Treatment of a subject and reduction of electric sensation using an alternating electric field 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 Mar. 30, 2022, the entire content of which is incorporated herein by reference.

Background Art

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

[0003] Alternating electric fields in the frequency range of 50 kHz - 1 MHz can also be used for the treatment of medical conditions other than tumors. For example, as described in U.S. Patent No. 10,967,167 (incorporated herein by reference in its entirety), an alternating electric field of, for example, 50 - 200 kHz increases the permeability of the blood - brain barrier (BBB) so that, for example, chemotherapeutic drugs can reach the brain. Also, as described in U.S. Patent No. 11,103,698 (incorporated herein by reference in its entirety), an alternating electric field of, for example, 50 - 500 kHz increases the permeability of cell membranes so that large molecules can pass through the cell membranes.

[0004] When using Optune (registered trademark) for the treatment of glioblastoma, one pair of arrays (10L, 10R) is placed on the left and right of the tumor, and another pair of arrays (10A, 10P) is placed in front of and behind the tumor. The Optune (registered trademark) signal generator 95 (a) applies an alternating voltage between arrays 10L and 10R for 1 second to induce an electric field in one direction through the tumor. Next, (b) an alternating voltage is applied between arrays 10A and 10P for 1 second to induce an electric field in another direction through the tumor. Then, during the treatment period, this two-step sequence (a) and (b) is repeated. Summary of the Invention Means for Solving the Problems

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

[0006] In some examples of the first method, further, a step of arranging a first set of one or more electrode elements on a first side of the target region, a step of arranging a second set of one or more electrode elements on a second side of the target region, a step of arranging a third set of one or more electrode elements on a third side of the target region, and a step of arranging a fourth set of one or more electrode elements on a fourth side of the target region are included.

[0007] In some examples of the first method, the first frequency is selected such that the electric field induced in the target region by applying an alternating voltage of 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 anti-mitotic effect. The second frequency is selected such that the electric field induced in the target region by applying an alternating voltage of 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 anti-mitotic effect. Also, the third frequency is selected such that the electric field induced in the target region by applying an alternating voltage of the third frequency between (a) both the first set and the third set of one or more electrode elements and (b) both the second set and the fourth set of one or more electrode elements enhances the permeability of the 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 50 kHz to 1 MHz, and the third frequency is 50 kHz to 300 kHz. In some examples of the first method, the alternating voltage of the third frequency is applied for at least 24 hours.

[0009] In some examples of the first method, (a) a step of applying an alternating voltage of the first frequency between a first set of one or more electrode elements and a second set of one or more electrode elements, and (b) a step of applying an alternating voltage of the 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 the 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 alternating voltage of a first frequency and to generate an alternating voltage of 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 alternating voltage of the first frequency and the alternating voltage of the second frequency. The switch bank is configured to route the alternating voltage of the first frequency such that the alternating voltage of 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 alternating voltage of the first frequency such that the alternating voltage of 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. Also, the switch bank is further configured to route the alternating voltage of the second frequency such that the alternating voltage of 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 in response to a third state of the at least one control input. The controller is programmed to 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 anti-mitotic effect, and the second frequency is selected to enhance 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 (i) set at least one control input to a first state and (ii) alternately repeat setting at least one control input to a second state at least 10,000 times. In some embodiments of the first device, after repeating (i) and (ii) at least 10,000 times, the controller is programmed to set at least one control input to a third state and then 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 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: (a) applying an alternating voltage of a first frequency between (i) both the first set and the third set of one or more electrode elements and (ii) both the second set and the fourth set of one or more electrode elements; and (b) applying an alternating voltage of a second frequency between (i) both the first set and the fourth set of one or more electrode elements and (ii) both the second set and the third set of one or more electrode elements. The first side and the second side are on opposite sides of the target region. The third side and the fourth side are on opposite sides of the target region. 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. Steps (a) and (b) are repeated alternately at least 10 times.

[0013] In some examples of the second method, the method further includes placing a first set of one or more electrode elements on or in the subject's body, placing a second set of one or more electrode elements on or in the subject's body, placing a third set of one or more electrode elements on or in the subject's body, and placing a fourth set of one or more electrode elements on or in 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 apparatus for applying a signal to a set of electrodes. The second apparatus includes at least one signal generator, a switch bank, and a controller. The at least one signal generator is configured to generate an alternating 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 an alternating voltage of a first frequency. The switch bank is configured to route the alternating voltage such that the alternating 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 alternating voltage such that the alternating 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. Also, 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 times.

[0016] In some embodiments of the second apparatus, the frequency of the alternating 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 voltage between a first set of one or more electrode elements on a first side of the body part or on the first side and a second set of one or more electrode elements on a second side of the body part or on the second side. 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 azimuth angle of at least 120° with respect to the longitudinal axis, in which the coverage rate by the electrode elements is at least one-third. The second set of one or more electrode elements defines a second azimuth angle of at least 120° with respect to the longitudinal axis, in which the coverage rate 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 alternating voltage is less than 1 MHz. In some examples of the third method, the frequency of the alternating voltage is less than 190 KHz. In some examples of the third method, the alternating 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 rate by the electrode elements within the first azimuth angle is at least half, and the coverage rate by the electrode elements within the second azimuth angle is at least half.

[0021] In some examples of the third method, the body part is the head, and the total area of the first set of one or more electrode elements is at least 40 cm 2 and the total area of the second set of one or more electrode elements is at least 40 cm 2 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 extends along the circumference over a first length of at least 15 cm, and the coverage rate by the electrode elements therein is at least one-third. Also, the second set of one or more electrode elements extends along the circumference over a second length of at least 15 cm, and the coverage rate by the electrode elements therein 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 alternating voltage is less than 1 MHz. In some examples of the fourth method, the frequency of the alternating voltage is less than 190 kHz. In some examples of the fourth method, the alternating voltage is applied for at least 24 hours.

[0025] In some examples of the fourth method, the coverage rate by the electrode elements within the first length is at least half, and the coverage rate 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 total area of the second set of one or more electrode elements is at least 40 cm 2 is.

Brief Description of the Drawings

[0027]

Figure 1

Figure 2A

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Figure 3A

Figure 3B

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Figure 5A

Figure 5B

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Figure 8B

DETAILED DESCRIPTION OF THE INVENTION

[0028] Hereinafter, various embodiments will be described in detail with reference to the accompanying drawings. In the drawings, like reference numerals represent like elements.

[0029] When treating a subject using an alternating electric field, the greater the amplitude, the higher the treatment effect. However, when the amplitude of the alternating electric field increases and / or when the frequency of the alternating electric field decreases (e.g., up to around 100 kHz), some subjects may feel an electric sensation effect when the direction of the alternating electric field changes. This electric sensation can be, for example, a vibration sensation, a perceptual abnormality, and / or a muscle fiber twitch or contraction sensation. The electric sensation is thought to occur from the interaction between the alternating electric field arranged near or adjacent to the transducer array and nerve cells (i.e., neurons). Also, due to these sensations, some subjects may stop continuing the treatment using the alternating electric field.

[0030] In this application, various approaches for reducing or eliminating the electric sensation while a subject is being treated with an alternating electric field will be described. These approaches rely on increasing the area of the transducer array that becomes active at specific times during the treatment. In some embodiments, this is achieved by applying an alternating signal between two pairs of transducer arrays at specific times (in contrast to the conventional approach of applying an alternating signal between two individual transducer arrays).

[0031] Assume that an alternating current of a specific frequency is coupled into the subject's body through a pair of electrodes placed on the subject's skin. If the current density (i.e., the value obtained by dividing the current flowing through any electrode by the area of that electrode), which may vary from person to person, is below the threshold value, no electrical sensation will occur. However, when the current density exceeds that threshold value, an electrical sensation begins to occur, and it becomes more pronounced as the current density further increases.

[0032] To illustrate this point, an example using numerical values is helpful. Assume that the conventional Optune (registered trademark) system shown in FIG. 1 is used to treat a glioblastoma in the subject's head using a 200 kHz TT field. FIGS. 2A - 2D show the Optune (registered trademark) transducer array used to treat the subject's head. Each of these transducer arrays contains nine circular electrode elements with a diameter of 2 cm (radius 1 cm). Thus, the total area of all the electrode elements within any transducer array is 9×3.14×1 2 = 28 cm 2 2.

[0033] Furthermore, assume that the output current of the conventional Optune system is 2 A. As described above, at certain time intervals, an alternating voltage is applied only between arrays 10L and 10R, inducing an electric field in the subject's head. The lines of the electric field run, on average, from left to right (i.e., in the direction of the dashed line in FIG. 3A). Also, at other time intervals, an alternating voltage is applied only between arrays 10A and 10P, inducing an electric field in the subject's head. The lines of the electric field run, on average, from front to back (i.e., in the direction of the dashed line in FIG. 3B). During the former interval, the current density in each of transducer arrays 10L and 10R is 2 A÷28 cm 2 = 71 mA / cm 2 2. During the latter interval, the current density in each of transducer arrays 10L and 10R is 2 A÷28 cm 2 = 71 mA / cm 2 2 (Note that in reality, the electric field lines are not straight lines. However, in FIGS. 3A / B and 5A / B, straight dashed lines are used to represent the general direction of the magnetic field lines.).

[0034] Here, in a specific subject (hereinafter referred to as "Subject #1"), assume that the threshold at which electroception starts to occur at a specific frequency is 60 mA / cm 2 Assume that this is the case. In this example, since the current density of each transducer array is 71 mA / cm 2 (i.e., higher than the threshold of Subject #1), Subject #1 experiences electroception. One approach to improving this situation is to lower the current to, for example, 1.5 A. As a result, the current density becomes 1.5 A ÷ 28 cm 2 = 54 mA / cm 2 which is below the electroception threshold of Subject #1. However, this approach is not optimal because the effectiveness of treatment usually decreases when the current is low.

[0035] FIG. 4 is a block diagram of an embodiment using another approach to reduce the current density of each transducer array without reducing the overall current. The transducer array 10 itself in this embodiment is similar to the above-described transducer array 10. However, the alternating voltage is applied to these transducer arrays 10 in different patterns as described below.

[0036] In the embodiment of FIG. 4, the AC signal generator 20 generates an AC output signal having two phases, and each phase is input to the 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 each of the first phase input and the four outputs, and wiring another four SPST solid state relays between each of the second phase input and the four outputs). The path when the AC output signal passes through the switch bank 25 is controlled by a signal transmitted from the 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 the two transducer arrays 10 and the other phase of the AC output signal to the other two transducer arrays 10.

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

[0038] Next, using the embodiment of FIG. 4, the transducer array on the head of subject #1 is energized using the same output current as in the original example (i.e., 2 A), and it is analyzed what happens when each phase of the AC output signal is simultaneously routed to the two transducer arrays 10. As explained above, the total area of all electrode elements within any transducer array is 28 cm 2 . However, since each phase of the AC output signal is simultaneously routed to the two transducer arrays 10, the same 2 A current is distributed over 2 × 28 cm 2 = 56 cm 2 . Therefore, the current density of each transducer array 10 is 2 A ÷ 56 cm 2 = 36 mA / cm 2 , which is below the electrogustometric threshold of 60 mA / cm of subject #1 2 . In fact, in this embodiment, the current could be increased to 3 A or more before reaching the electrogustometric threshold of subject #1.

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

[0040] Figures 5A and 5B are plan views of a subject's head being treated with an alternating electric field using four sets of transducer arrays 10A, 10P, 10L, and 10R respectively disposed on the front, rear, left, and right sides of the subject's head. The dashed lines in Figure 5A show a very rough approximation of the electric field lines when one phase of the alternating output signal is routed to both the front transducer array and the left transducer array 10A, 10L, and the other phase of the alternating signal is routed to both the rear array and the right array 10P, 10R. In this situation, the front transducer array and the left transducer array operate collectively as a first set of electrode elements, and the rear transducer array and the right transducer array operate collectively 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 within a second side of the head. The first side and the second side are on opposite sides of the longitudinal axis of the head.

[0042] In particular, the first set of one or more electrode elements collectively defines a first azimuth angle φ(L+A) with respect to the longitudinal axis, and the second set of one or more electrode elements collectively defines a second azimuth angle φ(R+P) with respect to the longitudinal axis (where the azimuth angles referred to here are measured in polar coordinates in a plane perpendicular to the longitudinal axis of the head).

[0043] The first azimuth angle φ(L+A) and the second azimuth angle φ(R+P) of 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 azimuth 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 at the instant an alternating voltage is applied between the left transducer array 10L and the right transducer array 10R, or φ(A) and φ(P) in FIG. 3B at the instant an alternating 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 included in each of the first and second sets of electrode elements. More specifically, the first set of one or more electrode elements exceeds 15 cm in total when measuring the circumference of the head, and the second set of one or more electrode elements exceeds 15 cm in total when measuring the circumference of the head. These distances are significantly larger than the circumference spanned collectively by the electrode elements active in the left transducer array 10L and the right transducer array 10R of a conventional Optune® system at the instant an alternating voltage is applied between these arrays, as shown in FIG. 3A. In some embodiments, these distances are even larger, and each of the first and second sets of one or more electrode elements extends over a span that exceeds 18, 20, or 25 cm in total when measuring the circumference of the head.

[0045] Regardless of whether the span of the active electrode elements is measured in azimuth at any given instant or in 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 empty 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 that extends from the beginning to the end of the arc φ(L+A), and the electrode elements cover at least half of the span that extends from the beginning to the end of the arc φ(R+P). (This means that the empty 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 FIG. 5B is similar to the situation described above in connection with FIG. 5A, but the dashed lines in FIG. 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 transducer array and the right transducer array 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 transducer array and the right transducer array operate collectively as a first set of electrode elements, and the rear transducer array and the left transducer array operate collectively as a second set of electrode elements.

[0047] Depending on the situation, it may be advantageous to repeatedly switch the direction of the alternating electric field between the direction shown in FIG. 5A and the direction shown in FIG. 5B. As an example, this may be the case when the alternating electric field is a TT field used for the treatment of tumors (this is because the sensitivity of the tumor to the electric field has a directionality). As another example, when the direction of the alternating electric field is repeatedly shifted, based on the shape of the transducer array with respect to the head, the applied range of the electric field within the head can be expanded. The hardware shown in FIG. 4 can implement this alternating operation between the direction of FIG. 5A and the direction of FIG. 5B, as will be 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 transducer array and the left transducer arrays 10A, 10L, and route the other phase of the AC signal to both the rear array and the right arrays 10P, 10R. Thereby, an electric field is induced 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 transducer array and the left transducer arrays 10P, 10L, and route the other phase of the AC signal to both the front array and the right arrays 10AP, 10R. Thereby, an electric field is induced in the direction of FIG. 5B. Next, these two steps are repeatedly alternated at least 10 times. The duration of each step in the sequence is from 10 milliseconds to 12 hours. In some embodiments, the duration of each step in the sequence is from 100 milliseconds to 1000 seconds, or from 200 milliseconds to 5 seconds (for example, 1 second).

[0049] Therefore, the hardware shown in FIG. 4 can be used to practice a method of applying an alternating electric field to a subject's target region using a first set of one or more electrode elements 10A disposed on a first side of the subject's target region, a second set of one or more electrode elements 10P disposed on a second side of the target region, 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. This method includes: (a) applying an alternating 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 alternating 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 region, (2) the third side and the fourth side are on opposite sides of the target region, (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 repeated alternately at least 10 times.

[0050] At some point prior to implementing this method, the first set, the second set, the third set, and the fourth set of all of the one or more electrode elements 10 are placed on or in the subject's body. Optionally, the first frequency and the second frequency may each be 50 kHz to 1 MHz, such as 100 kHz to 500 kHz, or 100 kHz to 300 kHz. In some embodiments, the first frequency and the second frequency may be the same.

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

[0052] As described above, an alternating electric field of a specific frequency (e.g., 100 - 500 kHz) can be used for the treatment of tumors, and an alternating electric field of a frequency lower than normal (e.g., 50 - 200 kHz) can enhance the permeability of the blood - brain barrier (BBB), making it easier for, for example, chemotherapeutic drugs to reach the brain. Therefore, combining the alternating electric field of the former frequency with chemotherapy enhanced by the alternating electric field of the latter frequency can be an effective approach for the treatment of brain tumors. See, for example, U.S. Patent No. 10,967,167, which is hereby incorporated by reference in its entirety.

[0053] The presence and intensity of the electric sensation are intensity - dependent effects, and the unpleasant electric sensation usually worsens as the electric field intensity increases. The presence and intensity of the electric sensation are also frequency - dependent effects. More specifically, if all other conditions are the same, the unpleasant electric sensation associated with an alternating electric field generally worsens at a lower frequency (e.g., 100 kHz) that is effective for enhancing the permeability of the BBB compared to the frequency (e.g., 200 kHz) that is most effective for the treatment of tumors (e.g., in the case of glioblastoma).

[0054] Suppose a patient with glioblastoma is encountered and it is desired to treat the patient with a TT field of 200 kHz. As shown in FIGS. 2A - D, when four transducer arrays are placed on the subject's head, glioblastoma can be treated using the conventional approach of switching the direction of the electric field. That is, (a) when an alternating voltage of 200 kHz is applied between arrays 10L and 10R for 1 second, an electric field is induced in the tumor, and as shown in FIG. 3A, the electric field lines run horizontally on average across the subject's head from left to right. Next, (b) when an alternating voltage of 200 kHz is applied between arrays 10A and 10P for 1 second, an electric field is induced in the tumor, and as shown in FIG. 3B, the electric field lines run from front to back on average. Next, this two - step sequence (a) and (b) is repeated, for example, 12 - 16 hours a day.

[0055] Also, in order to increase the permeability of the BBB of the same subject and enhance the efficacy of chemotherapeutic drugs administered, for example, every few weeks, it is desired to use an alternating current electric field of 100 kHz. By continuing to use the conventional approach of switching the direction of the electric field described in the previous paragraph and simply lowering the frequency of the alternating current electric field to 100 kHz, the subject may experience electric sensation. This is because the sensitivity to electric sensation is significantly higher at 100 kHz than at 200 kHz.

[0056] FIG. 7 is a block diagram of an embodiment that applies an alternating current electric field of 200 kHz in the L / R direction and the A / P direction using a conventional approach, and further reduces the current density of each transducer array while outputting an alternating current electric field of 100 kHz using the transducer array pairing concept described above in relation to FIGS. 4 - 6. The transducer array 10 itself of this embodiment is the same as the aforementioned transducer array 10. However, the alternating 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, and each phase is input to the switch bank 25. Various approaches for implementing the switch bank 25 will be apparent to those skilled in the art (wiring four SPST solid state relays between each of the first phase 100 kHz input and the four outputs, further adding four SPST solid state relays between each of the 100 kHz second phase input and the four outputs, further adding four SPST solid state relays between each of the first phase 200 kHz input and the four outputs, and further adding four SPST solid state relays between each of the 200 kHz second phase input and the four outputs, including but not limited to these). The path when the 100 kHz AC output signal passes through the switch bank 25 is controlled by a signal transmitted from the 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 route the other phase of the 100 kHz AC output signal to the other two transducer arrays 10 simultaneously.

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

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

[0060] In addition to routing the 100 kHz AC signal from the signal generator 20a to the four selected outputs as described above, the switch bank 25 is also configured to route the 200 kHz AC signal from the signal generator 20b to the four selected outputs via a different path. (a) Apply a 200 kHz AC voltage between the arrays 10L and 10R for, for example, 1 second to induce an electric field in the tumor, forming electric field lines that on average run from left to right across the subject's head as shown in FIG. 3A. Then (b) apply a 200 kHz AC voltage between the arrays 10A and 10P for, for example, 1 second to induce an electric field in the tumor, forming electric field lines that on average run from front to back as shown in FIG. 3B. Next, repeat this two-step sequence (a) and (b) for 12 to 16 hours every day. To do this, the controller 30 instructs the switch bank 25 to route one phase of the 200 kHz AC output signal to the left transducer array 10L and another phase of the 200 kHz AC signal to the right array 10R during a specific time period. When the switch bank 25 is configured in this way, these voltages induce an electric field in the subject's head that has electric field lines that on average run from left to right (i.e., in the direction of the dashed line in FIG. 3A). During other time periods, the controller 30 instructs the switch bank 25 to route one phase of the 200 kHz AC output signal to the front transducer array 10A and another 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 that has electric field lines that on average run from front to back (i.e., in the direction of the dashed line in FIG. 3B).

[0061] Figure 8A shows one suitable set of commands that may be issued by the controller 30 of FIG. 7 to implement this approach. During the 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 certain period of time (e.g., 1 second). Next, (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 certain period of time (e.g., 1 second). This two-step sequence (a) and (b) is repeated until t1, e.g., 12 to 16 hours per day. Next, during the time window between t1 and t2 (a window that is desirably 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) AC output signal to both the front transducer array and the left transducer array 10A, 10L, and the other phase of the third (e.g., 100 kHz) AC signal to both the rear array and the right array 10P, 10R. This induces an electric field in the direction of FIG. 5A.

[0062] FIG. 8B shows another suitable set of commands that may be issued by the controller 30 (FIG. 4) to execute 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. Next, during the time window between t1 and t2 (the window that is desirably 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) AC output signal to both the front transducer array and the right transducer arrays 10A, 10R, and route the other phase of the third (e.g., 100 kHz) AC signal to both the rear array and the left arrays 10P, 10L. Thereby, an electric field is induced in the direction of FIG. 5B.

[0063] Returning to FIG. 7, as shown in FIG. 7, instead of using separate 100 kHz and 200 kHz AC signal generators 20a, 20b, a single multi-frequency AC signal generator (not shown) operable at either 100 kHz or 200 kHz can be used. In these embodiments, the single multi-frequency AC signal generator is configured to respond to a frequency setting command from the controller, and as described above in connection with FIGS. 8A and 8B, the correct frequency needs to reach the correct output at the appropriate timing.

[0064] When implementing the approach described above in relation to either FIG. 8A or 8B, a method for treating a tumor in a target region of a subject's head and delivering a substance through the BBB of the target region can be practiced using the hardware shown in FIG. 4. This method includes the step of applying an alternating voltage of 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, wherein the first side and the second side are on opposite sides of the target region. This method further includes the step of applying an alternating 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, wherein the third side and the fourth side are on opposite sides of the target region, the third side is circumferentially disposed between the first side and the second side, and the fourth side is circumferentially disposed between the first side and the second side. Also, this method includes the step of applying an alternating voltage of a third frequency (e.g., 100 kHz) (i) between both the first set and the third set of one or more electrode elements 10A, 10L and (ii) between both the second set and the fourth set of one or more electrode elements 10P, 10R, wherein the third frequency is lower than the first frequency and the third frequency is lower than the second frequency. The alternating voltage of the first frequency, the alternating voltage of the second frequency, and the alternating voltage of the third frequency are applied at different time intervals respectively.

[0065] At some point prior to implementing this method, all of the first set, the second set, the third set, and the fourth set of one or more electrode elements 10 are disposed on the first side, the second side, the third side, and the fourth side of the target region respectively. This can be achieved, for example, by placing the sets of electrode elements on the subject's skin or embedding them under the subject's skin.

[0066] In some embodiments of this method, the first frequency (e.g., 200 kHz) is selected such that the electric field induced in the target region by applying an alternating voltage between the first set 10A of one or more electrode elements and the second set 10P of one or more electrode elements has an anti-mitotic effect. The second frequency (e.g., 200 kHz) is selected such that the electric field induced in the target region by applying an alternating voltage between the third set 10L of one or more electrode elements and the fourth set 10R of one or more electrode elements has an anti-mitotic effect. Also, the third frequency (e.g., 100 kHz) is selected such that the electric field induced in the target region by applying an alternating voltage of the third frequency (a) between both the first set and the third set of one or more electrode elements 10A, 10L and (b) between both the second set and the fourth set of one or more electrode elements 10P, 10R enhances 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, both the first frequency and the second frequency are 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 alternating voltage of the third frequency is applied for at least 24 hours. In some embodiments, (a) the step of applying an alternating voltage of the first frequency between the first set and the second set of one or more electrode elements 10A, 10P and (b) the step of applying an alternating voltage of the second frequency between the third set and the fourth set of one or more electrode elements 10L, 10R are repeatedly alternated at least 10,000 times. Assuming that each of step (a) and step (b) takes 1 second, this corresponds to a total of 20,000 seconds (i.e., about 5.5 hours).

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

[0069] Part of the above discussion focuses on applying an alternating electric field to the head of a subject to enhance the permeability of the blood-brain barrier. The same concept can be applied to other biological barriers physically present in other parts of the body (e.g., the intestinal epithelial barrier).

[0070] When using an alternating electric field for tumor treatment, as described above, it is desirable to use an electric field whose direction alternates between different directions. However, when the alternating electric field is used for other purposes (e.g., enhancing the permeability of the blood-brain barrier or other biological barriers), an electric field with a constant direction can be used.

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

[0072] The present invention has been disclosed with reference to specific embodiments, but numerous modifications, changes, and variations are possible to the described embodiments without departing from the scope and range of the invention defined by the appended claims. Accordingly, the present invention is not intended to be limited to the described embodiments, but rather is intended to have the full scope defined by the following claims and the equivalents thereof.

Claims

1. An apparatus for treating tumors in a target area and promoting the delivery of substances across the biological barrier of the target area, comprising: At least one signal generator configured to generate an alternating voltage of a first frequency and an alternating voltage of a second frequency, wherein the second frequency is lower than the first frequency; the signal generator; 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, wherein the switch bank is configured to receive the alternating voltage of the first frequency, wherein the switch bank is configured to receive the alternating voltage of the second frequency, wherein the switch bank is configured to route the alternating voltage of the first frequency such that the alternating voltage of 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, wherein the switch bank is configured to route the alternating voltage of the first frequency such that the alternating voltage of 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, wherein the switch bank is configured to route the alternating voltage of the second frequency such that the alternating voltage of 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 in response to a third state of the at least one control input; the switch bank; And a controller programmed to set (i) the at least one control input to the first state, (ii) the at least one control input to the second state, and (iii) the at least one control input to the third state at different time intervals.

2. The apparatus according to claim 1, wherein the first frequency is between 50 kHz and 1 MHz, and the second frequency is between 50 kHz and 300 kHz.

3. The apparatus according to claim 1, wherein the controller is programmed to repeatedly alternate (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.

4. ​ The controller of the apparatus according to claim 1 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 then leave the at least one control input in the third state for at least 12 hours.

5. An apparatus for applying a signal to a set of electrodes, comprising: at least one signal generator configured to generate an alternating 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, wherein the switch bank receives an alternating voltage of a first frequency, and the switch bank is configured to route the alternating voltage such that the alternating 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; and the switch bank is configured to route the alternating voltage such that the alternating 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; and a controller programmed to alternately repeat at least 10 times (i) a step of setting the at least one control input to the first state and (ii) a step of setting the at least one control input to the second state.

6. The apparatus according to claim 5, wherein the frequency of the alternating voltage is 50 kHz to 1 MHz.

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