Patent Application
20250160920
The invention is in the field of electroporation.
An objective of this invention is to achieve improved access and delivery of electroporation treatment to the body, primarily but not exclusively in the lumen. An example is treatment of tumour tissue with electroporation in the gastrointestinal lumen.
Existing devices for delivery of electroporation intraluminally suffer from an inability to fully access the lumen due to tumour obstruction wherein visibility, access and transit on an endoscope is impeded.
Intraluminal tumours can extend several centimetres in length and cover the full circumference of the lumen. Disease progression and application of existing treatment modalities can induce injury to the surrounding tissue causing scarring and stenosis of the lumen. This reduces the function of the lumen and greatly limits access endoscopically. Full dilation of malignant tissue in a lumen presents a high risk of perforation or tearing, resulting in emergency surgery with an associated high rate of mortality
Electroporation has become established as a safe and effective clinical tool which permeabilises the cell membrane and can enable the rapid passive diffusion and targeted uptake of therapeutic agents. However, application of an electrical field within a lumen is very challenging.
The application and positioning of two or more electrodes presents challenges within the lumen where access is limited and positioning of needle electrode(s) is impractical and if achievable may not ensure full coverage of the desired treatment area.
Existing alternative therapies involving tissue ablation (for example Radio Frequency Ablation, Microwave Ablation, Cryo Ablation) are associated with damage to the tissue structures including blood vessels and nerves and are associated with the risk of creation of unintended fistula. Thus, where these therapies are used, they are often used sparingly in their application in order to avoid inadvertent injury which in the case of cancer or pre-cancerous tissues treatment is in conflict with the physician's desire to remove or ablate all of the abhorrent tissue to prevent recurrence.
Electroporation leaves existing extracellular matrix and tissue structures intact and thus does not have these associated risks however its uptake thus far had been limited by the tools available for its delivery and targeting as up until now it has been most effectively applied where electrodes can be placed on two sides of the intended treatment zone.
The invention addresses these problems.
The invention provides an electroporation probe as set out in any of probe claims appended hereto, and an electroporation device as set out in any of device claims appended hereto, and a method of electroporation treatment according to any of the method claims appended hereto.
We describe an electroporation probe comprising an elongate support, the support comprising electrical conductors and being configured to extend through a lumen of a human or animal body extending in a longitudinal direction with a longitudinal axis from a proximal end to a distal end, the support supporting at least two electroporation electrodes connected to the conductors and being mounted to engage tissue in the wall of a lumen in use, and an electrode actuator.
In some examples, at least one electrode is deformable for radial expansion from a retracted position. In some examples, the probe comprises a plurality of electrodes spaced apart in the longitudinal direction, and said radial expansion causes surfaces of a pair of electrodes to move closer together in the longitudinal direction with radial expansion, thereby contributing to gripping of tissue which protrudes internally into a lumen.
In some examples, at least one electrode has an operative configuration with a central radial peak in a central region and being sloped on each longitudinal side of the central region.
In some examples, the probe comprises a spacer between juxtaposed electrodes, and said spacer prevents movement of each electrode closer to the other electrode at the longitudinal axis, and the proximal end of a proximal electrode and the distal end of a distal electrode (4) are each coupled to the actuator to cause said ends to move toward each other to compress the electrodes against the spacer.
In some examples, at least one of the electrodes has a shape memory and is configured for at least some of said radial expansion upon removal of a constraint.
In some examples, the actuator is configured to cause axial compression of at least one electrode to force at least some of said radial expansion. In some examples, the electrode has a preferred expanded shape memory state to guide initial radial expansion and the actuator is configured to cause further radial expansion.
In some examples, the actuator is configured to allow a user to sense a level of force required by the actuator to cause radial expansion, thereby providing a user indication of when tissue is engaged and to what extent the tissue is being pushed by said further radial expansion.
At least one electrode is configured for radial expansion to exert a radial force to dilate soft, compliant tissue yet conform to harder stenosed tissue without causing dissection or perforation, said force being in the range of 0.1 N/mm2 to 1 N/mm2.
In some examples, the electrode or an expandable body to which an electrode is mounted is formed from a laser cut tube, which has been heat set to a preferential expanded shape to which it will return at or below body temperature if unconstrained. At least one electrode comprises a mesh with a 1-over-1-under-1 strand braiding pattern of strands having diameters in the range of 0.02 mm to 0.25 mm diameter. In some examples, said electrode comprises a number of strands in the range of 8 to 96.
In some examples, at least one electrode comprises a mesh comprising a structural layer of 8 to 24 wires having a diameter in the range of 0.15 mm to 0.35 mm, and a fine layer of 24 to 96 wires of diameter in the range of 0.01 mm to 0.1 mm. In some examples, the length in the longitudinal direction of at least one electrode is in the range of 0.5 mm to 75 mm.
In some examples, the longitudinal distance between at least two electrodes is in the range of 1 mm to 40 mm, optionally 2 mm to 20 mm.
In some examples, the probe comprises at least two electrodes of different stiffness, configured for different levels of penetration into tissue.
In some examples, at least one electrode is mounted to, or itself forms, an expandible mesh with:
In some examples:
In some examples, at least one electrode is mounted to an expandable body for movement between said retracted and operative positions.
In some examples, the expandable body comprises an expandable mesh. In some examples, the expandable body comprises a mesh comprising at least two elements of different diameter and/or strength.
In some examples, the expandable body comprises a balloon to which an electrode is mounted.
In some examples, at least one electrode comprises a feature for extending radially into tissue in use. In some examples, the feature comprises a barb or a needle, and a laser cut tube has a barb feature as part of its laser cut pattern, optionally, one or more needle(s) may be shrouded. In some examples, at least one needle is shrouded.
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 and there is a separator between each successive electrode and the next electrode. In some examples, the probe comprises proximal and distal barrier balloons defining a space, in use, enclosing at least two expanding bodies, the space being to enclose aa fluid agent introduced into the space to assist electroporation.
In some examples, the probe further comprises an internal balloon to adjust volume of said space by being expanded to a desired extent.
In some examples, the internal balloon is located to act as an insulating spacer between juxtaposed balloons. In some examples, the probe comprises a spacer between axially spaced apart electrodes, and said spacer comprises a plurality of parallel spacer elements.
In some examples, at least one electrode has an operative position which is further from the longitudinal axis that the operative position of another electrode, and said electrodes are overlapped in the longitudinal axis but not contacting each other.
We also describe an electroporation device comprising a probe as described in any embodiment and an electrical drive for delivering pulses to the electrodes via the conductors.
In some examples, the electrical drive is configured to independently apply variable voltages, preferably from a generator linked with the proximal end of the probe. In some examples, the electrical drive is configured to provide pulses matching, or specific to, the electrode position.
In some examples, the actuator is configured to move the electrodes to an intermediate position between said retracted and operative positions, and the electrical drive is configured to provide pulses matching the intermediate electrode position. In some examples, the drive allows selective activation of specific electrodes.
In some examples, the device comprises an endoscope and wherein the probe has lateral dimensions in the retracted position to allow entry to the body via an endoscope instrument channel.
In some examples, at least some electrodes are movable axially, and the actuator is configured to move at least one electrode to optimise electrode spacing.
In some examples, the probe comprises a strain gauge or pressure sensor for providing feedback during electrode actuation, the sensor being configured to provide feedback on the force required to displace diseased tissue.
In some examples, the probe comprises a balloon expandable body to which at least one electrode is mounted and the actuator comprises a handle adapted to allow a user to feel the force required to inflate the balloon.
In some examples, the actuator comprises a mechanism and a user handle which is movable with a force related to the resistance to radial expansion of the electrode.
In some examples, the probe comprises a safety device to prevent application of force above a limit by an actuator. In some examples, the probe comprises a sensor for sensing patient tissue and/or for sensing the electrode position, and the actuator is configured to move the electrodes to a position in contact with tissue but not exerting forces in excess of 1 N/mm2 on the tissue, to reduce chance of tissue dissection, and optionally said sensor comprises a strain gauge.
In some examples, the probe comprises a sensor to provide electrical feedback to system such as an electrical drive of the electrodes or expanding body.
In some examples, the probe comprises a conduit extending distally for delivery of a fluid at or near the electrodes. In some examples, the device comprises a fluid controller for controlling delivery of a fluid via said conduit. The controller may be configured to control fluid delivery according to position of the electrodes. The electrical drive may configured to control drive pulses according to delivery of a fluid, for example according to timing and electrical characteristics of the fluid. The fluid controller may be configured to cause delivery of any one or more of a foam and a liquid, and the fluid may include a therapeutic agent.
The electrical drive may configured to vary pulse voltages according to sensed parameters including one or more selected from: electrode position, conductivity of the region at the electrodes, and therapy timing regime. The fluid controller may be configured to cause administration of a foam directly to both tissue and surface area surrounding the device.
The foam may include a cationic solution such as lidocaine HCL with the aim of reducing the electrical field strength required for electropermeabilisation of the cell membrane.
We also describe a method of use of the device comprising inserting the probe along a lumen of a human or animal body until the electrodes are located at a longitudinal position of tissue to be treated, and actuating the electrodes to perform electroporation treatment of the tissue.
In some examples, the probe comprises a plurality of longitudinally spaced-apart electrodes, and the probe is positioned to provide an electric field in a region between two electrodes for treatment of tissue in said region. The electrodes may advantageously be moved radially to expanded positions at which they converge together to cause pinching of tissue in said region. Said tissue may be a pre-cancerous nodular polyp.
In some examples, the probe is moved to a series of a plurality of longitudinal positions and the electrodes are actuated at each said longitudinal position, and the positions are chosen so that there is a desired level of overlap in treated regions to achieve a desired level of electroporation in each region. The extent of overlap may be chosen to achieve RE or IRE.
A fluid may be injected into a region between two spaced-apart electrodes, to enhance electroporation in said region.
We also describe an electroporation probe having an elongate support with electrical conductors and extending from a proximal end to a distal end, the support supporting at least two electroporation electrodes connected to the conductors and being mounted to engage tissue in the wall of a lumen in use.
Preferably, the probe comprises an actuator to move the electrode in a direction having a radial component from a retracted or collapsed position to an operative position for contact with tissue. The probe may be part of a medical pulsed field delivery device for delivery of electroporation treatment to tissue in cancerous or pre-cancerous regions of a lumen such as the gastrointestinal tract. Preferably, the expanding body of the electrode is configured to engage with the tissue with sufficient force to ensure electrical contact between the electrode and the tissue is maintained during delivery of pulsed field electroporation.
Preferably, the expanding body of the electrode is configured to conform to tissue structures which are rigid and non-pliable, rather than forcing these to move or compress, thus ensuring a large contact area between electrode and the tissue while simultaneously ensuring the electrode does not cause perforation or dissection of the luminal tissue. When tissue structures are flexible/pliable, the electrode stretches the tissue to ensure adequate contact.
The probe may have a plurality of electrodes. An electrode may be movable by being mounted to, by being engaged by, or by being an integral part of, an expanding body. The expanding body may comprise a balloon.
Where there is a plurality of electrodes, they may be mounted to radially opposing sides, for contact with tissue across which pulsed electric fields are applied. Preferably, the electrodes are arranged to be collapsed during device delivery into the lumen. In one example, the actuator is configured to move the electrodes to an intermediate position between said retracted and operative positions. Preferably the probe has lateral dimensions to allow entry to the body via an endoscope instrument channel. The probe may comprise an expandible body supporting the electrodes.
The expandible body may comprise an expandible metallic wire mesh. Such a mesh may be of stainless-steel wire or of a shape memory alloy such as Nitinol. The expandible body may comprise a polymer mesh with attached or overlayed electrically conductive elements acting as the electrode. Preferably, the expandible body comprises materials that can deform during actuation without undergoing plastic deformation that impacts the ability of the device to be actuated from its collapsed to its expanded form repeatedly.
At least one expanding body may be formed from a laser cut tube such as a Nitinol tube, and preferably the tube has been heat-set to a preferential 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 elongate member until such time as the user allows its return to its preferred shape, and such a member may comprise a pull wire attached to one end of the heat set Nitinol which holds the collapsed the frame until such time as the user allows its return to its preferred shape.
In another embodiment the expanding body (such as a laser cut tube or wire mesh) has not been heat set to a preferred expanded state but rather can be actuated to such state as a result of the mechanical configuration of its body through positive action by the user. This might be achieved through movement of a pull or push wire or tubular member. In these situations, when Nitinol is used, it may be used primarily for its super-elastic properties which allow it to experience increased localised strain, like that seen during delivery through tortuous anatomy, without permanent deformation of its structure such that it will remain functional after delivery. In order to achieve this Nitinol's Active Austenite Finish Temperature (AAFT) must be suitably tuned such that the material operates within its super-elastic temperature window at the temperature at which the device is used in its operating environment.
In yet another embodiment the movement from collapsed to expanded state for the expanding bodies is some combination of heat set shape and mechanical configuration of the body. Preferably the actuator comprises a sheath which constrains the heat set tube until such time as the user allows its return to its preferred shape, to allow its expansion to the operative position.
The Nitinol mesh may have a pre-programmed (memory) expanded form to guide the shape and position of the expandable body (a) at initial delivery and (b) as the body is further expanded. This programming of the expandable body as it is expanding will help maintain optimum electrode gap, thereby optimum electrical field and also optimum tissue engagement. In yet another embodiment the pre-programmed expanded form may have a shape which ensures inter electrode distance is well maintained regardless of diameter at which device is deployed.
In some examples, the probe comprises a plurality of sets of electrodes spaced apart in the longitudinal direction. At least some electrodes may be moveable in relation to the next electrode to optimise electrode spacing and ensure adequate tissue contact.
In some examples there are a plurality of electrodes and at least one electrode has an operative position which is further from the longitudinal axis that the operative position of another electrode. In one example said electrodes are overlapped in the longitudinal axis but not contacting each other.
Preferably, the electrodes and/or the expanding body are configured to cause tissue being treated to be pulled in between electrodes during their expansion to their operative positions. In one example, the electrodes and/or the expanding body are configured to cause tissue to be pinched between the electrodes.
In one example an expanding body comprises a balloon and the electrodes are embedded in or on the balloon surface. In one example at least one electrode and/or an expanding body comprises a feature for extending into tissue in use, the feature comprising for example a barb or a needle. In one example a laser cut tube has a barb feature as part of its laser cut pattern. One or more needles may be partially or fully shrouded.
Preferably, the probe comprising a sensor for providing feedback during electrode actuation. In one example the sensor is configured to provide feedback on the force required to displace diseased tissue. The probe may be configured to provide user haptic feedback such that a user can feel an increase in force required to actuate the electrode from its collapsed to its expanded form as it displaces diseased tissue.
In one example, the expandible body comprises a balloon and the actuator comprises a handle adapted to allow a user to feel the force required to inflate the balloon. In one example, the actuator comprises a mechanism and a user handle which is movable with a force related to the resistance, imparted by the tissues to be treated, to expansion of the expandible body.
In one example, the mechanism has low friction between moving members such that when actuated from collapsed to expanded form while the body is unconstrained the force required is consistently low. In one example, the actuator is configured to limit mechanical advantage so that a user can perceive a ramp-up in force needed to cause expansion of the expandible body.
In one example the probe may be constructed such that the user can feel the increase in force required to actuate the electrode from its collapsed to its expanded form as it displaces diseased tissue. In practice achieving this through design depends on the choice of user actuated handle, for example if this is applied to the balloon driven expansion and a syringe style handle is used the user will feel the force required to inflate the balloons provided the lumen through which the inflation media is sufficiently rigid and does not itself introduce “noise”. Achieving this with mechanical actuation, similarly, requires that the designer used suitably rigid materials for conveying actuation forces and desirably achieve low friction between all moving members such that when actuated from collapsed to expanded form while the device is in free air the force required is consistently low. It is also desirable to limit the amount of mechanical advantage given to the user during design of the actuation handle as this will correspondingly decrease their ability to perceive a ramp up in force that they need to apply in order to expand the expanding bodies.
In one example the probe may be constructed such that the user can feel the force required to actuate the electrode or electrodes from their collapsed to a partially expanded form such that the user determines that the electrodes are expanded sufficiently against tissue such as to create a reliable contact area with said tissue for delivery of electrical pulses with the understanding that additional expansion may result in undesirable effects on the lumen such as dissection or perforation. This may facilitate the end user in achieving successful safe treatment of areas which cannot be directly visualised, via the visual guidance of an endoscope's camera, or indirectly visualised using, using x-ray guidance. If end-users feel sufficiently comfortable with this mode of treatment this will allow treatment in a greater range of treatment settings including ambulatory healthcare settings.
In one example the probe may be constructed such that the electrodes actuation is mechanically or pneumatically connected such that during electrode actuation electrodes expand to different diameters depending on the lumen diameter and tissue stiffness surrounding the individual electrodes, in this way the user senses during performance of the action to actuate compound force feedback from the group of electrodes.
In one example the probe comprises a safety device to prevent application of force above a limit by the actuator, and the limit may be user defined. In one example the probe comprises a channel extending distally for delivery of a fluid, preferably at or near the electrode.
In one example, the probe comprises a sensor to provide electrical feedback to system such as an electrical drive of the electrodes or expanding body. In one example, the prove comprises a sensor for sensing patient tissue and/or for sending the electrode position, and the actuator is configured to move the electrodes to a position in contact with tissue but not exerting forces on the tissue, to reduce chance of tissue dissection.
We also describe an electroporation device comprising a probe of any example described herein, and an electrical drive for delivering pulses to the electrodes via the elongate support conductor. The electrical drive may be configured to independently apply variable voltages, preferably from a generator linked with the proximal end of the probe.
In one example, the electrical drive is configured to provide pulses matching, or specific to, the electrode position. In one example, the actuator is configured to move the electrodes to an intermediate position between said retracted and operative positions, and the electrical drive is configured to provide pulses matching the intermediate electrode position.
The actuator may be user-operable, or in other examples it is automatic. The drive may allow selective activation of specific electrodes. The device may comprise a conduit for delivery of a fluid via the elongate support. The device may comprise a fluid controller for controlling delivery of a fluid via said conduit. The controller may be configured to control fluid delivery according to position of the electrodes. Preferably, the electrical drive is configured to control drive pulses according to delivery of a fluid, for example according to timing and electrical characteristics of the fluid.
The fluid controller may be configured to cause delivery of any one or more of a foam and a liquid. The fluid may include a therapeutic agent.
Preferably, the electrical drive is configured to vary pulse voltages according to sensed parameters including one or more selected from: electrode position, conductivity of the region at the electrodes, and therapy timing regime.
In various examples, the expanding body is configured to engage with tissue with sufficient force to ensure electrical contact between the electrode and the tissue is maintained during delivery of pulsed field electroporation.
In various examples, the expanding body is configured to conform to tissue structures which are rigid and non-pliable.
In various examples, the expanding body comprises materials that can deform during actuation without undergoing plastic deformation.
In various examples, the expanding body comprises a mesh having a shape memory expanded form to guide the shape and position of the expanding body at initial delivery and as the body is further expanded, to maintain an optimum electrode gap.
In various examples, the expanded form has a shape which ensures inter-electrode distance is well maintained regardless of diameter at which device is deployed.
In various examples, the probe comprises a plurality of sets of electrodes spaced apart in the longitudinal direction, and at least some electrodes are moveable in relation to a next electrode to optimise electrode spacing and ensure adequate tissue contact.
In various examples, the probe is adapted to provide haptic feedback to allow a user to feel a force required to actuate the electrode or electrodes from their collapsed to a partially expanded form.
In various examples, the electrodes are mechanically or pneumatically connected to provide aid haptic feedback.
In various examples, the expanding body comprises a mesh network of a material such as nickel titanium alloy, Nitinol, strands interwoven to achieve a basket form which can be collapsed down by pulling the mesh ends in opposing direction using attached cuffs. In various examples, the mesh is constrained in a 1-over-1-under-1 pattern. In various examples, the expanding body comprises a 1-over-1-under-1 pattern braiding of strand diameters in the range of 0.02 mm to 0.25 mm diameter, preferably 0.1 mm to 0.2 mm diameter.
In various examples, the expanding body comprises wires of two or more different diameters or materials, one diameter or material which imparts the required strength to the body for actuation while the other diameter or material is more flexible and more tightly packed, imparting conforming characteristics to the expanding body and ensuring optimum tissue contact. In various examples, the expanding body is oversized for the intended treatment lumen by 20% to 800% diametrically, preferably 20% to 500%.
In various examples, the expanding body is oversized for the target vessel this contact area expands axially as the electrode is further actuated from collapsed to expanded state creating an annular cylindrical contact area which allows greater delivery of energy to the lumen and thus opportunity for larger electroporated volumes.
In various examples, the expanding body comprises strands of a material such as Nitinol, configured to undergo a heat set step in its production which imparts to it preferred electrode shapes which have desirable attributes.
In various examples, the probe further comprises a physical separator between axially juxtaposed expanding bodies. In various examples, the probe comprises at least four axially separated expanding bodies and there is a separator between each successive body and the next body.
In various examples, the probe comprises proximal and distal barrier balloons defining a space, in use, enclosing at least two expanding bodies, the space being to enclose aa fluid agent introduced into the space to assist electroporation. In various examples, the probe further comprises an internal balloon to adjust volume of said space by being expanded to a desired extent. In various examples, the internal balloon is located to act as an insulating spacer between juxtaposed balloons.
In various examples, the probe comprises at least two expanding bodies of different stiffness, configured for different levels of penetration into tissue. In various examples, the probe comprises at least two expanding bodies of different stiffness, configured for different levels of penetration into tissue, said differences being in response to per-body individual adjustment by an actuator.
In some examples, the expanding bodies are expanded by one user action but said expanding bodies control method is linked such that in expanding to contact tissue one or more expanding body may reach a greater expanded diameter than one or more other as a result of balancing of forces exerted by the tissue on the expanding bodies.
In some examples, the expanding body actuation can be independently controlled by the user allowing user control over individual electrode expanded diameter.
The invention will be more clearly understood from the following description of some embodiments thereof, given by way of example only with reference to the accompanying drawings in which:
Referring to
The drive may comprise a main controller linked with a user interface and with a probe drive circuit, the controller and the interface providing the user-side functions, whereas the drive circuit provides the pulses to probe electrodes.
The drive circuit comprises:
A touch screen interface is operably coupled to the drive controller which manages the generation of the high voltages and the pulse control, and the voltage, pulse duration, polarity and orientation. This level of control is achieved via the series of control circuits.
The controller is configured in some examples to apply to each electrode a ramp-up (tr) duration of less than 0.5 μs to a plateau (U) amplitude in the range of 100V to 3000V for a duration in the range of 1 μs to 5 μs, and a ramp-down (tf) duration from said voltage of less than 0.5 μs for each probe electrode terminal. The amplitude is in some examples in the range of 700V to 1600V and the pulse plateau duration is in the range of 1 μs to 3 μs, and preferably the energized on time during which pulses are delivered is in the range of 100 μs to 300 μs. Preferably, pulses are delivered in immediate succession. Preferably, the bipolar frequency is in the range of 100 kHz to 500 kHz.
The switch controller receives a low-voltage DC input of say 48 V. This input level sets the resultant pulse intensity level delivered to the probe 1. The switch controller adjusts the time that the transformer primary is energised to control the output voltage on the capacitors. Feedback from the output to the switch controller (with suitable isolation through medical grade optocoupler devices) enables the voltage to be precisely set and maintained. Thus, the capacitor output voltage can be varied over a large range (typically 100V to about 5 KV).
As shown in
The probe can expand in an occluded vessel. Preferably, at least one electrode is in the form of, or is mounted to, an expanding body (or “expandable body”, or “basket”) which will dilate compliant tissue to ensure adequate contact and encourage surrounding tissue to fall between the expanding bodies. In other embodiments, the expanding body is constructed as to conform to tissue structures which are rigid and non-pliable, rather than forcing these to dilate, move or compress, thus ensuring a large contact area between electrode and the tissue while simultaneously ensuring the electrode does not cause perforation or dissection of the luminal tissue.
The basket may be manufactured with Nitinol, taking advantage of the shape memory capabilities for expansion when unsheathed. However, more secure expansion may be incorporated into a hand controller, probably as a slider or thumb wheel mechanism for actuation. The device may be required to expand to different diameters based on the lumen being treated and the shape of the lesion being treated, which depends on the pre-cancerous tissue geometry or the stage of cancer, which influence tumour geometry, stage of cancer developed in the patient from 4 mm-40 mm. Again, this may be in the form of expansion control by the clinician using the hand control or a family of devices, each a different size performing the same task in differently occluded vessels. In various examples, the expanding body comprises wire of two or more different materials, one or more materials which impart the overall mesh shape but are non-conductive and constrains another material or materials which somewhat contributes to the mesh form but primarily act as the electrodes through which electrical pulses are delivered.
The expanding body may be made up from any desired number of struts (for example members extending from the elongate support, then approximately parallel to the longitudinal axis, and then back into the elongate support), for example 6 to 192 struts, and the struts may be arranged circumferentially. The axial parts of the struts act as the electrodes to deliver the pulses. Within the scope of the electrode design, the addition of sensors wired to the electrodes is possible. These sensors may include but are not limited to impedance sensors, location/device proximity sensors and temperature sensors for example.
The sensor may comprise a strain gauge or pressure sensor for providing feedback during electrode actuation, the sensor being configured to provide feedback on the force required to displace diseased tissue.
The expanding body may be made up of a mesh network of nickel titanium alloy, and/or Nitinol, and preferably strands are interwoven to achieve a basket-like form which can be collapsed down by pulling the mesh ends in opposing direction using attached cuffs. This mesh may be the tightly constrained 1-over-1-under-1 pattern most common in braided tubes or a less constrained pattern which allows more strand freedom such as the 1-over-2-under-2 pattern further enhancing the ability of the mesh to conform to irregular tissue morphologies. The mesh expanding body utilizing 1-over-1-under-1 pattern braiding may be comprised of strand diameters in the range of 1 mm to 10 mm diameter, preferably 4 mm to 8 mm diameter. Nitinol strands resulting in the ideal combination of strength, elasticity, current carrying capacity and surface area for conforming to irregular tissue morphology and delivering pulsed field electroporation.
The expanding body may comprise two or more different wire diameters or materials, one diameter or material which imparts the required strength to the basket for actuation while the other diameter or material is more flexible and more tightly packed, imparting conforming characteristics to the expanding body and ensuring optimum tissue contact. Nitinol wire diameters in the range of 0.125 mm to 0.25 mm, preferably in the range of 0.15 mm to 0.20 mm are desirable for provision of stiffness to the mesh basket form while Nitinol wire diameters in the range of 0.025 mm to 0.1 mm, preferably in the range of 0.025 mm to 0.075 mm are desirable for creation of a flexible mesh with small openings in between the larger diameter strands. For example, a basket of eight 0.2 mm diameter nitinol wires and forty 0.05 mm diameter Nitinol wires will have the enhanced strength of including some 0.2 mm diameter wires with a corresponding smaller wrap diameter and smaller inter wire gaps in the basket as a result of the inclusion of 0.05 mm diameter wires in greater number than would be possible with larger wire diameters.
An additional benefit of the use of a stiffer wire for overall electrode shape in conjunction with less stiff wire is the ability of this overall construction to be fine-tuned to improve the ability of the electrode to grip tissue as the less stiff wire will somewhat deform away upon contact with the tissue during deployment while the stiffer wire will deform to a lesser extent creating a surface that interacts with the tissue that could be described as bumpy or rough akin to the addition of ridges to tires to improve grip.
The expanding body in going from its collapsed to its expanded state to contact the target vessel the device may undergo a large percentage diameter change, up to 1000%. In addition, it may be oversized for the intended treatment lumen by 20 to 800 percent diametrically, preferably 20 to 500 percent. This additional oversizing ensures that during actuation from a collapsed to an expanded stated the electrode body encounters tissue and is forced to conform to said tissue due to the expanding bodies inherent design and material composition. Having contacted tissue at one point all around the vessel the electrode has a narrow electrical contact area that is circular or elliptical, were the electrode not oversized this may be the contact area for delivery of pulses. When the expanding body is oversized for the target vessel this contact area expands axially as the electrode is further actuated from collapsed to expanded state creating a cylindrical contact area which allows greater delivery of energy to the lumen and thus opportunity for larger electroporated volumes. For this reason, a larger percentage oversizing will allow the user to, through movement of the actuator controlling deployment, decide on the effective length of each electrodes contact area.
The expanding body may include strands of a memory material such as Nitinol and undergo an additional heat set step in its production which imparts to it preferred electrode shapes which have desirable attributes, for example the expanding body ends may be bulbous in shape resulting in more consistent inter electrode distance at varying treatment diameters. This in turn will result in more consistent v/cm electric field strengths imparted to treated tissue.
The expanding body may incorporate an outer and an inner series of electrodes that will be oppositely charged to provide optimal electroporation to the tissue. The wires are delivered through the lumen and will not be exposed. The device may have capabilities to deliver foam to the lesion via small holes in the electrode struts, down the devices elongate body in a lumen for said delivery or through the overlayed sheath. This will likely be the case for pre-cancerous or early-stage oesophageal or colon cancer treatment whereby the electrode struts are coated in a foam allowing for delivery of higher electroporation voltages.
The device may be wired internally through a multi lumen extrusion with 2 to 20 lumens and a sheath on top to contain the body from expanding. The active length of the electrode is between 5 mm and 150 mm in length which is the length of the lesion that can be treated circumferentially by the pulses delivered.
Each expanding body/electrode may be movable in relation to the next electrode to optimise electrode spacing and ensure adequate tissue contact. In one embodiment this is achieved through having each electrode attached to a separate elongate member, 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.
An alternative embodiment of the device incorporates spring-loaded deployment and recapturing functionality.
The electrically connected expanding bodies of any embodiment may include Nitinol, or another self-expanding material, making use of the shape memory capabilities of the material to conform to their original set shape when deployed from a delivery catheter under control of the clinician via the hand controller. The expanding bodies (‘baskets’) may comprise any of a range of other materials which can be designed such that they can be actuated from a collapsed to an expanded state. Another embodiment uses a polymeric balloon to expand a flexible electrode fabric in order to create a similar electrode shape. It is estimated the length of each expanded basket, in its expanded shape, will be 0.5 mm to 75 mm but more preferably 1 mm to 5 mm with a diameter of 4 mm to 40 mm. The distance between the baskets is ideally 2-20 mm (but could range from 1 to 40 mm).
In some embodiments the entire expanding body, such as a mesh, acts as the electrode, and in other embodiments a portion of the mesh is constructed of non-conductive elements or shrouded to prevent its acting as an electrode. This may be used in manufacturing a device where a subset of the full 3600 is configured to perform electroporation. A method of achieving this involves producing the mesh from both conductive and non-conductive wire.
To position the probe, in one example an endoscope is positioned upstream of the lesion and a guidewire is advanced through the narrowed Oesophagus before the sheathed device is advanced to the distal region of the malignant tissue.
Treatment may be performed with delivery of electroporation pulses alone or in combination with a therapeutic agent. Such agents include chemotherapeutic drugs, calcium or a foam solution.
The procedure is performed by placing the probe distal end at the distal end of the lesion, actuating/expanding the device and delivering the required pulse, then collapsing and retracting the device a known length before actuating again and pulsing to treat the next area. This can be repeated until the full tumour length is treated. The device in its initial positioning and deployment is essentially a bipolar electrode, with a capability of generating an electrical field in one place. When deployed, and preferably at least two electrodes expanded, the electrodes operate on multiple planes to generate a more homogenous electrical field.
In some cases, the length of the tumour will be greater than the distance between the electrodes (5-20 mm). During a procedure, for an occlusion of greater length than the gap between the electrode baskets, the pulses are delivered, and the device is collapsed before advancing further into the tumour (or if starting at the furthest point of the tumour, the device will be retracted rather than advanced). Once past the electroporated region, the device is redeployed, and pulses delivered. This process is repeated until the clinician is satisfied that they have covered the malignant tissue successfully. Some overlap of electroporated areas may be required to ensure full tumour treatment.
In another embodiment, the device may be configured such that clinically relevant irreversible electroporation is only achieved through two or more applications of the programmed pulse train to a given fragment of tissue. This may be advantageous for lesion lengths in excess of the length of the active portion of the device where an overlap region is required to prevent gaps between each pulse delivery and ensure adequate treatment. The clinician using the device can be trained to deliver a pulse, collapse, advance or retract the device by some portion of its active length, expand and deliver a subsequent pulse repeating this until the full lesion length has been covered with the overlap region which has undergone sufficient dosage being the treated region. This method of device configuration and use would lessen the potential for a clinician to miss portions of tissue as a result of inadvertent movement of the device by a distance in excess of the active length. This method of treatment would also decrease the impact of any single device placement being in some manner “sub-optimal”.
The actuator of the device may include a handle with a slider mechanism with multiple positions, allowing for expansion to a range of diameters from for example 2 to 30 mm depending on the presentation of the tumour. After being released from the sheath, a setting to lock the device in its expanded position and a collapsed setting to relax the basket allowing for the device to be pulled upstream to the next position. This part of the procedure varies with the drug delivery method, if present. The device may not need to be fully re-sheathed in some cases to be repositioned, the tension can be relaxed and the device pulled back through the lesion to the next treatment zone before the clinician re-deploys the device fully and locks the position.
In another embodiment, the device handle may include a slider mechanism for actuation of deployable needles from the device distal end. This may be achieved by movement of a push/pull elongate member which is attached to a sleeve. The sleeve may be manufactured from a laser cut tube from which the needles have been laser cut and remains part of or alternatively to a sleeve which the needles have been attached to by other means.
This force to cause actuation could equally be conveyed from user to the needle sleeve through pneumatic means.
In another embodiment, the parallel surfaces of a balloon, if present, may have attached a flexible electrode which would allow further electroporation to be delivered between the needles or in cases where use of the needles may pose excessive risk to the patient.
In another embodiment, a metal frame is used instead of a balloon to direct needles radially outward to contact the tissue. These may be deployed from the arms of a basket shape. The strut diameter is in one preferred example 0.6 mm (could be 0.3 to 1.9 mm in other examples). Heat set Nitinol may be used to deploy when unsheathed through a delivery sheath, ideally delivered through the biopsy channel of the endoscope but could also be delivered over a guide wire or a sheath attached to the outer surface or tip of the endoscope. The needles are deployed after the basket is expanded. Needles may be located in hollowed arms of the basket and deployed using a push pull mechanism which could be mechanical, electrical, magnetic, pneumatic or hydraulic.
A procedure may be performed endoscopically, using a live feed camera for guidance with either a single or double channel endoscope; this is dependent on the treatment method. For delivery of a fluid to enhance electroporation (for example IV Bleomycin and/or foam), a single channel endoscope is sufficient, while a double channel endoscope may be used for Calcium injection treatment method. An advantage of this device is that there is no visual obstruction or obscuring caused by the device blocking a camera lens. Hence, the clinician is more likely to achieve correct device placement for optimal performance.
In some examples, once the scope has been appropriately positioned in the distal region of the lesion, a guidewire is delivered 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, encouraging ingress of cancerous or pre-cancerous tissue before the electroporation pulses are delivered. At this point, the clinician may have the ability to increase/decrease the expanded diameter using a push/pull wire linked to the handheld controller. The device can then be re-sheathed and retracted along the lesion to the next treatment zone. This may be repeated until the full treatment zone has been electroporated successfully. For procedures involving foam or Calcium, additional steps are required.
The expanding bodies 3 and 4 of the probe 1 each comprises a mesh of strands which are all conductive.
The actuator has cables along the sheath 2 which allow the bodies 3 and 4 to be compressed to reduce the axial dimension but increase the radial dimension, as shown in
The non-conductive coupling or spacer 5 allows electrodes of the expanding bodies 3 and 4 to sit on opposite sides in the longitudinal direction of a tissue across which pulsed electric fields are applied. The shaft 6 has a proximal end which extends proximally so that a user can advance and withdraw the probe when required. The sheath 2 can be advanced over or retracted back off of the distal end of the probe providing protection during probe movement.
The term “electrode” is used to describe that portion of the probe that is configured to engage with the tissue to be treated, allowing the device to deliver electrical current through the tissue. The electrodes may, together with non-conducting parts of the expanding bodies 3 and 4, be regarded as an “engager” which engages the tissue to be treated in moving from a collapsed to an expanded state at the treatment site. These electrically connected expanding bodies are coupled non conductively to each other wherein the non-conductive coupling(s) allows elements of the expanding bodies to sit on opposing sides of a tissue or tissue across which pulsed electric fields are applied through application of independently variable voltages conducted from the drive or generator outside of the body. The entry of these electrically connected expanding bodies in a collapsed state allows their delivery to treatment sites which may have been narrowed, to varying degrees, by cancerous or non-cancerous lesions. In moving from their collapsed state to their expanded state these electrically connected expanding bodies engage tissue such as to capture tissue and facilitate a large surface contact area between the electrodes and the tissue. This expansion allows elements of the expanding bodies to sit on opposing sides of tissue across which pulsed electric fields are applied through application of independently variable voltages conducted from a generator outside of the body. A larger surface contact area between the electrodes and the tissue protects the tissue from excess current and excess heat and facilitates the delivery of a uniform electric field across the tissue.
There are two (or more in other examples) electrically connected expanding bodies colinear and in series along the probe longitudinal axis at set distances apart. These electrically connected expanding bodies are wired independently such that they are all capable of applying different voltages at different locations, for example each electrode may be individually controller and/or some may be controlled together as groups.
This embodiment has a centrally located lumen through which a guidewire can be used in order to direct advancement of the device through a partially occluded lumen. This embodiment produces an electrical field that is approximately cylindrical in shape wherein the direction of movement of electrons through the tissue and is substantially parallel with the centre line or longitudinal axis of the device and the centre line of the lumen being treated.
This probe is particularly effective when treating luminal tissue where the pre-cancerous or cancerous tissue is circumferential. The electrically connected expanding bodies may be wired such that they form two groups of bodies which when electrically active are at two set electrical potentials. These designs, when implemented with more than two expanding bodies (or “baskets”) substantially increase the length of the lumen which can be treated with one application of pulses.
Other embodiments are disclosed in which the engager comprises two or more electrically connected expanding bodies which are nested or overlapping along the longitudinal axis but which remain non-conductively coupled and in the expanded state, at least, maintaining a distance between electrodes such that they can be used to apply a pulsed electrical field to the tissue. These may produce an electric field approximately cylindrical in shape wherein the direction of movement of electrons is perpendicular to the longitudinal axis.
Embodiments are disclosed (for example in
Embodiments are disclosed in which the probe has shrouded needles which the user may choose to extend outward from the device body piercing into the tissue. These embodiments include versions where needle extension is user controlled or version where needle extension is preset.
Any of the above devices may further be configured to facilitate the delivery of a liquid or foam to the target tissue.
In another embodiment the expanding bodies are made from multiple different components around the circumference which are electrically insulated from each other thus allowing the physician to define that the electrical pulses are only applied to a portion of the circumference in situations where the lesion being treated is not fully circumferential.
Referring to
The body 200 has a laser cut tube construction 201 between couplers 202 and 203. In its preferable implementation this entire body acts as an electrode, the electrode itself being the expanding body. This achieves excellent electrode coverage. However, in some implementations portions of the mesh may be shrouded or be of a non-conductive material to prevent them acting as an electrode. Laser tube cutting is a convenient way to provide an electrode as an expanding body. The couplers 202 and 203 perform the same function as the couplers 102 and 103.
The body 300 has a flexible electrode 301 printed, attached to or laid upon a balloon in a zig-zag pattern circumferentially around the balloon, thereby allowing expansion and contraction. A variation on the features of the body 300 is shown in
As noted above barbs or other features for penetration of tissue for enhanced anchoring in the tissue may be provided, and as shown in
There may be any desired configuration of electrodes, and indeed the electrodes may include needle extensions which extend with a radial directional component for improved physical anchoring in tissue and greater penetration of the electrical field. As shown in
The expanding body may in some examples be constructed of a balloon catheter around which lie multiple needles which lie parallel to the catheter centreline and are enclosed within “shrouding” polymer tubes covering their sharp tips. These needles partially cover one first proximal end of the balloon and a second distal end of the balloon with their needle tips oriented toward the middle portion of the balloon, see
During usage inflation of the balloon re-orients the needle tips so that they are now oriented outwards radially from the catheter shaft, see
When inflating the balloon to re-orient the needles radially some tissue may be stiff and thus cause the needles to be pushed out of their intended and desired circumferential spacing. In such circumstances inflating the balloon fully to push back tissue, deflating partially to allow the needles spacing return to that intended and reinflating to the target balloon diameter may improve the needles spacing. Since each set of needles acts as a unified electrode at a given voltage, the electrical field is not sensitive to the variable needle spacing around the circumference caused by stiff tissue.
In one configuration the needles when emerging from the shroud tubes are substantially perpendicular to the centre line (longitudinal axis) of the catheter. In another configuration, the needles emerge with an interior angle formed between the needle tip centre line and the catheter centre line that is less than 89°, such angle being intended to modify the resulting electric field such that it is more uniform between the two electrode sets as each electrode sets needles are further apart circumferentially the further they extend from the central axis.
On the other hand,
In most examples of the invention the electrodes are spaced axially, but as illustrated in
Turning again to a probe with electrodes spaced axially,
In this example the purpose of the external balloons 1703 is to seal off the space between the expanding electrode bodies, and that of the internal balloon 1702 is to reduce the volume of space between the expanding electrode bodies and to keep a fixed distance between said electrode bodies. This arrangement allows very effective filling of the space between the expanding electrode bodies with a foam or other solution to adjust the conductivity to help ensure adequate electroporation. This also reduces the voltage required to generate an adequate electrical field.
It should be noted that the electrical field is controlled by the width of the contact area between the expanding electrode bodies 1704 and the tissue; the narrower the expanding electrode bodies the narrower the depth of field radially and vice versa.
In some preferred examples each electrode is configured to exert a radial force to dilate soft, compliant tissue yet conform to harder stenosed tissue without causing dissection or perforation, said force being in the range of 0.1 N/mm2 to 1 N/mm2.
These probes are advantageous in that the insulator lengths define the effective electrode distance and thus the distance for communication of electrical pulse waves can be considered fixed. These probes fix the effective electrode distance while allowing for some tissue between the electrodes to remain in-situ.
The colon, and even more so its inner mucosa can be readily manipulated by the moving baskets of the bolero thus drawing the target tissue in between the basket electrodes and thus bring the target tissue into the zone in which the strongest electric field will be delivered. The vessel wall is shown dipping in in
The ability to pull tissue, both healthy and abnormal, into the area in which the electric field strength is highest will allow successful treatment of abnormal tissue and the margins around and beneath these abnormal tissues thus lowering the risk of recurrence which is largely a result of incomplete resection with current therapies where risk inherent in said therapies prevent physicians from treating. The ability to pull, grip or move tissue is primarily influenced by the electrode material, size and shape. The electrodes wires or struts must be sufficiently stiff if made from mesh or laser cut material to allow the electrode to move tissue without simply conforming to the tissue in situations where the tissue is pliable.
The following descriptions are examples of how this is achieved with a two-electrode design, these methods can be used for greater than two electrodes but may need to be altered somewhat. By each electrode having a maximum diameter in excess of the resting diameter of the lumen by a percentage in the range of 20% to 800% and preferably in the range of 20% to 500% means that during expansion the outermost edge of the basket will begin to interact with lumen tissue before the device has been fully expanded, continued actuation moves this outer most diameter outwards but also forwards towards the centre between the two electrodes thus somewhat gripping the tissue.
The electrode's ability to grip the tissue can be improved through the addition of lumps, tines or barbs to the electrode struts or wire thus improving the grip in a local area. In the case of a heat set Nitinol frame or mesh its geometric shape can be chosen such that the electrode achieves the diameter at which it contacts the vessel either closer to the spacer (for example the spacer 1803 in
In addition, the ability to move the electrode bodies closer together during or after electrode expansion allows for the device to achieve a stronger tissue grip and potentially more consistent inter electrode distance than would otherwise be achievable. The ability to move the electrodes towards 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.
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 for the colon. This makes it particularly suitable for pulling tissue such as pre-cancerous nodules in the wall of the bowel, for example, but also in lumens such as anywhere in the GI tract oesophagus.
However, in other examples 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 m for the urethra.
As shown in
The physician may in many cases, be in an environment where the GI tract is obstructed and thus the endoscope camera will have a somewhat obstructed view. With the “overlap technique” of
The elongate support in various embodiments includes the guide wire and/or a shaft and an electrical conductor for conducting power to the electrodes. The electrodes may be individually driven via separate elongate conductors or driven together. The elongate support may also include one or more lumens as conduits for flow of a fluid to assist electroporation. The electroporation device may include a supply of fluid, such as a solution, or foam (gas and liquid). The fluid may be chosen for optimization of electrical characteristics and/or pharmaceutical or biological therapy. The fluid may be of any of the types described in our published patent specification WO2021/043779 the contents of which are incorporated herein by reference.
The fluid may be injected, or sprayed from, radial apertures in a shaft at or adjacent to the electrodes and/or via hollow needles which penetrate tissue in use. Such needles may have apertures along their length in addition to at their ends. The needles are connected to the proximal end/handle by means of an elongate member through which the solution is delivered.
The fluid may be in the form of a foam, being a liquid with very small bubbles of a gas. A foam may be used to enhance the permeabilization effect of electroporation, with particularly beneficial results for high frequency electroporation (greater than 100 KHz). Use of a foam is described in more detail below. In this specification the relative concentrations of liquid and gas in the foam are expressed by volume at atmospheric pressure, such as in a syringe when loaded with air and liquid.
The foam may be formed by any suitable means, and indeed it may be done manually by the clinician in a syringe.
A major benefit of utilising a foam for direct injection into the target tissue to be electroporated is that it can act as a carrier if required for the molecule of choice while its impact on tissue conductivity relative to a liquid is superior in that it minimises increases in the conductivity. The air or gas component of the foam bubbles have minimal conductivity relative to a liquid and enable a more favourable environment particularly in the case of high frequency (>100 kHz) pulses, minimising the current delivered and aiding in enhanced cell permeabilization.
The use of high frequency (>100 kHz) bipolar electrical pulses are advantageous for direct cell ablation or cell permeabilization for passive diffusion of molecules. The combination with a foam in some examples confers a benefit to the efficacy of the procedure (relative to using an equivalent liquid solution).
Non-foamed liquid when injected is rapidly diluted by the circulating blood volume. The interaction with blood decreases the efficacy of the liquid solution, due to binding with plasma proteins that ultimately reduces the number of active molecules. A foam on the other hand, is able to displace blood rather than mixing with it, increasing the contact time of a higher concentration of active agent with the tissue and thus resulting in greater efficacy. With foam, a lower concentration of agent can be used to obtain the same therapeutic effect as in their liquid counterpart, reducing the prevalence of side effects associated with higher concentrations.
A foam, due to the presence of bubbles of a gas such as air, is less conductive than the corresponding liquid solution and consequently results in lower currents, higher cell permeabilization and less pain sensation for the patient.
The presence of a cationic molecule within the solution or foam can reduce the electrical field strength required to electro permeabilise the cell wall. Examples of such cationic molecules include Lidocaine HCL.
Foam may in some examples be created by mixing albumin, gas, and a liquid solution, for example in a ratio of 1:4:1 by volume. Preferably, the ratio of gas (room air or CO2 gas for example) to liquid is in a range of 1:2 to 1:10 by volume.
Preferably, the foam used includes one or more of the following:
Preferably, the electroporation pulses advantageously have parameters as follows:
Injecting a foam directly into the environment surrounding the cells rather than a liquid-only substance with the same active agent results in a less conductive environment, enabling more efficient cell permeabilization aiding in the efficacy of electroporation-based treatments.
The efficacy of cell permeabilization (pores being created on the cell membrane) created by short bipolar electrical pulses (<50 μs) is impacted by the tissue conductivity. Higher conductivity of the liquid solution surrounding the cells will result in higher currents which is deleterious to the treatment resulting in poorer cell permeabilization and pain sensation in the patient.
Conductivity increases around the cell are caused in part by the volume of fluid in the area and the local injection of an electroporation solution, which may include a treatment molecule of choice (Calcium, Potassium, Bleomycin, Cisplatin, lidocaine HCL etc) and a large concentration of ions.
Utilising a foaming agent to deliver the therapeutic agent reduces the effect of a high conductivity on the efficacy of electroporation pulses to permeabilise cells.
A foam being made largely of gas or air is less conductive than the corresponding liquid solution and consequently results in lower currents, higher cell permeabilization and less pain sensation for the patient.
Use of a foam injected into the environment to be electroporated will beneficially facilitate the treatment and the degree of cell permeabilization by not increasing the conductivity to the degree that a comparable liquid solution would. The following table sets out some preferred parameter ranges where a foam is injected, but these ranges advantageously apply to liquid injection.
A foam may also be utilised to facilitate dispersion of a local anaesthetic into the tissue to be treated. The local anaesthetic may be lidocaine 5-20 mg/ml with or without adrenaline. Mepivacaine 10 to 30 mg/ml is another example of a local anaesthetic that could be used. Lidocaine HCL presents as a cationic form of lidocaine and can reduce the electrical field strength required for electropermeabilisation of the cell wall. The foam and local anaesthetic could be administrated in combination with a molecule of choice e.g. calcium or potassium ions, bleomycin, DNA; or it could be provided alone.
In one advantageous example the electrodes anchored to each other at the closest point with the opposing ends attached to two individual elongate members to facilitate compression which would impart a diameter increase in the electrodes and forcing them closer together to pinch the tissue. The electrodes may alternatively be self-expanding by shape memory material.
In one preferred example each electrode comprises a braided mesh of Nitinol or steel wire of diameter between 0.025 mm and 0.25 mm in a quantity of 8 to 96 wires and being arranged to collapse to sufficient size to fit through the biopsy channel (or other lumen) of an endoscope. The mesh engages with and stretches the tissue and forms a close-knit layer to ensure minimal apertures between the wires thereby providing a homogenous electrical field.
The mesh may have two separate layers, a structural layer of 0.15 mm to 0.35 mm wires in a quantity of 8 to 24 and a fine mesh layer of 0.01 mm to 0.1 mm wires in a quantity of 24 to 96, provide for an electrode which can collapse to sufficient size to fit through the biopsy channel (or other lumen) of an endoscope and where the structural layer would engage and stretch the tissue and the fines mesh layer would form a close knit layer to ensure minimal apertures between the wires thereby providing a homogenous electrical field.
It is preferred in some examples that there is heat setting of the electrodes such that they are predisposed to ‘grow’ parallel to the opposing electrode to achieve a consistent electrical field.
The actuator provides in some preferred examples an initial radial expansion to return to its predefined diameter. Further actuation of the handle promotes dilation of soft/compliant tissue, or, conforming to the shape of hard/stenosed tissue. The initial expansion may be to a diameter of 20 mm to 40 mm. It is easy to open the electrodes up “in free space” with the handle but is difficult to push them into tissue aggressively. Each electrode “wants” to expand and foreshorten and since it is so easy to open the mesh before it contacts tissue, once it contacts tissue it is immediately clear to the user as the force required to actuate increases drastically. This acts as a very evident safety feature.
The electrode outer diameter is designed to be larger than the relaxed diameter of the target anatomy but never to exceed the maximum dilated diameter of the anatomy to avoid damage/tearing. For example, for the colon this range is minimum of 10 mm and maximum of 40 to 60 mm. This also ensures adequate wall contact of the electrode.
In some advantageous examples, the actuation caused by the user is coupled to both electrodes in such a way that if one is constrained the other continues expanding—this ensures both electrodes open until they engage tissue and then provide a balanced pressure on the tissue at each electrode. The way we achieved this on current design is through the spacer/insulator 5 being attached to each electrode at its ends but otherwise free to move along the central shaft of the device.
It will be appreciated that the invention achieves optimal electroporation whilst avoiding the risk of dissection or perforation. The delivery system is capable of being delivered at a low profile, ideally through the biopsy channel of the endoscope, furthermore (a) for healthy tissue, the electrode embeds into the soft tissue and (b) for diseased tissue which is stenosed or having reduced elasticity, the electrode conforms to the surface of the treated tissue with a force that does not cause undue distention of the tissue resulting in tissue damage. Additionally, the tissue may be a mix of elastic and non-elastic tissue where the device must automatically accommodate both tissue types.
The probe of the invention provides low profile, catheter access to a narrowed or restricted lumen such as in the gastrointestinal tract.
There may be Bipolar electrode drive adjustable according to position between the collapsed and expanded (operative) states.
Treatment can be very effectively applied around a full circumference of a lumen or tissue.
The probe allows delivery of uniform, circumferential EP (electroporation) energy to a tumor. This is enhanced if the electrodes are flexible, on the surface of a flexible balloon, or due to flexibility of an expanding mesh or basket with sufficient stiffness to maintain electrode-tissue contact but not sufficient to cut into the tissue.
The probe allows delivery of EP energy to sufficient tumor volume and depth whilst minimizing risk of tissue dissection/lumen perforation. This is achieved particularly well where the probe includes tines or barbs, and/or where the electrode bodies are configured to pinch the tissue.
The probe may provide haptic feedback to assist optimal contact between the electrodes and patient tissue. Another optional advantageous feature is delivery of a fluid such as foam to the site to modulate conductivity.
Treatment can be applied around 360° (or variations in-between e.g. 180° electrical coverage, with 180° insulated/non-conductive elements to allow for circumstances where a full circumferential treatment is not required or desired), and there is excellent versatility due to the fact that any desired subset of the electrodes may be driven according to either user control inputs, or automatic feedback from sensors detecting parameters such as pressure of an electrode against tissue, degree of expansion or radial position of an electrode.
The devices allow tissue to fall between the arms/struts to maximise the volume of tissue treated.
Devices of the invention may be used for reversible electroporation for electroporation in combination with chemotherapy, Electrochemotherapy (ECT), or with calcium. It has the additional advantage that tumour tissues take up more of the active substance than healthy cells due to their increased conductivity and thus healthy cells can be within the treatment area without this causing excess additional risk to the patient.
Irreversible cell membrane permeabilisation may potentially be achieved at a reduced electrical field strength through the presence of a cationic solution.
The device allows for generation of a variety of electrical fields and can extend the depth of treatment into tissue depending on the specific tumour being treated. The invention is not limited to the embodiments described but may be varied in construction and detail.
| Number | Date | Country | Kind |
|---|---|---|---|
| 22159282.7 | Feb 2022 | EP | regional |
| 22193694.1 | Sep 2022 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2023/054883 | 2/27/2023 | WO |
