Patent ID: 12226148

DETAILED DESCRIPTION OF AN EMBODIMENT

This new electrode apparatus with a novel array of electrode elements provides a better electric field distribution.

The electrode assembly may be applied for any electroporation based treatment in the skin, or cutaneous and subcutaneous tumors, as well as for treatments in internal organs.

These treatments include delivery of drugs or genes by reversible electroporation, as well as irreversible electroporation.

The electrode apparatus of the invention can also be used for electroporation-based treatments of diseases in internal organs. This electrode assembly may be used endoscopically through a sheath, e.g. in the bladder. The electrode may also be adapted to a resectoscope, which is an endoscopic device used for the resection of bladder tumors. The electrode assembly is designed to have needle-shaped electrode elements that penetrate in the area that is to be treated, in order to apply an electric field that is capable to produce electroporation, i.e. permeabilization of the cell membrane of the target cells for the introduction of molecules that will induce the desired effect on the tissue. Electroporation-based treatments: electrochemotherapy, irreversible electroporation, electrogene-transfer, i.e. gene therapy, calcium electroporation, have shown promising results in the treatment of cancers of different histologies.

In the case of bladder cancer, in vitro and in vivo studies have shown that electrochemotherapy using mitomycin C and cisplatin is more effective than chemotherapy alone for experimental bladder cancer tumors and on the base of those findings, the inventors designed the electrode assembly according to the invention.

FIG.1shows a schematic representation of a lateral view (1A) and a frontal view (1B) view of an electrode assembly (1) having a main body (2) and six needle-shaped electrode elements (3) extending from the main body (2).

The six needle-shaped electrode elements are arranged into two arrays (11) and (12), having each three electrode elements, and having opposite polarity while in operation.

FIG.2shows an example of a 3D view of an electrode assembly according to some embodiments of the invention in which the electrode assembly comprises a device (4) having6needle-shaped electrode elements (5) with a length of 5 mm and an outer diameter of 0.4 mm arranged onto a circularly shaped platform. Each half of the circularly shaped platform is isolated from the other and electrically chargeable. These needle-shaped electrode elements are arranged in such a way that the holding platform with needle-shaped electrode elements may be fitted in an endoscope, allowing visualization of the bladder through standard optical endoscopic equipment. The dimension of the equipment allows for leads to be drawn through such an endoscope, thus making endoscopic electroporation possible under visual guidance and within the size constraints of an endoscopic device, as for example used in the bladder. The dimensions allow for both reversible and irreversible electroporation.

FIG.3shows calculated electric field intensity distribution in a top view for an electrode assembly according to some embodiments of the invention.

FIG.3shows intensities at half electrode element length, i.e. at 2.5 mm as a top view, i.e. when the electrodes are perpendicular to the paper.

The electrode offset distance (EOD) (6) is defined as the distance from in-line position i.e. the linear layout. EOD is therefore the distance of the central electrode element (10) from an imaginary straight line (7) between the first needle-shaped electrode element (8) and the ending needle-shaped electrode (9) of the at least three electrode elements having the same polarity.

In this example of an embodiment of the invention the EOD refers to the distance of the central electrode (10) from the imaginary straight line (7).

As mentioned above, the optimal offset will depend on the size and the number of electrode elements as well as on the distance between the opposed electrode elements. Size, shape and thickness of the electrode elements may also have an influence in determining the optimal offset value. It may therefore be assumed that scalability of the electrode apparatus and the electrode elements will influence the optimal offset values.

This electrode geometry is referred to as ‘reference’ in the following.

FIG.4shows a coverage optimization study showing the optimal EOD for having optimal coverage.

Coverage is defined as the shortest distance from the imaginary straight line (7) to the 550 V/cm iso-field line, which is the minimum field intensity required for sufficient treatment. Coverage is positive in the outwards direction with respect to the imaginary straight line (7).

InFIG.4the coverage (14) is indicated as the shortest distance between the imaginary straight line (7) and the 550 V/cm iso-line (13).

From the study it appears clear that optimal coverage (16) is achieved with an electrode offset distance between 1 and 1.5 mm, i.e. with an optimal coverage at EOD=1.25 mm.

This layout is referred to as ‘optimal’ in the following.

EOD=0 corresponds to the linear layout, and has negative iso-line distance.

The optimal coverage as mentioned above is at EOD=1.25 mm as shown inFIG.4.

The reference electrode geometry shown inFIG.3correspond to a coverage of 1.5 and is shown by point 15.

The difference between the linear and the optimal layout are shown inFIG.5AandFIG.6Arespectively.

FIGS.5B and6Bshow positioning of adjacent treatment fields with the above mentioned linear geometry (5A) and off-set central electrode element geometry (6A).

InFIGS.5B and6B, squares are inserted showing the planned treatment area. When performing treatments using electroporation the electrode apparatus will be moved so that the entire area is sequentially treated. By inserting into the previous electrode position, adequate coverage can be attempted. InFIG.5B(linear electrode) it can be seen that areas between the electrode elements of same polarity are not sufficiently covered, whereas inFIG.6Bthe coverage defects within the rectangular shape are not present, as a result of off-setting the central electrode element.

In conclusion,FIG.5Bshows that, during electroporation procedure, the movement of the electrode apparatus having linear arrays on the treated area will either lead to areas with low and thus inefficient electrical field or to substantial overlap and thus overexposure causing tissue damage.

On the contrary, the solution of the invention, as shown inFIG.6B, avoids the overlap issues and provides uniform electrical field to the treated area through the all electroporation procedure.

FIG.7shows electrical field calculation for the optimal layout at 80 V/cm coverage at 100 V between electrode elements of each array

In some embodiments, the electrode assembly may comprise further electrodes elements.

FIG.8shows electrical field calculation for an assembly of eight electrode elements of the electrode assembly in the reference layout.

FIG.9andFIG.10show electrical field calculations aiming at studying the effect of variable electrode elements radius and thickness.

FIG.9shows an eight electrode element configuration with electrode elements of equal thickness, i.e. 0.2 mm radius.

FIG.10shows an assembly having thinner end electrode elements, such as 0.15 mm in radius, while the central electrodes has a thickness of 0.20 mm radius. As the average distance to the opposing electrode element is smaller, the reduced radius of the of the first and ending electrode elements, does not affect coverage.

The average distance of the lateral electrode elements to the opposing electrode elements is less than that of the central electrodes. This renders variable radius feasible, i.e. it can be observed that there is no reduction of coverage having lateral electrode elements, i.e. the first and the ending electrodes, having reduced radius.

FIG.11shows electrical field calculation for an 8 electrode elements version of the electrode assembly in which all electrode elements have equal thickness (0.2 mm radius).

FIG.12shows electrical field calculation for a 8 electrode elements version of the electrode assembly, where first and ending needle are thinner, i.e. 0.15 mm radius, while the two central electrodes elements have a thickness of 0.2 mm radius.

The optimal layout applied to the eight-needle electrode assembly shows increased coverage compared to the reference layout. Non-equidistant and equidistant electrode element separations in each array show similar coverage.

FIGS.13A,13B and13Cshow concentric rings of electrode element arrays using the offset central electrode element principle.

The different polarity shown in the figures are examples of how the electrode assembly may be operated.

FIG.14AandFIG.14Bshow how perpendicular fields may be used in the electrode array set-up.

As shown inFIGS.14A and14Ban electrode apparatus may comprise four arrays located in a cross configuration so that the bipolar arrangement may be switch between opposite array so as to achieve desired perpendicular electrical fields.

FIG.15shows a flow-chart of an electroporation method for creating one or more electrical fields to generate an electroporation and/or electrophoretic effect in a target tissue in a luminal organ.

The method comprises:(S1) providing an electroporation assembly according to the first aspect of the invention;(S2) inserting the endoscopic sheath through tissues of a body or into a luminal organ and bring into a vicinity of a target region to be treated, while the retractable electrode assembly is in a retracted position;(S3) extending the retractable electrode assembly to an extended position to at least partially surrounding tissue in a target region to be treated; and(S4) transmitting from the retractable electrode assembly one or more electric pulses of specific amplitudes and durations to create one or more electric fields in the target region.

Although the present invention has been described in connection with the specified embodiments, it should not be construed as being in any way limited to the presented examples. The scope of the present invention is set out by the accompanying claim set. In the context of the claims, the terms “comprising” or “comprises” do not exclude other possible elements or steps. Also, the mentioning of references such as “a” or “an” etc. should not be construed as excluding a plurality. The use of reference signs in the claims with respect to elements indicated in the figures shall also not be construed as limiting the scope of the invention. Furthermore, individual features mentioned in different claims, may possibly be advantageously combined, and the mentioning of these features in different claims does not exclude that a combination of features is not possible and advantageous.