WO2023049954A1

WO2023049954A1 - Method, systems, apparatuses and devices for cardiac tissue characterization and ablation using reversible electroporation and electrolysis

Info

Publication number: WO2023049954A1
Application number: PCT/AU2022/051150
Authority: WO
Inventors: Michael CEJNAR; Luke Zhao; Christian Drescher; Roman GREIFENEDER
Original assignee: Microfield Global Pty Ltd
Priority date: 2021-10-01
Filing date: 2022-09-26
Publication date: 2023-04-06

Abstract

A device for generating electrical pulses for ablating cardiac tissue, the device comprising: a signal generator for producing one or more electrical pulses of a first predetermined voltage or current and duration, wherein the electrical pulse has a truncated pulse waveform which comprises of: a rising edge, a plateau, and a falling edge; the first predetermined voltage or current and duration having a voltage in the range of 200 to 1000 Volts, and a duration in the range between 5 to 100 ms; wherein when the electrical pulse is transmitted to cardiac tissue, reversible electroporation of cardiac tissue is induced.

Description

METHOD, SYSTEMS, APPARATUSES AND DEVICES FOR CARDIAC TISSUE

CHARACTERIZATION AND ABLATION USING REVERSIBLE

ELECTROPORATION AND ELECTROLYSIS

TECHNICAL FIELD

[0001] The present invention relates to methods, systems, apparatuses and devices used for characterization and ablating cardiac tissue via the combination of reversible electroporation energy and electrolysis for the purpose of diagnosis and treatment of cardiac arrhythmia.

BACKGROUND

[0002] Arrhythmia is a cardiac rhythm disorder that can be caused by both bradyarrhythmia (abnormally slow) and tachyarrhythmia (abnormally fast) heart rates/rhythms. An ageing population has led to an increase in these arrhythmias with cardiac fibrillation (AF) being the most common cardiac arrhythmia, placing patients at increased risk of thromboembolic events, heart failure, hospitalization and death. Arrhythmia symptoms include fatigue, breathlessness and syncope, and if left untreated can cause significant mortality and morbidity. If a patient is left untreated, the patient can have an abnormal heart rhythm condition. AF affects 2-3% of population and incidence rises with age, affecting over 5% those over the age of 60 years. While AF symptoms may range from no symptoms to debilitating arrhythmias; serious consequences resulting from AF such as cerebral stroke, heart failure and death, as well as subtler morbidities of multi-infarct dementia and progressive cardiac impairment are recognized.

Pharmaceutical therapy is frequently ineffective or intolerable and can be hazardous, which can cause haemorrhagic strokes or arrhythmias.

[0003] Over the past 20 years, methods have been developed to ablate the cardiac sources of AF either intra-cardially or epicardially using transvenous or surgical procedures, with over 100,000 such procedures performed in USA annually. Current cardiac ablation methods use thermal energies, such as heating to above 50°C by applied radiofrequency (RFA), ultrasound, or lasers; or cooling tissue to -50°C by various cryo-technologies. The dominant procedure uses transvenous electrode-tipped RFA catheters manipulated by physicians inside the heart aided by X-ray, 3D mapping systems and Intra-Cardiac Echocardiography (ICE) to place up to a hundred 3-5mm diameter discrete contiguous transmural lesions within the atria and around pulmonary veins (PV) to electrically isolate their sources of arrhythmia from the left atrium (PVI) and also create various blocks to electrical conduction in the left and right atria. Each lesion can take 1 or 2 minutes to locate and burn, and these procedures can take between 2 to 4 hours, and require some form of anaesthesia with 3-5 staff in a specialised operating room, which can cost between $30,000 to 50,000 each. Further, these procedures are only 70% effective with many patients exhibiting reconnection through the ablation lines and can require second or even third repeat procedures.

[0004] Increasingly complex and expensive RFA catheters have been developed to reduce ablation failures and procedural risk, in which the RFA catheter includes water cooled tips, temperature and contact force sensing catheters to increase energy delivery without gasification and arcing. The RFA catheter can also include rapid thermal diamond sensors for servo-controlled delivery of high energy RFA. Ablation failures stem from inadequate lesions and reconnection of partial lesions. The procedures also carry risks of serious complications including stroke, cardiac perforation, damage to adjacent organs including the oesophagus with risk of devastating atrioesophageal fistulae and phrenic nerve damage, and also carry harmful risks of subclinical pulmonary vein narrowing and creation of new arrhythmia. Consequently, physicians have sought devices for creating a complete circular ablation around pulmonary veins with a single energy application, a so called ‘one-shot’ therapy. Circular multi-electrode RFA catheters have generally failed due to anatomical issues and poor contact force. Thermal balloonbased devices have progressed from unsuccessful high-intensity focused ultrasound (HIFU) devices, to marketed laser devices, to a successful cryoballoon product, all of which however risk injury non-cardiac structures.

[0005] In the past 15 years, irreversible electroporation has been investigated as an alternative non-thermal cardiac ablation energy, with the potential benefits of instant application, cardioselectivity and action at a distance not requiring contact. The benefits of providing multi-electrode one-shot curvilinear ablation may allow faster lesion formation, with less risk to non-cardiac structures. The bioelectric phenomenon of electroporation is characterized by the permeabilization of the cell membrane through the application of very brief, pulses of high-amplitude electric fields. Lower electric fields produce reversible electroporation (RE) which creates temporary pores in the cellular lipid bilayer, which have been used for decades in introducing molecules such as DNA or siRNA and drugs into cells. RE techniques have been combined with anticancer drugs such as bleomycin to target cancerous tissues in the field of electro chemotherapy. Irreversible electroporation (IRE), using higher electric fields (>400V/cm for myocardium), in which the needles are introduced into tissues have been used successfully to selectively ablate prostate and liver cancers.

[0006] More recently, IRE has been applied to left cardiac endocardium via transvenous circular or looped multi-electrode catheters and has successfully and selectively electrically isolated pulmonary veins without evident side effects. Monophasic IRE pulses cause severe muscle spasms and therefore require muscle relaxants in addition to deep anaesthesia, which significantly compounds procedural risk. However, most recent early clinical trials of a biphasic pulse field ablation (PFA) remove this disadvantage, albeit requiring higher 2.5kV voltage pulses. Although demonstrated to be effective and cardioselective by sparing arteries, veins, nerves and the esophagus; the IRE field is however affected by varying tissue admittance and thus the extent and shape of ablation tends to be irregular and difficult to predict and control. Furthermore, IRE produces immediate but temporary electrical conduction block, which may become permanent by cellular apoptosis only tens of minutes to many hours later, potentially creating false procedure end-points (ie: tissue may be stunned for a short period of time leading to a false positive). These limitations raise concern about damaging unintended cardiac structures and creating inhomogeneous arrhythmogenic substrate.

[0007] Electrolysis has been used for minimally invasive tissue ablation since the early 1800's. The process of electrolysis occurs at electrode surfaces submerged in ionic conducting media, including tissues, where new chemical species are generated as a result of an electric potential-driven transfer of charge between ions or atoms in the electrode and the solution. The new chemical species can diffuse away from the electrode into tissues driven by the concentration gradient as well as electroosmotic diffusion. In physiological saline solutions, electrolysis also yield changes in pH, which results in an acidic region near the anode and a basic region near the cathode. Resulting tissue ablation is driven by two factors: a cytotoxic environment due to local changes in pH, as well as the cytotoxicity of some of the new chemical species formed during electrolysis. Electrolysis is a chemical ablation mechanism, and the extent of ablation is a function of the concentration of the diffused chemical species and the exposure time to these chemicals. The total amount of produced electrolytic products and thus the quantitative extent of ablation is related to the total charge delivered during the process.

[0008] Over the last two decades, substantial experimental and clinical research has been performed on electrolytic ablation, sometimes referred to as Electro-Chemical Therapy (EChT). Electrolytic ablation has several unique attributes. Firstly, its slow chemical diffusive and reactive nature dominates the timescale of the procedure. Secondly, the ablation processes at the anode and cathode differ due to the differences in the pH and the new electrolytic species created at each electrode, as well as due to the migration of water from the anode to the cathode driven by an electro-osmotic forces. Electrolysis may use very low voltages and currents, thereby offering benefits of safety and simplicity of instrumentation, however due to the slow process of diffusion having to deliver relatively high concentration of chemical species to effect the death of cells with initially intact cell membranes makes it an unfavourable lengthy procedure.

[0009] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

SUMMARY

[0010] PROBLEMS TO BE SOLVED [0011] It may be an advantage to apply a combination of electroporation and electrolysis to cardiac tissue for cardiac tissue ablation. Alone, the delivery of a pulse of a voltage and current to a cardiac tissue treatment site, wherein the magnitude and a duration of the pulse is selected to induce electroporation at the cardiac treatment site which by itself may not be intense enough to be ablative, and wherein the duration of the pulse is further selected to produce an amount of electrolytic products at that cardiac treatment site which by itself may not be concentrated enough to be ablative. Whereby the combination of the two allows the sub-lethally electroporated pores to facilitate entry into cells for the externally sub-lethally electrolytic products of sub-lethal concentration, and destroy cells from within. Electrolysis used in combination with electroporation for inducing cell death in cardiac tissue, which is referred to as E2 combination treatment throughout this specification.

[0012] The benefits of the E2 combination treatment may offer multitude of benefits arising from the lower required voltage, ablation geometry benefits from combining the two complimentary penetration geometries of chemical and electric modalities, and the cardioselective early cellular death from the chemical toxicity caused by electroporation.

[0013] It may be an advantage to use a lower voltage for the reversible electroporation component of E2, (For example, 400 to 1000 volts compared to 1500 to 2500 for electroporation alone (IRE)) which allow for simpler and more cost-effective generator being used. It may also allow for simpler and more cost-effective medical device design and construction as well as the potential adaptive application of E2 modality to existing catheters and instruments with modest modification. Lower voltage of E2, particularly when applied in bipolar manner also reduces unwanted muscle contraction reducing or eliminating need for deep aesthesia and muscle relaxants during procedure.

[0014] It may be a further advantage of the E2 modality to allow the application of the reversible electroporation voltage component alone without the electrolysis component which may cause the temporary stunning of the area which will be ablated by the combination therapy. This may allow the operator to safely and reversibly test the ablation site to ensure that no unintended conduction defects are created, which is analogous to the use of sub-lethal cryotherapy temperatures to test the safety of lesions before making them permanent.

[0015] It may be a further advantage to provide a geometry of overlapping penetration of the diffusive chemical electrolysis components of the E2 combination treatment with the tissue, as the current flowing from the electroporation electric field interacts with anisotropic tissue impedance which may provide a more predictable and controllable extent and shape of permanent ablation lesion with well-defined edges. This may be important to the verification of extent and permanence of conduction blocks or end-points during the clinical procedure as well as the avoidance of inadvertent ablation of adjacent cardiac tissues.

[0016] It may be a further advantage of the E2 combination treatment that the chemical cytotoxicity of the pH change and electrolysis products inside porated cells have been shown to produce early, within one hour, complete cardioselective cellular disruption almost certain to cause a definitive permanent conduction block. This also beneficially allows reliable early confirmation of permanent conduction block during the clinical procedure. This is in contrast to electroporation alone, (i.e. IRE), which by its nature causes a more delayed cellular death by cellular apoptosis, which makes confirmation of permanency of ablation lesions less certain, and also produces an uneven ablation lesion. The uneven ablation lesion may have an inner zone of IRE or permanent ablation where electric field is strong enough, surrounded by a zone of temporary stunning where lower electric field strengths cause only reversible myocardial stunning, potentially producing ablation lesions during the procedure which however recover some time, hours or days afterwards.

[0017] It may be an advantage to provide a method for cardiac tissue ablation according to a preferred embodiment of the disclosure which may include charging one or more charge storage elements to an initial voltage with a power supply, and discharging the charge storage element or charge storage elements. A preferred embodiment of the one or more charge storage elements may each comprise one or more capacitors for storing a predetermined amount or threshold of charge required for effecting treatment. It may be an advantage to provide a method for cardiac tissue ablation according to a preferred embodiment of the disclosure which may include charging a capacitance to an initial voltage with a power supply, and discharging the capacitance through pulse-shaping circuitry and an electrode to provide a pulse to a cardiac treatment site, wherein the pulse comprises a specific voltage with an exponential or similar decay shape principally defined by a time constant, which may be initially set or dynamically adjusted to the particular electrode geometry and conduction properties of the electrodes in order to deliver required energy for ablation without excessive formation of bubbles and electric arcing. It may be appreciated that reversible electroporation may be achieved by selecting an appropriate capacitance and/or selecting a truncating pulse waveform and/or neutralizing pH changes.

[0018] It may be an advantage to provide an apparatus for cardiac tissue ablation according to another preferred embodiment of the disclosure which may include an electrode or plurality of electrodes that may be configured to apply a pulse of voltage and current to an cardiac tissue treatment site, and a controller coupled to an electrode or catheter with a plurality of electrodes. The controller may be configured to provide an electronic signal to the electrode or plurality of electrodes, wherein the electronic signal may synchronize pulse with cardiac refractory period and determine a rising edge, a plateau, and a falling edge of the pulse appropriate for the electrode geometry and specific tissue interface characteristics. The said electronic signal may thus be configured generally or specific to each individual application to tissue to optimally induce a desired combination of electrolysis and electroporation at the cardiac treatment site.

[0019] It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

[0020] MEANS FOR SOLVING THE PROBLEM

[0021] A first aspect of the present invention may relate to a device for generating electrical pulses for ablating cardiac tissue, the device comprising: a signal generator for producing one or more electrical pulses of a first predetermined voltage or current and duration, wherein the electrical pulse has a truncated pulse waveform which comprises of: a rising edge, a plateau, and a falling edge. The first predetermined voltage or current and duration having a voltage in the range of 200 to 1000 Volts, and a duration in the range between 5 to 100 ms; wherein when the electrical pulse is transmitted to cardiac tissue, reversible electroporation of cardiac tissue is induced.

[0022] A second aspect of the present invention may relate to a device for generating electrical pulses for ablating cardiac tissue, the device comprising: a signal generator for producing one or more electrical pulses of a first predetermined voltage or current and duration, wherein the electrical pulse has a pulse waveform comprising a truncated waveform portion and a non-truncated waveform portion; wherein the pulse waveform comprises of: a rising edge, a plateau, and a falling edge. The first predetermined voltage or current and duration having a voltage in the range of 200 to 1000 Volts, and a duration in the range between 5 to 100 ms; wherein when the electrical pulse is transmitted to cardiac tissue, reversible electroporation of cardiac tissue is induced from the truncated portion of the pulse waveform, and wherein blood is electrolysed from the non-truncated portion of the pulse waveform.

[0023] Preferably, the electrical pulse is a pulse selected from the group of: single pulse, one or more pulses of equal amplitude, multiple pulses of equal amplitude, one or more pulses of varying amplitude, and multiple pulses of varying amplitude.

[0024] Preferably, the one or more pulses or multiple pulses are at least one selected from the group of: monophasic, biphasic, and multiphasic.

[0025] Preferably, the one or more electrical pulses are monopolar, wherein when the signal generator is configured for electrically communicating the electrical pulse to one electrode of a catheter.

[0026] Preferably, the one or more electrical pulses are bipolar, wherein when the signal generator is configured for electrically communicating the electrical pulse to one electrode and an adjacent electrode of a catheter by applying the voltage between the two adjacent electrodes, and wherein the adjacent electrodes are configured in opposing electrical polarity.

[0027] Preferably, the one or more electrical pulses is delivered from the signal generator or from one or more charge storage elements or multiple charge storage elements to more than one electrode of the catheter for electric field strength uniformity.

[0028] Preferably, the pulse waveform is composed of concatenating a plurality of waveforms, wherein each of the waveforms has at least one selected from the group of: of equal or varying amplitudes, equal or varying time interval durations, and same or different waveform shapes.

[0029] Preferably, the concatenated waveform is configured to be delivered within the refractory period of cardiac tissue.

[0030] Preferably, the pulse waveform is composed of concatenating a plurality of waveforms, wherein the polarity of the plurality of waveforms is one selected from the group of: monophasic, biphasic, and multiphasic.

[0031] A third aspect of the present invention may relate to a catheter adapted for ablating cardiac tissue, the catheter comprising: at least one electrical lead having a proximal end and a distal end and at least one lumen extending from the proximal end to the distal end. A handle at the proximal end, wherein the handle comprises a fluid connector and an electrical connector, wherein the fluid connector allows for injected fluid to flow in a first lumen; wherein the first lumen having an outlet at the distal end, wherein the outlet allows for the ejection of the injected fluid from the first lumen. One or more electrodes positioned at the distal end, wherein the electrode is electrically coupled with the electrical lead. The electrical connector for allowing electrical communication between the handle and a controller, wherein the controller is in electrical communication with a signal generator, and wherein the controller is in electrical communication with the switching of the one or more electrodes, wherein the controller allows for the electrode to deliver one or more predetermined electrical pulses at target tissue such that the predetermined pulse induces electroporation of target cardiac tissue and electrolysis of the blood.

[0032] Preferably, the one or more predetermined electrical pulses has a pulse waveform comprising a truncated waveform portion and a non-truncated waveform portion; wherein the pulse waveform comprises of: a rising edge, a plateau, and a falling edge; and wherein the predetermined electrical pulse has a voltage and duration, wherein the voltage is in the range of 200 to 1000 Volts, the capacitance in the range of 200 to 600 pF for monophasic pulses or 10 to 100 times higher for biphasic pulses, wherein the total duration is in the range between 5 to 100 ms, and wherein the number of pulses or pulse trains is in the range of 1 to 2; and wherein the electrical pulse to the at least one electrode allows for ablation depth of the target cardiac tissue is at least 2 mm.

[0033] Preferably, the injection fluid is one selected from the group of: physiological saline solution, heparin, contrast medium, and physiological saline solution with contrast medium.

[0034] Preferably, the controller is configured to dynamically control the one or more electrical pulses from the signal generator to the at least one electrode such that the at least one electrical pulse coincides with the tissue refractory period.

[0035] Preferably, the catheter comprises one or more sensing electrodes, wherein a first sensing electrode is configured for measuring the electrical impedance or cardiac signals of the target cardiac tissue.

[0036] Preferably, the catheter further comprises a cable junction box which is in electrical connection between the signal generator and the handle, wherein the cable junction box allows for the one or more electrodes to switch between sensing and delivering the one or more electrical pulses to the target cardiac tissue.

[0037] Preferably, the first electrical pulse initially selected for delivery to the one or more electrodes allows for reversible permeabilization of the target cardiac tissue, allowing electrolytic blood products or injected fluid into target cardiac tissue, wherein when electrophysiological testing from the electrode have confirmed the target cardiac tissue, a second electrical pulse for ablating the targeted cardiac tissue is delivered by the electrode.

[0038] Preferably, the handle has a bidirectional deflection mechanism and a friction control mechanism for inducing deflection friction and to hold the distal end of the catheter in a deflected configuration for target cardiac tissue contact; wherein the handle further comprises a slider mechanism for extending or retracting an expandable element when manoeuvring to target tissue; wherein the expandable element is positioned in a second lumen.

[0039] Preferably, one or more electrodes are positioned on the expandable element at the distal end of the catheter, wherein when expanded, the expandable element may allow for occluding blood flow locally where the electrodes are and blood may flow through the basket-shaped/expandable element. The expandable element optimises contact of the one or more electrodes to the target tissue; and wherein the one or more electrodes have a shape that is selected from the group of: trapezoid shaped electrodes; fan-blade shaped electrodes, diamond shaped electrodes, and circular shaped electrodes.

[0040] Preferably, the expandable element comprises a band of membrane at a latitude between a proximal end and a distal end of the expandable element; wherein the band of membrane is one selected from the group of: elastomeric material, and medical textiles.

[0041] Preferably, the width of the band of membrane is of a length equal or greater to the length of the electrode.

[0042] Preferably, the band of membrane formed from the elastomeric material is one material selected from the group of: polyurethane, and silicone -polyurethane copolymer.

[0043] Preferably, the band of membrane formed from the medical textile is a tightly knitted, woven or braided textile made from one material selected from the group of: polytetrafluroethylene, expanded polytetrafluroethylene, polyethylene terephthalate, and polyester. Preferably, the tightly knitted, woven or braided textile membrane has a mesh size of less than or equal to 160 pm.

[0044] Preferably, the band of membrane formed from a hybrid of the medical textile and the elastomeric material, wherein the medical textile is a loosely knitted, woven or braided textile made from one material selected from the group of: polytetrafluroethylene, expanded polytetrafluroethylene, polyethylene terephthalate, and polyester, and wherein the loose textile is coated with the elastomeric material to form a non-permeable membrane. Preferably, the loosely knitted, woven or braided textile membrane has a mesh size preferably in the range between greater than 160 pm to 1.5 mm.

[0045] Preferably, the trapezoid shaped electrodes are spaced in a uniform or non- uniform pattern radially around the expanded element, wherein the variation in shape configuration allows for a first electrode of a polarity and a second electrode of an opposite polarity.

[0046] Preferably, the first electrode and the second electrode have a different surface area.

[0047] Preferably, the fan-blade shaped electrodes are spaced radially from each other, wherein each blade of the interlocks with an opposing blade electrode of opposite polarity.

[0048] Preferably, the diamond shaped electrodes are spaced radially from each other with a connecting spline, wherein each diamond shaped electrode interlocks with an opposing diamond shaped electrode of opposite polarity.

[0049] Preferably, the circular shaped electrodes are in a staggered pattern, wherein the staggered pattern is one selected from the group of: in a decreasing diameter from the proximal to distal portion of the expandable element, and electrodes of different diameter adjacent to each other.

[0050] Preferably, the catheter further comprises a tip electrode of a polarity, wherein the at least one electrode on the expandable element has an opposite polarity, such that the one or more electrodes can hyperpolarize the targeted tissue.

[0051] Preferably, the electrode comprises an axial slotted relief for allowing the electrode to fold when contracting the expanded expandable element.

[0052] Preferably, a first electrode and a second electrode are elongate electrodes parallel relative to each other, wherein each of the elongate electrodes extend between the proximal end to the distal end.

[0053] Preferably, the handle comprises a user control for allowing an operator to control the delivery of the pulse to target tissue.

[0054] Preferably, the signal generator comprises an automatic setting, wherein the automatic setting allows the signal generator to automatically deliver the one or more electrical pulses from the signal generator to the one or more electrodes when a predetermined threshold of electrical signals from tissue contact is detected by the one or more electrodes. Preferably, the user control for pulse delivery enters the signal generator in a ready mode where the pulse is automatically triggered by the detection of electrical signals through the electrodes satisfying the condition for adequate tissue contact by a signal processing algorithm.

[0055] Preferably, the electrode is one material or alloys chosen from the group of: platinum, ruthenium, rhodium, palladium, osmium, iridium, gold, silver, titanium; and wherein the electrode further comprises a surface coating, wherein the surface coating is at least one selected from the group of: iridium oxide, ruthenium oxide, and platinum black. [0056] Preferably, the material or alloy chosen for the cathode is different to the material or alloy chosen for the anode.

[0057] A fourth aspect of the present invention may relate to an electrical pulse delivery system comprising: a catheter having one or more electrodes for conducting electrophysiological measurements or for delivering electrical pulses to cardiac tissue. A controller in electrical communication with the switching of one or more electrodes, wherein the controller is configured to receive a first measured electrophysiological data and determining the beginning of the refractory period of the cardiac tissue. A signal generator in electrical communication with the controller, wherein the controller selects for a first pulse waveform for the signal generator to generate based on the first measured electrophysiological data. The first pulse waveform is delivered as a first electrical pulse to the one or more electrodes to induce reversible electroporation of target cardiac tissue.

[0058] Preferably, after the delivery of the first electrical pulse, the electrode measures a second electrophysiological data of the electroporated cardiac tissue, wherein the second measured data is transmitted to the controller; wherein when the difference between the first and second measured data is within a predetermined threshold value, the controller dynamically selects for a second predetermined pulse waveform from the signal generator to generate; the second pulse waveform is delivered as a second electrical pulse to the one or more electrodes with a duration configured for electrolysing emitted conductive fluid from the catheter and for generating a predetermined amount of electrolytic products, wherein the generated electrolytic products can diffuse into the electroporated cardiac tissue to induce targeted cardiac tissue death.

[0059] Preferably, the first electrical pulse and is delivered within the refractory period.

[0060] A fifth aspect of the present invention may relate to a method for cardiac tissue ablation, the method comprising: delivering a pulse or a plurality of pulses of predetermined current or voltage to a cardiac treatment site; wherein the magnitude and the duration of a pulse is selected to induce electroporation at the cardiac treatment site, and wherein the duration of the pulse is further selected to produce an amount of electrolytic products at the cardiac treatment site.

[0061] Preferably, the result is reversible electroporation only. Preferably, the pulse waveform is truncated prior to significant electrolysis occurring. Preferably, the pulse waveform is biphasic and charge -balanced at a high frequency to prevent significant electrolysis occurring by chemical neutralization.

[0062] Preferably, the result is ablation caused by the combination of reversible electroporation and electrolysis. Preferably, the pulse comprises a voltage-controlled portion to determine the electric field strength and thereby induce the desired electroporation while the current is determined by the load, and a current-controlled portion to determine the charge delivered by Faraday’s law of electrolysis and thereby produce the desired amount of electrolysis where the current is independent of the load. Preferably, the pulse comprises a rising edge, a plateau, and a falling edge. Preferably, the falling edge comprises an exponential decay. Preferably, a width of the plateau and the slope of the falling edge are selected to avoid arcing at the treatment site.

[0063] Preferably, the pulse is adequate to sufficiently generate an amount of electrolytic products at the treatment site in combination with electroporation to induce cell death.

[0064] Preferably, the pulse is designed to deliver a particular electrical pulse amplitude, duration and shape for circumferential transmural ablation while avoiding arcing across the particular electrode geometry by providing adequate electrode separation.

[0065] Preferably, the pulse is designed to deliver a particular electrical pulse amplitude, duration and shape while also minimizing/avoiding excessive muscle contraction, achieved by steering the electrical currents in a focused, localized bipolar fashion through the configuration of electrode polarity, and electrode geometry.

[0066] Preferably, the pulse is designed to avoid excessive muscle contraction and deliver a particular electrical pulse amplitude, duration and shape that is monophasic, wherein the sign of the waveform does not change, in order to maximise the production of electrolytic species, or biphasic, wherein the sign of the waveform may change, which may be charge-balanced, in order to reduce unintended stimulation, allowing enough time for the diffusion of electrolytic products to avoid attenuating the ablative effect through neutralization, or not charge-balanced, in order to minimize neutralizing the ablative electrolytic species produced.

[0067] Preferably, the pulse waveform may be composed of concatenating a plurality of waveforms, where each waveform may be of equal or varying amplitude, or duration, of the same or different shape, and separated by a time interval of equal or varying duration, where the combined waveform is delivered within the refractory period.

[0068] Preferably, the pulse waveform may be composed by concatenating a plurality of waveforms, which may be all of the same polarity, i.e. monophasic, or of alternating polarities i.e. biphasic, or including time intervals between waveforms, i.e. multiphasic.

[0069] Preferably, the pulse waveform may be composed by concatenating a plurality of waveforms, which may predominantly cause electroporation followed by electrolysis, or electrolysis followed by electroporation, or electroporation followed by electrolysis then followed by electroporation, or electrolysis followed by electroporation then followed by electrolysis.

[0070] Preferably, one of the two treatments (electroporation or electrolysis) may be performed continuously while the other treatment is performed intermittently.

[0071] A sixth aspect of the present invention may relate to a method for cardiac tissue ablation, the method comprising: charging an energy storage element to an initial voltage with a power supply; and discharging the energy storage element through a pulse-shaping circuit to an electrode to provide a pulse to a treatment site, wherein the preferred embodiment of the pulse comprises a voltage having an exponential decay defined by a time constant. [0072] Preferably, the energy storage element is selected so the voltage of the pulse induces reversible electroporation at the treatment site.

[0073] Preferably, the pulse-shaping circuitry is configured so that the time constant provides a duration of the pulse, which is adequate to sufficiently generate an amount of electrolytic products at the treatment site to induce cell death.

[0074] Preferably, the pulse waveform may be the same through all electrodes, or be adjusted at individual electrodes or groups of electrodes for offsetting local differences between target volumes of cardiac tissue, by any of the variations above or a combination thereof.

[0075] Preferably, the E2 Pulse may be delivered through one or more charge storage elements to overcome electrical inhomogeneity in the targeted volume of cardiac tissue. More preferably, the E2 Pulse may be delivered through multiple charge storage elements to overcome electrical inhomogeneity in the targeted volume of cardiac tissue.

Preferably, the multiple charge storage elements may each be of the same type or each be of different types.

[0076] Preferably, the polarity of individual or groups of electrodes can be set in order to optimise the direction of the electric fields relative to the bulk fibre orientation of the target volume of cardiac tissue for maximising electroporation dosage.

[0077] Preferably, the pulse generator can select an arbitrary number of electrodes to be active in the pulse delivery, that is, carrying current from a charge storage element or a plurality of charge storage elements.

[0078] Preferably, the method includes limiting applied pulse current (amperage) using a current limiting circuit within the controller to prevent the controller from generating a electrode current load that could be harmful to the patient, thereby imposing an upper limit on the current that can be applied during each pulse delivery. [0079] A seventh aspect of the present invention may relate to a method for cardiac tissue ablation, the method comprising electrophysiological testing and tissue resistance measurement before, during and after applying a pulse of voltage or a current to a treatment site with an electrode.

[0080] Preferably, the method further comprises cardiac electrical signal and tissue resistance measurement of the treatment site pre- and post- pulse delivery; the calculated change in cardiac electrical signal and resistance is indicative of electroporation at the treatment site and an indicator of tissue viability and whether treatment was successful. Preferably, the method further comprises a non-ablative pre -pulse to reversibly disable cardiac tissue, measurement of cardiac electrical signals and tissue resistance before and after the pre-pulse and using the calculated change as an indicator of whether ablating the target tissue will produce effective treatment.

[0081] Preferably, the method further comprises electrophysiological testing, for sensing cardiac electrical signals, to synchronise pulse delivery within the refractory period in order to avoid inducing arrhythmia.

[0082] Preferably, the method further comprises discontinuing applying the pulse to the treatment site when a time period has elapsed, to control the pulse dosage or to avoid inducing arrhythmia.

[0083] Preferably, the method further comprises tissue resistance measurement, in order to determine the quality of electrode-tissue contact as a prerequisite for delivering E2 ablation.

[0084] Preferably, the method further comprises electrophysiological testing, for example, sensing cardiac electrical signals, stimulating cardiac electrical signals, or a combination, in order to determine the quality of electrode-tissue contact as a prerequisite for delivering E2 ablation. [0085] Preferably, the method further comprises digital signal processing of electrical measurements of the E2 pulse delivered, thereby computing relevant parameters such as voltage, current, charge delivered and energy delivered, thereby allowing a feedback loop to control the required ablation dosage.

[0086] Preferably, the method further comprises digital signal processing to detect abnormal and potentially harmful electrical events such electrical arcing, or shortcircuiting electrodes, and to prevent, control or terminate E2 delivery.

[0087] An eighth aspect of the present invention may relate to an apparatus/medical device for tissue ablation, the apparatus comprising: electrode(s) configured to deliver a pulse of voltage or a pulse of current to an cardiac treatment site; and a controller coupled to that electrode(s), the controller configured to provide an electronic signal to the electrode(s): either singularly or in pre-determined multi-electrode energy patters; wherein the electronic signal determines a rising edge, a plateau, and a falling edge of that pulse, wherein the rising edge, plateau, and falling edge of the pulse are configured to deliver electrolysis and electroporation at the treatment site.

[0088] Preferably, the catheter has a proximal end and a distal end. Preferably, the catheter having proximal user controls as part of a catheter handle for the purpose of bidirectional deflection; deflection friction control and extension cable connection fittings to connect to the electrodes. Preferably, the catheter having proximal user controls as part of the catheter handle for the purpose of initiating charging and delivering the pulse.

[0089] Preferably, the electrode(s) are comprised of pure or alloys of Platinum (Pt), or Ruthenium (Ru), or Rhodium (Rh), or Palladium (Pd), or Osmium (Os), or Iridium (Ir), or Gold (Au), Silver (Ag), Silver (Ag), or Titanium (Ti). Preferably, the materials may be used in various configurations such as but not limited to particles in conductive inks and/or conductive adhesives formulations, conductive thin films, coatings and foils. [0090] Preferably, the electrodes are a combination of different materials for Anode and Cathode electrodes to enhance/promote electrolysis (eg: Platinum has catalytic qualities that promote the proton reduction to Hydrogen (H2)).

[0091] Preferably, the electrode(s) comprises of activated surface coatings (e.g. Oxides of Iridium, or Ruthenium, or Platinum Black, or composites of these) which is added to the electrode to increase surface area and catalysing electrolysis.

[0092] Preferably, the electrode(s) comprises of single or multiple conductive and non- conductive/isolating layers that are merged together using mechanical, thermal or chemical means or a combination thereof.

[0093] Preferably, the electrode(s) are created through direct deposition of materials onto the expandable element utilizing technologies such as physical or chemical vapour deposition, sputtering, electroplating, printing or combinations of these technologies; wherein the materials may be of pure or alloys of Platinum (Pt), or Ruthenium (Ru), or Rhodium (Rh), or Palladium (Pd), or Osmium (Os), or Iridium (Ir), or Gold (Au), Silver (Ag), Silver (Ag), or Titanium (Ti).

[0094] Preferably, the catheter has at least one lumen extending through the catheter shaft and a plurality of electrodes attached to an expandable element. Preferably, the expandable element is a balloon. Preferably, the expandable element is designed to having a shape and compliance that allows to occlude the blood flow at the treatment site. Preferably, the expandable element has a proximal portion and a distal portion, the electrodes being attached to the distal portion. Preferably, the catheter having a proximal fluid connector that allows a fluid supply to be connected to deliver fluidic pressure expansion and fluidic negative pressure contraction to the expandable element.

Preferably, the expandable element has a control element located proximally in the catheter handle so that the expandable element can be extended distally when contracted to reduce overall size and allow for easy insertion and retrieval through introducer sheath. Preferably, the catheter having a proximal fluid connector that allows e.g. contrast medium to be injected through a central catheter lumen into the patient. Preferably, the expandable element has a central lumen/channel so that a secondary guidewire device can be received or inserted from the proximal handle in the same plane and telescopically extended distally to the expandable element. The secondary device being used for guiding and placing the expandable element onto Pulmonary Vein to deliver the ablation therapy methods from any one of the fifth aspect, sixth aspect, and seventh aspect of the present invention. Preferably, the treatment site are the pulmonary veins.

[0095] Preferably, the expandable element comprises a central lumen/channel so that a secondary multi electrode catheter device can be received or inserted from the proximal handle and advanced distally to pass beyond the distal portion of the expandable element. The secondary device being used for facilitating measurement of Pulmonary Vein conduction block using the multi electrode catheter for pacing and sensing distally within the Pulmonary Vein.

[0096] Preferably, the expandable element comprises an a-traumatic distal tip with a central lumen/channel to guide and house secondary medical devices inserted into the catheter lumen and to provide a terminating outlet to avoid blood entrapment.

[0097] Preferably, the expandable element comprises trapezoid shaped electrodes equally spaced radially on a pitch circle diameter, each trapezoid being wider proximally and gradually decreasing in size distally, so as to maintain a consistent spacing along the entire electrode length whilst providing the maximum possible surface area to induce electrolysis.

[0098] Preferably, the expandable element comprises trapezoid shaped electrodes equally spaced radially on a pitch circle diameter, each trapezoid being wider proximally and gradually decreasing in size distally, each trapezoid having a centrally configured axial relieving slot to facilitate a collapsible folding electrode feature for easier insertion and retraction through an introducer sheath.

[0099] Preferably, the expandable element comprises trapezoid shaped electrodes equally spaced radially on a pitch circle diameter, each trapezoid being wider proximally and gradually decreasing in size distally, each trapezoid having a series of relieving patterns that remove conductive material to increase flexibility of the electrode giving better compliance to the shape of the expandable element. The better shape compliance allows superior tissue contact when expanded and it allows for easier insertion and retraction through an introducer sheath when contracted.

[00100] Preferably, the expandable element comprises fan -blade shaped electrodes spaced radially, with interlocking Anode and Cathode patterns, the shape being optimised to create a multitude of local electrode bi-poles resulting in multi-directional electric fields with locally increased field strengths to improve tissue cell alignment and dosage control, variations in shape configuration can be optimized so that Cathodes and Anodes are differing in surface area.

[00101] Preferably, the expandable element comprises diamond shaped electrodes spaced in a uniform pattern radially around the balloon circumference, with interlocking Anode and Cathode patterns, the shape being optimized to create a multitude of local electrode bi-poles resulting in multi-directional electric fields with locally increased field strengths to improve tissue cell alignment and dosage control and the uniformity of shape guarantees the Cathodes and Anodes can be identical in surface area.

[00102] Preferably, the expandable element comprises trapezoid shaped electrodes equally spaced on a pitch circle diameter radially, each trapezoid being wider proximally and gradually decreasing in size distally, each trapezoid having wave-like patterns along the inner edges between electrodes, with patterns alternating between neighbouring electrodes to maintain a consistent spacing along the entire electrode length, which will result in local, high density multi-directional electric fields to allow for improved tissue cell alignment and dosage control, variations in shape configuration can be optimized so that Cathodes and Anodes are differing in surface area.

[00103] Preferably, the expandable element comprises circular shaped electrodes of different size and shapes, spaced in a uniform or non-uniform pattern radially around the balloon circumference. The variations in shape configuration can be optimized so that cathodes and anodes are differing in surface area and as a result can be optimized to induce electrolysis and reduce sparking/arcing risk. Each electrode element can be individually activated/connected which enables various possibilities to steer and shape the resulting electric field to improve dosage control and delivery as e.g. electrode elements that are not in tissue contact can be disconnected.

[00104] Preferably, the plurality of electrodes on the expandable element in geometries all connected as anode, with tip electrode(s) connected as cathode. The positively charged species on the anodes will hyperpolarize the surrounding tissue thereby reducing muscle excitability and hence reducing potential muscle contraction.

[00105] Preferably, a plurality of electrodes can be attached to a catheter shaft in a linear array either equally spaced or using spacing that is optimized to induce reversible electroporation and deliver electrolysis products while being optimised to suit the cardiac anatomical geometry. Preferably, the treatment site is inside the left and/or right atrium and/or outer surface of the left and/or right atria and/or ventricles.

[00106] A ninth aspect of the present invention may relate to a system that may use the apparatus of the eighth aspect together with any one of the methods as described in the fifth, sixth or seventh aspect. The system may be for the purpose of characterization and ablating cardiac tissue via the combination of reversible electroporation energy and electrolysis for the diagnosis and treatment of cardiac arrhythmia(s).

[00107] Preferably, the controller that delivers those methods via electrodes or plurality of electrodes can be configured to deliver E2 using either monopolar electroporation energy from at least one or more electrodes to a supplemental ground patch; or bipolar electroporation energy between electrodes within the apparatus, where adjacent electrodes or groups of electrodes alternate in polarity, delivering monophasic, biphasic or multiphasic electroporation energy, or a combination or both. [00108] Preferably, the system may be configured to record a tissue resistance measurement via the electrode or plurality of electrodes from the apparatus to ascertain if the treatment was successful and/or is indicative of electroporation at the treatment site.

[00109] Preferably, the system may also be configured to discontinue applying a pulse of any one of the methods as described in the fifth, sixth, or seventh aspect to the treatment site when a time period has elapsed, to control the pulse dosage or to avoid inducing arrhythmia.

[00110] Preferably, the system may be combined with other modalities for cardiac or other cardiac tissue treatment such as thermal ablation, cryoablation, radiation, chemical ablation, and/or gene therapy as a form of combined therapy delivery.

[00111] A tenth aspect of the present invention may relate to a basket-shaped electrode assembly that may comprise a plurality of splines and a plurality of conductive wires each having a proximal end and a distal end, wherein a spline is in electrical connection with a wire at the respective ends; a proximal locking ring and a distal locking ring, wherein the proximal end and the distal end of each spline and wire are secured at the respective locking rings. An electrode pad in connection between the proximal end and the distal end of a spline, wherein at least one layer of conductive or non-conductive material is appliable to the electrode pad such that one or more electrodes can be formed on the electrode pad.

[00112] Preferably, a membrane may be formed from an elastomeric material or a medical textile that covers the interelectrode and interspline space of the assembly.

[00113] Preferably, the membrane covers the interelectrode and interspline space of the assembly from a distal end of the electrode pad to the distal locking ring.

[00114] Preferably, a band of the membrane covers the interelectrode space of the assembly circumferentially between a proximal end to a distal end of the electrode pads. [00115] Preferably, the membrane formed from the elastomeric material is one material selected from the group of: polyurethane, and silicone -polyurethane copolymer.

[00116] Preferably, the membrane formed from the medical textile is a tightly knitted, woven or braided textile made from one material selected from the group of: polytetrafluroethylene, expanded poly tetrafluroe thylene, polyethylene terephthalate, and polyester. Preferably, the tightly knitted, woven or braided textile membrane has a mesh size of less than or equal to 160 pm.

[00117] Preferably, the membrane formed from a hybrid of the medical textile and the elastomeric material is a loosely knitted, woven or braided textile made from one material selected from the group of: polytetrafluroethylene, expanded polytetrafluroethylene, polyethylene terephthalate, and polyester; and wherein the loose textile is coated with the elastomeric material. Preferably, the loosely knitted, woven or braided textile membrane has a mesh size preferably in the range between greater than 160 pm to 1.5 mm.

[00118] Preferably, the proximal locking ring comprises a plurality of proximal cavities circumferentially spaced apart from each other, wherein a proximal cavity is adapted to engage with the proximal end of a spline.

[00119] Preferably, the distal locking ring comprises a plurality of distal cavities circumferentially spaced apart from each other, wherein a distal cavity is adapted to engage with the distal end of the spline.

[00120] Preferably, the proximal end and the distal end of the splines each have a hook element at the respective ends, wherein the hook elements secure the spline to the cavities and to be in electrical connection to the respective conductive wire.

[00121] Preferably, the width of the electrode pad is greater than the width of the spline. [00122] Preferably, the electrode pad is in connection between the proximal end and the distal end of a second spline.

[00123] In the context of the present invention, the words “comprise”, “comprising” and the like are to be construed in their inclusive, as opposed to their exclusive, sense, that is in the sense of “including, but not limited to”.

[00124] The invention is to be interpreted with reference to the at least one of the technical problems described or affiliated with the background art. The present aims to solve or ameliorate at least one of the technical problems and this may result in one or more advantageous effects as defined by this specification and described in detail with reference to the preferred embodiments of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

[00125] Figure 1 is a schematic illustration of an electrolysis-electroporation system according to an embodiment of the disclosure.

[00126] Figure 2 is a schematic illustration of various domains for electroporation and electrolysis, with respect to their effect on tissue and cell ablation, according to an embodiment of the disclosure.

[00127] Figure 3a is a schematic illustration of a pulse design in accordance with an example of the present disclosure, of an exponentially decaying pulse waveform design showing current as a function of time. The waveform may be considered as three distinct components Fl, a rising leading edge, F2, a plateau and F3, a falling edge, of amplitude and duration selected for the treatment. The shaded region represents the total electrical charge delivered, which is the integral of current over time. The total duration of an exponentially decaying waveform can be considered as five times the time constant r.

[00128] Figure 3b is a schematic illustration of a plurality of millisecond-scale waveforms which may be triangular (a), sinusoidal (b), exponentially decaying (c), or square (d); may be truncated (a*, b*, c*, d*); or of inverted polarity (a’, b’, c’, d’) in the context of a plurality of discrete pulses; or both inverted and truncated (a*’, b*’, c*’, d*’).

[00129] Figure 3c is a schematic illustration of three phases of E2 pulse therapy, commencing with a low amplitude pre-pulse TO, a high amplitude pulse train T1 which may be repeated N times, a time interval G1 and a low amplitude pulse T2, all in the millisecond scale, and may be delivered within the cardiac refractory period.

[00130] Figure 3d is a schematic illustration of examples arising from Figure 3b and Figure 3c, where an inverted rectangular pre -pulse TO is followed by three examples of T1 showing different combinations of waveforms, time interval durations and pulse polarities, which is followed by a time interval G1 and a low amplitude exponentially decaying waveform T2. The first example of T1 shows a sinusoidal waveform, followed by a 2 ms time interval, followed by an inverted triangular waveform, followed by a 1 ms time interval.

[00131] Figure 3e is a schematic illustration of a pulse design in accordance with an example of the present disclosure, showing variations on the exponentially decaying waveform. From left to right: a standard exponentially decaying waveform; an exponentially decaying waveform segmented into rectangular pulses where the amplitude of each rectangular pulse follows the contour of the exponentially decaying waveform; an exponentially decaying waveform segmented in a bipolar fashion by truncating and inverting polarity; an exponentially decaying waveform similarly segmented in a bipolar fashion by truncating and inverting polarity but with a long final pulse.

[00132] Figure 4 is a schematic illustration showing a pulse design in accordance with examples described herein over laid on a conventional pulse design.

[00133] Figure 5 is an E2 field vs tissue contact vs lesion depth according to an embodiment of the disclosure. [00134] Figure 6a shows diffusion of electrolytic products drawn as pH fronts (6.3) propagating from the electrodes (6.2) through an in vitro physiological gel phantom model (6.1). pH measurements were made at four locations (1, 2, 3, 4).

[00135] Figure 6b shows experimental data from the set-up shown in Figure 6a, showing pH change at each of the four measurement sites illustrated in Figure 6a, decreasing near the anode, thus becoming more acidic, and increasing near the cathode, thus becoming more basic, gradually over the span of 10 minutes and plateauing from around 5 minutes after E2 Pulse delivery. Cell death occurs in tissue with pH lower than acidic 6 or above basic 9, which was achieved at all measurement points within 10 minutes of pulse delivery.

[00136] Figure 6c is a table of experimental results according to an illustrative example according to an embodiment of the disclosure.

[00137] Figure 7 shows an exemplary complete system according to an embodiment of the disclosure.

[00138] Figure 8 shows a proximal view of an exemplary embodiment of medical device catheter embodiment of the disclosure.

[00139] Figure 9 shows an exemplary embodiment of a complete medical device E2 catheter with an expandable element and a plurality of electrodes of the disclosure.

[00140] Figure 10 shows an exemplary embodiment of a complete medical device E2 linear array catheter of the disclosure.

[00141] Figure 11 shows an exemplary embodiment of a "trapezoid shaped’ distal expandable elelctrode configuration of the disclosure.

[00142] Figure 12 shows an exploded view of different electrode coupon layers. [00143] Figure 13 shows an electrode coupon processing.

[00144] Figure 14 shows an exemplary embodiment of a "relieved trapazoid shaped ’ distal expandable elelctrode configuration of the disclosure.

[00145] Figure 15 shows an exemplary embodiment of a ‘matrix ’ distal expandable elelctrode configuration of the disclosure.

[00146] Figure 16a shows a distal expandable electrode ‘Anode’ and ‘Cathode’ configuration of the disclosure.

[00147] Figure 16b shows a top view of the distal expandable electrode of Figure 16a.

[00148] Figure 17 shows an exemplary embodiment of a distal ‘linear array’ electrode configuration of the disclosure.

[00149] Figure 18 shows an exemplary embodiment of a distal ‘linear pair’ electrode configuration.

[00150] Figure 19a shows an exemplary embodiment of an expandable element with a band of elastomer or fabric mesh, wherein the electrode pads are each mounted to the fabric mesh and are in electrical connection to an adjacent electrode pad. In this embodiment, each spline traverse between the electrode pad and the adjacent electrode pad. This figure also shows how the splines are connected to the proximal locking hub at one end and connected to the distal locking hub at the other end.

[00151] Figure 19b shows another exemplary embodiment of an expandable element with a band of elastomer or fabric mesh, wherein the proximal spline is connected to a middle portion of the proximal end of the electrode pad and wherein the distal spline is connected to a middle portion of the distal end of the electrode pad. [00152] Figure 19c shows another exemplary embodiment of an expandable element with a band of elastomer or fabric mesh, wherein the electrode pad is supporting/in electrical connection by two proximal splines and two distal splines. In this embodiment, the first proximal spline and the first distal spline is in respective connection to a first corner and a second corner of the first end of the electrode pad; and the second proximal spline and the second distal spline is in respective connection to a first corner and a second corner of the second end of the electrode pad.

[00153] Figure 20a shows a simplified front view of an exemplary embodiment of an expandable element having two concentric arrays of electrodes showing the polarity configuration. While the pattern of electrode polarity is shown, the polarity of each electrode can be changed to create a different pattern with a different electric field.

[00154] Figure 20b shows a simplified front view of another exemplary embodiment of an expandable element having two concentric arrays of electrodes showing a different polarity configuration to Figure 20a. Similarly, while the pattern of electrode polarity is shown, the polarity of each electrode can be changed to create a different pattern with a different electric field.

[00155] Figure 20c shows a simplified front view of another exemplary embodiment of an expandable element having two concentric arrays of electrodes showing another polarity configuration. Similarly, while the pattern of electrode polarity is shown, the polarity of each electrode can be changed to create a different pattern with a different electric field.

[00156] Figure 20d shows a simplified front view of another exemplary embodiment of an expandable element having two concentric arrays of electrodes showing another polarity configuration, in which the polarity of each electrode can be changed to create different electric fields in a multitude of directions locally. [00157] Figure 21a shows a perspective view of an embodiment of the nitinol basket showing the electrode pad being in electrical connection to a proximal spline and a distal spline.

[00158] Figure 21b shows a perspective view of the embodiment of the nitinol basket of Figure 21a showing electrical connection is alternately made at either to the distal spline (positive terminal) or proximal spline (negative terminal).

[00159] Figure 21c shows a deconstructed perspective view of the splines (one proximal spline and one distal spline) in connection with an electrode pad.

[00160] Figure 21d shows a top view of Figure 21c.

[00161] Figure 22a shows a perspective view of another preferred embodiment of the nitinol basket showing the electrode pad being in electrical connection to two proximal splines and two distal splines in such a configuration.

[00162] Figure 22b shows a perspective view of the embodiment of the nitinol basket of Figure 22a showing electrical connection is alternately made at either to the distal spline (positive terminal) or proximal spline (negative terminal).

[00163] Figure 22c shows a deconstructed perspective view of the splines (two proximal splines and two distal splines) in connection with an electrode pad.

[00164] Figure 22d shows a top view of Figure 22c.

[00165] Figure 23a shows the nitinol basket embodiment of Figure 22a with an additional elastomer internally covering the basket.

[00166] Figure 23b shows the nitinol basket embodiment of Figure 22a with an additional elastomer or fabric mesh internally covering the frontal hemisphere of the basket as illustrated. [00167] Figure 23c shows the nitinol basket embodiment of Figure 22a with a band of elastomer or fabric mesh having a width internally covering at least the length of the electrode pads positioned at a latitude between the proximal end and the distal end of the splines.

[00168] Figure 24a shows the nitinol basket embodiment of Figure 21a with an additional elastomer internally covering the basket.

[00169] Figure 24b shows the nitinol basket embodiment of Figure 21a with an additional frontal hemisphere elastomer or fabric mesh internally covering the hemisphere of the basket as illustrated.

[00170] Figure 24c shows the nitinol basket embodiment of Figure 21a with a band of elastomer or fabric mesh having a width internally covering at least the length of the electrode pads positioned at a latitude between the proximal end and the distal end of the splines.

[00171] Figure 25a shows a locking ring either at the proximal end or the distal end showing the securing mechanism to secure the spline to the locking ring as well to establish connection with the conductive wires. As Figure 25a shows two different splines to secure in the pocket, this locking ring is used for the nitinol basket embodiment of Figure 22a.

[00172] Figure 25b shows a cross-sectional view as indicated by A to A’ in Figure 25a showing the hook-like termination element at the proximal and distal end of spline to mechanically secure spline inside termination element and establishing connection with the conductive wires.

[00173] Figure 26a shows an expanded basket catheter with a central axially moveable elongate member in connection between the proximal locking hub and the distal locking hub. [00174] Figure 26b shows a semi collapsed basket catheter with a central axially moveable elongate member in connection between the proximal locking hub and the distal locking hub.

DESCRIPTION OF THE INVENTION

[00175] Preferred embodiments of the invention will now be described with reference to the accompanying drawings and non-limiting examples. Certain details are set forth below to provide a sufficient understanding of embodiments of the disclosure. However, it will be clear to one skilled in the art that embodiments of the disclosure may be practiced without these particular details. Moreover, the particular embodiments of the present disclosure described herein are provided by way of example and should not be used to limit the scope of the invention to these particular embodiments. In other instances, well known materials, components, processes, controller components, software, circuitry, timing diagrams, and / or anatomy have not been described or shown in detail in order to avoid unnecessarily obscuring of the embodiments.

[00176] E2 Modality

[00177] E2 combination treatment for better cardiac tissue ablation. This disclosure describes cardiac tissue ablation systems and methods that may utilize certain pulse designs and operational protocols that may advantageously allow for cardiac tissue ablation using the combined effect of electrolysis with electroporation (E2). Combining electroporation with electrolysis may produce a substantial increase in the extent of cardiac tissue ablation as compared to the ablation produced by the same dose of electrolysis or electroporation separately. This phenomenon may be attributed to the electrolytically produced chemicals that may pass through electroporatically permeabilized cell membrane into the interior of the cell, thereby causing non-thermal cell damage at much lower concentrations of electrolytic products than for intact cells and at much lower electroporative electric fields than required for permanent cell damage by this method alone. This mechanism of cardiac tissue ablation may be affected by the dose of chemical species produced by electrolysis at the electrodes, the process of electroosmotic diffusion of the chemical species from the electrodes into cardiac tissue, the permeabilization of the cell membrane in the targeted cardiac tissue, or combinations thereof.

[00178] Irreversible electroporation (IRE) had previously been performed using a series of short (e. g. in the order of nanoseconds to milliseconds) monopolar monophasic high voltage (over 900V to 3000V) high current rectangular pulses applied by contact electrodes to various tissues. Various tissues may include prostate, liver and the heart, producing highly parenchymal tissue-selective ablation lesions while preserving fibrous tissue, nerves, arteries and veins. Such currents, however, produce widespread nerve and muscle activation and tend to cause violent skeletal muscle contractions, necessitating deep anaesthesia with muscle paralysis of subjects. While electric fields applied to isotropic media produce highly predictable field geometries, cardiac tissue is anisotropic with lower impedance along the muscle fibres and tissue planes, which has been shown to cause irregular, stellate-like fields and current flows and thus uncontrolled irregular ablation lesion margins. While cardioselectivity of IRE minimizes ablation of unintended structures within the irregular field, unintended damage to nearby sensitive cardiac structures such as conduction pathways may occur. Moreover, such rectangular pulses have been shown to cause unintended electrolysis with the formation of a gas layer around the electrodes subject to ionization by the pulses and explosive electrical discharges or arcing causing uncontrolled barotrauma to tissues. While biphasic and multiphasic pulses with microsecond durations, so called pulsed field ablation (PFA), have been shown to greatly reduce or abolish skeletal muscle contractions and electrolysis-mediated electrical arcing, much higher voltages, up to 2500V are required to maintain ablation efficacy, increasing equipment complexity and potentially reducing control over the margin of the ablative field geometry.

[00179] Tissue may also be ablated by an electrolysis ablation process. Electrolysis generally refers to a process of inducing a chemical reaction that involves passing a direct current through an ionic solution via two electrodes. Electrolysis may facilitate the removal and / or addition of electrons from atoms and / or ions, which may lead to the formation of new products. For example, by passing a DC current through a saline solution (NaCl and H2O), hypochlorous acid ( HCIO ) may be formed. The products formed may be based, at least in part, on the ionic composition of the solution, and / or its pH. The amount of electrolysis products formed may be based at least in part on the magnitude of the applied electric charge determined by the current amplitude and duration for which the current is applied. The current may be generated by coupling a power source to the electrodes. Examples of power sources may include, but are not limited to, one or more, electrical network, or batteries, combinations thereof.

[00180] In preferred embodiments, electrolysis may be used in combination with electroporation for inducing cell death in cardiac tissue, generally referred to as E2 herein. The combination treatment may be more effective at ablation than with the individual treatments used alone, and / or may or achieve similar ablation but at substantially lower voltage and / or energies and / or time than with either of the treatments used alone.

[00181] E2 Combination treatment may overcome the problems of irreversible electroporation (IRE). Pulse designs and operation protocols are therefore described herein which may reduce these undesirable effects. For example, application of a single voltage-controlled or current-controlled pulse that may be of a longer (e. g. in the order of tens of milliseconds) duration but a lower voltage or current, and with a gradually decaying form, such as an exponential decay. Such a lower pulse voltage shape has been shown to advantageously reduce or minimize skeletal muscle contractions to a level similar to those produced by the widely used implantable defibrillators not requiring muscle paralysing agents. Such a decaying pulse, when appropriately shaped has also been experimentally shown to deliver the required electroporation energy (which is a function of electric field strength and time above certain thresholds), and simultaneously delivering adequate electric charge to produce the required amount of electrolytic products, for electrolysis ablation, while minimizing bubble formation and keeping the voltage-time product below the critical threshold for arcing through any existing bubbles at the electrodes, for the critical benefit of avoiding electric discharge or arcing though air bubbles generated at electrodes and allowing the time necessary for electrolysis products to diffuse into cardiac tissue to be effective in enhancing the cardiac tissue ablation. Preferably, the pulse comprises a voltage-controlled portion to determine the electric field strength and thereby induce the desired electroporation while the current is determined by the load, and a current-controlled portion to determine the charge delivered by Faraday’s law of electrolysis and thereby produce the desired amount of electrolysis where the current is independent of the load. In another embodiment, the irreversible electroporation may apply a first voltage-controlled pulse followed by a subsequent current-controlled pulse or a first current-controlled pulse followed by a subsequent voltage-controlled pulse. The waveform may comprise a voltage-controlled pulse, and similarly, the waveform may comprise a current-controlled pulse.

[00182] Figure 2 is a schematic illustration of various domains for electroporation and electrolysis. The illustration shown in Figure 2 is also given as electric field strength versus time. While Figure 2 is provided as an example of a typical curve, its characteristics (e.g. slope) may change with cell type. The values given on the axis are typical to mammalian cells. For typical electroporation protocols, the range of electric field thresholds for irreversible electroporation may be from several hundred V / cm (e.g. 200 V / cm) to over a thousand V/cm (e.g. 1.5 kV / cm). For reversible electroporation that range may be from below 100 V/cm (80 V / cm for muscle) to several hundred V / cm (460 V / cm for liver) and the time range for both RE and IRE thresholds is inversely proportional to the applied electric field and may also be from nanoseconds for high range voltages to milliseconds for low range voltages. Electrolysis occurs when current flows from the electrodes to cardiac tissue (electrons to and from ions) when the voltage exceeds a certain threshold prescribed by the electrochemical potential of the electrodes in relation to the solution. This threshold value may depend on the electrode material, composition of the solution, pH, and / or temperature. Typical values may be several volts, for example from 0.01 V to 10 V. The required duration of pulses for cellular death from electrolysis alone may be from several seconds to one to two hours depending on current and depth of penetration between electrodes required. In combination with RE, the pulse duration still affects the degree of ablation but is far shorter.

[00183] In Figure 2, the curve that displays values in which electroporation and / or electrolysis products cause cell death may include multiple regions. That curve may include regions in which cell death may be caused, from lower to higher voltages, by electrolysis alone, by combination of reversible electroporation and electrolysis (E2), and / or combination of irreversible electroporation and electrolysis and / or primarily electroporation. Within the embodiments as described in this specification, we define E2 to be the domain in the diagram located above the electrolysis cell death curve and above the reversible electroporation curve but below the irreversible electroporation curve.

Demonstrating whether a tissue ablation protocol is utilizing the E2 region exclusively, it may be done by determining if cell death produced by the protocol by abolishing the E2 electric pulse when the products of electrolysis are eliminated. For example by applying the pulse through a thin layer of flowing fluid which washes away electrolytic products, with the other parameters remaining unchanged, or when the products of electrolysis alone corresponding to the same E2 protocol are introduced in the absence of electric fields. It may also be demonstrated that ablation is not thermal by theoretical calculation from energy applied by E2 (for example 5 to 20 Joules) to the energy required to be applied by RF ablation (typically 20 watts for 10 to 45 seconds or 200 to 900 Joules) and by experimental direct temperature-sensitive dyes in tissue phantoms.

[00184] For cellular death, reducing Electric field prolongs the required minimal time of exposure. The diagram illustrated in Figure 2 illustrates that the minimal time of exposure to electric field required for cell death from E2 combination therapy involving electrolysis may increase as the electric field voltage decreases in the following steps:

(a) Irreversible electroporation with minimal incidental electrolysis, up to kilovolts per centimetre for single to tens of microseconds (e.g. 1.5 kV/cm for a of 0.1 microsecond to 10 microseconds, which is usually part of a pulse train), to

(b) Reversible electroporation with electrolysis, several hundred volts per centimetre for several milliseconds to tens of milliseconds (e.g. 200 V/cm for a pulse of 5 ms to 100 ms), to

(c) Sub-electroporation electric fields, therefore electrolysis alone, i.e. EChT, milliamps (electric fields usually not reported) for tens of minutes (e.g. <100 V/cm for 30 minutes to 120 minutes).

[00185] Prolonging electroporation time also increases electrolysis. For a given electric field strength, the electric current applied for over a threshold time may generate sufficient electrolysis to enable cell death to occur. The threshold amount of time required to generate sufficient electrolysis to enable cell death to occur may vary based on the specific combination of applied electric field strength and resulting tissue impedance.

[00186] There are five Defined Electroporation and Electrolysis and combination regions.

1. a region of reversible electroporation only ( RE );

2. a region of irreversible electroporation ( IRE ) only;

3. a region of reversible electroporation plus electrolysis ( RE + E );

4. a region of irreversible electroporation plus electrolysis ( IRE + E ), and

5. a region of electrolysis without electroporation ( E ).

[00187] Cardiac tissue ablation may be performed using electric field by selecting a field strength and time associated corresponding to the selected domains. The region RE + E (item 3) is relevant to the described invention, and is herein referred to as E2.

[00188] Pulse delivery modes. It should be noted that the electric field for electroporation and electrolysis may be applied as a single pulse or divided into one or more pulses or equal or varying amplitude or multiple pulses of equal or varying amplitude and the pulses may all be of same polarity i.e. monophasic or of alternating positive (+ve) and some negative (-ve) polarities, i.e. biphasic. The biphasic pulses may exhibit higher reversible and irreversible electroporation thresholds than monophasic, however may confer other advantages, such as reducing nerve and undesired muscle activation if short enough pulses (in the microseconds range). Extant electrolysis is irreversible, however biphasic pulses may reduce the amount of electrolysis produced compared to monophasic depending on pulse train characteristics (e.g. frequency, pulse duration, inter-pulse gap, inter-phase gap and phase amplitudes). The pulse waveform may be the same through all electrodes, or be adjusted for the local tissue substrate by any of the variations above or a combination thereof.

[00189] Pulse delivery may also be applied from the surface of either endomyocardium or epicardium by a single electrode with current return path via a distant large skin or intra-venous electrode, i.e. in monopolar mode, or by applying the voltage between two adjacent electrodes shown in Figure 5, proximal to the intended ablation site (several millimetres to several centimetres apart), i.e. bipolar mode. Pulse may also be delivered to myocardial tissue by two electrodes containing the cardiac tissue for ablation between them, for example, a device with one electrode placed in the epicardial space over the area to be ablated and the second electrode placed inside the heart under the said area, and E2 voltage pulse applied between the electrodes in a bipolar mode.

[00190] Multi-channel E2 pulse delivery increases electric field uniformity. In one embodiment, the E2 Pulse may be delivered from one or more charge storage elements or multiple charge storage elements to overcome electrical inhomogeneity in the targeted volume of cardiac tissue, in order to produce uniform electric fields resulting in uniform ablation at the required depth.

[00191] Delivery of E2 to left atrial pulmonary veins. An example method of cardiac tissue ablation through the delivery of electrolysis products to a targeted volume of cardiac tissue, in combination with the permeabilizing of the cell membrane of the cells in targeted volume of cardiac tissue may include, bringing electrodes in contact with or in proximity to, with intervening stationary conductive fluid, the surface of the targeted volume of cardiac tissue, delivering electric potential to the electrodes to generate electric fields that permeabilize the cell membrane in the targeted volume of cardiac tissue, delivering electric current and charge to the electrodes for generating the electrolytic products at the electrodes at an amount sufficient to ablate permeabilized cells in the targeted volume of cardiac tissue, and electro-osmotic diffusion which spreads the generated electrolytic products throughout the targeted volume of cardiac tissue.

[00192] Sequence of E2 operation. Permeabilization and production of electrolytic products may be done in any sequence that achieves the goal of bringing the products to the permeabilized cells in the targeted volume of cardiac tissue. This may be permeabilizing the volume of cells first and then producing the required amount of products of electrolysis next, generating the amount of electrolytic products first and permeabilizing the cell membrane next, permeabilizing the volume of cells first, generating the required products of electrolysis next and then permeabilizing the volume of cells again, simultaneously permeabilizing the cell membrane and producing the products of electrolysis, or any combination of these. The electrodes brought to the proximity of the cardiac tissue can serve for both electrolysis and electroporation or some of the electrodes may be dedicated for electroporation and others for electrolysis.

[00193] Figure 1 is a schematic illustration of a multimodality E2 ablation system according to a preferred embodiment of the disclosure. The multimodality electrolysis system may be capable of performing electrolysis and cellular permeabilization treatment with or without other treatments. The cellular permeabilization medical device 115 may also be referred to as a cellular electroporation device. The system is shown on the surface of cardiac tissue 10, however in the preferred embodiment, the system may include a controller 105 coupled to an electrolysis medical device 110 and a cellular permeabilization medical device 115, whereby the devices may be embodied in two separate or one single medical device, which may, in one example comprise conductive electrodes. The medical devices 110, 115 may be placed proximate to a treatment site on the surface of cardiac tissue 10, which may be inside or outside of the heart, applied by way of non-invasive transvenous devices like flexible catheters or by devices applied under direct vision during open chest or keyhole surgery.

[00194] As shown in Figure 1, the controller 105 may control the timing relative to heart rhythm, strength, and duration of treatments provided by the medical devices 110, 115. The controller 105 may, for example, be programmed to provide an electronic signal to the medical devices 110, 115. The electronic signal may control the timing of the treatment to coincide with cardiac refractory period to avoid inducing arrhythmias. The electronic signal may control the treatment dose, timing and magnitude of the current generated by the electrolysis medical device 110 and / or the cellular permeabilization medical device 115. The electronic signal may automatically or by operator settings customize treatment of the cardiac tissue 10 according to the specific geometry of medical devices 110 and 115 and / or according to the medical device 110 and 115 engagement and electrical impedance measured in specific patients.

[00195] In the preferred embodiment, the controller 105 may have an electronic device separate from devices 110 and 115, incorporating a pulse generator and a controller using analogue or digital control means and be remotely coupled to the medical devices 110, 115, by electrical conductors. A digitally controlled controller 105, may be implemented by a processor device embedded in the controller 105, or by an embedded processor in the medical device 110 or 115 or by a separate (not shown) general purpose desktop computer, tablet or smart phone used exclusively for this purpose or shared with other medical devices. The controller 105 may also could be integrated into devices 115 and 110 and powered by wires from a power supply or may be powered by integrated primary or rechargeable batteries.

[00196] The cellular permeabilization device 115 performs reversible permeabilization. In some embodiments, the cellular permeabilization device 115 is an electroporation device. The electroporation device may include one or more electrodes for conducting a current through cardiac tissue for permeabilizing cells. The permeability of the cells and / or the reversibility of the permeabilization may be based, at least in part, on the magnitude of the local electric field in the cardiac tissue and / or duration of the electroporation treatment.

[00197] In a preferred embodiment, an E2 Pulse of a lower dosage resulting in reversible permeabilization of the target volume of cardiac tissue may be performed prior to full E2 ablation, followed by electrophysiological testing to confirm the target, followed by a fully-dosed E2 Pulse to ablate the confirmed target volume of cardiac tissue, thereby increasing confidence in the success of the ablation therapy.

[00198] In another preferred embodiment of the invention, the electrolysis medical device 110 and cellular permeabilization medical device 115 may be incorporated in the same device/electrode which may comprise of a single or a plurality of individual electrodes arranged in linear or circular or other patterns such as in a medical device catheter. Said electrodes may apply E2 current pulse from the electrodes to a larger indifferent return electrode applied externally to the skin, i.e. monopolar mode, or said electrodes may apply E2 current between adjacent electrodes, such as 5 millimetres to several centimetres apart), creating lesions under and between the electrodes, i.e. bipolar mode. Electrodes may also be located on either side of myocardium to be ablated, such as in a bipolar mode with electrodes placed on the epicardial surface and on the inside of the heart under the epicardial electrode ablating a thickness of myocardium between, for example 2mm thick in the atrium or 5 to 10mm thick in the left ventricle.

[00199] For example, an E2 device system may combine electrolysis medical devices 110 and 115 with the controller 105 and provide one or more voltage or current pulses to the cardiac tissue 10 sufficient to have operation in the desired domain of electroporation and / or electrolysis and / or E2.

[00200] In one non-limiting example of the embodiment, a prototype E2 system, implemented based on the E2 system description below, was used with prototype electrodes, implemented based on the catheter description below, was used to apply E2 protocols on an in vitro physiological tissue phantom [6.1] using agar gel to determine pH changes over time. pH changes were assessed qualitatively by using pH dye added to the agar phantom prior to solidification (1.4% methyl red, 0.5% phenolphthalein, Sigma Aldrich, St Louis, MO) and quantitatively using a pH meter pushed into the agar phantom (testo 206-pH2, Croydon South, Vic., Australia). Two flat titanium electrodes [6.2] coated with iridium [6.2] were placed 4 mm apart beneath a flat piece of agar gel phantom. A single E2 pulse of 450 V exponentially decaying was applied to the agar phantom, delivering 47 mC of charge. pH was measured at 3 mm (“above anode” and “above cathode”) and 3.6 mm (“beyond anode” and “beyond cathode”) away from the electrodes, which was representative of the required ablation depth. Measurements were made at 30-second intervals, from immediately after E2 Pulse delivery, up to and including 10 minutes after E2 Pulse delivery. Colour changes near the electrodes were observed due to electrolysis. pH fronts [6.3] spread uniformly from the electrodes and thus do not require measurements at numerous locations for the same distance from the electrodes. The data was averaged from three repeats. Figure 6 shows that pH changed at both electrodes, decreasing near the anode, thus becoming more acidic, and increasing near the cathode, thus becoming more basic, gradually over the span of 10 minutes and plateauing from around 5 minutes after E2 Pulse delivery. pH changes near the anode developed faster than near the cathode. Cell death occurs in tissue with pH lower than acidic 6 or above basic 9, which was achieved at all measurement points within 10 minutes.

[00201] In one non-limiting example of the embodiment, a prototype E2 system, implemented based on the E2 system description below, was used with prototype electrodes, implemented based on the catheter description below, was used to apply E2 protocols on in vivo skeletal muscle tissue on sheep that were anaesthetized and sedated but not paralysed. Four flat titanium electrodes coated with iridium were placed 4 mm apart on a flat non-conducting plate representing the 2D projection of the 3D electrode geometry which is described/shown in Figure 11 [11.1]. All E2 Pulse protocols had a standardised monophasic exponentially decaying waveform. The E2 Pulse protocols used (A, B, C, D and E) are summarised in Table 1 (Figure 6). One or two E2 Pulses were applied at each ablation site, with a voltage between 400 V and 600 V, and a time constant between 12 ms and 40 ms, producing electric field strengths greater than 200 V/cm up to 5 mm from the electrodes. Each E2 Pulse was delivered simultaneously through the four electrodes, where adjacent electrodes had opposite electrical polarity. Electrodes were always positioned to align the bulk of the electric field in parallel to the muscle fibres, in order to maximise the electroporation dosage. The voltage and current of all E2 Pulse deliveries were measured using a calibrated oscilloscope (TPS2014B, Tektronix, Beaverton, OR). Muscle contraction induced by the E2 Pulse was assessed by a cardiologist present at the experiment on a scale of 1 (small twitch) to 5 (5 cm lift off). Tissue samples excised after 1 hour, rinsed to remove residual blood, fixed in 10% neutral pH-buffered formalin, and analysed with haematoxylin and eosin staining. Ablation depth was evaluated as the distance normal to the flat surface of the tissue using bright-field microscopy (Leica Aperio XT). No arcing, charring or other adverse events were observed, contraction was mild to moderate, and histological analysis showed continuous ablation depths sufficient for cardiac ablation thereby confirming the acceptability of all E2 Pulse protocols used (A, B, C, D and E). It may be appreciated that the examples provided are for explanatory purposes only and should not be considered to limit the scope of the disclosure.

[00202] The Pulse shape or the E2 Pulse Waveform may be shown in Figure 3. Figure 3 is a schematic illustration of a pulse design in accordance with an example of the present disclosure. The pulse shown in Figure 3 may be applied by the medical device 110 and / or 115 in some embodiments, and may be specified by the controller 105 in some embodiments. The overall E2 Pulse Waveform may comprise a single discrete pulse, that is, an electrical stimulus bounded by a time interval of zero amplitude prior and after, or may comprise a plurality of discrete pulses, that is, an electrical stimulus containing a plurality of time intervals of zero amplitude. Generally, a single discrete pulse may have three components — a rising leading edge (labelled Fl), a plateau (labelled F2) and a falling trailing edge (labelled F3), designed in a manner that optimizes the electric field (electroporation dosage), the charge delivered (electrolysis dosage), and avoiding adverse events such as arcing. Thus, the components Fl, F2 and F3 may be combined into a single discrete pulse of a variety of different shapes, including but not limited to triangular (a), sinusoidal (b), exponentially decaying (c), or square (d), may be truncated (a*, b*, c*, d*), and may be of inverted polarity (a’, b’, c’, d’) in the context of a plurality of discrete pulses, or both inverted and truncated (a*’, b*’, c*’, d*’). Use of a single pulse (as opposed to repeated pulses) during which electroporation and electrolysis both occur may be advantageous in some examples, such as applications where a large dose of electrical charge is required. Generally, an E2 Pulse Waveform is delivered within the refractory period of the heart and comprises a portion of the waveform designed to primarily produce reversible electroporation at a high amplitude, Tl, comprising a sequence of a single discrete pulse Pl, a time interval P2, a second, single discrete pulse P3, and a second time interval P4, a sequence that may be repeated a number of times N, lasting tens of milliseconds in total, a portion of the waveform designed to primarily produce electrolysis at a lower amplitude, T2, comprising a single discrete pulse P5 of low amplitude lasting tens of milliseconds, a time interval between Tl and T2, Gl, and a pre -pulse preceding Tl, TO, comprising a single discrete pulse P0 of low amplitude. A non-limiting example of the E2 Pulse Waveform shows TO comprising an inverted square wave (d’), Tl comprising Pl and P3 of contrasting shapes and polarity and where P2 is longer than P4, or comprising Pl and P3 of the same shape and polarity and P4 is longer than P2, or comprising Pl and P3 of the same shape but contrasting polarity and where P2 is omitted, and T2 comprising an exponentially decaying wave (c). Another non-limiting example of the E2 Pulse Waveform shows a sequence of discrete pulses following the envelope of an exponentially decaying wave (c), where the discrete pulses are of a different shape, same polarity and same duration, or of the same shape truncated, alternating polarity and same duration, or of the same shape truncated, alternating polarity and different durations.

[00203] Pulse Shape

[00204] It may be an advantage to use the E2 Pulse Shape or waveform as it may avoid arcing. Generally, the rising edge Fl may rise to a voltage sufficient to induce reversible electroporation electric fields throughout the targeted treated domain for the given electrode geometry and spacing. Example electric fields values for reversible electroporation include, but are not limited to voltages above 200 V / cm, as shown in Figure 2. The duration of the waveform may be in the order of milliseconds. The plateau portion F2 may last long enough that together with the rise time and decay time, it produces the desired electroporation effect. However, it may be desirable that the plateau portion F2 is short enough to prevent electric discharges (i.e. arcing) which may occur across a gaseous layer that may develop from gas-producing high energy electrolysis process near the electrodes. In some embodiments, the plateau may thus be advantageously infinitesimally small. The decaying voltage edge F3 may then be shaped in a time-decaying manner so that the local electric field across any developing gaseous layer near the electrodes never exceeds field strength and time necessary for ionization of the gas (30,000 V/cm and one to tens of microseconds) that would cause arcing, but may still provide an electric field for a longer period of time to generate adequate charge and electrolytic products in a sufficient quantity for cardiac tissue ablation. In some embodiments, the magnitude of the pulse and the exponential decay may be selected so that ablation occurs more from electroporation than electrolysis or vice versa. In some situations, the described single pulse is advantageous over another preferred embodiment of multiple pulse delivery, which is shown in Figure 4, which shows a single electroporation pulse, ending in predominantly electrolysis, for example, which may reduce severe muscle contractions and / or sparking/arcing while being more ablative. In some situations, a low-amplitude pre-pulse (as shown in Figure 3) P0 may stun the local muscle tissue, thereby to reduce or eliminate severe muscle contraction, or reduce the risk of inducing arrhythmia. In some situations, a biphasic waveform may equalize charge to reduce or eliminate muscle contractions, timed to avoid neutralizing the products of electrolysis, or bias charge delivered, in order to hyperpolarize the surrounding tissue, thereby reducing muscle excitability and the severity of muscle contractions.

[00205] In some embodiments the combination electrolysis and permeabilization may be combined with other modalities for cardiac or other cardiac tissue treatment such as thermal ablation, radiation, chemical ablation, and / or gene therapy as a form of combined therapy delivery. This may be multimodal as it is E2 combined with other modalities.

[00206] Electronic circuits may be used to generate a single pulse or a plurality of pulses including but not limited to those described/shown in Figure 3 and Figure 4, to apply to a cardiac treatment site. For example, a function generator may be coupled to the electrode(s) for generating alternate pulse shapes. The function generator may be coupled to the controller or controlled manually by a user. The function generator may generate a single pulse by charging a charge storage element, then discharging the charge storage element through ports coupled to the electrode(s), or a plurality of monophasic pulses by charging a charge storage element, then discharging the charge storage element partially through ports coupled to the electrode(s), pausing for a pre-determined time interval, then continuing to repeatedly discharge partially and pause briefly until the therapy is delivered, or a plurality of bipolar pulses charging a charge storage element, then discharging the charge storage element partially through ports coupled to the electrode(s), pausing for a pre-determined time interval, switching the ports coupled to the electrode(s) to reverse polarity, then continuing to repeatedly discharge partially, pause briefly and reverse polarity until the therapy is delivered.

[00207] In some embodiments, one treatment may be performed continuously while the other treatment is performed intermittently. The magnitude and duration of each treatment may be modulated independently of the other treatment. As such, this is Nonsimultaneous E2. For example, electrolysis may be performed continuously for several minutes while cellular permeabilization may be performed for several seconds each minute. The electrolysis may be discontinued while the cellular permeabilization continues to be performed. Other combinations of treatments may be possible. The time, duration, and order of the treatments may be chosen based at least in part on the desired effect on the target site, the size of the target site, and / or local physiological conditions of the target site.

[00208] E2 system description

[00209] Figure 7 shows a possible embodiment of a complete E2 system that is designed in accordance with the principles and inventions that are the subject of this patent. The system described in this embodiment can be used as a method to deliver the E2 ablation treatment modality (previously described in E2 Modality using the pulse shape design previously described in Pulse Shape) and as a method to characterise cardiac tissue pre and post E2 therapy. This preferred system embodiment may include the following elements and these elements are further described in the Catheter description below. [00210] In one preferred embodiment, the E2 system shown in Figure 7 include a pulse generator [7.1] to generate E2 pulses, a catheter [7.2.2] with operator-adjustable handle [7.2.1] to deliver the E2 pulse to the patient via E2 electrodes [7.2.3]. The E2 system may also include a user input console [7.4] to sense and use cardiac electrical signals and tissue impedance via the E2 electrodes [7.2.3] and/or other electrodes such as reference patches [7.3] prior to, during and after E2 therapy, via a cable junction box distribution system [7.5] for connecting cardiac electrical signals.

[00211] For the controller / generator / energy supply [7.1], in one preferred embodiment, the pulse generator is capable of delivering pulses of voltages and time constants appropriate for E2 therapy. For example, voltages in the range that produces electric fields of up to 400 V/cm at the required ablation depth, and time constants in the order of tens of milliseconds.

[00212] In one preferred embodiment, the pulse generator is capable of setting the polarity of individual electrodes, in order to optimise the direction of the electric fields relative to the bulk fibre orientation of the target volume of cardiac tissue for maximising electroporation dosage, or to deliver biphasic or multiphasic pulses for minimising unwanted muscle contraction.

[00213] In one preferred embodiment, the pulse generator is capable of selecting an arbitrary number of electrodes to be active in the pulse delivery that is, carrying current from a charge storage element or a plurality of charge storage elements.

[00214] In another preferred embodiment, the pulse generator is capable of delivering E2 pulses of different voltages and time constants through different pairs of electrodes, or groups of electrodes, in order to offset tissue inhomogeneities, or to focus electrical currents and electric fields towards a specific target such as a locally thicker volume of cardiac tissue, or away from a specific target, such as a volume of cardiac tissue outside of the required ablation zone. [00215] The catheter may be an electrode delivery apparatus device, in which the ablation catheter may contain multiple subcomponents such as the following:

[00216] The handle [7.2.1]. In all preferred embodiments, the proximal end of the catheter is terminated within a handle. The handle is designed to ergonomically support the procedure and to facilitate the introduction, navigation and retrieval of the catheter from and into the patient. Furthermore, it contains user controls [8.2 to 8.4], cable connectors [8.1.]. And in another preferred embodiment, the handle contains Fluid connectors [9.6] and access to an inner lumen which extents throughout the catheter [9.5] to allow the insertion of other guiding or mapping medical devices.

[00217] User controls [8.2 to 8.4]. In all preferred embodiments, the handle [7.2.1] contains a mechanism operated by the clinician to allow for bidirectional steering of the distal portion of the catheter through e.g. a lever [8.2]. The amount of force required to steer the catheter can be adjusted with e.g. a rotary knob [8.3] that increases or decreases the friction within the steering mechanism to allow for a more controlled operation and/or to temporary lock the steering angle. Furthermore, the handle may contain a user control such as a button or switch to allow the operator to initiate E2 generator charging and/or pulse delivery. The signal generator may further comprise an automatic setting, wherein the automatic setting allows the signal generator to automatically deliver the one or more electrical pulses from the signal generator to the one or more electrodes when a predetermined threshold of electrical signals from tissue contact is detected by the one or more electrodes. The signal generator may use a signal processing algorithm for determining a predetermined threshold of electrical signals detected by the one or more electrodes from tissue contact prior to the one or more electrodes automatically delivering the one or more generated pulse from the signal generator. It may be an advantage to have an automatic setting for minimising human error when determining when a user may deliver the electrical pulse to the target tissue.

[00218] Distal electrode configurations [7.2.3 & 11.1-11.4, 12.1-12.3, 13.1-13.4 and 14.1-14.2]. In a preferred embodiment, adjacent electrodes are configured in opposing electrical polarity, for example with one electrode [5.2] being connected to the positive terminal as the anode, and the other electrode [5.3] being connected to the negative terminal as the cathode, or vice versa. In another preferred embodiment, groups of adjacent electrodes may alternate in electrical polarity, for example with electrode

[5.2] representing a group of electrodes of the same polarity all connected to the positive terminal as the anode, and electrode [5.3] representing a second, separate group of electrodes being connected to the negative terminal as the cathode, or vice versa. In another preferred embodiment, the size, shape and configuration of the electrodes [5.2] and [5.3] may be specifically be tailored to the targeted cardiac treatment site. For example, the size of both electrodes [5.2] and [5.3] may be increased or decreased to adjust the total surface area, or individually increased or decreased to bias anodal and cathodal surface area, which results in an optimised distribution of current density and electrolysis production for a targeted cardiac treatment site and reducing the risk of arcing. In another preferred embodiment, electrodes or groups of electrodes [5.2] and

[5.3] distributed in a uniform, symmetrical, tessellating or otherwise optimised pattern throughout the portion of the catheter closest to the targeted cardiac treatment site in order to produce a uniform electric field and uniform electrolysis diffusion, in order to produce uniform ablation at the required depth.

[00219] Cable connectors [8.1]. In all preferred embodiments, the catheter handle contains a commonly used cable connector (e.g. Redel®) to either connect the electrodes directly or through a Cable junction box distribution system [7.5] to the E2 generator for the purpose of cardiac electrical signal sensing, pacing and ablation.

[00220] Fluid connectors [9.6]. The catheter handle contains commonly used fluid connectors (e.g. Luer lock) to allow for the injection of contrast medium, physiological saline solution, heparin or other fluids that may be necessary to be injected to the target region of the catheter as part of the procedure. These commonly used fluid connectors furthermore allow the use of a wide range of additional accessories such as Tuohy Borst Adapters.

[00221] Inner lumens for other guiding or mapping medical devices [9.5]. In one preferred embodiment (as shown in Figure 9), the catheter handle contains at least one lumen extending through the catheter of the catheter shaft. This internal lumen is to proximally receive another medical device such as a loop mapping catheter or guide wire and these other medical devices can then extend distally past the catheter tip and are as such, telescopically displaceable from each other. In one preferred embodiment, the second medical device can be a guidewire that can be used to guide the ablation device through tortuous anatomy, for example, the pulmonary vein pre/during E2 ablation therapy. In another preferred embodiment, the second medical device can be a mapping loop catheter and can be used for characterizing/validating pulmonary vein tissue conduction block post E2 ablation therapy.

[00222] Reference patches (when used eg. Return ground path during monopolar pulse delivery) [7.3]. In a preferred embodiment with a monopolar electrode configuration on the catheter, surface electrodes will be required as an electrical return path for the E2 pulse delivery.

[00223] User input console [7.4]. In a preferred embodiment, the diagnostic stimulator [7.4] uses digital signal processing algorithms to process cardiac electrical signals and tissue impedance, to assist in identifying anatomical substrate, characterising electrical tissue properties and perform automated pre- and post-ablation electrophysiological testing, for example, entry block or exit block. In one preferred embodiment, the diagnostic stimulator [7.4] is integrated with the pulse generator [7.1]. In another preferred embodiment, the diagnostic stimulator [7.4] has alarms relating to warning conditions associated with the measured cardiac electrical signals and tissue impedance.

[00224] Cable junction box distribution system [7.5]. In one preferred embodiment, a cable junction box distribution system [7.5] provides an additional option for connecting either ablation electrodes, to replace or complement E2 electrodes [7.2.3], or sensing electrodes, to replace or complement the reference patches [7.3]. In another preferred embodiment, the cable junction box distribution system [7.5] uses an interlock or a plurality of interlocks to switch between ablation and sensing electrodes, to prevent damage to any circuitry that is only intended to be used for sensing cardiac electrical signals and tissue impedance or pacing cardiac tissue, and unsuitable for high voltages.

[00225] Various cables for connection to ancillary Lab equipment (not shown). In one preferred embodiment, various cables interface between the E2 system and standard electrophysiology laboratory equipment. For example, the anaesthetist ECG monitor may be connected to the E2 system for synchronizing the E2 pulse.

[00226] Catheter description

[00227] In the preferred embodiment, the catheter’s electroporation electrodes and the catheter’s electrolysis electrodes are combined into electrodes that perform both electrolysis and electroporation. In some embodiments, the catheter’s electroporation electrodes and the catheter’s electrolysis electrodes can be separated.

[00228] It may be an advantage to provide a catheter that is steerable. The catheter handle [7.2.1] embodiment as shown in Figure 8 may also have a bidirectional deflection mechanism [8.2] that is activated proximally by the clinician. The catheter handle embodiment also has a friction control mechanism [8.3] that can be activated by the clinician to induce deflection friction and to hold the distal portion of the catheter in a deflected state when so required (eg: when desiring tissue contact once the anatomical cardiac location has been reached).

[00229] It may be an advantage to provide a catheter handle comprising a control element such as a button or switch [8.4] that is activated proximally by the clinician to initiate E2 charge and pulse delivery. This control element can be activated post anatomical location of the distal end of the catheter in the desired cardiac tissue location post confirmation. Alternative control elements for the clinician to initiate E2 charge and pulse delivery may be in the form of a foot pedal connected to the pulse generator and/or physical button(s) on the pulse generator and/or software button(s) as part of the user interface of the pulse generator. [00230] In all preferred embodiments, the electrodes are always placed at the distal end of the catheter and the aforementioned controls are placed proximately.

[00231 ] Materials for the electrodes may include pure or alloys including their oxides of Platinum (Pt) including Platinum black, or Iridium (Ir), or Ruthenium (Ru), or Rhodium (Rh), or Palladium (Pd), or Osmium (Os), or Gold (Au), or Silver (Ag), or Titanium (Ti). A particular material or alloy may be chosen as electrode material or surface coating which may improve electrolysis by catalysing related chemical reactions, e.g. reduces required overpotential. Surface coatings may be chemically and/or thermally activated to improve their efficiency. For example, electrodes may include Iridium oxide, or Ruthenium oxide, or Platinum black or composites of these deposited on Titanium, or any of the above mentioned materials or their alloys, which may improve the production of hypochlorous acid at the anode and alkaline water at the cathode respectively.

[00232] The combination of different materials for anode and cathode may optimise the production of certain electrolysis products that may be tailored for different clinical needs. For example, Platinum-Iridium alloy may be used if inert electrodes are desired. Electroporation electrodes may include the same or different materials as electrolysis electrodes. The electrode material for electroporation may be selected to avoid or significantly reduce electrolysis product formation from the electrodes that may introduce metals in the body systemically. The electrode material and surface topography may also be chosen to promote/enhance electrolysis, e.g. increase surface area by adding activated surface coatings. The electrodes may be in any number, size and shape of electrodes using separate electrode delivery approaches. Several example electrode formation embodiments are shown in Figures 11 to 18.

[00233] The electrodes for electrolysis may be the same electrodes that deliver electroporation. The electrodes may be in any number, size and shape using an integrated electrode approach. A number of different configurations may be used to integrate the delivery of electroporation and electrolysis (as previously defined) into a medical device catheter apparatus. The size, shape and configuration of the electrodes may be specifically tailored to the targeted cardiac treatment site. The electrode shapes and geometry ensure adequate surface area to promote required depth of continuous ablation via faradaic current and electrolysis being delivered into tissue under the electrodes. In the case of Pulmonary Vein Isolation, electrodes and catheter geometry are optimized to ensure adequate radial surface contact for complete circumferential PV antral ablation and with adequate depth, for example in the 3 to 5mm region.

[00234] In a preferred embodiment of the present invention, the catheter treatment device containing the electrodes consists of having a proximal end (the handle [9.1] Figure 9) and a distal end (an expandable element in form of a balloon with electrodes [9.2] shown in various electrode configurations in Figure 11 to Figures 16a and 16b) and at least one lumen extending through the catheter of the catheter shaft [9.5]. This lumen is proximally terminated with a commonly used fluid connector (e.g. Luer lock) [9.6] which allows for additional accessories to be connected (e.g. Tuohy Borst Adapters, x-Way Stopcock). The operator can use this internal lumen to inject fluids such as contrast medium for x-ray visibility, heparin, physiological saline solution and other fluids required during the procedure. Furthermore, this lumen allows to proximally receive another medical device such as a loop mapping catheter or guide wire and these other medical devices then extend distally from the expandable element [9.2] and are as such telescopically displaceable from each other. In a preferred embodiment, the second medical device can be a guidewire that can be used to guide the expandable element onto the pulmonary vein anatomy pre/during E2 ablation therapy. In another preferred embodiment, the second medical device can be e.g. a mapping loop catheter and can be used for characterizing/validating pulmonary vein tissue conduction block post E2 ablation therapy. Another lumen [9.4] for the purpose of injecting a fluid such as physiological saline solution that may be mixed with contrast medium for inflation, deflation and x-ray visibility of the balloon. This lumen extends from the balloon pass the catheter handle and is terminated with a commonly used fluid connector (e.g. Luer lock) that will allow for the use of a wide range of accessories such as a 1-Way Stopcock.

[00235] The catheter handle embodiment also may have a slider mechanism [9.3], as shown in Figure 9 that is activated proximally by the clinician. The slider mechanism control device [9.3] is activated by the clinician to extend telescopically the deflated expandable element (previously disclosed) when so required, for example when extending or retracting the catheter during anatomical manoeuvring to target cardiac tissue ablation locations. The extension and retraction embodiment allows use with other medical devices such as introducer sheaths during catheter electrode anatomical device location. When extended distally, the slider [9.3] allows the collapsed expandable balloon element [9.2] to reduce in overall outer diameter allowing it slide while travelling through the inner diameter of an introducer sheath lumen typically used in Electrophysiology (EP) procedures, without dislodging or jamming. Figures 26a and 26b show how the slider mechanism control device [9.3] can facilitate/operate the basket catheter [9.2] to expand or contract. The slider mechanism control device [9.3] may allow relative movement between the proximal locking ring [16.1.3] and a central inner tube [26.1.1] or central inner elongate member [26.1.1]. The central inner elongate member [26.1.1] may be in connection between the proximal locking ring [16.1.3] and the distal locking ring [16.1.3]. More particularly, for the balloon with electrodes configuration, the axial slider [9.3] moves either the distal end of the inner tube forward or the proximal end of the outer sheath backward to reduce the packing density in the collapsed stage by elongating the balloon. It could also advantageously offer a way for a user to manipulate the shape of the balloon when inflated - for example from spherical to elliptical to conform with the anatomy better. For the configuration with the basket-shaped electrode assembly [9.2] with the balloon on the inside (as shown in Figures 23a and 24a), the balloon helps to expand the basket. The axial slider [9.3] helps to expand and collapse the basket and reduce packing density in the collapsed stage, by elongating both the basket and the balloon. It could also advantageously offer a way for the user to manipulate the shape of the balloon and basket when expanded - for example from spherical to elliptical to conform with the anatomy better. For the configuration with the nitinol basket with membrane on distal/frontal hemisphere (as shown in Figures 23b and 24b) or as a band of membrane (as shown in Figures 23c and 24c), the axial slider [9.3] helps to expand and collapse the self-expanding nitinol basket and reduce packing density in the collapsed stage, by elongating both the basket and the membrane or the band. It could also advantageously offer a way for the user to manipulate the shape of the basket when expanded - for example from spherical to elliptical to conform with the anatomy better.

[00236] In one preferred embodiment of expanding the basket-shaped electrode assembly [9.2], there may be a central inner tube [26.1.1] or central elongate member

[26.1.1] within the basket-shaped electrode assembly [9.2], in which the central inner tube is in connection between the proximal locking ring [16.1.3] and the distal locking ring [16.1.3]. The central inner tube [26.1.1] may be axially telescopic or may be axially extending relatively from a distal end [26.1.3] of a proximal locking ring [16.1.3] towards the proximal end [26.1.4] of a proximal locking ring [16.1.3]. An outer sheath [26.1.2] may be in connection with the proximal end [26.1.4] of the proximal locking ring [16.1.3], in which the central inner tube [26.1.1] may traverse axially into the lumen of the outer sheath [26.1.2] when the central inner tube [26.1.1] axially traverses through the lumen of the proximal locking ring [16.1.3] when expanding the basket-shaped electrode assembly [9.2]. Whereby axially moving/reducing the length of the inner tube [26.1.1] which pulls the distal locking hub [16.1.3] closer to the proximal locking hub [16.1.3] will expand the basket-shape electrode assembly [9.2], and whereby when in an expanded configuration (as shown in Figure 26a), the expanded basket-shape electrode assembly [9.2] can be contracted to a semi-collapsed [9.2] (as shown in Figure 26b) configuration or to a collapsed configuration [9.2] (not shown) may be facilitated by controlling the slider mechanism control device [9.3] to axially move the central inner elongate member

[26.1.1] which in turn pushes the distal locking hub [16.1.3] away from the proximal locking hub [16.1.3].

[00237] In another preferred embodiment, there may be a central inner tube

[26.1.1] within the basket-shaped electrode assembly [9.2], in which the central inner tube [26.1.1] is in connection between the proximal locking ring [16.1.3] and the distal locking ring [16.1.3]. Preferably, the central inner tube [26.1.1] is in connection to the distal locking ring [16.1.3] only. An outer sheath [26.1.2] may be in connection with the proximal end [26.1.4] of the proximal locking ring [16.1.3], in which to expand the basket- shaped electrode assembly [9.2], the outer sheath [26.1.2] is axially moved towards the distal locking ring [16.1.3] which will also move the proximal locking ring [16.1.3] towards the distal locking ring [16.1.3]. Whereby axially moving the outer tube

[26.1.2] which pushes the proximal locking hub [16.1.3] closer to the distal locking hub

[16.1.3] will expand the basket-shape electrode assembly [9.2], and whereby when in an expanded configuration (as shown in Figure 26a), the expanded basket-shape electrode assembly [9.2] can be contracted to a semi-collapsed (as shown in Figure 26b) configuration or to a collapsed configuration (not shown) may be facilitated by controlling the slider mechanism control device [9.3] to axially move the outer tube [26.1.2] or outer sheath [26.1.2] which in turn pulls the proximal locking hub [16.1.3] away from the distal locking hub [16.1.3].

[00238] The balloon catheter may have electrodes that may be in a mono or a bipolar arrangement. In some embodiments, the electrodes may be included on a plurality of electrodes on an expandable element such as a balloon [9.2] as shown in Figure 9. For example, the one or more electrodes or multiple electrodes may have alternating cathodes and anodes for electrolysis and/or electroporation electrodes. Other examples of electrode combinations include, but are not limited to, catheters with a plurality of electrodes with alternating cathodes and anodes i.e. bipolar arrangement, catheters with one tip electrode and one reference surface pad electrode i.e. monopolar arrangement, one or more inactive electrodes, two surface electrodes, and / or combinations thereof. Other configurations of electrodes on one or more cardiac treatment sites may also be possible. The spacing between electrodes may also be adjusted to achieve a desired electrolysis and / or electroporation effect by shaping the diffusion of electrolytic products or the electric fields, respectively.

[00239] The distal expandable element [9.2] has a plurality of electrodes designed to increase the area of E2 ablation at margins of physical electrode contact with myocardium through occlusion of PV blood inflow and creation of static blood bridges from electrode to myocardium. This preferred embodiment has a balloon shape, and a semi-compliant electrode placement and delivery catheter design which ensures adequate electrode orientation to the PV and adequate circumferential PV antral contact via the right atrium and trans-cardiac septal approach despite wide anatomical variations in PV shape within human hearts. This preferred embodiment is also shaped to allow pulmonary venography while balloon electrodes contact myocardium to verify occlusion of pulmonary venous inflow, using a central lumen allowing injection of contract solution distal to the balloon.

[00240] It may be appreciated that catheter with an expandable element such as a balloon, may have alternative electrode arrangements. Figure 11 to Figure 16 illustrate examples of catheter balloon electrode configurations according to preferred embodiments of the disclosure that may be connected with the handle embodiment previously described. The expansion/contraction is delivered via the infusion of fluid via a connectable fitting [9.6] attached to the proximal catheter handle as shown in Figure 8.

[00241] In a preferred embodiment, Figure 11 illustrates example embodiment electrode configurations that are attached to an expandable element having a proximal and distal portion, the electrode array being attached to the distal half of the expandable element, e.g. balloon [9.2].

[00242] In another preferred embodiment [11.1], the plurality of electrodes are trapezoid shaped electrodes equally spaced radially on a pitch circle diameter, each trapezoid electrode being wider proximally and gradually decreasing in size distally. In this preferred embodiment, the shape is optimized to create on one hand a homogenous electric field extending far enough into the tissue to cause electroporation and on the other hand provide a larger electrode surface area to allow even diffusion of electrolytic products for ablation.

[00243] In another preferred embodiment [11.2], the plurality of electrode embodiment [11.2] are trapezoid shaped electrodes equally spaced radially on a pitch circle diameter, each trapezoid electrode being wider proximally and gradually decreasing in size distally with an additional axial slotted relief added [11.2.1]. This slotted relief allows the electrode to neatly fold in half allowing it to collapse upon deflation while fitting and travelling through the inner lumen of an introducer sheath typically used in EP procedures, without dislodging or jamming.

[00244] In another preferred embodiment [11.3], the plurality of electrode embodiment [11.2] are sandwiched between two non-conductive layers used to insulate / isolate the conductive layer of the electrode pad and only partially expose the conductive surface area as shown. The non-conductive layers are also used to bond the electrode assembly to the balloon surface. The level of compliance of the non-conductive layer may be chosen to provide strain relief as a transitional layer between the non-compliant conductive layer of the electrode and the expandable element.

[00245] In another preferred embodiment, as shown in Figure 12 [11.4], the entire electrode embodiment [11.2] is sandwiched between two non-conductive layers used to insulate / isolate the conductive layer and only a partial window is used to expose the conductive electrode pad as shown [11.4.1]. The non-conductive layers are also used to bond the electrode assembly to the balloon surface. The level of compliance of the non- conductive layer may be chosen to provide strain relief as a transitional layer between the non-compliant conductive layer of the electrode and the expandable element.

[00246] In a preferred embodiment, Figure 14 illustrates example embodiment electrode configurations that are attached to an expandable element having a proximal and distal portion, the electrode array being attached to the distal half of the expandable balloon [9.2].

[00247] In another preferred embodiment [12.1], the plurality of electrodes are trapezoid shaped electrodes equally spaced radially on a pitch circle diameter, each trapezoid electrode being wider proximally and gradually decreasing in size distally with an additional patterned slotted relief that removes conductive electrode material previously disclosed. The patterned slotted relief increases flexibility of the electrode improving its compliance to the anatomical target region in the inflated ablation ready state and during delivery and retrieval through an introducer sheath in the deflated state. [00248] In another preferred embodiment [12.2], the plurality of electrodes are trapezoid shaped electrodes equally spaced radially on a pitch circle diameter, each trapezoid electrode being wider proximally and gradually decreasing in size distally with an additional patterned slotted relief that removes conductive electrode material previously disclosed. The patterned slotted relief increases flexibility of the electrode giving better shape compliance for the expanded/contracted balloon shape during the inflated and during delivery and retrieval through an introducer sheath in the deflated state.

[00249] In another preferred embodiment [12.3], the plurality of electrodes are trapezoid shaped electrodes equally spaced radially on a pitch circle diameter, each trapezoid electrode being wider proximally and gradually decreasing in size distally with an additional patterned slotted relief that removes conductive electrode material previously disclosed. The patterned slotted relief increases flexibility of the electrode giving better shape compliance for the expanded/contracted balloon shape during the inflated and during delivery and retrieval through an introducer sheath in the deflated state.

[00250] In a preferred embodiment, Figure 15 illustrates example embodiment electrode configurations that are attached to an expandable element having a proximal and distal portion, the electrode array being attached to the distal half of the expandable balloon [9.2].

[00251] In another preferred embodiment [13.1], the electrodes are interlocking ‘fan-bladed’ shaped electrodes spaced radially. Each blade of the fan interlocks with an opposing opposite polarity blade with equally spaced clearance on all sides. In this preferred embodiment, the geometry is optimized to produce electric fields in a multitude of directions locally to optimise the electroporation dose for inhomogeneously oriented muscle fibres, whereby the electroporation dose is maximised for elongated cells when they are parallel to the electric field, thereby producing overall uniform electroporation depth in a defined pattern while minimizing the risk of ablation gaps. Furthermore, electrode surface area is increased to optimise the generation and diffusion of electrolytic products.

[00252] In another preferred embodiment [13.2] the electrodes are interlocking ‘diamond’ shaped electrodes spaced radially with a connecting spline. Each blade of the spline interlocks with an opposing and opposite polarity blade with equally spaced clearance on all sides. In this preferred embodiment, the geometry is optimized to produce electric fields in a multitude of directions locally to optimise the electroporation dose for inhomogeneously oriented muscle fibres, whereby the electroporation dose is maximised for elongated cells when they are parallel to the electric field, thereby producing overall uniform electroporation depth in a defined pattern while minimizing the risk of ablation gaps. Furthermore, electrode surface area is increased to optimise the generation and diffusion of electrolytic products.

[00253] In another preferred embodiment [13.3] the plurality of electrodes are of differing ‘segmented trapazoid shapes’ spaced in a uniform or non-uniform pattern radially around the balloon circumference. The variations in shape configuration can be optimized so that cathodes and anodes are differing in surface area. In this preferred embodiment, the geometry is optimized to produce electric fields in a multitude of directions locally to optimise the electroporation dose for inhomogeneously oriented muscle fibres, whereby the electroporation dose is maximised for elongated cells when they are parallel to the electric field, thereby producing overall uniform electroporation depth in a defined pattern while minimizing the risk of ablation gaps. Furthermore, electrode surface area is increased to optimise the generation and diffusion of electrolytic products.

[00254] In another preferred embodiment [13.4] the plurality of electrodes are ‘circular’ in shape, in a staggered pattern in an ever decreasing diameter from the proximal to distal portion of the balloon, being larger in diameter proximally and gradually decreasing in size distally, spaced in a uniform symmetrically decreasing pattern, radially around the balloon circumference. In this preferred embodiment, the geometry and electrode arrangement is optimized to produce electric fields in a multitude of directions locally to optimise the electroporation dose for inhomogeneously oriented muscle fibres, whereby the electroporation dose is maximised for elongated cells when they are parallel to the electric field, thereby producing overall uniform electroporation depth in a defined pattern while minimizing the risk of ablation gaps. The ability to individually deliver through various electrode combinations allows to shape, steer and bias the electric field locally and globally to achieve an optimal ablation result, e.g. only electrodes that are in tissue contact can be activated.

[00255] In another preferred embodiments of the ni tinol basket as shown in Figures 19a to 19c at [16.1] to [16.3], the proximal locking ring 16.1.3 may be similar to the distal locking ring 16.1.3. The proximal locking ring 16.1.3 may connect the proximal end of the spline, while the distal locking ring 16.1.3 may connect the distal end of the spline. For the nitinol basket embodiment as shown in Figure 19a at [16.1], a spline 16.1.4 may traverse between a first electrode pad 16.1.1 and an adjacent electrode pad 16.1.1. the first electrode pad 16.1.1 and the adjacent electrode pad 16.1.1 may each be mounted to a fabric mesh 16.1.6 or elastomer 16.1.6 of a mesh size that allows for occlude blood flow when the mesh is in contact to the treatment site. Each electrode pad 16.1.1 may have axial slotted relief 16.1.2 that may allow for easy folding when the expanded element 16.1 is at a contracted configuration. Similarly, the elastomer 16.1.6 or the fabric mesh may be able to stretch and be resilient enough to retain its shape after repeated expansions and contractions of the expandable element 16.1, 16.2, 16.3.

[00256] While the next preferred embodiments of the nitinol basket 16.2, 16.3 as shown in Figure 19b and 19c are different in that they each have at least one spline (proximal spline and a distal spline) in connection with the electrode pad 16.1.1, the mechanism for securing the ends of the spline to the locking ring 16.1.3 is the same. In another embodiment 16.2, as shown in Figure 19b, the proximal spline 16.1.4a may be in electrical connection to a middle portion 16.1.7a of the proximal end 16.1.7 of the electrode pad 16.1.1, while the distal spline 16.1.8 may be in electrical connection to a middle portion 16.1.8a of the distal end 16.1.8 of the electrode pad 16.1.1. The electrode pad 16.1.1 may be similarly mounted to the band of elastomer 16.1.5 or fabric mesh. In another embodiment 16.3, as shown in Figure 19c, there may be two proximal splines 16.1.4a and 16.1.4c, wherein each proximal spline (16.1.4a and 16.1.4c) may each support or be in electrical connection to a first corner 16.1.9a and a second corner 16.1.9c respectively of the proximal end 16.1.7 of the electrode pad 16.1.1. There may also be two distal splines (16.1.4b and 16.1.4d), wherein each distal spline (16.1.4b and 16.1.4d) may each support or be in electrical connection to a first corner 16.1.9b and a second corner 16.1.9d respectively of the distal end 16.1.8 of the electrode pad 16.1.1. The band of fabric mesh 16.1.5 may cover the area between the electrode 16.1.1 and the adjacent electrode 16.1.1.

[00257] In another preferred embodiment regarding polarity configuration of the electrodes as shown in Figures 20a to 20d at [17.1] to [17.4] respectively, the plurality of electrodes 17.1.1, 17.1.2 form two concentric arrays, where one concentric array of electrodes 17.1.1 is more distal than the second concentric array of electrodes 17.1.2. In this preferred embodiment, the geometry and electrode arrangement may be optimized to produce electric fields in a multitude of directions locally to optimise the electroporation dose for inhomogeneously oriented muscle fibres, whereby the electroporation dose is maximised for elongated cells when they are parallel to the electric field (shown by black arrows), thereby producing overall uniform electroporation depth in a defined pattern while minimizing the risk of ablation gaps. The ability to individually deliver through various electrode combinations allows to shape, steer and bias the electric field locally and globally to achieve an optimal ablation result, e.g. only electrodes that are in tissue contact can be activated (showing a ‘-ve’ [17.1.3] or ‘+ve’ [17.1.4] symbol). For example, in the polarity [17.1.3], [17.1.4] configuration/pattern of the electrodes 17.1.1, 17.1.2 as shown in Figure 20a at [17.1], the electric field (shown by black arrows) produced would be primarily parallel to the axis of the catheter, thereby targeting cells that are parallel to the catheter; in the polarity [17.1.3], [17.1.4] configuration/pattern of the electrodes 17.1.1, 17.1.2 as shown in Figure 20b at [17.2], the electric field (shown by black arrows) produced would be primarily perpendicular to the axis of the catheter, thereby targeting cells that are perpendicular to the catheter; in the polarity [17.1.3], [17.1.4] configuration/pattern of the electrodes 17.1.1, 17.1.2 as shown in Figure 20c at [17.3], a plurality of pulses would produce electric fields (shown by black arrows) that are primarily oblique to the axis of the catheter, thereby targeting cells that are oriented obliquely to the catheter; in the polarity [17.1.3], [17.1.4] configuration/pattern of the electrodes 17.1.1, 17.1.2 as shown in Figure 20d at [17.4], the electric field (shown by black arrows) produced may be a combination of different electric field orientations, thereby targeting cells that are oriented differently, about the circumference of the pulmonary vein, relative to the catheter. It may be appreciated that the polarity of each individual electrode can be changeable between a negative polarity [17.1.3] or a positive polarity [17.1.4] to generate a desired electric field or any desired pattern of electric field rather than a single polarity pattern of one polarity per concentric array.

[00258] In another preferred embodiment, as shown in Figure 16, the plurality of electrodes are all connected as the anode, with a tip electrode connected as the cathode, such that the production of positively charged species at the anodes will hyperpolarize the surrounding tissue, thereby reducing muscle excitability and the severity of muscle contractions. Anode electrodes can come in geometries described previously in the preferred embodiments [13.1] to [13.4].

[00259] Electrode adherence method. The preferred embodiments listed above and in Figure 11 to Figure 16 include methods of constructing electrodes on the surface of an expandable element, e.g. balloon surface. The expandable element may be semi or non- compliant. These electrodes can withstand delivery of large impulse currents, such as five (5) to ten (10) amps for up to 50 ms during E2 ablation, when in contact with cardiac tissue in the desired cardiac anatomical location.

[00260] Converted Electrode Coupon. A thin film or foil of an electrical conducive material listed may include pure or alloys including their oxides of Platinum (Pt) including Platinum black, or Iridium (Ir), or Ruthenium (Ru), or Rhodium (Rh), or Palladium (Pd), or Osmium (Os), or Gold (Au), or Silver (Ag), or Titanium (Ti) may be converted into an electrode coupon consisting of one or more layers or multiple layers as shown in Figure 13 to create electrode geometries [eg: 11.3 and 11.4]. The electrode geometry will be generated by laser cutting, chemical etching or similar process. Similarly, the geometry of an electrically insulating, compliant polymer layer (such as Thermoplastic polyurethane (TPU)) will be generated. The level of compliance of the electrically insulating layer may be chosen to provide a strain release between the non- or semi-compliant electrically conductive layer and the expandable element. In one preferred embodiment [11.3], the electrical conductive thin film or foil may be thermally or chemically adhered as top layer to one or multiple electrical isolating layers and only the tail extension is fully isolated with another non-conductive top layer. In another preferred embodiment [11.4], the electrical conductive thin film or foil may be completely embedded between at least two layers of electrical insulating material using a thermal or chemical adhesion process. In this preferred embedded electrode configuration

[11.4], pending on the geometry of the top insulation layer, a window cut-out [11.4.1] may be required to expose parts of the electrically conductive layer underneath.

[00261] A roughened surface of the electrically conductive layer may promote the adhesion process with the electrical isolating layers and also increase the electrode surface area improving electrolysis performance. Roughening the surface may be achieved by a mechanical process, chemical etching, material deposition such as physical vapour deposition (PVD) or chemical vapour deposition (CVD) or similar. An example of a layer stack-up is given in Figure 11 [11.4]. An electrical conductive thin film or foil

[11.4.4] has an e.g. 40 nm adhesion tie layer [11.4.3], [11.4.5] on either side to promote sufficient adhesion of following surface coating of e.g. 300 nm Iridium Oxide. The conductive layer arrangement is then sandwiched between two non-conductive polymer layers (e.g. TPU) [11.4.1], [11.4.7]. Figure 12 summarises a proposal of the main processing steps on how to manufacture individual coupon electrodes. Starting with the laser cutting of partial geometry segments and alignment features of two (2) non- conductive polymer layers and the conductive layer. The arrangement and alignment of these layers is shown followed by a joining process (e.g. thermal bonding) of all three (3) layers. In a last step, each individual electrode coupon is laser cut to their final geometry.

[00262] Direct Material Deposition. An alternative path to create conductive areas on an expandable element may be through direct material deposition. The expandable element may hereby be masked in a way to allow for direct deposition of the desired electrode geometry in materials listed before. Direct material deposition may be achieved but is not limited to processes such as Physical vapor deposition (PVD), Chemical Vapor Deposition (CVD), Electro-plating, printing or a combination of these processes. PVD describes a variety of vacuum deposition methods which can be used to produce thin films and coatings. CVD is a process in which the substrate is exposed to one or more volatile precursors, which react and/or decompose on the substrate surface to produce the desired thin film deposit. The material deposition may further occur at various expansion stages of the expandable element to reduce/optimise mechanical strains at the interface of the expandable element and the deposited material. As an example, an initial nm to pm thick seed layer may be deposited through sputtering onto the expandable element. Following layer build-up may be achieved with electroplating.

[00263] In another preferred embodiment of the expandable element, as shown in Figures 21a to 2 Id, the expandable element with a balloon within the expandable element or an expandable element which may be a nitinol basket with a membrane may have a first proximal spline 16.1.4a and a first distal spline 16.1.4b. The first proximal spline 16.1.4a may be in connection with a proximal end 16.1.7 of an electrode pad 16.1.1 and the first distal spline 16.1.4b may be in connection with a distal end 16.1.8 of the electrode pad 16.1.1. The electrode pad 16.1.1 is positioned between the first proximal spline 16.1.4a and the first distal spline 16.1.4b. The first proximal spline 16.1.4a may preferably be in connection to the middle portion 16.1.7a of the proximal end 16.1.7 of the electrode pad 16.1.1, and the first distal spline 16.1.4b may preferably be in connection to the middle portion 16.1.8a of the distal end 16.1.4b of the electrode pad 16.1.1. An advantage of this type using one proximal spline 16.1.4a and one distal spline 16.1.4b for an electrode pad 16.1.1 is that less materials are used. For reducing the electrode pad 16.1.1 being caught by the tortuous anatomy of the blood vessel, it may be appreciated that the corners of the electrode pad 16.1.1 may be rounded or curved. The opposite ends of the proximal splines may be in connection to a locking ring 16.1.3 or locking hub 16.1.3. The splines are flexible, curved and resilient elongated members, and defines the radially expandable basket-shape framework when the proximal and the distal end of the splines are connected between the proximal locking ring 16.1.3 and the distal locking ring 16.1.3 respectively.

[00264] In another preferred embodiment of the expandable element, as shown in Figures 22a to 22d, the expandable element or balloon which may be a nitinol basket may have a first 16.1.4a and a second proximal spline 16.1.4c and a first 16.1.4b and a second distal spline 16.1.4d. The first 16.1.4a and the second proximal spline 16.1.4c may each be in respective connection with a first corner 16.1.9a and a second corner 16.1.9c at the proximal end 16.1.7 of an electrode pad 16.1.1; and the first 16.1.4b and the second distal spline 16.1.4d may each be in respective connection with a first corner 16.1.9b and a second corner 16.1.9d at the distal end 16.1.8 of the electrode pad 16.1.1. The electrode pad 16.1.1 is positioned between the proximal splines 16.1.4a, 16.1.4c and the distal splines 16.1.4b, 16.1.4d. An advantage of this type using two proximal splines and two distal splines for the electrode pad 16.1.1 is it minimises the likelihood that a tortuous anatomy of the blood vessel or during catheter retrieval, may catch on the corners 16.1.9a to 16.1.9d of the electrode pad 16.1.1. It also provides more redundancies for electrical connection and number of anchoring points to the catheter. The opposite ends of the proximal splines may be in connection to a locking ring 16.1.5 or locking hub as shown in Figures 25a and 25b.

[00265] For the expandable element embodiments shown in Figures 21a to 2 Id, and 22a to 22d, each basket element is composed of an electrode pad 16.1.1 supported by either a single, centred spline; and/or two splines or a combination of using one centred spline to a proximal end 16.1.7 of the electrode pad 16.1.1 and two splines to the distal end 16.1.8 of the electrode pad 16.1.1; or a combination of using one centred spline to distal end 16.1.8 of the electrode pad 16.1.1 and two splines to the proximal end 16.1.7 of the electrode pad 16.1.1. The splines and electrode pad forming the basket shape structure are made of Nitinol (Ni Ti alloy) with super elastic, shape memory properties. It may be preferred that additional layers of conductive materials can be deposited onto the electrode pad and/or splines to form electrodes and conduction paths to connect to. To electrically isolate parts where required, layers of non-conductive materials can also be deposited onto the electrode pad and/or splines. As shown in Figure 21b and 22b, the proximal locking hub 16.1.3 or proximal locking ring may allow for the basket electrodes to be connected to a positive or negative terminal and providing a way to mechanically interlock the basket electrodes to the catheter , and the distalmost tip or distalmost hub 16.1.3 may have an opposite polarity to the proximal locking hub. In these nitinol basket embodiments, there may be alternating polarities between adjacent electrodes and these hubs may also be called terminal connections. When the distalmost hub 16.1.3 and the proximal connection hub 16.1.3 have different polarities, this may advantageously reduce the risk of short-circuits.

[00266] As shown in Figures 23 a and Figures 24a , the spherical basket shape may comprise an elastomer 16.1.5 which may cover between adjacent splines supporting an adjacent electrode pad, as well as covering the area defined between adjacent proximal splines to the proximal end of the electrode pad, and the area defined between adjacent distal splines to the distal end of the electrode pad. In this expandable element with a membrane, this configuration helps to occlude the Pulmonary vein to facilitate diffusion of electrolytic products after when the pulse has been delivered by the electrodes to the treatment site. The mesh may be of a sufficient size that can occlude the blood flow at the treatment site. Depending on the treatment use, the elastomer 16.1.5 may cover the distal and proximal hemisphere of the basket shape as shown in Figures 23 a and 24a.

[00267] In another embodiment, an elastomer, fabric mesh or medical textile may cover only the distal hemisphere/frontal hemisphere of the basket shape as shown in Figures 23b and 24b. So, the distal hemisphere of the basket shape is still occluding blood flow. In this embodiment, the electrodes exposed would help to occlude the Pulmonary vein at certain parts of the treatment site as well as to allow of electrolytic products. In another preferred embodiment, an elastomer, fabric mesh or medical textile 16.1.5 may be a band of a width corresponding to the length of electrode pad from the proximal end to the distal end, as shown in Figures 23c and 24c. This elastomer 16.1.5 or fabric mesh band may cover the interelectrode space of the nitinol basket whilst keeping the electrodes exposed which would allow for continuous blood flow through the nitinol basket, which may advantageously reduce stress on the cardiac system as well as reducing the pressure on the device itself which will make it easier to retain its position. As it is only a band of fabric mesh, it will allow user flexibility to only locally block blood flow at the target area/treatment site to facilitate diffusion of electrolytic products.

[00268] As shown in Figures 25a, the locking ring 16.1.3 may comprise pockets 25.1.2 where in each pocket 25.1.2 is adapted to receive and secure an end of at least one proximal spline 16.1.4a, 16.1.4c; or if the locking ring 16.1.3 is a distal locking ring, the pocket 25.1.2 is adapted to receive and secure an end of at least one distal spline 16.1.4b, 16.1.4d. While not shown, it may be appreciated that the most proximal locking hub or locking ring 16.1.3 may have a similar securing mechanism for securing the proximal end of the proximal spline. The locking ring 16.1.3 also has slots 25.1.4 for wires/conductive elements 25.1.1, where each slot 25.1.4 is adapted to receive and secure an end of a wire 25.1.1. The end of the spline may have a hook-like termination element 25.1.5 to mechanically secure the spline inside the locking hub and in which the wires 25.1.1 are also secured in the slot 25.1.4, the end of the spline may be in electrical connection with the wires 25.1.1.

[00269] The elastomeric material may be one material selected from the group of: polyurethane, and silicone-polyurethane copolymer; and the medical textile may be a knitted, woven or braided textile made from one material selected from the group of: polytetrafluroethylene, expanded polytetrafluroethylene, polyethylene terephthalate, and polyester. The elastomeric material or the medical textile may form a membrane that can block the blood flow. There may be three main options available: a) use any one material listed in the elastomeric material, OR b) use any one material listed in the medical textiles in a tightly knitted, woven or braided configuration (with the mesh size less than or equal to 160 pm), OR c) a hybrid approach, wherein a loosely woven, knitted or braided medical textile (loosely is mesh size in the size range of greater than 160 pm to 1.5mm) is coated with an elastomeric material to make the membrane non-permeable.

[00270] The process for manufacturing the membrane of an elastomeric material onto the basket-shaped electrode assembly may be via dip-or spray coating to form a membrane. The process for manufacturing the membrane by tightly knitting, woven or braided configuration may be attached to the splines of the basket via sewing, embroidery, ultrasonic welding or lamination process. Similarly, the process for manufacturing the hybrid membrane may first loosely knitting, woven or braiding configuration attached to the splines of the basket via sewing, embroidery, ultrasonic welding or lamination process followed by dip or spray coating any one of the listed elastomeric materials to form the membrane. Alternatively, the membrane may be formed by thermal forming to control characteristics such as pore size and compliance, which may offer isotropic stretch, and controlled radial and elongation properties. This alternative process of manufacturing may be applicable for membranes formed by the medical textile approach or the hybrid approach.

[00271] Alternative electrode arrangement on Linear Catheter. Figure 17 illustrates an embodiment of a linear array electrode configuration on an insulated shaft for linear ablation of cardiac tissue. The quantity and spacing of the electrodes can be optimized to induce E2. The tip electrode [14.1] is active and can be used for Electroporation, electrolysis and/or to sense / characterize cardiac tissue. Subsequent shaft electrodes [14.2] can also be used for Electroporation, electrolysis and/or to sense / characterize cardiac tissue. The method of electrode construction for the linear electrode array is such that a plurality of at least eight [x8] electrodes [14.2] can be adhered to internal conductors within a small, such as 3mm diameter (9Fr), intra-cardiac catheter shaft [14.3] while being able to carry large impulse currents such as 5-10 A for 50ms for the purpose of E2 therapeutic delivery.

[00272] Alternative electrode arrangement on Linear Catheter. Figure 18 illustrates a preferred embodiment of a paired linear electrode configuration on an insulated shaft for linear ablation of cardiac tissue. The spacing of the paired electrodes is such that a long linear lesion set is delivered from the middle outwards via overlapping E2 fields. The tip electrode [15.2] is used as a housing to ensure the dual paired electrodes [15.1] maintain a precise parallel configuration. The electrodes are long in shape and ensure a longer continuous bi-polar linear lesion is delivered as opposed to traditional conventional paired sets of small electrodes. The method of electrode construction for the linear electrode pair [15.1] can be adhered to internal conductors within a small, intra-cardiac catheter shaft torque tube [15.3] while being able to carry large impulse currents such as 5-10 A for 50ms for the purpose of E2 therapeutic delivery.

[00273] Electrode arrangement summary. It may be appreciated that the examples shown in Figure 11 to Figure 18 are for illustrative purposes only, and other electrode configurations are possible within the boundaries of the E2 system that are optimized to sense and ablate via E2.

[00274] Electrode feedback loop. The embodiments listed above and in figures Figure 11 to Figure 18 include a method sensing cardiac electrical signals and tissue impedance from the electrodes to advantageously determine adequacy of electrode contact with cardiac tissue prior to E2 delivery. This method senses cardiac electrical signals and tissue impedance from the electrodes before and after ablation to characterize viability of tissue and determine adequacy of ablation to serve as an endpoint and any locate gaps in ablation. This method senses cardiac electrical signals from the electrodes or another device before ablation to synchronize the E2 delivery with the refractory period of the heart in order to avoid inducing arrhythmia. The Electrical circuit method described above also includes logic for sensing cardiac potentials, then generating required E2 pulses, and switching between the two, measuring energy delivery, terminating delivery when appropriate, and is tolerant of current spikes from arcing and shorting of electrodes, using those inputs to control or prevent E2 delivery.

[00275] In one preferred embodiment, the pulse generator device [7.1] measures the delivered voltage and current, and uses digital signal processing to detect abnormal electrical events such electrical arcing, which produces discontinuous current waveforms, and short-circuiting electrodes, which show low impedance, and to prevent, control or terminate E2 delivery. [00276] In another preferred embodiment, the E2 system includes sensors and digital signal processing for sensing cardiac electrical signals and tissue impedance, prior to and after E2 delivery to provide data for acute clinical endpoints.

[00277] Clinical Applications and benefits

[00278] Advantages of E2. Many regions of cardiac tissue may benefit from the use of the combination of E2. The reduced energy requirement and reduced treatment times compared to traditional thermally based energy sources may overcome limitations that previously discouraged the use of either electroporation or electrolysis regardless of the benefits of each on a standalone basis. The combination of both may overcome the limitations and enable a multitude of cardiac tissue characterization and ablation use.

[00279] Advantages of E2 for PVI. The treatment of Pulmonary Vein Isolation by the combination of electroporation and electrolysis may be an enhanced treatment approach for Cardiac Fibrillation. The targeted treatment site may be accessed minimally invasively by transmural catheter placement. The configuration of the device and the electrodes may deliver the combination of electroporation and electrolysis in an optimal manner for the targeted cardiac tissue/location. The types of cardiac locations for E2 ablation may include right atrium, left atrium, pulmonary veins, right ventricle, and left ventricle.

[00280] Intended Applicable Arrhythmias. The combination of electroporation and electrolysis, E2, may be an effective clinical approach for both Cardiac Flutter, Cardiac Fibrillation, Supraventricular Tachycardia (SVT), Ventricular Tachycardia (VT) and Ventricular Fibrillation (VF).

[00281] Other smaller ablation targets. The E2 protocol may also be used to selectively ablate small volumes of tissue in the heart such as a cavo-tricuspid isthmus line. [00282] Control for E2 Dose - non-specific. Another preferred embodiment may utilize a method to control the dose of the amount of electrolysis product produced and applied to the cardiac treatment site.

[00283] Although the invention has been described with reference to specific examples, it will be appreciated by those skilled in the art that the invention may be embodied in many other forms, in keeping with the broad principles and the spirit of the invention described herein.

[00284] The present invention and the described preferred embodiments specifically include at least one feature that is industrial applicable.

Claims

74 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A device for generating electrical pulses for ablating cardiac tissue, the device comprising: a signal generator for producing one or more electrical pulses of a first predetermined voltage or current and duration, wherein the electrical pulse has a truncated pulse waveform which comprises of: a rising edge, a plateau, and a falling edge; the first predetermined voltage or current and duration having a voltage in the range of 200 to 1000 Volts, and a duration in the range between 5 to 100 ms; wherein when the electrical pulse is transmitted to cardiac tissue, reversible electroporation of cardiac tissue is induced.

2. A device for generating electrical pulses for ablating cardiac tissue, the device comprising: a signal generator for producing one or more electrical pulses of a first predetermined voltage or current and duration, wherein the electrical pulse has a pulse waveform comprising a truncated waveform portion and a non-truncated waveform portion; wherein the pulse waveform comprises of: a rising edge, a plateau, and a falling edge; the first predetermined voltage or current and duration having a voltage in the range of 200 to 1000 Volts, and a duration in the range between 5 to 100 ms; wherein when the electrical pulse is transmitted to cardiac tissue, reversible electroporation of cardiac tissue is induced from the truncated portion of the pulse 75 waveform, and wherein blood is electrolysed from the non-truncated portion of the pulse waveform. The device according to any one of claims 1 to 2, wherein the electrical pulse is a pulse selected from the group of: single pulse, one or more pulses of equal amplitude, and one or more pulses of varying amplitude. The device according to claim 3, wherein the one or more pulses are at least one selected from the group of: monophasic, biphasic, and multiphasic. The device according to claim 4, wherein the one or more electrical pulses are monopolar, wherein when the signal generator is configured for electrically communicating the electrical pulse to one electrode of a catheter. The device according to claim 4, wherein the one or more electrical pulses are bipolar, wherein when the signal generator is configured for electrically communicating the electrical pulse to one electrode and an adjacent electrode of a catheter by applying the voltage between the two adjacent electrodes, and wherein the adjacent electrodes are configured in opposing electrical polarity. The device according to claim 6, wherein the one or more electrical pulses is delivered from the signal generator from one or more charge storage elements to more than one electrode of the catheter for electric field strength uniformity. 76 The device according to any one of claims 1 to 7, wherein the pulse waveform is composed of concatenating a plurality of waveforms, wherein each of the waveforms has at least one selected from the group of: of equal or varying amplitudes, equal or varying time interval durations, and same or different waveform shapes. The device according to claim 8, wherein the concatenated waveform is configured to be delivered within the refractory period of cardiac tissue. The device according to any one of claims 8 to 9, wherein the pulse waveform is composed of concatenating a plurality of waveforms, wherein the polarity of the plurality of waveforms is one selected from the group of: monophasic, biphasic, and multiphasic. The device according to claim 10, wherein the concatenated waveform allows for any alternating series of (a) inducing electroporation, and (b) electrolysis of conductive fluid. A catheter adapted for ablating cardiac tissue, the catheter comprising: at least one electrical lead having a proximal end and a distal end and at least one lumen extending from the proximal end to the distal end; a handle at the proximal end, wherein the handle comprises a fluid connector and an electrical connector, wherein the fluid connector allows for injected fluid to flow in a first lumen; wherein the first lumen having an outlet at the distal end, 77 wherein the outlet allows for the ejection of the injected fluid from the first lumen; one or more electrodes positioned at the distal end, wherein the electrode is in electrical communication with the electrical lead; the electrical connector for allowing electrical communication between the handle with a controller, wherein the controller is also in electrical communication with a signal generator, and wherein the controller is in electrical communication with the switching of the one or more electrodes, wherein the controller allows for the electrode to deliver one or more predetermined electrical pulses to the target tissue such that the predetermined pulse induces electroporation of target cardiac tissue and electrolysis of the blood. The catheter according to claim 12, wherein the one or more predetermined electrical pulses has a pulse waveform comprising a truncated waveform portion and a non-truncated waveform portion; wherein the pulse waveform comprises of: a rising edge, a plateau, and a falling edge; and wherein the predetermined electrical pulse has a voltage and duration, wherein the voltage is in the range of 200 to 1000 Volts, wherein the duration is in the range between 5 to 100 ms. The catheter according to any one of claims 12 to 13, wherein the injection fluid is one selected from the group of: physiological saline solution, heparin, contrast medium, and physiological saline solution with contrast medium. 78 The catheter according to any one of claims 12 to 14, wherein the controller is configured to dynamically control the one or more electrical pulses from the signal generator to the at least one electrode such that the at least one electrical pulse coincides with the tissue refractory period. The catheter according to any one of claims 12 to 15, wherein the catheter comprises one or more sensing electrodes, wherein a first sensing electrode is configured for measuring the electrical impedance or cardiac signals of the target cardiac tissue. The catheter according to any one of claims 12 to 16, further comprising a cable junction box which is in electrical connection between the signal generator and the handle, wherein the cable junction box allows for the one or more electrodes to switch between sensing and delivering the one or more electrical pulses to the target cardiac tissue. The catheter according to any one of claims 12 or 17, wherein the first electrical pulse initially selected for delivery to the one or more electrodes allows for reversible permeabilization of the target cardiac tissue, allowing electrolytic blood products or injected fluid into target cardiac tissue, wherein when electrophysiological testing from the electrode have confirmed the target cardiac tissue, a second electrical pulse for ablating the targeted cardiac tissue is delivered by the electrode. 79 The catheter according to any one of claims 12 to 18, wherein the handle has a bidirectional deflection mechanism and a friction control mechanism for inducing deflection friction and to hold the distal end of the catheter in a deflected configuration for target cardiac tissue contact; wherein the handle further comprises a slider mechanism for extending or retracting an expandable element when manoeuvring to target tissue; wherein the expandable element is positioned in a second lumen. The catheter according to claim 19, wherein one or more electrodes are positioned on the expandable element at the distal end of the catheter, wherein when expanded, the expandable element allows for local occlusion of blood flow and for optimising contact of the one or more electrodes to the target tissue; and wherein the one or more electrodes have a shape that is selected from the group of: trapezoid shaped electrodes; fan-blade shaped electrodes, diamond shaped electrodes, and circular shaped electrodes. The catheter according to any one of claims 19 to 20, wherein the expandable element comprises a band of membrane at a latitude between a proximal end and a distal end of the expandable element; wherein the band of membrane is one selected from the group of: elastomeric material, and medical textiles. The catheter according to claim 21, wherein the width of the band of membrane is of a length equal or greater to the length of the electrode. 80 The catheter according to claim 22, wherein the band of membrane formed from the elastomeric material is one material selected from the group of: polyurethane, and silicone-polyurethane copolymer. The catheter according to claim 22, wherein the band of membrane formed from the medical textile is a tightly knitted, woven or braided textile made from one material selected from the group of: polytetrafluroethylene, expanded polytetrafluroethylene, polyethylene terephthalate, and polyester. The catheter according to claim 22, wherein the band of membrane formed from a hybrid of the medical textile and the elastomeric material, wherein the medical textile is a loosely knitted, woven or braided textile made from one material selected from the group of: polytetrafluroethylene, expanded polytetrafluroethylene, polyethylene terephthalate, and polyester, and wherein the loose textile is coated with the elastomeric material. The catheter according to any one of claims 20 to 25, wherein the trapezoid shaped electrodes are spaced in a uniform or non-uniform pattern radially around the expanded element, wherein the variation in shape configuration allows for a first electrode of a polarity and a second electrode of an opposite polarity. The catheter according to claim 26, wherein the first electrode and the second electrode have a different surface area. The catheter according to any one of claims 20 to 26, wherein the fan-blade shaped electrodes are spaced radially from each other, wherein each blade of the interlocks with an opposing blade electrode of opposite polarity. The catheter according to any one of claims claim 20 to 26, wherein the diamond shaped electrodes are spaced radially from each other with a connecting spline, wherein each diamond shaped electrode interlocks with an opposing diamond shaped electrode of opposite polarity. The catheter according to any one of claims 20 to 26, wherein the circular shaped electrodes are in a staggered pattern, wherein the staggered pattern is one selected from the group of: in a decreasing diameter from the proximal to distal portion of the expandable element, and electrodes of different diameter adjacent to each other. The catheter according to any one of claims 19 to 30, further comprising a tip electrode of a polarity, wherein the at least one electrode on the expandable element has an opposite polarity, such that the one or more electrodes can hyperpolarize the targeted tissue. The catheter according to any one of claims 19 to 31, wherein the electrode comprises an axial slotted relief for allowing the electrodes to fold when deflating the expanded expandable element. The catheter according to claim 12, wherein a first electrode and a second electrode are elongate electrodes parallel relative to each other, wherein each of the elongate electrodes extend between the proximal end to the distal end. The catheter according to any one of claims 12 to 33, wherein the handle comprises a user control for allowing an operator to control the delivery of the pulse to target tissue. The catheter according to claim 34, wherein the signal generator comprises an automatic setting, wherein the automatic setting allows the signal generator to automatically deliver the one or more electrical pulses from the signal generator to the one or more electrodes when a predetermined threshold of electrical signals from tissue contact is detected by the one or more electrodes. The catheter according to any one of claims 12 to 35, wherein the electrode is one material or alloys chosen from the group of: platinum, ruthenium, rhodium, palladium, osmium, iridium, gold, silver, titanium; and wherein the electrode further comprises a surface coating, wherein the surface coating is at least one selected from the group of: iridium oxide, ruthenium oxide platinum black. The catheter according to claim 36, wherein the material or alloy chosen for the cathode is different to the material or alloy chosen for the anode. 83 An electrical pulse delivery system comprising: a catheter having one or more electrodes for conducting electrophysiological measurements or for delivering electrical pulses to cardiac tissue; a controller in electrical communication with the switching of one or more electrodes, wherein the controller is configured to receive a first measured electrophysiological data and determining the beginning of the refractory period of the cardiac tissue; a signal generator in electrical communication with the controller, wherein the controller selects for a first pulse waveform for the signal generator to generate based on the first measured electrophysiological data; the first pulse waveform is delivered as a first electrical pulse to the one or more electrodes to induce reversible electroporation of target cardiac tissue. The electrical pulse delivery system of claim 38, wherein after the delivery of the first electrical pulse, the electrode measures a second electrophysiological data of the electroporated cardiac tissue, wherein the second measured data is transmitted to the controller; wherein when the difference between the first and second measured data is within a predetermined threshold value, the controller dynamically selects for a second predetermined pulse waveform from the signal generator to generate; the second pulse waveform is delivered as a second electrical pulse to the one or more electrodes with a duration configured for electrolysing blood and for generating a predetermined amount of electrolytic blood products, wherein the 84 generated electrolytic blood products can diffuse into the electroporated cardiac tissue to induce targeted cardiac tissue death. The electrical pulse delivery system of claim 38, wherein the first electrical pulse is delivered within the refractory period. A basket-shaped electrode assembly comprising: a plurality of splines and a plurality of conductive wires each having a proximal end and a distal end, wherein a spline is in electrical connection with a wire at the respective ends; a proximal locking ring and a distal locking ring, wherein the proximal end and the distal end of each spline and wire are secured at the respective locking rings; an electrode pad in connection between the proximal end and the distal end of a spline, wherein at least one layer of conductive or non-conductive material is appliable to the electrode pad such that one or more electrodes can be formed on the electrode pad. The basket-shaped electrode assembly of claim 41, wherein a membrane formed from an elastomeric material covers the interelectrode and interspline space of the assembly. The basket-shaped electrode assembly of claim 42, wherein the membrane covers the interelectrode and interspline space of the assembly from a distal end of the electrode pad to the distal locking ring. 85 The basket-shaped electrode assembly of claim 43, wherein a band of the membrane covers the interelectrode space of the assembly circumferentially between a proximal end to a distal end of the electrode pads. The basket-shaped electrode assembly according to any one of claims 42 to 44, wherein the membrane formed from the elastomeric material is one material selected from the group of: polyurethane, and silicone -polyurethane copolymer. The basket-shaped electrode assembly according to any one of claims 42 to 45, wherein the membrane formed from the medical textile is a tightly knitted, woven or braided textile made from one material selected from the group of: polytetrafluroethylene, expanded polytetrafluroethylene, polyethylene terephthalate and polyester. The basket-shaped electrode assembly according to any one of claims 42 to 46, wherein the membrane formed from a hybrid of the medical textile and the elastomeric material is a loosely knitted, woven or braided textile made from one material selected from the group of: polytetrafluroethylene, expanded polytetrafluroethylene, polyethylene terephthalate and polyester; and wherein the loose textile is coated with the elastomeric material. The basket-shaped electrode assembly according to any one of claims 41 to 47, wherein the proximal locking ring comprises a plurality of proximal cavities 86 circumferentially spaced apart from each other, wherein a proximal cavity is adapted to engage with the proximal end of a spline. The basket-shaped electrode assembly according to claim 48, wherein the distal locking ring comprises a plurality of distal cavities circumferentially spaced apart from each other, wherein a distal cavity is adapted to engage with the distal end of the spline. The basket-shaped electrode assembly according to any one of claims 48 to 49, wherein the proximal end and the distal end of the splines each have a hook element at the respective ends, wherein the hook elements secure the spline to the cavities and to be in electrical connection to the respective conductive wire. The basket-shaped electrode assembly according to any one of claims 41 to 50, wherein the width of the electrode pad is greater than the width of the spline. The basket-shaped electrode assembly according to any one of claims 41 to 51, wherein the electrode pad is in connection between the proximal end and the distal end of a second spline.