Patent Application
20160096015
The present invention concerns a device and a method for electroporation, in general and more specifically the present invention concerns a device and method for administering therapeutical molecules, such as a drug, an isotope or genetic material enhanced by electric pulses causing electroporation of and/or electrophoretic effects in a target region of a patient's body.
In the treatment of diseases in the brain, e.g. brain cancer, as well as diseases in other anatomical areas of a body, physical access to a diseased tissue region may be a challenge. This is especially the case if the diseased region lies deep within the body of the patient. Furthermore, efficient delivery and subsequent uptake of therapeutic molecules, such as a drug or genetic compound, to an anatomical target tissue is often a problem.
Electroporation is a known method used to deliver drugs and genetic material to various biologic tissues, where the uptake of these substances into tissue cells is enhanced through the application of electric pulses of specific amplitude. The delivery of drugs by electroporation is also known as electro-chemotherapy (ECT) and the delivery of genes as Electro Gene Transfer (EGT). In ECT and EGT applications, electroporation is used to create a transient permeabilization of the cell membranes in a target tissue area with the purpose of enhancing the uptake of the chemotherapeutic agents as well as the uptake and expression of genetic materials.
In addition to the delivery of therapeutic molecules, electroporation has a stand-alone application that is known as irreversible electroporation (IRE). In IRE, the amplitude of electric pulses is increased beyond the levels used in ECT and EGT, which creates a permanent permeabilization of the cell membranes in a target tissue area with the purpose of promoting cell death through cell leakage.
In order to provide an efficient electroporation two or more electrode poles have to be brought into—or into close vicinity of—the region to be treated (target region). Examples of devices used for Electroporation are known from U.S. Pat. No. 5,674,267 and U.S. Pat. No. 6,278,895. These devices consist of an array of needle-type electrodes arranged as individual electrodes inserted via some external plate-shaped element providing a fixed distance between and relative position of the individual needles. If the target region is situated in a remote region of the body, such as the deeper regions of the brain, the placement of electrodes may in itself be harmful to intervening tissue through which the electrodes need to traverse in order to be located in the desired region. Furthermore, a large access area must be available, and for applications in the brain this will entail creating a large hole in the patient's skull. Therefore, it is evident that the mentioned prior art devices are only well-suited for treatment in target regions in close proximity to an outer surface of the body, because an attempt to treat deeper-lying regions would cause excessive trauma to the intervening tissue.
There is thus a need for an electroporation device and an electroporation method that overcomes the shortcomings of the presently known devices and methods. It is an object of the present invention to provide such a device and method. It is a further object of the invention to provide an electroporation device which can be manoeuvred to deeper-lying regions of the body or to regions that are otherwise difficult to access, and to do so with the least amount of injury to the tissue. E.g. for applications in the brain, it is an objective to provide a device necessitating the smallest possible entry hole while providing the largest possible electric field. A further object of the invention is to provide an electroporation device capable of delivering an improved, flexible and more efficient electric field in order to enhance the transfer of e.g. a drug, isotopes, genetic materials or other therapeutical molecules through cell membranes of a target tissue/region. By providing an improved, more efficient and more readily controlled electrical field, the energy applied through electrodes to the tissue may be reduced. Thereby, unintended damages to the tissue, especially the tissue immediately surrounding the electrodes may be reduced. There is furthermore a need for a device constituting an alternative to the known devices.
These and other objectives of the invention are obtained by an electroporation device comprising a handle section; an elongate introducer shaft connected to said handle section, said introducer shaft having a distal tip; and a set of electrodes having respective distal ends, each electrode being slidably arranged within said introducer shaft and said tip from a retracted position, where said distal ends are enclosed within said introducer shaft, to an exposed position, where said distal ends extend from said distal tip; wherein said electrode distal ends are deflectable away from a longitudinal axis of said shaft when deployed/extended to their extended position, such that at least one planar projection taken in a plane perpendicular to said longitudinal axis of a distance between a pair of distal ends of said electrodes is larger than a maximal extent of a cross-section of said introducer shaft, said cross-section taken in a plane perpendicular to said longitudinal axis L at a distal end of said introducer shaft.
A significant advantage of the presently described device is that it allows insertion of multiple electrodes to a sub-surface tissue region or target region of a patient's body while causing minimal tissue displacement and damage to intervening tissue. This advantageous effect is obtained due to the small outer extent/diameter or profile of the invasive portion, i.e. the shaft or at least the distal part thereof, of the present device in a direction transversal to the direction of insertion.
The device according to the invention allows sub-surface generation of a pattern of electrode end points (distal ends) resembling e.g. a planar or spatial ellipse or ellipsoidal shape or any other regular or irregular spatial geometric shape that will provide an efficient electric field of controllable shape, suitable for the varying anatomical/geometric shapes of the target regions found in real patients. Furthermore, this can be obtained under such sub-surface circumstances (deeper-lying/difficulty accessible regions) as is not possible with prior art devices, through the sub-surface deployment of multiple electrodes that are angled away from the introducer shaft and comprise respective un-insulated end-points, preferably placed in an equidistant relationship, that may circumscribe the outer periphery of such an ellipsoid or other geometric shape in the target region.
In an embodiment of the electroporation device, the deflection of said distal ends of said electrodes, when in their extended position, is provided by a curving of distributor channels provided in said distal tip. Alternatively or additionally, the deflection of said distal ends of said electrodes, when in their extended position, is provided by tension characteristics of at least a section (in an elongate direction) of said electrodes, i.e. by a biasing of said electrode or electrode section. Alternatively or additionally said electrodes are formed in a material comprising a shape memory alloy.
In one embodiment the distal tip may alternatively or additionally be formed with a substantially smooth, rounded, non-cutting shape with a substantially smooth, non-cutting transition to the introducer shaft proper. Thus, the device has no sharp edges, and injuries to the tissue can be minimized.
In an embodiment the distal tip is connectable to said introducer shaft. Alternatively the tip is formed integrally with the shaft.
In yet another embodiment each of said electrode distal ends can be advanced individually to their extended positions. Thereby, the extended distribution of the electrodes, and thus the shape of the electrical field, may be adapted to the individual target tissue. Alternatively, the electrodes may be advanced or extended from the tip in subsets of electrodes or as one set of electrodes, e.g. such that the length of the individual electrodes are adapted to the target tissue shape.
In yet another embodiment the electrodes are extendable such that said distal ends are extendable to form a spatial distribution around a volume of target tissue/a target region. In one embodiment thereof, the distal ends are extendable to form a substantially spherical distribution pattern. Alternatively at least a subset of said distal ends is extendable to form an ellipsoid pattern in a plane parallel to said longitudinal axis of the introducer shaft.
In any of the above mentioned embodiments said electrodes may be slideably arranged in electrically insulated guide channels formed in the shaft and tip. Alternatively or additionally, said electrodes may be provided with an electric insulation coating, the distal-most part of the electrode distal ends being un-insulated to form point electrodes.
The sub-surface generation of an electric field having a geometric shape resembling an ellipse or other three-dimensional shape will provide a more homogeneous tissue coverage. The subsequent application of short and intense electric pulses to two or more of these, preferably equidistant, electrodes will result in a potential difference between the positive and the negative electrodes and a resulting electric field will be generated between these two or more electrodes.
According to an advantageous embodiment of the invention said introducer shaft further comprises a delivery channel through which a dose of therapeutical molecules can be administered, said delivery channel extending through the length of said shaft and terminating through said distal tip. The delivery channel is provided through the shaft along an elongate axis thereof in order to accommodate the delivery of a dose of therapeutical molecules to the region in the vicinity of the tip of the shaft when the device is inserted into the region of a target tissue. Thus, local administration of therapeutic molecules to a target region can be enhanced. However, it is understood that the device may also be applied in combination with systemic administration of therapeutical molecules, where the electroporation will enhance local uptake of therapeutic molecules in tissue cells in the region/vicinity of the electrodes.
In an embodiment said delivery channel is connectable to an external therapeutic molecule delivery system comprising a therapeutic molecule reservoir and pumping means for administering said therapeutic molecules through said delivery channel. Alternatively, the handle part comprises a therapeutic molecule delivery system comprising a therapeutic molecule reservoir and pumping means for administering said therapeutic molecules through said delivery channel. In either embodiment of the device comprising a delivery channel said device may further be adapted to for introducing e.g. a surgical tool or an ultrasound probe through said delivery channel. This adaptation may comprise a suitable sizing of the delivery channel and/or suitable connection means between the device and the surgical tool. In an alternative embodiment a separate channel may be provided in the shaft for the insertion of a surgical tool or an ultrasound probe.
In one embodiment said introducer shaft has a circular cross section with an outer diameter of 15 mm or less, preferably of 10 mm or less, more preferably of 5 mm or less. However, other cross sections may be provided as well, e.g. oval. in this case the above mention dimensions may apply to the maximal extent across the cross section.
In yet another embodiment the introducer shaft may comprise an outer tube and an inner electrode assembly guide received in said outer tube, and where said electrodes are slideably arranged in electrode guide channels formed in said inner electrode assembly guide. In an embodiment said electrode guide channels are formed in a set of cylindrical guide sheaths that are received in semi-open channels distributed in a longitudinal direction along the periphery of said inner electrode assembly guide. In another embodiment, the introducer shaft may be provided by a multitude of electrode guide channel tubes, each configured to receive one or more electrodes.
The introducer shaft may in one embodiment be rigid. However, in other embodiments the introducer shaft may be flexible and/or steerable, the latter embodiment especially being suitable for insertion through body cavities/transvenous applications.
Such flexible and/or steerable applications may be endoscopic or catheter-based applications in natural channels or lumens in the body, where a flexible/steerable shaft 10 is desirable. Introduction of the device may be through natural anatomical openings or through suitable entry sites such as for instance the femoral artery. Alternatively or additionally, laparoscopic applications through an opening in the abdominal cavity or other areas of the anatomy are envisioned, where the shaft may be introduced via an introducer such as a laparoscope with a working channel or a similar introducer sheath. Such an introducer may, e.g. have a cutting edge, or a removable trocar with a trocar tip that may be removed after insertion of the introducer to facilitate insertion.
In an embodiment, the shaft is substantially straight. However, in other embodiments the shaft may be curved, in order to provide the opportunity to be used in particular anatomic regions (e.g. for tumours of the head and neck) or to circumvent e.g. fragile tissue regions.
Preferably the device comprises 10 or more electrodes. Thus, the electrodes, in extended position, may be spatially distributed to enhance the formation of a spatial electrical field The device, in yet other embodiments comprises 12, 16 or more electrodes.
The device, in yet another embodiment comprises 32 electrodes. In one particular embodiment, said electrodes are slideably arranged within guide channels distributed in groups of four in each of eight cylindrical guide sheaths.
In respect to all of the previously mentioned embodiments an electric stimulus generator may be integrated into the handle section of the device. Alternatively, the device comprises means for connecting/attaching the device electrodes to an external electric stimulus generator.
In one embodiment each electrode or group of electrodes is individually assignable to pass an electrical current, such that the emission of electric stimuli can be provided from individual electrodes or groups of electrodes. Thus an enhanced control of an induced electrical field may be provided. The control or assignment of the individual electrodes or groups of electrodes may be provided by a suitable electronic control unit provided either in the handle part of the device, in the external electronic stimulus generator or as a stand-alone unit.
The tip of the introducer shaft may be a rounded, smooth, atraumatic tip adapted for spreading tissue, thus causing minimal damage to the tissue through which it is to be moved. This is advantageous especially for intravenous applications or applications in e.g. the brain. However, the tip may in other embodiments be provided with a sharpened or cutting tip or a pointed tip that is e.g. suitable for percutaneous applications.
The object of the invention is further obtained by an electroporation method comprising the steps of providing an electroporation device, the device comprising an elongate introducer shaft having a distal tip; and a set of electrodes having respective distal ends, each electrode being slidably arranged within said introducer shaft from a retracted position, where said distal ends are enclosed within said introducer shaft, to an extended position, where said distal ends extend from said distal tip; the method further comprising the steps of inserting said introducer shaft through tissues of a body and bring said distal tip into a vicinity of a target region of tissue to be treated, while said electrodes are in said retracted position; extending said electrodes to said extended position, such that said electrode distal ends are deflected away from a longitudinal axis of said shaft in such a way that at least one planar projection taken in a plane perpendicular to said longitudinal axis of a distance between a pair of distal ends of said electrodes is larger than a maximal extent of a cross-section of said introducer shaft, said cross-section taken in a plane perpendicular to said a longitudinal axis at a distal end of said introducer shaft; administering a dose of therapeutic molecules to said body; and applying through said electrodes one or more electric pulses, e.g. in a specific sequence to the target region tissue to create a transient permeabilization of cell membranes of tissue in said target region.
In one embodiment of the electroporation method according to the invention said dose of therapeutic molecules is administered systemically. In another embodiment of the electroporation method according to the invention said dose is administered locally in the vicinity of the target region. Such local administration may advantageously be delivered before, during or after extending said electrodes, through a delivery channel extending through the length of said shaft and terminating through said distal tip. Alternatively said dose may be delivered locally through a suitable addition injection/infusion device.
The object of the invention may further be obtained by one aspect of a method of generating an electric field in a target region of a patient, comprising the steps of inserting into the vicinity of the target region a set of electrodes, having respective distal ends, enclosed (in a first retracted position) within a single elongate introducer shaft having a distal tip; extending at least a pair of said electrodes to a position extended from their position within said shaft, such that said electrode distal ends are deflected away from a longitudinal axis of said shaft in such a way that at least one planar projection taken in a plane perpendicular to said longitudinal axis of a distance between a pair of distal ends of said electrodes is larger than a maximal extent of a cross-section of said introducer shaft, said cross-section taken in a plane perpendicular to said a longitudinal axis at a distal end of said introducer shaft; and applying through said electrodes one or more electric pulses to the target tissue.
In an embodiment of this aspect of the method of generating an electric field in a target tissue of a patient, the electrodes are point electrodes which are positioned such that when a sequence of electric pulses is applied through some or all of said electrodes an ellipsoid or spatially ellipsoid electric field is generated between some of or all the points that are positioned in the tissue. In a further embodiment said ellipsoid or spatial ellipsoid field is generated by positioning said point electrodes in an ellipsoid or spatially ellipsoid configuration at least partly surrounding or enclosing said target tissue. In yet another embodiment said point electrode distal ends are positioned in substantially circular parallel layers, where the position of the point electrodes in a section perpendicular to said circular layers defines an ellipsoid configuration. In a further embodiment the electric field is generated in the tissue by applying a sequence of electric pulses between at least sixteen point electrodes in at least four essentially parallel, consecutive layers comprising at least four point electrodes in each layer and such that said sequence comprises the steps of generating at least some pulses travelling from at least one of the electrodes in first positive layer of point electrodes to at least one of the electrodes in a first negative layer of point electrodes placed in equidistant relation to the electrodes in the first layer, while other pulses simultaneously travel from at least one of the electrodes in a second positive layer to at least one of the electrodes in a second layer of point electrodes, respectfully.
The object of the invention is further obtained by another aspect of a method of generating an electric field in a target tissue of a patient, comprising the steps of inserting into the vicinity of a target tissue a set of point electrodes, having respective electrically conductive distal ends, and positioning said electrode distal ends in a spatial formation surrounding or enclosing at least partly said target tissue; applying through said point electrodes a sequence of electric pulses to the target tissue.
In an embodiment of this other aspect of the method of generating an electric field in a target tissue of a patient, the point electrodes are positioned such that when a sequence of electric pulses is applied through said electrodes an ellipsoid or spatially ellipsoid electric field is generated in the tissue. In a further embodiment said ellipsoid or spatial ellipsoid field is generated by positioning said point electrodes in an ellipsoid or spatially ellipsoid configuration at least partly surrounding or enclosing said target tissue. In yet an embodiment said point electrode distal ends are positioned in substantially circular parallel layers and where the position of the point electrodes in a section perpendicular to said circular layers defines an ellipsoid configuration. In a further embodiment the electric field is generated in the tissue by applying a sequence of electric pulses between at least sixteen point electrodes in at least four essentially parallel, consecutive layers comprising at least four point electrodes in each layer and such that said sequence comprises the steps of generating at least some pulses travelling from at least one of the electrodes in a first positive layer of point electrodes to at least one of the electrodes in a first negative layer of point electrodes placed in equidistant relation to the electrodes in the first layer, while other pulses simultaneously travel from at least one of the electrodes in a second positive layer to at least one of the electrodes in a second negative layer of point electrodes, respectively.
The invention is advantageously applied in electro-chemotherapy, electro gene therapy especially for treatment of brain cancers, and other diseases of the brain. The present disclosure describes the invention from this point of view, but it is understood that the device according to the invention may also be adapted for applications in the treatment of diseases of e.g. the liver, lung, kidney or other soft or hard tissues. The invention may further be applied in the field of irreversible electroporation.
The device and method may be applied to treatment of humans as well as animals.
In the present document the term shaft should be taken to mean an elongate structure that is either rigid or flexible/bendable/steerable, and either substantially straight or forming a uniform curve at least over a section of the length of the shaft.
In the following the invention will be described in further detail with reference to the drawing. The figures show ways of implementing the present invention and are not to be construed as being limiting to other possible embodiments falling within the scope of the attached claim set.
In
The introducer shaft 10 comprises a centrally located delivery channel 20 (see
In an alternative embodiment (not shown), the channel 20 may be configured to receive an elongate delivery system, e.g. in the form of a tubing, that may reach from the storage means into the region to be treated. Such a delivery system may comprise a syringe connected to said tubing, in such a way that the channel is adapted to receive e.g. a distal section of said tubing.
In yet another alternative embodiment (not shown), the device 1 may provide an integrated therapeutic molecule delivery system comprising delivery means with advancing/pumping means and/or a storage for a medicament/drug, isotope or a genetic material solution, being integrated in the handle section 100.
The electroporation device 1 and the delivery channel 20 may also be configured by e.g. appropriate coupling means and/or dimensioning to receive and guide for instance an ultrasound probe, a surgical tool or another tool for minimally invasive manipulation of tissue. Thus the device 1 can be used in a flexible way, where for example it is not necessary to remove the device 1 and replace it with another specialized surgical tool, if the operator/surgeon encounters unexpected obstacles/difficulties prior to, during or following the electroporation process.
The shaft 10 further comprises a plurality of guide channels 50 (see
In an alternative embodiment (not shown) each guide channel 50 may be provided, at least along a section of the shaft 10, by individual tubes, the shaft 10, in said section being formed by the set of individual tubes.
Each electrode 60 has a proximal end 62, extending into the handle section 100, a distal end 61 and an intermediate region 63 electrically connecting the proximal end 62 and the distal end 61 of each electrode 60.
The proximal ends 62 of the electrodes 60 are configured to act as connectors, thus providing a means of connecting the electrodes 60 to an electric stimulus generator 120 that supplies single electric pulses or sequences of electric pulses according to electroporation protocols for drug and gene delivery. The electric pulses are intended to generate an electric field for the purpose of creating transient permeabilization of cell membranes and/or an electrophoretic effect in the vicinity of the distal ends 61 of said electrodes 60 when the introducer device 1 is placed in or close to a target tissue area and the electrodes 60 are forwarded to an extended position, see further regarding the use of the device below.
The electrodes 60 are connectable to an external electric stimulus generator 120 via an electronic connector (cable) 121 at the handle section 120 as shown in
The configuration of the proximal ends 62 of the electrodes 60 further permits movement of the electrodes 60 between a first retracted position and a second extended position in a deployment sequence that will be further described below.
The intermediate regions 63 of the electrodes 60 are movably received in said electrode guide channels 50 running through the introducer shaft from the proximal end 12 to the distal end 11 at the distal tip 13. Preferably, each electrode 60 has its own channel 50 to support and protect it and insulate it from the other electrodes 60, as shown in
Electrode end points at the distal ends 61 of the electrodes 60 are movably received in distributor channels 70 formed in the distal tip 13, and extending to the outer surface of said distal tip 13. Each distributor channel 70 further communicates with a corresponding guide channel 50 in the shaft proper 10. Thus, movement of the electrodes 60 in a longitudinal direction (with respect to the longitudinal axis of the shaft 10) between a first retracted position where the distally disposed end points 61 of the electrodes 60 are concealed within the distal tip 13, and a second extended position, where the end points 63 of the electrodes 60 are extended from the distal tip 13, is allowed.
In an alternative embodiment (not shown), the device may only have distributor channels 70 formed in the distal tip 13, the electrodes 60 being contained in a hollow shaft 10, the individual channels 50 being left out.
While positioned in the first retracted position, which is the default mode of the device 1, the end points at the distal ends 61 of the electrodes 60 are held in storage in the distributor channels 70 in the distal tip 13, thus permitting the minimally invasive insertion of the device 1, i.e. with minimal damage to surrounding tissue.
The distributor channels 70 are shaped to ensure deployment of the distal ends 61 of the electrodes 60 in a predetermined pattern where a largest distance D1 (See
Alternatively, the deflection away from said longitudinal axis L may be provided by e.g. a pre-tensioning or biasing of said electrodes 60. Such tensioning may be provided by a suitable choice of materials, e.g. a shape memory alloy such as Nitinol, or by forming the (flexible) electrode e.g. in a bent shape, such that when it is arranged in a straight guide channel 50 of the shaft 10 it is held in tension. The individual electrodes 60 or set of electrodes may have an individual biasing such that the electrodes may, when extended from their retracted position in the shaft 10/tip 13 form a desired spatial pattern around the target tissue.
Further, the desired spatial distribution of the part of the electrodes extending from the tip 13 may be provided by a combination of the shape of the tip distributor channels 70 and a biasing of the electrodes 60.
In use, the electronic connection means (not shown) at the proximal ends 62 of the electrodes 60 are connected to a suitable electric stimulus generator 120. The shaft 10 of the introducer device 1 is then inserted, e.g. through a bore hole in a patient's skull or an incision in the patient's skin and introduced to the target region of the patient's body. The precise location of the target region and thereby for the bore/incision may be identified by means of ultrasound, CT, MR or another suitable means, and the correct position of the tip 13 of the introducer shaft 10 (post insertion) may be verified by similar means prior to, during or after deployment of the electrodes. When a correct position of the tip 13 of the introducer shaft 10 has been obtained relative to the target tissue, an operator may deliver a suitable chemotherapeutic agent, in fluid or liquid form, or a dose of genetic material or other substance through the delivery channel 20 and into the tissue region to be treated.
Before, during or after delivery of the drug or genetic material through the delivery channel, the operator may deploy some or all the elongate electrodes 60 in a desired pattern. Deployment is performed by actuating a suitable deployment mechanism at the handle section 100 or at the proximal end 12 of the shaft 10, and results in the longitudinal motion of all or some the electrodes 60 along the axis of the introducer shaft 10 from the first retracted position—as shown in
Upon deployment of some or all of the electrodes to their extended position, an operator may actuate the electric stimulus generator 120 to deliver one or more pulses, e.g. a sequence of short and intense pulses to the tissue to be treated (target tissue). To ensure a suitable distribution of pulses and the thereby induced electric fields in the target tissue, pulses may be assigned to alternating specific electrodes 60 in a sequential pattern that may be tailored to suit the anatomy of the individual region of the body to be treated and/or the geometry of the specific malignant target tissue. Such assignment may be obtained for instance by suitable manipulation of the electric stimulus generator, e.g. through programmable electronic control means.
Upon pulse delivery, the operator may retract the elongate electrodes 60 to their retracted position by suitably manipulating the deployment mechanism in the handle section 100, and the device may be removed from the body of the patient. Alternatively, the operator may reposition the device 1 after having retracted the elongate electrodes 60, potentially permitting multiple pulse applications covering a larger area in a single device insertion.
The electrode introducer device 1 shown in
Each electrode is formed in an electrically conductive material. Parts of the electrodes may be formed with an electrically insulating coating or sheathing, such that only the most distal ends 61 (points) of the electrodes 60 are un-insulated. Thus, the electric pulses will create an electric field spanning the distance from point to point (distal end 61 to distal end 61), and a readily controllable firing pattern and thus a more controllable and accurate electric field may thus be generated by suitable selection and assignment of electrodes. For completeness it is to be understood that the entire length or part of the entire length of the electrodes 60 may also be electrically un-insulated, provided that the guide channels 50 and the distributor channels 70 are formed in an electrically insulating material.
As shown in
As can be appreciated from
Further, some of the electrodes 60 may be formed in such a way that they undertake a curved path through the tissue such that when advanced forward towards their extended position they will initially be deflected away from the central longitudinal axis L of the shaft 10, and will then reflect back such that the distal tip closes in on the central, longitudinal axis of the shaft 10, when advanced further. Thus, when fully extended, such an electrode 60 will describe a gently U-shaped or substantially, softened Q-shaped curve. This may be accomplished by providing electrodes in an elastic material or a shape memory alloy such as Nitinol or by providing different section (lengthwise) of the electrodes with different biases (pre-tensionings).
Yet further, guiding channels may be shaped to impose on the electrodes certain paths through the tissue. For instance, it may be advantageous to impose on the electrodes a strictly linear path through the tissue, as the electrodes will then be able to withstand much higher loads without buckling—as opposed to electrodes given a curving path.
The deployment mechanism for the electrodes 60 may be manually driven or motorized (e.g. electronically controlled). The deployment mechanism may be adapted to advance all electrodes simultaneously as a set, or individually, or in groups (subsets) of electrodes 60. When the electrodes are advanced simultaneously, different electrode patterns may be achieved through a predetermined composition of electrodes of suitable lengths, shapes (by tensioning, alternative cross-sections predisposing the wire for certain directions of movement or by adequate shaping of guide channels) and materials. The device 1 according to the invention may further be controlled by an electronic control unit (not shown), either incorporated in the device 1 or connectable to the device 1 through a cable or a wireless connection. In the wireless configuration, a suitable power supply is preferably located inside the device. The electronic control unit may be programmable, such that a desired electrode pattern may be programmed prior to a surgical procedure.
In alternative embodiments (not shown), and as mentioned above, a partially disposable device variation of the above described embodiments is proposed, with a disposable introducer shaft 10 and non-disposable (re-usable) handle section 100 comprising a deployment mechanism with interfaces to electrodes formed in the disposable introducer shaft 10 and a electronic connections that may be customized to individual electrical stimulus generators 120.
The shaft may in all embodiments be formed in a plastic or metallic material such as titanium, stainless steel or an injection moulded polymeric material. The outer diameter of the shaft is preferably five (5) millimetres or smaller, preferably between gauge 17 to 14 incl. The wall thickness of the shaft is preferably between 0.05 mm and 0.25 mm. The guide channels 50, 70 may be formed in a suitable material, e.g. formed in a thermoplastic elastomer or a similar electrically insulating material. The electrodes 60 may be formed in an electrically conductive material such as titanium, stainless steel or the like
In the following, an aspect of the invention, suited in particular for applications within the brain, e.g. in the treatment of brain cancer or genetic deficiencies will be described in further detail with reference to
In alternative embodiments a partially disposable device is proposed, with a disposable introducer shaft 10 and non-disposable (re-usable) handle section 100 comprising a deployment mechanism with interfaces to electrodes formed in the disposable introducer shaft 10 and a connector that may be customized to individual electric stimulus generators 120.
The introducer shaft 10 comprises the following:
The handle section 100 comprises the following:
In use, the connector plug of the device is connected to a suitable electric stimulus generator 120. The device 1 is then inserted through a bore hole in the patient's skull and introduced to the target region of the patient's body/brain. The precise location may be identified by means of ultrasound, CT, MR or another suitable means, and the correct position of the introducer shaft 10 prior to deployment may be verified by similar means. As described above, in other embodiments, the stimulus generator may be integrated in the handle section.
When a correct position of the introducer shaft 10 has been obtained, an operator may deliver a suitable chemotherapeutic agent or dose of genetic material through the central channel 111, 107, 93, 20 and into the tissue region to be treated. Delivery is done by inserting the elongate, length-adjusted and properly dulled needle of a syringe 115 in the central hole of the end cap and advancing it until no further motion is possible. The operator may then empty the syringe barrel 115 by pressing the syringe plunger, whereupon the liquid in the syringe is expelled into the tissue to be treated.
Before, during or upon delivery, the operator may deploy the elongate electrodes 62 in a predefined pattern. Deployment is done by moving the deployment slider 102 from its first retracted position towards its second advanced position until further movement is prevented by the end of the motion control slots 112. Said movement results in the motion of the electrodes 60 from the first retracted to the second advanced position. The distributor channels 70 in the distal tip 13 are shaped to provide each individual electrode 60 with a unique, preferably essentially linear path through the tissue and a unique end-point, and the goal is to enable the creation of an electrode pattern that may have a larger diameter (or maximum extent in a plane perpendicular to the longitudinal axis of the shaft 10) than the introducer shaft 10 and may ensure optimal distribution of the short and intense pulses and the thereby derived electric fields in the tissue to be treated. In one particular preferred embodiment the un-insulated electrode tips (distal ends 61) are positional and positioned with their end-points at least partially surrounding or enclosing the target region of tissue in such a way that the distal ends 61 describe or define the outer periphery of a spherical/spatial ellipse. In said preferred embodiment the 32 electrodes are organized in four layers, each layer having a different diameter and consisting of eight electrodes 60 with their end-points (distal ends 61) describing a circular pattern in a plane perpendicular to the axis of the introducer shaft 10.
Upon deployment, an operator may activate the electric stimulus generator 120 to deliver a sequence of preferably short and intense electric pulses, for example square-wave pulses, to the tissue to be treated. To ensure a suitable distribution of pulses and the consequent electric fields in the tissue to be treated (target tissue), pulses may be assigned to alternating specific electrodes 60 in a pattern that may be tailored to suit the anatomy of the individual region of the body to be treated and/or the geometry of the specific malignant target tissue. In an embodiment, at least some of the end-points 61 of the electrodes 60 are placed in equidistant relation to other electrode end points 61, and at least some pulses are assigned to equidistant pairs of electrodes. Thus, a homogenous or heterogeneous, controllable three-dimensional electric field can be created in the target tissue.
In a further embodiment the un-insulated electrode 60 tips are positionable in such a pattern that their end-points 61 outline an outer periphery of an ellipsoid or an ellipse in a plane taken parallel to the longitudinal axis of the shaft 10—corresponding to what is illustrated by reference E in
Upon pulse delivery, the operator may retract the elongate electrodes 60 to their first retracted position by moving the deployment slider 102 from the second advanced position to the first retracted position whereby the electrodes are retracted to their default position within the distal tip 13, and the device 1 may be removed from the body of the patient. Alternatively, the operator may reposition the device after having retracted the elongate electrodes 60, potentially permitting multiple pulse applications covering a larger area in a single device insertion.
In either of the above embodiments a separate channel (not shown) or a portion of the delivery channel 20 may be used to deliver a saline solution to enhance the Electroporation process by increasing tissue conductivity. A saline solution may also be introduced via the delivery channel 20 proper. In either case suitable means for connecting the channel 20 to a source of saline solution may preferably be provided at the handle section. 100
As described above, the cross-sectional shape of the electrodes is preferably essentially circular. However, in other embodiments, other cross sectional shapes may be applied. The diameter and cross-sectional shape of the distributor channels 70 are in any event preferably dimensioned for the desired electrode diameter and cross-sectional shape, in order to provide the best possible support for the electrodes, without limiting their ability to be moved from their retracted position to their extended position (and back).
In either of the above described embodiments, the electrode diameter is preferably 0.4 mm or smaller, such as 0.3 mm, 0.25 mm including electrically insulating coating. The diameter of the electrodes 60 is typically correlated to the stiffness of the electrodes, such that the thicker the electrode, the stiffer the electrode. For some applications a stiff electrode may be necessary, e.g. if the tissue is tough. In soft tissue a less stiff electrode may be applied.
Also depending on the application, the tip of the electrodes may be configured such that it may cut through tissue or it may be smooth in order to more gently spread the tissue.
Further, the electrodes may biased (e.g. pre-tensioned) in such a way that their geometrical configuration in their extended state varies with the extent to which they have been extended beyond the distal tip 13 of the shaft 10. This may be applied be providing the electrodes 60 with different tension characteristics along the lengthwise direction of the electrodes. Thus, a very flexible electroporation device may be obtained.
In the description above and in the drawings, the delivery channel 20 has been illustrated to be centrally located within the shaft 10. However the delivery channel 20 may be asymmetrically located within the shaft, with respect to its cross sectional position. In other embodiments (not shown) the single delivery channel 20 may be replaced by a plurality of smaller delivery channels, each having an outlet at the tip 13. Thereby a more even distribution of an injected therapeutic molecule solution can be obtained.
As described above, a surgical tool or the like may be inserted via the delivery channel 20. The invention also concerns a combination of an electroporation device having a delivery channel according to any of the embodiments described above and an therapeutic molecule solution injection device. The therapeutic molecule solution injection device comprises an elongate hollow part adapted for the delivery channel 20, and a steerable outlet tip. The elongated hollow part is adapted in length, such that the steerable outlet tip can be extended beyond the tip 13 of the electroporation device. The steerable outlet tip may be used to administer a dose of therapeutic molecule solution in a precise location in the target tissue.
Alternatively, or in addition to the combination with therapeutic molecule solution injection device, the electroporation device may have a steerable tip 13. This may be provided by having control rods or strings extending through the shaft 10 to the tip 13, the tip e.g. being pivotally mounted at the distal end of the shaft 10, pivotably about an axis either parallel to the elongate axis of the shaft or perpendicular (or at another angle) to the axis of the shaft. The extent to which the tip 13 may be steered is of course dependant on the stiffness of the electrodes, and a flexible alignment between the channels 50 in the shaft and the channels 70 in the tip 13. By providing a steerable tip 13, the flexibility and reach of the electroporation device may be enhanced, since for also a larger target tissue volume, a single entry hole/channel, formed by the shaft 10 through the surrounding (healthy) tissue is necessary. Thus the reach of the electrodes may be expanded by a turning of the tip 13 or a combination of a turning of the shaft and a tipping of the tip 13 (when the electrodes are in retracted position in the shaft) Thereby the applied electrical field can be repositioned, in a sequence until the entire target tissue may be covered. Further the direction of the outlet of the delivery channel may be altered in order to provide for a more precise delivery of a therapeutical molecule solution. The steerable tip 13 may be combined with the above mentioned therapeutic molecule solution injection device in order to further enhance the reach and flexibility of the drug delivery. However, the steerable tip 13 may also be applied in embodiments without a delivery channel, i.e. embodiments suitable for systemic introduction of drugs or for irreversible electroporation.
The electrodes may also be prepared with/covered by/impregnated with a drug or DNA molecule compound that may be dissolvable in an electrical field. Thereby, a drug etc. may be released from the electrodes when an electrical field is applied to the target tissue via the electrodes. Thereby the delivery channel 20 may be spared. However, the drug impregnated electrodes may also be used with embodiments having a delivery channel 20 in order to release multiple drugs or in order to save the delivery channel for e.g. a field enhancing saline solution as described above.
| Number | Date | Country | Kind |
|---|---|---|---|
| PA 2006 00788 | Jun 2006 | DK | national |
| Number | Date | Country | |
|---|---|---|---|
| 60812601 | Jun 2006 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12304440 | Jun 2009 | US |
| Child | 14966827 | US |
