Electroporation Device

Abstract

A pulsed electric field delivery device (1) for delivering electroporation treatment to cancerous and precancerous regions of the gastrointestinal tract is described. The pulsed electric field delivery device (1) has a first extension body (3) nonconductively coupled to a second extension body (4), the nonconductive coupling (5) allowing elements of the extension body to seat on opposite sides of the tissue across which the pulsed electric field is applied. An elongated shaft (6) has a proximal end that extends outside the patient so that the user can advance and withdraw the device when needed. The device also includes an elongated member or sheath (2) that can be advanced over and retracted from the distal end of the device, providing protection during device movement. The electrodes (3, 4) are positioned to radially expand and approach each other to sandwich the diseased tissue being treated.

Description

[Technical field]

[0001] The present invention is in the field of electroporation.

[0002] It is an object of the present invention to achieve improved access and delivery of electroporation treatments to the body, primarily, but not exclusively, in lumens. One example is the treatment of tumor tissue with electroporation in the gastrointestinal lumen. [Background technology]

[0003] Existing devices for intraluminal electroporation delivery suffer from the problem of being unable to fully access the lumen due to tumor obstruction which prevents visibility, access and passage for an endoscope.

[0004] Intraluminal tumors can extend for several centimeters in length and cover the entire circumference of the lumen. Disease progression and application of existing treatment modalities can induce damage to the surrounding tissue, resulting in scarring and narrowing of the lumen. This reduces the function of the lumen and severely limits endoscopic access. The extension of malignant tissue throughout the lumen presents a high risk of perforation or laceration, leading to emergency surgery with associated high mortality.

[0005] Electroporation has been established as a safe and effective clinical tool to permeabilize cell membranes, allowing rapid passive diffusion and targeted absorption of therapeutic agents. However, application of an electric field within a lumen is extremely challenging.

[0006] Affixation and placement of two or more electrodes presents challenges within the lumen where access is limited and placement of a needle electrode(s) is impractical, and, even if achievable, may not ensure total coverage of the desired treatment area.

[0007] Existing alternative treatments, including tissue ablation (e.g., radiofrequency ablation, microwave ablation, cryoablation), are associated with damage to tissue structures, including blood vessels and nerves, and with the risk of unintended fistula formation. Therefore, when these treatments are used, they are often used sparingly in their application to avoid inadvertent damage, which conflicts with the physician's desire to remove or ablate all of the bad tissue to prevent recurrence in the case of cancer or precancerous tissue treatment. Electroporation leaves the existing extracellular matrix and tissue structures intact, and therefore does not have these associated risks. Although its incorporation into the body has been limited so far by the tools available for its delivery and targeting, electroporation has been most effectively applied so far when electrodes can be placed on both sides of the intended treatment zone. Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention addresses these problems. [Means for solving the problem]

[0009] The present invention provides an electroporation probe according to any of the probe claims appended hereto, an electroporation device according to any of the device claims appended hereto, and an electroporation treatment method according to any of the method claims appended hereto.

[0010] The inventors have described an electroporation probe comprising an elongate support, the support comprising electrical conductors and configured to extend from a proximal end to a distal end through a lumen of a human or animal body extending longitudinally about a longitudinal axis, the support supporting at least two electroporation electrodes connected to the conductors and mounted to engage tissue within the wall of the lumen in use, and an electrode actuator.

[0011] In some instances, at least one electrode is deformable for radial expansion from a retracted position. In some instances, the probe includes a plurality of longitudinally spaced electrodes, the radial expansion causing surfaces of a pair of electrodes to longitudinally approach one another via radial expansion, thereby contributing to grasping tissue protruding into the lumen.

[0012] In some examples, at least one electrode has a central radial tip at a central region and has an actuation configuration that is tapered on each longitudinal side of the central region.

[0013] In some examples, the probe includes a spacer between the juxtaposed electrodes that prevents movement of each electrode closer to the other in the longitudinal axis, and the proximal end of the proximal electrode and the distal end of the distal electrode (4) are each coupled to an actuator that moves the ends toward each other to compress the electrodes against the spacer.

[0014] In some instances, at least one of the electrodes has shape memory and is configured for at least a portion of said radial expansion when the constraint is removed.

[0015] In some examples, the actuator is configured such that axial compression of at least one electrode forces at least a portion of the radial expansion. In some examples, the electrodes have a preferred expanded shape memory state to induce an initial radial expansion, and the actuator is configured to effect further radial expansion.

[0016] In some examples, the actuator is configured to allow a user to sense the level of force required by the actuator to effect radial expansion, thereby providing a user indication of when tissue is engaged and how far the tissue will be pushed by said further radial expansion.

[0017] At least one electrode is configured for radial expansion to dilate soft, pliable tissue without dissecting or perforating, but to apply a radial force to accommodate harder, strictured tissue, the force being less than 0.1 N / mm 2 ~1N / mm 2 is within the range.

[0018] In some examples, the electrodes or the expandable body to which the electrodes are attached are formed from laser cut tubing that is heat set into a preferential expanded shape to which it will return below body temperature if unconstrained. At least one electrode comprises a mesh having a 1-over-1-under-1 strand braid pattern of strands having diameters in the range of 0.02 mm to 0.25 mm diameter. In some examples, the electrode comprises a plurality of strands in the range of 8 to 96.

[0019] In some examples, at least one electrode comprises a mesh comprising a structural layer of 8-24 wires having a diameter in the range of 0.15 mm to 0.35 mm and a thin layer of 24-96 wires having a diameter in the range of 0.01 mm to 0.1 mm. In some examples, the longitudinal length of at least one electrode is in the range of 0.5 mm to 75 mm.

[0020] In some examples, the longitudinal distance between the at least two electrodes is in the range of 1 mm to 40 mm, optionally 2 mm to 20 mm.

[0021] In some instances, the probe comprises at least two electrodes of different stiffness configured for different levels of penetration into tissue.

[0022] In some examples, at least one electrode is attached to or forms an expandable mesh, the expandable mesh comprising: A metal wire having a diameter in the range of 0.1 mm to 0.35 mm to provide rigidity to the mesh; and Metal wires with diameters in the range of 0.01mm to 0.1mm for mesh flexibility has.

[0023] In some examples: The probe is for treatment of the GI tract and has a maximum diameter after radial expansion in the range of 30 mm to 60 mm; or The probe is for treatment of the urethra and has a maximum diameter after radial expansion in the range of 10 mm to 15 mm; or The probe is for treatment of the bile duct and has a maximum diameter after radial expansion in the range of 4 mm to 10 mm.

[0024] In some instances, at least one electrode is attached to the expandable body for movement between the contracted position and the actuated position.

[0025] In some instances, the expandable body comprises an expandable mesh. In some instances, the expandable body comprises a mesh comprising at least two elements of different diameters and / or strengths.

[0026] In some instances, the expandable body comprises a balloon to which the electrodes are attached.

[0027] In some examples, at least one electrode comprises a feature for extending radially into tissue during use. In some examples, the feature comprises a barb or needle, and the laser cut tube has a barb feature as part of its laser cut pattern, and optionally, one or more needle(s) may be coated. In some examples, at least one needle is coated.

[0028] In some examples, the probe comprises a physical separator between axially juxtaposed electrodes. In some examples, the probe comprises at least four axially separated electrodes, with a separator between each successive electrode and the next. In some examples, the probe comprises proximal and distal barrier balloons that, in use, define a space enclosing at least two expandable bodies, the space for enclosing a fluid agent introduced into the space to assist in electroporation.

[0029] In some instances, the probe further comprises an internal balloon that can be expanded to a desired extent to adjust the volume of the space.

[0030] In some instances, the inner balloon is positioned to act as an insulating spacer between the apposed balloons. In some instances, the probe comprises a spacer between the axially spaced electrodes, the spacer comprising a plurality of parallel spacer elements.

[0031] In some instances, at least one electrode has an actuation position that is further from the longitudinal axis than an actuation position of another electrode, the electrodes overlapping on the longitudinal axis but not touching each other.

[0032] We also describe an electroporation device that includes a probe as described in any embodiment and an electrical driver for delivering pulses to the electrodes via conductors.

[0033] In some examples, the electrical driver is configured to independently apply a variable voltage, preferably from a generator linked to the proximal end of the probe, hi some examples, the electrical driver is configured to provide pulses that are matched to or specific to the electrode location.

[0034] In some examples, the actuator is configured to move the electrodes to an intermediate position between the contracted position and the actuated position, and the electrical driver is configured to provide pulses that correspond to the intermediate electrode positions. In some examples, the driver allows for selective activation of specific electrodes.

[0035] In some instances, the device comprises an endoscope and the probe has a lateral dimension in a retracted position that allows for entry into the body through an endoscope instrument channel.

[0036] In some examples, at least some of the electrodes are axially movable, and the actuator is configured to move at least one electrode to optimize electrode spacing.

[0037] In some examples, the probe includes a strain gauge or pressure sensor for providing feedback during electrode actuation, the sensor being configured to provide feedback regarding the force required to displace the diseased tissue.

[0038] In some examples, the probe comprises a balloon-expandable body to which at least one electrode is attached, and the actuator comprises a handle adapted to enable a user to feel the force required to inflate the balloon.

[0039] In some examples, the actuator comprises a mechanism and a user handle that is movable by a force related to the resistance to radial expansion of the electrodes.

[0040] In some examples, the probe includes a safety device that prevents the actuator from exerting excessive force. In some examples, the probe includes a sensor for sensing patient tissue and / or for sensing electrode position, and the actuator is in contact with the tissue but is capable of exerting a force of less than 1 N / mm on the tissue. 2to a position where the electrode does not exert a force exceeding 100 Hz to reduce the possibility of tissue incision, and optionally the sensor comprises a strain gauge.

[0041] In some instances, the probe includes a sensor that provides electrical feedback to a system such as an electrical driver for the electrode or an extension body.

[0042] In some examples, the probe includes a distally extending conduit for delivery of fluid at or near the electrodes. In some examples, the device includes a fluid controller for controlling delivery of fluid through the conduit. The controller may be configured to control the fluid delivery according to the position of the electrodes. The electrical driver may be configured to control the drive pulses according to the delivery of the fluid, e.g., according to the timing and electrical properties of the fluid. The fluid controller may be configured to provide delivery of any one or more of a foam and a liquid, the fluid may include a therapeutic agent.

[0043] The electrical driver may be configured to vary the pulse voltage according to sensed parameters including one or more selected from electrode position, electrical conductivity of the region of the electrode, and treatment timing regimen. The fluid controller may be configured to effect administration of bubbles both directly to the tissue and to the surface area surrounding the device.

[0044] The foam may contain a cationic solution, such as lidocaine HCL, to reduce the electric field strength required for electropermeabilization of the cell membrane.

[0045] The inventors also describe a method of using the device, which includes inserting a probe along a lumen of a human or animal body until an electrode is positioned longitudinally of the tissue to be treated, and activating the electrode to perform electroporation treatment of the tissue.

[0046] In some examples, the probe includes a plurality of longitudinally spaced electrodes, the probe being positioned to provide an electric field in a region between two of the electrodes for treatment of tissue in said region. The electrodes may be advantageously moved radially to an expanded position in which the electrodes are closer to one another resulting in pinching of tissue in said region. The tissue may be a precancerous nodule polyp.

[0047] In some instances, the probe is moved to a series of multiple longitudinal positions and the electrodes are activated at each of the longitudinal positions, the positions being selected so that there is a desired level of overlap in the area to be treated to achieve a desired level of electroporation in each area. The degree of overlap may be selected to achieve RE or IRE.

[0048] Fluid can be injected into the region between the two spaced apart electrodes to enhance electroporation in said region.

[0049] The inventors have also described an electroporation probe having an elongate support having an electrical conductor and extending from a proximal end to a distal end, the support supporting at least two electroporation electrodes connected to the conductor and mounted to engage tissue within the wall of a lumen in use.

[0050] Preferably, the probe comprises an actuator for moving the electrode in a direction having a radial component from a contracted or collapsed position to an actuated position for contacting the tissue. The probe may be part of a medical pulsed electric field delivery device for delivering electroporation treatment to tissue in a cancerous or pre-cancerous region of a lumen, such as the gastrointestinal tract. Preferably, the extending body of the electrode is configured to engage the tissue with sufficient force to ensure that electrical contact between the electrode and the tissue is maintained during delivery of the pulsed electric field electroporation.

[0051] Preferably, the expanding body of the electrode is configured to conform to rigid and inflexible tissue structures rather than forcing the tissue structures to move or compress, thus ensuring that the electrode does not result in perforation or dissection of the luminal tissue, while at the same time ensuring that there is a large contact area between the electrode and the tissue. When the tissue structure is flexible / compliant, the electrode stretches the tissue to ensure proper contact.

[0052] The probe can have multiple electrodes. The electrodes can be movable by being attached to, engaged by, or being an integral part of the expansion body. The expansion body can include a balloon.

[0053] When multiple electrodes are present, the electrodes may be mounted on radially opposing sides for contacting tissue to which the pulsed electric field is applied. Preferably, the electrodes are arranged to collapse during delivery of the device into the lumen. In one example, the actuator is configured to move the electrodes to an intermediate position between the retracted position and the actuated position. Preferably, the probe has a lateral dimension to allow entry into the body through an endoscope instrument channel. The probe may comprise an expandable body supporting the electrodes.

[0054] The expandable body can comprise an expandable metal wire mesh. Such a mesh can be made of stainless steel wire or a shape memory alloy such as Nitinol. The expandable body can comprise a polymer mesh with attached or overlaid conductive elements that act as electrodes. Preferably, the expandable body comprises a material that can deform during actuation without undergoing plastic deformation that affects the ability of the device to be repeatedly actuated from its collapsed configuration to its expanded configuration.

[0055] At least one expansion body may be formed from a laser cut tube, such as a Nitinol tube, preferably heat set into a preferred expanded shape to which it will return at or below body temperature if unconstrained. The tube may be held in its collapsed configuration by a user-controlled elongated member, which may comprise a pull wire attached to one end of the heat set Nitinol that holds the collapsed frame until such time as the user allows the frame to return to its preferred shape.

[0056] In another embodiment, the expansion body (such as a laser cut tube or wire mesh) is not heat set to a preferred expanded state, but rather may be actuated to such state as a result of the mechanical configuration of the body through positive action by the user. This may be accomplished through movement of a pull or push wire or tubular member. In these situations, if Nitinol is used, it may be used primarily for its superelastic properties that allow it to experience increased localized strains such as those found during delivery through tortuous anatomical structures, such that it will remain functional after delivery without permanent deformation of its structure. To accomplish this, the Active Austenite Finish Temperature (AAFT) of Nitinol must be properly adjusted so that the material functions within its superelastic temperature window at the temperatures at which the device will be used in its operating environment.

[0057] In yet another embodiment, the movement from the collapsed state to the expanded state for the expanding body is some combination of the heat set shape and mechanical configuration of the body. Preferably, the actuator comprises a sheath that restrains the heat set tube until such time as the user allows the heat set tube to return to its preferred shape to allow expansion of the heat set tube to the actuated position.

[0058] The nitinol mesh can have a preprogrammed (stored) expansion configuration to guide the shape and position of the expandable body (a) upon initial delivery and (b) as the body is further expanded. Programming the expandable body will help maintain optimal electrode gap, and thereby optimal electric field, and also optimal tissue engagement, as it expands. In yet another embodiment, the preprogrammed expansion configuration can have a shape that ensures that inter-electrode distance is adequately maintained regardless of the diameter to which the device is deployed.

[0059] In some instances, the probe comprises a set of multiple longitudinally spaced electrodes, at least some of which may be movable relative to the next to optimize electrode spacing and ensure proper tissue contact.

[0060] In some examples, there are multiple electrodes and at least one electrode has an actuation position further from the longitudinal axis than an actuation position of another electrode, hi one example, the electrodes overlap on the longitudinal axis but do not touch each other.

[0061] Preferably, the electrodes and / or the expansion body are configured to draw the tissue to be treated between the electrodes to the activated position of the electrodes during expansion of the electrodes. In one example, the electrodes and / or the expansion body are configured to sandwich the tissue between the electrodes.

[0062] In one example, the expansion body comprises a balloon and the electrodes are embedded in or on the balloon surface. In one example, at least one electrode and / or the expansion body comprises features for extending into tissue during use, the features comprising, for example, barbs or needles. In one example, a laser cut tube has barb features as part of its laser cut pattern. The needle or needles may be partially or completely coated.

[0063] Preferably, the probe comprises a sensor for providing feedback during electrode actuation. In one example, the sensor is configured to provide feedback regarding the force required to displace diseased tissue. The probe may be configured to provide tactile feedback to the user so that the user can feel the increase in force required to actuate the electrode from its collapsed configuration to its expanded configuration as the electrode displaces diseased tissue.

[0064] In one example, the expandable body comprises a balloon and the actuator comprises a handle adapted to allow a user to feel the force required to inflate the balloon, hi one example, the actuator comprises a mechanism and a user handle that is movable by a force related to the resistance provided by the tissue being treated to the expansion of the expandable body.

[0065] In one example, the mechanism has low friction between the moving members such that the force required is consistently low when the body is actuated from the collapsed configuration to the expanded configuration while unconstrained, hi one example, the actuator is configured to limit the mechanical advantage such that the user can perceive a ramp-up in the force required to effect expansion of the expandable body.

[0066] In one example, the probe may be constructed so that the user can feel the increase in force required to actuate the electrode from its collapsed configuration to its expanded configuration as it displaces diseased tissue. In practice, achieving this through design depends on the choice of user-actuated handle; for example, if this applies to balloon-driven expansion and a syringe-style handle is used, the user will feel the force required to inflate a balloon provided through the lumen in which the inflation medium is sufficiently rigid and does not introduce "noise" itself. Achieving this through mechanical actuation similarly requires that the designer use a suitably rigid material to transmit the actuation force and desirably achieve low friction between all moving parts, so that when actuated from the collapsed configuration to the expanded configuration, the force required while the device is in free gas is consistently low. It is also desirable to limit the amount of mechanical advantage given to the user during the design of the actuation handle, since it will correspondingly reduce the user's ability to perceive the ramp-up of the force the user needs to apply to expand the expansion body.

[0067] In one example, the probe is constructed such that the user can feel the force required to actuate one or more electrodes from their collapsed configuration to a partially expanded configuration, thereby allowing the user to determine that the electrodes are sufficiently expanded against the tissue, such as to create a reliable contact area with said tissue for delivery of an electrical pulse, with the understanding that further expansion may result in undesirable effects on the lumen, such as dissection or perforation. This can facilitate the end user achieving successful and safe treatment of areas that cannot be directly visualized via the visual guidance of the endoscope's camera, or are indirectly visualized using x-ray guidance. If the end user feels sufficiently comfortable using this treatment mode, this will allow treatment in a wider range of treatment settings, including emergency outpatient settings.

[0068] In one example, the probe may be configured such that electrode actuation is mechanically or pneumatically connected such that during electrode actuation, the electrodes expand to different diameters depending on the lumen diameter and tissue stiffness surrounding the individual electrodes, and thus the user senses a combined force feedback from the group of electrodes while performing the actuating action.

[0069] In one example, the probe includes a safety device that prevents application of force by the actuator beyond a limit, which limit can be user defined. In one example, the probe includes a channel extending distally for delivery of fluid, preferably at or near the electrode.

[0070] In one example, the probe includes a sensor that provides electrical feedback to a system such as an electrical driver for the electrode or an extension body, In one example, the probe includes a sensor for sensing patient tissue and / or transmitting electrode position, and an actuator configured to move the electrode to a position in contact with the tissue but not exerting a force against the tissue to reduce the possibility of tissue dissection.

[0071] The inventors also describe an electroporation device comprising an electrical driver for supplying pulses to the electrodes via the probe and elongated supporting conductor of any of the examples described herein. The electrical driver may be configured to independently apply a variable voltage, preferably from a generator linked to the proximal end of the probe.

[0072] In one example, the electrical driver is configured to provide a pulse that is adapted to or specific to the electrode position, hi one example, the actuator is configured to move the electrode to an intermediate position between the contracted position and the actuated position, and the electrical driver is configured to provide a pulse that is adapted to the intermediate electrode position.

[0073] The actuator may be user operable or in other examples the actuator is automatic. The driver may allow selective activation of specific electrodes. The device may comprise a conduit for the supply of fluid through the elongate support. The device may comprise a fluid controller for controlling the supply of fluid through said conduit. The controller may be configured to control the fluid supply according to the position of the electrodes. Preferably the electrical driver is configured to control the drive pulses according to the supply of fluid, for example according to timing and electrical properties of the fluid.

[0074] The fluid controller may be configured to provide any one or more of a supply of foam and liquid. The fluid may include a therapeutic agent.

[0075] Preferably, the electrical driver is configured to vary the pulse voltage according to sensed parameters including one or more selected from electrode position, electrical conductivity in the region of the electrode, and treatment timing regime.

[0076] In various examples, the expansion body is configured to engage tissue with sufficient force to ensure that electrical contact between the electrode and the tissue is maintained during delivery of pulsed electric field electroporation.

[0077] In various examples, the expander body is configured to conform to rigid, inflexible tissue structures.

[0078] In various examples, the expansion body includes a material that can deform during actuation without undergoing plastic deformation.

[0079] In various examples, the expansion body comprises a mesh having a shape-memory expansion configuration to guide the shape and position of the expansion body during initial delivery and as the body is further expanded to maintain an optimal electrode gap.

[0080] In various examples, the expanded configuration has a shape that ensures that inter-electrode distance is maintained sufficiently regardless of the diameter to which the device is deployed.

[0081] In various examples, the probe comprises a set of multiple longitudinally spaced electrodes, with at least some of the electrodes movable relative to the next to optimize electrode spacing and ensure proper tissue contact.

[0082] In various examples, the probe is adapted to provide tactile feedback to enable the user to feel the force required to actuate one or more electrodes from their collapsed configuration to at least a partially expanded configuration.

[0083] In various examples, the electrodes are mechanically or pneumatically connected to provide tactile feedback.

[0084] In various examples, the expansion body comprises a mesh network of material such as nickel titanium alloy, nitinol, braided strands, etc., to achieve a basket configuration that can be collapsed by pulling the mesh ends in opposite directions using an attached cuff. In various examples, the mesh is constrained in a 1-over-1-under-1 pattern. In various examples, the expansion body comprises a 1-over-1-under-1 strand braid pattern with a diameter in the range of 0.02 mm to 0.25 mm diameter, preferably 0.1 mm to 0.2 mm diameter.

[0085] In various examples, the expander body comprises wires of two or more different diameters or materials, one diameter or material providing the required strength for the body for operation while the other diameter or material provides more flexible, more tightly packed, conforming characteristics for the expander body to ensure optimal tissue contact. In various examples, the expander body is diametrically oversized for the intended treatment lumen by 20%-800%, preferably 20%-500%.

[0086] In various examples, the expansion body is oversized for the target conduit, and this contact area expands axially as the electrode is further actuated from the collapsed state to the expanded state, creating an annular-cylindrical contact area that allows for a greater delivery of energy to the lumen, and therefore the opportunity for a larger electroporation volume.

[0087] In various examples, the extension body comprises strands of material, such as Nitinol, that are configured to undergo a heat curing step during its production that imparts a preferred electrode shape with desirable attributes to the extension body.

[0088] In various examples, the probe further comprises a physical separator between the axially juxtaposed expanding bodies. In various examples, the probe comprises at least four axially separated expanding bodies, with a separator between each successive body and the next.

[0089] In various examples, the probe includes proximal and distal barrier balloons that, in use, define a space enclosing at least two expansion bodies, the space being for enclosing a fluid agent introduced into the space to assist in electroporation. In various examples, the probe further includes an internal balloon for adjusting the volume of the space by expanding to a desired extent. In various examples, the internal balloon is positioned to act as an insulating spacer between the juxtaposed balloons.

[0090] In various examples, the probe includes at least two expansion bodies of different stiffness configured for different levels of penetration into tissue, the difference being responsive to individual adjustment of each body by an actuator.

[0091] In some instances, the expansion bodies are expanded by the action of a single user, but the expansion body control methods are linked such that when expanding to contact tissue, one or more expansion bodies can reach a larger expanded diameter than one or more other expansion bodies as a result of balancing the forces applied to the expansion bodies by the tissue.

[0092] In some instances, expansion body actuation may be independently controlled by the user, allowing user control over individual electrode expansion diameters.

[0093] The invention will be more clearly understood from the following description of some embodiments of the invention, given by way of example only, with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0094] [Figure 1] Figure 1(a) is a side view of an electroporation probe of the present invention in a partially expanded state with a delivery sheath retracted, Figure 1(b) is a view of the device in a collapsed state, and Figure 1(c) is a pair of views showing movement of an expansion element and corresponding tissue capture. [Diagram 2] FIG. 11 is a pair of diagrams showing how the conceptual area electroporated by the electric field changes when a pulse is delivered in the fully collapsed state, and the change when in the fully expanded state. [Figure 3(a)] FIG. 1 shows one stage of the complete treatment of a portion of a lumen in seven stages from device introduction to pulse application. [Figure 3(b)] FIG. 1 shows one stage of the complete treatment of a portion of a lumen in seven stages from device introduction to pulse application. [Figure 3(c)] FIG. 1 shows one stage of the complete treatment of a portion of a lumen in seven stages from device introduction to pulse application. [Figure 3(d)] FIG. 1 shows one stage of the complete treatment of a portion of a lumen in seven stages from device introduction to pulse application. [Figure 3(e)] FIG. 1 shows one stage of the complete treatment of a portion of a lumen in seven stages from device introduction to pulse application. [Figure 3(f)] FIG. 1 shows one stage of the complete treatment of a portion of a lumen in seven stages from device introduction to pulse application. [Figure 3(g)] FIG. 1 shows one stage of the complete treatment of a portion of a lumen in seven stages from device introduction to pulse application. [Figure 4] Figure 4(a) is a side view diagram without barbs to show the difference in field size as a result of the addition of barbs / tines to an extended body, and Figure 4(b) is a side view diagram with barbs to show the difference in field size as a result of the addition of barbs / tines to an extended body. [Diagram 5] Figure 5(a) is a diagram showing an example of an electrically connected extension body for an electroporation probe of the present invention, which is a wire mesh, Figure 5(b) is a diagram showing an example of an electrically connected extension body for an electroporation probe of the present invention, which is a laser cut tube, and Figure 5(c) is a diagram showing an example of an electrically connected extension body for an electroporation probe of the present invention, which is a balloon with a conductive overlay or embedment. [Figure 6] 1 is a diagram showing a single balloon acting as an expansion body to expand two separate electrodes. [Figure 7] 1A-1C are top views of laser cut patterns (not to scale) without (left) and with (right) barbs, showing how the barbs are implemented as part of the laser cutting process. [Figure 8] Figure 8(a) shows that the device of the present invention can expand to different extents, and Figure 8(b) shows that the device of the present invention can expand to different extents. [Figure 9]Figure 9(a) is a diagram showing the probe with the radial needle electrodes in its collapsed state, Figure 9(b) is a diagram showing the probe with the radial needle electrodes in its expanded state, and Figure 9(c) is a diagram showing the probe with the radial needle electrodes in its expanded state with the needle electrodes extending outward. [Figure 10] Figure 10(a) is a side view of a device in which the electrically connected extension bodies partially or completely overlap each other along the device centerline and have different radial dimensions, and Figure 10(b) is an end view of a device in which the electrically connected extension bodies partially or completely overlap each other along the device centerline and have different radial dimensions. [Figure 11] FIG. 13 is a side view of an extension basket of another probe of the present invention; [Figure 12] FIG. 13 is a side view of an extension basket of another probe of the present invention; [Figure 13] Figure 13(a) is a perspective view of an alternative probe having, in this case, three extension bodies, and Figure 13(b) is a side view of an alternative probe having, in this case, three extension bodies. [Figure 14] FIG. 13 illustrates a probe in which the expanded body of the device is a mesh made from a non-conductive weave with conductive material interwoven at regular intervals. This is shown in two possible variations showing how the number and position of the conductive elements can be altered. [Figure 15] FIG. 15 shows a probe similar to that of FIG. 14, but axially compressed to half its original length, illustrating how the conductive strands remain parallel to each other and do not touch as a result of the compression. [Figure 16] FIG. 1 is a side view of an expansion body in which there are 20 strands, all of the same diameter. [Figure 17] FIG. 13 is a side view of an expansion body also having 12 strands of the same diameter. [Figure 18]FIG. 13 is a side view of an expansion body having 12 strands of intermediate diameter and 36 strands of smaller diameter providing smaller mesh gaps. [Figure 19] Figure 19(a) is a side view of a series of expanding bodies spaced apart by balloon spacers with short basket-to-basket distances, and Figure 19(b) is a side view of a series of expanding bodies spaced apart by balloon spacers with short basket-to-basket distances. [Figure 20] FIG. 20(a) is a side view of a device having two centrally offset expanded electrode meshes at one of three stages of use with an expanded balloon barrier between the two expanded electrode meshes that limits the shortest inter-electrode distance the tissue will experience during pulse application. FIG. 20(b) is a side view of a device having two centrally offset expanded electrode meshes at one of three stages of use with an expanded balloon barrier between the two expanded electrode meshes that limits the shortest inter-electrode distance the tissue will experience during pulse application. FIG. 20(c) is a side view of a device having two centrally offset expanded electrode meshes at one of three stages of use with an expanded balloon barrier between the two expanded electrode meshes that limits the shortest inter-electrode distance the tissue will experience during pulse application. [Figure 21] FIG. 1 illustrates a probe having a single pair of expansion baskets and separator balloons between the baskets (one balloon proximal to the proximal basket and one balloon distal to the distal basket), where the central separator balloon has a smaller radial extent than the other two balloons. [Figure 22] 11A-11C are schematic side views of the probe in use, where user actuation at the proximal end causes the basket to deform to different degrees relative to the shape of the tissue surrounding it. [Diagram 23] A set of 12 images showing test results arranged as 3 rows of 4 images for 4 mm, 6 mm, and 8 mm diameters, showing the effect of electroporation with a given type of expansion body. [Figure 24]1 is a set of diagrams showing the overall outer extent of the expandable body of the present invention, namely, oval, cone, square, and "dog bone" shapes. [Diagram 25] 1 is a pair of diagrams of the device showing the location of the insulated wires that ensure insulation of the axially separated bodies. [Figure 26] FIG. 13 is a side view of a device in which the spacer comprises a plurality of spacer elements parallel to the longitudinal axis. [Figure 27] FIG. 13 is a side view of a device in which the spacer comprises a plurality of spacer elements parallel to the longitudinal axis. [Figure 28] Figure 28(a) is a side view showing the operation of the device of Figure 1 for the treatment of a nodular precancerous tumor in the intestine, Figure 28(b) is a side view showing the operation of the device of Figure 1 for the treatment of a nodular precancerous tumor in the intestine, and Figure 28(c) is a side view showing the operation of the device of Figure 1 for the treatment of a nodular precancerous tumor in the intestine. [Figure 29] Figure 29(a) is a diagram showing a small area due to a complete irreversible electroporation (IRE) treatment, and Figure 29(b) is a diagram showing a completely overlapping IRE area for continuous IRE treatment along the length of the lumen. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0095] 1-4, an electroporation probe 1 of the present invention for linking with an electroporation electric drive is shown. The probe 1 is for delivering electroporation treatment to cancer and precancerous regions of the gastrointestinal tract. The probe 1 comprises a sheath 2, within which is a shaft 6, within which is a feed wire 7. Two conductive wires (not shown) extend within the shaft 6 to link the electric drive to a set of electrodes on the extension bodies 3 and 4 separated along the longitudinal axis by an insulating spacer 5. The electroporation device of the present invention comprises the probe 1 and an electric drive. The drive can be, for example, a drive described in our published specification WO2021 / 043779, the contents of which are incorporated herein by reference.

[0096] The driver may comprise a main controller linked to a user interface and a probe driver circuit, the controller and interface providing the user side functions while the driver circuit provides pulses to the probe electrodes.

[0097] The drive circuit is a pulse control unit that is isolated from the rest of the drive by an opto-isolator to prevent high voltage from being inadvertently transmitted to the low voltage control electronics; a high voltage generator having a transformer to provide up to 5 kV across the capacitor; a pulse switching controller for delivering high frequency bipolar pulses to the array of seven probe electrodes; Voltage setting and maintenance circuitry Equipped with.

[0098] The touch screen interface is operatively coupled to a drive controller, which manages the generation and pulse control of the high voltages, as well as the voltage, pulse duration, polarity, and orientation. This level of control is achieved by a series of control circuits.

[0099] The controller may, in some examples, provide a ramp-up (t) of less than 0.5 μs to a plateau (U) amplitude in the range of 100 V to 3000 V for a duration in the range of 1 μs to 5 μs. r ) duration, and ramp down from the above voltage (t f The pulses are preferably applied in rapid succession to each electrode at a bipolar frequency of 100 kHz to 500 kHz. The amplitude is in some examples in the range of 700 V to 1600 V, the pulse plateau duration is in the range of 1 μs to 3 μs, and preferably the excitation on-time during which the pulses are delivered is in the range of 100 μs to 300 μs. Preferably, the pulses are delivered in rapid succession. Preferably, the bipolar frequency is in the range of 100 kHz to 500 kHz.

[0100] The switch controller receives a low voltage DC input, for example 48V. This input level sets the resulting pulse intensity level that is supplied to probe 1. The switch controller adjusts the time the transformer primary is energized to control the output voltage on the capacitor. Feedback from the output to the switch controller (with suitable isolation through a medical grade optocoupler device) allows the voltage to be precisely set and maintained. Thus the capacitor output voltage can vary over a wide range (typically from 100V to around 5KV).

[0101] As shown in Figure 1(a), each electrode 3 and 4 is an expanded body having a central radial tip at its central region and a sloped region on each longitudinal side of the central region. Figure 1(b) shows the expanded body when collapsed, and Figure 1(c) shows the bodies 3 and 4 when engaging tissue around a lumen, in this case the GI tract. As is evident from this diagram, the expanded body tends to pinch and engage tissue such that the tissue resides within a notional area or cylindrical area defined by the tips of the expanded body. The top and bottom diagrams of Figure 1(c) show different examples of this.

[0102] The probe can expand within the occluded blood vessel. Preferably, at least one electrode is in the form of or attached to an expansion body (or "expandable body" or "basket") that will expand soft tissue to ensure proper contact between the expansion body and allow the surrounding tissue to enter. In other embodiments, the expansion body is constructed to conform to the rigid, inflexible tissue structure rather than forcing the tissue structure to expand, move, or compress, thus ensuring a large contact area between the electrode and the tissue while at the same time ensuring that the electrode does not perforate or dissect the luminal tissue.

[0103] The basket may be fabricated of Nitinol, utilizing shape memory capabilities to expand upon being unsheathed. However, a more secure expansion may be incorporated into the hand controller, perhaps as a slider or thumbwheel mechanism for actuation. The device may be required to expand to different diameters, from 4mm to 40mm, based on the geometry of the lesion being treated, the stage of cancer the patient has, which depends on the geometry of the lumen being treated, and the geometry of the pre-cancerous tissue, or on the stage of the cancer that affects the tumor geometry. Again, this may be in the form of expansion control by the clinician using a hand control, or a family of devices, each of different sizes performing the same task in a differently occluded conduit. In various examples, the expansion body comprises wires of two or more different materials, one or more of which gives the overall mesh shape but is non-conductive and constrains another one or more materials that contribute to the mesh form to some extent, but act primarily as electrodes through which the electrical pulses are delivered.

[0104] The expansion body may be comprised of any desired number of struts (e.g., members extending from the elongated support, then generally parallel to the longitudinal axis, then back to the elongated support), e.g., 6-192 struts, and the struts may be arranged circumferentially. The axial portions of the struts act as electrodes to deliver the pulses. Within the electrode design, the addition of sensors wired to the electrodes is contemplated. These sensors may include, but are not limited to, impedance sensors, location / device proximity sensors, and temperature sensors, for example.

[0105] The sensor may comprise a strain gauge or pressure sensor to provide feedback during electrode actuation, the sensor being configured to provide feedback regarding the force required to displace the diseased tissue.

[0106] The expansion body may be comprised of a mesh network of nickel titanium alloy and / or nitinol and preferably woven strands to achieve a basket-like configuration that can be collapsed by pulling the mesh ends in opposite directions using an attached cuff. The mesh may be a tightly constrained 1-over-1-under-1 pattern, as is most common in braided tubes, or a less constrained pattern that allows for greater strand freedom, such as a 1-over-2-under-2 pattern that further enhances the mesh's ability to conform to irregular tissue morphology. Mesh expansion bodies utilizing 1-over-1-under-1 pattern braiding may consist of strand diameters ranging from 1 mm to 10 mm diameter, preferably 4 mm to 8 mm diameter. Nitinol strands provide an ideal combination of strength, elasticity, current carrying capacity, and surface area to conform to irregular tissue morphology and deliver pulsed electric field electroporation.

[0107] The expansion body may comprise two or more different wire diameters or materials, one diameter or material providing the strength required for the basket for actuation, while the other diameter or material provides more flexible, more tightly packed, conforming properties for the expansion body to ensure optimal tissue contact. Nitinol wire diameters in the range of 0.125mm to 0.25mm, preferably in the range of 0.15mm to 0.20mm, are desirable to provide stiffness to the mesh basket configuration, while Nitinol wire diameters in the range of 0.025mm to 0.1mm, preferably in the range of 0.025mm to 0.075mm, are desirable to create a flexible mesh with small openings between the larger diameter strands. For example, a basket of 8 0.2mm diameter Nitinol wires and 40 0.05mm diameter Nitinol wires will have the increased strength of including several 0.2mm diameter wires in the basket, with a corresponding smaller wrap diameter and smaller inter-wire gaps as a result of including a greater number of 0.05mm diameter wires than would be possible with the larger wire diameter.

[0108] An additional benefit of using stiffer wires for the overall electrode geometry in conjunction with less stiff wires is the ability of this overall configuration to be fine-tuned to improve the electrode's ability to grip tissue, as the less stiff wires will deform to a certain extent when in contact with tissue during deployment, while the stiffer wires will deform to a lesser extent, creating a surface that interacts with the tissue that can be described as uneven or rough, similar to the addition of grooves to a tire, to improve grip.

[0109] When the expansion body transitions from its collapsed state to its expanded state to contact the target conduit, the device may undergo a large percentage of diameter change, up to 1000%. Additionally, the device may be diametrically oversized by 20% to 800%, preferably 20% to 500%, for the intended treatment lumen. This further oversizing ensures that during actuation from the collapsed state to the expanded state, the electrode body encounters tissue and is forced to conform to said tissue by the unique design and material composition of the expansion body. Upon contacting tissue at one point throughout the conduit, the electrode has a narrow electrical contact area that is circular or elliptical, which can be the contact area for delivering the pulse if the electrode is not oversized. When the expansion body is oversized for the target conduit, this contact area expands axially as the electrode is further actuated from the collapsed state to the expanded state, creating a cylindrical contact area that allows for more delivery of energy to the lumen and therefore the opportunity for a larger electroporation volume. For this reason, a larger percentage of oversizing would allow the user to determine the effective length of each electrode contact area through movement of the actuator that controls the deployment.

[0110] The extended body includes strands of memory material, such as Nitinol, and may undergo an additional heat curing step during its production that imparts a shape with desirable attributes to the preferred electrodes. For example, the extended body ends may be bulbous in shape, resulting in a more consistent inter-electrode distance across varying treatment diameters. This, in turn, results in a more consistent v / cm field strength imparted to the treated tissue.

[0111] The extension body can incorporate a series of outer and inner electrodes that will be oppositely charged to provide optimal electroporation of the tissue. The wires will be fed through the lumen and not exposed. The device can have the ability to feed foam to the lesion via small holes in the electrode struts, down the elongated body of the device within the lumen for said feeding or through an overlaid sheath. This will likely be the case for pre-cancerous or early stage esophageal or colon cancer treatments where the electrode struts are coated with foam, allowing for the delivery of higher electroporation voltages.

[0112] The device may be internally wired through a multi-lumen extruder with 2-20 lumens inside and a sheath on top to prevent the body from expanding. The effective length of the electrode is 5mm to 150mm in length, the length of the lesion that can be treated circumferentially by the pulses delivered.

[0113] Each extension body / electrode can be movable relative to the next to optimize electrode spacing and ensure proper tissue contact. In one embodiment, this is accomplished through each electrode being attached to a separate elongate member, with each elongate member stacked inside the next, with the ability to slide independently of each other. The user would control the sliding action via a hand controller.

[0114] An alternative embodiment of the device incorporates a spring-loaded deployment and recapture feature.

[0115] The electrically connected expanding body of any embodiment may comprise Nitinol or another self-expanding material, taking advantage of the shape memory ability of the material to conform to its original hardened shape when deployed from the delivery catheter under the control of the clinician by the hand controller. The expanding body ("basket") may comprise any of a range of other materials, which may be designed to be actuated from a collapsed state to an expanded state. Another embodiment uses a polymer balloon that expands a flexible electrode fabric to create a similar electrode shape. It is estimated that the length of each expanding basket will be 0.5mm to 75mm, but more preferably 1mm to 5mm, in its expanded shape, with a diameter of 4mm to 40mm. The distance between the baskets is ideally 2 to 20mm (but could range from 1mm to 40mm).

[0116] In some embodiments, the entire expansion body, such as a mesh, acts as an electrode, while in other embodiments, a portion of the mesh is constructed of non-conductive elements or is coated to prevent it from acting as an electrode. This can be used when manufacturing a device where a subset of the full 360° is configured to perform electroporation. Methods to achieve this include producing the mesh from both conductive and non-conductive wires.

[0117] Sample Use To place the probe, in one example, an endoscope is placed upstream of the lesion and a guidewire is advanced through the narrowed esophagus before the sheathed device is advanced distal to the malignant tissue.

[0118] Treatment may be performed by delivery of electroporation pulses alone or in combination with therapeutic agents, including chemotherapy drugs, calcium, or foam solutions.

[0119] The procedure is performed by placing the probe distal tip at the distal end of the lesion, activating / expanding the device, delivering the required pulse, and then collapsing and retracting the device a known length before activating and pulsing again to treat the next area. This can be repeated until the entire tumor length has been treated. The device in its initial position and deployment is essentially a bipolar electrode with the ability to generate an electric field at one location. Once deployed, and preferably with at least two electrodes expanded, the electrodes operate on multiple planes to generate a more uniform electric field.

[0120] In some cases, the length of the tumor will be longer (5-20 mm) than the distance between the electrodes. During the procedure, in the event of an occlusion of a length greater than the gap between the electrode baskets, a pulse is delivered and the device is collapsed before being advanced further into the tumor (or, if starting at the furthest point of the tumor, the device will be retracted rather than advanced). Once past the area to be electroporated, the device is redeployed and a pulse is delivered. This process is repeated until the clinician is satisfied that the malignant tissue has been successfully covered. Some overlap of the electroporated area may be required to ensure complete tumor treatment.

[0121] In another embodiment, the device may be configured such that clinically meaningful irreversible electroporation is only achieved through two or more applications of the programmed pulse train to a given section of tissue. This may be advantageous for lesion lengths that exceed the length of the active portion of the device, where an overlapping area is needed to prevent gaps between each pulse delivery and ensure proper treatment. A clinician using the device may be trained to deliver a pulse, collapse, advance or retract the device a portion of its active length, expand, deliver a subsequent pulse, and repeat until the entire lesion length is covered by the overlapping area that has received a sufficient dose, which is the area to be treated. This method of device configuration and use will reduce the likelihood that the clinician will miss multiple portions of tissue as a result of inadvertently moving the device a distance that exceeds the active length. This method of treatment will similarly reduce the impact of any single device placement being to some degree "sub-optimal."

[0122] The actuator of the device may include a handle with a slider mechanism with multiple positions, allowing expansion to a range of diameters, e.g., 2-30 mm, depending on the tumor presentation. After release from the sheath, a setting that locks the device in its expanded position and a collapsed setting that loosens the basket, allowing the device to be pulled upstream to the next position. This portion of the procedure varies with the drug delivery method, if any. The device may not need to be fully resheathed in some cases to be repositioned, tension is released, and the device can be pulled back through the lesion to the next treatment zone before the clinician fully redeploys the device and locks it into position.

[0123] In another embodiment, the device handle can include a slider mechanism for actuation of the deployable needle from the device distal end. This can be accomplished by movement of a push / pull elongate member attached to a sleeve. The sleeve can be manufactured from a laser cut tube from which the needle is laser cut and remains a part of, or alternatively is a sleeve to which the needle is attached by other means.

[0124] The force which effects actuation may similarly be transmitted from the user to the needle sleeve by pneumatic means.

[0125] In another embodiment, the parallel planes of the balloon, if present, may be fitted with flexible electrodes that allow additional electroporation to be delivered between the needles in cases where the use of needles may pose excessive risk to the patient.

[0126] In another embodiment, a metal frame is used in place of a balloon to direct the needles radially outward to contact the tissue. They can be deployed from basket-shaped arms. The strut diameter is 0.6 mm in one preferred example (in other examples it can be 0.3-1.9 mm). Heat-set nitinol can be used to deploy when pulled through a delivery sheath, ideally delivered through the biopsy channel of the endoscope, but could also be delivered trailing over a guidewire or sheath attached to the outer surface or tip of the endoscope. The needles are deployed after the basket is expanded. The needles are located within the hollow arms of the basket and can be deployed using a push-pull mechanism that can be mechanical, electrical, magnetic, pneumatic, or hydraulic.

[0127] The procedure may be performed endoscopically using a live feed camera for guidance with a single or dual channel endoscope. This depends on the procedure. In the case of delivery of fluids (e.g., IV Bleomycin and / or foam) to enhance electroporation, a single channel endoscope is sufficient, while a dual channel endoscope may be used for calcium injection procedures. The advantage of this device is that there is no visual obstruction or obscuration caused by devices blocking the camera lens. Thus, the clinician is more likely to achieve correct device placement for optimal performance.

[0128] In some instances, once the endoscope is properly positioned in the distal region of the lesion, a guidewire is fed through the working channel before the device is advanced. The guidewire is removed and the device is unsheathed, expanding the electrode body, such as a Nitinol basket. The body is fully expanded, allowing the cancerous or precancerous tissue to enter before an electroporation pulse is delivered. At this point, the clinician may have the ability to increase / decrease the expanded diameter using a push / pull wire linked to a handheld controller. The device may then be resheathed and retracted along the lesion to the next treatment zone. This may be repeated until the entire treatment zone has been successfully electroporated. For procedures involving bubbles or calcium, additional steps are required.

[0129] The extended bodies 3 and 4 of the probe 1 each comprise a mesh of strands which are all electrically conductive.

[0130] The actuator has cables along the sheath 2 that allow the bodies 3 and 4 to be compressed to reduce the axial dimension but increase the radial dimension, as shown in Figures 3(f) and 3(g).

[0131] 2 illustrates the use of the probe, with a "+" symbol and a peripheral outline showing a notional area, indicated by the numeral 10, that encompasses tissue that is expected to achieve successful electroporation through the application of an electrical pulse. When bodies 3 and 4 are collapsed, the area is narrow, but when bodies 3 and 4 are expanded, it is much wider.

[0132] Figure 3(a)-(g) shows the use of probe 1 in a top-down sequence (a)-(e) with more diagrams: (a) Pushing the distal end of the probe so that the guidewire 7 enters the luminal region where tissue is to be treated. (b) Shaft 6 enters this region. (c) and (d) The shaft (or sleeve) is retracted to expose the dilator bodies 3 and 4 within the lumen (L) where the greatest narrowing due to the lesion occurs. (e)-(g) This causes the expanding bodies 3 and 4 to expand initially with a longer longitudinal dimension, and as the tips enter the tissue the longitudinal dimension decreases and the volume between the bodies 3 and 4 decreases. In an alternative arrangement, the radial expansion may be effected fully or partially by axial compression by an actuator.

[0133] FIG. 4(a) shows an example of use for comparison with the device of FIG. 4(b). The device of FIG. 4(b) has similar components but has barbs 11 that contribute to the extended electric field. The barbs 11 increase engagement with tissue. Incorporating conductive barbs electrically connected to the electrodes allows for improved tissue engagement, anchoring the device and extending the depth of the electric field into the surrounding tissue. As shown, the barbs 11 are best configured to extend in a direction that has a radial component for penetration into the tissue.

[0134] A non-conductive coupling or spacer 5 allows the electrodes of the extension bodies 3 and 4 to seat on either side of the longitudinal length of tissue across which a pulsed electric field is applied. The shaft 6 has a proximal end that extends proximally to allow the user to advance and withdraw the probe when needed. The sheath 2 can be advanced over or retracted from the distal end of the probe to provide protection during probe movement.

[0135] The term "electrode" is used to describe the portion of the probe that is configured to engage the tissue to be treated and allows the device to deliver current through the tissue. The electrode, together with the non-conductive portions of the extension bodies 3 and 4, may be considered as the "engager" that engages the tissue to be treated as it moves from a collapsed state to an expanded state at the treatment site. These electrically connected extension bodies are non-conductively coupled to each other, and the non-conductive coupling(s) allow the elements of the extension bodies to seat on either side of the tissue, or on tissue across which a pulsed electric field is applied through application of an independent variable voltage conducted from a driver or generator outside the body. The entry of these electrically connected extension bodies into the collapsed state allows the delivery of the extension bodies to a treatment site that may be narrowed to various degrees by cancer or precancerous lesions. As the extension bodies move from their collapsed state to their expanded state, these electrically connected extension bodies engage the tissue, such as to capture the tissue and allow a large surface contact area between the electrode and the tissue. This expansion allows elements of the expanded body to seat on either side of tissue across which a pulsed electric field is applied through the application of independent variable voltages conducted from a generator outside the body. The larger surface contact area between the electrodes and the tissue protects the tissue from excessive current and excessive heat and promotes the delivery of a uniform electric field across the tissue.

[0136] There are two (or in other examples, three or more) electrically connected extension bodies in series collinear along the longitudinal axis of the probe at a set distance apart. These electrically connected extension bodies are independently wired such that the extension bodies can all apply different voltages at different locations, e.g., each electrode can be controlled individually and / or some can be controlled together as a group.

[0137] This embodiment has a centrally located lumen through which a guidewire can be used to direct progression of the device through a partially occluded lumen. This embodiment generates an electric field that is approximately cylindrical in shape, with the direction of electron travel through tissue being substantially parallel to the centerline or longitudinal axis of the device and the centerline of the lumen being treated.

[0138] This probe is particularly effective when treating luminal tissue where the pre-cancerous or cancerous tissue is circumferential. The electrically connected extension bodies can be wired to form two groups of bodies that are at two set potentials when electrically enabled. These designs, when implemented with three or more extension bodies (or "baskets"), substantially increase the length of the lumen that can be treated with a single application of a pulse.

[0139] Other embodiments are disclosed in which the engager comprises three or more electrically connected expansion bodies that are nested or overlapping along a longitudinal axis but remain non-conductively coupled and in an expanded state, maintaining at least the distance between the electrodes such that the electrodes may be used to apply a pulsed electric field to tissue. These can generate an electric field that is approximately cylindrical in shape, with the direction of electron movement perpendicular to the longitudinal axis.

[0140] Embodiments are disclosed (e.g., in FIG. 4(b)) in which the electrodes have tines or barbs that protrude from the edge of the expansion body and act to extend the field penetration further into the tissue without cutting into the tissue or requiring a correspondingly larger expansion diameter. If a larger field size can be achieved with a corresponding smaller expansion diameter, this may result in less ductal resection and greater physician comfort with device use.

[0141] Embodiments are disclosed in which the probe has a user-selectable shielded needle that extends outward from the device body and penetrates tissue, including versions in which the needle extension is user controlled or where the needle extension is preset.

[0142] Any of the above devices may be further configured to facilitate delivery of a liquid or foam to a target tissue.

[0143] In another embodiment, the expansion body is made from multiple different components around the circumference that are electrically insulated from each other, thus allowing the physician to define that in situations where the lesion to be treated is not completely circumferential, the electrical pulses are only applied to a portion of the circumference.

[0144] With reference to Figures 5(a), (b) and (c), the expanding bodies 100, 200 and 300 are shown. The body 100 has a wire mesh 101 between couplers 102 and 103 against an elongated support. The couplers 102 and 104 are pulled together to compress the body 101 axially, thereby expanding the body 101 radially. This has a significant effect when engaging diseased tissue within the wall of a lumen, and when used together, a pair of electrodes combine to grip the tissue for highly effective engagement for electroporation procedures. In effect, the outer rims of the electrodes approach each other based on the basic geometry of the electrodes, as also shown in Figures 3(e) and (f) where the spacer maintains an axial gap between the pair of electrodes and the outer couplers are pulled towards the central spacer. This also occurs when the radial expansion is due to shape memory. This also contributes to the gripping effect.

[0145] Body 200 has a laser cut tube configuration 201 between couplers 202 and 203. In the preferred implementation, the entire body acts as the electrode, and the electrode itself is an extended body. This achieves excellent electrode coverage. However, in some implementations, certain portions of the mesh can be coated or of a non-conductive material to prevent certain portions from acting as electrodes. Laser tube cutting is a convenient way to provide electrodes as extended bodies. Couplers 202 and 203 perform the same functions as couplers 102 and 103.

[0146] The body 300 has flexible electrodes 301 printed, attached, or mounted on the balloon in a zigzag pattern circumferentially around the balloon, allowing it to expand and contract. A variation on the features of the body 300 is shown in Figure 6, where the body 400 has a balloon 404 with electrodes 402 and 403 at each longitudinal end, with each electrode attached to the shaft 401 printed, attached, or mounted on the balloon in a zigzag pattern circumferentially around the balloon. The balloon can have only one electrode, as shown in Figure 5(c), or the balloon can have three or more electrodes.

[0147] As mentioned above, barbs or other features for tissue penetration may be provided to enhance fixation within tissue, and as shown in FIG. 7, laser cut pattern 500 has electrode length 501, and on the right side, the laser cut pattern has length 551 with barbs 552.

[0148] 8(a) and (b) show how the probe 600 can have full electrode mesh extension bodies 601 and 602 that can spread to different degrees, mediated by the user or governed by tissue stiffness. Feedback on tissue impedance between the electrically connected extension bodies can be used to modify the input voltage so that the largest volume of tissue experiences an electric field within the relevant voltage / cm window. Alternatively, the feedback can be tactile to the user, who then stops sliding the handle, thereby preventing the device from creating a dissection within the lumen. As shown in FIG. 8(a) and (b), the annular boundary of the volume between the bodies 601 and 602 has different angles to the longitudinal axis and different maximum lengths B and B', and, in fact, different minimum lengths A and A'. The smaller dimension B' indicates that the ends of the meshes 601 and 602 that face each other converge to help create a pinching effect that grips the diseased tissue extending inwardly into the lumen.

[0149] needle electrode The electrodes may be in any desired configuration, and in fact may include needle extensions that extend with a radial component for improved physical anchoring and deeper penetration of the electric field into the tissue. As shown in Figures 9(a), (b), and (c), a probe 700 has a balloon 701 at each end of which resides a needle 702 that holds a circular array of needles, or in an alternative configuration, extends from a sleeve under the action of an actuator that comprises one or more push / pull wires coupled to a body that is a tube from which a needle profile is cut.

[0150] The expansion body may in some instances consist of a balloon catheter around which reside multiple needles that lie parallel to the catheter centerline and are enclosed in a "shrouding" polymer tube that covers the sharp tips of the needles. The needles partially cover the first proximal end of the balloon and the second distal end of the balloon with the needle tips oriented toward the central portion of the balloon. See FIG. 9(c). The needles are preferentially manufactured from a shape memory alloy, such as nickel titanium (NiTi) or perhaps another self-expanding material, to take advantage of both the high levels of strain that these materials can undergo before undergoing plastic deformation and the shape memory capabilities that the material exhibits. Alternative embodiments may have needles made from 304 stainless steel or other materials typically used for hypodermic needles. Any of these materials may be platinum or gold plated. Additionally, a set of these needles may be attached together at their thick ends or along their barrels so that they may be moved relative to one another as a single unit. In one configuration, the needles are laser cut from a single metal tube and then polished to somewhat round the laser cut profile, thus reducing the number of different parts needed to build the device.

[0151] In use, inflation of the balloon reorients the needle tips so that they are now oriented radially outward from the catheter shaft. See Figures 6 and 9. Actuation of the slider, push button, or thumb wheel moves these needles forward within their respective tubes and thus radially outward into the surrounding tissue. An electrical pulse can now be applied between the two sets of needles to induce Reversible Electroporation (RE) or Irreversible Electroporation (IRE) as desired in the tissue immediately surrounding the electrode needles between the electrode needles. After application of the desired treatment to the target area, the user retracts the needles and deflates the balloon. The needles return to their default setting shape allowing them to fit outside the deflated balloon. The device can now move to a new treatment area until all the tissue requiring treatment has been addressed. The needles help to deliver electroporation energy deeper into the tissue without over-inflating / over-compressing the tissue. The needles are sufficiently long to allow the needles to be deployed from the device to a depth appropriate for treating the targeted pre-cancerous or cancerous tissue, for example, 2-8 mm.

[0152] When the balloon is inflated to radially reorient the needles, some tissues are stiff and therefore may push the needles out of their intended and desired circumferential spacing. In such situations, fully inflating the balloon to push back the tissue, partially deflating to allow needle spacing back to its intended spacing, and reinflating to the target balloon diameter can improve needle spacing. Because each set of needles acts as an integrated electrode at a given voltage, the electric field is not affected by the variable needle spacing around the circumference caused by stiff tissue.

[0153] In one configuration, the needles are substantially perpendicular to the centerline (longitudinal axis) of the catheter as they emerge from the jacket tube. In another configuration, the needles emerge with an included angle formed between the needle tip centerline and the catheter centerline that is less than 89°. Such an angle is intended to modify the resulting electric field to be more uniform between the two electrode sets, because the needles of each electrode set extend farther from the central axis, the further apart they are in the circumferential direction.

[0154] Sample steps for using the device The physician retracts the protective sheath until it is distal to the balloon and needle electrode. The physician inflates the balloon, which radially orients the polymer tube and thus the contained needle. Actuation of a slider / thumb wheel / button on the handle moves the needle set forward within the polymer tube, causing the needle set to extend outwardly into the surrounding tissue. An electrical pulse is then relayed between the extended needles such that the tissue between the needles at one end of the balloon and the needle at the other end is effectively reversibly electroporated (RE). The needle is then retracted, the balloon is deflated, and the device can be moved to treat another location.

[0155] 10(a) and (b) show a probe 800 in which the electrodes overlap one another partially or completely along the device centerline (longitudinal axis). This is achieved by the electrodes tapering outwardly, then parallel to the axis, and then inwardly. Electrode 801 has an axial portion that is further from the axis than electrode 802. In this case, each alternating electrode has a different radial dimension and a different charge when in use, but the pattern may be different, such as a shift to a larger radial dimension on one side of the axis compared to the other side.

[0156] 11 and 12, on the other hand, show an expanding body 900 having a central post 901 supporting two separate laser cut electrodes 902 and 903 that are co-expanding and circumferentially spaced apart.

[0157] In most instances of the invention, the electrodes are axially spaced, however, as shown in Figures 10-12, the electrodes can be circumferentially spaced.

[0158] Referring again to the probes having axially spaced electrodes, Figures 13(a) and (b) show a probe 1000 having three longitudinally spaced extension bodies 1001, 1002, and 1003 supported by a shaft 1010. It will be appreciated that any desired number of electrodes of any of the types mentioned may be attached to the shaft.

[0159] 14 and 15 show examples of expansion bodies with both electrodes and non-conductive strands, in this case a braided mesh identified as 1100, 1150, 1200, and 1250. Each has a combination of non-conductive strands 1101, strands of one polarity 1102, and strands of the opposite polarity 1103. As is evident from these diagrams, any desired combination of strand numbers, strand distribution, and strand thickness is possible in manufacture. The braided mesh used to construct such devices would ideally be highly constrained with each strand passing in series over one strand and under the next, thus ensuring that the non-conductive strands 1101 are sufficiently constrained that the conductive strands 1102 and 1103 do not contact under most circumstances. The well-constrained nature of the device allows for short inter-electrode distances to be achieved while still allowing the use of lower voltages to achieve similar levels of field strength in tissue. This may enable the achievement of IRE in conduits, which has not previously been achievable due to the input voltages required with current devices and the associated muscle and pain responses seen with such large input voltages.

[0160] 16 shows an expansion body 1300 in which there are 20 strands 1301, all of the same diameter, and all of which are conductive. This is provided primarily as a comparison for FIG.

[0161] 17 shows an expansion body 1350 having twelve strands 1351, also of the same diameter, and also all conductive. Again, this is provided primarily as a comparison for FIG.

[0162] 18 shows an expanded body 1400 with 12 strands 1401 of intermediate diameter and 36 strands 1402 of smaller diameter providing a smaller mesh gap, all of the wires being conductive as electrodes. The resulting arrangement has a combination of increased strength provided by the larger diameter wire, smaller mesh gap size achievable with the smaller diameter wire, and wraps down under smaller end collars than could be achieved with an expanded body having a similar mesh gap size but without using multiple wire diameters in its configuration.

[0163] 19(a) and (b) show a probe 1500 with a series of six baskets 1501, each basket separated from its neighbor by a catheter balloon 1502 to ensure repeatable inter-basket distance or any relative motion between the electrode device and the conduit regardless of the target conduit diameter. A shorter inter-basket distance can be achieved with the balloon spacer 1502 compared to without the balloon spacer 1502 because the balloon spacer 1502 reduces the risk of basket-to-basket contact that would result in a short circuit and consequent damage to the attached pulse generator. A shorter basket distance is desirable to enable application of IRE treatment to tissue without the high voltages that current devices are required to supply due to the larger inter-electrode distance.

[0164] 20(a), (b), and (c) show a sequence of three stages of unfolding a probe 1600 having proximal and distal baskets 1601 and 1602 with an extended support 1603 therebetween. The baskets 1601 and 1602 are heat set to have a shape that is offset toward the center between the baskets, which ensures that each electrode contacts the conduit near the edge of the extended support 1603, which ensures a reliable minimum inter-electrode distance.

[0165] 21 shows a probe 1700 having two expanding electrode bodies 1704 surrounded by two expanding balloons 1703 intended to create an enclosed area into which a fluid agent, such as a foaming agent, can be delivered. Furthermore, the space 1701 between the balloons 1703 has another expanding balloon 1702, which is purposely designed to be smaller in diameter than the target conduit, helping to reduce the volume of the enclosed area, thus allowing the foam to fully fill said volume. Pressurized delivery of the foam into the enclosed volume can increase the uptake of the foam and its active ingredients into the surrounding target tissue.

[0166] In this example, the purpose of the outer balloon 1703 is to seal the space between the extended electrode bodies, and the purpose of the inner balloon 1702 is to reduce the volume of the space between the extended electrode bodies and maintain a fixed distance between the electrode bodies. This arrangement allows for very effective filling of the space between the extended electrode bodies with a foam or other solution, helping to adjust the conductivity and ensure proper electroporation. This also reduces the voltage required to generate a proper electric field.

[0167] It should be noted that the electric field is controlled by the width of the contact area between the extended electrode body 1704 and the tissue; the narrower the extended electrode body, the shallower the radial electric field depth, and vice versa.

[0168] FIG. 22 shows a probe 1800 having two longitudinally spaced electrodes that themselves form an expansion body 1801 and 1802 separated by a spacer 1803, which defines the interelectrode distance between the baskets. The basket 1801 conforms to the surrounding hard tissue 1804, while the basket 1802 deforms the soft tissue 1805 where it is located. Both baskets have the same or nearly the same configuration. However, the actuation of both baskets is linked such that the force applied by the user at the handle is translated into the expansion of each basket to the extent achievable by the force. This is achieved through mechanical or pneumatic coupling of the basket movements. The user can feel the resistance to the expansion provided by actuating the coupler to move axially to expand the electrodes.

[0169] In some preferred examples, each electrode is configured to apply a radial force that expands soft, pliable tissue without causing dissection or perforation, but conforms to harder, constricted tissue, the force being less than 0.1 N / mm 2 ~1N / mm 2 is within the range.

[0170] FIG. 23 is a set of 12 images showing the results of the test, arranged as three rows of four images for 4 mm, 6 mm, and 8 mm diameters, respectively, showing the effect of electroporation with an extended body. All images were generated by a single prototype device of the design shown in FIG. 22 deployed in a well-understood potato model for electroporation. The use of 2,3,5-triphenyltetrazolium chloride (TTC) at a concentration of 0.5% for staining of the "electroporated potato" allows direct visualization of the extent to which the potato cell wall was disrupted by the applied electric field pulse. This prototype had a fixed distance between the electrodes. It can be seen that by increasing the input voltage, and therefore the electric field strength, from left to right, the depth of the electroporated plant tissue increases for each given channel diameter. Moving from a 4mm channel to a 6mm and 8mm diameter channel shows that the electroporated cross-sectional areas at the different diameters can be approximately the same in size, but extend into the surrounding tissue to a lesser extent when the diameter at which the pulse is delivered is larger. This means that a device of this design can be used in large occluded lumens where the intention is to treat very deeply, and in less occluded lumens where the desire is to treat the luminal surface without extending beyond the surface into the tissue.

[0171] FIG. 24 is a set of four diagrams showing the overall outer extent of the expanded body of the device of the present invention: oval 2000, cone 2100, square 2200, and "dog bone" 2300. The oval body shapes are similar to those shown in FIG. 22. These devices can be used in conduits of widely varying diameters and shapes, and as the oval body expands within the conduit, the electrodes will contact the conduit being treated at a distance from the spacer that defines the inter-electrode distance, which will vary depending on the conduit size, tissue flexibility, and shape. With two electrodes in line, the effective electrode distance, i.e., the inter-electrode distance where each electrode contacts the tissue, may possibly be much longer than the intended inter-electrode distance defined by the length of the spacer 1803. This increase in distance will therefore result in a lower v / cm for treatment application, and possibly a less effective treatment. This may be mitigated by having other shapes, heat set or mechanically defined, for the expanded electrodes similar to those shown. Shape 2100 is particularly preferred for treating tissue that protrudes into a lumen in pieces, because two of electrodes 2100 with wider ends facing each other are particularly suited to pinching such tissue.

[0172] FIG. 25 is a pair of diagrams showing devices 2500 and 2600 with extension bodies 2501 and 2601 that are insulated at their proximal and distal ends to prevent the possibility of short circuit development. Probe device 2500 shows a basket 2501 with strands on both sides that are coated with insulating material. One way this can be achieved would be through a dip coating manufacturing step. Probe device 2600 shows a basket 2601 that is topped with an insulating overlay that expands with the basket. In most situations, they only need to extend from the axis for a portion of the radial distance on the inner ends of the extension bodies. It will be appreciated that the use of a balloon between the extension bodies helps ensure repeatable separation and minimizes the need for insulated wire strands.

[0173] 26 shows a probe 2700 having a catheter 2701, an elongate support 2702, a proximal extension body 2703, a distal extension body 2704, and a guidewire 2705. In this case, the bodies are separated by eight parallel spacer members 2706 evenly spaced circumferentially about the longitudinal axis.

[0174] FIG. 27 shows the narrower extension bodies 2703 and 2704 stretched in the longitudinal direction. This shows that the spacer members 2706 follow the change in radial dimension. As the mesh expands, the spacers help maintain separation even at the furthest position from the axis. In some instances, there may be more than one spacer element, the number being selected to help achieve consistent maintenance of the desired separation between the extension bodies both at the longitudinal axis and radially outward from the longitudinal axis. This results in less variation in the distance between the contact points of each basket electrode when the device is used in conduits of different diameters.

[0175] These probes are advantageous in that the length of the insulation defines the effective electrode distance, and thus the distance for the delivery of the electrical pulse wave can be considered fixed. These probes fix the effective electrode distance while allowing some tissue between the electrodes to remain in situ.

[0176] 28(a), (b), and (c) show the progression of movement of probe 1 such that bodies 3 and 4 are evenly spaced on either side of a nodular polyp tumor T such as may be found in pre-cancerous intestine B. As shown in FIG. 28(c), longitudinal contraction of bodies 3 and 4 can have the effect of pinching the polyp tumor and pulling it radially inward, thereby contributing to achieving a comprehensive treatment.

[0177] The colon, and especially its inner mucosa, can be easily manipulated by the moving basket of the Bolero, thus pulling the target tissue between the basket electrodes and thus bringing it into the zone where the strongest electric field will be delivered. The duct wall is shown in Figure 28(c) with the vessel wall lowered in to aid in treatment at the stalk of the mass, which is the key to a complete treatment.

[0178] The ability to draw both healthy and abnormal tissue into the areas of highest field strength allows for successful treatment of the abnormal tissue and the margins around and under such abnormal tissue, thus lowering the risk of recurrence, which is primarily a result of incomplete ablation due to current treatments whose inherent risks prevent physicians from treating them. The ability to pull, grasp, or move tissue is primarily affected by the electrode material, size, and shape. The electrode wire or strut must be sufficiently stiff if made from a mesh or laser cut material to allow the electrode to move the tissue without simply conforming to it in situations where the tissue is flexible.

[0179] The following is an example of how this is accomplished with a two electrode design, these methods can also be used for three or more electrodes, but may need to be modified to some extent. By having each electrode have a maximum diameter that exceeds the resting diameter of the lumen by a percentage in the range of 20%-800%, preferably 20%-500%, means that during expansion, the outermost edge of the basket will begin to interact with the luminal tissue before the device is fully expanded, and continued actuation will move this outermost diameter outward, but also forward toward the center between the two electrodes, thus gripping the tissue to some extent.

[0180] The ability of the electrode to grip tissue can be improved through the addition of lumps, tines, or barbs to the electrode struts or wires, thus improving grip in localized areas. In the case of a heat-set Nitinol frame or mesh, the geometry can be selected such that the electrode achieves a diameter where it contacts the conduit near the spacer between the electrodes (e.g., spacer 1803 in FIG. 22) or further away from the spacer, depending on the intended tissue gripping strategy. This modifies the path in space through which the individual elements of the electrode travel. For example, the electrode shape identified as 2100, if used in a two-electrode device, will have the largest diameter of its body nearest the electrode spacer 1803. As a product of its heat-set shape, there is an abrupt change in wire mesh strand orientation immediately adjacent to the spacer 1803. This results in a large localized strain being present within this bend region when it is held down or restrained prior to actuation, and therefore when the electrode is allowed by the actuator to return towards its predetermined heat-set shape this results in an immediate hinging of this side of the electrode towards the tissue, which then occurs on both sides of the target tissue resulting in a gripping action-like effect.

[0181] Additionally, the ability to move the electrode bodies closer together during or after electrode expansion allows the device to achieve a stronger tissue grip, and perhaps a more consistent inter-electrode distance, than would otherwise be achievable. The ability to move the electrodes toward each other requires that the device be constructed such that the actuating members have sufficient tensile strength to create and maintain a grip on the tissue.

[0182] In the case of the colon, it is preferred that the electrodes can expand from about 1-2 mm pre-deployment to about 60 mm, and preferably to a maximum diameter in the range of 30 mm to 60 mm. This makes them particularly suitable for pulling tissue such as pre-cancerous nodules within the wall of the intestine, but also within the lumen, such as elsewhere in the GI tract esophagus.

[0183] However, in other instances, such as treatment of the bile duct, the maximum diameter is preferably in the range of 4 mm to 10 mm or 10 mm to 15 mm, as in the urethra.

[0184] As shown in Fig. 29(a), if the tissue to be treated is larger than the spacing between the expansion bodies, the surgeon can move the probe 1 in predetermined increments that provide treatment ranges 3001, 3002, and 3003. However, the electric field generated may not be sufficient to achieve IRE, so these increments can be shortened to have treatments where all longitudinal spaces overlap, as shown in Fig. 29(b). The surgeon can choose, for example, to have no overlap when RE is required, but to have full overlap when IRE is required.

[0185] Physicians are often in environments where the GI tract is blocked and therefore the endoscopic camera will have a somewhat blocked field of view. With the "overlap technique" of Figs. 29(a) and (b), the physician may be less concerned with each placement of the device whether it is in the exact location the physician intended. This means that the physician will be more comfortable using a device that aids in device uptake. When the probe is placed in a duct with a highly variable geometry, the expected field shape from the device will vary as a result of the presence of cancer, strictures, or patient anatomy. Using the overlap technique will mean that the importance of each particular placement will decrease as the device is repeatedly placed and repositioned. Correct selection of the delivered dose will result in the patient receiving one long "averaged" field that generates IRE in the area required, eliminating "cold" spots caused by small fluctuations in device placement or contact.

[0186] Fluid injection The elongated support in various embodiments includes a guidewire and / or shaft and an electrical conductor for conducting power to the electrodes. The electrodes may be driven individually or together by separate elongated conductors. The elongated support may also include one or more lumens as conduits for fluid flow to assist in electroporation. The electroporation device may include a supply of fluids, such as solutions or bubbles (gases and liquids). The fluids may be selected for optimization of electrical properties and / or drug or biological therapy. The fluids may be of any of the types described in our published patent specification WO2021 / 043779, the contents of which are incorporated herein by reference.

[0187] Fluids may be injected or sprayed from radial apertures in the shaft at or adjacent to the electrode and / or through a hollow needle which penetrates tissue in use. Such a needle may have apertures along its length as well as at its end. The needle is connected to a proximal end / handle by an elongate member through which the solution is delivered.

[0188] The fluid may be in the form of bubbles, which are liquids with very small bubbles of gas. Bubbles may be used to enhance the permeabilization effect of electroporation, with particularly beneficial results for high frequency (greater than 100 KHz) electroporation. The use of bubbles is described in more detail below. In this specification, the relative concentrations of liquid and gas in bubbles are expressed by volume at atmospheric pressure, such as in a syringe when loaded with air and bubbles.

[0189] The foam may be formed by any suitable means, in fact it may be done manually by the clinician within the syringe.

[0190] The primary advantage of utilizing bubbles for direct injection into the target tissue to be electroporated is that the bubbles can act as a carrier if required for the molecule of choice, while their effect on tissue conductivity compared to liquids is superior in that they cause minimal increase in conductivity. The air or gas component of the bubbles has infinitesimal conductivity compared to liquids, allowing for a more favorable environment, especially for high frequency (>100 kHz) pulses, minimizing the current delivered and aiding in increased cell permeabilization.

[0191] The use of high frequency (>100 kHz) bipolar electric pulses is advantageous for direct cell ablation or cell permeabilization for passive diffusion of molecules. Combination with bubbles in some instances benefits the efficacy of the procedure (compared to using an equivalent liquid solution).

[0192] When injected, bubble-free liquids are quickly diluted by the circulating blood volume. Interaction with blood reduces the effectiveness of the liquid solution by binding with plasma proteins that ultimately reduce the number of active molecules. Foam, on the other hand, can displace blood rather than mix with it, increasing the contact time of a higher concentration of active agent with tissues and therefore resulting in greater effectiveness. Foam allows a lower concentration of drug to be used to obtain the same therapeutic effect as its liquid equivalent, reducing the prevalence of side effects associated with higher concentrations.

[0193] The bubbles are less conductive than the corresponding liquid solutions due to the presence of gas bubbles such as air, resulting in lower currents, higher cell permeabilization, and less pain sensation to the patient.

[0194] The presence of cationic molecules within the solution or bubbles can reduce the electric field strength required to electropermeabilize the cell wall. An example of such a cationic molecule includes lidocaine HCL.

[0195] The bubbles may be created, in some instances, by mixing albumin, gas, and liquid solutions, for example, in a volume ratio of 1:4:1. Preferably, the ratio of gas (e.g., room air or CO2 gas) to liquid is within a volume ratio of 1:2 to 1:10.

[0196] Preferably, the foam used is one of the following: Albumin, human serum albumin; 10-50%, preferably 15-30% volume concentration; Polidocanol (0.5-5% by volume) or sodium tetradecyl sulfate (STS) (0.5-5% by volume) Includes one or more of: STS and polidocanol are individually sclerosing agents, whereas albumin is not a sclerosing agent and polidocanol is also a local anesthetic.

[0197] Albumin is simply a foaming agent, whereas polidocanol and STS are both foaming and sclerosing agents (they are irritants and directly induce cell death).

[0198] The activator (molecule to be introduced) in solution is Calcium ion, Ca++ (2mMol to 150mMol); Potassium (2mMol to 100mMol); Lidocaine; Lidocaine HCL; Bleomycin; Cisplatin; DNA; and / or RNA may include one or more of:

[0199] Preferably, the electroporation pulse advantageously has the following parameters: Bipolar pulses of 0.05μs to 5μs pulse length delivered in trains with "on" excitation times of 0.1μs to 1000μs per train, repeated up to 1000 times at frequencies between 1kHz and 1000KHz. has.

[0200] Using the same active agent, injecting bubbles directly into the environment surrounding the cells, rather than a liquid-only material, provides a less conductive environment, allowing for more efficient cell permeabilization and aiding the effectiveness of electroporation-based procedures.

[0201] The effectiveness of cell permeabilization (holes are created on the cell membrane) produced by short (<50 μs) bipolar electric pulses is affected by tissue conductivity: a higher conductivity of the liquid solution surrounding the cells will result in a larger current that is detrimental to the treatment, resulting in poorer cell permeabilization and pain sensation in the patient.

[0202] The increased conductivity around the cells is brought about in part by the volume of fluid in the area and the localized injection of electroporation solution, which can contain a treatment molecule of choice (calcium, potassium, bleomycin, cisplatin, lidocaine HCL, etc.) and a large concentration of ions.

[0203] Utilizing a foaming agent to deliver therapeutic agents reduces the effect of high conductivity on the effectiveness of the electroporation pulse to permeabilize cells.

[0204] Bubbles made primarily of gas or air are less conductive than the corresponding liquid solutions, resulting in lower currents, higher cell permeabilization, and less pain sensation for the patient.

[0205] The use of bubbles injected into the electroporated environment advantageously facilitates the degree of treatment and cell permeabilization by not increasing electrical conductivity to the extent that a comparable liquid solution would. The following table sets forth some preferred parameter ranges when bubbles are injected, although these ranges advantageously apply to liquid injections. [Table 1]

[0206] The foam may be similarly utilized to facilitate the dispersion of local anesthetic into the tissue being treated. The local anesthetic may be lidocaine 5-20 mg / ml, without or with adrenaline. Mepivacaine 10-30 mg / ml is another example of a local anesthetic that may be used. Lidocaine HCL presents as a cationic form of lidocaine and can reduce the electric field strength required for electropermeabilization of the cell wall. The foam and local anesthetic may be administered in combination with a molecule of choice, e.g., potassium or potassium ions, bleomycin, DNA, or it may be provided alone.

[0207] advantage In one advantageous example, electrodes fixed together at their closest points with both ends attached to two individual elongate members facilitate compression, which imparts a diameter increase in the electrodes, forcing them closer together to pinch the tissue. The electrodes may advantageously be self-expanding with a shape memory material.

[0208] In one preferred example, each electrode comprises a woven mesh of nitinol or steel wires, in quantities of 8-96 wires, with a diameter of 0.025 mm to 0.25 mm, arranged to collapse to a size sufficient to fit through the biopsy channel (or other lumen) of an endoscope. The mesh engages and stretches the tissue, forming a tightly woven layer to ensure minimal apertures between the wires, thereby providing a homogenous electric field.

[0209] The mesh can have two separate layers, a structural layer of 0.15mm-0.35mm wires in a quantity of 8-24 and a thin mesh layer of 0.01mm-0.1mm wires in a quantity of 24-95, providing an electrode that can be collapsed to a size sufficient to fit through the biopsy channel (or other lumen) of an endoscope; the structural layer will engage and stretch the tissue, and the thin mesh layer will form a tightly woven layer to ensure minimal apertures between the wires, thereby providing a homogenous electric field.

[0210] In some instances, it may be preferable for there to be thermal set of the electrodes such that the electrodes tend to "grow" parallel to the opposing electrodes in order to achieve a consistent electric field.

[0211] The actuator provides an initial radial expansion to return to its preferred diameter in some preferred examples. Further actuation of the handle promotes expansion of soft / flexible tissue or conforms to the shape of hard / constricted tissue. The initial expansion can be to a diameter of 20mm to 40mm. It is easy to spread the electrode "in free space" with the handle, but difficult to actively push the electrode into tissue. Each electrode "want" to expand and contract, and since it is very easy to spread the mesh before it contacts tissue, this is immediately apparent to the user as the force required to actuate increases dramatically once the mesh contacts tissue. This acts as a very obvious safety feature.

[0212] The outer diameter of the electrode is designed to be larger than the uncoiled diameter of the target anatomy to avoid damage / tearing, but never exceed the maximum dilated diameter of the anatomy. For example, for the colon, this ranges from a minimum of 10 mm and a maximum of 40-60 mm. This also ensures adequate wall contact of the electrode.

[0213] In some advantageous examples, actuation provided by the user is coupled to both electrodes such that if one electrode is constrained, the other electrode continues to expand. This ensures that both electrodes expand until they engage the tissue and then provide balanced pressure to the tissue at each electrode. The way this is accomplished with the current design is through a spacer / insulator 5 that is attached to each electrode at its ends but is otherwise free to move along the central shaft of the device.

[0214] It will be appreciated that the present invention achieves optimal electroporation while avoiding the risk of dissection or perforation. The delivery system can be delivered with a low profile, ideally through the biopsy channel of an endoscope, and furthermore (a) in the case of healthy tissue, the electrodes are embedded within the soft tissue, and (b) in the case of diseased tissue that is constricted or has reduced elasticity, the electrodes conform to the surface of the tissue to be treated with a force that does not result in excessive expansion of the tissue resulting in tissue damage. Furthermore, the tissue can be a mixture of elastic and inelastic tissue, and the device must automatically accommodate both tissue types.

[0215] The probe of the present invention provides low profile catheter access to narrowed or restricted lumens, such as within the gastrointestinal tract.

[0216] There may be a bipolar electrode driver that is adjustable according to position between the collapsed and expanded (actuated) states.

[0217] The treatment can be applied very effectively around the entire circumference of a lumen or tissue.

[0218] The probe allows for uniform circumferential EP (electroporation) energy delivery to the tumor, which is enhanced by the flexibility of the electrodes on the surface of a flexible balloon, or an expanding mesh or basket that has enough stiffness to maintain electrode-tissue contact, but not enough to cut into the tissue.

[0219] The probe allows for delivery of EP energy to sufficient tumor volume and depth while minimizing the risk of tissue dissection / lumen perforation, which is particularly well accomplished when the probe includes tines or barbs and / or the electrode body is configured to pinch tissue.

[0220] The probe can provide tactile feedback to assist in optimal contact between the electrodes and the patient tissue. Another optional advantageous feature is the delivery of a fluid, such as a foam, to the site to adjust the electrical conductivity.

[0221] Ability to deliver high voltages to tissue while reducing current Great versatility exists in that treatment can be applied around 360° (or variations in between, e.g., 180° electrical coverage with 180° insulating / non-conductive elements to allow for situations where full circumferential treatment is not needed or desired), and any desired subset of electrodes can be driven according to user controlled input or automatic feedback from sensors detecting parameters such as pressure of the electrodes against the tissue, degree of expansion, or radial position of the electrodes.

[0222] The device allows tissue to enter between the arms / struts to maximize the volume of tissue treated.

[0223] The device of the invention can be used for reversible electroporation in combination with chemotherapy, electrochemotherapy (ECT) or for electroporation with calcium. The device has the additional advantage that tumor tissue, due to its increased electrical conductivity, takes up more active substances than healthy tissue and therefore healthy cells can be in the treatment area without this resulting in excessive additional risks to the patient.

[0224] Irreversible cell membrane permeabilization can likely be achieved at reduced electric field strength through the presence of cationic solutions.

[0225] The device allows for the generation of various electric fields and can extend the depth of treatment into the tissue depending on the particular tumor being treated. The invention is not limited to the described embodiments, which may vary in configuration and details.

Claims

1. An electroporation probe (2700), comprising: an elongated support (2701, 2702) comprising an electrical conductor and configured to extend from a proximal end to a distal end through a lumen of a human or animal body extending longitudinally relative to a longitudinal axis; at least two electroporation electrodes (2703, 2704) supported by said support, connected to said conductors and mounted to engage tissue within the wall of the lumen in use; A spacer between the axially juxtaposed electrodes (2703, 2704); an electrode mechanical actuator; the at least one electroporation electrode being deformable for radial expansion from a contracted position; The spacer has a plurality of parallel spacer elements (2706). Electroporation probe (1).

2. An electroporation probe as described in claim 1, wherein the radial expansion causes the surfaces of a pair of electrodes (3, 4) to approach each other in the longitudinal direction by the radial expansion, thereby contributing to grasping tissue protruding into the lumen.

3. 3. An electroporation probe according to claim 1 or 2, wherein the proximal end of the proximal electrode (3) and the distal end of the distal electrode (4) are respectively coupled to the actuator to move the ends (102, 103) towards each other to compress the electrodes against the spacer.

4. An electroporation probe as described in any one of claims 1 to 5, wherein at least one of the electrodes (2703, 2704) has shape memory and is configured for at least a portion of the radial expansion when a constraint is removed.

5. An electroporation probe as described in any one of claims 1 to 4, wherein the actuators (102, 103) are configured such that axial compression of at least one electrode forces at least a portion of the radial expansion.

6. An electroporation probe as described in claim 5, wherein the electrodes (3, 4) have a preferred expanded shape memory state to induce an initial radial expansion, and the actuators (2, 5, 6, 7) are configured to provide further radial expansion.

7. An electroporation probe as described in claim 6, wherein the actuator is configured to allow a user to sense the level of force required by the actuator to effect radial expansion, thereby providing a user indication of when tissue is engaged and how far the tissue will be pushed by the further radial expansion.

8. The electroporation probe of claim 1, wherein at least one electrode (3, 4) is configured for radial expansion to expand soft, pliable tissue without causing incision or perforation, but to apply a radial force to accommodate harder, constricted tissue, said force being less than 0.1 N / mm ２ ~1N / mm ２ Electroporation probes within the range of

9. An electroporation probe as described in any one of claims 1 to 8, wherein at least one electrode comprises a mesh having a structural layer of 8 to 24 wires having a diameter in the range of 0.15 mm to 0.35 mm and a thin layer of 24 to 96 wires having a diameter in the range of 0.01 mm to 0.1 mm.

10. An electroporation probe as described in any one of claims 1 to 9, wherein the longitudinal length of at least one electrode is within the range of 0.5 mm to 75 mm.

11. An electroporation probe as described in any one of claims 1 to 10, wherein the longitudinal distance between at least two electrodes is within the range of 1 mm to 40 mm, optionally 2 mm to 20 mm.

12. The electroporation probe according to claim 1, the probe is for treatment of the GI tract and has a maximum diameter after radial expansion in the range of 30 mm to 60 mm; or the probe is for treatment of the urethra and has a maximum diameter after radial expansion in the range of 10 mm to 15 mm; or An electroporation probe, wherein the probe is for treating a bile duct and has a maximum diameter after radial expansion in the range of 4 mm to 10 mm.

13. Electroporation probe according to any one of claims 1 to 12, wherein at least one electrode comprises a feature (11) for extending radially into tissue in use.

14. An electroporation probe as described in claim 13, wherein the features comprise barbs or needles (11), the laser cut tube (500) has barb features as part of the laser cut pattern of the laser cut tube (500), and optionally one or more needles can be coated.

15. An electroporation probe as claimed in any one of claims 1 to 14, wherein the probe (1500) comprises at least four axially separated electrodes (1501), with a spacer between each successive electrode and the next.

16. An electroporation probe as claimed in any one of claims 1 to 15, said probe comprising proximal and distal barrier balloons (1703) which, in use, define a space enclosing at least two extended body electrodes (1704), said space being for enclosing a fluid agent introduced into said space to assist in electroporation.

17. The electroporation probe according to claim 1, The probe comprises a catheter (2701) and an elongated support (2702); An electroporation probe, wherein there are eight parallel spacer members (2706) between said two electrodes, said spacer members being evenly spaced circumferentially about said longitudinal axis.

18. An electroporation device comprising a probe as claimed in any one of claims 1 to 17 and an electrical drive for supplying pulses to the electrode via the elongated support conductor.

19. A device as described in claim 18, wherein the electrical drive is preferably configured to independently apply a variable voltage from a generator linked to the proximal end of the probe.

20. A device as described in claim 18 or claim 19, wherein the electrical drive is configured to provide a pulse that is adapted to the electrode position or a pulse that is specific to the electrode position.

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