EP1100580A1 - Electrodes d'electroporation - Google Patents

Electrodes d'electroporation

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Publication number
EP1100580A1
EP1100580A1 EP99935311A EP99935311A EP1100580A1 EP 1100580 A1 EP1100580 A1 EP 1100580A1 EP 99935311 A EP99935311 A EP 99935311A EP 99935311 A EP99935311 A EP 99935311A EP 1100580 A1 EP1100580 A1 EP 1100580A1
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EP
European Patent Office
Prior art keywords
electrodes
electrode
electroporation
individually
addressable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99935311A
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German (de)
English (en)
Inventor
Andrew W. Hannaman
Robert M. Bernard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ichor Medical Systems Inc
Original Assignee
Ichor Medical Systems Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ichor Medical Systems Inc filed Critical Ichor Medical Systems Inc
Publication of EP1100580A1 publication Critical patent/EP1100580A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0412—Specially adapted for transcutaneous electroporation, e.g. including drug reservoirs
    • A61N1/0416—Anode and cathode
    • A61N1/0424—Shape of the electrode

Definitions

  • the present invention relates to the delivery of electrical waveforms and, more particularly, to the design of electrodes and electrode arrays for efficient delivery of electrical waveforms in vivo.
  • Electroporation refers to the application of electric fields of sufficient intensity and duration as to induce transient increases in cell membrane permeability in the affected tissue.
  • the cell membrane is a selectively permeable barrier that greatly inhibits the penetration of many molecules into the cytosol.
  • the application of brief electric fields of sufficient intensity causes cell membranes to destabilize, increasing the exchange of molecules between cells and their environment.
  • electroporation can be used to temporarily overcome the membrane barrier and greatly increase the intracellular concentration of normally impermeant substances.
  • Rols et al. (Biophysical J ' . 58: 1089-1098 (1990)) describe electroporation as a threshold dependent phenomenon, in that the electric field intensity must be higher than a critical threshold to induce cell permeability.
  • the extent to which the cell membrane is permeabilized is dependent on many factors which include the physical properties of the cell as well as the parameters of the electroporation protocol. Provided that the electric field strength is not too high and the pulse duration not too long, cells can be permeabilized without a significant decrease in viability (Zimmerman in "Rev. Physiol. Biochem. Pharmacol. " 105:177, Springer- Verlag, New York,(1986)).
  • Electroporation was first applied as a method of inserting normally impermeable molecules into the cytosol of cells in culture.
  • the most common techniques utilize a cuvette with large conductive plate electrodes which produce the required electric field within an ionic buffer solution.
  • This buffer solution is a suspension of the cells to be porated as well as the molecules to be inserted into the cell cytosol.
  • the parameters of the electroporation sequence e.g. waveform, number, intensity, and duration
  • the electric field strength must be increased in order to achieve the critical voltage difference across the membrane.
  • a first order approximation of the required electric field intensity is given by the equation:
  • Figure 1 illustrates the voltage potential and electric field strength generated between two plates in an electroporation cuvette. While there is a negligible loss in field strength at the plate buffer interface, the generated electric field intensity is constant throughout the buffer solution and equivalent to the applied electric field.
  • Electrodes of needle type construction acutely placed in tissue, and spaced approximately 0.5 - 2cm apart.
  • the voltage applied to these electrodes is based on this spacing.
  • the authors often describe the field strengths required as volts per centimeter (V/cm) of spacing. Therefore, to achieve a field strength of lOOOV/cm between a pair of electrodes 0.5cm apart, it is suggested that a voltage of 500V would need to be applied.
  • electroporation is considered to be a threshold-dependent phenomenon, with inherent upper limits due to the risk of cell lysis, a two electrode system is poorly suited to establish uniform electric field coverage, i.e., uniform electroporation, in the tissue targeted for treatment.
  • Mir also describes a pulse applicator which applies a voltage proportional to the distance separating the two needles. If the needles are not spaced too far apart, then the problem of field divergence in a bipolar system can be minimized. Mir discloses that a spacing of 0.65cm between each pair of electrodes is considered optimal.
  • One improved array is described as a hexagon with six 28 gauge (0.35mm) stainless steel needles spaced equidistant around the circumference of a tumor mass. Opposed pairs of needles are pulsed together in order to provide a convergence of the electric fields within the target region. After pulsing a pair of needles, a switch is rotated 60° to the next active pair.
  • Hofmann et al. (1996) propose a second configuration to address this issue.
  • An array consisting of needle electrodes oriented at 90° angles and spaced 0.65cm apart. This forms an array of squares, each with two pairs of opposed needles which are pulsed simultaneously to achieve more homogeneous fields within the region. After each pulse, the polarity relationship between electrodes is rotated by 90°, and the needles are pulsed again. Each rotation produces a new pair of opposed needles and. continues until all four configurations have been pulsed. Larger volume tumors are treated by adding additional needles in a repetitive geometric pattern. Like the original two electrode systems, the voltage applied between each pair of needles is based solely on the intra electrode distance.
  • the applied voltages are determined based on the same "Volts/cm" paradigm described for the plate electrode system.
  • the required field strength is determined for the application and the applied voltage is calculated based solely on the electrode spacing.
  • the array In order to provide an electrode array for the clinical use of electroporation, the array must be efficient in the application of fields to the large volumes of tissue required for many treatments. Depending on the tumor site, the region required for the treatment of a solid tumor can often have a diameter of three centimeters or more (Jain, R. , Scientific American 271(l):58-65 (1994)).
  • the volume of tissue treated by an electrode array can be increased by two methods: (1) Increasing the intra electrode distance, and (2) Increasing the number of electrodes in the array.
  • Each of these methods has limitations which act to restrict efficient expansion of the array.
  • increasing the distance between electrodes requires an increase in applied voltage commensurate with the increase in spacing.
  • higher voltages can result in unacceptable damage to the tissue near the electrodes.
  • there are practical and anatomical considerations which limit the use of large numbers of electrodes. Due to an incremental risk of surgical complication associated with each electrode placement, the number of electrodes should be kept to the minimum necessary. In order to achieve the optimal array size, the intra-electrode spacing, the number of electrodes, and the risks associated with each need to be considered.
  • the present invention provides an electrode apparatus and system which facilitate the efficient delivery of electrical waveforms, and in particular, delivery to a predetermined three dimensional region of tissue within a patient. Electrical waveforms of certain parameters, comprising many different therapeutic objectives and techniques, may be efficiently delivered through the present invention while mmimizing the risk of trauma to the patient.
  • the invention provides an array comprised of electrodes with a cross section optimized so that therapeutic field strengths can be generated in tissue with the lowest possible applied voltage.
  • This aspect of the invention comprises an electrode system for the delivery of electroporation-inducing electrical waveforms to a patient comprising a plurality of individually-addressable elongate electrodes, each independently having a cross sectional surface dimension of E s , are located within a predetermined three-dimensional space in a patient.
  • the ratio of the cross-sectional surface dimension of any selected pair of adjacent electrodes having opposite polarity to the distance (L) separating said adjacent electrodes is expressed by the formula
  • X (E S+ + E,) 2 /L wherein X is a value greater than approximately 2mm 2 /mm. Where the array consists of at least three individually -addressable elongate electrodes, X will have a value greater than approximately 0.75mm 2 /mm.
  • An electrical impulse generating means will be operatively connected to the individually-addressable electrodes for generating electroporation-inducing electrical fields between the electrodes.
  • a method is provided to determine the optimal electrode cross section for a given array based on the geometric relationship of the component electrodes.
  • Use of this method will allow the array parameters (e.g. electrode spacing "L", number of electrodes, applied voltage) to be adjusted and optimized for more efficient generation of the necessary electric fields.
  • the result of this optimization would be an array which could more closely approximate the perfectly homogeneous distribution of electric fields observed during in vitro applications.
  • Figure 1A is a three dimensional perspective view of a pair of plate electrodes and the electric field generated between them
  • Figure IB is a graph depicting the electric field strength and voltage generated by the plate electrodes and their relationship to locations between the plate electrodes
  • Figure 2A is a depiction of a pair of plate electrodes applied to a tumor mass in the epidermal region, and Figure 2B illustrates the typical voltage and electric field profile generated between electrode plates in the relationship depicted in Figure 2A;
  • Figure 3A is a two dimensional schematic view depicting the field lines and approximate electric field intensity for a two electrode model, wherein the intra- electrode distance is L and the dashed box positioned midway between the two electrodes indicates the region of lowest electric field strength, and
  • Figure 3B is a graphic representation of the relationship between the distance from the electrode and the electric field strength;
  • Figure 4 is a graphic representation of the improvement in electric field distribution obtained when needle electrodes are combined into more complex arrays, in which Figure 4A depicts the electric field strengths measured over 1mm increments for a bipolar electrode system, Figure 4B depicts the field strength profile of electrodes establishing a square configuration, and Figure 4C depicts the field strength profile of electrodes establishing a rectangular configuration characteristic of a hexagonal array;
  • Figure 5 is a two dimensional depiction of the approximate change in the density of field lines for one of the electrodes in a bipolar system, wherein the scale representations are of electrodes with a diameter of 0.3 and 1.0mm;
  • Figure 6 is a graphical representation of the voltage and electric field profile generated between a bipolar needle electrode system with a intra electrode spacing of
  • Figure 7 is a graphical representation of the voltage profile generated by various bipolar electrode systems with an intra electrode distance of 2cm and electrode diameter ranging from 0.3mm to 2.4mm;
  • Figure 8 is a graphical representation of the relationship between intra electrode spacing and the applied voltage required to generate an electric field of 50 V/mm in the center of a bipolar electrode system;
  • Figure 9 is a graphical representation of the results produced by a system as described in Example 4, illustrating the percentage of the applied voltage measured over one millimeter in the center of a bipolar electrode system for electrodes of various diameters;
  • Figure 10 is a graphical representation of the results produced by a system as described in Example 5, illustrating the decrease in voltage 2mm from the pulse electrode for bipolar systems with electrodes of various diameters;
  • Figure 11 depicts the improvement in electric field distribution when 1.1mm diameter electrodes are incorporated into more complex arrays, wherein Figure 11A depicts the electric field profile generated by a bipolar system, Figure 1 IB depicts the electric field profile generated by a square configuration, and Figure 11C depicts the electric field profile generated by a rectangular configuration characteristic of a hexagonal array; and
  • Figure 12 is a graphic description of the improvement in field uniformity derived from the use of a conductive solution around each of the electrodes in a bipolar system.
  • the present invention provides apparatus and methods which facilitate the efficient delivery of electrical waveforms, and in particular waveform delivery to a predetermined three dimensional region of tissue within a patient. Electrical waveforms of certain parameters employed in many different therapeutic techniques may efficiently be delivered through the present invention. These techniques can be performed while minimizing the risk of associated trauma in the patient.
  • the present invention provides an array of individual electrodes which efficiently deliver electrical waveforms to a predetermined region of tissue within a patient.
  • One aspect of this efficiency is to maximize the electrical waveform intensity and uniformity for a given intra-electrode distance while minimizing the actual number of electrodes which will ensure complete coverage of the predetermined treatment region.
  • This aspect of the invention comprises an electrode system for the delivery of electroporation-inducing electrical waveforms to a patient comprising a plurality of individually-addressable elongate electrodes, each independently having a cross sectional surface dimension of E s , are located within a predetermined three-dimensional space in a patient.
  • An electrical impulse generating means will be operatively connected to the individually-addressable electrodes for generating electroporation-inducing electrical fields between the electrodes.
  • Electric fields will be established within the target tissue by delivery of electrical waveforms to preselected electrodes, desirably such electrodes will be individually-addressable so as to provide the ability to focus and concentrate the electrical fields to insure substantial uniformity throughout the region of tissue to be treated.
  • the parameters of the waveform, geometry of the electrode array, and electrode characteristics will define the electric field strength E (in V/mm) at any given point within the tissue.
  • Each tissue system will have its own characteristics which determine the critical field strength for optimum therapeutic effect. Variation between different types of tissue are due to cell size, cell type, and the electrical properties of the tissue itself. Generally, the field strength varies inversely with the size of the cells contained within the tissue.
  • Mammalian tissue generally requires field strengths of between approximately 200V/cm to 3000V/cm for electroporation. If the tissue has abnormal resistive values or if it is very susceptible to damage, then the waveform parameters are desirably adjusted accordingly.
  • the voltage applied to electrodes is reported in the literature as a function of the distance between those electrodes ("L"), typically in V/cm. Based upon the literature pertaining to tissue electroporation, it appears that a higher voltage commensurate with larger L becomes problematic compared to a lower voltage and the proportionately smaller L. This suggests that one practicing in vivo electroporation cannot simply expand L to any desired distance and expect an overall satisfactory therapeutic effect.
  • threshold level electric field strengths generated by the electrodes would be evenly distributed across, and completely confined to, the target area. This ideal distribution would be similar to that of the electroporation cuvette illustrated in Figure 1.
  • FIG. 2 illustrates the typical voltage and electric field profile generated by plate electrodes applied to skin. As can be seen from the figure, there is a significant drop in voltage at the electrode skin interface due to the drastic change in resistance, as well as the poor electrical contact between the electrode plates and the skin. Even when conductive paste or gel is utilized to improve the interface between the electrode plates and the skin, a significant portion of the voltage is dissipated in the outer layers of the skin.
  • the needle type electrodes traditionally used in tissue applications cannot produce the homogeneous fields provided by the relatively large plate electrodes found in electroporation cuvettes.
  • the experimental results represented in Figure 4 demonstrate that different array configurations generate quite different electric field distributions. Therefore, the required field strength for an array cannot be determined without first considering the geometric relationship of the component electrodes.
  • the present invention provides an array comprised of elongate rod type electrodes which have an optimized cross section.
  • This cross section is predetermined and based on the applications for which the array will be used.
  • One application for which this type of array is particularly suited is in the generation of electric fields in tissue for the purposes of electroporation.
  • An optimal electrode array is one that can generate the necessary electric fields throughout the target tissue with the fewest number of electrodes, lowest applied voltage, and least amount of collateral tissue damage. This corresponds to an array which can efficiently generate homogenous, threshold level fields throughout a target region of tissue.
  • FIG. 5 illustrates the change in density of the electric field lines when the same voltage is applied to electrodes of different diameter. This improvement in the electric field distribution would allow a lower applied voltage to generate the same effective field strengths in the tissue.
  • Tissue damage due to high field strengths and local heating is the limiting factor for the amount of voltage which can be applied to an electrode array.
  • This tissue damage always occurs first in the region of high current density immediately surrounding the electrodes. This is due to the high electric field strengths generated at the electrode/tissue interface. Therefore, with an increase in the electrode diameter, higher voltages could be applied without the risk of tissue damage, because the field strengths near the electrodes have been distributed across a larger surface area. If higher voltages can be applied to the electrodes, while maintaining safe field strengths in the tissue, then the intra-electrode distance "L" can be increased. As discussed earlier, with an increase in "L", fewer electrodes are necessary to treat a given region of tissue and establish electric fields of sufficient strength for electroporation.
  • Examples of this invention have indicated that the relationship between the cross section of the electrode, the electrode spacing, and the applied voltage determines the field strengths present in the target region. These tests suggest that the threshold electric fields necessary for electroporation are not generated efficiently when spacing and applied voltage are the only variables taken into consideration. If traditional needle type electrodes (diameter s 0.3mm) are used to generate an electric field, there is a nonlinear relationship between the electric field strength and the position between the electrodes. Testing related to this concept demonstrates that rapid changes in voltage (i.e. electric field strength) occur near the electrodes while a much slower rate of change occurs in the intermediate region (see Figure 6) .
  • the present invention demonstrates that an applied voltage of 650V is used to generate a potential difference of 50V across one mm precisely between two needle electrodes spaced 0.5cm apart.
  • the voltage will be 850V.
  • This figure corresponds to an applied voltage of approximately 1300V/cm. It should be noted that the measurements were taken on the center line in the middle of the electrode pair, which is not the weakest point in the region (electric field strength at a given point decreases with the square of the average distance from the two electrodes) .
  • the applied voltage would be distributed evenly throughout the tissue. This ideal distribution corresponds to uniform field strengths across equivalent volumes of tissue. If the diameter of the electrodes is increased, the applied voltage required to generate a target field strength is reduced. This corresponds to a more linear distribution of the electric field (see Figure 7) . As the electrode diameter is increased, the electric field distribution begins to approach the flat profile characteristic of plate electrodes. This indicates that the electric field strength is more evenly distributed across the entire tissue. Thus, the present invention provides that sufficient voltages can be achieved throughout the tissue without excessively high field strengths near the electrodes.
  • each type of electrode array has a characteristic field distribution based on the geometric relationship of the electrodes and the typical pulsing pattern. As indicated by the results illustrated in Figure 4, improvement in field distribution can be derived through the use of more efficient arrays and pulsing patterns.
  • the applied voltage used for each array will be dependent on its characteristic field distribution as well as the electrode spacing and cross section.
  • the utilization of larger diameter electrodes with such complex electrode arrays results in a substantial improvement in field distribution, which can approach that of the plate type electrodes.
  • the electrode diameter useful to generate an acceptable field profile is dependent on the geometric relationship (i.e. intra electrode distance and spatial orientation) and pulsing pattern of the electrodes.
  • the use of efficient array designs will provide adequate field uniformity with electrodes of smaller diameter. Due to their inefficiency, bipolar electrodes require a much larger electrode diameter to produce an acceptable electric field profile.
  • an improvement in electric field distribution can also be derived by altering the conductivity of the medium near the electrodes.
  • the infusion of a highly conductive (relative to the medium) solution near both electrodes in a bipolar array can lead to a more effective distribution of the electric fields throughout the medium.
  • By increasing the conductivity of the medium in the electrode region a less drastic drop in voltage is observed near the electrode, leading to a more homogeneous distribution of fields over the entire area of the array.
  • This concept could be clinically useful for tissue which cannot accommodate electrodes with larger cross sections.
  • a saline solution with ionic strength optimized to be effective as well as bio-compatible could be infused through or around array electrodes to shunt high field strengths away from the adjacent tissue region.
  • the electrode diameter is too large it may result in mechanical damage to the tissue.
  • electrodes of 4mm or larger in diameter could safely be employed.
  • the most common electrode diameters employed in the practice of the invention will be between 0.5 and 2.5mm.
  • a surgeon or someone skilled in the art will determine the type of array to be used. Based on the type of tissue to be treated, the surgeon will then select an approximate electrode cross section. The electrodes will be selected by balancing the benefits of a larger diameter with treatment objectives and safety issues. After an appropriate electrode diameter has been selected, the intra-electrode spacing "L" can be determined as well as applied voltages known to be safe and effective.
  • X (E s+ + E s .) 2 /L wherein the ratio of the cross-sectional surface dimension of any selected pair of adjacent electrodes having opposite polarity (+/-) to the distance (L) separating said adjacent wherein X is a value greater than approximately 2mm 2 /mm.
  • the array consists of at least three individually-addressable elongate electrodes, X will have a value greater than approximately 0.75mm 2 /mm.
  • X ⁇ (E r+ 2 + E r . 2 )/L
  • E r+ and E r . are the radii of two opposite polarity electrodes in electrical communication with each other.
  • electrodes should have a diameter of greater than 0.5mm. Due to the relative inefficiency of the bipolar system, electrodes employed in this fashion should have a diameter of greater than 0.7mm. For some applications, such as the local infusion of treatment related compounds, it may be deemed desirable to use hollow core needle electrodes. In these cases the electrode efficiency calculation, X, should be based on a solid core electrode of identical dimension. Improvements in electrode efficiency are provided at the electrode/tissue interface and are therefore related to the external profile of the electrode, regardless of the interior shape.
  • electrodes in the array will be of surgical quality, bio-compatible, and capable of withstanding the demands of implantation and use in a patient.
  • Materials commonly employed in the construction of such electrodes include nickel titanium, gold, silver, stainless steel, platinum, platinum iridium alloys, graphite, ceramic, and the like.
  • the electrodes will be elongate with a tip shaped so as to simplify the surgical implantation of the electrode in the patient.
  • the electrode material should be rigorously tested in conditions similar to that which it will be used. For instance, testing has shown that corrosion begins to occur on the anodic (electron collecting) electrode when some grades of stainless steel are pulsed 5-10 times in a conductive saline solution.
  • the relatively sharp points may provoke arcing of the electric field, particularly at the electrode delivering the electrons in the propagation of the electric field (i.e. the cathodic electrode).
  • the point of the electrode distal from the source of electrical signals includes a radius of curvature sufficient to substantially eliminate arcing at the electric field strengths utilized in the practice of the present invention, for example in the range of 0.1 to 1mm.
  • Another source of electrical arcing between electrodes is due to an imbalance between the cathodic and anodic electrodes. If there is a significant difference in the surface areas of the cathodic and anodic portions of the circuit there is an increased risk of arcing at the electrode with the smaller surface area.
  • Electrode parameters such as effective length, electrode material, and diameter can drastically effect the arcing behavior and should be considered in the design of the electrode array.
  • these electrodes will be connected to a electrical impulse generating means including a suitable power supply capable of generating the proper electrical signals.
  • the most common signal employed in tissue electroporation is a square wave pulse of amplitude 0.1 - 3 kV.
  • the BTX T-820 pulser (Genetronics, San Diego, CA) is sufficient for generating this type of signal.
  • various other pulse generators e.g Cytopulse model PA-
  • a high voltage switching mechanism When an electrode array consists of individually addressed electrodes, a high voltage switching mechanism will be provided in order to change the state of the electrodes. Such a mechanism would generally either be mechanically or digitally controlled and capable of changing the electrical state of an electrode singly or in conjunction with other electrodes in the array.
  • Example 1 System to Measure Electric Field Strengths
  • the electrodes consist of stainless steel rods (source) of 2cm length and diameter ranging from 0.3mm to 3.18mm. Knox gelatin dissolved in a 0.45 % saline solution is used to create a conductive gel. After it begins to solidify the saline gel is molded around the electrodes and used as a conductive medium for the electric pulses.
  • Cytopulse model PA-2000 electroporation pulse generator (Cytopulse, Inc.,
  • the probes After connecting the electrodes to the PA-2000 pulse generator and applying pulses, the probes are placed at different locations within the conductive gel. By measuring the electric potential at two probes separated by a known distance the voltage difference (i.e. the electric field strength) between the two points can be determined.
  • Example 1 In order to determine the characteristics of the electric field generated by a bipolar electrode system the method described in Example 1 can be employed.
  • Two stainless steel electrodes of 0.3mm diameter are spaced exactly 2.0cm apart.
  • One electrode is designated the pulse electrode and the other a ground electrode.
  • Tektronix 10X probes will be attached to the pulse electrode for the entire test.
  • the second probe is then attached to a stereotaxic device. In this way the second probe can be placed in precise locations between the electrodes.
  • the testing consists of measuring the voltage differences between the two probes at different positions.
  • the stereotaxic apparatus moves a probe in 1mm increments from the pulse electrode to the ground electrode. A voltage difference measurement is taken at each increment.
  • Figure 7 illustrates the results of this evaluation. It can be concluded from this example that there is a nonlinear relationship between the electric field strength and the position between the electrodes. A majority of the voltage drop occurs in the regions surrounding the two electrodes. In Figure 7 it can be seen that roughly 25% of the total voltage drop occurs within 2.0mm of the pulse electrode. Another 25 % of the total voltage drop is experienced in the 2.0mm near the ground electrode. Therefore approximately 50% of the total voltage applied to the electrodes is lost in regions which comprise only 20% of the area between the electrodes.
  • Electrodes of larger diameter are evaluated according to the procedure outlined in Example 2 to determine the effect of diameter on distribution of electric fields.
  • Stainless steel electrodes, spaced at 2.0cm, with diameters of 1.13mm, 1.57mm, and 2.38mm are evaluated and compared to the 0.3mm electrodes which have been used in the prior art.
  • Figure 7 illustrates the results of this evaluation, with the linear voltage distribution of ideal plate electrodes included as a reference. It can be seen that with an increase in electrode diameter, the voltage position relationship becomes more linear, indicating a more homogeneous distribution of the field strengths. For example, with an electrode diameter of 2.38mm one finds that only 30% of the applied voltage is lost in the region around the electrodes (20% of the total). This compares favorably to the 50% voltage drop observed in the same area for the 0.3mm electrodes in Example 2.
  • Example 4 Effect of Electrode Diameter and Spacing on Electric Field Distribution Experiments are performed in order to determine how the generation of electric fields is affected by the diameter and spacing of the electrodes. Using the system outlined in Example 1 , electrodes of various diameters and spacing can be tested to determine the applied voltage useful to generate a target field strength over 1mm on the center line between to electrodes. The two probes described in Example 1 are placed exactly 1mm apart in the stereotaxic apparatus. In this way, the probes can easily be moved to a specific location in relation to the electrode while maintaining a 1.0mm separation. Electrodes of 0.3mm, 1.13mm, 1.57mm, 2.38mm, and 3.18mm are tested at spacings ranging from 4mm to 34mm. It should be noted that electrode spacing is measured from the inside edge of each electrode to insure that any difference in the electric fields between different diameters is not due to the electrodes being placed in closer proximity.
  • Example 1 Since damage to tissue undergoing electroporation can be correlated to excessively high field strengths near the electrodes, it is important to understand how field distribution can improve the safety of electroporation. Evaluations are performed using the apparatus described in Example 1 to analyze the effect of electrode diameter on field strengths near the electrode surface. The testing should be comprised of electrodes spaced 2.0cm apart with diameters of 0.3mm, 1.13mm, 1.57mm, 2.38mm, and 3.18mm.
  • Testing of field strengths near the electrode is performed by connecting one probe to the pulse electrode and placing the other in the stereotaxic apparatus. The probe can then be placed in various locations relative to the pulse electrode in order to measure the electric field strengths near the electrode.
  • Example 6 Large Diameter Electrodes Incorporated into Complex Arrays
  • Example 1 The system described in Example 1 is employed to determine the effect of larger diameter electrodes in the generation of electric fields by more complex arrays.
  • Electrodes of diameter 0.3mm and four electrodes of diameter 1.13mm are placed in a square orientations with "L" equal to 0.65cm (inside edge to inside edge).
  • Four electrodes of diameter 0.3mm and four electrodes of diameter 1.13mm are placed into a rectangular orientation with the a major axis dimension of 1.0cm.
  • This shape corresponds to a single configuration of a hexagonal electrode array.
  • Each array is pulsed in a parallel bipolar format. This type of parallel pulsing causes a compression of the electric fields in the region between the bipolar pairs and results in a better overall field distribution. Voltage readings are taken throughout the array area to determine the field profile as well as the region of weakest field strength.
  • Figure 11 A, 11B and 11C show a comparison between the two complex arrays and the original bipolar array for each electrode diameter. As can be seen, an improvement in field distribution is obtained by the use of more complex arrays as well as increased electrode diameter.
  • Example 7 Use of conductive solutions to improve propagation of electric fields.
  • Example 8 The test system described in Example 8 is also useful for the evaluation of electrical arcing at the distal tip of the electrodes. It has been observed that when a threshold voltage is exceeded a spark is produced at the cathodic electrode tip, leading to unstable current flow. The threshold voltage for arcing is affected by the radius of curvature of the electrode tip. Sharp points have a lower threshold for arcing, and smaller diameter electrodes exhibit more pronounced sparks. Based on these observations, it appears that the arcing is caused by excessive current densities at the electrodes, and can be alleviated by using electrodes of larger diameter with smooth, rounded tips.
  • the total surface area of the anodic and cathodic electrodes should be balanced to reduce the potential for electrical arcing. Effective electrode length and electrode number should both be considered to insure that a cathodic and anodic balance exists.

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Abstract

L'invention concerne des électrodes, un appareil (A) et des systèmes à réseaux d'électrodes qui améliorent les effets thérapeutiques d'ondes électriques appliquées in vivo au moyen d'un arrangement où les plaques à électrodes respectent des ratios particuliers entre des surfaces et des distances de séparation entre les plaques à électrodes (X1, X2).
EP99935311A 1998-07-20 1999-07-20 Electrodes d'electroporation Withdrawn EP1100580A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US11935298A 1998-07-20 1998-07-20
US119352 1998-07-20
PCT/US1999/012836 WO2000004949A1 (fr) 1998-07-20 1999-07-20 Electrodes d'electroporation

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EP1100580A1 true EP1100580A1 (fr) 2001-05-23

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