Patent Description:
The embodiments described herein relate generally to medical devices for therapeutic electrical energy delivery, and more particularly to systems for delivering electrical energy in the context of ablating tissue rapidly and selectively by the application of suitably timed pulsed voltages that generate irreversible electroporation of cell membranes, in conjunction with the application of suitable regional cooling to enhance electroporation selectivity and efficacy.

In the past decade or two the technique of electroporation has advanced from the laboratory to clinical applications, while the effects of brief pulses of high voltages and large electric fields on tissue has been investigated for the past forty years or more. It has been known that the application of brief high DC voltages to tissue, thereby generating locally high electric fields typically in the range of hundreds of Volts/centimeter can disrupt cell membranes by generating pores in the cell membrane. While the precise mechanism of this electrically-driven pore generation or electroporation is not well understood, it is thought that the application of relatively large electric fields generates instabilities in the lipid bilayers in cell membranes, causing the occurrence of a distribution of local gaps or pores in the membrane. If the applied electric field at the membrane is larger than a threshold value, the electroporation is irreversible and the pores remain open, permitting exchange of material across the membrane and leading to apoptosis or cell death. Subsequently the tissue heals in a natural process.

Some known processes of adipose tissue reduction by freezing, also known as cryogenically induced lipolysis, can involve a significant length of therapy time. In contrast, the action of irreversible electroporation can be much more rapid. Some known tissue ablation methods employing irreversible electroporation, however, involve destroying a significant mass of tissue, and one concern the temperature increase in the tissue resulting from this ablation process.

While pulsed DC voltages are known to drive irreversible electroporation under the right circumstances, the examples of electroporation applications in medicine and delivery methods described in the prior art do not sufficiently discuss specificity and rapidity of action, or methods to treat a local region of tissue with irreversible electroporation while not applying electroporation to adjoining regions of tissue.

Thus, there is a need for selective energy delivery for electroporation and its modulation in various tissue types as well as pulses that permit rapid action and completion of therapy delivery. There is also a need for more effective generation of voltage pulses and control methods, as well as appropriate devices or tools addressing a variety of specific clinical applications. Such more selective and effective electroporation delivery methods can broaden the areas of clinical application of irreversible electroporation including therapeutic treatment to reduce the volume of adipose or fat tissue and the treatment of tumors of various types. <CIT> discloses a septoplasty instrument. <CIT> discloses an electroporation system with voltage control feedback for clinical applications. <CIT> discloses systems and methods for cardiac tissue electroporation ablation. <CIT> discloses apparatus for reducing sweat production. Documents <CIT> and <CIT> disclose further relevant background art.

The embodiments described herein address the need for tools for rapid and selective application of irreversible electroporation therapy as well as pulse generation and control methods. The process of irreversible electroporation can be induced even without the flow of current when a polarizing high voltage is applied to generate a suitably large electric field in a region of interest. The embodiments described herein can result in well-controlled and specific delivery of electroporation in an efficacious manner.

In accordance with one aspect of the invention, there is provided an apparatus as defined in claim <NUM>. Optional features are defined in the dependent claims. The methods described hereinafter are exemplary only and do not form part of the invention. Brief Description of the Drawings.

Medical systems, tools and methods are disclosed for the selective and rapid application of DC voltage to drive electroporation. In some embodiments, an apparatus includes a clamp, a first electrode head and a second electrode head. The clamp includes a first arm and a second arm, each configured to exert opposing forces to maintain a target tissue disposed therebetween. The first electrode head is coupled to the first arm. The first electrode head includes a first electrically insulating contact surface, a first electrode and a first cooling unit. The first contact surface is configured to contact a first portion of the target tissue. The first cooling unit is configured to maintain the first portion of the target tissue at a first target temperature. The second electrode head is coupled to the second arm, and includes a second electrically insulating contact surface, a second electrode and a second cooling unit. The second contact surface is configured to contact a second portion of the target tissue. The second cooling unit is configured to maintain the second portion of the target tissue at a second target temperature. The first electrode and the second electrode are collectively configured to deliver a voltage pulse to the target tissue.

In some embodiments, an apparatus includes a voltage pulse generator configured to produce a pulsed voltage waveform, and an electrode controller. The electrode controller is configured to be operably coupled to the voltage pulse generator and a medical clamp. The medical clamp includes a plurality of electrodes. The electrode controller is implemented in at least one of a memory or a processor, and includes a feedback module, a cooling module and a pulse delivery module. The feedback module is configured to determine a temperature of a target tissue to which the medical clamp is coupled. The cooling module is configured to produce a signal to a cooling unit of the medical clamp to maintain a portion of the target tissue at a target temperature. The pulse delivery module is configured to deliver an output signal associated with the pulsed voltage waveform to the plurality of electrodes.

In some examples, a non-transitory processor readable medium storing code representing instructions to be executed by a processor includes code to cause the processor to determine a temperature of a target tissue to which a medical clamp is coupled. The medical clamp includes a plurality of electrodes. The code further includes code to produce a signal based at least in part on the temperature of the target tissue. The signal is delivered to a cooling unit of the medical clamp to maintain a portion of the target tissue at a target temperature. The code further includes code to deliver an output signal associated with the pulsed voltage waveform to the plurality of electrodes when the target tissue is at the target temperature.

In some examples, a method includes receiving, at a feedback module of an electrode controller, a signal associated with a temperature of a target tissue to which a medical clamp is coupled. The medical clamp includes a plurality of electrodes. A signal based at least in part on the temperature of the target tissue is produced. The signal is then delivered to a cooling unit of the medical clamp to maintain a portion of the target tissue at a target temperature. The method includes delivering an output signal associated with the pulsed voltage waveform to the plurality of electrodes when the target tissue is at the target temperature.

In some embodiments, an irreversible electroporation system includes a DC voltage/signal generator and a controller capable of being configured to apply voltages to a selected multiplicity of electrodes. Further, the controller is capable of applying control inputs whereby selected pairs of anode-cathode subsets of electrodes can be sequentially updated based on a pre-determined sequence. In some embodiments, the controller can further receive at least one temperature input, and based on a temperature input the controller can modify or update a control parameter that can help to maintain a temperature value near a region of interest. The generator can output waveforms that can be selected to generate a sequence of voltage pulses in either monophasic or biphasic forms and with either constant or progressively changing amplitudes.

Devices are disclosed for the selective electroporation ablation of particular tissue type (e.g., adipose tissue) while preserving surrounding tissue of other types. In some embodiments, the system can include a means for sensing electrode separation, and the electrode voltage applied can be determined based on a sensed separation or distance measure. This determination can be fully or partially automatic, or manual.

In some embodiments, a system uses temperature to selectively ablate tissue as the threshold of irreversible electroporation is temperature-dependent, utilizing means such as the suitable use of cooling fluid or solid state cooling methods to locally raise the irreversible electroporation threshold electric field value and thereby selecting the predominant tissue type or region it is desired to ablate. In contrast to the process of adipose tissue reduction by freezing, also known as cryogenically induced lipolysis, which uses lower temperatures to directly freeze adipose tissue, the lowered temperatures according to an embodiment assist in the selective action of irreversible electroporation, a much more rapid process than freezing.

In some embodiments, an irreversible electroporation system includes a DC voltage/signal generator and a controller that is configured to apply voltages to a selected multiplicity or a subset of electrodes. In some embodiments, a temperature measurement device such as a thermistor measures temperature at or near a portion of an electrode device. The controller is capable of applying control inputs whereby the temperature at or near a portion of the device is maintained within a narrow range of desired values. Preferably, the temperature at or near an electrode or electrode head surface contacting a patient anatomy is maintained at or near a value that is lower than body temperature. In some embodiments, the application of DC voltage pulses is made only when the temperature is within a narrow range of values around a desired value. In some embodiments, at least one control input for temperature control takes the form of rate of flow of a cooling fluid, while in another embodiment, the control input is a voltage that drives a thermoelectric heat pump. Further, in some embodiments, the electrode clamp device disclosed here incorporates a sensor to measure a separation distance, based on which the electroporation voltage value is selected.

A DC voltage for electroporation can be applied to subsets of electrodes identified as anode and cathode respectively on opposite sides of an anatomical region it is desired to ablate. The DC voltage is applied in brief pulses sufficient to cause irreversible electroporation and can preferably be in the range of <NUM> kV to <NUM> kV and more preferably in the range <NUM> kV to <NUM> kV, so that an appropriate threshold electric field value of at least around <NUM> Volts/cm is effectively achieved in the tissue (for example, adipose tissue) to be ablated. In some embodiments, the DC voltage generator setting for irreversible electroporation is automatically identified by the electroporation system based on a sensed distance measuring the spatial separation between electrodes of opposing polarities. In an alternate embodiment, the DC voltage value is selected directly by a user from a suitable dial, slider, touch screen, or any other user interface. In some embodiments, while transient currents may be induced in the tissue upon voltage application or removal, there are no other (steady state) currents as the electrodes are insulated from the subject anatomy. A region or volume of tissue where the electric field is sufficiently large for irreversible electroporation to occur is ablated during the DC voltage pulse application. At the same time, the application of surface cooling raises the electroporation threshold of tissue near the surface and prevents the occurrence of irreversible electroporation in this surface layer.

As used in this specification, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, the term "a member" is intended to mean a single member or a combination of members, "a material" is intended to mean one or more materials, "a processor" is intended to mean a single processor or multiple processors; and "memory" is intended to mean one or more memories, or a combination thereof.

As used herein, the terms "about" and "approximately" generally mean plus or minus <NUM>% of the value stated. For example, about <NUM> would include <NUM> and <NUM>, about <NUM> would include <NUM> to <NUM>, about <NUM> would include <NUM> to <NUM>.

A schematic diagram of the electroporation system according to an embodiment is shown in <FIG>. The system includes a DC voltage/signal generator <NUM> is driven by a controller unit <NUM> that interfaces with a computer device <NUM> by means of a two-way communication link <NUM>. The controller can perform channel selection and routing functions for applying DC voltages to appropriate electrodes that have been selected by a user or by the computer <NUM>, and apply the voltages via a multiplicity of leads (shown collectively as <NUM>) to an electrode device <NUM>. The electrode device <NUM>, and any of the electrode devices described herein can be similar to the ablation catheters described in <CIT> ("the '<NUM> PCT Application).

Some of the leads <NUM> from the controller <NUM> can also carry control signals to adjust temperature at or near the electrode device. In an alternate embodiment, the control signals from the controller <NUM> can be routed to a different unit (not shown) such as a cooling pump for example, to control cooling fluid flow rate). The electrode device <NUM> can also send information and/or signals to the controller <NUM>, such as temperature data from sensors mounted on or near the electrode device. Such feedback signals are indicated by the data stream <NUM>, which can be sent via separate leads. While the DC voltage generator <NUM> sends a DC voltage to the controller <NUM> through leads <NUM>, the voltage generator is driven by control and timing inputs <NUM> from the controller unit <NUM>.

In some embodiments, the electrode controller can include one or more modules and can automatically control the temperature of a target tissue, adjust a characteristic of the voltage waveform based on the spacing between adjacent electrodes, or the like. For example, <FIG> shows an electroporation system according to an embodiment that includes an electrode controller <NUM> and a signal generator <NUM>. The electrode controller <NUM> is coupled to a computer <NUM> or other input / output device, and is configured to be operably coupled to a medical device <NUM>. The medical device <NUM> can be one or more of the medical clamps of the types shown and described herein. Further the medical device <NUM> can be coupled to, disposed about and/or in contact with a target tissue T. In this manner, as described herein, the electroporation system, including the electrode controller <NUM> and the signal generator <NUM>, can deliver voltage pulses to the target tissue for therapeutic purposes.

The controller <NUM> can include a memory <NUM>, a processor <NUM>, and an input / output module (or interface) <NUM>. The controller <NUM> can also include a temperature control module <NUM>, a feedback module <NUM>, and a pulse delivery module <NUM>. The electrode controller <NUM> is coupled to a computer <NUM> or other input / output device via the input / output module (or interface) <NUM>.

The processor <NUM> can be any processor configured to, for example, write data into and read data from the memory <NUM>, and execute the instructions and/or methods stored within the memory <NUM>. Furthermore, the processor <NUM> can be configured to control operation of the other modules within the controller (e.g., the temperature control module <NUM>, the feedback module <NUM>, and the pulse delivery module <NUM>). Specifically, the processor <NUM> can receive a signal including user input, temperature data, distance measurements or the like and determine a set of electrodes to which voltage pulses should be applied, the desired timing and sequence of the voltage pulses and the like. In other embodiments, the processor <NUM> can be, for example, an application-specific integrated circuit (ASIC) or a combination of ASICs, which are designed to perform one or more specific functions. In yet other embodiments, the microprocessor can be an analog or digital circuit, or a combination of multiple circuits.

The memory device <NUM> can be any suitable device such as, for example, a read only memory (ROM) component, a random access memory (RAM) component, electronically programmable read only memory (EPROM), erasable electronically programmable read only memory (EEPROM), registers, cache memory, and/or flash memory. Any of the modules (the temperature control module <NUM>, the feedback module <NUM>, and the pulse delivery module <NUM>) can be implemented by the processor <NUM> and/or stored within the memory <NUM>.

As shown, the electrode controller <NUM> operably coupled to the signal generator <NUM>. The signal generator includes circuitry, components and/or code to produce a series of DC voltage pulses for delivery to electrodes included within the medical device <NUM>. For example, in some embodiments, the signal generator <NUM> can be configured to produce a biphasic waveform having a pre-polarizing pulse followed by a polarizing pulse. The signal generator <NUM> can be any suitable signal generator of the types shown and described herein.

The pulse delivery module <NUM> of the electrode controller <NUM> includes circuitry, components and/or code to deliver an output signal associated with the pulsed voltage waveform produced by the signal generator <NUM>. This signal (shown as signal <NUM>) can be any signal of the types shown and described herein, and can be of a type and/or have characteristics to be therapeutically effective. In some embodiments, the pulse delivery module <NUM> receives input from other portions of the system, and can therefore send the signal <NUM> to the appropriate subset of electrodes, as described herein.

The electrode controller <NUM> includes the temperature control module <NUM>. The temperature control module <NUM> includes circuitry, components and/or code to produce a control signal (identified as signal <NUM>) that can be delivered to the cooling unit (not shown) of the medical device <NUM> to facilitate cooling of a portion of the tissue T.

In some examples, the ablation controller and signal generator can be mounted on a rolling trolley, and the user can control the device using a touchscreen interface that could possibly be in the sterile field. The touchscreen can be for example an LCD touchscreen in a plastic housing mountable to a standard medical rail or post and can be used to select the electrodes for ablation and to ready the device to fire. The interface can for example be covered with a clear sterile plastic drape. The operator can select the electrodes involved in an automated sequence, if any. The touch screen graphically shows the catheters that are attached to the controller. In one example the operator can select electrodes from the touchscreen with appropriate graphical buttons. The ablation sequence can be initiated by holding down a hand-held trigger button that is possibly in a sterile field. The hand-held trigger button can be illuminated red to indicate that the device is "armed" and ready to ablate. The trigger button can be compatible for use in a sterile field and when attached to the controller can be illuminated a different color, for example white. In someexamples, the "armed" state of the trigger can depend on whether the electrode temperature is within a desired range of values; if not, an appropriate control signal is applied to bring the temperature back to the desired range. When the device is firing, the trigger button flashes in sequence with the pulse delivery in a specific color such as red. The waveform of each delivered pulse is displayed on the touchscreen interface.

The waveforms for the various electrodes can be displayed and recorded on the case monitor and simultaneously outputted to a standard data acquisition system. With the high voltages involved with the device, the outputs to the data acquisition system are protected from voltage and/or current surges. The waveform amplitude, period, duty cycle, and delay can all be modified, for example via a suitable Ethernet connection.

In some embodiments, a system (generator and controller) according to an embodiment can deliver rectangular-wave pulses with a peak maximum voltage of up to about <NUM> kV into a load with an impedance in the range of <NUM> Ohm to <NUM> Ohm for a maximum duration of <NUM>. In some embodiments the maximum duration can be <NUM>. The load can be part of the electrode circuitry, so that power is harmlessly dissipated in the load. Pulses can be delivered in a multiplexed and synchronized manner to a multi-electrode device with a duty cycle of up to <NUM> % (for short bursts). The pulses can generally be delivered in bursts, such as for example a sequence of between <NUM> and <NUM> pulses interrupted by pauses of between <NUM> and <NUM>. In one embodiment, the multiplexer controller is capable of running an automated sequence to deliver the impulses/impulse trains (from the DC voltage signal/impulse generator) to the tissue target as a sequence of pulses over electrodes. The controller system is capable of switching between subsets of electrodes located on the electrode device.

In some embodiments, the controller can have several pulse sequence configurations that provide the operator with at least some variety of programming options. In one configuration, the controller can switch electrode configurations of a bipolar set of electrodes (cathode and anode) sequentially along the length of an electrode clamp device. The user can control the application of DC voltage with a single handheld switch. A sterile catheter or catheters can be connected to the voltage output of the generator via a connector cable. In oneexample, the user activates the device with a touch screen. The generator can remain in a standby mode until the user is ready to apply pulses at which point the user/assistant can put the generator into a ready mode via the touchscreen interface. Subsequently the user can select the sequence and the active electrodes.

In some embodiments, any of the systems described herein can select an appropriate voltage value based on a distance measurement between electrodes of opposing polarities. In this manner, the system can ensure that an electric field sufficient to cause irreversible electroporation is applied up to the desired depth.

The controller and generator can output waveforms that can be selected to generate a sequence of voltage pulses in either monophasic or biphasic forms and with either constant or progressively changing amplitudes. <FIG> shows a square or rectangular wave pulse train where the pulses <NUM> have a uniform height or maximum voltage. <FIG> shows an example of a balanced biphasic rectangular pulse train, where each positive voltage pulse such as <NUM> is immediately followed by a negative voltage pulse such as <NUM> of equal amplitude and opposite sign. While in this example the biphasic pulses are balanced with equal amplitudes of the positive and negative voltages, in other embodiments an unbalanced biphasic waveform could also be used as may be convenient for a given application.

A train of multiple DC voltage pulses can be applied to ensure that sufficient tissue ablation has occurred. Further, the user can repeat the delivery of irreversible electroporation over several successive pulse trains for further confidence.

Yet another example of a waveform or pulse shape that can be generated by any of the systems described herein is illustrated in <FIG>, which shows a progressive balanced rectangular pulse train. In this pulse train, each distinct biphasic pulse has equal-amplitude positive and negative voltages, but each pulse such as <NUM> is larger in amplitude than its immediate predecessor <NUM>. Other variations such as a progressive unbalanced rectangular pulse train, or indeed a wide variety of other variations of pulse amplitude with respect to time can be conceived and implemented by those skilled in the art based on the teachings herein.

The time duration of each irreversible electroporation rectangular voltage pulse could lie in the range from <NUM> nanosecond to <NUM> milliseconds, with the range <NUM> microseconds to <NUM> millisecond being more preferable and the range <NUM> microseconds to <NUM> microseconds being still more preferable. The time interval between successive pulses of a pulse train could be in the range of <NUM> microseconds to <NUM> millisecond, with the range <NUM> microseconds to <NUM> microseconds being more preferable. The number of pulses applied in a single pulse train (with delays between individual pulses lying in the ranges just mentioned) can range from <NUM> to <NUM>, with the range <NUM> to <NUM> being more preferable. As described in the foregoing, a pulse train can be driven by a user-controlled switch or button, in one example preferably mounted on a hand-held joystick-like device. In one mode of operation a pulse train can be generated for every push of such a control button, while in an alternate mode of operation pulse trains can be generated repeatedly during the refractory periods of a set of successive cardiac cycles, for as long as the user-controlled switch or button is engaged by the user.

All of these parameters can be determined by the design of the signal generator, and in various embodiments could also be determined by user control as may be convenient for a given clinical application. The specific examples and descriptions herein are exemplary in nature and variations can be developed by those skilled in the art based on the material taught herein without departing from the scope according to an embodiment, which is limited only by the attached claims.

In some embodiments, an irreversible electroporation ablation system of the type shown and described herein can be used for adipose tissue (or fat) ablation for the reduction or elimination of adipose tissue. As mentioned earlier, various tissue or cell types have different irreversible electroporation thresholds. Fat cells typically have an irreversible electroporation threshold in the range of <NUM> Volts/cm. <FIG> shows an electrode clamp device that externally clamps onto a fold of skin on a patient anatomy, with electrode clamp arms <NUM> connected to a clamp head <NUM> including springs, screw or other tightening mechanisms for firmly positioning the electrodes in a clamped position. The electrode clamp arms end in electrode heads <NUM> that incorporate cooling coils <NUM> that carry a cooling fluid at a temperature sufficient to cool and maintain the skin temperature at about approximately <NUM> degrees Celsius (<NUM> degrees Fahrenheit). A cooling system and drive pump (not shown) with a controllable fluid flow rate supply coolant to maintain the electrode temperature at or near a suitably low value (such as, for example, <NUM> degrees Celsius (<NUM> degrees Fahrenheit)). The electrodes are shown clamping on to tissue in the form of a layer of skin <NUM> with fatty tissue <NUM> beneath the skin. Each electrode itself is located internally within its electrode head and the latter is made of insulating material, so that no conductor touches the patient surface. <FIG> shows an example of electric field lines <NUM> generated in the tissue when a DC voltage is applied across the electrodes.

As shown in <FIG>, since the patient-contacting surfaces are insulators, there is no steady state charge transfer or direct current within the tissue. However, the polarizing electric field applied in pulses can generate irreversible electroporation in the tissue and generate induced or transient currents in the tissue. The irreversible electroporation threshold of tissue increases as temperature decreases. Thus, by cooling the electrodes and the layer of skin, the skin tissue's electroporation threshold can be increased beyond the approximately <NUM> V/cm threshold value of fat tissue. When a DC electric field of suitable strength is applied, fat (indicated by <NUM> in <FIG>) can therefore be selectively ablated by electroporation while maintaining the integrity of skin tissue (indicated by <NUM> in <FIG>) as long as the applied electric field is in the range between the irreversible electroporation thresholds of adipose tissue and the cooled skin tissue.

<FIG> is a schematic illustration of an electrode head of the electrode clamp device showing the electrodes or electroporation probes <NUM> situated within an outer casing <NUM>. Coolant coils <NUM> within each electrode head keep the electrode head surface cold and maintain the skin temperature at approximately <NUM> degrees Celsius (<NUM> degrees Fahrenheit). The patient-contacting surface <NUM> of each electrode head is an insulator, so that there is no direct current transfer between the electrodes. The parallel electrodes act like capacitor plates for very brief periods as DC voltage pulses are applied for irreversible electroporation. The electric field <NUM> generated between the electrodes in the tissue region serves to polarize the tissue and generate irreversible electroporation in the fat or adipose tissue. The voltage pulses induce brief transient currents in the tissue when the field changes but no steady state direct current. Thus with this device, inductive irreversible electroporation can be generated. The applied DC voltage can be made to depend on the distance between the electrodes. In one embodiment, the electrode clamp can have a discrete number of possible relative positions of the electrodes with pre-determined separation distances. Based on the separation, a sufficient voltage that generates at least an approximately <NUM> Volts/cm electric field between the electrodes can be computed by the electroporation system and applied for the selective irreversible electroporation of adipose tissue.

<FIG> shows an electrode clamp device that externally clamps onto a fold of skin on a patient anatomy, with electrode clamp arms <NUM> and <NUM> connected to a clamp head <NUM> including a screw mechanism <NUM> for firmly positioning the electrodes in a clamped position around a portion of patient anatomy, with a fixed distance between electrode arms. The top electrode arm <NUM> has disposed along it electrode heads <NUM>, <NUM> and <NUM> respectively aligned with electrode heads <NUM>, <NUM> and <NUM> on the bottom electrode arm <NUM>. In <FIG>, the lower electrode arm <NUM> is fixed to a mount (not shown) and the screw mechanism allows for the vertical motion of electrode arm <NUM> relative to electrode arm <NUM>, thereby permitting adjustment of the separation distance between the arms over a range of values. In some embodiments, the electrode heads can incorporate thermoelectric cooling modules for keeping the patient-contacting face of each electrode at a cooled temperature significantly below body temperature (for example, the patient contacting face of the electrode can be maintained in a narrow range around <NUM> degrees Celsius (<NUM> degrees Fahrenheit)). This can be done with a thermoelectric or solid state cooling module by applying an appropriate voltage or current to the cooling module. Solid state cooling has the advantage of having no moving parts with corresponding convenience of design and implementation.

As an example, referring to <FIG> bipolar leads <NUM>, <NUM> and <NUM> attach to electrode heads <NUM>, <NUM> and <NUM> respectively in order to control the temperature on the patient contacting electrode face of each electrode. When an appropriate voltage is applied across a Peltier cooling module, it functions as a heat pump, transferring heat from one face of the module to the other. Furthermore, each electrode head, or at least each electrode arm, can incorporate a temperature sensing unit such as a thermistor <NUM> shown attached to leads <NUM> on electrode arm <NUM>. The data from the temperature sensing unit is read by the controller (not shown in <FIG>) or to a computer where the temperature data is utilized to generate an appropriate control signal for the purpose of maintaining electrode face temperature by using any of a range of control schemes or methods, for example PID (Proportional-Integral-Derivative) control.

<FIG> is a schematic illustration of an electrode head incorporating means for solid state or thermoelectric cooling. A metal electrode <NUM> for high voltage DC application abuts a ceramic cover <NUM> on one side (with the outside face of the ceramic cover being a patient contacting face) and a thermoelectric or Peltier cooling module <NUM> on the other. The top face of the cooling module <NUM> is adjacent to a ceramic cover <NUM>, so that the entire electrode head has ceramic faces on both top and bottom faces.

<FIG> schematically illustrates a thermoelectric or Peltier cooling unit, a multiplicity of which can be arranged to form a Peltier cooling module. The thermoelectric unit comprises a p-type semiconductor <NUM> (such as for example Lead Telluride) electrically in series with an n-type semiconductor <NUM> (such as for example Bismuth Telluride) and connected by a metallic connection <NUM>. At the same time, the semiconductors <NUM> and <NUM> are thermally connected in parallel. The disjoint ends of the p-type semiconductor and the n-type semiconductor are connected to metallic terminal electrodes <NUM> and <NUM> respectively with negative and positive electric polarities or voltages respectively, and the electrodes <NUM> and <NUM> abut a ceramic cover <NUM>. When a voltage is applied to the terminal electrodes (so that terminal <NUM> is at a negative electric potential relative to terminal <NUM>), a current flows from the n-type semiconductor <NUM> through the series connection <NUM> and through the p-type semiconductor <NUM>. The respective charge carriers in each semiconductor move from the top to the bottom, and correspondingly there is a heat flux that transports heat from the top face <NUM> of the Peltier cooling unit to the bottom face <NUM>. Correspondingly <NUM> is turned into the "cold" or lower temperature face and <NUM> into the "hot" or higher temperature face of the Peltier cooling unit.

<FIG> schematically depicts a chain of Peltier cooling units connected to form a thermoelectric cooling module. In this example, the module <NUM> comprises Peltier cooling units <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> connected in a chain so as to spread approximately uniformly over an area and such that all the units have for example a "hot side" on the bottom and a "cold" side on the top. An appropriate voltage can be applied across the end terminal leads <NUM> and <NUM> in order to drive a heat flux between the top and bottom sides and maintain a cold surface.

Thermoelectric heat pump modules are commercially available, for example from sources such as TE Technology, Inc. of Traverse City, Michigan, USA and appropriate configurations convenient for the electrode clamp devices according to an embodiment can be arrived at by those skilled in the art.

<FIG> schematically illustrates one geometry of use of the electrode clamp device, wherein a portion <NUM> of skin and adipose tissue <NUM> disposed around a patient anatomy <NUM> is clamped between electrode arms <NUM> and <NUM> for electroporation ablation. <FIG> is an illustration of an electrode clamp device with electrode arms <NUM> and <NUM> wherein their respective electrode heads <NUM> and <NUM> are longitudinally disposed and have large aspect ratios, as shown schematically therein. As shown in the geometry depicted schematically in <FIG>, such an arrangement could be used to clamp, in a lengthwise disposition, a portion of skin and adipose tissue <NUM> disposed around a patient anatomy <NUM> between electrode arms <NUM> and <NUM> for electroporation ablation.

In some embodiments, the time for which a cold temperature is maintained at the patient contacting surface of the electrode head is monitored and varied, so that the cooling control is applied in time in a pulse-like format. This is done in order to maintain a surface layer of tissue at a suitably low or cold temperature, while ensuring that deeper regions of tissue undergo no more than marginal cooling. The thermal diffusivity D of skin tissue is known to be in the range of <NUM><NUM>/s. From standard heat diffusion theory, in a time T the depth x to which a temperature change applied at the surface is propagated is given (in two dimensions) by <MAT>; in <NUM> seconds of cooling, we have x ~ <NUM>, about the thickness of skin tissue. In one mode of operation of the system according to an embodiment, the cooling of the electrodes is performed in discrete time intervals in the range of <NUM> seconds to <NUM> seconds, followed by a pulse train application, the entire duration of the pulse train being in the range of less than about <NUM> seconds. Thus, the application of cooling could also be performed in pulses. The next ablation in the same tissue region is performed, if necessary, after another cooling pulse is applied over a discrete time interval, and so on. In some embodiments, a heating pulse could follow a cooling pulse in order to ensure that the temperature in the interior of the tissue does not fall below a threshold value. Such a heating pulse can be applied when a thermoelectric or Peltier heat pump is used simply by reversing the polarity of the (voltage) control signal to the heat pump, and the heating pulse could have a duration in the range between <NUM> and <NUM> seconds.

<FIG> illustrates schematically one embodiment, where the electrode clamp device with electrode arms <NUM> and <NUM> with respective electrode heads <NUM> and <NUM> further has a sensor for measuring separation distance, in the form of an electromagnetic transmitter <NUM> on electrode arm <NUM> and an electromagnetic receiver coil <NUM> on electrode arm <NUM>. Leads <NUM> and <NUM> respectively connect to receiver <NUM> and transmitter <NUM>. Based on the signal intensity received by the receiver <NUM>, the distance of separation d indicated by <NUM> in the FIG. can be measured. For example, if the axes and centers of the transmitter and receiver sensors are aligned, and a current I flows through the transmitter (of radius a), the magnetic field B at the center of the receiver is given by <MAT> where µ<NUM> is the magnetic permeability of free space. If the current in the transmitter is sinusoidal with circular frequency ω, the time varying magnetic field induces a voltage in the receiver given to a good approximation by <MAT> Where A is the area of the receiver. Thus by measuring the induced voltage V, the separation distance d can be determined.

While in <FIG> the transmitter and receiver sensors for distance determination were located at a separation away from the electrode heads to mitigate electromagnetic interference with the metallic electrodes, in an alternate embodiment, the transmitter and receiver sensors could be integrated within an electrode head, as shown schematically in <FIG>. In <FIG>, the transmitter <NUM> is incorporated in electrode head <NUM> of lower electrode arm <NUM>, while receiver sensor <NUM> is incorporated in electrode head <NUM> of upper electrode arm <NUM>. Also shown are other electrode heads <NUM>, <NUM>, <NUM> and <NUM>. With this arrangement, the induced voltage at the receiver is calibrated over a range of separations of the electrode arms, in effect generating a lookup table. The electromagnetic interference of the electrode heads is implicitly accounted for by this calibration process; subsequently, given a measured induced voltage at the receiver, the separation distance can be determined from the calibration data.

While the foregoing described one method of separation distance determination based on an electromagnetic scheme purely for illustrative and exemplary purposes, it should be apparent that a variety of other methods are available for this purpose such as for example schemes based on the use of ultrasound transmitters and receivers or infrared transmitters and receivers. Based on the teachings herein, those skilled in the art could arrive at an implementation that may be convenient for a specific application.

With a separation distance between electrode heads thus determined, the applied voltage to the electrode heads is then correspondingly determined based on a desired irreversible electroporation threshold value. For example, if the distance between electrode heads is measured to be <NUM>, and the desired irreversible electroporation threshold value is an electric field of <NUM> Volts/cm, it is clear that a voltage of at least <NUM> kV (desired electric field times distance) needs to be applied between the electrodes in order to meet or exceed the threshold value for irreversible electroporation.

Some examples described herein relate to a computer storage product with a non-transitory computer-readable medium (also can be referred to as a non-transitory processor-readable medium) having instructions or computer code thereon for performing various computer-implemented operations. The computer-readable medium (or processor-readable medium) is non-transitory in the sense that it does not include transitory propagating signals per se (e.g., a propagating electromagnetic wave carrying information on a transmission medium such as space or a cable). The media and computer code (also can be referred to as code) may be those designed and constructed for the specific purpose or purposes. Examples of non-transitory computer-readable media include, but are not limited to: magnetic storage media such as hard disks, floppy disks, and magnetic tape; optical storage media such as Compact Disc/Digital Video Discs (CD/DVDs), Compact Disc-Read Only Memories (CD-ROMs), and holographic devices; magneto-optical storage media such as optical disks; carrier wave signal processing modules; and hardware devices that are specially configured to store and execute program code, such as Application-Specific Integrated Circuits (ASICs), Programmable Logic Devices (PLDs), Read-Only Memory (ROM) and Random-Access Memory (RAM) devices.

Examples of computer code include, but are not limited to, micro-code or micro-instructions, machine instructions, such as produced by a compiler, code used to produce a web service, and files containing higher-level instructions that are executed by a computer using an interpreter. For example, embodiments may be implemented using imperative programming languages (e.g., C, Fortran, etc.), functional programming languages (Haskell, Erlang, etc.), logical programming languages (e.g., Prolog), object-oriented programming languages (e.g., Java, C++, etc.) or other suitable programming languages and/or development tools. Additional examples of computer code include, but are not limited to, control signals, encrypted code, and compressed code.

While various specific examples and embodiments of systems and tools for selective tissue ablation with irreversible electroporation were described in the foregoing for illustrative and exemplary purposes, it should be clear that a wide variety of variations and alternate embodiments could be conceived or constructed by those skilled in the art based on the teachings according to the disclosure. While specific methods of control and DC voltage application from a generator capable of selective excitation of sets of electrodes were disclosed together with temperature control, persons skilled in the art would recognize that any of a wide variety of other control or user input methods can be implemented. Likewise, while the foregoing described a range of specific tools or devices for more effective and selective DC voltage application for irreversible electroporation through an externally applied electrode clamp device, other device constructions or variations could be implemented by one skilled in the art by employing the principles and teachings disclosed herein in the treatment of excessive adipose tissue, tumor ablation, or a variety of other medical applications.

Furthermore, while the present disclosure describes specific embodiments and tools involving the use of temperature to selectively ablate tissue by taking advantage of the temperature-dependence of the threshold of irreversible electroporation and the application of specific cooling methodologies for exemplary purposes, it should be clear to one skilled in the art that a variety of methods and devices for fluid pumping and control, for tissue or electrode cooling, or even for tissue heating through the delivery of focused kinetic energy or electromagnetic radiation could be implemented utilizing the methods and principles taught herein.

Claim 1:
An apparatus, comprising:
a clamp including a first arm (<NUM>) and a second arm (<NUM>), the first arm and the second arm configured to exert opposing forces to maintain a target tissue disposed between the first arm and the second arm;
a first electrode head (<NUM>) coupled to the first arm, the first electrode head including a first electrically insulating contact surface (<NUM>), a first electrode (<NUM>) and a first cooling unit (<NUM>), the first contact surface configured to contact a first portion of the target tissue, the first cooling unit configured to maintain the first portion of the target tissue at a first target temperature; and
a second electrode head (<NUM>) coupled to the second arm, the second electrode head including a second electrically insulating contact surface (<NUM>), a second electrode (<NUM>) and a second cooling unit (<NUM>), the second contact surface configured to contact a second portion of the target tissue, the second cooling unit configured to maintain the second portion of the target tissue at a second target temperature, characterized in that
the first electrode and the second electrode collectively configured to deliver a DC voltage pulse waveform configured to irreversibly electroporate the target tissue with no direct current transfer between the electrodes.