Patent Description:
Tumor Treating Fields, or TTFields, are low intensity (e.g., <NUM>-<NUM> V/cm) alternating electric fields within the intermediate frequency range (<NUM>-<NUM>). This non-invasive treatment targets solid tumors and is described in <CIT>. TTFields disrupt cell division through physical interactions with key molecules during mitosis. TTFields therapy is an approved mono-treatment for recurrent glioblastoma, and an approved combination therapy with chemotherapy for newly diagnosed patients. These electric fields are induced non-invasively by transducer arrays (i.e., arrays of electrodes) placed directly on the patient's scalp. TTFields also appear to be beneficial for treating tumors in other parts of the body. Laboratory research has begun to test intermediate frequency alternating electric fields (Tumor Treating Fields, or TTFields) to sub-cutaneous tumors and orthotropic tumors located in the torso of small animals (e.g., mice). <CIT>describes treating bacteria with electric fields. <CIT> describes methods for treating glioblastoma, and examples of apparatuses suitable for use in treating live patients with combined TTField and drug therapy. <CIT> Al and <CIT> both describe embodiments in which isolects for applying TTFields are incorporated in a skin patch. The skin patch can be a self-adhesive flexible patch with one or more pairs of isolects. The patch includes internal insulation (formed of a dielectric material) and the external insulation and is applied to skin surface that contains a tumor either on the skin surface or slightly below the skin surface. <CIT> describes a transducer array for use in TTFields therapy that is particularly suited for use in treating abdominal or thoracic cancers. The transducer array has features that increase its flexibility and adhesion to the patient's skin, including a branching configuration and a correspondingly branching top covering adhesive-backed layer. Additionally, a skin-level adhesive layer is provided beneath the flex circuit to which the electrode elements are attached, to help ensure thorough, lasting adhesion of the transducer array to the patient's skin over the course of treatment.

Described herein, in various aspects, is a treatment assembly according to the invention comprising an inner layer having an inner surface and an outer surface. Optionally, the treatment assembly can be positioned on animal test subjects, which can optionally be undergoing TTFields or control treatments. In accordance with the invention, the inner layer defines a plurality of openings extending therethrough. The treatment assembly further comprises a plurality of plates, each plate being at least partially received within a respective opening of the plurality of openings of the inner layer. The treatment assembly further comprises treatment circuitry comprising a cable having a plurality of electrical leads and a plurality of lead ends, each electrical lead being electrically connected to a respective lead end of the plurality of lead ends. A cover layer is attached to the outer surface of the inner layer and overlie the plurality of lead ends of the cable. The plurality of lead ends are in contact with respective plates of the plurality of plates to define a plurality of electrodes, each electrode of the plurality of electrodes comprising a respective lead end and a respective plate.

At least one plate of the plurality of plates can comprise a ceramic plate.

At least one plate of the plurality of plates can comprise a glass plate.

At least one electrode of the plurality of electrodes can be configured to generate an electric field through a corresponding plate of the plurality of plates.

The plurality of electrodes of the treatment circuitry can have respective top surfaces. The cover layer can extend across the top surfaces of the electrodes of the cable.

Each plate of the plurality of plates can have a lower surface and an opposing upper surface. The treatment assembly can further comprise a layer of hydrogel on the lower surface of each plate of the plurality of plates.

The treatment circuitry can further comprise at least one temperature sensor.

The inner layer and the cover layer can cooperate to define a hole through the treatment assembly. The hole can be configured to receive a subcutaneous tumor therethrough.

The treatment assembly can further comprise a cap that extends across the hole and defines a receptacle therein that is configured to receive the subcutaneous tumor. The cap can be attached to the cover layer.

The plurality of plates can be are positioned radially outwardly of the hole defined through the treatment assembly.

The cap can comprise a peripheral rim. The treatment assembly can further comprise an adhesive ring that overlies the peripheral rim and secures the cap to the cover layer.

The treatment assembly can have a longitudinal dimension in a pre-use configuration. The cover layer can comprise a biocompatible non-woven adhesive. The nonwoven adhesive can be elastic in the longitudinal dimension.

In a use configuration, the cable can extend perpendicularly or substantially perpendicularly relative to the longitudinal dimension.

The inner layer can comprise a biocompatible breathable polyurethane adhesive on the inner surface of the inner layer.

The cover layer can have an inner surface that comprises a biocompatible nonwoven adhesive.

The plurality of electrodes can comprise a plurality of electric field-generating electrodes. The plurality of electric field-generating electrodes can be configured to transmit an electric field through corresponding plates of the plurality of plates.

The treatment circuitry can further comprise a plurality of thermistors.

A respective electrode of the plurality of electrodes and a respective thermistor of the plurality of thermistors can be in communication with each plate of the plurality of plates.

The treatment assembly can weigh less than <NUM> grams.

The treatment assembly can be sufficiently flexible to circumferentially conform to a portion of a torso of the animal subject.

The cable can comprise an end connector positioned on an end of the cable opposite the plurality of electrodes. The end connector can be configured to permit connection of the cable to an electrical signal generator.

The treatment assembly can further comprise a release layer that contacts the biocompatible breathable polyurethane adhesive on the inner surface of the inner layer.

The release layer can have a shape that is complementary to a shape of the cover layer.

The cover layer can define at least one tab portion that extends beyond the inner layer.

The at least one tab portion can comprise two opposing tab portions that are complementary to one another when the cover layer defines a circumferential loop.

The plurality of openings can comprise a plurality of longitudinally spaced openings.

The treatment circuitry and the cable can be unitarily constructed as a flexible printed circuit board.

A method of making a treatment assembly can comprise positioning the plurality of plates within respective openings in the inner layer of the treatment assembly, positioning each electrode of the plurality of electrodes of the treatment circuitry in contact with a plate of the plurality of plates, and attaching the cover layer to the outer surface of the inner layer. The cover layer can overlie the plurality of electrodes of the treatment circuitry.

The method can further comprise applying a layer of hydrogel to lower surfaces of each plate of the plurality of plates.

The lower surfaces of at least two plates of the plurality of plates can share a layer of hydrogel.

A method not defined by the appended claims can comprise electrically coupling at least a portion of the electrodes of the treatment assembly to an electrical signal generator and attaching the treatment assembly to an animal subject having a tumor. The plates of the treatment assembly can surround at least a portion of the tumor. The electrical signal generator can be used to generate an electrical signal (e.g., an electric potential). The at least a portion of the electrodes of the treatment assembly can be used to deliver the electrical signal through corresponding plates of the plurality of plates, thereby generating an electric field.

The tumor can be an organ tumor. In a pre-use configuration, the plurality of openings and the plurality of plates can be longitudinally spaced along a longitudinal axis of the treatment assembly. In a use configuration, the plurality openings and the plurality of plates can be circumferentially spaced about a torso of the animal subject to surround the organ tumor.

The tumor can be a subcutaneous tumor. The plurality of openings can be radially spaced from a hole extending through the treatment assembly. The hole can receive at least a portion of the subcutaneous tumor.

The method can further comprise positioning a cap over the subcutaneous tumor and securing the cap to the cover layer of the treatment assembly.

Using the electrical signal generator to generate the electrical signals can comprise sequentially generating first and second electrical signals. Using said at least a portion of the electrodes of the treatment assembly to generate, from the electrical signal, the electric field can comprise using first and second electrodes to generate, from the first electrical signal, a first electric field across the tumor and using third and fourth electrodes to generate, from the second electrical signal, a second electric field across the tumor.

The first and second electric fields can have respective axes of propagation, and the axis of propagation of the first electric field can intersect the axis of propagation of the second electric field.

Using the electrical signal generator to generate an electrical signals can comprise generating the electrical signals at a frequency of between <NUM> and <NUM>. The electrical signals can correspond to an alternating current provided at a frequency of between <NUM> and <NUM> (or <NUM> to <NUM> or at or about <NUM>) that is configured to produce a TTField as further disclosed herein.

The animal subject can be a member of an experimental group. The method can further comprise electrically coupling at least a portion of the electrodes of a control heating device to an electrical signal generator. The control heating device can be attached to a second animal subject having a tumor. The second animal subject can be a member of a control group. The heaters of the second treatment assembly can surround at least a portion of the tumor. The electrical signal generator can be used to generate heat through heaters of the control heating device. The at least a portion of the electrodes of the second treatment assembly can deliver the heat through corresponding plates of the plurality of plates. The heat generated by the control heating device can simulate heat generated by the first treatment assembly during delivery of the electric field.

A control heating device can comprise circuitry comprising a plurality of zones that are positioned in a spaced configuration that matches a configuration of the plurality of electrodes of the treatment assembly, at least one heater positioned in each zone of the plurality of zones, at least one temperature sensor, and a cable in communication with the at least one heater and the at least one temperature sensor of the circuitry.

The at least one temperature sensor can comprise a plurality of temperature sensors, wherein each temperature sensor of the plurality of temperature sensors is positioned at each zone of the plurality of zones.

The circuitry and the cable can be unitarily constructed as a flexible printed circuit board.

The control heating device can further comprise an inner layer having an upper surface and comprising a plurality of openings and a cover layer extending across the upper surface of the inner layer. Each of the zones can be disposed within an opening of the plurality of openings.

Additional advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

These and other features of the preferred embodiments of the invention will become more apparent in the detailed description in which reference is made to the appended drawings. Embodiments of the invention are illustrated by <FIG>.

The present invention now will be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the invention are shown. Indeed, this invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. It is to be understood that this invention is not limited to the particular methodology and protocols described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention.

Many modifications and other embodiments of the invention set forth herein will come to mind to one skilled in the art to which the invention pertains having the benefit of the teachings presented in the foregoing description and the associated drawings. Therefore, it is to be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

As used herein the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, use of the term "an electrode" can refer to one or more of such electrodes, and so forth.

All technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs unless clearly indicated otherwise.

As used herein, the term "at least one of" is intended to be synonymous with "one or more of. " For example, "at least one of A, B and C" explicitly includes only A, only B, only C, and combinations of each.

Optionally, in some aspects, when values are approximated by use of the antecedent "about," it is contemplated that values within up to <NUM>%, up to <NUM>%, up to <NUM>%, or up to <NUM>% (above or below) of the particularly stated value can be included within the scope of those aspects. Similarly, use of "substantially" (e.g., "substantially parallel") or "generally" (e.g., "generally planar") should be understood to include embodiments in which angles are within about ten degrees, or within five degrees, or within one degree.

The word "or" as used herein means any one member of a particular list and also includes any combination of members of that list.

It is to be understood that unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of aspects described in the specification.

In the following description and claims, wherever the word "comprise" or "include" is used, it is understood that the words "comprise" and "include" can optionally be replaced with the words "consists essentially of" or "consists of" to form another embodiment.

The following description supplies specific details in order to provide a thorough understanding. Nevertheless, the skilled artisan would understand that the apparatus, system, and associated methods of using the apparatus can be implemented and used without employing these specific details. Indeed, the apparatus, system, and associated methods can be placed into practice by modifying the illustrated apparatus, system, and associated methods and can be used in conjunction with any other apparatus and techniques conventionally used in the industry.

TTFields, also referred to herein as alternating electric fields, are established as an anti-mitotic cancer treatment modality because they interfere with proper micro-tubule assembly during metaphase and eventually destroy the cells during telophase and cytokinesis. The efficacy increases with increasing field strength and the optimal frequency is cancer cell line dependent with <NUM> being the frequency for which inhibition of glioma cells growth caused by TTFields is highest. For cancer treatment, non-invasive devices were developed with capacitively coupled transducers that are placed directly at the skin region close to the tumor. For patients with Glioblastoma Multiforme (GBM), the most common primary, malignant brain tumor in humans, the system for delivering TTFields therapy is called the OPTUNE™ system (Novocure Ltd.

Because the effect of TTFields is directional with cells dividing parallel to the field affected more than cells dividing in other directions, and because cells divide in all directions, TTFields are typically delivered through two pairs of transducer arrays that generate perpendicular fields within the treated tumor. More specifically, for the OPTUNE system, one pair of electrodes is located to the left and right (LR) of the tumor, and the other pair of electrodes is located anterior and posterior (AP) to the tumor. Cycling the field between these two directions (i.e., LR and AP) ensures that a maximal range of cell orientations is targeted.

Although TTFields have been approved for use in certain patients, there is a need for systems that permit reliable, consistent, and safe testing of TTFields in animal test subjects. In small animal (e.g., mice) studies in which electrical components are coupled to the animals, the animals frequently chew or otherwise damage the electrical components. Additionally, when the animals are tethered using a cable, the animals frequently cause twisting of the cable. When too much slack is provided in such cables, the animals can easily turn over, leading to damage or incorrect positioning of the electrical components. When insufficient slack is provided in such cables, the movement of the animal can be too restricted. Further, it can be difficult to couple electrical components to animals without significant adjustment and repositioning.

Disclosed herein, in various aspects and with reference to <FIG>, is a system <NUM> for providing TTFields to test subjects <NUM> (e.g., animal test subjects such as mice). The system <NUM> can comprise one or more cage assemblies <NUM> to receive and house one or more test subjects. Some test subjects in an experimental group <NUM> can be fitted with a TTField treatment assembly <NUM>, <NUM>', <NUM>" (<FIG>, <FIG>, and <FIG>) that can comprise a transducer array for providing treatment to the test subjects. Other test subjects in a control group <NUM> can be fitted with a control heater treatment assembly <NUM>,<NUM>' (<FIG>) that is configured to provide the same weight and heat as a TTField treatment assembly <NUM>, <NUM>', <NUM>". A plurality of TTField treatment assemblies <NUM>, <NUM>', <NUM>" can communicatively couple to a TTField generator <NUM>. Optionally, the TTField generator can be a generator provided as part of an INOVITRO laboratory research system (NOVOCURE GMBH). Similarly, a plurality of control heater treatment assembly <NUM> can communicatively couple to the same or a separate TTField generator <NUM> (or other generator capable of initiating heat through the control heater treatment assembly as further disclosed herein). A computer <NUM> can communicatively couple to the TTField generator <NUM>. The computer <NUM> can control the output of the TTField generator(s) <NUM> as well as log data from the TTField generator <NUM>, the treatment assemblies <NUM>, <NUM>', <NUM>", the control heater treatment assembly <NUM>, and/or the test subjects <NUM>.

The TTField treatment assemblies <NUM>, <NUM>', <NUM>" and control heater treatment assemblies <NUM> can communicate with the TTField generator <NUM> via respective cables <NUM> (<FIG>). To enable the test subject to move freely within the cage assembly <NUM> without winding the cable <NUM>, the cable <NUM> can extend to, and couple to, a swivel <NUM> (also interchangeably referred to herein as a swivel assembly <NUM>). The swivel <NUM> can, in turn, couple to a second cable <NUM> that extends to, and couples to, the TTField generator <NUM>. Thus, the swivel <NUM>, as further disclosed herein, can enable electrical communication from the TTField generator <NUM>, through the second cable <NUM>, through the swivel assembly <NUM>, and to the cable <NUM> for communicating with the treatment assemblies <NUM>, <NUM>', <NUM>" while inhibiting winding of the cable <NUM>.

Referring to <FIG>, the cage assembly <NUM> can include a main body <NUM>. The main body <NUM> can comprise a floor <NUM> that defines a floor area having a major dimension. Optionally, the floor <NUM> can be rectangular or generally rectangular with corners <NUM>. Optionally, the corners <NUM> can be rounded. The corners can have, for example, a radius of about <NUM>. The major dimension can be a maximum diagonal between the corners <NUM> of the cage. The main body <NUM> can further comprise one or more sidewalls <NUM>. For example, the main body <NUM> can comprise a front sidewall 108A, an opposing rear sidewall 108B, and a pair of opposing sidewalls 108C that extend between respective edges of the front sidewall 108A and rear sidewall 108B. The intersections between the respective sidewalls can define rounded corners <NUM>. Optionally, the sidewalls <NUM> can converge in a direction toward the floor <NUM> (i.e., slope inwardly moving in a downward direction) to provide draft angles for enabling manufacturing via injection molding. Optionally, the floor can comprise padding as is commonly used in conventional animal cages. The padding can be, for example, sawdust. Food pellets can be placed on the floor of the enclosure for foraging. A conventional water bottle can attach to the cage for hydrating the test subject. Optionally, the cage can comprise an opening within a sidewall of each enclosure to receive a dispensing portion of the conventional water bottle.

In exemplary aspects, and as shown in <FIG>, the sidewalls <NUM> can define a plurality of apertures <NUM> for ventilation. One or more filters <NUM> can optionally cover the plurality of apertures in each sidewall <NUM>. A frame <NUM> can extend about a perimeter of the filter <NUM> and receive fasteners (e.g., nuts <NUM> and bolts <NUM>) to attach to the main body <NUM> of the cage assembly <NUM>. In this way, the cage assembly is sealed so that all or substantially all ventilation to each enclosure travels through the at least one filter before entering a ventilation opening. Optionally, as shown in <FIG>, a single filter <NUM> can cover a plurality of apertures <NUM> (optionally, all the apertures) of a sidewall <NUM>. The filter can be removable, autoclavable, and replaceable. The filter can minimize penetration of infectious materials and bodies while enabling rapid air exchange. It is contemplated that a net, screen, grate, airpermeable membrane, or other permeable structure can be positioned between the plurality of apertures <NUM> in the cage and the filter <NUM> to inhibit the test subjects from chewing on the filter.

As shown in <FIG>, a door <NUM> can pivotably couple to the main body portion <NUM> by a pair of hinges <NUM>. In use, the door <NUM> can be moveable about and between (<NUM>) a closed position in which the door <NUM> cooperates with the sidewalls to provide the enclosure(s); and (<NUM>) an open position in which the door is pivoted away from the interior of the cage assembly to provide one or more openings through which the interior of the cage assembly can be accessed.

A cover <NUM> can extend across a top of the main body <NUM>. The cover <NUM> can releasably attach to the main body <NUM> via latch <NUM>. The latch <NUM> can pivotably attach to the main body <NUM> via hinges <NUM>. A latch <NUM> that is pivotable about a hinge <NUM> can attach to the door <NUM>. The latch <NUM> can releasably engage a catch on top of the cover <NUM> for holding the door <NUM> in a closed position. Optionally, the cover <NUM> can comprise one or more swivel housings <NUM> that are configured to receive at least a portion of a swivel as further disclosed herein.

A partition <NUM> can define a common sidewall that divides the interior of the cage into a first enclosure <NUM> and a second enclosure <NUM>. The partition <NUM> can optionally be removable. The main body can optionally define a slot into which the partition <NUM> can be inserted. The partition <NUM> can define an opening <NUM> (optionally, a plurality of openings) between the first enclosure <NUM> and the second enclosure <NUM> for allowing respective test subjects <NUM> in each of the first and second enclosures to interact with each other (e.g., through vocal interaction, through scent, through body warmth, and the like). Thus, the first enclosure <NUM> and second enclosures <NUM> can each have respective sidewalls (or sidewall portions) defined by the front sidewall 108A, the door <NUM>, the rear sidewall 108B, a sidewall 108C extending between the front and rear sidewalls, and the partition <NUM>. In these examples, it is contemplated that the floor area within each enclosure can have a respective major dimension, which can be equal a maximum diagonal between corners of the enclosure.

The sidewalls (e.g., main body <NUM> and partition <NUM>) and cover can optionally comprise polycarbonate and can optionally be autoclavable. Portions of the cage, such as, for example, the main body <NUM> and cover <NUM>, can be transparent so that the test subject can be observed while closed in the cage.

Referring to <FIG>, a shelter subassembly <NUM> can extend inwardly from the partition <NUM> into each of the first enclosure <NUM> and the second enclosure <NUM>. Within each enclosure, the shelter subassembly <NUM> can comprise an arcuate roof, a pair of parallel walls extending vertically downward from the arcuate roof, and, optionally, a floor cover extending between bottom edges of the sidewalls of the shelter subassembly. Within each enclosure, the shelter subassembly <NUM> can project from the partition <NUM> a select distance D. Optionally, the distance D can be about <NUM>-<NUM> centimeters. It is contemplated that the distance D can be selected so that the cable will not restrict the test subject from interacting with the test subject of the opposing enclosure. For example, the cable can be strapped to the back of the test subject a select spacing, d, away from the subject's head. In this way, the test subject cannot chew on the cable. This select spacing can also enable the test subject to enter the shelter subassembly before the cable touches the shelter subassembly. Further, the cable can be sufficiently flexible to bend upon contact with the shelter subassembly. The select distance that the shelter subassembly <NUM> protrudes from the partition <NUM> can be selected so that the test subject (e.g., at least the nose and/or face of the test subject) can at least reach a plane defined by the partition <NUM> when the cable is fully taut against the shelter subassembly. As further disclosed herein, the cable length can be a function of the enclosure's dimensions. Thus, the select distance D that the shelter subassembly <NUM> protrudes from the partition <NUM> can be a function of the cable length and the enclosure's height and width dimensions.

The covers <NUM> for the first enclosure and the second enclosure can be unitarily constructed as a cover assembly <NUM>. Optionally, the cover assembly <NUM> can comprise swivel housings <NUM>. In these aspects, the cover assembly <NUM> can further comprise swivels <NUM>, as further disclosed herein, with the swivels positioned within respective swivel housings <NUM>. The cover assembly <NUM> can comprise first and second openings between the first and second enclosures and their respective swivels <NUM>. The first and second openings can provide communication to enable the cable of the treatment assembly to couple to the respective swivel. Each swivel can be in overlying relation to a respective one of the first and second openings. According to various aspects, each swivel can extend through a respective opening in the cover assembly and at least partially into a respective enclosure to receive a respective cable. In further embodiments, each cable can extend through a respective one of the first and second opening to couple to the respective swivel.

Referring to <FIG>, the distance between the cover <NUM> and the floor <NUM> can define a cage height. In order to prevent the test subject from having sufficient slack in the cable <NUM> in order to flip over or get tangled with the cable, the cage assembly can have a select cage height, h, that is a function of the length, R<NUM>, and width, R<NUM>, of each enclosure. For example, cable <NUM> can have a select length to prevent providing enough slack for the test subject to wrap the cable around its body. According to some optional aspects, the dimensions of each enclosure <NUM>,<NUM> can be selected so that the test subject can access the corners of the cage, but when the test subject is positioned directly below the attachment of the cable to the swivel <NUM>, the cable does not have enough slack to hang or extend downwardly from the back of the test subject and touch the floor of the cage. To maximize the usable area for a given cage height, the cable can extend from directly above a center of the floor space of each enclosure. Accordingly, the height of the cage can be selected as a function of the major dimension of the cage floor (of a given enclosure) and the height of the test subject. For example, the height can be selected based on the following equation: <MAT> where h is the height of the cage, R<NUM> is a length of the enclosure, R<NUM> is width of the enclosure, and a is the height of the animal. Thus, the height can be a function of the major dimension of the cage floor, Y, according to the following equation: <MAT> A typical test subject mouse can have a height (a) of <NUM>. Thus, in some examples, the cage height, h, in millimeters, can be a function of the maj or dimension of the cage floor, Y (in millimeters), according to the following equation: <MAT>.

More generally, the height of the cage can be selected as the major dimension of the cage floor (of a respective enclosure) multiplied by a factor. According to some aspects, the cage can have a height of at least <NUM> times the major dimension of the cage floor, at least <NUM> times the major dimension of the cage floor, at least <NUM> times the major dimension of the cage floor, at least <NUM> times the major dimension of the cage floor, or at least the major dimension of the cage floor, or at least <NUM> times the major dimension of the cage floor, or at least <NUM> times the major dimension of the cage floor.

In some exemplary embodiments, the floor of the cage assembly can have a length of about <NUM> and a width of about <NUM>. Thus, with a partition dividing the length of the floor, each enclosure can have a floor with a long side of <NUM> and a short side of <NUM>. Thus, the floor area of each enclosure can have a major dimension of <NUM> (equal to the maximum diagonal between corners of the enclosure). Thus, it is contemplated that the height of the cage can have a minimum height of at least <NUM>, providing a height that is about <NUM> times the major dimension of the cage floor. According to various aspects, the floor area of each enclosure can have a minimum major dimension of at least <NUM>, between about <NUM> and about <NUM> millimeters, between about <NUM> millimeters and about <NUM>, between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, or above <NUM>. In some embodiments, the cage height can be about <NUM>. In further embodiments, the height of the cage can be at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, or at least <NUM>.

It is contemplated that the above equations for selecting the height of the cage are not absolute because the cable has some amount of rigidity (i.e., the cable has a limit to its flexibility), thereby limiting the ability of the cable to reach the floor of the cage. Thus, it is contemplated that the height of the cage can be less than the minimum heights of the above equations while still providing a sufficient cage height to prevent entanglement of the test subject.

Optionally, the cage can comprise a feeder (e.g., a food tray or food dispenser). The feeder can optionally couple to the partition <NUM> or other sidewall so that the feeder remains suspended.

Referring to <FIG>, the treatment assembly <NUM> can be configured for providing TTFields to an organ tumor. The treatment assembly <NUM> can comprise a flexible circuit board <NUM> that includes a connector end <NUM>, and one or more lead ends <NUM> at the ends of respective electrical leads <NUM> opposite the connector end <NUM>. The electrical leads <NUM> can be provided as components of a cable <NUM>. Optionally, the flexible circuit board <NUM> can be configured to couple to a swivel <NUM>. The cable <NUM> can be elongate and sufficiently flexible to allow an amount of twisting without requiring a swivel. The connector end <NUM> can optionally be a USB-C connector (e.g., a male USB-C connector). It is contemplated that the use of a flexible circuit board <NUM> as disclosed herein can provide a plurality of electrical leads <NUM> as part of a unified structure, thereby avoiding tangled cables or wires and minimizing the space occupied by the electrical leads. Thus, in some aspects, the cable <NUM> can be defined by a portion of the flexible circuit board <NUM>.

In a pre-use configuration, as shown in <FIG>, the lead ends <NUM> can be spaced along a longitudinal dimension <NUM> of the treatment assembly <NUM>. Optionally, the lead ends <NUM> can be arranged in one or more longitudinally extending rows. For example, the lead ends <NUM> can be arranged in two rows of four lead ends, wherein the two rows extend in the longitudinal dimension <NUM>. As another example, the one or more longitudinally extending rows can comprise a single row of lead ends <NUM>. However, it is contemplated that any desired arrangement of lead ends can be used. The cable <NUM> can extend perpendicularly, or substantially perpendicularly relative to the longitudinal dimension <NUM>.

Each lead end <NUM> can be configured to engage or couple to a respective plate <NUM>. Thus, the treatment assembly <NUM> can comprise a plurality of electrodes, with each electrode comprising a lead end <NUM> that is in contact with or otherwise coupled to a respective plate <NUM>. In some optional embodiments, at least one (optionally, each) plate <NUM> can be a ceramic plate. In other embodiments, such as those in which the treatment assembly <NUM> functions as a control heating device, it is contemplated that at least one (optionally, each) plate can be a glass plate. In still further aspects, other types of electrodes are contemplated, such as, for example, electrodes formed from metal or other electrically conductive materials.

The treatment assembly <NUM> can comprise an inner layer <NUM> having an outer surface <NUM> and an inner surface <NUM>. The inner layer <NUM> can comprise a biocompatible, breathable adhesive, such as, for example, polyurethane. In some embodiments, the inner layer can comprise VANCIVE MED 9598A polyurethane film with acrylic adhesive. The inner layer <NUM> can define a plurality of openings <NUM> therethrough for receiving respective plates <NUM>. The openings <NUM> can be longitudinally spaced along the inner layer. Although depicted as receiving individual plates, it is contemplated that each opening can optionally receive a plurality of plates (e.g., two plates) therein.

The plates <NUM> can have upper surfaces <NUM> and lower surfaces <NUM>. The upper surfaces can be disposed against the electrical leads <NUM>. A layer of hydrogel <NUM> can be disposed against the lower surfaces <NUM> of each of the plates <NUM>. The layer of hydrogel <NUM> can optionally cover at least two adjacent plates <NUM>. Optionally, the layer of hydrogel <NUM> can cover the lower surfaces <NUM> of the plates <NUM> and adjoining portions of the inner surface of the inner layer <NUM>. The layer of hydrogel <NUM> can be, in some optional aspects, about <NUM> thick. The hydrogel <NUM> can comprise, for example, AG625 sensing gel made by AXELGAARD.

A cover layer <NUM> can attach to the outer surface <NUM> of the inner layer <NUM>. The cover layer <NUM> can overlie the plurality of electrical leads <NUM> of the flexible circuit board <NUM>. The cover layer <NUM> can comprise one or more tab portions that extend beyond a perimeter of the inner layer <NUM>. For example, the cover layer <NUM> can comprise two opposing tab portions <NUM> that are complementary to one another when the cover layer defines a circumferential loop (e.g., when wrapped around a torso of a test subject, as further disclosed herein). Optionally, the tab portions <NUM> can be about half of the width of the cover layer where they intersect a main body portion of the cover layer. When the cover layer is wrapped around the torso of the test subject, the tab portions <NUM> can extend past each other to attach to respective portions of the cover layer on ends of the cover layer opposite the respective tab portions.

According to some optional aspects, the cover layer can have an inner surface that comprises a biocompatible non-woven adhesive. The non-woven adhesive can optionally be elastic in the longitudinal dimension <NUM>. In some embodiments, the cover layer can comprise Product No. <NUM> medical nonwoven tape made by <NUM>.

A release layer <NUM> can contact and cover the underside of the biocompatible breathable polyurethane adhesive on the inner surface <NUM> of the inner layer <NUM> as well as the underside of the hydrogel layer <NUM>. The release layer can protect the adhesive prior to attaching the treatment assembly to the test subject. The release layer <NUM> can have a shape that is complementary to the shape of the cover layer <NUM>. The release layer can comprise separate tabs <NUM> that are configured to cover the tab portions <NUM> of the cover layer <NUM>.

The treatment assembly can comprise at least one temperature sensor <NUM> (not shown, but the temperature sensors <NUM> can have corresponding positions to the temperature sensors <NUM> and <NUM>' of <FIG> and <FIG>), such as, for example, thermistors or thermocouples. The at least one temperature sensor can optionally be integral to the flexible circuit board <NUM>. The at least one temperature sensor can comprise a plurality of temperature sensors. For example, a temperature sensor can be positioned on the flexible circuit board <NUM> proximate to each lead end <NUM>. The temperature sensor(s) <NUM> can provide feedback to prevent overheating of the treatment assembly or causing burns to the test subject. For example, based on temperature readings from the temperature sensors <NUM> exceeding a threshold (e.g., <NUM>), the TTField generator <NUM> can adjust or stop induction of TTFields at one or more electrodes. Additionally the system <NUM> can receive feedback from the temperature sensors <NUM> in order to maintain a consistent temperature in control heater treatment assemblies that are disclosed further herein. Optionally, the temperature sensors can be positioned within respective holes in the respective plates to measure the temperature between the plates and the hydrogel. In further aspects, the temperature sensors can be positioned on sides of the respective plates opposite the hydrogel, thereby avoiding the need for forming holes in the plates (and potentially making the plates undesirably fragile). In further embodiments, the temperature sensors can be positioned at portions of the hydrogel to the side of the respective plates (e.g., within three millimeters of the plate edge). For example, as shown in <FIG>, pairs of plates <NUM> can share a single layer of hydrogel <NUM>, and each temperature sensor can be positioned between a respective pair of plates.

The portion of the treatment assembly bearing against the test subject (e.g., excluding the weight of the cable) can optionally weigh less than about ten percent of the body weight of the subject. For example, the portion of the treatment assembly bearing against the test subject can weigh less than about <NUM> grams for a typical mouse.

The treatment assembly can be sufficiently flexible to conform to a portion of a torso of the test subject <NUM>. Optionally, in a pre-use configuration as shown in <FIG>, the treatment assembly has a length in the longitudinal dimension <NUM> that is sufficient to extend around a girth of the torso of the test subject (when positioned on the animal and during use). Optionally, the treatment assembly can be pre-formed into a three dimensional shape that is configured to be complementary to the shape of the torso of the test subject <NUM>.

Optionally, a kit can comprise a plurality of treatment assemblies <NUM> having varying lengths in the longitudinal dimension <NUM> (in pre-use configurations). In this way, a test subject can be fitted with a properly sized treatment assembly (depending upon the girth/circumference of the animal). For example, the properly sized treatment assembly can snugly wrap around the girth of the torso of the test subject. Optionally, an additional cover material (that can be, for example, the same material as the outer layer) can be provided for reinforcing attachment to the test subject and sealing edges of the adhesive materials from dirt and debris that could inhibit good contact.

Referring to <FIG>, a treatment assembly <NUM>' can be configured for treating a subcutaneous tumor. The treatment assembly <NUM>' can have a generally similar construction as that of the treatment assembly <NUM>, having an inner layer <NUM>' defining openings <NUM>' that receive plates <NUM>' therein. Optionally, it is contemplated that hydrogel <NUM>' can be received within openings <NUM>'. A flexible circuit board <NUM>' can comprise a cable <NUM>', a connector end <NUM>' that is configured to couple to a swivel <NUM> (<FIG>), and one or more lead ends <NUM>' at the lead ends opposite the connector end <NUM>'. The lead ends <NUM>' can be configured to couple to respective plates <NUM>'. An outer layer <NUM>' can be attached to respective upper surfaces of the inner layer and the lead ends. A release layer <NUM>', comprising separate tabs <NUM>', can attach to an underside of the inner layer <NUM>' and hydrogel <NUM>'. The outer layer <NUM>' and release layer <NUM>' can be similarly constructed to that of the outer layer <NUM> and release layer <NUM>.

The inner layer <NUM>', circuit board <NUM>', and cover layer <NUM>' can cooperate to define a through-hole <NUM>' that extends through the thickness of the treatment assembly <NUM>' (other than an inner release layer, when present) and is configured to receive a subcutaneous tumor. Optionally, the through-hole <NUM>' can have a diameter of between ten and fifteen mm. Optionally, the through-hole <NUM>' can have a maximum diameter of about fifteen mm. A cap <NUM>', defining a receptacle <NUM>' therein that is configured to receive an outwardly extending portion of a subcutaneous tumor, can extend across the through-hole <NUM>'. The cap <NUM>' can be attached to the cover layer <NUM>. For example, the cap <NUM>' can define a radially extending peripheral rim <NUM>'. An adhesive ring <NUM>' can engage the flange <NUM>' and outer layer <NUM>' to secure the cap <NUM>' to the outer layer. The cap <NUM>' can inhibit dirt and debris (e.g., sawdust floor cover) from entering the hole and inhibiting contact between the treatment assembly and the test subject.

In exemplary aspects, the openings <NUM>' within which plates <NUM>' are received can have a predetermined relationship relative to through-hole <NUM>'. Optionally, in these aspects, and as shown in <FIG> and <FIG>, the openings <NUM>' can be circumferentially spaced about a perimeter of the through hole <NUM>' (and, thus, the subcutaneous tumor, when the tumor extends through the through-hole <NUM>').

According to some aspects, a kit can comprise a plurality of treatment assemblies <NUM>' having through-holes <NUM>' of varying diameters and correspondingly varyingly sized caps <NUM>'. The plurality of treatment assemblies <NUM>' having through-holes of varying diameters can optionally have correspondingly varying spacing between lead ends <NUM>' and plates <NUM>'. In this way, the test subject <NUM> can be fitted with a treatment assembly <NUM>' that is suitably sized for its subcutaneous tumor. Optionally, the kit can further comprise a plurality of caps (optionally, same-sized and/or of varying sizes) so that the caps can be replaced over the course of the treatment.

The length of the cables <NUM>,<NUM>' can be selected based on the enclosure dimensions so that the test subject <NUM> cannot get wrapped up by or entangled with the cable. Some amount of slack can be attached to the test subject's back in order to reduce the amount of free length of the cable. Thus, the cable can have an operative portion that is not attached to the test subject, wherein the operative portion can define an operative length of the cable. According to some aspects, the operative length of the cable can be selected so that the cable does not have sufficient length to hang from the test subject's back and touch the floor when the test subject is directly below the swivel. Thus, it can be understood that a maximum operative length of the cable can be approximated as the height of the cage (or the height at which the cable attaches to the swivel) plus two times the height of the test subject. In further aspects, the cable length can be selected so that the cable does not have enough slack to hang from the back of the test subject to within a threshold distance, t, (<FIG>) of the floor of the cage. Thus, a maximum operative length of the cable can be approximated as the height from the floor at which the cable attaches to the swivel plus two times the height of the test subject, minus two times the threshold distance. Optionally, the threshold distance can be zero millimeters, one millimeter, two millimeters, four millimeters, six millimeters, ten millimeters, or more. In some aspects, the threshold distance can range from about <NUM> to about <NUM> or from about <NUM> to about <NUM>. It is still further contemplated that because of the limited flexibility of the cable, the length of the operative portion of the cable can be slightly greater than two times the height of the subject plus the height of the cable without the cable being able to reach the floor of the cage.

To construct a treatment assembly <NUM>, each plate of a plurality of plates <NUM> can be positioned within openings in the inner layer of the treatment assembly. For example, in some embodiments, a pair of plates can be positioned within each opening. Alternatively, a single plate can be positioned within each opening. Each lead end of the plurality of lead ends can be positioned in contact with a respective plate of the plurality of plates. As stated previously, lead ends, when coupled with plates as disclosed herein, form respective electrodes. The cover layer can be attached to the outer surface of the inner layer so that the cover layer overlies the plurality of electrodes. A layer of hydrogel can be applied to lower surfaces of each plate of the plurality of plates. In some aspects, a pair of plates positioned within a shared opening in the inner layer can also share a layer of hydrogel. Optionally, hydrogel can be applied over adjoining portions of the inner surface of the inner layer.

Referring to <FIG>, in further aspects, it is contemplated that a treatment assembly <NUM>" can be configured to be positioned at least partly on the head of the test subject. For example, a head-covering portion 9a of the treatment assembly <NUM>" can be coupled to at least a portion of the head of a mouse as shown in <FIG>. The head-covering portion 9a of the treatment assembly <NUM>" can comprise a head-wearable layer <NUM> that is configured to extend over a portion of the head of the test subject and be coupled to the test subject through an adhesive that is positioned on one or more inner surfaces of the head-wearable layer <NUM>. The treatment assembly <NUM>" can further comprise a torso-covering portion 9b that is configured to be positioned on the body (e.g., torso) of the test subject (e.g., wrapped around the body/torso of the test subject, as further disclosed herein). The torso-covering portion 9b of the treatment assembly <NUM>" can comprise an inner adhesive wearable layer <NUM> that is configured to engage the body (optionally, the skin) of the test subject. A flexible circuit board <NUM> can comprise a plurality of lead ends. An end <NUM> of the flexible circuit board can be in communication with the TTFields generator <NUM> (<FIG>). An inner adhesive patch <NUM> can be coupled to a skin engagement side of the adhesive portion <NUM> with a portion of the flexible circuit board <NUM> positioned therebetween. An outer wearable layer <NUM> can be coupled at an outer side of the torso-covering portion 9b of the treatment assembly.

Plates (e.g., ceramic plates) <NUM> can be coupled to the lead ends of the flexible circuit board. Hydrogel <NUM> can be positioned below the ceramic plates to engage the skin of the patient. The inner adhesive wearable layer <NUM> of the torso-covering portion 9b can define at least one opening (optionally, a plurality of openings) that receives a corresponding portion of hydrogel <NUM>.

In accordance with embodiments of the invention, the flexible circuit board <NUM> comprises a plurality of lead ends (and, accordingly a plurality of electrodes <NUM>) that are configured to be positioned on the head of the test subject and one or more lead ends (e.g., two lead ends) (and, accordingly a plurality of electrodes <NUM>) that are configured to be positioned on the body (e.g., torso) of the test subject. In exemplary aspects, the plurality of lead ends (for positioning on the head) are configured to underlie the head-wearable layer <NUM>, and the one or more lead ends (for positioning on the torso) are configured to underlie the outer wearable layer <NUM> of the torso-covering portion 9b, with each lead end overlying a respective ceramic plate <NUM> and hydrogel portion <NUM>. Optionally, the plurality of lead ends that are configured to be positioned on the head of the test subject can comprise a first group of lead ends (e.g., three lead ends, corresponding to electrodes 602a) that are configured to be positioned on a first side (relative to a median plane <NUM> that bisects the test subject into left and right sides) of the head of the test subject and a second group of lead ends (e.g., three lead ends, corresponding to electrodes 602b) that are configured to be positioned on a second opposing side (relative to the median plane) of head of the test subject. The one or more lead ends that are configured to be positioned on the body (e.g., torso) of the test subject can comprise a first lead end (corresponding to electrode 604a) that is positioned on the first side of the body of the test subject relative to the median plane and a second lead end (corresponding to electrode 604b) that is positioned on the second side of the body of the test subject relative to the median plane. Referring to <FIG>, it is contemplated that the first lead end that is positioned on the first side of the body can cooperate with the second group of lead ends on the second side of the head of the test subject to provide TTFields, and the second lead end that is positioned on the second side of the body (torso) can cooperate with the first group of lead ends on the first side of the head of the test subject to provide TTFields. The TTFields can be provided in an alternating fashion to provide or promote crossing of TTFields.

In accordance with embodiments of the invention, the flexible circuit board <NUM> comprises an undulating (e.g., switchback), serpentine, wavelike, or zig-zag portion (generally referred to as an "alternating-profile portion" <NUM>) that is configured to promote flexibility to allow the test subject to move its neck. In use, it is contemplated that the alternating profile of this portion of the flexible circuit board <NUM> can provide a reduced starting length (to avoid unnecessary slack in the cable) while also permitting straightening to increase the length and accommodate movement (e.g., neck extension, twisting, and turning) of the test subject. In these aspects, and as shown in <FIG> and <FIG>, the alternating-profile portion can be positioned between the head-covering portion 9a and the torso-covering portion 9b. It is further contemplated that the alternating-profile portion of the flexible circuit board <NUM> can be positioned between the plurality of lead ends (for positioning on the head) and the at least one lead end (for positioning on the torso).

Exemplary, non-limiting dimensions of the treatment assembly <NUM>" are provided in millimeters within <FIG>.

It is contemplated that the materials and properties of the inner adhesive wearable layer <NUM> of the torso-covering portion 9b can be the same or similar to those of the cover layers <NUM>, <NUM>' disclosed herein with respect to treatment assemblies <NUM>, <NUM>'. Similarly, it is contemplated that the materials and properties of the hydrogel <NUM> of the treatment assembly <NUM>" can be the same or similar to those of the hydrogel <NUM>, <NUM>' disclosed herein with respect to treatment assemblies <NUM>, <NUM>'. It is further contemplated that the materials and properties of the plates <NUM> of the treatment assembly <NUM>" can be the same or similar to those of the plates <NUM>, <NUM>' disclosed herein with respect to treatment assemblies <NUM>, <NUM>'. It is further contemplated that the materials and properties of the flexible circuit board <NUM> can be the same or similar to those of the flexible circuit board <NUM>, <NUM>' disclosed herein with respect to treatment assemblies <NUM>, <NUM>'. It is still further contemplated that the materials and properties of the head-wearable layer <NUM> and the outer wearable layer <NUM> of the treatment assembly <NUM>" can be the same or similar to those of cover/outer layers <NUM>, <NUM>' disclosed herein with respect to treatment assemblies <NUM>, <NUM>'.

Referring to <FIG>, a control heater treatment assembly <NUM> can be coupled to a control test subject and can be configured to mimic many or all or substantially all of the aspects of the treatment assembly <NUM>. Likewise, a control heater treatment assembly <NUM>' can be configured to mimic or all or substantially all of the aspects of the treatment assembly <NUM>' and can have a similar construction and operation to that as described for the control heater treatment assembly <NUM>. Similarly, a control heater treatment assembly can be configured to mimic all or substantially all of the aspects of the treatment assembly <NUM>" and can have a similar construction and operation to that as described for control heater treatment assembly <NUM>. For example, the control heater treatment assembly <NUM> can be configured to generate heat to maintain a similar temperature against the control test subject's skin, thereby limiting differences between aspects of the control group and the test group. As another example, the control heater treatment assembly <NUM> can be configured to have substantially or generally the same weight as the treatment assemblies that are capable of generating TTFields as further disclosed herein.

The control heater assembly <NUM> can comprise a flexible circuit board <NUM>. The flexible circuit board <NUM> can include a cable <NUM> and a connector end <NUM> that is configured to couple to a swivel <NUM>. The flexible circuit board can comprise a plurality of resistive heaters positioned in locations corresponding to where the electrodes are positioned in a treatment assembly <NUM>. For example, the flexible circuit board <NUM> can comprise eight zones <NUM> (e.g., two rows of four zones <NUM>) where the electrodes would be in a corresponding treatment assembly. More generally, the flexible circuit board <NUM> can have any desired number of zones, each zone corresponding to a location of an electrode in a corresponding treatment assembly. Optionally, each zone <NUM> can comprise two resistive heaters <NUM> (shown schematically in <FIG> as a single unit that is disassociated from the circuit board <NUM> and in <FIG> in detail as components of the circuit board <NUM>). A temperature sensor <NUM> can be disposed in each zone <NUM>, optionally, in a center of each zone <NUM> equally spaced between the heaters <NUM>. The heaters <NUM> can optionally comprise glass plates.

Optionally, the control heater assembly <NUM> can comprise an inner layer <NUM> that defines a plurality of through-holes through which the heaters <NUM> can be positioned. Optionally, the control heater assembly <NUM> can comprise a cover layer <NUM> that extends across the upper side of the flexible circuit board. A release liner <NUM> can releasably attach a lower surface of the inner layer. The inner layer <NUM> and cover layer <NUM> can comprise the same materials and the same geometry of the corresponding treatment assembly in order to feel similar to the test subject. Optionally, a layer of hydrogel <NUM> can cover the lower sides of the flexible circuit board <NUM>. Likewise, a control heater assembly <NUM>' can have a corresponding structure to that of the treatment assembly <NUM>', having a flexible circuit board <NUM>', an inner layer <NUM>', a release liner <NUM>', a cover liner <NUM>', a cap <NUM>', and an adhesive ring <NUM>'. Similarly, a control heater assembly that simulates the shape, weight, heat, and otherwise perceived experience of the treatment assembly <NUM>" is further contemplated.

The control heater assembly <NUM> can couple to the TTFields generator <NUM> via the swivel <NUM>. The swivel <NUM> can control the output of the resistive heaters <NUM> based on feedback from the temperature sensors <NUM>. In some embodiments, the control heater assembly <NUM> can maintain a set temperature (e.g., <NUM> or <NUM> degrees Celsius) to mimic the temperature that the corresponding treatment assemblies <NUM>,<NUM>', <NUM>" reach as a byproduct of providing TTFields. In further embodiments, control heater assembly <NUM> can be selectively controlled to maintain a temperature that matches the temperature of treatment assemblies on corresponding test subjects receiving TTFields treatment.

The control heater assembly <NUM>, <NUM>' can further have a weight that is similar to that of the respective treatment assembly <NUM>, <NUM>', <NUM>". Thus, the control heater assembly can create the same perceived experience in the test subject. In this way, effects of the TTFields on the tumor development can be isolated from other aspects of the testing procedure.

In exemplary aspects, kits having both control heater assemblies <NUM>, <NUM>' and treatment assemblies <NUM>, <NUM>', <NUM>" can be provided. In these aspects, it is contemplated that each treatment assembly provided in the kit can have a corresponding/counterpart control heater assembly positioned within the same kit, thereby maximizing uniformity among control and experimental/treatment groups.

It is contemplated that embodiments disclosed herein can, in addition to providing TTFields, be used to provide other electric currents, fields, and heat to different body parts of test subjects.

In some optional aspects, a wide treatment assembly (and corresponding control heater assembly) for a test subject with a wide torso can have a length of about <NUM> to about <NUM> (relative to the longitudinal axis <NUM>), a width of about <NUM> to about <NUM> (optionally, <NUM> to <NUM>), and a thickness of about <NUM> to about <NUM>. In some optional aspects, a narrow treatment assembly (and corresponding control heater assembly) for a test subject with a narrow torso can have a length of about <NUM> to about <NUM>, a width of about <NUM> to about <NUM> (optionally, <NUM> to <NUM>), and a thickness of about <NUM> to about <NUM>. In further optional aspects, a treatment assembly for a subcutaneous tumor (and corresponding control heater assembly) can have a length of about <NUM> to about <NUM>, a width of about <NUM> to about <NUM>, and a thickness of about <NUM> to about <NUM>.

It is contemplated that the test subjects can be prone to chew or gnaw on the treatment assemblies <NUM>, <NUM>', <NUM>" or the control heater treatment assemblies <NUM>, <NUM>'. Referring to <FIG>, in order to inhibit such behavior, it is contemplated that a collar <NUM> can be ring-shaped. Optionally, the collar <NUM> can have two opposing ends that couple together to form the ring shape. For example, the collar <NUM> can comprise a protrusion <NUM> positioned at a first end <NUM> that is configured to be received into one or more holes <NUM> in an opposing second end <NUM>. The protrusion <NUM> can have an enlarged distal end that has a diameter that is greater than the diameter of the one or more holes <NUM> so that once inserted into a hole, it cannot inadvertently fall out (due to engagement between the surfaces of the protrusion and the portion of the second end that defines the hole). It is contemplated that the one or more holes <NUM> can comprise a plurality of holes <NUM> spaced about the circumferences of the collar <NUM> so that the collar can have a selectable operative diameter, depending on the hole into which the protrusion <NUM> is inserted, in order to adapt the collar to differently sized test subjects.

Optionally, the collar <NUM> can have an inner surface <NUM> that is jagged, serrated, or toothed. Optionally, the collar <NUM> can have an outer surface <NUM> that is axially tapered. The collar <NUM> can be oriented so that the outer surface tapers in a direction away from the head of the test subject.

It is contemplated that both excessive weight of the collar and sound reflection can reduce the life of the test subject. Accordingly, in some aspects, the collar <NUM> can define a plurality of holes <NUM> that can optionally extend axially therethrough (through the thickness of the collar). The holes <NUM> can reduce the amount of material, and thus, the weight of the collar as well as minimize sound reflection that can cause stress to the test subject.

The collar <NUM> can optionally be flexible. Optionally, the collar can comprise polymer, such as, for example, silicone.

Referring to <FIG> and <FIG>, the swivel <NUM> can be mounted to the cover <NUM> within the swivel housing <NUM>. The swivel housing <NUM> can comprise a sidewall <NUM> that is integral to the cover <NUM>. The swivel housing <NUM> can receive a removable inner circumferential insert <NUM>. The swivel housing can further comprise a top cover <NUM> that couples to the sidewall <NUM>.

The swivel <NUM> can comprise a damper plate <NUM> that attaches to the top cover <NUM> via screws or other fasteners. The top cover <NUM> can be a part of the swivel module. The damper plate <NUM> can couple to a motor mounting plate <NUM> via screws <NUM>. The swivel <NUM> can have a central axis <NUM>, and the motor <NUM> can rotate about the central axis <NUM>. A motor <NUM> can couple to the motor mounting plate <NUM> via screws <NUM>. A rotatable base <NUM> can attach to the motor <NUM> via screws <NUM>. Thus, the rotatable base can be rotatable with respect to the motor mounting plate <NUM> via the motor. A bearing housing <NUM> can couple to the rotatable base <NUM> via standoffs <NUM>. The rotatable base <NUM> can define a depending tab <NUM> that can couple to a flexible circuit assembly <NUM>.

In some optional aspects, the top cover <NUM> can comprise at least one input device (e.g., a button) that is configured to start and stop therapy (e.g., TTField or heat). Optionally, the at least one input device can comprise a plurality of input devices, with each input device being configured to control operation of a different component of the system. In some aspects, respective input devices can be configured to control TTField application and heat application. In further aspects, an input device can be configured to start and stop operation of the swivel. In further aspects, the top cover <NUM> can comprise a display that is configured to show information, such as, for example, experiment identification information (e.g., cage number, electrode type) or an operation mode (e.g., idle, therapy, heat, pause). In various aspects, the top cover <NUM> can provide a communication port that can be in communication with the swivel <NUM> to provide communication between the signal generator <NUM> (<FIG>) and a treatment/control heater assembly.

Referring also to <FIG> and <FIG>, the flexible circuit assembly <NUM> can comprise a printed circuit board (PCB) <NUM> having an input/output connector <NUM> attached thereto. The connector <NUM> can provide communication to the upper portion of the swivel. The printed circuit board <NUM> can define a patterned portion <NUM> that extends between a base portion <NUM> and a cable connector end <NUM>. The patterned portion <NUM> can have a structure that enables the printed circuit board <NUM> to twist so that the connector end <NUM> can pivot with respect to the base portion <NUM>, as further described herein. In exemplary aspects, the patterned portion <NUM> can have a serpentine, wavelike, zig-zag, or undulating pattern. A pair of sensor connector portions <NUM> can extend from the base portion <NUM>.

Referring also to <FIG>, the bearing housing <NUM> can house a bearing <NUM> (e.g., a ball bearing or a nylon bearing) that can receive and support a pivot body <NUM> within its inner race. The pivot body <NUM> can define a slot <NUM> therein that can receive the connector end <NUM> of the printed circuit board <NUM>. The slot <NUM> can receive and engage the connector end <NUM> so that as the connector end pivots about the central axis <NUM>, the pivot body can correspondingly pivot. (Although the Figures show the connector end <NUM> remaining in place as the pivot body pivots, it should be understood that, in use, the connector end pivots with the pivot body. ) The pivot body <NUM> can define a cantilevered tab <NUM> that extends parallel to the central axis <NUM>.

A centralizing spring <NUM> can extend from a standoff <NUM> that is attached to the bearing housing <NUM> to engage a protrusion <NUM> or other radially extending surface that is spaced from or extends away from the central axis <NUM> of the swivel <NUM>. The centralizing spring <NUM> can bias the pivot body <NUM> to a neutral position <NUM>. In use, when the printed circuit board <NUM> is under no or substantially no torque, then the pivot body can be in the neutral position <NUM>.

Referring to <FIG>, <FIG>, a pair of sensors <NUM> (e.g., electro-optical sensors, such as, for example, VISHAY TCPT1600X01 sensors) can attach to the bearing housing <NUM> via respective sensor mounts <NUM>. The sensors <NUM> can be in communication with the PCB <NUM> at the sensor connector portions <NUM>. The sensors <NUM> can be in communication with a processor (e.g., a PLC controller on a circuit board <NUM>, as shown in <FIG>). The sensors can have a light source, a photodetector, and a light path between the light source and the photodetector. The sensors <NUM> can be positioned so that when the pivot body <NUM> is in the neutral position, the cantilevered tab <NUM> can block both of the sensors <NUM>. The test subject, as it walks within the cage, can twist the cable <NUM> (<FIG>), thereby applying a torsion to the pivot body <NUM> and causing the pivot body to pivot from its neutral position. When the pivot body pivots sufficiently from the neutral position <NUM> in a first direction <NUM> (see <FIG>), the cantilevered tab <NUM> can be outside of the light path of a first sensor 356A, and the first sensor can detect light from the light source in the photodetector. In this way, the swivel <NUM> can detect a twist of the cable in the first direction. The processor can cause the motor <NUM> to rotate in the first direction <NUM> to relieve the torsion on the cable. Optionally, the swivel can be configured to remain stationary until a minimum threshold angle from the neutral position <NUM> is reached in order to prevent excessive movement that can cause wear on the motor. Optionally, the motor can rotate a minimum angular distance in order to minimize excessive numbers of small movements. Likewise, when the pivot body pivots sufficiently from the neutral position <NUM> in a second direction <NUM> (opposite the first direction), a second optic sensor 356B can detect such a condition, and the processor can cause the motor to rotate in the second direction to relieve the torsion on the cable. In this way, the swivel can limit the amount of twisting in the cable <NUM> to thereby allow free movement of the test subject within the cage.

A limiter <NUM> can attach to each sensor mount <NUM>. Each limiter <NUM> can comprise a centrally extending portion that can act as a stop to prevent the pivot body from pivoting more than a threshold angle from the neutral position <NUM>, thereby preventing the printed circuit board <NUM> from breaking.

The pivot body <NUM> can define a connector <NUM> that is configured to receive the connector end <NUM>,<NUM>', <NUM>,<NUM>' of the flexible circuit board and electrically couple the flexible circuit board to the PCB <NUM>. For example, the connector <NUM> can comprise a USB-C connector that is complementary to the connector end of the flexible circuit board (e.g., a female USB-C connector). Optionally, the connector <NUM> can comprise a CAN bus connection.

The swivel can comprise a slip ring that can maintain electrical communication through the swivel to thereby enable communication between the treatment assemblies <NUM> (or treatment assemblies <NUM>' or treatment assemblies <NUM>"), heater assemblies <NUM>, or heater assemblies <NUM>') and the TTFields generator <NUM>. The slip ring can enable communication of at least twenty communication channels.

The computing device <NUM> can be in communication with the swivel <NUM> (e.g., through cable <NUM> or another cable) in order to track and/or log various metrics. In further aspects, the computing device <NUM> can be embodied as the controller on the PCB <NUM> (<FIG>). For example, the metrics can include some or all of the following metrics: a number of rotations, a number of rotations in a first select duration, a frequency of motor movements, a frequency of motor movements in a second select duration, a number of motor movements comprising a change in direction, a number of motor movements in a third select duration comprising a change in direction, a duration of constant movement, and a log of motor movements and the corresponding time of the motor movements. Such metrics can be indicative of abnormal behavior in the test subjects. Further, such metrics can be indicative of malfunctioning of the swivel <NUM>. In some aspects, a warning (e.g., a warning light or audible alarm) can be activated to notify a user that the swivel <NUM> is malfunctioning or the test subject is behaving abnormally. In further aspects, the computing device or controller in communication with the swivel can be configured to receive a user input. The user input can define one or more thresholds, such as, for example, a frequency threshold (e.g., a frequency of changes in direction of rotation) or a time threshold (e.g., a duration of constant rotation threshold). Upon exceeding the respective thresholds, the warning can be activated.

In further aspects, the computing device can generate and output a log report comprising at least one of the metrics that is collected. The log report can further output a comparison of the metrics based on comparisons to average metrics. The average metrics can be the average metrics for similar test subjects or for average metrics for a given subject over a select time period (e.g., over the course of an hour, a day, or a week). For example, the average metrics can comprise an average amount of movement that the test subject moves each day. Thus, it is contemplated that a decreasing amount of movement each day can be indicative of degrading health of the test subject. It is further contemplated that an excessively high amount of movement or an excessively low amount of movement in comparison to other similar test subjects can indicate relative health of the test subject. It is further contemplated that the monitoring of various metrics can allow for identification of modifications to ensure that animal subjects survive through the end of an experimental period.

Referring to <FIG>, a plurality of test subjects <NUM> of an experimental group <NUM> can be fitted with a respective treatment assembly. The treatment assembly can be selected to treat the particular tumor (e.g., a treatment assembly <NUM> for an organ tumor or a treatment assembly <NUM>' for a subcutaneous tumor). The treatment assembly can be properly sized. For example, for the organ tumor, the longitudinal length of the treatment assembly can be suitable to snugly wrap around the girth of the torso of the test subject along the torso at the given tumor. For a subcutaneous tumor, the through hole and cap of the treatment assembly can be selected to fit the subcutaneous tumor with minimal excess space. The length of the cable of the treatment assembly can be selected, as disclosed herein, to enable the test subject to freely travel the floor area of the enclosure while not providing excess length that can enable tangling. The release liner can be removed to allow the adhesive to engage the test subject's skin. The test subject's fur can be removed at the application area with a trimming device and/or a hair removal cream (e.g., VEET hair removal cream). Similarly, test subjects <NUM> of the control group can be fitted with respective control heater treatment assemblies <NUM> or control heater treatment assemblies <NUM>' (to match the experimental group's counterpart).

The treatment assembly can be positioned on the body so that the electrodes are positioned as close as possible to the tumor. In various aspects, the treatment assembly (or control heater assembly) can be positioned on the body of the test subject so as to minimize or eliminate interruption of natural movements. For example, if the treatment assembly can be positioned away from the hind legs or the front legs of a mouse to allow natural movements. The treatment assembly can be selected based at least in part on the size of the mouse. For example, a narrow treatment assembly can be positioned on a mouse weighing less than <NUM> grams, and a wide treatment assembly can be positioned on a mouse weighing greater than <NUM> grams.

The treatment array (or control heater assembly) can be oriented so that the cable extends toward the tail/hind end of the test subject. It is contemplated that the subcutaneous treatment assembly and control heater assemblies can have formed bends (e.g., <NUM> degree bends) that can enable the cable to extend to the middle of the back of the test subject and then extend along the back toward the hind end. The formed bends can be provided in either direction, depending on the side of the test subjection on which the subcutaneous tumor is positioned. An adhesive (e.g., plaster) can be disposed on the test subject to promote adherence of the treatment assembly (or control heater assembly).

The test subjects can be placed within respective enclosures of cage assemblies. The connector end of each treatment assembly and control heater treatment assembly <NUM> can be attached to a respective swivel.

The treatment assemblies can be controlled to provide TTFields to the test subjects. For example, referring to <FIG>, TTFields from <NUM>-<NUM> (optionally, <NUM>-<NUM>) can be delivered to an organ tumor <NUM> (<FIG>) or a subcutaneous tumor <NUM>' (<FIG>). Optionally, the TTFields can be delivered sequentially in separate axes of propagation (to provide alternating fields). For example, a first pair of opposing electrodes can apply a first electric field across the tumor along a first axis of propagation <NUM>. A second pair of electrodes that are positioned so as to have a second axis of propagation <NUM> that is perpendicular or substantially perpendicular to the first axis of propagation can alternate with the first pair of opposing electrodes to provide alternating fields across the tumor. For the treatment assembly <NUM>, each electrode can cooperate with a respective electrode positioned farthest from its location (e.g., on the other side of the body of the test subject) to provide alternating TTFields. Optionally, each electrode can be independently controlled to provide a tailored treatment. The control heater treatment assemblies can be controlled via a TTField generator or other controller to provide placebo heat to match or substantially match the temperatures of the treatment assemblies. The treatments can optionally continue for about <NUM>-<NUM> weeks.

The tumors of the experimental group and the control group can be compared during and after treatment. For example, for subcutaneous tumors, while leaving the treatment assembly attached to the subject, the cap can be removed to expose the tumor, and the tumor size can be measured with calipers. Organ tumors can be measured via, for example, Magnetic Resonance Imaging (MRI), ultrasound (US), or computed tomography (CT) scans. The treatment assemblies can be removed prior to such scans.

<FIG> shows a system <NUM> including an exemplary configuration of a computing device <NUM> for use in the system <NUM>.

The computing device <NUM> may comprise one or more processors <NUM>, a system memory <NUM>, and a bus <NUM> that couples various components of the computing device <NUM> including the one or more processors <NUM> to the system memory <NUM>. In the case of multiple processors <NUM>, the computing device <NUM> may utilize parallel computing.

The bus <NUM> may comprise one or more of several possible types of bus structures, such as a memory bus, memory controller, a peripheral bus, an accelerated graphics port, and a processor or local bus using any of a variety of bus architectures.

The computing device <NUM> may operate on and/or comprise a variety of computer readable media (e.g., non-transitory). Computer readable media may be any available media that is accessible by the computing device <NUM> and comprises, non-transitory, volatile and/or non-volatile media, removable and non-removable media. The system memory <NUM> has computer readable media in the form of volatile memory, such as random access memory (RAM), and/or non-volatile memory, such as read only memory (ROM). The system memory <NUM> may store data such as temperature data <NUM> (i.e., data from signals received by the electrodes) and/or program modules such as operating system <NUM> and TTField provision software <NUM> that are accessible to and/or are operated on by the one or more processors <NUM>.

The computing device <NUM> may also comprise other removable/non-removable, volatile/non-volatile computer storage media. The mass storage device <NUM> may provide non-volatile storage of computer code, computer readable instructions, data structures, program modules, and other data for the computing device <NUM>. The mass storage device <NUM> may be a hard disk, a removable magnetic disk, a removable optical disk, magnetic cassettes or other magnetic storage devices, flash memory cards, CD-ROM, digital versatile disks (DVD) or other optical storage, random access memories (RAM), read only memories (ROM), electrically erasable programmable read-only memory (EEPROM), and the like.

Any number of program modules may be stored on the mass storage device <NUM>. An operating system <NUM> and TTField provision software <NUM> may be stored on the mass storage device <NUM>. One or more of the operating system <NUM> and TTField provision software <NUM> (or some combination thereof) may comprise program modules and the TTField provision software <NUM>. Temperature data <NUM> may also be stored on the mass storage device <NUM>. Temperature data <NUM> may be stored in any of one or more databases known in the art. The databases may be centralized or distributed across multiple locations within the network <NUM>.

A user may enter commands and information into the computing device <NUM> using an input device (not shown). Such input devices comprise, but are not limited to, a keyboard, pointing device (e.g., a computer mouse, remote control), a microphone, a joystick, a scanner, tactile input devices such as gloves, and other body coverings, motion sensor, and the like. These and other input devices may be connected to the one or more processors <NUM> using a human machine interface <NUM> that is coupled to the bus <NUM>, but may be connected by other interface and bus structures, such as a parallel port, game port, an IEEE <NUM> Port (also known as a Firewire port), a serial port, network adapter <NUM>, and/or a universal serial bus (USB).

A display device <NUM> may also be connected to the bus <NUM> using an interface, such as a display adapter <NUM>. It is contemplated that the computing device <NUM> may have more than one display adapter <NUM> and the computing device <NUM> may have more than one display device <NUM>. A display device <NUM> may be a monitor, an LCD (Liquid Crystal Display), light emitting diode (LED) display, television, smart lens, smart glass, and/ or a projector. In addition to the display device <NUM>, other output peripheral devices may comprise components such as speakers (not shown) and a printer (not shown) which may be connected to the computing device <NUM> using Input/Output Interface <NUM>. Any step and/or result of the methods may be output (or caused to be output) in any form to an output device. Such output may be any form of visual representation, including, but not limited to, textual, graphical, animation, audio, tactile, and the like. The display <NUM> and computing device <NUM> may be part of one device, or separate devices.

The computing device <NUM> may operate in a networked environment using logical connections to one or more remote computing devices 1014a,b,c. A remote computing device 1014a,b,c may be a personal computer, computing station (e.g., workstation), portable computer (e.g., laptop, mobile phone, tablet device), smart device (e.g., smartphone, smart watch, activity tracker, smart apparel, smart accessory), security and/or monitoring device, a server, a router, a network computer, a peer device, edge device or other common network node, and so on. Logical connections between the computing device <NUM> and a remote computing device 1014a,b,c may be made using a network <NUM>, such as a local area network (LAN) and/or a general wide area network (WAN). Such network connections may be through a network adapter <NUM>. A network adapter <NUM> may be implemented in both wired and wireless environments. Such networking environments are conventional and commonplace in dwellings, offices, enterprise-wide computer networks, intranets, and the Internet. It is contemplated that the remote computing devices 1014a,b,c can optionally have some or all of the components disclosed as being part of computing device <NUM>.

Application programs and other executable program components such as the operating system <NUM> are shown herein as discrete blocks, although it is recognized that such programs and components may reside at various times in different storage components of the computing device <NUM>, and are executed by the one or more processors <NUM> of the computing device <NUM>. An implementation of electrode data processing software <NUM> may be stored on or sent across some form of computer readable media. Any of the disclosed methods may be performed by processor-executable instructions embodied on computer readable media.

Claim 1:
A treatment assembly (<NUM>") comprising:
an inner layer (<NUM>, <NUM>) having an inner surface and an outer surface, wherein the inner layer defines a plurality of openings extending therethrough;
a plurality of plates (<NUM>), each plate being at least partially received within a respective opening of the plurality of openings of the inner layer;
treatment circuitry comprising:
a cable having a plurality of electrical leads (<NUM>, <NUM>); and
a plurality of lead ends (<NUM>, <NUM>), each electrical lead being electrically connected to a respective lead end of the plurality of lead ends; and
a cover layer (<NUM>, <NUM>) attached to the outer surface of the inner layer and overlying the plurality of lead ends of the cable,
wherein the plurality of lead ends are in contact with respective plates of the plurality of plates to define a plurality of electrodes (<NUM>, <NUM>), each electrode of the plurality of electrodes comprising a respective lead end and a respective plate,
wherein the plurality of electrodes comprises a plurality of head electrodes (<NUM>) that are configured to be positioned on a head of a test subject and a plurality of torso electrodes (<NUM>) that are configured to be positioned on a torso of the test subject, wherein the treatment circuitry comprises a serpentine portion (<NUM>) that extends from the plurality of torso electrodes to the plurality of head electrodes.