Patent Publication Number: US-2021161582-A1

Title: Electroporation system and method

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority to U.S. Provisional Patent Application Ser. No. 62/943,000 filed Dec. 3, 2019, the disclosure of which is hereby incorporated by reference in its entirety. 
    
    
     BACKGROUND OF THE DISCLOSURE 
     a. Field of the Disclosure 
     The present disclosure relates generally to medical devices that are used in the human body. In particular, the present disclosure relates to electroporation systems and methods of controlling electroporation systems. 
     b. Background 
     Various therapies are used to treat various conditions afflicting the human anatomy. Cardiac arrhythmias, for example are sometimes treated using ablation therapy. When tissue is ablated, or at least subjected to ablative energy generated by an ablation generator and delivered by an ablation catheter, lesions form in the tissue. Electrodes mounted on or in ablation catheters are used to create tissue necrosis in cardiac tissue to correct conditions such as atrial arrhythmia (including, but not limited to, ectopic atrial tachycardia, atrial fibrillation, and atrial flutter). Arrhythmia (i.e., irregular heart rhythm) can create a variety of dangerous conditions including loss of synchronous atrioventricular contractions and stasis of blood flow that can lead to a variety of ailments and even death. It is believed that the primary cause of atrial arrhythmia is stray electrical signals within the left or right atrium of the heart. The ablation catheter imparts ablative energy (e.g., radiofrequency energy, cryoablation, lasers, chemicals, high-intensity focused ultrasound, etc.) to cardiac tissue to create a lesion in the cardiac tissue. This lesion disrupts undesirable electrical pathways and thereby limits or prevents stray electrical signals that lead to arrhythmias. 
     One candidate for use in therapy of cardiac arrhythmias is electroporation. Electroporation therapy involves electric field-induced pore formation on the cell membrane. The electric field may be induced by applying a direct current (DC) signal delivered as a relatively short-duration pulse. Such a pulse may be repeated to form a pulse train. When such an electric field is applied to tissue in vivo, the cells in the tissue are subjected to trans-membrane potential, which opens the pores on the cell wall, hence the term electroporation. Electroporation may be reversible (i.e., the temporally-opened pores will reseal) or irreversible (i.e., the pores will remain open). For example, in the field of gene therapy, reversible electroporation (i.e., temporarily open pores) is used to transfect high molecular weight therapeutic vectors into the cells. In other therapeutic applications, a suitably configured pulse train alone may be used to cause cell destruction, for instance by causing irreversible electroporation (IRE). 
     SUMMARY OF THE DISCLOSURE 
     The present disclosure is directed to an electroporation system including a catheter shaft, at least one electrode coupled to the catheter shaft at a distal end thereof, and an electroporation generator coupled in communication with the at least one electrode. The electroporation generator configured to supply a biphasic pulse signal to the at least one electrode. The biphasic pulse signal includes a first phase having a first polarity and a first pulse duration, and a second phase having a second polarity opposite to the first polarity, and a second pulse duration. Each of the first phase and second phase has a voltage amplitude of at least 500 volts and a pulse duration of less than 20 microseconds. The second phase is generated at a non-zero interval following the first phase. 
     The present disclosure is further directed to a method including supplying, by an electroporation generator, a first phase of a biphasic pulse signal to at least one electrode coupled at a distal end of a catheter shaft. The first phase has a first polarity and a first pulse duration. The method further includes supplying a second phase of the biphasic pulse signal to the at least one electrode. The second phase has a second polarity opposite to the first polarity, and a second pulse duration. Each of the first phase and second phase has a voltage amplitude of at least 500 volts and a pulse duration of less than 20 microseconds. The second phase is generated at a non-zero interval following the first phase. 
     The present disclosure is further directed to an electroporation generator including a positive high-voltage direct current (+HVDC) supply having a first polarity, a negative high-voltage direct current (−HVDC) supply having a second polarity opposite the first polarity, a plurality of semiconductor switches connected in a bridge configuration to regulate application of the +HVDC supply and the −HVDC supply to first and second conductors for a catheter, and a microcontroller communicatively coupled to the plurality of semiconductor switches. The microcontroller is configured to control commutation of the plurality of semiconductor switches to transmit a biphasic pulse signal through the first and second conductors for the catheter. 
     The present disclosure is further directed to a method of generating a pulse signal. The method includes supplying a positive high-voltage direct current (+HVDC) supply having a first polarity to a plurality of semiconductor switches connected in a bridge configuration, supplying a negative high-voltage direct current (−HVDC) supply having a second polarity opposite the first polarity to the plurality of semiconductors, and commutating the plurality of semiconductor switches to apply the +HVDC supply to a first conductor of a catheter and to apply the −HVDC supply to a second conductor of the catheter for a first duration. The method further includes commutating the plurality of semiconductor switches, after the first duration, to electrically disconnect the first conductor and the second conductor from the +HVDC supply and the −HVDC supply for a second duration, and commutating the plurality of semiconductor switches, after the second duration, to apply the +HVDC supply to the second conductor and to apply the −HVDC supply to the first conductor for a third duration. The method further includes commutating the plurality of semiconductor switches, after the third duration, to electrically disconnect the first conductor and the second conductor from the +HVDC supply and the −HVDC supply. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a schematic and block diagram view of a system for electroporation therapy. 
         FIG. 2  is a side view of an exemplary electrode assembly suitable for use in the system of  FIG. 1 , illustrated in the form of an electrode loop assembly. 
         FIG. 3  is an end view of the electrode loop assembly of  FIG. 2 . 
         FIG. 4  is a perspective view of another exemplary electrode assembly suitable for use in the system of  FIG. 1 , illustrated in the form of a basket electrode assembly. 
         FIG. 5  is a perspective view of another exemplary electrode assembly suitable for use in the system of  FIG. 1 , illustrated in the form of a grid electrode assembly. 
         FIG. 6  is a side view of another exemplary electrode assembly suitable for use in the system of  FIG. 1 , illustrated in the form of an expandable electrode assembly. 
         FIG. 7  is a plot illustrating an exemplary pulse signal that may be generated by an electroporation generator of the system of  FIG. 1 . 
         FIG. 8  is plot illustrating a burst signal that includes two pulse signals generated at a pulse period. 
         FIG. 9  is plot illustrating multiple burst signals generated at a repeating burst period. 
         FIG. 10  is a schematic diagram of an exemplary electroporation generator for use in the system of  FIG. 1 . 
         FIG. 11  is a flow diagram of an exemplary method of generating a pulse signal, such as the pulse signal shown in  FIG. 7 . 
     
    
    
     Corresponding reference characters indicate corresponding parts throughout the several views of the drawings. It is understood that that Figures are not necessarily to scale. 
     DETAILED DESCRIPTION OF THE DISCLOSURE 
     The present disclosure relates generally to medical devices that are used in the human body. In particular, in many embodiments, the present disclosure relates to electroporation systems and methods for controlling such electroporation systems. The disclosed embodiments may lead to more consistent and improved patient outcomes in electroporation therapy procedures. For example, embodiments of the present disclosure utilize electroporation pulse signals having specific parameters (e.g., voltage amplitude, pulse width or duration, pulse period, and burst period) that facilitate reducing or minimizing undesirable or unintended IRE, such as skeletal muscle excitation and generation of gasses within a patient. It is contemplated, however, that the described features and methods of the present disclosure as described herein may be incorporated into any number of systems as would be appreciated by one of ordinary skill in the art based on the disclosure herein. 
     Referring now to the drawings,  FIG. 1  illustrates an exemplary embodiment of a system  10  for electroporation therapy. In general, the various embodiments include an electrode assembly disposed at the distal end of a catheter. As used herein, “proximal” refers to a direction toward the end of the catheter near the clinician and “distal” refers to a direction away from the clinician and (generally) inside the body of a patient. The electrode assembly includes one or more individual, electrically-isolated electrode elements. In some embodiments, each electrode element, also referred to herein as a catheter electrode, is individually wired such that it can be selectively paired or combined with any other electrode element to act as a bipolar or a multi-polar electrode. 
     System  10  may be used for irreversible electroporation (IRE) to destroy tissue. In particular, system  10  may be used for electroporation-induced primary necrosis therapy, which refers to the effects of delivering electrical current in such manner as to directly cause an irreversible loss of plasma membrane (cell wall) integrity leading to its breakdown and cell necrosis. This mechanism of cell death may be viewed as an “outside-in” process, meaning that the disruption of the outside wall of the cell causes detrimental effects to the inside of the cell. Typically, for typical plasma membrane electroporation, electric current is delivered as a pulsed electric field in the form of short-duration direct current (DC) pulses between closely spaced electrodes capable of delivering an electric field strength sufficient to cause irreversible electroporation in the targeted cells. As described in more detail herein, the system  10  is configured to deliver an electroporation pulse signal having a relatively high voltage and low pulse duration as compared to at least some prior electroporation systems. The waveforms generated by system  10  and applied to catheter electrodes facilitate reducing and/or preventing skeletal muscle stimulation during IRE therapy. 
     Irreversible electroporation through a multielectrode hoop catheter may enable pulmonary vein isolation in as few as one shock per vein, which may produce much shorter procedure times compared to sequentially positioning a radiofrequency (RF) ablation tip around a vein. It should be understood that the mechanism of cell destruction in electroporation is not primarily due to heating effects, but rather to cell membrane disruption through application of a high-voltage electric field. Thus, electroporation may avoid some possible thermal effects that may occur when using RF energy. This “cold” or “non-thermal” therapy thus has desirable characteristics. 
     It should be understood that while the energization strategies are described as involving DC pulses, embodiments may use variations of DC pulses and remain within the spirit and scope of the invention. For example, exponentially-decaying pulses, exponentially-increasing pulses, and combinations thereof may be used. Moreover, while system  10  is described herein with respect to IRE ablation therapy, it should be understood that system  10  may be used, additionally or alternatively, for other forms of ablation therapy, including, for example and without limitation, radiofrequency (RF) ablation. 
     System  10  includes a catheter electrode assembly  12  including at least one catheter electrode configured to be used as briefly outlined above and as described in greater detail below. Electrode assembly  12  is incorporated as part of a medical device such as a catheter  14  for electroporation therapy of tissue  16  in a body  17  of a patient. In the illustrative embodiment, tissue  16  comprises heart or cardiac tissue. It should be understood, however, that embodiments may be used to conduct electroporation therapy with respect to a variety of other body tissues. 
       FIG. 1  further shows a plurality of return electrodes designated  18 ,  20 , and  21  that are diagrammatic of the body connections that may be used by the various sub-systems included in the overall system  10 , such as an electroporation generator  26 , an electrophysiology (EP) monitor such as an ECG monitor  28 , a visualization, navigation, and/or mapping system  30  for visualization, mapping and navigation of internal body structures. In the illustrated embodiment, return electrodes  18 ,  20 , and  21  are patch electrodes. It should be understood that the illustration of a single patch electrode is diagrammatic only (for clarity), and that such sub-systems to which these patch electrodes are connected may, and typically will, include more than one patch (body surface) electrode. In other embodiments, return electrodes  18 ,  20 , and  21  may be any other type of electrode suitable for use as a return electrode including, for example, one or more catheter electrodes. Return electrodes that are catheter electrodes may be part of electrode assembly  12  or part of a separate catheter (not shown). In some embodiments, for example, system  10  includes a bipolar catheter electrode assembly that includes a plurality of electrode pairs, where each electrode pair includes two electrodes with one electrode functioning as the return electrode. 
     System  10  may further include a main computer system  32  (including an electronic control unit  50  and data storage-memory  52 ), which may be integrated with system  30  in certain embodiments. System  32  may further include conventional interface components, such as various user input/output mechanisms  34   a  and a display  34   b , among other components. 
     In some embodiments, electroporation generator  26  and/or computer system  32  may be programmed or otherwise configured to run an algorithm that identifies and/or selects which electrodes or electrode pairs of electrode assembly  12  to energize. That is, electrodes or electrode pairs of electrode assembly  12  may be selectively energized based on, for example, anatomical location of the electrode(s) and/or contact between the electrode(s) and tissue  16 . For example, system  10  may include a suitable detector and tissue sensing circuit that identify which electrodes of electrode assembly  12  have characteristics (e.g., if electrical characteristics, then for example, impedance, phase angle, reactance, etc.) indicative of contact with tissue  16 . Electroporation generator  26  and/or computer system  32  may then select which electrodes or electrode pairs of catheter assembly  12  to energize based on the electrodes identified as being in contact with tissue  16 . By way of example, if a basket catheter is inserted into the antrum of a pulmonary vein, electroporation generator  26  and/or computer system  32  may determine which electrode(s) to activate based on contact with tissue  16 , or even the specific anatomical location within the heart. Suitable components and methods for identifying electrodes in contact with tissue are described, for example, in U.S. Pat. No. 9,289,606, the disclosure of which is incorporated herein by reference in its entirety. 
     In the illustrative embodiment, catheter  14  includes a cable connector  40 , or interface, a handle  42 , and a shaft  44  having a proximal end  46  and a distal end  48 . Catheter  14  may also include other conventional components not illustrated herein such as a temperature sensor, additional electrodes, and corresponding conductors or leads. The connector  40  provides mechanical and electrical connection(s) for cable  56  extending from generator  26 . The connector  40  may comprise conventional components known in the art and, as shown, is disposed at the proximal end of catheter  14 . 
     Handle  42  provides a location for the clinician to hold catheter  14  and may further provide means for steering or guiding shaft  44  within body  17 . For example, handle  42  may include means to change the length of a guidewire extending through catheter  14  to distal end  48  of shaft  44  or means to steer shaft  44 . Moreover, in some embodiments, handle  42  may be configured to vary the shape, size, and/or orientation of a portion of the catheter. Handle  42  is also conventional in the art and it will be understood that the construction of handle  42  may vary. In an alternate exemplary embodiment, catheter  14  may be robotically driven or controlled. Accordingly, rather than a clinician manipulating a handle to advance/retract and/or steer or guide catheter  14  (and shaft  44  thereof in particular), a robot is used to manipulate catheter  14 . Shaft  44  is an elongated, tubular, flexible member configured for movement within body  17 . Shaft  44  is configured to support electrode assembly  12  as well as contain associated conductors, and possibly additional electronics used for signal processing or conditioning. Shaft  44  may also permit transport, delivery and/or removal of fluids (including irrigation fluids and bodily fluids), medicines, and/or surgical tools or instruments. Shaft  44  may be made from conventional materials such as polyurethane and defines one or more lumens configured to house and/or transport electrical conductors, fluids or surgical tools. Shaft  44  may be introduced into a blood vessel or other structure within body  17  through a conventional introducer. Shaft  44  may then be advanced, retracted and/or steered or guided through body  17  to a desired location such as the site of tissue  16 , including through the use of guidewires or other means known in the art. 
     In some embodiments, catheter  14  is a hoop catheter (shown, for example, in  FIGS. 2 and 3 ), sometimes referred to as a spiral or loop catheter, having catheter electrodes distributed about one or more hoops at the distal end of shaft  44 . The diameter of the hoop(s) (sometimes referred to herein as “loops”) may be variable. In some embodiments, the hoop catheter diameter is variable by about ten millimeters (mm) between a minimum diameter and a maximum diameter. The minimum diameter in some embodiments may be selected between about thirteen mm and about twenty mm when the catheter  14  is manufactured. With a ten mm range of variability, such catheters would have a maximum diameter between twenty-three mm and thirty mm. In other embodiments, the hoop diameter is variable between about fifteen mm and about twenty eight mm, between about thirteen mm and about twenty-three mm, or between about seventeen mm and about twenty-seven mm. Alternatively, the catheter may be a fixed diameter hoop catheter or may be variable between different diameters. In some embodiments, catheter  14  has fourteen catheter electrodes (e.g., grouped as seven pairs of catheter electrodes). In other embodiments, catheter  14  includes ten catheter electrodes, twenty catheter electrodes, or any other suitable number of electrodes for performing electroporation. In some embodiments, the catheter electrodes are ring electrodes. Alternatively, the catheter electrodes may be any other suitable type of electrodes, such as single sided electrodes or electrodes printed on a flex material. In various embodiments, the catheter electrodes have lengths of 1.0 mm, 2.0 mm, 2.5 mm, and/or any other suitable length for electroporation. 
       FIGS. 2 and 3  illustrate an exemplary electrode assembly  12  suitable for use in system  10 , illustrated in the form of an electrode hoop or loop assembly  200 .  FIG. 2  is a side view of electrode loop assembly  200  with a variable diameter loop  202  coupled at the distal end  302  of a catheter shaft  300 .  FIG. 3  is an end view of variable diameter loop  202  of electrode loop assembly  200 . As shown in  FIGS. 2 and 3 , electrode loop assembly  200  extends from a proximal end  204  to a distal end  206 , and includes an outer sleeve  208  formed in the shape of a loop, and a plurality of catheter electrodes  210  mounted on outer sleeve  208 . Proximal end  204  of electrode loop assembly  200  is coupled to catheter shaft  300  via a suitable coupler  212 . Electrodes  210  may be used for a variety of diagnostic and therapeutic purposes including, for example and without limitation, cardiac mapping and/or ablation (e.g., IRE ablation). For example, electrode loop assembly  200  may be configured as a bipolar electrode assembly for use in bipolar-based electroporation therapy. More specifically, electrodes  210  may be configured as electrode pairs (e.g., cathode-anode electrode pairs) and electrically coupled to electroporation generator  26  (e.g., via suitable electrical wire or other suitable electrical conductors extending through catheter shaft  44 ) such that adjacent electrodes  210  are energized with opposite polarities to generate a potential and corresponding electric field between adjacent electrodes  210 . In other embodiments, any combination of electrodes  210  may be configured as electrode pairs (e.g., cathode-anode electrode pairs), including, for example and without limitation, adjacent electrodes, non-adjacent electrodes, and any other combination of electrodes that enables system  10  to function as described herein. As described above, for example, electroporation generator  26  and/or computer system  32  may selectively energize certain electrodes  210  of electrode loop assembly  200  to form electrode pairs based on contact between electrodes  210  and tissue  16 . In yet other embodiments, electrode loop assembly  200  may be configured other than as a bipolar electrode assembly, such as a unipolar or monopolar electrode assembly. In such embodiments, electrode  18  may function as the return electrode. 
     In the illustrated embodiment, variable diameter loop  202  includes fourteen catheter electrodes  210  evenly spaced around the circumference of variable diameter loop  202 . In other embodiments, variable diameter loop  202  may include any suitable number of catheter electrodes  210  made of any suitable material. Each catheter electrode  210  is separated from each other catheter electrode by an insulated gap  216 . In the example embodiment, each catheter electrode  210  has a same length  218  (shown in  FIG. 3 ) and each insulated gap  216  has a same length  220  as each other gap  216 . Length  218  and length  220  are both about 2.5 mm in the example embodiment. In other embodiments, length  218  and length  220  may be different from each other. Moreover, in some embodiments, catheter electrodes  210  may not all have the same length  218  and/or insulated gaps  216  may not all have the same length  220 . In some embodiments, catheter electrodes  210  are not spaced evenly around the circumference of variable diameter loop  202 . 
       FIG. 4  is a perspective view of another exemplary electrode assembly  12  suitable for use in system  10 , illustrated in the form of a basket electrode assembly  400 . Basket electrode assembly  400  includes a basket  402  coupled to a catheter body  404  by a suitable proximal connector  406 . Basket  402  includes a plurality of splines  408  and a distal coupler  410  at which each of splines  408  terminates. In some embodiments, such as the illustrated embodiment, basket electrode assembly  400  may also include irrigation tubing  412  (e.g., to supply fluids to basket electrode assembly  400 ). In other embodiments, irrigation tubing  412  may be omitted. Each of the plurality of splines  408  includes at least one electrode  414 . In the illustrated embodiment, each of the plurality of splines includes eight electrodes  414 , although each spline  408  may include more than or less than eight electrodes  414 . 
     Electrodes  414  may be used for a variety of diagnostic and therapeutic purposes including, for example and without limitation, cardiac mapping and/or ablation (e.g., IRE ablation). For example, basket electrode assembly  400  may be configured as a bipolar electrode assembly for use in bipolar-based electroporation based electroporation. More specifically, electrodes  414  positioned on adjacent splines  408  may be configured as electrode pairs (e.g., cathode-anode electrode pairs) and electrically coupled to electroporation generator  26  (e.g., via suitable electrical wire or other suitable electrical conductors extending through catheter shaft  44 ) such that electrodes  414  on adjacent splines  408  are energized with opposite polarities to generate a potential and corresponding electric field between electrodes  414  of adjacent splines  408 . In other embodiments, electrodes  414  positioned along the same spline  408  may be configured as electrode pairs. In yet other embodiments, any combination of electrodes  414  may be configured as electrode pairs, including, for example and without limitation, adjacent electrodes, non-adjacent electrodes, electrodes on adjacent splines, electrodes on non-adjacent splines, and any other combination of electrodes that enables system  10  to function as described herein. As described above, for example, electroporation generator  26  and/or computer system  32  may selectively energize certain electrodes  414  of basket electrode assembly  400  to form electrode pairs based on contact between electrodes  414  and tissue  16 . In other embodiments, basket electrode assembly  400  may be configured other than as a bipolar electrode assembly, such as a unipolar or monopolar electrode assembly. In such embodiments, electrode  18  may function as the return electrode. 
       FIG. 5  is a perspective view of another exemplary electrode assembly  12  suitable for use in system  10 , illustrated in the form of a planar or grid electrode assembly  500 . Grid electrode assembly  500  includes a paddle  502  coupled to a catheter body  504 . In the illustrated embodiment, catheter body  504  includes body electrodes  506 ,  508 , and  510  coupled thereto. In the illustrated embodiment, paddle  502  includes a first spline  512 , a second spline  514 , a third spline  516 , and a fourth spline  518  coupled to catheter body  504  by a proximal coupler and coupled to each other by a distal connector  520  at a distal end of paddle  502 . In one embodiment, first spline  512  and fourth spline  518  can be one continuous segment, and second spline  514  and third spline  516  can be another continuous segment. In other embodiments the various splines can be separate segments coupled to each other. The plurality of splines can further comprise a varying number of electrodes  522 . The electrodes in the illustrated embodiment can comprise ring electrodes evenly spaced along the splines. In other embodiments the electrodes can be evenly or unevenly spaced and the electrodes can comprise point or other types of electrodes. 
     Electrodes  522  may be used for a variety of diagnostic and therapeutic purposes including, for example and without limitation, cardiac mapping and/or ablation (e.g., IRE ablation). For example, grid electrode assembly  500  may be configured as a bipolar electrode assembly for use in bipolar-based electroporation based electroporation. More specifically, adjacent electrodes  522  may be configured as electrode pairs (e.g., cathode-anode electrode pairs) and electrically coupled to electroporation generator  26  (e.g., via suitable electrical wire or other suitable electrical conductors extending through catheter shaft  44 ) such that adjacent electrodes  522  are energized with opposite polarities to generate a potential and corresponding electric field between adjacent electrodes  522 . Adjacent electrodes  522  that form a bipole pair may be located along the same spline (e.g., electrodes  522  along first spine  512 ) or across adjacent splines. In one embodiment, for example, electrode pairs may be formed between one electrode  522  (e.g., a cathode) located on first spline  512  and another, adjacent electrode  522  (e.g., an anode) located on adjacent second spline  514 . In other embodiments, any combination of electrodes  522  may be configured as electrode pairs (e.g., cathode-anode electrode pairs), including, for example and without limitation, adjacent electrodes, non-adjacent electrodes, electrodes on adjacent splines, electrodes on non-adjacent splines, and any other combination of electrodes that enables system  10  to function as described herein. As described above, for example, electroporation generator  26  and/or computer system  32  may selectively energize certain electrodes  522  of grid electrode assembly  500  to form electrode pairs based on contact between electrodes  522  and tissue  16 . In other embodiments, grid electrode assembly  500  may be configured other than as a bipolar electrode assembly, such as a unipolar or monopolar electrode assembly. In such embodiments, electrode  18  may function as the return electrode. 
     First spline  512 , second spline  514 , third spline  516 , and fourth spline  518  are generally aligned in the same (topological) plane. Although paddle  502  is illustrated as relatively flat or planar in  FIG. 5 , it should be understood that paddle  502  may bend, curl, buckle, twist, and/or otherwise deform. Accordingly, the plane defined by paddle  502  and splines  512 ,  514 ,  516 , and  518  may correspondingly deform, such that the plane is a non-flat topological plane. 
       FIG. 6  is a perspective view of another exemplary electrode assembly  12  suitable for use in system  10 , illustrated in the form of an expandable electrode assembly  600 . Electrode assembly  600  extends axially from a proximal end  602  of electrode assembly  600  to a distal end  604  of electrode assembly  600 , generally along a longitudinal axis  606 . Proximal end  602  is coupled to catheter shaft  44  (e.g., to a distal end of shaft  44 ) via a suitable coupler (not shown). In the exemplary embodiment, a guidewire  608  extends axially through shaft  44  and through electrode assembly  600 . Guidewire  608  may be manipulated (e.g., using handle  42 ) to adjust a position of electrode assembly  600  within body  17 . 
     Electrode assembly  600  generally includes an expandable isolation member  610  and a pair of electrodes  612 ,  614 . More specifically, expandable isolation member  610  extends between a proximal end  616  of expandable isolation member  610  and a distal end  618  of expandable isolation member  610 . Electrodes  612 ,  614  are arranged adjacent proximal end  616  and distal end  618  of expandable isolation member  610 , respectively, such that expandable isolation member  610  is disposed axially between electrodes  612 ,  614 . A proximal electrode  612  is adjacent proximal end  616  of expandable isolation member  610  and is proximate to proximal end  602  of electrode assembly  600 . Likewise, a distal electrode  614  is adjacent distal end  618  of expandable isolation member  610  and is proximate to distal end  604  of electrode assembly  600 . Distal end  618  of expandable isolation member  610  is proximal to distal end  604  of electrode assembly  600  in the exemplary embodiment. 
     Electrodes  612 ,  614  may be used for a variety of diagnostic and therapeutic purposes including, for example and without limitation, cardiac mapping and/or ablation (e.g., IRE ablation). For example, electrode assembly  600  may be configured as a bipolar electrode assembly for use in bipolar-based electroporation therapy. Specifically, electrodes  612 ,  614  can be individually electrically coupled to generator  26  (e.g., via suitable electrical wire or other suitable electrical conductors extending through catheter shaft  44 ) and configured to be selectively energized (e.g., by electroporation generator  26  and/or computer system  32 ) with opposite polarities to generate a potential and corresponding electric field therebetween, for IRE therapy. That is, one of electrodes  612 ,  614  is configured to function as a cathode, and the other is configured to function as an anode. Electrodes  612 ,  614  may be any suitable electroporation electrodes. In the exemplary embodiment, electrodes  612 ,  614  are ring electrodes. Electrodes  612 ,  614  may have any other shape or configuration. It is realized that the shape, size, and/or configuration of electrodes  612 ,  614  may impact various parameters of the applied electroporation therapy. For example, increasing the surface area of one or both electrodes  612 ,  614  may reduce the applied voltage needed to cause the same level of tissue destruction. Moreover, although each of proximal electrode  612  and distal electrode  614  are illustrated as single electrodes, either or both of proximal electrode  612  and distal electrode  614  may be alternatively embodied as two or more discrete electrodes. Further, while electrode assembly  600  is described as a bipolar electrode assembly, it should be understood that in some embodiments, electrode assembly  600  may configured as a unipolar or monopolar electrode assembly and use a patch electrode (e.g., return electrode  18 ) as a return or indifferent electrode. 
     In the exemplary embodiment, expandable isolation member  610  is configurable between a collapsed configuration (not shown) and an expanded configuration (as shown in  FIG. 6 ). For example, expandable isolation member  610  is delivered in the collapsed configuration to the target location of tissue  16  within body  17  (e.g., axially disposed within catheter shaft  44 ) and transitioned to the expanded configuration at the target location. Expandable isolation member  610  is configured to sealingly engage with tissue  16  at the target location and to inhibit electrical communication between electrodes  612 ,  614  (e.g., by at least partially insulating distal electrode  614  from proximal electrode  612 ). More specifically, expandable isolation member  610 , is formed from an electrically insulating material. Therefore, a current flow  622  between proximal electrode  612  and distal electrode  614  is diverted around expandable isolation member  610 .  FIG. 6  depicts a plurality of current flows  622  of varying shape and magnitude of diversion around expandable isolation member  610 . In some embodiments, the shape and size of expandable isolation member  610  may be selected to influence current flow  622  therearound (e.g., a magnitude of diversion, a shape or direction of the resulting current flow  622 , etc.). 
     Moreover, expandable isolation member  610  is configured to sealingly engage tissue  16  when in the expanded configuration. In one exemplary embodiment, expandable isolation member  610  includes a circumferential sealing surface  620  configured for sealing engagement with tissue  16  such that expandable isolation member  610  inhibits fluid communication and, consequently, electrical communication (e.g., current flow), between the electrodes  612 ,  614  when engaged with tissue of the patient. For example, where expandable isolation member  610  is used for pulmonary vein isolation (PVI) or to isolate other cylindrical or tubular tissue (e.g., other vasculature tissue), expandable isolation member  610  inhibits or substantially prevents the flow of blood therearound. Therefore, when electrodes  612 ,  614  are energized, current  622  flows therebetween through tissue  16  adjacent expandable isolation member  610 , rather than through blood. In this way, the electroporation therapy may be more localized and, therefore, require reduced applied voltage to cause the desired amount of cell destruction. Specifically, fluid (e.g., blood) is more electrically conductive than tissue, therefore current flows through blood more readily than through tissue, and electroporation therapy is less effective. By blocking the blood flow, the current  622  between electrodes  612 ,  614  is diverted through adjacent tissue  16 , thereby increasing the effectiveness of electroporation therapy at a given voltage. 
     In the exemplary embodiment, expandable isolation member  610  includes an outer layer  624  formed or constructed from an electrically insulating material. For example, outer layer  624  may include polyethylene terephthalate (PET). Outer layer  624  made include any other suitable material that is electrically insulating and able to accommodate expansion and contraction of electrode assembly  600 . In certain embodiments, as shown in  FIG. 6 , expandable isolation member  610  is embodied as an inflatable balloon. In such embodiments, the inflatable balloon is coupled to a fluid source  626  for selectively inflating the balloon (e.g., when electrode assembly  600  has been advanced to the target location within body  17  and has been deployed from catheter shaft  44 ). In some embodiments, the fluid source includes a dielectric fluid, such as deionized water, saline, carbon dioxide gas, nitrous oxide gas, and/or air. In other embodiments, expandable isolation member  610  may be selectively expanded using other means, such as an expandable frame (e.g., a frame formed from a shape-memory material) retained within outer layer  624 . 
     Although expandable isolation member  610  is shown in  FIG. 6  as having an elongated spherical shape, expandable isolation member  610  may have any other shape or configuration the enables sealing—and, therefore, inhibiting fluid and/or electrical communication between electrodes  612 ,  614 . The particular shape and/or configuration may be selected for the particular tissue isolation desired. For example, in other embodiments, isolation and tissue destruction within solid or planar tissue, such as the wall of a heart chamber (as opposed to the relatively cylindrical isolation of a vessel), may be desired. In such embodiments, distal end  618  of expandable isolation member  610  may be inverted and concave, and distal electrode  614  is positioned within the concavity of distal end  618 . Distal end  618  may be engaged or pressed against the tissue to seal or isolate distal electrode  614  from proximal electrode  612 , such that current flow  622  between electrodes  612 ,  614  is diverted through the tissue (e.g., of the heart chamber wall) engaged with distal end  618 . 
     It is contemplated that full sealing between expandable isolation member  610  and the adjacent tissue  16  may not occur. For example, circumferential sealing surface  620  may not be fully engaged with tissue  16 , and some fluid (blood) flow past circumferential sealing surface  620  may occur. In some embodiments, complete engagement or sealing is not necessary for electroporation therapy to proceed successfully. The level of sealing may be ascertained using a variety of methods. In some embodiments, introducing fluoroscopic contrast materials are introduced into the blood stream upstream of expandable isolation member  610 , and the presence or amount of contrast material downstream of expandable isolation member  610  is determined using x-rays. In other embodiments, Doppler ultrasound is used to determine the level of fluid flow past expandable isolation member  610 . In still other embodiments, impedance between electrodes  612 ,  614  is measured before and after placement of electrode assembly  600  at the target location; a threshold shift in impedance reflects sufficient sealing. In yet other embodiments, electrode assembly  600  includes a pressure transducer (not shown) on distal end  604  that is used to measure fluid pressure to reflect the level of sealing between expandable isolation member  610  and tissue  16 . Additional and/or alternative methods to determine the level of sealing may be used. Moreover, any of the above-described methods can be employed iteratively. Specifically, an initial level of sealing may be determined, and, in response, a position of electrode assembly  600  may be adjusted. A subsequent level of sealing may be determined, and so forth, until an adequate or sufficient level of sealing is reached (e.g., based on threshold values and/or physician determination). 
     Moreover, based on the determined level of sealing using any of the above methods (or any other suitable method), an appropriate level of voltage to be applied may be selected. A reduced level of sealing may require an increased applied voltage. 
     It should be understood that electrode assembly  12  is not limited to the specific constructions shown and described herein, and may include any other suitable electrode assembly and have any other suitable construction that enables system  10  to function as described herein. By way of example, electrode assembly  12  may have the same or similar construction as electrode assemblies described in U.S. Pat. No. 10,136,829, U.S. Patent Application Publication Nos. 2018/0014751 and 2019/0201688, International Patent Application Publication No. WO2018/208795, and U.S. Provisional Patent Application Ser. Nos. 62/861,135, 62/842,654, and 62/983,200, the disclosures of which are incorporated herein by reference in their entirety. 
     Referring again to  FIG. 1 , the visualization, navigation, and/or mapping system  30  can comprise an electric field-based system, or, sometimes referred to as an impedance based system, such as, for example, that having the model name EnSite NAVX™ system and commercially available from Abbott Laboratories, and as generally shown with reference to U.S. Pat. No. 7,263,397 titled “Method and Apparatus for Catheter Navigation and Location and Mapping in the Heart,” the entire disclosure of which is incorporated herein by reference. The visualization, navigation, and/or mapping system  30  can also include other commercially available systems, including the EnSite™ Velocity™ or EnSite Precision™ cardiac mapping and visualization systems of Abbott Laboratories. In other exemplary embodiments, the visualization, navigation, and/or mapping system  30  can comprise other types of systems, such as, for example and without limitation: a magnetic field-based system such as the CARTO System (now in a hybrid form with impedance- and magnetically-driven electrodes) available from Biosense Webster, or the gMPS system from MediGuide Ltd. In accordance with a combination electric field-based and magnetic field-based system, the catheter can include both electrodes as impedance-based electrodes and one or more magnetic field sensing coils. Commonly available fluoroscopic, computed tomography (CT), and magnetic resonance imaging (MRI)-based systems can also be used. 
     Electroporation generator  26  is configured to energize the electrode element(s) in accordance with an electroporation energization strategy, which may be predetermined or may be user-selectable. For electroporation-induced primary necrosis therapy, generator  26  may be configured to produce an electric current that is delivered via electrode assembly  12  as a pulsed electric field in the form of short-duration DC pulses transmitted between closely spaced electrodes (e.g., electrode pairs of electrode assembly  12 ) and capable of delivering an electric field strength of about 0.1 to 1.0 kV/cm (e.g., at the tissue site). The voltage amplitude and pulse duration needed for irreversible electroporation are inversely related. For example, as pulse durations are decreased, the voltage amplitude must be increased to achieve electroporation. 
     In some embodiments, the electrodes of electrode assembly  12  may be energized sequentially such that only some of electrodes are energized at a given time. That is, not all electrodes of electrode assembly  12  are energized simultaneously. In some embodiments, for example, a first pair of electrodes may be energized according to an electroporation energization strategy, and subsequently, a second pair of electrodes may be energized according to the electroporation energization strategy. The sequential energization of electrodes may continue on to a third pair of electrodes, a fourth pair of electrodes, and so on. The pairs of electrodes may include adjacent or non-adjacent electrodes. By way of example, where an electrode assembly includes a plurality of electrodes sequentially numbered  1  through n according to position (i.e., the second electrode is adjacent to the first electrode and the third electrode), the electrodes may be sequentially energized as pairs by energizing, in sequence, the first and second electrodes, the third and fourth electrodes, the fifth and sixth electrodes, and so on. In another example, the electrodes may be sequentially energized as pairs by energizing, in sequence, the first and second electrodes, the second and third electrodes, the third and fourth electrodes, and so on. In yet another example, the electrodes may be sequentially energized as pairs by energizing, in sequence, the first and third electrodes, the second and fourth electrodes, the third and fifth electrodes, and so on. Additional systems and methods for sequentially energizing electrodes of an electrode assembly are described, for example, in U.S. Provisional Patent Application Ser. No. 63/109,520, filed Nov. 4, 2020, the disclosure of which is incorporated herein by reference in its entirety. Sequential energization may be used in both monopolar and bipolar configurations. 
     In the exemplary embodiment, electroporation generator  26 , sometimes also referred to herein as a DC energy source, is a biphasic electroporation generator  26  configured to generate a series of DC pulses with alternating polarities—i.e., consecutive DC pulses that produce current in alternating directions. In other embodiments, electroporation generator is a monophasic or polyphasic electroporation generator. In some embodiments, electroporation generator  26  is configured to output energy in DC pulses at selectable energy levels, such as fifty joules, one-hundred joules, two-hundred joules, and the like. Other embodiments may have more or fewer energy settings, and the values of the available settings may be the same or different. In some embodiments, electroporation generator  26  outputs or generates a DC pulse having a peak magnitude of between about 500 V and about 3.5 kV, between about 600 V and 2.5 kV, between about 800 V and about 3.5 kV, between about 600 V and about 2.0 kV, between about 800 V and about 2.5 kV, between about 1.0 kV and about 3.5 kV, between about 600 V and about 1.5 kV, between about 800 V and about 2.0 kV, or between about 1.0 kV and about 2.5 kV. Other embodiments may output or generate any other suitable voltage. 
     A variable impedance  27  allows the impedance of the system to be varied. Moreover, variable impedance  27  may be used to change one or more characteristics, such as amplitude, duration, pulse shape, and the like, of an output of electroporation generator  26 . Although illustrated as a separate component, variable impedance  27  may be incorporated in catheter  14  or generator  26 . Variable impedance  27  includes one or more impedance elements, such as resistors, capacitors, or inductors (not shown) connected in series, parallel, or combinations of series and/or parallel. In the illustrated embodiment, variable impedance  27  is connected in series with catheter  14 . Alternatively, the impedance elements of variable impedance  27  may be connected in parallel with catheter  14  or in a combination of series and parallel with catheter  14 . Moreover, in other embodiments, the impedance elements of variable impedance  27  are connected in series and/or parallel with return electrode  18 . Some embodiments include more than one variable impedance  27 , each of which may include one or more impedance elements. In such embodiments, each variable impedance  27  may be connected to a different catheter electrode or group of catheter electrodes to allow the impedance through each catheter electrode or group of catheter electrodes to be independently varied. In other embodiments, the impedance of system  10  may not need to be varied and variable impedance  27  may be omitted. 
     Electroporation generator  26  is configured to generate and supply a pulse signal to electrodes of electrode assembly  12  configured to reduce, minimize, or prevent undesirable or unintended effects of IRE. For example, previous IRE therapy systems may cause skeletal muscle contractions due to the application of high-amplitude, short-duration DC electrical (IRE) pulses. Such skeletal muscle contractions are generally undesirable, for example, because they can render electroanatomical maps (e.g., collected prior to IRE therapy) inaccurate by shifting a patient&#39;s body. Additionally, previous IRE therapy systems may generate undesirable gasses within a patient, for example, at the electrodes. 
     Pulse signals generated by electroporation generator  26  are specifically shaped (e.g., by controlling the phases, amplitude, and pulse duration) to prevent activation of skeletal muscles and nerves (e.g., Phrenic nerve), as well as the myocardium. By avoiding activation of the myocardium, the pulse signals generated by electroporation generator do not have to be timed or gated based on the cardiac cycle or rhythm (e.g., along the R-wave). More specifically, pulse signals generated by electroporation generator  26  are shaped to have a pulse duration and voltage amplitude below the strength-duration curve associated with nerve stimulation or muscle activation. The pulse signals generated by electroporation generator  26  are relatively high strength (i.e., voltage) and frequency (i.e., short pulse duration). By way of example, pulse signals generated by electroporation generator  26  can have a voltage amplitude in the range of 500 V to 3.5 kV, 600 V to 2.5 kV, 800 V to 3.5 kV, 600 V to 2.0 kV, 800 V to 2.5 kV, 1.0 kV to 3.5 kV, 600 V to 1.5 kV, 800 V to 2.0 kV, or 1.0 kV to 2.5 kV, and a pulse duration in the range of 1 nanosecond to 100 microseconds (μs), 1 nanosecond to 50 μs, 0.1 μs to 100 μs, 1 nanosecond to 20 μs, 0.1 μs to 50 μs, 1 μs to 100 μs, 1 nanosecond to 15 μs, 0.1 μs to 20 μs, 0.5 μs to 50 μs, 1 nanosecond to 10 μs, 0.1 μs to 15 μs, 1 nanosecond to 5 μs, 0.1 μs to 10 μs, 0.1 μs to 5 μs, less than 5 μs, less than 4 μs, less than 3 μs, and less than 2 μs. In other embodiments, pulse signals generated by electroporation generator  26  can have a voltage amplitude less than 500 V or greater than 3.5 kV, and can have a pulse duration greater than 100 μs or less than 1 nanosecond. In general, the voltage amplitude and pulse duration needed for efficacious IRE (e.g., to produce continuous lesions) are inversely related, and are selected within a voltage and duration range to avoid nerve stimulation or muscle activation. 
       FIG. 7  is a plot illustrating an exemplary pulse signal  700  generated by electroporation generator  26 , wherein the vertical axis represents voltage (V) and the horizontal axis represents time (T). As shown in  FIG. 7 , pulse signal  700  is a biphasic pulse signal including a first phase  702  having a first voltage amplitude  704  with a first polarity and a first pulse duration  706 , and a second phase  708  having a second voltage amplitude  710  with a second polarity opposite to the first polarity and a second pulse duration  712 . The illustrated pulse signal  700  also includes a third, zero-voltage phase  714  (i.e., pulse signal  700  has a voltage output of zero) separating second phase  708  from first phase  702  such that second phase  708  is generated at a non-zero interval  716  following first phase  702 . In other embodiments, pulse signal  700  may not include third phase  714  such that second phase  708  is generated immediately following first phase  702 . 
     In the illustrated embodiment, first phase  702  has a positive voltage, and second phase  708  has a negative voltage. In other embodiments, first phase  702  may have a negative voltage, and second phase  708  may have a positive voltage. Additionally, while pulse signal  700  is shown and described as a biphasic signal in the illustrated embodiment, pulse signal  700  may be other than a biphasic signal in other embodiments (e.g., pulse signal  700  may be monophasic or polyphasic). 
     Further, in the illustrated embodiment, first phase  702  and second phase  708  have the same voltage amplitude or magnitude, and the same pulse duration (i.e., first pulse duration  706  is equal to second pulse duration  712 ). That is, pulse signal  700  is a symmetric pulse signal. In other embodiments, first phase  702  may have a different voltage amplitude or magnitude and/or pulse duration than second phase  708  such that pulse signal  700  is asymmetric. 
     First phase  702  and second phase  708  may generally have any suitable voltage amplitude and pulse duration sufficient to cause ablation by IRE while at the same time avoiding skeletal muscle stimulation. In some embodiments, for example, each of first voltage amplitude  704  and second voltage amplitude  710  is in the range of 500 V to 3.5 kV, 600 V to 2.5 kV, 800 V to 3.5 kV, 600 V to 2.0 kV, 800 V to 2.5 kV, 1.0 kV to 3.5 kV, 600 V to 1.5 kV, 800 V to 2.0 kV, or 1.0 kV to 2.5 kV, and each of first pulse duration  706  and second pulse duration  712  is in the range of 1 nanosecond to 100 μs, 1 nanosecond to 50 μs, 0.1 μs to 100 μs, 1 nanosecond to 20 μs, 0.1 μs to 50 μs, 1 μs to 100 μs, 1 nanosecond to 15 μs, 0.1 μs to 20 μs, 0.5 μs to 50 μs, 1 nanosecond to 10 μs, 0.1 μs to 15 μs, 1 nanosecond to 5 μs, 0.1 μs to 10 μs, 0.1 μs to 5 μs, less than 5 μs, less than 4 μs, less than 3 μs, and less than 2 μs. In one particular embodiment, each of first voltage amplitude  704  and second voltage amplitude  710  is about 1.0 kV, and each of first pulse duration  706  and second pulse duration  712  is about 2 μs. In another particular embodiment, each of first voltage amplitude  704  and second voltage amplitude  710  is about 1.4 kV, and each of first pulse duration  706  and second pulse duration  712  is about 2 μs. 
     Interval  716  of third phase  714  is generally selected to be of sufficient duration to prevent or avoid first phase  702  and second phase  708  of pulse signal  700  from activating or stimulating skeletal muscle. Interval  716  is generally less than 50 μs, and can be, for example and without limitation, less than 30 μs, less than 20 μs, less than 15 μs, less than 10 μs, less than 5 μs, less than 4 μs, less than 3 μs, less than 2 μs, and even less than 1 μs. In the illustrated embodiment, interval  716  is about 2.5 μs. In another particular embodiment, interval  716  is about 2 μs. 
     In some embodiments, the voltage amplitude of pulse signal  700  (i.e., first phase  702  and second phase  708 ) may be selected based on the type of electrode assembly  12  used in system  10 . More specifically, certain types of electrode assemblies may be rated for higher voltages than other electrode assemblies, and pulse signal  700  may be tuned accordingly. In some embodiments, for example, pulse signal  700  (i.e., first phase  702  and second phase  708 ) may have a higher voltage amplitude when used with a loop-type electrode assembly (e.g., electrode loop assembly  200  shown in  FIGS. 2 and 3 ) as compared to a basket-type electrode assembly (e.g., basket electrode assembly  400  shown in  FIG. 4 ). In one particular embodiment, voltage amplitude of pulse signal  700  is in the range of 1 kV to 2.5 kV when used with a loop-type electrode assembly, and in the range of 800 V to 1.5 kV when used with a basket-type electrode assembly. 
     Characteristics of the pulse signal  700  (e.g., voltage amplitude, first and second pulse durations  706 ,  712 , etc.) may also be tuned according to whether the electrode assembly  12  is configured as a monopolar electrode assembly or a bipolar electrode assembly. For example, skeletal muscle recruitment may be more prominent in monopolar IRE as compared to bipolar IRE. Accordingly, the pulse signal used in monopolar IRE may have narrower or more stringent ranges of acceptable pulse characteristics (e.g., voltage amplitude and pulse durations) as compared to bipolar IRE. 
     In one example, a loop-type electrode assembly (e.g., electrode loop assembly  200  shown in  FIGS. 2 and 3 ) configured as a monopolar electrode assembly may utilize a pulse signal  700  having a voltage amplitude in the range of 500 V to 3.5 kV, or in the range of 800 V to 3.0 kV, and first and second pulse durations  706  and  712  in the range of 0.5 μs to 3.0 μs, or in the range of 0.5 μs to 1.5 μs. A loop-type electrode assembly (e.g., electrode loop assembly  200  shown in  FIGS. 2 and 3 ) configured as a bipolar electrode assembly may utilize a pulse signal  700  having a voltage amplitude in the range of 500 V to 3.5 kV, or in the range of 600 V to 1.4 kV, and first and second pulse durations  706  and  712  in the range of 0.5 μs to 3 μs, or in the range of 1 μs to 1.5 μs. 
     In another example, a basket-type electrode assembly (e.g., basket electrode assembly  400  shown in  FIG. 4 ) configured as a monopolar electrode assembly may utilize a pulse signal  700  having a voltage amplitude in the range of 500 V to 3.5 kV, and first and second pulse durations  706  and  712  in the range of 0.5 μs to 3 μs. A basket-type electrode assembly (e.g., basket electrode assembly  400  shown in  FIG. 4 ) configured as a bipolar electrode assembly may utilize a pulse signal  700  having a voltage amplitude in the range of 500 V to 3.5 kV, and first and second pulse durations  706  and  712  in the range of 0.5 μs to 3 μs. 
     In another example, a grid electrode assembly (e.g., grid electrode assembly  500  shown in  FIG. 5 ) configured as a monopolar electrode assembly may utilize a pulse signal  700  having a voltage amplitude in the range of 500 V to 3.5 kV, and first and second pulse durations  706  and  712  in the range of 0.5 μs to 3 μs. A grid electrode assembly (e.g., grid electrode assembly  500  shown in  FIG. 5 ) configured as a bipolar electrode assembly may utilize a pulse signal  700  having a voltage amplitude in the range of 500 V to 3.5 kV, and first and second pulse durations  706  and  712  in the range of 0.5 μs to 3 μs. 
     In yet another example, an expandable electrode assembly (e.g., expandable electrode assembly  600  shown in  FIG. 6 ) configured as a bipolar electrode assembly may utilize a pulse signal  700  having a voltage amplitude in the range of 500 V to 3.5 kV, in the range of 500 V to 2.5 kV, the range of 600 V to 3.0 kV, in the range of 600 V to 2.5 kV, or in the range of 800 V to 2.5 kV, and first and second pulse durations  706  and  712  in the range of 400 nanoseconds to 20 μs, or in the range of 500 nanoseconds to 1.5 μs. Additionally, the pulse signal  700  used for an expandable electrode assembly (e.g., expandable electrode assembly  600  shown in  FIG. 6 ) may have an interval  716  between the first phase  702  and the second phase  708  in the range of 350 nanoseconds to 1 ms, or in the range of 500 nanoseconds to 1.5 μs. 
     Electroporation generator  26  may generate pulse signal  700  in a repeating pattern such that a plurality of pulse signals  700  are generated and applied to electrodes of electrode assembly  12  at a repeating pulse period. Such plurality of pulse signals  700  are collectively referred to herein as a burst signal. 
       FIG. 8  illustrates an example burst signal  800  including two pulse signals  700  generated at a pulse period  802 . Pulse period  802  may be any suitable period that enables system  10  to function as described herein. By way of example, pulse period  802  may be in the range of 0.5 milliseconds (ms) to 50 ms, 1 ms to 50 ms, 0.5 ms to 30 ms, 1 ms to 30 ms, 0.5 ms to 25 ms, 0.5 ms to 20 ms, 1 ms to 25 ms, 0.5 ms to 10 ms, 1 ms to 20 ms, 1 ms to 10 ms, 0.5 ms to 5 ms, and 1 ms to 5 ms. In the illustrated embodiment, pulse period  802  is about 4 ms. In some embodiments, pulse period  802  is selected to allow a power supply (e.g., a capacitor) of electroporation generator  26  to recharge to a sufficient voltage to maintain the voltage amplitude of pulse signal  700  at or near the target voltage amplitude (e.g., at least 90% of a target voltage amplitude). 
     In some embodiments, electroporation generator  26  may generate burst signals in a repeating pattern such that a plurality of burst signals are generated and applied to electrodes of electrode assembly  12  at a repeating period, referred to as a burst period.  FIG. 9 , for example, illustrates an example burst signal  900  generated at a repeating burst period  902 . Burst period  902  may be any suitable period that enables system  10  to function as described herein. By way of example, burst period  902  may be in the range of 50 ms to 5 seconds (s), 100 ms to 5 s, 100 ms to 2 s, 100 ms to 1 s, 200 ms to 1 s, 200 ms to 800 ms, and 300 ms to 700 ms. In the illustrated embodiment, burst period  902  is about 500 ms. In some embodiments, burst period  902  is selected to allow a power supply (e.g., a capacitor) of electroporation generator  26  to recharge to a sufficient voltage to maintain the voltage amplitude of pulse signal  700  at or near the target voltage amplitude (e.g., at least 90% of a target voltage amplitude). Additionally or alternatively, burst period  902  may vary based on a patient&#39;s cardiac cycle or rhythm. In one embodiment, for example, the burst signal  900  is generated according to an R-wave gating strategy (e.g., in sync with a patient&#39;s heart rate). In such embodiments, the burst signal  900  may be generated in response to or triggered based on detection of an R-wave in an electrocardiogram. In such embodiments, the burst period  902  may be variable (i.e., not fixed or constant). For example, the burst period  902  may vary within the range of 500 ms to 1.5 s, within the range of 600 ms and 1.2 s, or within any other suitable range that enables system  10  to function as described herein. Such burst periods and gating strategies may be used in connection with any of the electrode assemblies described herein. 
     The plot illustrated in  FIG. 9  includes two burst signals  900 , though it should be understood that electroporation generator  26  may generate more than two burst signals  900 . By way of example, electroporation generator  26  may generate a series of burst signals  900  (i.e., at a repeating burst period  902 ) that includes at least 5 burst signals, at least 10 burst signals, at least 20 burst signals, at least 30 burst signals, at least 40 burst signals, at least 50 burst signals, at least 75 burst signals, at least 100 burst signals, or up to 200 burst signals. In other embodiments, electroporation generator  26  may generate a series of more than 200 burst signals at a repeating burst period. 
     Further, in the illustrated embodiment, burst signal  900  includes 5 pulse signals  700 , although it should be understood that burst signal  900  may include any suitable number of pulse signals  700  that enables system  10  to function as described herein. By way of example, burst signal  900  can include at least 10 pulse signals, at least 15 pulse signals, at least 20 pulse signals, at least 30 pulse signals, at least 40 pulse signals, at least 50 pulse signals, at least 75 pulse signals, at least 100 pulse signals, at least 150 pulse signals, or up to 200 pulse signals. In other embodiments, burst signal  900  may include less than 5 pulse signals  700  or greater than 200 pulse signals  700 . In one particular embodiment, burst signal  900  includes 50 pulse signals  700 , and has a burst period  902  of 0.5 s. In another particular embodiment, burst signal  900  includes 1,000 pulse signals  700 , and has a burst period  902  of 0.5 s. Such burst signals and burst periods are suitable for use with any of the electrode assemblies described herein. 
     The relatively high voltages and short pulse durations of the pulse signals generated by electroporation generator  26  may result in significant electromagnetic interference (EMI), or noise, being introduced into electroporation generator  26 , its components, catheter  14 , or tissue  16  of the patient, and potentially adversely affecting operation of system  10 . Accordingly, embodiments of the present disclosure include certain features to reduce sources of noise and to mitigate the effects of the high frequency high voltage switching within electroporation generator  26  for the purpose of producing the high-amplitude short duration pulse signals. 
     For example,  FIG. 10  is a schematic diagram of exemplary electroporation generator  26 . Electroporation generator  26  includes a microcontroller  1002  or other programmable processing device that controls generation of the pulse signals in response to a trigger signal  1004 . Trigger signal  1004  may be generated internal to electroporation generator  26  or externally by another system. In certain embodiments, trigger signal is a discrete logic-level DC signal supplied to microcontroller  1002  as a result of, for example, an at least momentary closure of a switching circuit by a switch or button actuated by a user. In response to trigger signal  1004 , microcontroller  1002  initiates a single pulse, a burst of pulses, or a plurality of bursts, for example. 
     Microcontroller  1002 , in generating a single pulse signal, generates a first pulse control signal  1006  and a second pulse control signal  1008  for the purpose of controlling a plurality of semiconductor switches. First pulse control signal  1006  and second pulse control signal  1008  are logic level DC signals generated by microcontroller  1002 . The semiconductor switches may be any suitable power semiconductor capable of a high-voltage standoff, high current conduction, and operable at a high frequency, such as an insulated-gate bipolar transistor (IGBT). In the embodiment of  FIG. 10 , the semiconductor switches are implemented as IGBTs  1010 ,  1012 ,  1014 ,  1016  connected in a bridge configuration to regulate application of positive high voltage DC (+HVDC) supply  1018  and negative high voltage DC (−HVDC) supply  1020  to catheter  14  and, more specifically, first and second conductors  1022  and  1024  that deliver the pulse signal to electrode assembly  12 . Microcontroller  1002 , in generating a burst of pulse signals, controls IGBTs  1010 ,  1012 ,  1014 ,  1016  to commutate at a high frequency (e.g., about 500 kilohertz) to produce each pulse signal. 
     Microcontroller  1002  is communicatively coupled and electrically isolated from IGBTs  1010 ,  1012 ,  1014 ,  1016  by an opto-isolator  1026 . Opto-isolator  1026 , also referred to as an opto-coupler, prevents, for example, noise generated by high frequency switching of IGBTs  1010 ,  1012 ,  1014 ,  1016  from reaching microcontroller  1002 . Opto-isolator  1026  relays first pulse control signal  1006  and second pulse control signal  1008  from microcontroller  1002  to a logic circuit  1028  that translates the two logic level DC signals into four gate driving signals  1030 ,  1032 ,  1034 ,  1036 . Logic circuit  1028  derives each of gate driving signals  1030 ,  1032 ,  1034 ,  1036  from first pulse control signal  1006  and second pulse control signal  1008 , and ensures that gate driving signals  1030 ,  1032 ,  1034 ,  1036  do not connect, or short, the opposite-polarity HVDC supplies (+HVDC supply  1018  and −HVDC supply  1020 ), for example, momentarily during a transition from a +HVDC phase to a −HVDC phase of the pulse signal. For example, in certain embodiments, logic circuit  1028  derives gate driving signals  1034  and  1036  as inversions of gate driving signals  1030  and  1032 . 
     Generally, in at least some embodiments, microcontroller  1002  does not source sufficient current to drive the gates of IGBTs  1010 ,  1012 ,  1014 ,  1016 . Gate current for power semiconductor switches typically rises with high voltage and high current capacity. Accordingly, electroporation generator  26  includes gate drivers  1038 ,  1040 ,  1042 ,  1044  for operating IGBTs  1010 ,  1012 ,  1014 ,  1016 , respectively. Gate drivers  1038 ,  1040 ,  1042 ,  1044  further isolate microcontroller  1002  and other aspects of the digital circuit from the high-voltage high-current portions of electroporation generator  26 . Gate drivers  1038 ,  1040 ,  1042 ,  1044  control commutation of IGBTs  1010 ,  1012 ,  1014 ,  1016  according to gate driving signals  1030 ,  1032 ,  1034 ,  1036 . Gate drivers  1038 ,  1040 ,  1042 ,  1044  drive gates of IGBTs  1010 ,  1012 ,  1014 ,  1016  through gate driving impedances  1046 ,  1048 ,  1050 ,  1052 . Gate driving impedances  1046 ,  1048 ,  1050 ,  1052  are selected both to produce a sufficient current rise through IGBTs  1010 ,  1012 ,  1014 ,  1016  and to avoid oscillatory responses by IGBTs  1010 ,  1012 ,  1014 ,  1016 . In certain embodiments, gate driving impedances  1046 ,  1048 ,  1050 ,  1052  are resistors in the range of 6-8 ohms. In at least some embodiments, gate driving impedances  1046 ,  1048 ,  1050 ,  1052  are 6.8 ohm resistors. 
     Electroporation generator  26  may be implemented, in certain embodiments, on one or more printed circuit boards (PCBs) on which microcontroller  1002 , opto-isolator  1026 , logic circuit  1028 , gate drivers  1038 ,  1040 ,  1042 ,  1044 , and IGBTs  1010 ,  1012 ,  1014 ,  1016  may be disposed. At least some traces on the PCB conduct high-voltage DC that is switched at a high frequency. For example, traces connecting +HVDC supply  1018  to IGBTs  1010 ,  1012 ,  1014 ,  1016 , and traces supplying current from IGBTs  1010 ,  1012 ,  1014 ,  1016  to terminals  1056  and  1058  for first and second conductors  1022  and  1024  each carry the pulse signal generated by high-frequency switching of IGBTs  1010 ,  1012 ,  1014 ,  1016 , and thus are susceptible to introducing noise to electroporation generator  26 . In certain embodiments, such traces should be sufficiently wide and as short as possible to reduce the introduction of noise resulting from the periodic high di/dt conditions on those traces. In certain embodiments, these traces should be at least 0.12 inches wide. Likewise, at least some traces conduct significant amounts of high-frequency switched current for the purpose of driving gates of IGBTs  1010 ,  1012 ,  1014 ,  1016 . For example, traces extending between gate drivers  1038 ,  1040 ,  1042 ,  1044  and their respective IGBTs  1010 ,  1012 ,  1014 ,  1016  are each also susceptible to introducing noise resulting from high di/dt conditions on those traces. Accordingly, those traces should also be sufficiently wide and as short as possible to reduce the introduction of noise. In certain embodiments, for example, the traces between gate drivers  1038 ,  1040 ,  1042 ,  1044  and their respective IGBTs  1010 ,  1012 ,  1014 ,  1016  should be at least 0.06 inches wide. 
     In certain embodiments, electroporation generator  26  includes additional components between each of gate drivers  1038 ,  1040 ,  1042 ,  1044  and IGBTs  1010 ,  1012 ,  1014 ,  1016 . For example, in certain embodiments, one or more capacitors are coupled in parallel with the gate of the semiconductor switch to function as a current supply for driving that gate. In certain embodiments, one or more diodes are coupled in parallel with the gate of the semiconductor switch to function, for example, as transient voltage suppression or as current blocking devices. In certain embodiments, one or more EMI suppression devices are coupled to the gate driving branch to mitigate noise originating from, for example, high frequency switching of IGBTs  1010 ,  1012 ,  1014 ,  1016 . 
     In certain embodiments, electroporation generator  26  includes one or more impedance matching circuits (not shown) connected in series with the high-voltage DC output, i.e., in series with first and second conductors  1022  and  1024 . The impedance matching circuits mitigate impedance discontinuities that may occur or that may be inherent at various portions of the high-voltage DC transmission line formed by the traces or other conductors between +HVDC supply  1018 , −HVDC supply  1020 , and electrode assembly  12  of catheter  14 . For example, an impedance discontinuity may exist where catheter  14  connects to electroporation generator  26 , which may result in signal reflections within electroporation generator  26  that ultimately manifest as noise and losses in system  10 . 
     +HVDC supply  1018  and −HVDC supply  1020  are opposite polarity DC voltage levels. For example, in certain embodiments, +HVDC supply  1018  may be at a potential of about 3500 VDC and −HVDC supply  1020  may be at a potential of about zero, or effectively ground. Electroporation generator  26 , in at least some embodiments, includes a high-voltage capacitor  1054  to function as the high voltage current source for electrode assembly  12 . A single pulse signal includes a first phase having a first polarity high voltage, a second phase having about potential of zero volts, and a third phase having a second polarity high voltage. Catheter  14  supplies the high voltage pulse signal over first and second conductors  1022  and  1024 . Accordingly, the polarity of the high voltage pulse signal can be switched by alternatingly applying, in time, +HVDC supply  1018  to first conductor  1022  and second conductor  1024 , and −HVDC supply  1020  to second conductor  1024  and first conductor  1022 . Likewise, 0 VDC is achieved by disconnecting both first and second conductors  1022  and  1024  and allowing their potential to float. Consequently, due to the conductive properties of a blood/saline solution in the body  17  of the patient, there should be no potential between electrodes of electrode assembly  12 , and thus no potential between first and second conductors  1022  and  1024 . 
     For example, where +HVDC supply  1018  is at a potential of about 3500 VDC and −HVDC supply  1020  is at a potential of about 0 VDC, the first phase of the pulse signal is produced by closing IGBT  1010  and opening IGBT  1014  to apply +HVDC supply  1018  to first conductor  1022 ; and closing IGBT  1012  and opening IGBT  1016  to apply −HVDC supply  1020  to second conductor  1024 , thereby producing a +3500 VDC signal for a first duration. After the first duration, IGBT  1010  and IGBT  1012  are opened to allow the potential of first and second conductors  1022  and  1024  to float, thereby producing 0 VDC for the second phase of the pulse signal for a second duration. After the second duration, IGBT  1014  is closed to apply −HVDC supply  1020  to first conductor  1022 , and IGBT  1016  is closed to apply +HVDC supply  1018  to second conductor  1024 , thereby producing a −3500 VDC signal for a third duration. After the third duration, IGBT  1014  and IGBT  1016  are opened to return the potential across first and second conductors  1022  and  1024  to 0 VDC. 
       FIG. 11  is a flow diagram of an example method  1100  of generating a pulse signal. Referring to  FIGS. 10 and 11 , the method includes supplying  1102  +HVDC supply  1018  having a first polarity to a plurality of semiconductor switches, such as IGBTs  1010 ,  1012 ,  1014 ,  1016  connected in a bridge configuration. −HVDC supply  1020 , having a second polarity opposite the first polarity, is supplied  1104  to the plurality of semiconductors. To generate the biphasic pulse signal, microcontroller  1002  controls commutation of IGBTs  1010 ,  1012 ,  1014 ,  1016 . More specifically, the plurality of semiconductors are each commutated  1106  to apply +HVDC supply  1018  to first conductor  1022  of catheter  14  and to apply the −HVDC supply  1020  to second conductor  1024  of catheter  14  for a first duration. The plurality of semiconductors are each then commutated  1108 , after the first duration, to electrically disconnect first conductor  1022  and second conductor  1024  from +HVDC supply  1018  and −HVDC supply  1020  for a second duration. The plurality of semiconductors are each then commutated  1110 , after the second duration, to apply +HVDC supply  1018  to second conductor  1024  and to apply −HVDC supply  1020  to first conductor  1022  for a third duration. The plurality of semiconductors are each then commutated  1112 , after the third duration, to electrically disconnect first and second conductors  1022  and  1024  from +HVDC supply  1018  and −HVDC supply  1020 . 
     Although certain steps of the example method are numbered, such numbering does not indicate that the steps must be performed in the order listed. Thus, particular steps need not be performed in the exact order they are presented, unless the description thereof specifically require such order. The steps may be performed in the order listed, or in another suitable order. 
     Although the embodiments and examples disclosed herein have been described with reference to particular embodiments, it is to be understood that these embodiments and examples are merely illustrative of the principles and applications of the present disclosure. It is therefore to be understood that numerous modifications can be made to the illustrative embodiments and examples and that other arrangements can be devised without departing from the spirit and scope of the present disclosure as defined by the claims. Thus, it is intended that the present application cover the modifications and variations of these embodiments and their equivalents. 
     This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the disclosure, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.