Treating subjects with alternating electric fields and reducing electrical sensations by pairing transducer arrays

Abstract

When alternating electric fields are used to treat a subject (e.g., when TTFields are used to treat tumors or when alternating electric fields are used to increase the permeability of the blood-brain barrier), some subjects experience an unpleasant electrosensory effect. This electrosensation can be reduced or eliminated by increasing the area of ​​the transducer array that is active at a particular time during treatment. In some embodiments, this is accomplished by applying an alternating signal between two sets of transducer arrays at a particular time (as opposed to the conventional method of applying an alternating signal between two separate transducer arrays).

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 the growth of cancer cells. 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. TT fields at 200 kHz are FDA approved for the treatment of glioblastoma (GBM) and can be delivered, for example, via a conventional Optune® system, shown diagrammatically in FIG. 1. TT fields are delivered to the patient via four transducer arrays 10 (i.e., electrode arrays) that are placed on the patient's skin in close proximity 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 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 in its entirety by reference), alternating electric fields with frequencies between, for example, 50 and 200 kHz can 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 in its entirety by reference), alternating electric fields with frequencies between, for example, 50 and 500 kHz can increase the permeability of cell membranes, allowing larger molecules to pass through the cell membrane.

[0004] When Optune® is used to treat glioblastoma, one pair of arrays (10L, 10R) are placed on the left and right sides of the tumor, and another pair of arrays (10A, 10P) are placed in front and behind the tumor. The Optune® signal generator 95 (a) applies an AC voltage between arrays 10L and 10R for 1 second to induce an electric field in one direction through the tumor, and then (b) applies an AC voltage between arrays 10A and 10P for 1 second to induce an electric field in the other direction through the tumor. This two-step sequence (a) and (b) is then repeated for the duration of the treatment. 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 in the target, the first method comprising applying an alternating voltage of 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, the first method comprising applying an alternating voltage of 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 alternating 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, where the third frequency is lower than the first frequency and the third frequency is lower than the second frequency. The alternating voltage at the first frequency, the alternating voltage at the second frequency, and the alternating voltage at the third frequency are each applied for a different time interval.

[0006] Some examples of the first method further include 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 such that an electric field induced in the target area 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 the target area 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. Also, 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 one or more electrode elements and (b) between both the second and fourth sets of one or more electrode elements increases the permeability of a biological barrier in the target area. 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 area and facilitating delivery of a substance across a biological barrier in the target area. 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 inputs the AC voltage at the first frequency and inputs the AC voltage at 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 further 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 is further configured to route the alternating voltage at the second frequency such that the alternating voltage at the second frequency is present (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 the 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 set at least one control input to a third state after repeating (i) and (ii) at least 10,000 times, and thereafter leave 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 of applying an alternating electric field to a target area of ​​a subject's body using a first set of one or more electrode elements disposed on a first side of the target area, a second set of one or more electrode elements disposed on a second side of the target area, 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 second method includes the steps of (a) applying an alternating voltage of 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 alternating voltage of 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 area. The third and fourth sides are on opposite sides of the target area. 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 ten 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 a signal 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 inputs an AC voltage of a first frequency. The switch bank is configured to route the AC voltage 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, in response to a first state of the at least one control input. The switch bank is also configured to route the AC voltage 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, in response to a second state of the at least one control input. The controller is also programmed to alternate between (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 times.

[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 of 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 set of one or more electrode elements disposed on a first side or on the first side of the body part and a second set of one or more electrode elements disposed on a second side or 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 defines a first azimuthal angle of at least 120° with respect to the longitudinal axis, within which the coverage by the electrode elements is at least one third. The second set of one or more electrode elements defines a second azimuthal angle of at least 120° with respect to the longitudinal axis, within which the coverage by the electrode elements is at least one third.

[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 azimuth angle is at least 135° and the second azimuth 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 It is.

[0022] Another aspect of the present application relates to a fourth method of applying an alternating electric field to a subject's head having a longitudinal axis and a circumference. The fourth method includes 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 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, where the coverage of the electrode elements is at least one-third. And, the second set of one or more electrode elements extend along the circumference over a second length of at least 15 cm, where the coverage of the electrode elements is at least one-third.

[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 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 It is. [Brief description 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. 2 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. 2 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] FIG. 13 is a 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] FIG. 13 is a 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 electric fields in the directions of FIG. 5A and FIG. 5B at different times. [Figure 7] FIG. 13 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 FIG. 3A, FIG. 3B, and FIG. 5B at different times. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

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

[0030] This application describes various approaches to reduce or eliminate electrical sensations while a subject is being treated with an alternating electric field. These approaches rely on increasing the area of ​​the transducer array that is active at a particular time during treatment. In some embodiments, this is accomplished by applying an alternating signal between two pairs of transducer arrays at a particular time (as opposed to the traditional approach of applying an alternating 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. When the current density (i.e., the current through any electrode divided by the area of ​​that electrode) falls below a threshold (which may vary from person to person), no electrical sensation occurs. However, when the current density exceeds that threshold, electrical sensations begin to occur, and become more noticeable as the current density is further increased.

[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 the treatment to the subject's head. Each of these transducer arrays contains nine circular electrode elements, each 2 cm in diameter (1 cm radius). Thus, the total area of ​​all electrode elements in any transducer array is 9 × 3.14 × 1 2 =28cm 2 It is.

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

[0034] Here, in a particular subject (hereinafter referred to as "subject #1"), the threshold at which electrical sensation begins to occur at a particular 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 lower the current to, for example, 1.5 A. This would result in a current density of 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, AC voltages are applied to the 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 way, these voltages induce an electric field at 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 way, these voltages induce an electric field at 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 energize the transducer arrays on the head of subject #1 using the same output current as in the original example (i.e., 2A) and analyze what happens when each phase of the AC output signal is routed simultaneously to two transducer arrays 10. As explained above, the total area of ​​all electrode elements in any transducer array is 28 cm 2 However, because 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 Indeed, in this embodiment, the current could be increased to above 3 A before the electrosensory threshold of subject #1 was reached.

[0039] As explained above, when each phase of the AC output signal is routed simultaneously to two transducer arrays 10, the current of the AC output signal is spread over a significantly larger area, while the spread of electrode elements in active use at any instant in time, whether measured in area (see above) or in other units such as azimuth angle or circumference (see below), is significantly larger than the spread of 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, 10L, and another phase of the AC signal is routed to both the rear and right arrays 10P, 10R. In this situation, the front and left transducer arrays collectively operate as a first set of electrode elements, and the rear and right transducer arrays collectively operate as a second set of electrode elements.

[0041] In this situation, an alternating electric field is applied to the subject's head by applying an alternating 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 side and the second side 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 Figure 5A are each at least 120°, and in some embodiments, these angles are each at least 135°. These angles are significantly greater 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 Figure 3A (the instants 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 Figure 3B (the instants 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 first set of one or more electrode elements spans a total of more than 15 cm when measured around the circumference of the head, and the second set of one or more electrode elements spans a total of more than 15 cm when measured around the circumference of the head. These distances are significantly greater than the circumference spanned collectively by the active electrode elements in the left transducer array 10L and the right transducer array 10R of a conventional Optune® system at the moment that 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 first and second sets of one or more electrode elements spanning a total of more than 18, 20, or 25 cm when measured around the circumference of 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) (which means that the free 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) (which means that the free space between the electrode elements covers less than half of the span). The coverage within these spans may 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, but 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 TT field 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 geometry 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] FIG. 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, 10L, and another phase of the AC signal to both the rear and right arrays 10P, 10R. This induces an electric field in the direction of FIG. 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, 10L, and another phase of the AC signal to both the front and right arrays 10AP, 10R. This induces an electric field in the direction of FIG. 5B. These two steps are then alternated at least 10 times. The duration of each step in the sequence ranges from 10 ms to 12 h. In some embodiments, the duration of each step in the sequence is between 100 ms and 1000 s, or between 200 ms and 5 s (eg, 1 s).

[0049] 4 may 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 the steps of (a) applying an AC voltage of 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) applying an AC voltage of 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 ten 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 in 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] The method can be used to apply an alternating electric field to a variety of body parts, including, but not limited to, the chest, abdomen, and head. When 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 cm2 It is.

[0052] As explained above, alternating electric fields of certain frequencies (e.g., 100-500 kHz) can be used to treat tumors, while alternating electric fields of lower than normal frequencies (e.g., 50-200 kHz) can increase the permeability of the blood-brain barrier (BBB), making it easier for chemotherapy drugs to reach the brain. Thus, combining alternating electric fields of the former frequency with chemotherapy enhanced by alternating electric fields of the latter frequency can be an effective approach to treat 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 being worse at higher field strengths. 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 that are effective at increasing BBB permeability (e.g., 100 kHz) compared to the frequencies that are most effective at treating tumors (e.g., 200 kHz for glioblastoma).

[0054] Suppose we encounter a patient with glioblastoma and want to treat him with a 200 kHz TT field. If we place four transducer arrays on the subject's head, as shown in Figure 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 electric field lines running from side to side on average across the subject's head, as shown in Figure 3A. Then, (b) applying a 200 kHz AC voltage between arrays 10A and 10P for 1 second induces an electric field in the tumor, with the electric field lines running from front to back on average, as shown in Figure 3B. Then, this two-step sequence (a) and (b) is repeated for, say, 12-16 hours a day.

[0055] Now suppose we want to use a 100 kHz alternating electric field to increase the permeability of the BBB in the same subject, and thus the efficacy of a chemotherapy drug that is administered, for example, every few weeks. If we continue to use the traditional approach of switching the electric field direction described in the previous paragraph and simply reduce the frequency of the alternating electric field to 100 kHz, the subject may experience an electric sensation. This is because the 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 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 field. The transducer array 10 in this embodiment is itself similar to the transducer array 10 previously described. However, the AC voltage is applied to these transducer arrays 10 in a different pattern, as described below.

[0057] In this embodiment of FIG. 7, the first AC signal generator 20a generates a 100 kHz 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 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 the switch bank 25 is controlled by a signal 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 100 kHz AC output signal to two transducer arrays 10 and to 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 way, these voltages induce an electric field in the subject's head with field lines that run diagonally on average (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 way, these voltages induce an electric field in the subject's head with field lines that run diagonally on average (i.e., in the direction of the dashed lines in FIG. 5B).

[0059] Thus, the embodiment of FIG. 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 electrical sensations can be improved or eliminated by configuring the switch bank 25 (operating in response to commands from the controller 30) 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 the other two transducer arrays 10. Operating the transducer arrays in pairs in this manner reduces the current density in each transducer array, eliminating or improving the 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 via different paths to the four selected outputs, (a) applying a 200 kHz AC voltage 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 FIG. 3A, and then (b) applying a 200 kHz AC voltage 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 FIG. 3B, and then repeating this two-step sequence (a) and (b) for 12 to 16 hours each day. To do this, the controller 30 directs the switch bank 25 to route one phase of the 200 kHz AC output signal to the left transducer array 10L and the other phase of the 200 kHz AC signal to the right array 10R during a particular time. When the switch bank 25 is configured in this way, 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, the controller 30 directs the switch bank 25 to route one phase of the 200 kHz AC output signal to the front transducer array 10A and the other phase of the 200 kHz AC signal to the rear array 10P. When the switch bank 25 is configured in this way, 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 period of 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 period of 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 chemotherapy administration), the controller 30 issues a command to the 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 of FIG. 5A.

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

[0064] Implementing the approach described above in relation 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 side and the second side 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 side and the second side, and the fourth side being circumferentially disposed between the first side and the second side. 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, where the third frequency is lower than the first frequency and the third frequency is 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, respectively, of the target area. 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 the method, the first frequency (e.g., 200 kHz) is selected such that the electric field induced in the target area 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 such that the electric field induced in the target area 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. And, the third frequency (e.g., 100 kHz) is selected such that the electric field induced in the target area by applying an AC voltage of 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 area.

[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 and second set of one or more electrode elements 10A, 10P, and (b) applying an AC voltage at a second frequency between a third and fourth set of one or more electrode elements 10L, 10R are alternately repeated at least 10,000 times, corresponding to a total of 20,000 seconds (i.e., about 5.5 hours) assuming steps (a) and (b) each take 1 second.

[0068] Although the above description focuses on the situation of applying an alternating 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 alternating electric fields 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 alternating electric fields are used 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 covered with a layer of dielectric material on the side facing the subject's body), but in alternative embodiments may be a conductive electrode element (e.g., a metal plate).

[0072] Although the present invention has been disclosed with reference to specific embodiments, numerous modifications, changes, and variations are possible 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 its full scope as 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 is circumferentially disposed between the first side and the second side; and (i) applying an alternating 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 method, wherein the alternating voltage of the first frequency, the alternating voltage of the second frequency, and the alternating voltage of the third frequency are each applied for different time intervals.

2. positioning a first set of the one or more electrode elements on a first side of the target area; positioning a second set of the one or more electrode elements on a second side of the target area; positioning a third set of the one or more electrode elements on a third side of the target area; The method of claim 1 , further comprising: disposing 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 area 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 a 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. The method of claim 1 , wherein the alternating voltage at the third frequency is applied for at least 24 hours.

7. (a) 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; 2. The method of claim 1 , wherein (b) the steps of 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 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 alternating voltage at a first frequency and to generate an alternating 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 an AC voltage of the second frequency; the switch bank is configured to route, in response to a first state of the at least one control input, an alternating voltage at the first frequency such that the alternating voltage at the first frequency is present between the first output terminal and the second output terminal; the switch bank is configured to route the alternating current voltage at the first frequency such that the alternating current voltage at the first frequency is present between the third output terminal and the fourth output terminal in response to a second state of the at least one control input; a switch bank configured, in response to a third state of the at least one control input, to route the alternating current voltage at the second frequency such that the alternating current 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; 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; 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 (i) set the at least one control input to the first state and (ii) set 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 to cause the at least one control input to remain in the third state for at least 12 hours.

13. 1. A method of applying an alternating electric field to a target area within a subject's body using a first set of one or more electrode elements disposed on a first side of the target area, a second set of one or more electrode elements disposed on a second side of the target area, 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, comprising: (a) applying an alternating voltage at a first 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; (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 said 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 a body of a subject; 14. The method of claim 13, further comprising placing the fourth set of one or more electrode elements on or within the subject's body.

15. 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 to route an AC voltage such that, in response to a second state of the at least one control input, 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 ten 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 with respect to the longitudinal axis of at least 120°, within which coverage by the electrode elements is at least one third; The method, wherein the second set of one or more electrode elements subtend a second azimuthal angle with respect to the longitudinal axis of at least 120°, 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 alternating voltage is applied for at least 24 hours.

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

25. a coverage by electrode elements within the first azimuthal angle of at least half; 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 a 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 a subject's head, 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 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 alternating voltage is applied for at least 24 hours.

32. a coverage of the electrode elements within the first length of the electrode member of at least half the electrode; 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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