Patent Description:
A tumor can be treated by resection to remove all or a portion of the tumor, thereby leaving a resection cavity. Often, when doing so, not all of the tumor cells are extracted. For example, for brain tumors, such as glioblastoma, a bulk of the tumor can be removed, but portions (often, finger-like roots) of the tumor can be interlaced with healthy cells. Thus, peripheral tumor cells cannot be resected without also removing or destroying a substantial quantity of healthy cells, which can be undesirable.

Accordingly, after resection of the bulk of the tumor, a secondary treatment process can treat the remaining cells surrounding the resection cavity (e.g., within the peritumoral region). One such treatment includes tumor-treating electrical fields (TTFields). However, upon resection of the bulk of the tumor, the cavity is backfilled with fluid that is highly electrically conductive. Accordingly, a substantial portion of the TTFields pass directly through the fluid within the cavity, thereby reducing efficacy of the TTFields in treating the tumor cells surrounding the cavity.

<CIT> discloses methods, systems and apparatuses for optimizing transducer array placement. The one or more transducer arrays comprise electrodes made from any material with a high dielectric constant. For example, one or more insulated ceramic discs. The electrodes are configured to not come into direct contact with the skin as the electrodes are separated from the skin by a layer of conductive hydrogel. Also disclosed are transducer array constructions that use non-ceramic dielectric materials positioned over a plurality of flat conductors.

The invention provides a system according to claim <NUM>. Embodiments are provided by the dependent claims.

A system comprises at least one first electrode, at least one second electrode, and a nonconductive material positioned between the at least one first electrode and the at least one second electrode. A signal generator is in electrical communication with each one of the at least one first electrode and the at least one second electrode. The signal generator is configured to generate electric fields between the at least one first electrode and the at least one second electrode.

A nonconductive, biocompatible material is configured for receipt into a resection cavity. The nonconductive material defines an inner passageway that is configured to fill with fluid to conduct electric fields therethrough.

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 wherein:.

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, if further aspects, when values are approximated by use of "approximately," "substantially," and "generally, " 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.

Except where otherwise indicated, the word "or" as used herein can mean any one member of a particular list and, in other optional aspects, can include 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.

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.

<FIG> shows an example apparatus <NUM> for electrotherapeutic treatment as disclosed herein. Generally, the apparatus <NUM> may be a portable, battery or power supply operated device that produces alternating electrical fields within the body by means of stimulation zones as disclosed herein (e.g., transducer arrays or electrodes). The apparatus <NUM> may comprise an electrical field generator <NUM> and one or more stimulation zones (shown in this exemplary configuration as transducer arrays <NUM>). The apparatus <NUM> may be configured to generate tumor treating fields (TTFields) (e.g., at <NUM>) via the electrical field generator <NUM> and deliver the TTFields to an area of the body through the stimulation zones (e.g., one or more transducer arrays <NUM> or electrodes). The electrical field generator <NUM> may be powered by a battery and/or power supply.

As shown in <FIG>, each transducer array <NUM> can comprise a plurality of electrodes or transducers <NUM>. As used herein, features described with respect to electrodes are also applicable to transducers, and vice versa, unless otherwise indicated. Accordingly, the terms electrode and transducer are used interchangeably herein. In exemplary aspects, the transducers <NUM> can capacitively couple an AC signal into a subject's body. In further aspects, the transducers <NUM> can comprise a layer of conductive material, such as a layer of at least one metal (e.g., stainless steel, gold, and/or copper). Additionally, or alternatively, it is contemplated that the transducers <NUM> can comprise one or more layers of conductive adhesive (e.g., hydrogel). Exemplary transducers <NUM> can further comprise dielectric material. Optionally, the transducers <NUM> can comprise ceramic discs, such as described in <CIT>. In additional or alternative aspects, it is contemplated that the transducers <NUM> can comprise polymer insulating layers and/or other insulating material.

The electrical field generator <NUM> may comprise a processor <NUM> in communication with a signal generator <NUM>. The electrical field generator <NUM> may comprise control software <NUM> configured for controlling the performance of the processor <NUM> and the signal generator <NUM>.

The signal generator <NUM> may generate one or more electric signals in the shape of waveforms or trains of pulses. The signal generator <NUM> may be configured to generate an alternating voltage waveform at frequencies in the range from about <NUM> to about <NUM> (preferably from about <NUM> to about <NUM> or from about <NUM> to about <NUM>) (e.g., the TTFields). The voltages are such that the electrical field intensity in tissue to be treated is typically in the range of about <NUM> V/cm to about <NUM> V/cm.

One or more outputs <NUM> of the electrical field generator <NUM> may be coupled to one or more conductive leads <NUM> that are attached at one end thereof to the signal generator <NUM>. The opposite ends of the conductive leads <NUM> are connected to the one or more stimulation zones (e.g., transducer arrays <NUM>) that are activated by the electric signals (e.g., waveforms). The conductive leads <NUM> may comprise standard isolated conductors with a flexible metal shield and may be grounded to prevent the spread of the electrical field generated by the conductive leads <NUM>. The one or more outputs <NUM> may be operated sequentially. Output parameters of the signal generator <NUM> may comprise, for example, an intensity of the field, a frequency of the waves (e.g., treatment frequency), and a maximum allowable temperature of the one or more stimulation zones (e.g., transducer arrays <NUM>). The output parameters may be set and/or determined by the control software <NUM> in conjunction with the processor <NUM>. After determining a desired (e.g., optimal) treatment frequency, the control software <NUM> may cause the processor <NUM> to send a control signal to the signal generator <NUM> that causes the signal generator <NUM> to output the desired treatment frequency to the one or more stimulation zones (e.g., transducer arrays <NUM>). Similarly, it is contemplated that the processor <NUM> can be in communication with a temperature sensor (e.g., a thermistor or thermocouple) that is configured to measure temperature at a respective transducer array, and when a temperature threshold is reached, the control software <NUM> can cause the processor <NUM> to decrease a frequency and/or intensity of the electric signal provided by the signal generator. In further aspects, it is contemplated that the processor <NUM> can be in communication with a sensor that is configured to measure an intensity of the electric field generated by the apparatus <NUM>, and the control software <NUM> can cause the processor <NUM> to decrease or increase a frequency and/or intensity of the electric signal to achieve a desired decrease or increase in the field intensity.

The one or more stimulation zones (e.g., transducer arrays <NUM>) may be configured in a variety of shapes and positions so as to generate an electrical field of the desired configuration, direction and intensity at a target volume so as to focus treatment. Optionally, the one or more stimulation zones (e.g., transducer arrays <NUM>) may be configured to deliver two perpendicular field directions through the volume of interest (e.g., a target region).

Referring to <FIG>, a target region <NUM> can be a region adjacent to (optionally, surrounding) a resection cavity <NUM>. That is, at least a portion of a tumor can be resected (e.g., in a resection surgery or other surgical procedure) to form the resection cavity <NUM>. A nonconductive material <NUM> can be positioned within the resection cavity <NUM>. As used herein, the term "nonconductive material" refers to a material that is not electrically conductive and that does not conduct electric fields. Optionally, the nonconductive material <NUM> can be implanted in the resection cavity <NUM> during the surgery in which the resection is performed. In further aspects, the nonconductive material <NUM> can be implanted in a subsequent surgery (separate from and following the surgery in which the resection is performed). In further aspects, the nonconductive material <NUM> can be injected into the resection cavity <NUM> or inserted through a port or stent that provides access to the resection cavity. At least one first electrode 15a and at least one second electrode 15b can be positioned relative to the resection cavity <NUM> so that electric fields between the at least one first electrode and the at least one second electrode travel through the target region <NUM>. For example, as shown in <FIG>, in some optional aspects, the first electrode 15a and second electrode 15b can be positioned with the resection cavity <NUM> therebetween. Using the electric field generator <NUM>, tumor-treating electric fields <NUM> can be generated between the at least one first electrode 15a and the at least one second electrode 15b. Referring to <FIG> and <FIG>, the nonconductive material <NUM> can cause the electric fields <NUM> to circumvent (avoid passing through), generally circumvent, or at least partially circumvent the resection cavity. Moreover, the nonconductive material <NUM> can displace volume that is typically filled with conductive fluid (e.g., cerebrospinal fluid (CSF)), thereby eliminating a low-resistance pathway that is conventionally available to the electric fields when the nonconductive material is not present. Accordingly, use of the nonconductive material <NUM> can increase the concentration of tumor-treating fields passing through the target region <NUM>, thereby improving efficacy of the treatment. For example, as shown in the models of <FIG> and <FIG>, the nonconductive material <NUM> can increase the concentration of electric fields surrounding the nonconductive material, indicated by the lighter area surrounding the dark circle in <FIG> relative to the area surrounding the dark circle in <FIG>.

In various aspects, the nonconductive material <NUM> can be biocompatible. In some optional aspects, the nonconductive material <NUM> can comprise, or be embodied as, a scaffold, a hydrogel, a film, or a three-dimensionally (3D) printed construct.

In aspects in which the nonconductive material <NUM> is a 3D printed construct, the nonconductive material can comprise one of a hydrogel or a polyimide.

In aspects in which the nonconductive material <NUM> is a scaffold, the scaffold can optionally be a nanofibrous scaffold or a hybrid scaffold. In some aspects, the scaffold can optionally comprise natural polymer. For example, the scaffold can comprise one or more of hyaluronic acid, fibrin, chitosan, gelatin, agarose, collagen, or combinations thereof. In further aspects, scaffold can comprise synthetic polymer. For example, the scaffold can comprise one or more of Polyethylene Glycol (PEG), polypropylene fumarate (PPF), polyanhydride, polycaprolactone (PCL), polyphosphazene, polyether ether ketone (PEEK), polylactic acid (PLA), poly (glycolic acid) (PGA), or combinations thereof.

In some aspects, the scaffold can be a three-dimensional (3D) bi-layer scaffold. Said three-dimensional (3D) bi-layer scaffold can optionally comprise biological decellularized human amniotic membrane (AM) with viscoelastic electrospun nanofibrous silk fibroin (ESF).

In some aspects, the nonconductive material comprises a biosheet (e.g., optionally, a silicone biosheet). The biosheet can optionally be a thin structure that covers at least a portion of a surface defining the resection cavity. Thus, in some optional aspects, the biosheet can define and/or surround an inner volume. Optionally, the inner volume of the biosheet can receive and fill with fluid from the body. Optionally, the biosheet can comprise a mesh. In some optional aspects, the biosheet can solidify once implanted. In use, prior to solidifying, it is contemplated that the shape of the biosheet can be selectively adjusted to match or complement a shape of at least a portion of a resection cavity.

In some optional aspects, the nonconductive material can comprise a chemotherapy agent that is configured to be released into the target region <NUM>. For example, the chemotherapy agent can comprise, for example, a taxane such as paclitaxel (I), docetaxel (II), cabazitaxel (III), and any other taxane or taxane derivatives, non-limiting examples of which are taxol B (cephalomannine), taxol C, taxol D, taxol E, taxol F, taxol G, taxadiene, baccatin III, <NUM>-deacetylbaccatin, taxchinin A, brevifoliol, and taxuspine D, and also include pharmaceutically acceptable salts of taxanes. In further aspects, the nonconductive material can comprise a nanogel. The nanogel can have one or more chemotherapy agents that are configured for slow release. For example DNA nanogels can be comprise structures that biomarker FEN1 can recognize and cut. Some exemplary nanogels for providing chemotherapy are provided in <NPL>. Further exemplary nanogels for delivering chemotherapy are provided in <NPL>.

In some optional aspects, the nonconductive material can comprise an antibacterial agent. In this way, the nonconductive material can serve the additional purpose of inhibiting infection. Exemplary antibacterial agents include, for example and without limitation, macrolides, clindamycin, and doxycycline. In some optional aspects, a nanogel can be used to deliver one or more antibacterial agents, as described for example, in<NPL>.

Optionally, the nonconductive material can be configured to break down and be absorbed by the body (i.e., be bioabsorbable). In further aspects, the nonconductive material can be configured not to break down. Optionally, the nonconductive material <NUM> can be removed after treatment such that the nonconductive material <NUM> functions as a temporary insert. For example, a stent or port can provide access to the nonconductive material <NUM> to permit removal of the nonconductive material after a desired amount (e.g., duration) of treatment with the nonconductive material. In this example, it is contemplated that a stent or port can extend through or be in fluid communication with an opening through a portion of the body of a patient (e.g., a hole formed through the cranium of the patient, or an access port formed in the torso (e.g., abdomen or back) of the patient). In further aspects, the nonconductive material can be left within the patient indefinitely (or until such time as the nonconductive material is absorbed by the body).

In some optional aspects, the nonconductive material <NUM> can comprise an oil. Accordingly, in some optional aspects, the nonconductive material <NUM> can be a fluid that fills, and conforms to the shape of, at least a portion of the resection cavity <NUM>. As further described herein, in further optional aspects, the nonconductive material <NUM> can compose both a rigid material and a fluid material.

Accordingly, in some optional aspects, the nonconductive material <NUM> can have a defined structure and geometry. For example, optionally, the nonconductive material can be shaped to be complementary to the geometry of the resection cavity. Optionally, the nonconductive material can be spherical. In further aspects, the nonconductive material can be oblong, cylindrical, polyhedral, irregularly shaped, or amorphous. In still further aspects, other shapes are contemplated depending on patient anatomy and geometry of the resection cavity. Optionally, the nonconductive material <NUM> can support the matter surrounding the resection cavity to inhibit collapse thereof. In further aspects, the nonconductive material can have a structure that is configured to conform to the shape of the resection cavity. In yet further aspects, the nonconductive material <NUM> can comprise both a portion having a defined structure and a fluid that is configured to conform to the shape of the resection cavity.

Depending on the size, shape, and location of the target region <NUM> and the resection cavity <NUM>, in some (but not all) situations a nonconductive material <NUM> forming a complete electric field barrier therethrough can lead to a sub-optimal distribution of electric field throughout the entire target region. Accordingly, referring also to <FIG>, in some optional aspects, the nonconductive material <NUM> can be embodied as a nonconductive body <NUM> comprising a biocompatible material. The nonconductive body <NUM> can define at least one pathway therethrough for electric fields to travel. For example, in some aspects, the nonconductive body <NUM> can be hollow, defining an outer surface <NUM> and an interior volume <NUM> (e.g., a shell having a thickness of less than <NUM>, about <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, no more than <NUM>, or greater than <NUM>). The nonconductive body <NUM> can further comprise a plurality of openings <NUM> between (or otherwise in fluid communication with) the outer surface <NUM> and the interior volume <NUM>. In these aspects, it is contemplated that the inner volume <NUM> can fill with fluid (e.g., CSF) so that the nonconductive body <NUM> defines an inner passageway <NUM> between at least two openings of the plurality of openings <NUM>, which can optionally be positioned on opposing sides of the nonconductive body. Said inner passageway <NUM> can conduct electric fields therethrough. Moreover, the inner passageway <NUM> can cause fields to converge and concentrate within the resection cavity while also maintaining an effective field strength throughout the target region. Accordingly, as shown in <FIG>, a portion <NUM> of the electric fields <NUM> can enter through openings <NUM> on one side of the nonconductive body <NUM> and exit through openings on the other (optionally, opposed) side of the nonconductive body. For example, it is contemplated that a first plurality of openings (for example, two, three, four, or more openings) can be positioned on a first side of the nonconductive body <NUM>, and a second plurality of openings (for example, two, three, four, or more openings can be positioned on a second (optionally, opposed side) of the nonconductive body. Optionally, the number of openings in the first plurality of openings can be equal to the number of openings in the second plurality of openings. In further aspects, it is contemplated that each side of the nonconductive body <NUM> can have a single opening <NUM> that is in fluid communication with the interior volume <NUM>. In still further optional aspects, it is contemplated that the total area of the opening(s) on the first side of the nonconductive body can be equal or substantially equal to the total area of the opening(s) on the second side of the nonconductive body. Although discussed above as a single inner passageway <NUM>, it is contemplated that the nonconductive body <NUM> can define a plurality of inner passageways, such as for example and without limitation, at least first and second inner passageways that extend between respective pairs of openings, with the openings of each pair being positioned on opposing sides of the nonconductive body.

In some aspects, the plurality of openings <NUM> can be positioned in an even distribution across the nonconductive body <NUM>. In further aspects, the plurality of openings <NUM> can be concentrated at areas (e.g., clusters), optionally disposed at opposing ends of the nonconductive body <NUM>. The openings <NUM> can be formed in a scaffold, a 3D printed construct, or a biosheet. Optionally, the openings <NUM> can be round (e.g., circular or oblong), rectangular slots, or any suitable shape. Optionally, each opening can have an area therethrough of at least <NUM><NUM>, at least <NUM><NUM>, from <NUM><NUM> to <NUM><NUM>, at least <NUM><NUM>, or less than <NUM><NUM>. The nonconductive body <NUM> can have two openings <NUM>, at least two openings, at least <NUM> openings, at least <NUM> openings, at least <NUM> openings, or fewer than <NUM> openings. Optionally, the openings <NUM> can collectively have an area that is at least <NUM>% or at least <NUM>% or no more than <NUM>% or from <NUM>% to <NUM>% of the outer surface area of the nonconductive body <NUM>. In further aspects, the inner passageway <NUM> can be defined by one or more bores through the nonconductive body <NUM> or by any other structure that provides electrical communication therethrough.

In further optional aspects, the nonconductive body <NUM> can define one or more pathways therethrough that can fill with fluid. For example, the nonconductive body <NUM> can comprise open cell foam that can fill with fluid. Accordingly, such a nonconductive body <NUM> can inhibit a portion of the electric fields therethrough, thereby directing a portion of the electric field around the outer circumference of the nonconductive body.

The resection cavity can optionally be within the brain of the patient. In further aspects, the resection cavity can be within the liver of the patient. In yet further aspects, the resection cavity can be within a lung of the patient. In yet still further aspects, it is contemplated that the resection cavity can be anywhere else (e.g., within any selected organ) in the body of the patient.

With reference to <FIG>, in some exemplary aspects, a computing device <NUM> can be used to determine an optimal treatment plan in conjunction with usage of the disclosed nonconductive materials <NUM>. In these aspects, the computing device <NUM> can comprise a processor <NUM> and a memory <NUM> storing processor-executable instructions that, when executed by the processor, cause the computing device to determine one or more features of the optimal treatment plan. Exemplary computing devices include, for example and without limitation, 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. In exemplary aspects, the processor <NUM> of the computing device <NUM> can be communicatively coupled (e.g., via wired or wireless connection) to the processor <NUM> of the electrical field generator <NUM> such that the computing device <NUM> can direct operation of the field generator <NUM> to achieve the optimal treatment plan. In these aspects, it is contemplated that the computing device <NUM> and the electrical field generator <NUM> can comprise respective transmitters, receivers, transceivers, and/or cables that are configured to permit such communication. Alternatively, in other aspects, the processor <NUM> of the electrical field generator <NUM> can be configured to determine an optimal treatment plan in the manner of the disclosed computing device <NUM>.

Claim 1:
A system comprising:
at least one first electrode (15a);
at least one second electrode (15b);
a signal generator (<NUM>) in electrical communication with each one of the at least one first electrode and the at least one second electrode, wherein the signal generator is configured to generate electric fields (<NUM>) between the at least one first electrode and the at least one second electrode; and
a nonconductive material (<NUM>) configured to be positioned between the at least one first electrode and the at least one second electrode, wherein the nonconductive material defines an inner passageway (<NUM>) that is configured to fill with fluid to conduct electric fields therethrough when the nonconductive material is positioned between the at least one first electrode and the at least one second electrode.