CN101495056B - Electrode introducer device - Google Patents

Abstract

An electroporation device 1 comprising a handle section 100; an elongate introducer shaft 10 connected to said handle section 100, said introducer shaft 10 having a distal tip 13; and a set of electrodes 60 having respective distal ends 61, each electrode 60 being slidably arranged within said introducer shaft 10 from a retracted position, where said distal ends 61 are enclosed within said introducer shaft 10, to an exposed position, where said distal ends 61 extend from said distal tip 13; wherein said electrode distal ends 61 are deflectable away from a longitudinal axis L of said shaft 10 when deployed/extended to their extended position, such that at least one planar projection taken in a plane perpendicular to said longitudinal axis L of a distance D1 between a pair of distal ends 61 of said electrodes 60 is larger than a maximal extent D2 of a cross-section of said introducer shaft 10, said cross-section taken in a plane perpendicular to said longitudinal axis L at a distal end 11 of said introducer shaft 10.

Description

Electrode introducer device

technical field

The present invention relates to devices and methods for electroporation, and generally and more particularly to methods for enhancing the response to, for example, drugs, isotopes or Devices and methods for the administration of therapeutic molecules such as genetic materials.

Background technique

In the treatment of disease in the brain, such as brain cancer, and disease in other anatomical regions of the body, physical access to diseased tissue regions can be a challenge. This is especially a problem if the diseased area is located deep within the patient's body. Furthermore, efficient delivery and subsequent uptake of therapeutic molecules, such as pharmaceutical or genetic compounds, to target tissues of anatomical structures is often a problem.

Electroporation is a known method for delivering pharmaceuticals and genetic material to various physiological tissues, wherein the uptake of these substances into tissue cells is enhanced by the application of electrical pulses of a specific amplitude. Drug delivery by electroporation is also known as electrochemotherapy (ECT) and gene delivery as electrogene transfer (EGT). In ECT and EGT applications, electroporation is used to create a temporary permeabilization of cell membranes in the target tissue area in order to enhance the uptake of chemotherapeutic agents and the uptake and accessibility of genetic material.

Besides the delivery of therapeutic molecules, electroporation has a separate application known as irreversible electroporation (IRE). In IRE, to promote cell death through cellular leakage, the amplitude of electrical pulses is increased beyond the levels used in ECT and EGT, which creates permanent permeabilization of the cell membrane in the target tissue area.

In order to provide efficient electroporation, two or more electrodes have been placed in or in close proximity to the area to be treated (target area). Examples of devices for electroporation are known from US 5 674 267 and US 6 278 895. These devices comprise needle electrode arrays arranged as individual electrodes interposed by some external paddle members which provide a fixed distance between individual needles and between individual needle relative positions. If the target region is in a distant region of the body, such as a deeper region of the brain, the placement of the electrodes may itself be detrimental to the intervening tissue through which the electrodes need to pass to be placed in the desired region. Also, a large access area must be obtained, and for applications in the brain this would necessitate the creation of large holes in the patient's skull. It is therefore clear that the mentioned prior art devices are only well suited for treatments in target areas in close proximity to the outer surface of the body, since attempts to treat deeper areas would cause excessive trauma of the intervening tissues.

purpose of invention

There is thus a need for electroporation devices and electroporation methods that overcome the shortcomings of currently known devices and methods. It is an object of the present invention to provide such an apparatus and method. It is yet another object of the present invention to provide an electroporation device that manages to gain access to deeper regions of the body or to other difficult to access areas, and does so with a minimal amount of tissue damage. For example for applications in the brain, the aim is to provide a device that requires the smallest possible entrance aperture while providing the largest possible electric field. Yet another object of the present invention is to provide an electroporation device capable of delivering an improved flexible and more efficient electric field to enhance the delivery of e.g. drugs, isotopes, genetic material or other therapeutic molecules across the cell membrane of the target tissue/area . By providing an improved more efficient and more controllable electric field, the energy applied to the tissue by the electrodes can be reduced. As a result, unintended damage to tissue, especially tissue surrounding the electrode, can be reduced. There is also a need for a device which constitutes an alternative to the known device.

Contents of the invention

These and other objects of the present invention are achieved by an electroporation device comprising: a handle portion; an elongated introducer shaft connected to the handle portion, the introducer shaft having a distal tip; and a set of electrodes , having a respective distal end, each electrode being slidably disposed on the within the introducer shaft and the tip; wherein the distal end of the electrode, when deployed/extended to its extended position, is offset from the longitudinal axis of the shaft such that the distance from the pair of distal ends of the electrode At least one planar projection in a plane perpendicular to the longitudinal axis is greater than the maximum width of a cross-section of the introducer shaft along a direction perpendicular to the longitudinal axis L at the distal end of the introducer shaft Flat intercept.

A significant advantage of the presently described device is that it allows for the insertion of multiple electrodes into subcutaneous tissue regions or target regions of a patient's body while causing minimal tissue movement and damage to intervening tissues. This advantageous fact is achieved due to the small outer width/diameter or profile of the device of the invention along the intrusive part, ie the shaft, or at least the distal part thereof, transverse to the insertion direction.

The device according to the invention allows subcutaneous generation of electrode terminal (distal) patterns resembling planar or spatial ellipsoids or ellipsoids or any other regular or irregular spatial geometry, which will provide suitable for altering real in-patient findings. Effective controllable shape of the electric field for the anatomy/geometry of the target zone. Furthermore, this can be achieved in subcutaneous situations not possible with prior art devices (deep locations/hard-to-access areas) by subcutaneous deployment of multiple electrodes inclined away from the introducer axis and comprising preferably The respective uninsulated end points are provided in an equidistant relationship that may limit the perimeter of such an ellipsoid or other geometric shape in the target area.

In an embodiment of the electroporation device, when in its extended position, deflection of said distal end of said electrode is provided by bending a distribution channel provided in said distal end. Alternatively, or in addition, when in its extended position, the deflection of the distal end of the electrode is through the stretching properties of at least a portion of the electrode (in the direction of elongation), i.e. through the electrode or electrode partial bias to provide. Alternatively, or in addition, the electrodes are formed in a material comprising a shape memory alloy.

In one embodiment, the distal tip may alternatively or additionally be formed in a substantially smooth rounded non-cutting shape with a substantially smooth non-cutting transition to the introducer shaft. Thus, the device has no sharp edges and damage to tissue can be minimized.

In embodiments, the distal tip is connectable to the introducer shaft. Optionally, the tip is integrally formed with the shaft.

In another embodiment, each of said electrode distal ends is individually advanceable to its extended position. Thereby, the extended profile of the electrodes, and thus the shape of the electric field, can be adapted to the respective target tissue. Alternatively, the electrodes may be advanced or extended from the tip in electrode subsets or sets of electrodes, for example with the length of each electrode adapted to the shape of the target tissue.

In another embodiment, the electrode is extendable such that the distal end is extendable to form a spatial distribution of a volume around the target tissue/region of interest. In one embodiment thereof, the distal end is extendable to form a substantially spherical distribution pattern. Optionally, at least a subset of said distal ends may extend to form an ellipsoidal pattern in a plane parallel to said longitudinal axis of said introducer axis.

In any of the above embodiments, the electrode is slidably disposed in an electrically insulating guide channel formed in the shaft and tip. Alternatively or additionally, the electrodes may be provided with an electrically insulating coating, the distal-most part of the electrode's distal end being uninsulated to form a point electrode.

Generation of a subcutaneous electric field with a geometry similar to an ellipse or other three-dimensional shape would provide more homogeneous tissue coverage. Subsequent application of short and strong electrical pulses to two or more of these preferably equidistant electrodes will generate a potential difference between the positive and negative electrodes and a resultant electric field will be generated between these two or more electrodes.

According to an advantageous embodiment of the present invention, said introducer shaft further comprises a delivery channel through which a dose of therapeutic molecule can be administered, said delivery channel extending through the length of said shaft and through said distal tip termination. The delivery channel is provided through the shaft along its elongated axis to accommodate delivery of a dose of therapeutic molecules to a region near the tip of the shaft when the device is inserted into the region of target tissue. Thus, local delivery of the therapeutic molecule to the target area can be enhanced. However, it will be appreciated that the device may also be used in conjunction with systemic administration of therapeutic molecules, wherein electroporation will enhance local uptake of therapeutic molecules in tissue cells in the region/proximity of the electrodes.

In one embodiment, the delivery channel is connectable to an external therapeutic molecule delivery system comprising a therapeutic molecule reservoir and a pumping device for administering the therapeutic molecule through the delivery channel. Optionally, the handle portion includes a therapeutic molecule delivery system comprising a therapeutic molecule reservoir and a pumping device for administering the therapeutic molecule through the delivery channel. In each of the embodiments of the device comprising a delivery channel, the device may be further adapted to introduce eg a surgical tool or an ultrasound probe through the delivery channel. This variant may include a suitably sized delivery channel and/or suitable connection means between the device and the surgical tool. In an alternative embodiment, a separate channel may be provided in the shaft for insertion of surgical tools or ultrasound probes.

In one embodiment, the introducer shaft has a circular cross-section with an outer diameter of 15 mm or less, preferably 10 mm or less, more preferably 5 mm or less. However, other cross-sections may also be provided, for example oval, in which case the above-mentioned dimensions may apply across the cross-section up to a maximum width.

In yet another embodiment, the introducer shaft may comprise an outer tube and an inner electrode assembly guide received in said outer tube, and wherein said electrode is slidably disposed in a channel formed in said inner electrode assembly guide. in the electrode guide channel. In one embodiment, the electrode guiding channels are formed with a set of cylindrical guiding sleeves accommodated in semi-open channels longitudinally distributed along the outer circumference of the inner electrode assembly guiding means. In another embodiment, the introducer shaft may be provided through a plurality of electrode guide channel conduits, each configured to accommodate one or more electrodes.

The introducer shaft can be rigid in one embodiment. However, in other embodiments the introducer shaft may be flexible and/or steerable, the latter embodiments being particularly suitable for insertion through body cavity/venous applications.

Such flexible and/or steerable applications may be endoscopic or catheter-based applications in natural passages or lumens in the body where a flexible/steerable shaft 10 is desired. The device may be introduced through a natural anatomical orifice or through a suitable entry site, such as the femoral artery. Alternatively or additionally, a laparoscopic application through a hole in the abdominal cavity or other region of the anatomy is conceivable, wherein the shaft can be introduced through an introducer eg with a working channel or similar introduction cannula. Such an introducer may, for example, have a cutting edge or a removable trocar with a trocar end that is removed after the introducer is inserted to facilitate insertion.

In one embodiment, the shaft is substantially straight. However, in other embodiments, the shaft is bendable to provide the possibility for use in specific anatomical areas (eg tumors of the head and neck) or around areas of fragile tissue, for example.

Preferably the device comprises 10 or more electrodes. Thus, the electrodes in the extended position can be spatially distributed to facilitate the formation of a steric electric field. In yet another embodiment, the device comprises 12, 16 or more electrodes.

In yet another embodiment, the device comprises 32 electrodes. In a particular embodiment, said electrodes are slidably arranged in guide channels distributed in four sets of eight cylindrical guide cannulae.

As with all of the preceding embodiments, the electrical stimulation generator may be incorporated into the handle portion of the device. Optionally, the device comprises means for connecting/fixing the device electrodes to an external electrical stimulation generator.

In one embodiment, each electrode or set of electrodes may be individually configured to pass electrical current such that the delivery of electrical stimulation may be provided by an individual electrode or set of electrodes. Thus, enhanced control of the induced electric field may be provided. Control or setting of individual electrodes or groups of electrodes may be provided by suitable electronic control means provided with an external electronic stimulation generator in the handle portion of the device or as a separate device.

The tip of the introducer shaft may be a rounded, smooth atraumatic end adapted to stretch tissue, thus causing minimal trauma to the tissue it moves through. This is particularly advantageous for intravenous applications or applications eg in the brain. However, in other embodiments the tip may be provided with a sharpened or cut tip or tip, eg suitable for percutaneous application.

The objects of the present invention are further achieved by a method of electroporation comprising providing an electroporation device comprising an elongate introducer shaft having a distal tip; and a set of electrodes having respective distal ends, each An electrode is slidably disposed on the introducer shaft and the tip from a retracted position wherein the distal end is enclosed within the introducer shaft to an exposed position wherein the distal end extends from the distal tip the method further comprising the steps of: inserting the introducer shaft through tissue of the body and bringing the distal tip into proximity to the target area to be treated while the electrodes are in their retracted positions; The electrode is extended to the extended position such that the distal end of the electrode is offset from the longitudinal axis of the shaft in such a way that it is perpendicular to the longitudinal axis of the distance between a pair of distal ends of the electrode. At least one planar projection in the plane is greater than the maximum width of a cross-section of the introducer shaft taken at the distal end of the introducer shaft along a plane perpendicular to the longitudinal axis; a dose of therapeutic molecules to the body; and applying one or more electrical pulses, eg, in a specific sequence, to target area tissue via said electrodes to cause temporary permeabilization of tissue cell membranes in said target area.

In one embodiment of the electroporation method according to the invention, said dose of therapeutic molecule is administered systemically. In another embodiment of the electroporation method according to the invention, said agent is administered locally near the target area. Such local administration may advantageously be delivered before, during or after extending said electrode through a delivery channel extending through the length of said shaft and terminating through said distal tip. Alternatively, the medicament may be delivered locally by suitable additional injection/infusion devices.

The objects of the invention are also achieved by an aspect of a method of generating an electric field in a target area of a patient, said method comprising the steps of inserting in the vicinity of said target area a set of electrodes having respective distal ends of a single elongated introducer shaft at the tip; at least one pair of said electrodes extending to a position extending from said in-shaft position thereof such that said electrode distal ends extend from the longitudinal axis of said shaft in such a deviated in such a way that at least one plane projection in a plane perpendicular to the longitudinal axis of the distance between the pair of distal ends of the electrodes is greater than the maximum width of the cross-section of the introducer axis at the taken along a plane perpendicular to the longitudinal axis at the distal end of the introducer shaft; and applying one or more electrical pulses to the target tissue through the electrodes.

In an embodiment of this aspect of the method of generating an electric field in a target tissue of a patient, the electrodes are point electrodes arranged such that when a sequence of electrical pulses is applied through some or all of the electrodes, an ellipsoidal or spatially ellipsoidal field Generated between some or all points set in the tissue. In other embodiments, the ellipsoidal or spatial ellipsoidal field is generated by arranging the point electrodes in an ellipsoidal or spatial ellipsoidal configuration that at least partially surrounds or encloses the target tissue. In yet another embodiment, the distal ends of the point electrodes are arranged in substantially circular parallel layers, wherein the position of the point electrodes in the portion perpendicular to the circular layers defines an ellipsoidal structure. In yet another embodiment, the electric field is passed through said tissue by applying a sequence of electrical pulses between at least sixteen point electrodes in at least four substantially parallel successive layers including at least four point electrodes in each layer, and causing said sequence to comprise the step of generating respectively generating at least some pulses which move from at least one electrode in the first positive layer of point electrodes to point electrodes equidistantly arranged with respect to the electrodes in the first layer At least one electrode in the first negative layer, while other pulses simultaneously move from at least one electrode in the second positive layer to at least one electrode in the second layer of point electrodes.

The objects of the invention are also achieved by another aspect of the method of generating an electric field in target tissue of a patient, said method comprising the steps of: inserting into the vicinity of the target tissue a set of point electrodes, said point electrodes having respective electrically conductive Distal end, and the distal end of the electrode is arranged in a space form surrounding or enclosing at least part of the target tissue; a sequence of electrical pulses is applied to the target tissue through the point electrode.

In an embodiment of this other aspect of the method of generating an electric field in target tissue of a patient, the point electrodes are configured to generate an ellipsoidal or spatially ellipsoidal electric field in the tissue when a sequence of electrical pulses is applied through the electrodes. In other embodiments, the ellipsoidal or spatial ellipsoidal electric field is arranged by arranging the point electrodes in an ellipsoidal or spatial ellipsoidal structure that at least partially surrounds or encloses the target tissue. In yet another embodiment, the distal ends of the point electrodes are arranged in substantially circular parallel layers, and wherein the position of the point electrodes in the portion perpendicular to the circular layers defines an ellipsoidal structure. In other embodiments, by applying a sequence of electrical pulses in said tissue between at least sixteen point electrodes in at least four substantially parallel consecutive layers including at least four point electrodes in each layer, and causing all The described sequence comprises the step of generating an electric field by respectively generating at least some pulses which are moved from at least one electrode in a first positive layer of point electrodes to an equidistant arrangement with respect to the electrodes in the first layer At least one electrode in the first negative layer of point electrodes, while other pulses simultaneously move from at least one electrode in the second positive layer to at least one electrode in the second negative layer of point electrodes.

The present invention is particularly advantageously used in electrochemotherapy and electrogenetic therapy for the treatment of brain cancer and other brain diseases. This disclosure describes the invention from this perspective, but it will be appreciated that devices according to the invention may also be suitable for use in the treatment of diseases such as liver, lung, kidney or other soft or hard tissues. The invention can also be used in the field of irreversible electroporation.

The devices and methods can be used in the treatment of humans as well as animals.

In this document, the term shaft is understood as an elongate structure, which may be rigid or flexible/bendable/manipulable, and which is substantially straight or forms the same bend over at least part of the length of said shaft.

Description of drawings

The present invention will be described in further detail below with reference to the accompanying drawings. The figures show implementations of the invention and should not be construed as limiting other possible embodiments falling within the scope of the appended claim set.

Figure 1 shows a perspective view of electrodes introduced into an electroporation device according to an embodiment of the present invention;

Figure 2 shows the distal end of an embodiment of an introducer device according to the invention in a perspective view;

Figure 3 shows a cross-section through the distal end of the introducer device shown in Figure 2 with the electrodes in a retracted position;

Figure 4 shows a cross-section through the distal end of the introducer device shown in Figure 2 with the electrodes in an advanced position;

Figure 5 shows a perspective view of the distal end of the introducer device shown in Figure 2, showing the extent of the advancing electrodes;

Figure 6 shows a partially cut-away cross-sectional view of an electrode introducer device according to another embodiment of the present invention;

Figure 7 shows the distal end of the introducer shaft of the introducer device shown in Figure 6 in an exploded cross-sectional view;

Figure 8 shows a detail of the introducer device shown in Figure 6 in an exploded view;

Figure 9 shows a front view of the distal end of a device according to one embodiment of the present invention, with two layers of electrodes extending distally visible;

Figure 10 shows some of the electrodes extending from the distal end of the device shown in Figure 9, showing the pulse firing pattern between these electrodes; and

FIG. 11 shows the resultant pattern of the electric field induced in the target tissue by the pulsing pattern shown in FIG. 10 .

Detailed ways

In Fig. 1 is shown an electrode introduced into an electroporation device 1 according to an embodiment of the present invention. The device 1 comprises a handle portion 100 and an elongated introducer shaft 10, preferably of a length suitable for accessing deeper tissue regions. The length of shaft 10 may be suitable for the intended use. The shaft 10 is connected to the handle portion 100 and has a distal end 11 and a proximal end 12 adjacent the handle portion 100 . The shaft may in one embodiment be fixedly connected to the handle portion. In other embodiments, the shaft is removably mounted to the handle portion 100, and may include suitable means for establishing a temporary connection, such as for conducting electrical impulses. Disposed at the distal end 11 of the shaft 10 is a distal tip 13 preferably shaped to allow passage through interlayers of tissue while causing minimal damage to said tissue. . The distal tip 13 has a round non-cut shape. In other embodiments (not shown), the distal tip may be provided with a cutting edge or point, ie a sharp tip. These latter embodiments are for example well suited for transdermal applications. In each case, the distal tip 13 may be integrally formed with the introducer shaft 10 , or it may be a separate component joined to the distal end 11 of the introducer shaft 10 . Due to the removable/detachable tip 13, and/or the detachable shaft 10, the length of the device and thus the reach can be adapted by proper choice of the shaft. Also, this allows for one-time use of components that are only inserted into the patient. The need to sterilize the components to be inserted into the patient can thus be eliminated.

The introducer shaft 10 includes a centrally disposed delivery channel 20 (see FIG. 3 ) that runs through the shaft 10 along the longitudinal axis L of the shaft 10 from the proximal end 12 to the distal end 11 and extends through the distal tip. 13, the channel 20 has a proximal end 22 and a distal end 21. At the distal end 21 of the channel 20 , one or more outlets 25 are provided in the distal tip 13 to administer an amount of fluid/drug compound adjacent the distal tip 13 . In the embodiment shown in the figures, one outlet 25 is provided, however, the channel 20 may be divided at the distal end 21 into a plurality of microchannels each having an outlet at the distal tip 13 . The proximal end 22 of the channel 20 extends through the shaft 10 to the handle portion 100 and is adapted for connection to a drug/genetic material delivery device (115) comprising a drug/medication storage device and/or Means (eg pump or plunger, etc.) for passing the medicament from the storage device to the target tissue through the channel 20 . The delivery means may be provided in simple form by a syringe 115, connected to the delivery channel 20 through the handle part 100, for example by tubing.

In an alternative embodiment (not shown), the channel 20 may be configured to accommodate an elongated conveyor system, for example in the form of a pipe, which may pass from the storage device into the area to be treated. Such a delivery system may comprise a syringe connected to said tubing in such a way that the channel is adapted to receive eg a distal portion of said tubing.

In another alternative embodiment (not shown), the device 1 may be provided with an integrated therapeutic molecule delivery system comprising a delivery device with an advancement/pumping device integrated into the handle portion 100 and/or with Storage devices for solutions of medicaments/drugs, isotopes or genetic material.

The electroporation device 1 and delivery channel 20 may also be configured, eg by suitable connection means, and/or be sized to receive and guide eg an ultrasound probe, surgical tool or other tool for minimally tissue invasive procedures. Thus, the device 1 can be used in a flexible manner, wherein, for example, if the operator/surgeon encounters unexpected obstacles/difficulties before, during or after electroporation, there is no need to remove the device 1 and use other special surgical tools replace it.

The shaft 10 also includes a plurality of guide channels 50 (see FIGS. 3 and 4 ) distributed around the central channel 20 and extending from the proximal end 12 to the distal end 11 of said shaft 10 and through the distal tip 13 . Each guide channel 50 is adapted to guide one or more elongate electrodes 60 which can be positioned relative to the shaft 10 in a first retracted position as shown in FIG. 3 and in FIG. 4 . It is movable between the second extended position shown.

In an alternative embodiment (not shown), each guide channel 50 may be provided by a single conduit along at least a portion of the shaft 10 in which portion the shaft 10 is formed by a single set of conduits.

Each electrode 60 has a distal end 61 , a proximal end 62 extending to the handle portion 100 , and an intermediate region 63 electrically connecting the proximal end 62 and the distal end 61 of each electrode 60 .

Proximal end 62 of electrode 60 is configured to serve as a connector, thus providing a means for connecting electrode 60 to electrical stimulation generator 120, which provides individual electrical stimulation according to electroporation protocols for drug and gene delivery. pulse or sequence of electrical pulses. The electrical pulses are used to generate an electric field for forming in the vicinity of the distal end 61 of the electrode 60 when the introducing device 1 is placed in or close to the target tissue area and the electrode 60 is advanced to the extended position Transient permeabilization of cell membranes and/or electroporation effects, see further below regarding the use of the device.

The electrodes 60 may be connected to an external electrical stimulation generator 120 through an electrical connector (cable) 121 at the handle portion 120 shown in FIG. 1 . In an alternative embodiment, the electrical stimulation generator 120 may be integrally formed with the introducer device, preferably in the handle portion 100 .

The configuration of the proximal end 62 of the electrode 60 also allows the electrode 60 to move between a first retracted position and a second extended position during a deployment sequence described further below.

An intermediate region 63 of the electrode 60 is movably housed in said electrode guide channel 50 extending through the introducer shaft at the distal tip 13 from the proximal end 12 to the distal end 11 . Preferably, each electrode 60 has its own channel 50 for supporting and protecting the electrode and insulating it from the other electrodes 60, as shown in FIGS. bundled together, as shown in Figure 6. The electrode guide channel 50 allows the electrode 60 to move longitudinally between a first retracted position and a second extended position.

The electrode terminal at the distal end 61 of the electrode 60 is movably housed in a distribution channel 70 formed in the distal tip 13 and extending to the outer surface of said distal tip 13 . Each distribution channel 70 also communicates with a corresponding guide channel 50 in the shaft 10 . Thus, allowing the electrode 60 to longitudinally (with respect to the longitudinal axis of the shaft 10) a first retracted position in which the distally disposed terminal end 61 of the electrode 60 is hidden in the distal tip 13 and in which the terminal end 63 of the electrode 60 extends from the distal tip 13 to move between the second extended position.

In an alternative embodiment (not shown), the device may have only the distribution channel 70 formed in the distal tip 13, with the electrode 60 housed in the hollow shaft 10, omitting the separate channel 50.

When set in the first retracted position, i.e. the default mode of the device 1, the termination at the distal end 61 of the electrode 60 remains stored in the distribution channel 70 in the distal tip 13, thus allowing minimally invasive insertion of the device 1, i.e. Minimal damage to surrounding tissue.

The distribution channel 70 is shaped to ensure that the distal ends 61 of the electrodes 60 are deployed in a predetermined pattern with a maximum distance D1 between a pair of oppositely disposed electrode terminals 61 in a plane transverse to the longitudinal axis of the introducer shaft (see FIG. 5 ) greater than the diameter or maximum extension D2 of the introducer shaft 10 /distal tip 13 in a plane perpendicular to the longitudinal axis of the introducer shaft 10 . Thus, it is possible to use a single introducer shaft 10 through a single channel to access tissue at a deeper location, such as in the brain, deploy the intermediate tissue during insertion, and when the tip 13 reaches the target tissue, the electrodes can be extended through the target tissue and/or in the Extend around the target tissue. This allows the operator (surgeon) to treat target tissue regions or volumes having a cross-sectional dimension/length greater than the cross-sectional diameter of the introducer shaft 10 , where the cross-section is taken in a plane perpendicular to the longitudinal axis of the introducer shaft 10 . In order to provide the distribution of the distal end 61 of the electrode 60 as described above, the distribution channels 70 are formed with at least some of the channels 70 bent outwards, i.e. away from the longitudinal central axis L of the introducer shaft 10 (as from there to the corresponding guide channels 50 in the shaft 10). distal end 11 and towards the connection of the outer surface of the distal tip 13 where the distribution channel 70 terminates). Each of the distribution channels 70 or groups of distribution channels 70 may be provided with a different respective shape/offset/bend to ensure a specific pattern or distribution of the extension electrodes 60 during use.

Alternatively, a deviation from the longitudinal axis L may be provided by, for example, a pre-stretching or biasing of the electrodes 60 . Such stretching may be provided by appropriate choice of material, e.g. a shape memory alloy such as nickel or by electrodes formed (bendable), e.g. Keep stretching. Each electrode 60 or set of electrodes may have an individual bias so that when the electrodes are extended from their retracted position on the shaft 10/tip 13, the electrodes may form a desired spatial pattern around the target tissue.

Furthermore, the desired spatial distribution of the portion of the electrode extending from the tip 13 may be provided by a combination of the shape of the tip distribution channel 70 and the biasing of the electrode 60 .

In use, an electrical connection (not shown) at the proximal end 62 of the electrode 60 is connected to a suitable electrical stimulation generator 120 . The shaft 10 of the introduction device 1 is then inserted, eg, through a hole in the patient's skull or an incision in the patient's skin, and introduced into the target area of the patient's body. The precise position of the target area and thus the precise position for the hole/incision can be determined by ultrasound, CT, MR or other suitable means, and the correct position of the tip 13 of the introducer shaft 10 (rod insertion) prior to electrode placement, During or after the course can be demonstrated by similar means. When the correct position of the tip 13 of the introducer shaft 10 has been achieved relative to the target tissue, the operator may deliver the appropriate chemotherapeutic agent or a dose of genetic material or other substance in fluid or liquid form through the delivery channel 20 and to the area to be treated middle.

The operator may deploy some or all of the elongate electrodes 60 in a desired pattern before, during or after delivery of the agent or genetic material through the delivery channel. Deployment is accomplished by actuating a suitable deployment mechanism at the handle portion 100 or at the proximal end 12 of the shaft 10, and causing the axis along the introducer shaft 10 from a first retracted position as shown in FIG. The longitudinal movement of all or some of the electrodes 60 in the second advanced position shown is performed. The distribution channel 70 in the distal tip 13 is shaped to provide each individual electrode 60 with a unique passage through the tissue as it advances from the tip 13, which enables the formation of an electrode pattern in which a longitudinal direction transverse to the introducer axis 10 The distance D1 between oppositely arranged electrode terminals 61 in the plane of the shaft is greater than the diameter D2 of the introducer shaft 10 in the same transverse plane (or the portion of the shaft 10 perpendicular to the longitudinal axis of the shaft 10 if the shaft is not of circular cross-section maximum width in ).

When some or all of the electrodes are deployed to their extended positions, the operator can actuate the electrical stimulation generator 120 to deliver one or more pulses, such as a sequence of short and intense pulses, to the tissue to be treated (the target tissue). In order to ensure proper distribution of the pulses, and thereby induce an electric field in the target tissue, the pulses can be set to alternate specific electrodes 60 in a sequential pattern, which can be tailored to the appropriate anatomy and/or specific malignancy of each region of the body to be treated. The geometry of the target tissue. Such a setting can be obtained, for example, by appropriate control of the electrical stimulation generator, for example by means of a programmable electronic control device.

When the pulse is delivered, the operator can retract the elongate electrode 60 to its retracted position by manipulating the deployment mechanism in the handle portion 100, and the device can be removed from the patient's body. Optionally, the operator may reset the device 1 after the elongated electrodes 60 have been retracted, possibly allowing multiple pulse applications covering a larger area than a single device insertion.

The electrode introducer device 1 shown in FIGS. 2-5 is shown with eight guide channels 50 , distribution channels 70 and electrodes 60 . However, a device according to the invention may be provided with any number of electrodes 60 . The distribution of the guide channels 50 in the cross-section of the introducer shaft 10 shown in FIGS. 2-5 is such that the electrodes all extend in a plane parallel to the longitudinal axis of the introducer shaft 10 . However, the electrodes 60 and their guiding (and distribution) channels 50 ( 70 ) may be arranged around the entire circumference of the channels 20 in the shaft 10 , or around said delivery channels 20 in other patterns.

Each electrode is formed of conductive material. Portions of the electrodes may be formed using an electrically insulating coating or sleeve so that only the most distal ends 61 (terminations) of the electrodes 60 are not insulated. Thus, the electrical pulse will form an electric field across the distance from terminal to terminal (distal end 61 to distal end 61) and form an easily controllable emission pattern, which can thus be produced by proper selection and placement of electrodes in a more controllable and precise manner. the electric field. For the sake of completeness, it should be understood that the entire length or part of the entire length of the electrode may also be electrically non-insulating, provided that the guide channel 50 and the distribution channel 70 are formed of an electrically insulating material.

As shown in FIG. 5 , the device can be configured such that the distal end 61 of the electrode 60 can form an ellipsoidal electric field E as a result of the pattern of the electrode 60 . The target tissue can be imagined as being located in the ellipsoidal region E shown in the figure. Some electrodes 60 are thus advanced through the target tissue when guided to their extended position. In other embodiments of the invention, it is conceivable that the electrode pattern can be formed such that the target area can be surrounded by electrode terminals (distal ends) 61 in various three-dimensional patterns such as spherical or spherical ellipsoidal or ellipsoidal patterns.

As can be appreciated from FIG. 5, the device according to the invention can be modified to have electrode sets 60 which can extend from the distal tip 13 to different distances along the longitudinal axis of the shaft 10 so that the distal end 61 of each set is positioned In a common plane perpendicular to the longitudinal axis of shaft 10. In Figure 5, four sets of two electrodes extend to different distances from the distal tip 13, thus forming the ellipsoid E described above.

Also, some of the electrodes 60 may be formed in such a way that they take a curved path through the tissue so that when advanced forward toward their extended position, they will initially deviate from the central longitudinal axis L of the shaft 10 and will then fold back so that when advanced further Advancement closes the distal tip on the central longitudinal axis of shaft 10. Thus, when fully extended, such an electrode 60 will describe a generally U-shaped or substantially generally Ω-shaped curve. This can be achieved by providing the electrodes in an elastic material or a shape memory alloy such as nickel, or by providing electrode sections (lengthwise) with different deflections (pre-stretching).

Also, the guide channel can be shaped to impose some path through the tissue on the electrode. For example, it is advantageous to impose a linear path through tissue on the electrode, as the electrode will be able to resist higher loads without deformation, as opposed to an electrode given a curved path.

The deployment mechanism for electrode 60 may be manually actuated or motorized (eg, electronically controlled). The deployment mechanism may be adapted to advance all electrodes simultaneously as a group of electrodes 60 or individually or in groups (subgroups). Different electrode patterns can be obtained by a predetermined composition of electrodes of appropriate length, shape (by stretching, alternative cross-section prearrangement of wires for movement in a certain direction, or by appropriate shaping of guiding channels) and material when the electrodes are simultaneously advanced . The device 1 according to the invention may also be controlled by electronic control means (not shown) which are either incorporated in the device 1 or may be connected to the device 1 by a cable or a wireless connection. In a wireless configuration, an appropriate power supply is preferably provided inside the device. The electronic control unit can be preprogrammed so that the desired electrode pattern can be programmed prior to the surgical procedure.

In an alternative embodiment (not shown), and as described above, a variation of the disposable device of the above-described embodiment is presented, having a disposable introducer shaft 10 and a non-disposable (reusable) handle portion 100, the The non-disposable (reusable) handle portion 100 includes a deployment mechanism with an interface to a disposable introducer shaft 10 and customizable electrical connections to each electrical stimulation generator 120 . The shaft may in all embodiments be formed in plastic or metal materials such as titanium, stainless steel, or injection molded polymer materials. The outer diameter of the shaft is preferably five (5) millimeters or less, preferably between a standard size of 17 and 14 inches. The wall thickness of the shaft is preferably between 0.05 mm and 0.25 mm. The guide channels 50, 70 may be formed of a suitable material, for example a thermoplastic elastomer or similar electrically insulating material. Electrode 60 may be formed of an electrically conductive material such as titanium, stainless steel, or the like. In the following, an aspect of the invention, particularly suitable for applications in the brain, eg in the treatment of brain cancer or genetic defects, will be further described with reference to Figures 6-8. With regard to the aspects of the invention shown in the preceding figures, the same reference numerals will be used for similar parts. The electrode introducer device 1 includes an introducer shaft 10 and a handle portion 100 . The introducer shaft 10 is intended to be inserted into a patient and is fixedly connected to a handle portion 100 .

In an alternative embodiment, a partially disposable device is proposed having a disposable introducer shaft 10 and a non-disposable (reusable) handle portion 100 comprising a deployment mechanism, There is an interface to the disposable introducer shaft 10 and electrical connections to each electrical stimulation generator 120 that can be customized.

The introducer shaft 10 comprises the following parts:

- Outer tubing 15, having a proximal end 11 and a distal end 12, preferably formed in plastic or metal such as titanium, stainless steel or an injection molded polymer material. The outer diameter D2 of the pipe is preferably five (5) millimeters or less. The wall thickness of the outer pipe is preferably between 0.05mm and 0.25mm, and the length of the pipe is preferably between 50mm and 500mm depending on the particular application.

- Internal electrode assembly guide means 16, preferably formed from a thermoplastic elastomer or similar electrically insulating material. An inner electrode assembly guide 16 is placed in the lumen of the outer tube 15 . The electrode assembly guide 16 has a straight proximal end and a straight distal end, including faces disposed perpendicular to the longitudinal axis. The electrode assembly guide 16 includes eight straight semi-open passages 17, which are distributed around the periphery of the electrode assembly guide 16 in a circular pattern, partly sunk in the periphery of the electrode assembly guide 16, and run from the proximal end 12 in parallel tracks. Extends to distal end 11 anteriorly. In addition, the electrode assembly guide 16 has a central bore/delivery channel 20 that provides fluid passage and/or a working channel for surgical instruments. The periphery of the electrode guide assembly 16 fits into the lumen of the outer conduit.

- Eight electrode assemblies, each electrode assembly comprising a cylindrical guide sleeve 30 . The guide sleeve 30 is preferably formed of a thermoplastic elastomer or similar electrically insulating material, and is received in the straight semi-open channel 17 in the electrode assembly guide 16 and is securely secured therein. The cylindrical guide sheath 30 has a straight proximal end 32 and a distal end 31 . The interior of each electrode assembly guide sleeve 30 includes four mutually electrically insulated electrode channels 50 extending in parallel from the proximal end 32 to the distal end 31 and in a pattern similar to a rectangle in which the electrode channels 50 are placed in the corners. distributed. The proximal end of each electrode channel 50 includes an electrode support region having a first slightly increased diameter of about 20 mm for receiving a respective support sleeve mounted on the proximal end 62 of each electrode 60 . Furthermore, the electrode assembly includes a total of thirty-two elongated, preferably cylindrical electrodes 60 formed of an electrically conductive material such as titanium, stainless steel, etc., each electrode having a proximal end 62, a distal end 61, and an intermediate region 63. Approximately 20 mm from the proximal end 62 of each electrode 60 may provide a 20 mm long support sleeve (not shown) surrounding a portion of the intermediate region 63 of the electrode 60 . The support sleeve is meant to provide support to the individual electrodes to prevent deformation or bending during the deployment sequence, and is configured to slide into the electrode support region as the electrode moves from its retracted position to its advanced position during deployment ( electrode channel 50 on the guide cannula 30). Each electrode 60 is preferably covered with an electrically insulating layer except for the distal tip, which remains uninsulated. Also, the electrodes 60 are divided into groups of 4, and each group of electrodes is inserted into the cylindrical guide sleeve 30 , one electrode in each electrode channel 50 . Insertion is performed such that the proximal end 62 of the electrode 60 protrudes approximately 30 mm from the proximal end of the guide sheath 30 and the distal end 61 of the electrode 60 protrudes approximately 40 mm from the distal end of the guide sheath 30 .

- Eight arrays of bushings 80 each configured to receive and guide four electrodes 60 , each having a proximal end 82 and a distal end 81 and four arrays of channels 83 . An array of bushings 80 is provided in the extension of each of the eight electrode assemblies (guide sheaths 30 ), configured to engage said assembly and guide sheaths 30 , and to accommodate the four elongate electrodes 60 , wherein the electrode 60 protrudes from the distal end 31 of the assembly/guide sheath 30 in a manner that prevents deformation or bending of the electrode during the deployment sequence. To accomplish this, the proximal end 82 of the bushing 80 of each array is configured to align the channels 83 of the four arrays with the four electrode channels 50 of the electrode assembly/guide sheath 30 . The paths of the array channels 83 of the bushings 80 of each array are configured to change the pattern of the elongated electrodes from a rectangular pattern configuration when protruding from the electrode assembly/guide sleeve 30 to a configuration as they emerge from the bushings 80 of the array. Linear mode when extended. Since the eight electrode assemblies/guide sleeves 30 are distributed in a circular pattern, and the eight arrays of bushings 80 are provided in the prolongation of the assembly, a radial pattern can be formed by properly orienting the arrays of bushings 80 .

- The distal tip 13, which is an intermediate extension of the electrode assembly guide 16 and is aligned with the electrode assembly guide 16. The distal tip 13 includes eight elongated, generally triangular-shaped septum means 40, each having a proximal end 42 and a tapered, circular distal end 41, a circular outer surface 43, and a circular outer surface 43 with two faces 44a, 44b. internal part. One face 44b is smooth and one face 44a includes four distributed grooves 70 extending from the proximal end 42 towards the distal end 41 while each is curved with a predetermined unique curvature towards the outer circular surface 43 of the diaphragm means 40 . The faces 44a, 44b meet at a 45 degree angle to form a wedge. A circular cutout 45 is removed from the tip of the wedge. The proximal end 42 of the baffle device 40 has a reduced height and is inserted into the distal end 11 of the outer tube 15 and is tightly fixed with the outer tube 15 while the distal ends 41 of the baffle device 40 intersect to form a torpedo-like tip 13. The circular cutout 45 forms a central hole 46 aligned with the transfer channel 20 of the electrode assembly guide 16 when all eight wedge-shaped separator devices 40 are secured together by the outer pipe 15 . The baffle means 40 are oriented so that the smooth face 44b of one baffle means 40 is positioned against the face 44a comprising the four distribution grooves 70 of the adjacent baffle means 40, whereby each baffle means 40 forms four distribution channels 70, a total of 32 channels. Each distribution channel 70 is configured to accommodate a particular elongated electrode 60, wherein the electrode 60 protrudes from its respective array of bushings 80 and allows it to move between a first retracted position and a second advanced position (in order to in the same manner as shown in Figures 3 and 4, respectively). In its first retracted position, all electrodes 60 with their distal ends 61 are fully placed in the distribution channel 70 . As the electrode is advanced as part of the deployment sequence, the distal end 61 of the electrode 60 moves out of the distribution channel 70 to protrude from the distal tip 13 . Each electrode is given its own path, and protrudes from the far tip 13 in its own direction as it advances. Thus, by providing 32 electrodes movable between a first retracted and a second advanced position, each electrode having a unique path extending away from the distal tip 13 and terminating in a unique terminal, it is possible as previously described A three-dimensional model of the electrode terminal 60 is generated.

- A circular adapter plate 90 fixedly secured to the proximal end 62 of the elongated electrode 60 and placed adjacent to the proximal end of the electrode assembly guide 16 . The adapter plate 90 is longitudinally movable between a first retracted and a second advanced position. The proximal ends 62 of the elongate electrodes are inserted into the holes 92 of the adapter plate 90 in a pattern similar to that of the electrodes 60 when the electrodes 60 protrude from the guide sleeve 30, and the support sleeve of each electrode is securely secured to the adapter plate 90. . The adapter plate 90 also includes a central hole 93 aligned with the transfer channel 20 of the electrode assembly guide 16 and two guide pins 91 placed on and protruding from the periphery of the adapter plate 90 opposite to each other.

The handle portion 100 includes the following parts:

- A generally cylindrical housing 101, preferably formed of plastic or other suitable material. The housing includes two halves, each having inner and outer surfaces, a proximal end, a distal end, and an intermediate region.

- Deployment slider 102, preferably formed of plastic or similar non-conductive material, and movable in and relative to said housing 101 between a first retracted and a second advanced position. The deployment slider 102 has a proximal end 104 and a distal end 104 and is operatively connected to the adapter plate through two connecting clips 105 . The connecting clip 105 is configured to engage with the guide pin 91 of the adapter plate 90 and is slidably fixed in the groove 109 of the housing 101 . The distal end of the deployment slider includes 32 tabs 106 configured to receive the proximal end 62 of the electrode 60 when the electrode is extended from the adapter plate 90 . The connector 106 is electrically connected to the distal end of a flexible lead (not shown) that conducts electrical pulses from the electrical stimulation generator 120 to the electrodes 60 . The proximal end of the lead wire is connected to a connection plug which constitutes an interface to the electrical stimulation generator 120 . The deployment slider 102 also includes a central hole 107 aligned with the central hole 93 in the adapter plate 90, and two or more finger handles 108 radially protruding away from the outer surface of the housing 101, and perforated in the finger handles 108 middle. The finger grip 108 allows the operator to move the deployment slide 102 between a first retracted position and a second advanced position to advance the electrode 60 . The distal half of the housing 101 is securely secured to the introducer shaft 10 such that the proximal portion of the shaft 10 as well as the adapter plate 90 and the deployment slide 102 are located in the housing 101 . Towards the far part of the inner surface of each half of the housing 101 is a groove 109 configured to accommodate the two connecting clips 105 of the deployment slide 102 . In the proximal extension of the groove 109 is provided a movement control slot 112 (see FIG. 1 ), which extends to the proximal end of each half. The movement control slot 112 is configured to accommodate the two finger handles 108 of the deployment slider 102 and allows longitudinal movement of the slider 102 between a first retracted and a second advanced position. The proximal end of the housing 101 is threaded to receive an end cap 110 which serves the dual functions of closing the handle portion 101 and securing the proximal ends of the two halves of the housing 101 together. Also, one half portion includes an outlet configured to receive the leads 121 , 122 as they extend from the deployment slide 102 .

- An end cap 110 comprising: an outer shell with threads on its inner surface; and an inner support cylinder with a circumference corresponding to the circumference of the inner surface of the housing. The end cap also includes a central hole 111 that aligns with the central hole in the deployment slide 102 and is configured to accommodate the tubing of the drug dispenser.

In use, the connector plug of the device is connected to a suitable electrical stimulation generator 102 . The device 1 is then inserted through a hole in the patient's skull and introduced into the target area of the patient's body/brain. The exact position can be determined by ultrasound, CT, MR or other suitable means, and the correct position of the introducer shaft 10 prior to deployment can be demonstrated in a similar manner. As noted above, in other embodiments, the stimulus generator may be incorporated into the handle portion.

When the correct position of the introducer shaft 10 is obtained, the operator can deliver the appropriate chemotherapeutic agent or a dose of genetic material through the central channel 111, 107, 93, 20 and into the tissue region to be treated. Delivery is performed by inserting the elongated length-adjustable and suitably blunted needle of syringe 115 into the central hole of the end cap and advancing it until no further movement is possible. The operator can then empty the syringe barrel 115 by depressing the syringe plunger, and the liquid in the syringe expels into the tissue to be treated.

The operator may deploy the elongated electrodes 62 in a predetermined manner before, during, or during delivery. Deployment occurs by moving the deployment slide 102 from its first retracted position towards its second advanced position until further movement is prevented by the end of the movement control slot 112 . The movement results in movement of the electrode 60 from the first retracted to the second advanced position. The distribution channel 70 in the distal tip 13 is shaped to provide each individual electrode 60 with a unique, preferably substantially linear path through tissue and a unique termination, and the goal is to be able to form The electrode pattern is large in diameter (or maximum width in a plane perpendicular to the longitudinal axis of shaft 10 ) and can ensure optimal distribution of short and strong pulses and thus obtain an electric field in the tissue to be treated. In a particularly preferred embodiment, the uninsulated electrode tip (distal end 61) is positional and is arranged such that its terminal end at least partially surrounds or encloses the target area of tissue in such a way that distal end 61 describes or forms a spherical/spatial ellipse the periphery. In the preferred embodiment, 32 electrodes are arranged in four layers, each layer having a different diameter, and comprising eight electrodes 60 terminating (distal end 61 ) in a plane perpendicular to the axis of shaft 10 Depicted as a circle pattern.

When deployed, the operator can actuate the electrical stimulation generator 120 to deliver a series of preferably short and intense electrical pulses, such as square wave pulses, to the tissue to be treated. In order to ensure proper distribution of the pulses and thus the electric field in the tissue to be treated (the target tissue), the pulses can be set to change the pattern of a particular electrode 60, which can be modified to suit the regions of the body to be treated and/or the specific cancerous target tissue. anatomy. In one embodiment, the terminals 61 of at least some electrodes 60 are arranged equidistantly with respect to other electrode terminals 61, and at least some pulses are arranged as equidistant pairs of electrodes. Thus, a homogeneous or heterogeneous controllable three-dimensional electric field can be formed in the target tissue.

In yet another embodiment, the tip of the uninsulated electrode 60 may be arranged in such a pattern that its terminal end 61 forms, in a plane taken along the longitudinal axis parallel to the axis 10, an ellipsoid corresponding to that shown by reference numeral E in FIG. 5 or Oval outer contour. In this embodiment, and as further shown in FIG. 9, the 32 electrodes 60 are numbered a-d in substantially parallel order (a being the topmost (with respect to the distal tip 13)/farthest (with respect to the user/surgeon) layer) Arranged in four layers (in a plane perpendicular to the longitudinal axis of shaft 10), each layer includes eight electrodes numbered 1-8, the terminals of which are depicted as ovals perpendicular to the axis of the introducer shaft or circular patterns. In FIG. 9, the top layer a and the bottom layer d of electrode 60 have been deleted for clarity to show layers b(b1-b8) and c(c1-c8).

The efficiency of electroporation can be improved by changing the order in which the control pulses are issued, thereby creating a controlled electric field. In one proposed pulse sequence, at least some pulses are arranged to move from electrodes in layer a to electrodes in layer c arranged equidistantly with respect to the electrodes in layer a, while other pulses are typically split between layers b and d. Move between equal distances of the electrodes. In a particular firing sequence, the pulse travels from the positive electrodes a1 and a2 to the negative electrodes c6 and c5, and at the same time the pulse travels from the positive electrodes b1 and b2 to the negative electrodes d6 and d5, as shown in Figure 10, which only shows The electrode distal end 61 is mentioned, the others 24 are removed for clarity. The pulse will travel the shortest possible distance (assuming uniform resistance in the target tissue), for this purpose the electric field can be shaped and controlled by placing the electrodes so that the firing of electrodes in different layers can be at equidistant positive and negative opposite electrode terminals between parts (61) (terminal electrodes). Thus, an elongated three-dimensional electric field F as shown in FIG. 11 is generated. The location of the electric field can be varied by varying the setup of pulses to otherwise equidistant positive and negative electrodes in an appropriate pattern to cover the largest possible tissue volume.

When the pulse is delivered, the operator can retract the elongate electrode 60 to its first retracted position by moving the deployment slider 102 from the second advanced position to the first retracted position, whereby the electrode retracts to its distal tip. 13 and the device 1 is removable from the patient's body. Optionally, the operator can reset the device after the elongated electrodes 60 have been retracted, potentially allowing multiple pulse applications covering a larger area than a single device insertion.

In each of the above-described embodiments, a separate channel (not shown) or a portion of delivery channel 20 may be used to deliver saline to enhance the electroporation process by increasing tissue conductivity. Physiological saline can also be properly introduced through delivery channel 20 . In each case, suitable means for connecting the channel 20 to the saline surface may preferably be provided at the handle portion 100 .

As mentioned above, the cross-sectional shape of the electrode is preferably substantially circular. However, in other embodiments, other cross-sectional shapes may be used. The diameter and cross-sectional shape of the distribution channels are in any case preferably dimensioned for the desired electrode diameter and cross-sectional shape in order to provide the best possible support for the electrode without restricting its movement from its retracted position to Its extended position (and rear) capabilities.

In each of the above embodiments, the electrode diameter is preferably 0.4 mm or less, eg 0.3 mm, 0.25 mm including an electrically insulating coating. The diameter of the electrode 60 is generally related to the stiffness of the electrode, such that the thicker the electrode, the stiffer the electrode. For some applications, stiff electrodes may be required, for example, if the tissue is tough. In soft tissue, electrodes with less stiffness can be used.

The tip of the electrode can also be configured, depending on the application, so that it can cut through tissue or it can be smooth to spread out the tissue more gently.

Furthermore, the electrode may be biased (eg pre-stretched) in such a way that its geometry in the extended state changes to the extent that it has been extended beyond the distal tip 13 of the shaft 10 . This can be used by providing the electrode 60 with different stretch properties along the length of the electrode. Thus, a very flexible electroporation device can be obtained.

In the above description and in the figures, the transfer channel 20 has been shown concentrically arranged in the shaft 10 . However, the transfer channel 20 can be arranged asymmetrically in the shaft with respect to its cross-sectional position. In other embodiments (not shown), the single transfer channel 20 may be replaced by a plurality of smaller transfer channels each having an outlet at the tip 13 . A more uniform distribution of the injected therapeutic molecule solution can thereby be achieved.

Surgical tools and the like may be inserted through delivery channel 20 as described above. The invention also relates to the combination of an electroporation device having a delivery channel according to any of the above embodiments and a therapeutic molecule solution injection device. The therapeutic molecule solution injection device includes an elongated hollow portion adapted for delivery channel 20 and a steerable outlet port. The elongated hollow portion is of such a length that the steerable outlet port can extend beyond the tip 13 of the electroporation device. The steerable outlet port can be used to administer a dose of the therapeutic molecule solution in a precise location in the target tissue.

Alternatively, or in addition to being combined with a therapeutic molecule solution injection device, the electroporation device may have a steerable tip 13 . This can be provided by having a control rod or cord extending through the shaft 10 to a tip 13, which is for example pivotally mounted at the distal end of the shaft 10, either about an axis of elongation parallel to the shaft or perpendicular to (or at) other angles) the axis of the shaft pivots. The degree to which the tip 13 is maneuverable will of course depend on the stiffness of the electrodes and the flexible alignment between the channel 50 in the shaft and the channel 70 in the tip 13 . By providing a steerable tip 13, the flexibility and reach of the electroporation device can be provided, also due to the large target tissue volume, a single entry hole/channel formed by the shaft 10 through the surrounding (healthy) tissue is a must of. Thus, the reach of the electrode can be enlarged by rotation of the tip 13 or a combination of rotation of the shaft and rotation of the tip 13 (when the electrode is in the retracted position in the shaft). The applied electric field can thereby be reset sequentially until the entire target tissue is covered. Also, the direction of the outlet of the delivery channel can be changed to provide more precise delivery of the therapeutic molecule solution. The steerable tip 13 can be combined with the therapeutic molecule solution injection device described above to further enhance the reach and flexibility of drug delivery. However, the steerable tip 13 can also be used in embodiments without delivery channels, ie embodiments suitable for symmetrical introduction of drugs by irreversible electroporation.

The electrodes can also be prepared/covered/infused with medicines or DNA molecular compounds that are soluble in the electric field. Thus, when an electric field is applied to the target tissue through the electrodes, medicines and the like can be released from the electrodes. The transfer channel 20 can thus be omitted. However, drug-infused electrodes may also be used with embodiments having delivery channels 20 to release multiple drugs or to save delivery channels for, for example, electric field enhanced saline as described above.

Claims (26)

1. An electroporation device (1), comprising: handle part (100); an elongated introducer shaft (10) connected to said handle portion (100), said introducer shaft (10) having a distal tip (13); and A set of electrodes (60) having respective electrode distal ends (61), each electrode (60) being slidably disposed on said introducer shaft (10) and said distal tip (13) from a retracted position to an exposed position ), wherein, in the retracted position, the electrode distal end (61) is enclosed within the introducer shaft (10), and in the exposed position, the electrode distal end (61) is removed from the distal tip (13) extend out; Wherein, the electrode distal end (61) can deviate from the longitudinal axis (L) of the shaft (10) when deployed/extended to its extended position, so that a pair of electrode distal ends ( 61) the distance (D1) projected in at least one of the planes perpendicular to said longitudinal axis (L) is greater than the maximum width (D2) of the cross-section of said introducer shaft (10), said transverse a section taken along a plane perpendicular to said longitudinal axis (L) at the distal end (11) of said introducer shaft (10); wherein, when in its extended position, deflection of said electrode distal end (61) of said electrode (60) is provided by bending of a distribution channel (70) formed in said distal tip (13); wherein said distal tip (13) is formed in a substantially smooth circular non-cutting shape with a substantially smooth non-cutting transition to said introducer shaft (10); and Wherein, said electrode distal end (61) extends to the distal end of said distal tip (13) in a completely linear path. 2. The electroporation device (1) according to claim 1, comprising at least ten electrodes (60). 3. The electroporation device (1) according to claim 1, wherein electrical pulses are transmittable from one electrode (60) of the device (1) to the other electrode (60). 4. The electroporation device (1) according to claim 1 or 2, wherein the introducer shaft (10) further comprises a delivery channel (20) through which a dose of therapeutic molecules can be delivered to The delivery channel (20) extends throughout the length of the shaft (10) and terminates through the distal tip (13). 5. The electroporation device (1) according to claim 1, wherein the distal tip (13) is detachable from the introducer shaft (10). 6. The electroporation device (1) according to claim 1 or 2, wherein each of the electrodes (60) is advanceable individually or in groups to its extended position. 7. The electroporation device (1 ) according to claim 1 or 2, wherein the electrodes (60) are extendable such that the electrode distal ends (61 ) form a spatial distribution around a volume of target tissue. 8. The electroporation device (1 ) according to claim 7, wherein the electrodes (60) are extendable such that the electrode distal ends (61 ) form a substantially spherical distribution pattern. 9. The electroporation device (1) according to claim 7, wherein said subset of electrodes (60) is extendable such that said electrode distal ends (61 ) are extended parallel to said longitudinal axis An ellipsoidal pattern (E) is formed in the plane of (L). 10. The electroporation device (1) according to claim 1 or 2, wherein the electrode (60) is slidably arranged in an electrically insulating guiding channel (50). 11. The electroporation device (1) according to claim 1 or 2, wherein said electrode (60) is provided with an electrically insulating coating, the outermost portion of said electrode distal end (61 ) of said electrode (60) The far part is uninsulated to form a point electrode. 12. The electroporation device (1) according to claim 4, wherein said delivery channel (20) is a central delivery channel connectable to an external therapeutic molecule delivery system (115), said external therapeutic molecule delivery system (115) comprising a therapeutic molecule reservoir and pumping means for administering said therapeutic molecule through said central delivery channel. 13. The electroporation device (1) according to claim 4, wherein the handle portion (100) comprises a therapeutic molecule delivery system comprising a therapeutic molecule storage and a device for passing through the delivery channel ( 20) An actuation device for administering said therapeutic molecule. 14. The electroporation device (1 ) according to claim 4, wherein the device (1 ) is further adapted to introduce a surgical tool or an ultrasound probe through the delivery channel (20). 15. The electroporation device (1 ) according to claim 1 or 2, wherein the introducer shaft (10) has a circular cross-section with an outer diameter (D2) of 15 mm or less. 16. The electroporation device (1) according to claim 1 or 2, wherein the introducer shaft (10) comprises an outer tube (15) and an inner electrode assembly guide housed in the outer tube (15) device (16), and wherein said electrode (60) is slidably disposed in an electrode guide channel (50) formed in said inner electrode assembly guide (16). 17. The electroporation device (1) according to claim 16, wherein the electrode guide channel (50) is formed with a set of cylindrical guide sleeves (30), and the set of cylindrical guide sleeves (30) ) are housed in longitudinal semi-open channels (17) distributed radially along the outer circumference of said internal electrode assembly guide (16). 18. The electroporation device (1 ) according to claim 17, comprising 32 electrodes (60). 19. The electroporation device (1) according to claim 18, wherein the electrodes (60) are slidably arranged in four groups of guide channels ( 50). 20. The electroporation device (1) according to claim 1, wherein each electrode (60) is individually arrangeable such that the emission of electrical stimulation can be provided from an individual electrode (60). 21. The electroporation device (1 ) according to claim 20, wherein an electrical stimulation generator is incorporated into the handle portion (100) of the device (1 ). 22. The electroporation device (1 ) according to claim 20, having means for connecting the electrodes (60) of the device (1 ) to an external electrical stimulation generator. 23. The electroporation device (1 ) according to claim 1 or 2, wherein the introducer shaft (10) has a circular cross-section with an outer diameter (D2) of 10 mm or less. 24. The electroporation device (1 ) according to claim 1 or 2, wherein the introducer shaft (10) has a circular cross-section with an outer diameter (D2) of 5 mm or less. 25. An electroporation system, said system comprising an electroporation device (1) according to any one of claims 1-20, and an electrical stimulation generator, wherein said system is adapted to pass Application of a series of electrical pulses between electrodes (60) provides an electric field in the target tissue to provide temporary cell membrane permeabilization of cells in the target tissue. 26. An electroporation system, said system comprising an electroporation device (1) according to claim 21 or 22, wherein said system is adapted by applying a series of The electrical pulses provide an electric field in the target tissue to provide temporary permeabilization of cell membranes of cells in the target tissue.

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