TWI805954B - Applying tumor treating fields (ttfields) via electrodes embedded into skull implants - Google Patents

Abstract

Tumors inside a person's head (e.g., brain tumors) can be treated using tumor treating fields (TTFields) by positioning capacitively coupled electrodes on opposite sides of the tumor, and applying an AC voltage between the electrodes. Unlike the conventional approach (in which all of the electrodes are positioned on the person's scalp) at least one of the electrodes is implemented using an implanted apparatus. The implanted apparatus includes a rigid substrate shaped and dimensioned to replace a section of the person's skull. At least one electrically conductive plate is affixed to the inner side of the rigid substrate, and a dielectric layer is disposed on the inner side of the conductive plate or plates. An electrically conductive lead is used to apply an AC voltage to the conductive plate or plates.

Description

Application of Tumor Therapy Electric Fields (TTFields) via electrodes embedded in skull implants

The present invention relates to devices and methods for treating tumors in the human head by applying Tumor Treating Electric Fields (TTFields) through electrodes embedded in skull implants.

Cross References to Related Applications

This application claims the benefit of U.S. Provisional Application 62/880,893, filed July 31, 2019, which is hereby incorporated by reference in its entirety.

Tumor Therapeutic Fields or TTFields are low intensity AC electric fields (eg, 1 to 3 V/cm) in the mid-frequency range (eg, 100 to 500 kHz) that inhibit cancer cell growth. This non-invasive treatment targets solid tumors and is described in US Patent 7,565,205, which is incorporated herein by reference in its entirety. The 200KHz TTField is FDA-approved for the treatment of glioblastoma (GBM), and can be delivered, for example, via the Optune ^™ system. Optune ^™ includes a field generator and two pairs of transducer arrays (ie, electrode arrays) placed on the patient's shaved head. One pair of arrays was positioned on the left and right side of the tumor, and the other pair was positioned on the front and back of the tumor.

One aspect of the invention relates to a first device. The first device includes a rigid base plate shaped and dimensioned to replace a segment of a skull. The substrate has an inner side and an outer side. The first device also includes a conductive plate having an inner side and an outer side. The outside of the board is attached to the inside of the substrate. The first device also includes a dielectric layer disposed on the inner side of the board; and a conductive lead having an inner end and an outer end. The inner end of the lead is disposed in electrical contact with the board, the lead passes through the substrate, and the outer end of the lead is configured to receive an electrical signal from an external device.

Some embodiments of the first apparatus further include a temperature sensor positioned adjacent to the dielectric layer. Optionally, such embodiments can further include at least one wire passing through the substrate and terminating at the temperature sensor, wherein the wire is configured to transmit electrical signals from the temperature sensor to an external device. Optionally, in these embodiments, the temperature sensor includes a thermistor.

In some embodiments of the first device, the dielectric layer includes a ceramic layer having a dielectric constant of at least 10,000. In some embodiments of the first device, the dielectric layer comprises a thin flexible layer of a high dielectric polymer.

Another aspect of the invention relates to a second device. The second device includes a rigid base plate shaped and dimensioned to replace a segment of a skull. The substrate has an inner side and an outer side. The second device also includes a plurality of conductive plates, each conductive plate having an inner side and an outer side. The outside of each board is attached to the inside of the substrate. The second apparatus also includes a dielectric layer disposed on the inner side of each board; and a first conductive lead having an inner end and an outer end. The inner end of the first lead is arranged to be in electrical contact with the first of the boards, the first lead passes through the substrate, and the outer end of the first lead is configured to receive an electrical signal from an external device.

Some embodiments of the second apparatus further include a second conductive lead having an inner end and an outer end. The inner end of the second lead is arranged to be in electrical contact with the second of the boards, the second lead passes through the substrate, and the outer end of the second lead is configured to receive an electrical signal from an external device.

Some embodiments of the second apparatus further include additional conductive leads disposed to electrically connect the first of the plates with the second of the plates.

Some embodiments of the second apparatus further include a temperature sensor positioned adjacent to the dielectric layer. Optionally, such embodiments can further include at least one wire passing through the substrate and terminating at the temperature sensor, wherein the wire is configured to transmit electrical signals from the temperature sensor to an external device. Optionally, in these embodiments, the temperature sensor includes a thermistor.

In some embodiments of the second device, the dielectric layer includes a ceramic layer having a dielectric constant of at least 10,000. In some embodiments of the second device, the dielectric layer comprises a thin flexible layer of high dielectric polymer.

Another aspect of the invention relates to a first method of treating tumors in the human head. The first method comprises positioning a first set of electrodes on the inside of the first cranial implant on a first side of the tumor; positioning a second set of electrodes on a second side of the tumor opposite the first side; and An AC voltage is applied between the first set of electrodes and the second set of electrodes to generate an alternating electric field across the tumor.

In some cases of the first method, the second set of electrodes is positioned on the inside of the first cranial implant. In some cases of the first method, the second set of electrodes is positioned on the inside of the second cranial implant. In some cases of the first method, the second set of electrodes is positioned on an outer surface of the human head.

10A: Implants

10L: Implant

10P: Implant

10R: Implants

10: Implants

10': Implant

10": Implants

11: AC field generator

15: skull

20: Substrate

22: Conductive plate

24: Dielectric layer

26: Lead

32: Conductive plate

34: Dielectric layer

36: Lead

37: Internal wiring

[ FIG. 1 ] Depicts a specific example of the incorporation of transducer arrays into four skull implants.

[ FIG. 2 ] Depicts a first embodiment for implementing any of the cranial implants depicted in FIG. 1 .

[ Fig. 3 ] Depicts a second embodiment for implementing any of the cranial implants depicted in Fig. 1 .

[Fig. 4] depicts the first method for implementing any one of the cranial implants depicted in Fig. 1 Three specific examples.

Various specific examples are described in detail below with reference to the accompanying drawings, wherein like reference numerals refer to like elements.

In a patient with glioblastoma, when the Optune ^™ transducer array is positioned on the patient's shaved head, the electric field must travel twice through the patient's scalp and skull in order to reach the tumor. This situation introduces two problems. First, the presence of the skull between the transducer array and the tumor makes it more difficult to aim the field at the desired location in the brain (ie, the tumor bed). And second, due to the attenuation of the electric field introduced by the skull and scalp, the voltage and current applied to the transducer array must be relatively high (e.g., about 50 VAC and about 1 A) in order to obtain a therapeutically effective dose in the tumor bed. value of the electric field.

Figure 1 depicts a specific example of ameliorating these problems by incorporating a transducer array into one or more cranial implants. In the illustrated example, cranial implants 10L and 10R are positioned on the left and right sides of the patient's skull 15, respectively; AC field generator 11 (a) applies an AC voltage between electrodes in cranial implant 10A and electrodes in cranial implant 10P for a first time interval (eg, 1 second); then (b) applies an AC voltage between electrodes in cranial implant 10P; The AC voltage is applied between the electrodes in implant 10L and the electrodes in cranial implant 10R for a second time interval (eg, 1 second); then the two-step sequence (a) and (b) is repeated for the duration of the treatment.

FIG. 2 depicts a first embodiment for implementing any of the cranial implants 10A/10P/10L/10R depicted in FIG. 1 . In this embodiment, rigid base plate 20 is shaped and dimensioned to replace a section of the skull. Base plate 20 has an inner side and an outer side, and can be formed using any of a number of conventional methods for forming cranial implants, including but not limited to 3D printing. In some preferred embodiments, the area of the substrate 20 is at least 5 cm ² .

The conductive plate 22 is attached to the inner side of the substrate 20 . This plate 22 is preferably metal (for example, copper, steel, etc.), but alternative conductive materials can also be used. The shape of the plate 22 can be customized to match the contour of the substrate 20, and the outside of the plate 22 can be attached to the substrate 20 using any of a number of conventional methods including, but not limited to, 3D printing and adhesives. A dielectric layer 24 is disposed on the inner side of the board 22 .

In many cases it is preferable to capacitively couple the electric field into the target area. The conductive plate 22 and dielectric layer 24 form a capacitor, and the coupling of the electric field into the tumor is improved with higher capacitance. One method for achieving high capacitance is to implement dielectric layer 24 using a ceramic dielectric material having a dielectric constant of at least 10,000, similar to the method used in the conventional Optune ^™ system. An alternative method for increasing capacitance is to use a thin flexible layer of a high-k polymer as the dielectric layer 24 .

Any portion of conductive plate 22 not covered by dielectric 24 should be covered by a suitable insulator (eg, medical grade polysilicon) to prevent non-capacitive coupling between conductive plate 22 and tissue in the patient's head.

The inner ends (eg, wires) of the conductive leads 26 are placed in electrical contact with the board 22 . Leads 26 pass through substrate 20 and the outer ends of leads 26 are configured to accept electrical signals from an external device such as field generator 11 depicted in FIG. 1 . This can be achieved, for example, by providing terminals at the outer ends of the leads 26 .

For example, assume that the four sets of devices 10 depicted in FIG. 2 are positioned on all four sides of the patient's head (ie, left, right, front, and back, respectively). Field generator 11 generates AC voltages on wires leading to implants 10A and 10P, followed by AC voltages on wires leading to implants 10L and 10R (as described above, in a repeating and alternating sequence). The corresponding AC current will travel through the wires 26 until it reaches the conductive plate 22 in each of the implants 10A/10B/10L/10R. Due to the presence of the dielectric layer 24, the required electric field will be applied into the tumor bed via capacitive coupling.

Preferably, at least one temperature sensor (eg, a thermistor, not shown) is integrated into each implant 10A/10P/10L/10R to reduce the risk of overheating any part of the patient's brain. In some embodiments, suitable wiring (not shown) passes through the substrate 20 and is used to route signals from the temperature sensors to the system's controller (which may be located, for example, in the field generator 11 shown in FIG. 1 . ). In an alternate embodiment, the system can be configured to communicate wirelessly with temperature sensing using any of a variety of well-known methods. Meter communication.

FIG. 3 is similar to the FIG. 2 embodiment, except that instead of using a single conductive plate 22 and a single dielectric layer 24 (as in the FIG. 2 embodiment), a plurality of smaller conductive plates 32 and smaller dielectric layers are used 34. Each of these smaller conductive plates 32 may be circular, if desired. Each of the smaller dielectric layers 34 may be a ceramic coating disposed on the smaller conductive plate 32, if desired.

In the embodiment of FIG. 3, a single lead 36 passes through the substrate 20 to one of the conductive plates 32, and internal wiring 37 is used to route current to the other conductive plates. Alternatively, as depicted in FIG. 4 , internal wiring may be omitted if each of the conductive plates 32 is provided with its own leads 36 passing through the substrate 20 .

It is worth noting that since the electric field does not have to pass through the scalp or skull, for any given desired field strength at the tumor, the voltage and current used in this particular example can be significantly lower than those used in the conventional Optune ^™ system. voltage and current. (This is because in the conventional Optune ^™ system, the electrodes are all positioned on the patient's shaved scalp, which means that the electric field has to traverse the scalp and skull twice to reach the tumor.)

Furthermore, when transducer arrays are incorporated into cranial implants, the planning of treatment can be simplified so that the desired field is presented in the tumor bed because electrical connections between the transducer arrays on opposite sides of the tumor Paths are simplified. Finally, incorporating transducer arrays into cranial implants can improve treatment planning where the location of surgical wounds or skin abnormalities may prevent the application of conventional Optune ^™ transducer arrays to specific locations on the patient's skin surface.

It should be noted that Figure 1 depicts the incorporation of all electrodes into respective cranial implants 10A/10P/10L/10R. But in an alternative embodiment, only some sets of electrodes are incorporated into the cranial implant, and the remaining sets of electrodes are positioned outside the patient's skull (as in the conventional TTField treatment using Optune ^™ ). For example, one set of electrodes could be positioned in the cranial implant 10A on the anterior side of the patient's head, and the sets of electrodes on the right, left, and back sides could all be positioned outside the patient's skull.

In other alternative embodiments, two or more sets of electrodes are incorporated into a single cranial implant. For example, a single generally hemispherical skull implant can be mounted on the patient's head in place of The upper hemisphere of the patient's skull, and all four sets of electrodes can be incorporated into a single cranial implant (ie, on the left, right, anterior, and posterior inner walls of the implant).

Although the invention has been disclosed with reference to certain specific examples, numerous modifications, changes and variations to the described specific examples are possible without departing from the field and scope of the invention as defined in the appended claims . Thus, it is intended that the invention not be limited to the particular examples described, but that it have its full scope as defined by the language of the following claims and their equivalents.

10A: Implants

10L: Implant

10P: Implant

10R: Implants

11: AC field generator

15: skull

Claims (14)

An apparatus comprising: a rigid base plate shaped and dimensioned to replace a segment of a skull, the base plate having an inner side and an outer side; a conductive plate having an inner side and an outer side, wherein the conductive plate outer side attached to the inner side of the substrate; a dielectric layer disposed on the inner side of the conductive plate; and a conductive lead having an inner end and an outer end, wherein the inner end of the lead is disposed in electrical contact with the conductive plate , wherein the lead wire passes through the substrate, and wherein the outer end of the lead wire is configured to receive an electrical signal from an external device. The apparatus of claim 1, further comprising a temperature sensor positioned adjacent to the dielectric layer. The apparatus of claim 2, further comprising at least one wire passing through the substrate and terminating at the temperature sensor, wherein the wire is configured to transmit an electrical signal from the temperature sensor to the external device . The device according to claim 3, wherein the temperature sensor comprises a thermistor. The apparatus of claim 1, wherein the dielectric layer comprises a ceramic layer having a dielectric constant of at least 10,000. The device of claim 1, wherein the dielectric layer comprises a flexible thin layer of high dielectric polymer. An apparatus comprising: a rigid base plate shaped and dimensioned to replace a segment of a skull, the base plate having an inner side and an outer side; a plurality of conductive plates each having an inner side and an outer side, each conducting the outside of the board is attached to the inside of the substrate; a dielectric layer disposed on the inner side of each conductive plate; and a first conductive lead having an inner end and an outer end, wherein the inner end of the first lead is disposed so as to be in contact with the first of the conductive plates An electrical contact, wherein the first lead passes through the substrate, and wherein the outer end of the first lead is configured to receive an electrical signal from an external device. The device of claim 7, further comprising a second conductive lead having an inner end and an outer end, wherein the inner end of the second lead is arranged to be in electrical contact with the second of the conductive plates, wherein the second lead passing through the substrate, and wherein the outer end of the second lead is configured to receive electrical signals from the external device. The apparatus of claim 7, further comprising an additional conductive lead disposed to electrically connect the first of the conductive plates with the second of the conductive plates. The apparatus of claim 7, further comprising a temperature sensor positioned adjacent to the dielectric layer. The apparatus of claim 10, further comprising at least one wire passing through the substrate and terminating at the temperature sensor, wherein the wire is configured to transmit an electrical signal from the temperature sensor to the external device . The apparatus of claim 11, wherein the temperature sensor comprises a thermistor. The apparatus of claim 7, wherein the dielectric layer comprises a ceramic layer having a dielectric constant of at least 10,000. The device of claim 7, wherein the dielectric layer comprises a flexible thin layer of high dielectric polymer.

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