transducer arrays on the subject's head, as shown in Figures 2A–D, we can treat the glioblastoma using a conventional approach of switching electric field direction. That is, (a) applying a 200 kHz AC voltage between arrays 10L and 10R for 1 second induces an electric field in the tumor, with the field lines running from side to side across the subject's head, as shown in Figure 3A. Next, (b) applying a 200 kHz AC voltage between arrays 10A and 10P for 1 second induces an electric field in the tumor, with the field lines running from front to back, as shown in Figure 3B. This two-step sequence (a) and (b) is then repeated, for example, 12–16 hours per day.

[0055] Now, suppose we want to use a 100 kHz AC electric field to increase BBB permeability in the same subject, potentially enhancing the efficacy of a chemotherapy drug administered every few weeks. Continuing with the traditional field direction switching approach described in the previous paragraph, we simply lower the AC field frequency to 100 kHz, which could potentially cause the subject to experience an electric sensation. This is because sensitivity to electric sensations is significantly higher at 100 kHz than at 200 kHz.

[0056] 7 is a block diagram of an embodiment that applies a 200 kHz AC electric field in the L / R and A / P directions using the conventional approach, and further uses the transducer array pairing concept described above in connection with FIGS. 4-6 to reduce the current density in each transducer array while outputting a 100 kHz AC electric field. The transducer arrays 10 in this embodiment are similar to the transducer arrays 10 described above. However, the AC voltages are applied to these transducer arrays 10 in a different pattern, as described below.

[0057] In this embodiment of FIG. 7 , first AC signal generator 20a generates a 100 kHz AC output signal having two phases, each of which is input to switch bank 25. Various approaches for implementing switch bank 25 will be apparent to those skilled in the art (including, but not limited to, wiring four SPST solid-state relays between the first phase 100 kHz input and each of the four outputs, adding four SPST solid-state relays between the 100 kHz second phase input and each of the four outputs, adding four SPST solid-state relays between the first phase 200 kHz input and each of the four outputs, and adding four SPST solid-state relays between the 200 kHz second phase input and each of the four outputs). The path of the 100 kHz AC output signal through switch bank 25 is controlled by a signal from controller 30. The switch bank 25 (operating in response to commands from the controller 30) is configured to simultaneously route one phase of the 100 kHz AC output signal to two transducer arrays 10 and simultaneously route the other phase of the 100 kHz AC output signal to the other two transducer arrays 10.

[0058] For example, the switch bank 25 can be instructed to route one phase of the 100 kHz AC output signal to both the front and left transducer arrays 10A, 10L, and another phase of the 100 kHz AC signal to both the rear and right arrays 10P, 10R. When the switch bank 25 is configured in this manner, these voltages induce an electric field in the subject's head with field lines that run, on average, diagonally (i.e., in the direction of the dashed lines in FIG. 5A). The switch bank 25 can also be instructed to route one phase of the 100 kHz AC output signal to both the rear and left transducer arrays 10P, 10L, and another phase of the 100 kHz AC signal to both the front and right arrays 10A, 10R. When the switch bank 25 is configured in this manner, these voltages induce an electric field in the subject's head with field lines that run, on average, diagonally (i.e., in the direction of the dashed lines in FIG. 5B).

[0059] 7 can be used to improve or eliminate electrical sensations at frequencies below 100 kHz using the approach described above in connection with FIGS. 4-6. More specifically, the switch bank 25 (operating in response to commands from the controller 30) can be configured to simultaneously route one phase of the 100 kHz AC output signal to two transducer arrays 10 and simultaneously route another phase of the 100 kHz AC output signal to two other transducer arrays 10, thereby improving or eliminating electrical sensations. Operating the transducer arrays in pairs in this manner reduces the current density in each transducer array, thereby eliminating or improving electrical sensations at 100 kHz.

[0060] In addition to routing the 100 kHz AC signal from signal generator 20a to the four selected outputs as described above, switch bank 25 is also configured to route the 200 kHz AC signal from signal generator 20b to the four selected outputs via different paths, and the following sequence is performed: (a) a 200 kHz AC voltage is applied between arrays 10L and 10R for, e.g., 1 second, to induce an electric field in the tumor, forming electric field lines that run, on average, from side to side across the subject's head, as shown in Figure 3A; then (b) a 200 kHz AC voltage is applied between arrays 10A and 10P for, e.g., 1 second, to induce an electric field in the tumor, forming electric field lines that run, on average, from front to back, as shown in Figure 3B; and then this two-step sequence (a) and (b) is repeated 12 to 16 hours each day. To do this, during certain times, controller 30 directs switch bank 25 to route one phase of the 200 kHz AC output signal to left transducer array 10L and route the other phase of the 200 kHz AC signal to right array 10R. When switch bank 25 is configured in this manner, these voltages induce an electric field in the subject's head with electric field lines that run, on average, from left to right (i.e., in the direction of the dashed lines in FIG. 3A). During other times, controller 30 directs switch bank 25 to route one phase of the 200 kHz AC output signal to front transducer array 10A and route the other phase of the 200 kHz AC signal to rear array 10P. When switch bank 25 is configured in this manner, these voltages induce an electric field in the subject's head with electric field lines that run, on average, from front to back (i.e., in the direction of the dashed lines in FIG. 3B).

[0061] FIG. 8A illustrates one suitable set of commands that may be issued by the controller 30 of FIG. 7 to implement this approach. During a time window between t0 and t1, the controller 30 (a) issues a command to the switch bank 25 to route one phase of the first (e.g., 200 kHz) AC output signal to the left transducer array 10L and the other phase of the first (e.g., 200 kHz) AC signal to the right transducer array 10R. This induces an electric field in the direction of FIG. 3A for a fixed time (e.g., 1 second). Then, (b) issues a command to the switch bank 25 to route one phase of the second (e.g., 200 kHz) AC output signal to the front transducer array 10A and the other phase of the second (e.g., 200 kHz) AC signal to the rear transducer array 10P. This induces an electric field in the direction of FIG. 3B for a fixed time (e.g., 1 second). This two-step sequence (a) and (b) is repeated, for example, 12-16 hours each day, until t1. Then, during a time window between t1 and t2 (a window that is preferably synchronized in time with the administration of chemotherapy), controller 30 issues a command to switch bank 25 to route one phase of the third (e.g., 100 kHz) AC output signal to both the anterior and left transducer arrays 10A, 10L, and route the other phase of the third (e.g., 100 kHz) AC signal to both the posterior and right arrays 10P, 10R. This induces an electric field in the direction shown in Figure 5A.

[0062] Figure 8B shows another suitable set of commands that may be issued by controller 30 (Figure 4) to implement this approach. Controller operation during the time window between t0 and t1 is the same as that described above in connection with Figure 8A. Next, during the time window between t1 and t2 (a window that is preferably synchronized in time with chemotherapy administration), controller 30 issues commands to switch bank 25 to route one phase of the third (e.g., 100 kHz) AC output signal to both the anterior and right transducer arrays 10A, 10R, and route another phase of the third (e.g., 100 kHz) AC signal to both the posterior and left arrays 10P, 10L. This induces an electric field in the direction of Figure 5B.

[0063] Returning to Figure 7, instead of using separate 100 kHz and 200 kHz AC signal generators 20a, 20b as shown in Figure 7, a single multi-frequency AC signal generator (not shown) capable of operating at either 100 kHz or 200 kHz can be used. In these embodiments, the single multi-frequency AC signal generator would need to be configured to respond to frequency setting commands from the controller to ensure that the correct frequencies arrive at the correct outputs at the appropriate times, as described above in connection with Figures 8A and 8B.

[0064] Implementing the approach described above with reference to either FIG. 8A or 8B, the hardware shown in FIG. 4 can be used to practice a method for treating a tumor in a target region of a subject's head and delivering a substance through the BBB to the target region. The method includes applying an AC voltage at a first frequency (e.g., 200 kHz) between a first set of one or more electrode elements 10A disposed on a first side of the target region and a second set of one or more electrode elements 10P disposed on a second side of the target region, the first and second sides being on opposite sides of the target region. The method further includes applying an AC voltage at a second frequency (e.g., 200 kHz) between a third set of one or more electrode elements 10L disposed on a third side of the target region and a fourth set of one or more electrode elements 10R disposed on a fourth side of the target region, the third side being circumferentially disposed between the first and second sides, and the fourth side being circumferentially disposed between the first and second sides. The method also includes applying an AC voltage at a third frequency (e.g., 100 kHz) between (i) both the first and third sets of one or more electrode elements 10A, 10L and (ii) both the second and fourth sets of one or more electrode elements 10P, 10R, the third frequency being lower than the first frequency and the third frequency being lower than the second frequency. The AC voltage at the first frequency, the AC voltage at the second frequency, and the AC voltage at the third frequency are each applied for different time intervals.

[0065] At some point prior to performing the method, a first set, a second set, a third set, and a fourth set of one or more electrode elements 10 are all positioned on a first side, a second side, a third side, and a fourth side of the target area, respectively, This can be accomplished, for example, by placing the sets of electrode elements on the subject's skin or by implanting them under the subject's skin.

[0066] In some embodiments of this method, the first frequency (e.g., 200 kHz) is selected so that the electric field induced in the target region by applying an AC voltage between the first set of one or more electrode elements 10A and the second set of one or more electrode elements 10P has an antimitotic effect. The second frequency (e.g., 200 kHz) is selected so that the electric field induced in the target region by applying an AC voltage between the third set of one or more electrode elements 10L and the fourth set of one or more electrode elements 10R has an antimitotic effect. Additionally, the third frequency (e.g., 100 kHz) is selected so that the electric field induced in the target region by applying an AC voltage at the third frequency (a) between both the first and third sets of one or more electrode elements 10A, 10L and (b) between both the second and fourth sets of one or more electrode elements 10P, 10R increases the permeability of the BBB in the target region.

[0067] Optionally, the first frequency and the second frequency are the same. For example, when treating glioblastoma, the first frequency and the second frequency are both 200 kHz. In some embodiments, the first frequency and the second frequency are each between 50 kHz and 1 MHz, and the third frequency is between 50 kHz and 300 kHz. In some embodiments, the AC voltage at the third frequency is applied for at least 24 hours. In some embodiments, the steps of (a) applying an AC voltage at a first frequency between a first set and a second set of one or more electrode elements 10A, 10P and (b) applying an AC voltage at a second frequency between a third set and a fourth set of one or more electrode elements 10L, 10R are alternately repeated at least 10,000 times, which, assuming steps (a) and (b) each take 1 second, corresponds to a total of 20,000 seconds (i.e., approximately 5.5 hours).

[0068] Although the above description focuses on the situation of applying an AC electric field to a subject's head, a similar approach can be used on other parts of the body, including, but not limited to, organs within the torso.

[0069] While some of the above discussion has focused on applying an alternating electric field to a subject's head to increase the permeability of the blood-brain barrier, similar concepts can be applied to other biological barriers (e.g., the intestinal epithelial barrier) that are physically present in other parts of the body.

[0070] When using alternating electric fields to treat tumors, it is desirable to use electric fields that alternate between different directions, as described above. However, when alternating electric fields are used for other purposes (e.g., to increase the permeability of the blood-brain barrier or other biological barriers), electric fields whose direction remains constant can be used.

[0071] In some embodiments, each electrode element in each transducer array 10L, 10R, 10A, and 10P is a capacitively coupled electrode element (i.e., a conductive plate with a layer of dielectric material covering the side facing the subject's body), but in alternative embodiments, it may be a conductive electrode element (e.g., a metal plate).

[0072] Although the present invention has been disclosed with reference to particular embodiments, numerous modifications, changes, and variations can be made to the described embodiments without departing from the sphere and scope of the invention as defined in the appended claims. Accordingly, it is intended that the present invention not be limited to the described embodiments, but rather have the full scope defined by the following claims and equivalents thereof.

Claims

1. 1. A method for treating a tumor in a target area and delivering a substance across a biological barrier in said target area, comprising: applying an alternating voltage at a first frequency between a first set of one or more electrode elements disposed on a first side of the target area and a second set of one or more electrode elements disposed on a second side of the target area; the first side and the second side are on opposite sides of the target area; and applying an alternating voltage at a second frequency between a third set of one or more electrode elements disposed on a third side of the target area and a fourth set of one or more electrode elements disposed on a fourth side of the target area; the third side and the fourth side are on opposite sides of a target area; the third side is circumferentially disposed between the first side and the second side; the fourth side being circumferentially disposed between the first side and the second side; and (i) applying an alternating current voltage at a third frequency between both the first and third sets of the one or more electrode elements, and (ii) between both the second and fourth sets of the one or more electrode elements; the third frequency is lower than the first frequency; the third frequency being lower than the second frequency; The AC voltage of the first frequency, the AC voltage of the second frequency, and the AC voltage of the third frequency are applied at different time intervals.

2. positioning the first set of one or more electrode elements on a first side of the target area; positioning the second set of one or more electrode elements on a second side of the target area; positioning the third set of one or more electrode elements on a third side of the target area; The method of claim 1 , further comprising: positioning a fourth set of the one or more electrode elements on a fourth side of the target area.

3. the first frequency is selected such that an electric field induced in the target region by applying an alternating voltage at the first frequency between the first set of one or more electrode elements and the second set of one or more electrode elements has an antimitotic effect; the second frequency is selected such that an electric field induced in a target region by applying an alternating voltage at the second frequency between the third set of one or more electrode elements and the fourth set of one or more electrode elements has an antimitotic effect; 2. The method of claim 1, wherein the third frequency is selected such that an electric field induced in the target area by applying an alternating voltage at the third frequency (a) between both the first and third sets of the one or more electrode elements, and (b) between both the second and fourth sets of the one or more electrode elements, increases the permeability of a biological barrier in the target area.

4. The method of claim 3 , wherein the first frequency and the second frequency are the same.

5. the first frequency and the second frequency are each between 50 kHz and 1 MHz; The method of claim 1 , wherein the third frequency is between 50 kHz and 300 kHz.

6. 10. The method of claim 1, wherein the AC voltage at the third frequency is applied for at least 24 hours.

7. (a) applying an alternating current voltage at the first frequency between the first set of one or more electrode elements and the second set of one or more electrode elements; 2. The method of claim 1, wherein (b) applying the alternating voltage at the second frequency between the third set of one or more electrode elements and the fourth set of one or more electrode elements is alternately repeated at least 10,000 times.

8. 1. A device for treating a tumor in a target area and facilitating delivery of a substance across a biological barrier in said target area, comprising: at least one signal generator configured to generate an AC voltage at a first frequency and to generate an AC voltage at a second frequency; a signal generator, the second frequency being lower than the first frequency; a switch bank having at least one control input, a first output terminal, a second output terminal, a third output terminal, and a fourth output terminal; the switch bank receives an AC voltage of the first frequency; the switch bank receives the AC voltage of the second frequency; the switch bank is configured to route the AC voltage at the first frequency such that the AC voltage at the first frequency appears between the first output terminal and the second output terminal in response to a first state of the at least one control input; the switch bank is configured to route the AC voltage at the first frequency such that the AC voltage at the first frequency appears between the third output terminal and the fourth output terminal in response to a second state of the at least one control input; the switch bank configured, in response to a third state of the at least one control input, to route the AC voltage at the second frequency such that the AC voltage at the second frequency appears (a) between both the first output terminal and the third output terminal, and (b) between both the second output terminal and the fourth output terminal; and a controller programmed to: (i) set the at least one control input to the first state, (ii) set the at least one control input to the second state, and (iii) set the at least one control input to the third state at different time intervals.

9. the first frequency is selected to provide an antimitotic effect; 9. The device of claim 8, wherein the second frequency is selected to increase the permeability of a biological barrier.

10. the first frequency is between 50 kHz and 1 MHz; 9. The apparatus of claim 8, wherein the second frequency is between 50 kHz and 300 kHz.

11. 9. The apparatus of claim 8, wherein the controller is programmed to alternately repeat (i) setting the at least one control input to the first state and (ii) setting the at least one control input to the second state at least 10,000 times.

12. 9. The apparatus of claim 8, wherein the controller is programmed to set the at least one control input to the third state after repeating (i) and (ii) at least 10,000 times, and thereafter leave the at least one control input in the third state for at least 12 hours.

13. 1. A method of applying an alternating current electric field to a target region within a subject's body using a first set of one or more electrode elements positioned on a first side of the target region, a second set of one or more electrode elements positioned on a second side of the target region, a third set of one or more electrode elements positioned on a third side of the target region, and a fourth set of one or more electrode elements positioned on a fourth side of the target region, comprising: (a) applying an alternating voltage at a first frequency (i) between both the first and third sets of one or more electrode elements, and (ii) between both the second and fourth sets of one or more electrode elements; (b) applying an alternating voltage at a second frequency (i) between both the first and fourth sets of one or more electrode elements, and (ii) between both the second and third sets of one or more electrode elements; the first side and the second side are on opposite sides of the target area; the third side and the fourth side are on opposite sides of the target area; the third side is circumferentially disposed between the first side and the second side; the fourth side is circumferentially disposed between the first side and the second side; The method, wherein the steps (a) and (b) are alternately repeated at least 10 times.

14. placing the first set of one or more electrode elements on or within a subject's body; placing the second set of one or more electrode elements on or within the subject's body; placing the third set of one or more electrode elements on or within the subject's body; 14. The method of claim 13, further comprising placing the fourth set of one or more electrode elements on or in the subject's body.

15. 14. The method of claim 13, wherein the first frequency and the second frequency are each between 50 kHz and 1 MHz.

16. The method of claim 13 , wherein the first frequency and the second frequency are the same.

17. 1. An apparatus for applying a signal to a set of electrodes, comprising: at least one signal generator configured to generate an AC voltage; A switch bank having at least one control input, a first output terminal, a second output terminal, a third output terminal, and a fourth output terminal, the switch bank receives an AC voltage at a first frequency; the switch bank is configured, in response to a first state of the at least one control input, to route an AC voltage such that an AC voltage appears (a) between both the first output terminal and the third output terminal, and (b) between both the second output terminal and the fourth output terminal; the switch bank configured, in response to a second state of the at least one control input, to route an AC voltage such that an AC voltage appears (a) between both the first output terminal and the fourth output terminal, and (b) between both the second output terminal and the third output terminal; and a controller programmed to alternately repeat the steps of (i) setting the at least one control input to a first state, and (ii) setting the at least one control input to a second state at least 10 times.

18. 18. The apparatus of claim 17, wherein the frequency of the AC voltage is between 50 kHz and 1 MHz.

19. 1. A method of applying an alternating electric field to a body part of a subject, comprising: the body part has a longitudinal axis; The method comprises: applying an alternating voltage between a first set of one or more electrode elements disposed on or in a first side of the body part and a second set of one or more electrode elements disposed on or in a second side of the body part; the first side and the second side include a step on opposite sides of a longitudinal axis; the first set of one or more electrode elements subtend a first azimuthal angle of at least 120° relative to the longitudinal axis, within which coverage by the electrode elements is at least one-third; The method wherein the second set of one or more electrode elements subtends a second azimuthal angle of at least 120° relative to the longitudinal axis, within which coverage by the electrode elements is at least one-third.

20. the first set of one or more electrode elements is a set of capacitively coupled electrode elements; The method of claim 19 , wherein the second set of one or more electrode elements is a set of capacitively coupled electrode elements.

21. 20. The method of claim 19, wherein the frequency of the AC voltage is less than 1 MHz.

22. 20. The method of claim 19, wherein the frequency of the AC voltage is less than 190 kHz.

23. 20. The method of claim 19, wherein the AC voltage is applied for at least 24 hours.

24. the first azimuthal angle is at least 135°; 20. The method of claim 19, wherein the second azimuthal angle is at least 135 degrees.

25. the coverage by the electrode elements within the first azimuthal angle is at least half; 20. The method of claim 19, wherein the coverage by electrode elements within the second azimuthal angle is at least half.

26. the body part is the head, The first set of one or more electrode elements has a total area of ​​at least 40 cm ２ and The second set of one or more electrode elements has a total area of ​​at least 40 cm ２ 20. The method of claim 19, wherein:

27. 1. A method of applying an alternating electric field to the head of a subject, comprising: the head has a longitudinal axis and a circumference; The method comprises: applying an alternating voltage between a first set of one or more electrode elements disposed on a first side of the subject's head and a second set of one or more electrode elements disposed on a second side of the subject's head; the first side and the second side include a step on opposite sides of a longitudinal axis; the first set of one or more electrode elements extends circumferentially over a first length of at least 15 cm, with at least one-third coverage by the electrode elements; The method wherein the second set of one or more electrode elements extends along a second length of at least 15 cm around the circumference, with at least one-third coverage by the electrode elements.

28. the first set of one or more electrode elements is a set of capacitively coupled electrode elements; 28. The method of claim 27, wherein the second set of one or more electrode elements is a set of capacitively coupled electrode elements.

29. 28. The method of claim 27, wherein the frequency of the AC voltage is less than 1 MHz.

30. 28. The method of claim 27, wherein the frequency of the AC voltage is less than 190 kHz.

31. 28. The method of claim 27, wherein the AC voltage is applied for at least 24 hours.

32. a coverage by the electrode elements within the first length of the electrode element of at least half; 28. The method of claim 27, wherein the coverage by the electrode elements within the second length is at least half.

33. The first set of one or more electrode elements has a total area of ​​at least 40 cm ２ and The second set of one or more electrode elements has a total area of ​​at least 40 cm ２ 28. The method of claim 27, wherein:

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