TW202216234A - 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 Treatment Fields (TTFields) via Electrodes Embedded in Skull Implants

Cross-references to related applications

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

Tumor treatment electric fields or TTFields are low-intensity alternating electric fields (eg, 1 to 3 V/cm) that inhibit cancer cell growth in the mid-frequency range (eg, 100 to 500 kHz). This non-invasive treatment targets solid tumors and is described in US Pat. No. 7,565,205, which is incorporated herein by reference in its entirety. The 200 KHz 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 to the left and right of the tumor, and the other pair of arrays was positioned anterior and posterior to the tumor.

One aspect of the present invention pertains to a first device. The first apparatus includes a rigid substrate shaped and sized 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 outer side of the board is attached to the inner side of the base plate. 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 ends of the leads are positioned in electrical contact with the board, the leads pass through the substrate, and the outer ends of the leads are configured to accept electrical signals from external devices.

Some embodiments of the first apparatus further include a temperature sensor positioned adjacent to the dielectric layer. Optionally, such embodiments may 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 flexible thin layer of high dielectric polymer.

Another aspect of the present invention relates to a second device. The second apparatus includes a rigid substrate shaped and sized 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 has an inner side and an outer side. The outer side of each plate is attached to the inner side of the base plate. The second device also includes a dielectric layer disposed on the inside of each plate; and a first conductive lead having an inner end and an outer end. The inner end of the first lead is disposed in electrical contact with a first of the boards, the first lead passes through the substrate, and the outer end of the first lead is configured to accept electrical signals 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 disposed in electrical contact with a second of the boards, the second lead passes through the substrate, and the outer end of the second lead is configured to accept electrical signals from an external device.

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

Some embodiments of the second apparatus further include a temperature sensor positioned adjacent to the dielectric layer. Optionally, such embodiments may 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 comprises a ceramic layer having a dielectric constant of at least 10,000. In some embodiments of the second device, the dielectric layer comprises a flexible thin layer of high dielectric polymer.

Another aspect of the invention pertains to a first method of treating a tumor in a human head. The first method includes positioning a first set of electrodes on an inner side of a 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 instances of the first method, the second set of electrodes is positioned on the inside of the first cranial implant. In some instances of the first method, the second set of electrodes is positioned on the inside of the second cranial implant. In some instances of the first method, the second set of electrodes is positioned on the outer surface of the human head.

In a patient with glioblastoma, when the Optune™ transducer array is positioned on the patient's shaved head, the electric field must pass through the patient's scalp and skull twice 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 target the field to the desired location in the brain (ie, the tumor bed). And secondly, 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 (eg, about 50 VAC and about 1 A) in order to obtain therapeutically effective treatment in the tumor bed. Electric field of effective magnitude.

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

FIG. 2 depicts a first specific example for implementing any of the cranial implants 10A/10P/10L/10R depicted in FIG. 1 . In this particular example, rigid substrate 20 is shaped and sized to replace a section of the skull. Substrate 20 has an inner side and an outer side, and can be formed using any of a variety 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 . The plate 22 is preferably metal (eg, copper, steel, etc.), although alternative conductive materials may 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 variety 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 region. Conductive plate 22 and dielectric layer 24 form a capacitor and use higher capacitance to improve coupling of the electric field into the tumor. 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 that used in conventional Optune™ systems. An alternative method for increasing capacitance is to use a flexible thin layer of high dielectric polymer as dielectric layer 24 .

Any portion of the conductive plate 22 not covered by the dielectric 24 should be covered by a suitable insulator (eg, medical grade polysiloxane) to prevent non-capacitive coupling between the conductive plate 22 and the 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 the substrate 20 and the outer ends of the leads 26 are configured to accept electrical signals from external devices, such as the 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 produces an AC voltage on the wires leading to implants 10A and 10P, and then AC voltages on the wires leading to implants 10L and 10R (as described above, in a repeating and alternating sequence). The corresponding AC current will travel through the wire 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 of any part of the patient's brain. In some embodiments, appropriate wiring (not shown) passes through the substrate 20 and is used to route signals from the temperature sensor 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 may be configured to wirelessly communicate with the temperature sensor using any of a variety of conventional methods.

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 ceramic coatings disposed on the smaller conductive plates 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 deliver current to the other conductive plates. Alternatively, as depicted in FIG. 4, if each of the conductive plates 32 has its own leads 36 that pass through the substrate 20, the internal wiring may be omitted.

Notably, since the electric field does not have to pass through the scalp or skull, for any given desired field strength at the tumor, the voltages and currents used in this particular example can be significantly lower than those used in conventional Optune™ systems. 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 must traverse the scalp and skull twice to reach the tumor.)

Furthermore, when the transducer array is incorporated into a cranial implant, the planning of the treatment can be simplified so that the desired field is presented in the tumor bed due to the electrical current between the transducer arrays on opposite sides of the tumor Paths are simplified. Finally, incorporating transducer arrays into cranial implants can improve treatment planning in situations where the location of surgical wounds or skin abnormalities may prevent application of conventional Optune™ transducer arrays to specific locations on a 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 alternate embodiment, only some sets of electrodes are incorporated into the skull implant, and the remaining sets of electrodes are positioned outside the patient's skull (as in conventional TTField treatments using Optune™). For example, one set of electrodes may be positioned in the skull implant 10A on the anterior side of the patient's head, and the sets of electrodes on the right, left, and posterior sides may 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 cranial implant can be mounted on the patient's head to replace the upper hemisphere of the patient's skull, and all four sets of electrodes can be incorporated into a single cranial implant (that is, within the implant on the left, right, front and rear inner walls).

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

none

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

[ FIG. 2 ] depicts a first specific example for implementing any of the cranial implants depicted in FIG. 1 .

[ FIG. 3 ] depicts a second specific example for implementing any of the cranial implants depicted in FIG. 1 .

[ FIG. 4 ] depicts a third specific example for implementing any of the cranial implants depicted in FIG. 1 .

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

10A: Implants

10L: Implants

10P: Implants

10R: Implants

11: AC Field Generator

15: Skull

Claims (18)

A device comprising: a rigid base plate shaped and sized to replace a section of a skull, the base plate having medial and lateral; a conductive plate having an inner side and an outer side, wherein the outer side of the plate is attached to the inner side of the substrate; a dielectric layer disposed on the inner side of the board; 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 board, wherein the lead passes through the substrate, and wherein the outer end of the lead is configured to receive electricity from an external device Signal. The apparatus of claim 1, further comprising a temperature sensor positioned adjacent 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 electrical signals from the temperature sensor to the external device . The apparatus of 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 apparatus of claim 1, wherein the dielectric layer comprises a flexible thin layer of high dielectric polymer. A device comprising: a rigid base plate shaped and sized to replace a section of a skull, the base plate having medial and lateral; a plurality of conductive plates, each conductive plate has an inner side and an outer side, wherein the outer side of each plate is attached to the inner side of the substrate; a dielectric layer disposed on the inner side of each plate; and a first conductive lead having inner and outer ends, wherein the inner end of the first lead is disposed in electrical contact with a first of the boards, wherein the first lead passes through the substrate, and wherein the first lead The outer end of a lead is configured to receive electrical signals from an external device. 7. The apparatus 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 disposed in electrical contact with a second of the plates, wherein the second lead passes through through the substrate, and wherein the outer ends of the second leads are configured to receive electrical signals from the external device. The apparatus of claim 7, further comprising an additional conductive lead positioned to electrically connect the first of the plates with the second of the 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 electrical signals 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 apparatus of claim 7, wherein the dielectric layer comprises a flexible thin layer of high dielectric polymer. A method of treating a tumor in a human head, the method comprising: positioning a first set of electrodes on the inside of a 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 was applied between the first set of electrodes and the second set of electrodes to generate an alternating electric field across the tumor. The method of claim 15, wherein the second set of electrodes is positioned on the inside of the first cranial implant. The method of claim 15, wherein the second set of electrodes is positioned on the inside of the second cranial implant. The method of claim 15, wherein the second set of electrodes is positioned on the outer surface of the person's head.

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