Patent Description:
Cardiac arrhythmias can often be corrected by means of ablation, or destroying, of those cardiac cells that originate, support, or otherwise contribute to the propagation of errant conduction pathways or signals in the heart that ultimately interfere with normal cardiac electrical activity and function. For example, arrhythmias in specific cases such as the relatively thin tissue of the atrium may manifest as atrial fibrillation, or, when present in or involving the thicker tissue of the ventricles, may cause other serious conditions such as ventricular tachycardia.

Of the various forms of energy that may be delivered to accomplish tissue ablation, exposure of tissue to pulsed electric fields to produce irreversible electroporation (IRE) is one of the fastest and most controlled. The use of this energy depends on the type of tissue being targeted for ablation and the pulse parameters may need to be tailored specifically to accomplish the desired result. While IRE is effective, it is limited to tissue encompassed by the isopotential surface extent of the electric field threshold for tissue death.

Other forms of ablation such as radiofrequency (RF) use more energy to raise the temperature of the target cells and surrounding tissue until the target cells die. This can be associated with undesired thermal effects outside or even within the target region. However, at even a sub-lethal level of temperature increase, the biological processes associated with these thermal ablations have other desirable characteristics. For example, with the application of heat through RF energy, the cell membranes become more energetic and dynamic with proteins becoming more mobile and ultimately the membranes may in general become easier to disrupt.

In the presence of charge delivery to an electrode, the effect in biological mediums within a cell or the extracellular fluid can be the creation of chemical species capable of inducing cellular damage or death with varying degrees of effect and longevity. The types and total effect can vary according to the manner in which the electrical energy is applied.

Additionally, although the use of pulsed field ablation (PFA) to induce IRE is generally safe and effective, in some cases the voltage required to be applied to the tissue-contacting electrodes may be unacceptably high, due to potential loss of electrical isolation on conductors within the treatment device, which may lead to failure of the device from short circuits and ohmic heating of the conductors within the device.

Documents <CIT>, <CIT> and <CIT> disclose relevant background art.

The invention is defined in the appended independent claim.

The methods described herein do not form part of the invention.

This disclosure provides a method of multiple waveform energy delivery to perform a series of sequential functions on the tissue targeted for ablation. This may include high-amplitude short-pulse-duration biphasic charge-neutral pulses followed by or combined with a series of lower amplitude non-charge-neutral pulses delivered between or in conjunction with the high amplitude pulses. These lower-amplitude pulses may be monophasic or biphasic with a DC offset, such that they impart current flow through the affected tissue. In any case, the pulses should be very short, less than <NUM> microseconds in pulse duration and preferably less than about <NUM> microseconds to avoid induction of arrhythmias. Within such tissues, this DC energy between anode and cathode will produce changes in acid-base balance along with active oxygen species at the anode that will enhance and increase targeted cell death. Such a system will include charge monitoring from the power generator to determine microcoulombs of charge that are imparted to the tissue. Similar but lower-amplitude non-charge-neutral deliveries may also be used to stun tissue. Extremely short, low-amplitude pulses have the potential to impart charge to a targeted tissue site without causing ablation but having the effect of stunning or briefly causing inactivation of these excitable cells.

In one embodiment, a medical system includes: a first treatment device; a second treatment device; and an energy generator in communication with the first and second treatment devices, the energy generator being programmed to: deliver charge-neutral pulses; and deliver non-charge-neutral pulses between the charge-neutral pulses.

In one aspect of the embodiment, the energy generator is further programmed to deliver the charge-neutral pulses at a first amplitude and the non-charge-neutral pulses at a second amplitude, the first amplitude being greater than the second amplitude.

In one aspect of the embodiment, the non-charge-neutral pulses are one of monophasic and biphasic.

In one aspect of the embodiment, the non-charge-neutral pulses have a direct current offset. In one aspect of the embodiment, the system is configured to deliver charge-neutral and non-charge neutral pulses to an area of target tissue, delivery of the non-charge-neutral pulses imparting a charge to the target tissue. In one aspect of the embodiment, the energy generator is further programmed to deliver non-charge-neutral pulses at a third amplitude, the third amplitude being less than each of the first and second amplitudes.

In one aspect of the embodiment, each of the first and second treatment devices includes at least one treatment electrode that is configured to be inserted into an area of target tissue.

In one aspect of the embodiment, the at least one treatment electrode is a needle-shaped electrode.

In one aspect of the embodiment, the at least one treatment electrode is a helical-shaped electrode.

In one aspect of the embodiment, the at least one treatment element is in fluid communication with a fluid source, the at least one treatment element including a plurality of apertures configured to deliver fluid from the fluid source to the area of target tissue.

In one aspect of the embodiment, the energy generator is further programmed to deliver pulsed radiofrequency energy one of concurrently with or independently from the delivery of the non-charge-neutral pulses and the charge-neutral pulses. In one aspect of the embodiment, the pulsed radiofrequency energy is one of unipolar and bipolar, the pulsed radiofrequency energy being delivered for a predetermined period of time before the delivery of the non-charge-neutral pulses and the charge-neutral pulses, the predetermined period of time being sufficient to heat the tissue to a temperature that is lower than a temperature at which tissue ablation occurs.

In one embodiment, a medical system includes: a treatment device including: an elongate body having a proximal portion and a distal portion defining a distal tip; a first electrode, the first electrode defining the distal tip; and a second electrode being configured to at least partially puncture an area of tissue, the second electrode extending distally from the first electrode; and an energy generator in communication with the treatment device, the energy generator being programmed to: deliver charge-neutral pulses through the second electrode, the second electrode being configured to be an anodic electrode during the delivery of non-charge-neutral pulses; deliver non-charge-neutral pulses between the charge-neutral pulses from the second electrode; deliver pulsed radiofrequency energy through the first electrode one of concurrently with and independently from delivery of the non-charge-neutral pulses and the charge-neutral pulses; establish a predetermined charge level; calculate a total amount of charge delivered to the target tissue, the total amount of charge being based on a number and duration of the delivered non-charge-neutral pulses; and automatically adjust delivery of the non-charge-neutral pulses to maintain the predetermined charge level.

In one embodiment, a method for delivering energy to an area of target tissue includes: positioning a first treatment device at a first location relative to the area of target tissue; positioning a second treatment device at a second location relative to the area of target tissue; delivering biphasic charge-neutral pulses between the first and second treatment devices at a first amplitude; and delivering non-charge-neutral pulses between the first and second treatment devices at a second amplitude.

In one aspect of the embodiment, the first amplitude is greater than the second amplitude.

In one aspect of the embodiment, the first amplitude is greater than the second amplitude non-charge-neutral pulses are one of monophasic and biphasic.

In one aspect of the embodiment, the first location is within a first chamber of the patient's heart in contact with endocardial tissue and the second location is within a second chamber of the patient's heart proximate the first location.

In one aspect of the embodiment, the first location is within a chamber of the patient's heart in contact with endocardial tissue and the second location is within a pericardial space around the patient's heart.

In one aspect of the embodiment, the first location is within a chamber of the patient's heart in contact with endocardial tissue and the second location is within one of a coronary arterial blood vessel and a venous blood vessel.

In one aspect of the embodiment, the method further includes, before delivering biphasic charge-neutral pulses between the first and second treatment devices at the first amplitude, delivering energy between the first and second treatment devices, the energy being sufficient to heat cardiac tissue to a temperature of between <NUM> and <NUM>.

In one embodiment, a method for electrolyzing an area of target tissue may include positioning a treatment device having a plurality of electrodes in contact with an area of target tissue, delivering biphasic energy pulses between at least two of the plurality of electrodes to at least one of stun and ablate cells within the area of target tissue, and then delivering at least one of monophasic energy pulses and continuous direct current to the cells within the area of target tissue to ablate the cells within the area of target tissue.

The devices, systems, and methods disclosed herein are for ablating tissue using a multiple waveform energy delivery that may include high amplitude short pulse duration biphasic charge-neutral pulses combined or sequenced with a series of lower amplitude non-charge neutral pulses delivered between or in conjunction with the high amplitude pulses. These lower amplitude pulses may be monophasic or biphasic with a DC offset, such that they impart current flow through the affected tissue. In any case, the pulses should be very short, less than <NUM> microseconds in pulse duration and preferably less than about <NUM> microseconds to avoid induction of arrhythmias. Within such tissues, this DC energy between anode and cathode will produce changes in acid-base balance along with active oxygen species at the anode that will enhance and increase targeted cell death. Such a system will include charge monitoring from the power generator to determine micro coulombs of charge that are imparted to the tissue. Similar but lower amplitude non charge neutral deliveries may also be used. Extremely short, biphasic, high-amplitude, high-voltage, charge-neutral pulses may be delivered to ablate or incapacitate an area of tissue, and may also have the effect of stunning tissue beyond the area of ablation. Non-charge-neutral, low-amplitude, monophasic energy may then be delivered to the same area of tissue to further ablate or incapacitate the tissue. Delivering non-charge-neutral energy may have arrhythmogenic effects; however, this energy may be delivered safely due to the inactivation of the tissue by the previously delivered short, biphasic, high-amplitude energy. Further, toxic compounds generated by the non-charge-neutral energy may extend the area of ablation even deeper into the tissue. The method may also include optimizing tissue for electroporation by the delivery of energy, such as relatively low voltage AC pulsed currents, continuous RF, and/or pulsed RF or microwave energy, to heat the tissue before, during, or after delivering monophasic and/or biphasic electroporation energy.

Before describing in detail exemplary embodiments that are in accordance with the disclosure, it is noted that components have been represented where appropriate by conventional symbols in drawings, showing only those specific details that are pertinent to understanding the embodiments of the disclosure so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having the benefit of the description herein.

As used herein, relational terms, such as "first," "second," "top" and "bottom," and the like, may be used solely to distinguish one entity or element from another entity or element without necessarily requiring or implying any physical or logical relationship or order between such entities or elements.

In addition, the term "in fluid communication with" may be used to describe a fluid pressure or flow connection between points, such as a fluid connection on the handle of a device that delivers fluid through a passage in the catheter to an electrode or distal site on the device.

Referring now to the drawing figures in which like reference designations refer to like elements, an embodiment of a medical system is shown in <FIG>, generally designated as "<NUM>. " The device components have been represented where appropriate by conventional symbols in the drawings, showing only those specific details that are pertinent to understanding the embodiments of the present invention so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having the benefit of the description herein. Moreover, while certain embodiments or figures described herein may illustrate features not expressly indicated on other figures or embodiments, it is understood that the features and components of the system and devices disclosed herein are not necessarily exclusive of each other and may be included in a variety of different combinations or configurations.

As noted above, the effectiveness of IRE may depend on the isopotential surface extent of the electric field threshold for tissue death. When performing electroporation, there is a region nearest the delivering electrodes that may experience an electrical field sufficient to cause cell death. Beyond that is a region that has been subjected to electroporation, but at a level that is reversible and, therefore, the cells will restore their function. Beyond that reversibly electroporated region is tissue that only experiences minimal, if any, effects from the applied field. Within this secondary region, where the cells have increased permeability for treatment, a pulsing routine such as described below capable of producing toxic chemical species both within the cells and intracellular space can expand the permanently ablated region. The regions with increased permeability allow for the uptake of these damaging chemical species and can reduce the survival of the reversible region and potentially beyond. This can for example allow for an ultimately deeper and/or larger lesion for treating arrhythmias in thicker cardiac tissue or during irreversible ablation of cells in other target tissue.

When applying electric pulses or electric currents to the excitable cells of the cardiac myocardium, care must be taken to avoid generation of arrhythmias or aberrant cardiac conduction. Methods by which this may be accomplished include: <NUM>) the delivery of extremely short pulses that have a pulse width and amplitude which is insufficient to produce cardiomyocyte depolarization; <NUM>) initial delivery of charge-neutral (or balanced charge) biphasic pulses to stun and/or ablate tissue before delivering monophasic or continuous direct current; <NUM>) delivery of localized charge imbalances with an overall charge balance maintained in the heart; <NUM>) periodically alternating the electrodes serving as anode versus cathode in order to alternate the type of chemistry created at each electrode; and <NUM>) a system to monitor and control the amount of charge delivered to the tissue with automation to adjust the level of pulse imbalance to maintain a desired or predetermined charge level.

Additional means may be employed to enhance the effectiveness of such enhanced ablations. One preferred method may include delivery of electrodes to within the distal arterial circulation to add cytotoxic electrolysis products to the blood supply being delivered to the targeted tissues to enhance the ablative effect of electric field exposure. In addition, dual electrode bipolar helix or needle electrodes may be employed to produce localized lethal chemical milieu deeper within the ventricular myocardium to enhance the ablative effects of electric field exposure.

In addition to or instead of the production of toxic chemical species, the target tissue may be heated prior to, during, and/or after the delivery of electroporation energy in order to enhance the effectiveness of the electroporation procedure. For example, tissue may be heated by delivering relatively low voltage AC pulsed currents, continuous radiofrequency, and/or pulsed radiofrequency or microwave energy before, during, and/or after the delivery of electroporation energy.

One embodiment of the system <NUM> may generally include a first treatment device <NUM> and a second treatment device <NUM> in communication with a control unit or energy source, such as a radiofrequency pulsed field ablation energy generator <NUM> (for example, as shown in <FIG>). In another embodiment, the system <NUM> may generally include a single treatment device <NUM> and a generator <NUM> (for example, as shown in <FIG>). The generator <NUM> may be configured to deliver both high amplitude short pulse duration biphasic charge-neutral pulses and lower amplitude non-charge neutral pulses delivered. In one embodiment, the generator <NUM> may additionally be configured to deliver pulsed radiofrequency energy sufficient to heat tissue to a target temperature.

Each of the first <NUM> and second <NUM> treatment devices (or, alternatively, the single treatment device <NUM>) may include an elongate body <NUM>, <NUM>' passable through a patient's vasculature and/or proximate to a tissue region for diagnosis or treatment. For example, the treatment device(s) <NUM>, <NUM> may be catheters that can access various cardiac locations, such as the atria, the ventricles, and/or the pericardial space, by such delivery means as femoral, radial, and/or sub-xiphoid access. Each elongate body <NUM>, <NUM>' may define a proximal portion <NUM>, <NUM>', a distal portion <NUM>, <NUM>', and a longitudinal axis <NUM>, <NUM>', and may further include one or more lumens disposed within the elongate body <NUM>, <NUM>' that provide mechanical, electrical, and/or fluid communication between the elongate body proximal portion <NUM>, <NUM>' and the elongate body distal portion <NUM>, <NUM>'. For example, the elongate body <NUM>, <NUM>' may include a central lumen <NUM>, <NUM>'.

In the non-limiting system example shown in <FIG>, each treatment device <NUM>, <NUM> may include at least one electrode <NUM> that is configured to at least partially puncture or be inserted into myocardial tissue (which may be referred to herein as an invasive electrode). The at least one invasive electrode <NUM> may be configured to be retracted into and extended from the distal end of the elongate body or may be in a fixed position at the distal end of the elongate body. As a non-limiting example, the first treatment device <NUM> may include a needle-like or needle-shaped energy delivery electrode <NUM> and the second treatment device <NUM> may include a helical-shaped energy delivery electrode <NUM>' that is configured to be rotated (or screwed) into the target tissue (for example, as shown in <FIG>). Alternatively, the first treatment device <NUM> may include the helical energy delivery electrode <NUM> and the second treatment device <NUM> may include the needle-like energy delivery electrode <NUM>', or both treatment devices <NUM>, <NUM> may have the same type of electrode <NUM>, <NUM>'. Further, other suitable types of electrodes may be used for delivering the energy in the manner discussed herein. For example, each device may include one or more electrodes <NUM> that are configured for the delivery of treatment energy but that are not configured to be embedded or inserted within tissue, which may be referred to herein as "flat" electrodes 40A (as shown in <FIG>, <FIG>, and <FIG>). Additionally, each device may also include a distal tip electrode 40B (as shown in <FIG>, <FIG>, <FIG>, and <FIG>). When referring to electrodes in general, rather than specifically to <NUM>', 40A, 40A', 40B, or 40B', reference number "<NUM>" may be used herein for simplicity. The electrode(s) <NUM> may be composed of any suitable material, such as one or more electrically conductive metals, including gold, platinum, platinum-iridium alloy, tantalum, silver, silver-chloride, and/or tantalum with various forms of tantalum oxide surfaces. Although the distal ends <NUM>, <NUM>' of the devices <NUM>, <NUM> are shown as having a fixed diameter (for example, focal catheters), it will be understood that the electrodes <NUM> may additionally or alternatively be on an expandable portion of the device(s), such as an expandable balloon.

When only one device <NUM> is used to deliver energy (for example, the device shown in <FIG>), the device <NUM> may include more than one electrode <NUM>, and adjacent electrodes <NUM> may have opposite polarities. However, when the intent is to create electrochemical products of the direct electric current, some physical separation may be maintained between the electrode(s) serving as the anode(s) and the electrode(s) serving as the cathode(s), such that the chemical moieties created at the anode(s) remain relatively contained within the targeted region of tissue and unable to readily mix with the chemical milieu created at the cathodic electrode(s). This may allow for the greatest tissue cytotoxic effect from the locally created chemicals. Additionally, one or both anode and cathode electrodes may be embedded in some way within the tissue. For example, if the electrode <NUM> is in the form of a needle (such as that shown in <FIG> and <FIG>), the electrode <NUM> may be able to penetrate into the tissue, or an electrode of the device <NUM> may be delivered into the lumen of a distal artery where the blood perfusion flow targets the desired area to be ablated.

Further, each invasive electrode may be configured to deliver hypertonic solution, such as a hypertonic and ionic solution, and/or a solution containing a high calcium concentration, to the target treatment site to enhance the formation of lethal chemical byproducts at the site. As a non-limiting example, at least one invasive electrode <NUM> may be in fluid communication with a fluid source, the fluid source containing one or more hypertonic and ionic solutions, and the at least one invasive electrode <NUM> may have one or more orifices or apertures <NUM> through which the solution may pass to the tissue site (for example, as shown in <FIG>).

Still further, each device <NUM>, <NUM> may include more than one type of electrode for delivering more than one type of energy. As a non-limiting example, the system may include a single device <NUM> that includes both an invasive electrode <NUM> and a distal tip electrode 40B (as shown in <FIG>). As a non-limiting example, the flat electrode 40B may define the distal tip of the device and the invasive electrode <NUM> may extend distally from the flat electrode 40B. A device having such a configuration may be able to deliver both pulsed RF energy with the distal tip electrode 40B and pulse combinations (for example, high-voltage, short-pulse-duration, biphasic, charge-neutral pulses combined with a series of lower-amplitude, non-charge-neutral pulses delivered between the high-amplitude pulses) with the invasive electrode <NUM>. The flat electrode 40B may also be able to deliver energy for heating the tissue, such as relatively low voltage AC pulsed currents, continuous RF, and/or pulsed RF or microwave energy. The invasive electrode <NUM> and the distal tip electrode 40B may be activated to deliver energy simultaneously, in series, or in an alternative fashion during a single treatment procedure.

Each device <NUM>, <NUM> may include a handle <NUM> coupled to the elongate body proximal portion <NUM>. Each handle <NUM> may include circuitry for identification and/or use in controlling of the treatment device(s) <NUM>, <NUM> or another component of the system <NUM>. Additionally, the handle <NUM> may also include connectors that are mateable to the control unit <NUM> to establish communication between the device(s) <NUM>, <NUM> and one or more components or portions of the control unit <NUM>. The handle <NUM> may also include one or more actuation or control features that allow a user to control, deflect, steer, or otherwise manipulate a distal portion of the device(s) <NUM>, <NUM> from the proximal portion of the device. For example, the handle <NUM> may include one or more components such as a lever or knob for manipulating the elongate body <NUM> and/or additional components of the device(s) <NUM>, <NUM>.

The system <NUM> may include other components such as a navigation system, an imaging system, or other system components or add-on components for collecting and conveying information from and to the user, for delivering treatment energy to the patient, and/or for collecting data from the tissue or other parts of the patient and/or system. The generator <NUM> may include one or more controllers, software modules, and/or processing circuitry <NUM> configured to execute instructions or algorithms to provide for the automated operation and performance of the features, sequences, calculations, or procedures described herein and/or required for a given medical procedure. In one embodiment, the processing circuitry <NUM> may include a processor and a memory. The memory may be in electrical communication with the processor and have instructions that, when executed by the processor, configure the processor to receive, process, or otherwise use signals from the device(s) <NUM>, <NUM>. Further, the processing circuitry <NUM> may include a charge monitoring device <NUM> to calculate a total amount of change (for example, in microcoulombs) that is delivered to the tissue.

Although not shown, the system <NUM> may include one or more sensors to monitor the operating parameters throughout the system, including for example, pressure, temperature, flow rates, volume, power delivery, impedance, pH level, or the like in the control unit <NUM> and/or the treatment device(s) <NUM>, <NUM>, in addition to monitoring, recording or otherwise conveying measurements or conditions within the device(s) <NUM>, <NUM> and/or the ambient environment at the distal portion of the device(s) <NUM>, <NUM>. The sensor(s) may be in communication with the control unit <NUM> for initiating or triggering one or more alerts or therapeutic delivery modifications during operation of the device(s) <NUM>, <NUM>. One or more valves, controllers, or the like may be in communication with the sensor(s) to provide for the controlled dispersion or circulation of fluid through the lumens/fluid paths of the device. Such valves, controllers, or the like may be located in a portion of the device(s) and/or in the control unit <NUM>.

The generator <NUM> may be configured to deliver high-voltage, high-amplitude, short-pulse-duration, biphasic, charge-neutral pulses combined with a series of lower-amplitude, non-charge-neutral pulses delivered between the high-amplitude pulses. This delivery scheme may be referred to herein as a pulse combination. Such pulse combinations may include the delivery of single high-amplitude biphasic pulses of short pulse duration (of, for example, a duration of <NUM>), each followed by a low-amplitude monophasic pulse (of, for example, a duration of <NUM>) or a series of low-amplitude monophasic pulses (of, for example, a pulse duration of <NUM>). In another embodiment, a continuous series of, for example, <NUM> biphasic high-amplitude, (of, for example, greater than <NUM> V), short-pulse-duration pulses may be delivered, followed by a series of low-amplitude (of, for example, less than <NUM> V) monophasic pulses. The lower amplitude pulses may be monophasic or biphasic with a direct current (DC) offset, or unbalanced biphasic pulses, such that they impart charge to the target tissue. Within the affected target tissue, this DC current may produce changes in the tissue's acid-base and may produce certain active oxygen species that may enhance and increase targeted cell death. That is, the delivery of DC current through the tissue may result in electrolysis, which produces chemically active molecules that enhance tissue necrosis in the region of tissue in which they are generated. Different chemical reactions take place at the anode and at the cathode, which may result in different chemical species produced at each. The anode produces oxidative reactions and a low pH, while the cathode produces a high-pH, reducing chemical environment. Additionally, in alternating or subsequent pulse combinations, the charge balance may be reversed and/or reduced with subsequent deliveries in the procedure creating competing cytotoxic species that act differently for effecting cell death or competing with remaining species at the effective positive or negative electrode locations (subsequently reversed) to cease or minimize further damage from the initial electrolyzing. A complex variety of peroxides, hydroperoxides, nitrogen oxides, chlorates, as well as reactive compounds containing phosphorous, sulfur nitrogen, and/or various metal ion components may be formed, which are highly cytotoxic. The effects of these chemical species may be enhanced by inserting the treatment electrode(s) <NUM> into the tissue, such as by those configurations shown in <FIG>, <FIG>, <FIG>, and <FIG>. This method of energy delivery may enhance lesion formation without arrhythmogenic consequences within relatively thick target tissues, such as in the ventricles. The generator <NUM> may also be configured to deliver similar, but of lower-amplitude, charge-neutral pulses to stun and/or ablate the target tissue. Extremely short (for example, between approximately <NUM> to <NUM> in duration), lower-amplitude pulses delivered at a rate of between approximately <NUM> and <NUM> may have the potential to impart charge to a target tissue site, thereby ablating at least a portion of the target tissue site and stunning at least a portion of the target tissue site beyond the ablated portion. This cellular inactivation may help prevent the inducement of arrhythmia in the tissue as a result of subsequent ablation energy delivery.

The generator <NUM> may also be configured to deliver energy for heating tissue, such as relatively low voltage AC pulsed currents (of, for example, less than <NUM> V), continuous RF, and/or pulsed RF or microwave energy, before, during, or after delivering monophasic and/or biphasic electroporation energy.

<FIG> show waveforms of energy that may be delivered to induce electroporation of myocardial cells. The waveforms represent voltage delivered (y-axis) over time (x-axis). <FIG> shows a configuration that imparts charge to the tissue by omission of the reversed biphasic components later in a pulse train or in subsequently applied trains, as long as the net charge, relative positive charge versus negative charge, is sufficiently different between the phases to result in aggregated charge in the target tissue. <FIG> shows exemplary pulsed RF energy delivery to warm tissue, then biphasic energy pulses for stunning and/or ablating the tissue, and monophasic pulses delivered thereafter for inducing electrolysis (to further ablate the tissue). <FIG> shows a waveform of a typical monophasic energy delivery.

<FIG> show exemplary waveforms of biphasic and/or monophasic energy pulses used as discussed herein to induce or enhance electrolysis without inducing further or additional cardiac arrhythmia. The waveforms shown in <FIG> include a DC offset as discussed herein and/or different ways of unbalancing the delivered charge, whether in the same train or sequentially. For example, <FIG> shows a monophasic waveform that includes a DC offset, <FIG> shows a biphasic waveform that includes a DC offset, <FIG> shows a monophasic waveform with concurrent delivery of DC energy, <FIG> shows an asymmetric biphasic waveform, and <FIG> shows an asymmetric biphasic waveform in which the relative anode versus cathode is reversed.

Turning to <FIG>, various methods of destroying target tissue through electroporation are shown generally and described. In general, these methods involve one or more steps to "prime" or optimize the target tissue for electroporation, thereby increasing the depth and volume of tissue that is ablated by delivery of electroporation energy. For example, this tissue optimization may involve the delivery of biphasic, non-charge-neutral energy to create toxic chemical byproducts and/or may involve the application of energy, such as pulsed RF energy, to heat the tissue. Both or either of which may lower the threshold electric field strength at which cells will incur irreversible membrane damage and, therefore, cell death. This, in turn, may reduce the amount of voltage that is required to induce irreversible electroporation and reduce the likelihood of device and/or generator faults or failure. Further, one or both of these methods of tissue optimization may be used in a given procedure, and they may be used before, during, and/or after the delivery of electroporation energy. For example, cells may experience a period of increased permeability even after the delivery of electroporation energy has ended. Therefore, the creation of toxic chemical byproducts and/or application of heat to electroporated tissue may still enhance overall treatment results.

Referring to <FIG>, a general method of treating tissue with one or two devices is shown. In the first step <NUM>, a first device <NUM> and a treatment <NUM> device may be positioned within the patient's body at one or more locations that will result in the delivery of treatment energy to tissue at the target treatment location. For example, the devices <NUM>, <NUM> may be treatment devices. In a second step <NUM>, energy may be delivered between the first <NUM> and second <NUM> devices to optimize tissue at the target treatment location for ablation. In one embodiment, energy may be delivered between the first <NUM> and second <NUM> devices to stun and/or ablate the tissue between the first <NUM> and second <NUM> devices, which includes tissue at the target treatment location. For example, extremely short, biphasic, high-amplitude, high-voltage, charge-neutral pulses may be delivered to tissue at the target treatment site. In addition to reducing the risk of generating an arrhythmia with the delivery of charge-neutral ablation energy, this energy delivery may be used to determine optimal target ablation sites before commencement of the delivery of additional ablation energy. The energy delivered in the second step <NUM> does not impart charge to the tissue. Additionally or alternatively, in another embodiment, pulsed RF energy may be delivered between the first <NUM> and second <NUM> devices to heat the tissue to a temperature that is generally lower than a temperature at which hypothermal tissue ablation occurs, but to a temperature that is high enough to enhance tissue ablation by electroporation.

In the third step <NUM>, energy may be delivered between the first <NUM> and second <NUM> devices to ablate or further ablate, such as electroporate, the tissue at the target treatment location. The second step <NUM> is shown in <FIG> as occurring before the third step <NUM> for simplicity; however, the second step <NUM> may occur before, during, and/or after the third step <NUM>. In some embodiments, the second <NUM> and third <NUM> steps may occur as a single treatment step. For example, the single treatment step combining the second <NUM> and third <NUM> steps may include using the first <NUM> and second <NUM> devices to deliver high-amplitude, short-pulse-duration, biphasic, charge-neutral pulses combined with a series of lower-amplitude, non-charge-neutral pulses delivered between the high-amplitude pulses, in order to electroporate the target tissue and to induce formation of cytotoxic chemical species to be taken up by the permeabilized cells.

In an optional fourth step <NUM>, the charge monitoring device <NUM> may calculate the total amount of energy delivered to the target tissue throughout the procedure. Thus, the delivered energy may be recorded at all stages of the procedure in which energy is delivered to the tissue. The processing circuitry <NUM> may be configured to establish or determine a total amount of delivered energy at which the processing circuitry <NUM> may automatically cease the delivery of ablation energy or at which the system <NUM> will alert the user to manually end the delivery of ablation energy (which may be referred to herein as a predetermined charge threshold). If the total amount of delivered energy is equal to or greater than the predetermined charge threshold, the processing circuitry <NUM> may automatically cease the delivery of ablation energy or will alert the user to manually end the delivery of ablation energy. Further, the processing circuitry <NUM> may be configured to use data about the total amount of delivered energy to confirm that the required DC offset is being delivered, to confirm that the delivered charge is not excessive enough to obscure EGM recordings and/or to provide feedback to the user that the user may expect a transient impact on the EGM recordings of an EP device, and/or to confirm that the total amount of delivered charge is not excessive (for example, that an amount capable of causing arrhythmia or death is not being delivered to the patient).

Although <FIG> shows a method using two devices <NUM>, <NUM>, the method may be performed using only one device <NUM>. In that case, the monophasic deliveries may be delivered in a bipolar manner. To accomplish this, the device may include more than one electrode <NUM> (for example, the flat electrodes as shown in <FIG>), and adjacent electrodes <NUM> may have opposite polarities. However, when the intent is to create electrochemical products of the direct electric current, some physical separation may be maintained between the electrode(s) serving as the anode(s) and the electrode(s) serving as the cathode(s), such that the chemical moieties created at the anode(s) remain relatively stagnant in the tissue and unable to readily mix with the chemical milieu created at the cathodic electrode(s). This may allow for the greatest tissue cytotoxic effect from the locally created chemicals. Additionally, one or both anode and cathode electrodes may be embedded in some way within the tissue. For example, if the electrode <NUM> is in the form of a needle (such as that shown in <FIG> and <FIG>), the electrode <NUM> may be able to penetrate into the tissue, or an electrode of the device <NUM> may be delivered into the lumen of a distal artery where the blood perfusion flow targets the desired area to be ablated.

As a first non-limiting example of a method of treatment according to <FIG>, the first treatment device <NUM> may be positioned within the heart on an endocardial surface. If the first treatment device <NUM> includes an electrode <NUM> that is configured to be inserted into the tissue, the distal portion of the device and the electrode <NUM> may be manipulated to insert or screw the electrode into the target tissue. Alternatively, if the device <NUM> includes one or more flat electrodes <NUM>, the distal portion of the device may be positioned such that the flat electrodes <NUM> are in contact with the target tissue. The second treatment device <NUM> may be positioned on the opposing wall of the heart from the location of the first treatment device <NUM>, in a different heart chamber. The electrode(s) <NUM> of the second treatment device <NUM> may be positioned similar to those of the first treatment device <NUM>. One of the two treatment devices may serve as an anode and the other of the two treatment devices may serve as a cathode. However, when a biphasic pulse is delivered, each may serve as the anode and cathode during some phase of the energy delivery (that is, the roles of anode and cathode may alternate during biphasic pulse delivery). Pulsed DC energy may be delivered between the two devices <NUM>, <NUM>, thus producing electrolysis within the intervening tissues.

In a second non-limiting example of a method of treatment according to <FIG>, the first treatment device <NUM> may be positioned within the patient's body at one or more locations that will result in the delivery of treatment energy in the target treatment site(s). As a non-limiting example, the first treatment device <NUM> may be positioned within the heart on an endocardial surface. If the first treatment device <NUM> includes an electrode <NUM> that is configured to be inserted into the tissue, the distal portion of the device and the electrode <NUM> may be manipulated to insert or screw the electrode into the target tissue. Alternatively, if the device <NUM> includes one or more flat electrodes <NUM>, the distal portion of the device may be positioned such that the flat electrodes <NUM> are in contact with the target tissue. The second treatment device <NUM> may be positioned within a coronary arterial or venous blood vessel. Pulsed DC energy may be delivered between the two devices <NUM>, <NUM>, thus producing electrolysis within the intervening tissues. The current flow could be preferentially directed such that the device functioning as the anode is located closest to the tissue targeted for ablation.

In a third example of a method of treatment according to <FIG>, the first treatment device <NUM> may be positioned within the patient's body at one or more locations that will result in the delivery of treatment energy in the target treatment site(s). As a non-limiting example, the first treatment device <NUM> may be positioned within the heart on an endocardial surface. If the first treatment device <NUM> includes an electrode <NUM> that is configured to be inserted into the tissue, the distal portion of the device and the electrode <NUM> may be manipulated to insert or screw the electrode into the target tissue. Alternatively, if the device <NUM> includes one or more flat electrodes <NUM>, the distal portion of the device may be positioned such that the flat electrodes <NUM> are in contact with the target tissue. The second treatment device <NUM> may be positioned within the pericardial space, in contact with the epicardium. Likewise, if the first treatment device <NUM> includes an electrode <NUM> that is configured to be inserted into the tissue, the distal portion of the device and the electrode <NUM> may be manipulated to insert or screw the electrode into the target tissue. A non-limiting example of device <NUM>, <NUM> positioning is shown in <FIG>, in which a first device <NUM> is located proximate the endocardial surface and includes an invasive electrode <NUM> that is inserted into the myocardial tissue, and the second device <NUM> is located proximate the epicardial surface or within the pericardial space and also includes an invasive electrode <NUM>' that is inserted into the myocardial tissue. Pulsed DC energy may be delivered between the two devices <NUM>, <NUM>, thus producing electrolysis within the intervening tissues. The current flow could be preferentially directed such that the device functioning as the anode is located closest to the tissue targeted for ablation.

Referring now to <FIG>, exemplary methods are shown and described in more detail. A method of treating tissue using two devices and optimizing the tissue using heat is shown in <FIG>. In addition to or instead of optimization method discussed above in the third step <NUM> of <FIG>, one or both devices <NUM>, <NUM> may be used to deliver pulsed RF energy for a predetermined time period, the predetermined time being sufficient to heat the cells to a target temperature. Heating the tissue may reduce the threshold electric field strength of the tissue that is required to cause irreversible cell membrane damage. The temperature increase required, and thus the target temperature, to achieve increased electroporation effectiveness may be less than the minimum temperature that would be required to achieve cell death by thermal means alone (approximately <NUM>). Further, in circulating blood, an electrode-tissue interface temperature of approximately <NUM> is accepted as not producing blood protein denaturation or other injurious effects. In one embodiment, the tissue may be optimized by heating to a temperature of at least approximately <NUM>° C and as high as approximately <NUM>. That is, the tissue may be heated to a temperature of between approximately <NUM> and approximately <NUM>. At these temperatures, the sub-lethal heat may be driven as deep as possible into the target tissue, which may thereby increase the depth of electroporation ablation. To heat the tissue, the device(s) may deliver relatively low voltage AC pulsed currents, continuous RF or pulsed RF or microwave energy. After the first and second devices <NUM>, <NUM> may be positioned at one or more target treatment locations in the first step <NUM>, one or both device(s) <NUM>, <NUM> may be used to deliver (for example, to deliver simultaneously) pulsed RF energy to heat the cells at the target treatment location in the second step <NUM> prior to ablation. For example, the energy delivered in the second step <NUM> may have the waveform shown in the first portion of <FIG>. In one embodiment, the pulsed RF energy is delivered for a predetermined time before the delivery of the non-charge-neutral pulses and the charge-neutral pulses, the predetermined period of time being sufficient to heat the tissue to a temperature of at least approximately <NUM>° C and up to approximately <NUM>. In another embodiment, the generator includes a feedback system that monitors a temperature recorded by one or both device(s) <NUM>, <NUM> to ensure the tissue is not overheated above a temperature of at least approximately <NUM> and up to approximately <NUM>.

In the third step <NUM>, high-voltage, short-pulse-duration, biphasic, charge-neutral pulses may be delivered between the devices <NUM>, <NUM> to incapacitate the tissue between the devices <NUM>, <NUM> at the target treatment location. In the fourth step <NUM>, non-charge-neutral pulsed energy may then be delivered between the devices <NUM>, <NUM> to ablate the tissue located between the devices <NUM>, <NUM> at the target treatment location. Additional pulsed RF energy may optionally be delivered after all delivery of electroporation energy has ended. The third step <NUM> is shown in <FIG> as occurring before the fourth step <NUM> for simplicity; however, the third step <NUM> may occur before, during, and/or after the fourth step <NUM>. In some embodiments, the third <NUM> and fourth <NUM> steps may occur as a single treatment step. For example, the high-voltage, short-pulse-duration, biphasic, charge-neutral pulses of the third step <NUM> may be delivered sequentially with, simultaneously with, or alternating with the series of lower-amplitude, non-charge-neutral pulses of the fourth step <NUM>.

In an optional fifth step <NUM>, the charge monitoring device <NUM> may calculate the total amount of energy delivered to the tissue at the target treatment location throughout the procedure and compare the total amount of delivered energy to the predetermined charge threshold. Thus, the delivered energy may be recorded at all stages of the procedure in which energy is delivered to the tissue. The processing circuitry <NUM> may be configured to establish or determine a total amount of delivered energy at which the processing circuitry <NUM> may automatically cease the delivery of ablation energy or at which the system <NUM> will alert the user to manually end the delivery of ablation energy (which may be referred to herein as a predetermined charge threshold). If the total amount of delivered energy is equal to or greater than the predetermined charge threshold, the processing circuitry <NUM> may automatically cease the delivery of ablation energy or will alert the user to manually end the delivery of ablation energy. Further, the processing circuitry <NUM> may be configured to use data about the total amount of delivered energy to confirm that the required DC offset is being delivered, to confirm that the delivered charge is not excessive enough to obscure EGM (intracardiac electrogram) recordings and/or to provide feedback to the user that the user may expect a transient impact on the EGM recordings of an EP device, and/or to confirm that the total amount of delivered charge is not excessive (for example, that an amount capable of causing arrhythmia or death is not being delivered to the patient).

Referring now to <FIG>, a flow chart for a further exemplary method of delivery energy to tissue is shown. In the method of <FIG>, a single device <NUM> having a plurality of electrodes <NUM> is used at a location remote from the target treatment location. Adjacent electrodes <NUM> of the plurality of electrodes <NUM> may have opposite polarities. In the first step <NUM>, the device <NUM> may be positioned within the patient's body at one or more locations that will result in the delivery of treatment energy in the target treatment site(s). In one embodiment, the device <NUM> is positioned within an arterial blood vessel of the heart, such as within a distal coronary artery, proximate a target treatment location within the heart. In the second step <NUM>, high-voltage, short-pulse-duration, biphasic, charge-neutral pulses may be delivered between the plurality of electrodes <NUM><NUM> to stun and/or ablate the tissue. The coronary arteries extend from the aorta to the outside of the heart, thereby supplying blood to the heart. The device <NUM> may be positioned within a coronary artery, and any toxins produced by the delivery of energy by the device <NUM> at this location may have a desired effect on the tissue at the target treatment location.

In the third step <NUM>, the device <NUM> may deliver lower-amplitude, non-charge-neutral, pulsed energy between the plurality of electrodes <NUM> while in place within the coronary artery to ablate the tissue at the target treatment location. In an optional fourth step <NUM>, the charge monitoring device <NUM> may calculate the total amount of energy delivered to the tissue at the target treatment location throughout the procedure and compare the total amount of delivered energy to the predetermined charge threshold. If the total amount of delivered energy is equal to or greater than the predetermined charge threshold, the processing circuitry <NUM> may automatically cease the delivery of ablation energy or will alert the user to manually end the delivery of ablation energy.

Referring now to <FIG>, a flow chart for a further exemplary method of delivery energy to tissue is shown. In the method of <FIG>, a first device <NUM> is used at a location remote from the target treatment location and a second device <NUM> is used at the target treatment location. In the first step <NUM>, the device <NUM> may be positioned within the patient's body at one or more locations that will result in the delivery of treatment energy in the target treatment site(s). In one embodiment, the device <NUM> is positioned within an arterial blood vessel of the heart, such as within a distal coronary artery, proximate a target treatment location within the heart. In the second step <NUM>, the second device <NUM> is positioned at or proximate the target treatment location. Each of the first <NUM> and second <NUM> devices may include one or a plurality of electrodes <NUM>. In one embodiment, the target treatment location may be at a location within the left ventricle of the heart. A non-limiting example of device <NUM>, <NUM> placement is shown in <FIG>, in which the first device <NUM> is within the left ventricle and the second device <NUM> is within the coronary artery.

In a third step <NUM>, high-voltage, short-pulse-duration, biphasic, charge-neutral pulses may be delivered between first <NUM> and second <NUM> devices to stun and/or ablate tissue between the first <NUM> and second <NUM> devices, which may include tissue at the target treatment location. For example, energy may be delivered between selected one or more of the plurality of electrodes <NUM> on the first device and one or more electrodes of the plurality of electrodes <NUM> on the second device <NUM> to stun and/or ablate tissue at the target treatment location. In the fourth step <NUM>, lower-amplitude, non-charge-neutral, pulsed energy may be delivered from or between one or more of the plurality of electrodes <NUM> of the second device <NUM> to ablate the tissue at the target treatment location. In the fifth step <NUM>, high-voltage, short-pulse-duration, non-charge-neutral energy may be delivered between one or more of the plurality of electrodes <NUM> of the first device <NUM> (for example, anodic electrodes) and one or more of the plurality of electrodes <NUM> of the second device <NUM> to further stun and/or ablate tissue at the target treatment location. In an optional sixth step <NUM>, the charge monitoring device <NUM> may calculate the total amount of energy delivered to the tissue at the target treatment location throughout the procedure and compare the total amount of delivered energy to the predetermined charge threshold. If the total amount of delivered energy is equal to or greater than the predetermined charge threshold, the processing circuitry <NUM> may automatically cease the delivery of ablation energy or will alert the user to manually end the delivery of ablation energy.

As a non-limiting example, the first treatment device <NUM> may be positioned within the heart on an endocardial surface. If the first treatment device <NUM> includes an electrode <NUM> that is configured to be inserted into the tissue, the distal portion of the device and the electrode <NUM> may be manipulated to insert or screw the electrode into the target tissue. Alternatively, if the device <NUM> includes one or more flat electrodes <NUM>, the distal portion of the device may be positioned such that the flat electrodes <NUM> are in contact with the target tissue. The second treatment device <NUM> may be positioned on the opposing wall of the heart from the location of the first treatment device <NUM>, in a different heart chamber. The electrode(s) <NUM> of the second treatment device <NUM> may be positioned similar to those of the first treatment device <NUM>. One of the two treatment devices may serve as an anode and the other of the two treatment devices may serve as a cathode. However, when a biphasic pulse is delivered, each may serve as the anode and cathode during some phase of the energy delivery (that is, the roles of anode and cathode may alternate during biphasic pulse delivery). Pulsed DC energy may be delivered between the two devices <NUM>, <NUM>, thus producing electrolysis within the intervening tissues.

The devices, systems, and methods disclosed herein may be used to treat existing cardiac arrhythmias without inducing further or additional arrhythmias. To accomplish this, short pulses of energy may be delivered to the target tissue, and biphasic pulses may be delivered initially to immobilize the underlying myocytes. A localized charge imbalance may be induced to create a local toxic chemical environment, but that creates an overall charge balance within the heart. Further, alternating anode/cathode energy delivery configurations may be used to enhance cell death using one, and then the other electrode polarity to produce both chemical species at each electrode site. The system may also be used to monitor and control the amount of charge delivered to the tissue. As a non-limiting example, the processing circuitry <NUM> may configured to calculate a total amount of charge delivered to the target tissue during the entire treatment procedure, or at least a portion of the treatment procedure, and to automatically adjust the level of pulse imbalance to maintain a desired or predetermined charge level. The total amount of charge may be based on, for example, the number and duration of non-charge-neutral pulses delivered to the target tissue.

The devices, systems, and methods disclosed herein may also be used to enhance the effects of ablation. For example, a needle-shaped or helical-shaped energy delivery electrode may be used to deliver hypertonic and ionic solution(s) to the target tissue site. Further, one or more invasive electrodes may be inserted into the myocardial tissue, thereby producing localized lethal chemical products deeper within the myocardium. Still further, the system and device(s) may be used to produce electrolysis products within a distal arterial supply, which products may then travel to the target myocardial tissue to enhance the effects of the cardiac ablation. Combinations of any or all of these techniques may be used to, for example, deliver energy between electrodes in arteries, between and/or from invasive electrodes, and/or between and/or from endocardial electrodes and/or epicardial electrodes.

Claim 1:
A medical system (<NUM>), the system comprising:
a first treatment device (<NUM>) including at least one treatment electrode (<NUM>) selected from the group consisting of a needle-shaped electrode and a helical-shaped electrode;
a second treatment device (<NUM>) including at least one treatment electrode (<NUM>') selected from the group consisting of a needle-shaped electrode and a helical-shaped electrode; and
an energy generator (<NUM>) in communication with the first and second treatment devices, the energy generator being programmed to:
deliver charge-neutral pulses; characterized in that the energy generator is further programmed to
deliver non-charge-neutral pulses between the charge-neutral pulses, wherein
the charge-neutral pulses are delivered at a first amplitude and the non-charge-neutral pulses being delivered at a second amplitude, the first amplitude being greater than the second amplitude.