Patent Description:
Surgical excision of a tumor can result in an infection and leave a scar. Furthermore, if there are more tumors, every cancerous tumor should be identified and individually excised by a surgeon. This can be time consuming and expensive, not to mention uncomfortable for patient or experiment subjects.

Cancerous tumors that are internal to a patient or experiment subject may be especially difficult to remove, let alone detect and treat. Many patient or experiment subjects' lives are turned upside down by the discovery of cancer in their bodies, sometimes which have formed relatively large tumors before being detected.

A "nanosecond pulsed electric field," sometimes abbreviated as nsPEF, includes an electric field with a sub-microsecond pulse width of between <NUM> nanoseconds (ns) and <NUM> nanoseconds, or as otherwise known in the art. It is sometimes referred to as sub-microsecond pulsed electric field. NsPEFs often have high peak voltages, such as <NUM> kilovolts per centimeter (kV/cm), <NUM> kV/cm, to <NUM> kV/cm. Treatment of biological cells with nsPEF technology often uses a multitude of periodic pulses at a frequency ranging from <NUM> per second (Hz) to <NUM>,<NUM>.

NsPEFs have been found to trigger apoptosis in cancerous tumors. Selective treatment of such tumors with nsPEFs can induce apoptosis within the tumor cells without substantially affecting normal cells in the surrounding tissue due to its non-thermal nature.

An example of nsPEF applied to biological cells is shown and described in <CIT>), which is incorporated herein by reference in its entirety for all purposes. <CIT> discloses a high-intensity pulsed electric field (HIPEF) vitrectomy apparatus configured for insertion into an eye. The vitrectomy apparatus includes a HIPEF probe comprising at least one electrode and a probe shaft with an atraumatic tip for retinal protection. In some embodiments, the vitrectomy apparatus also has a central aspiration lumen. <CIT> discloses an electrosurgical system and method for ablating, resecting, or cutting body structures, the system comprising an electrosurgical probe having a shaft with a distal bifurcated end to provide first and second arms, which support the first and second looped or partially looped electrodes. <CIT> discloses systems and methods for securing a screen-type active electrode to the distal tip of an electrosurgical device particularly useful for removing tissue within joints. A securing electrode is disposed through the screen electrode and mechanically joined to an insulative support body while also creating an electrical connection and mechanical engagement with the screen electrode. <CIT> discloses an apparatus and method for performing non-invasive treatment of the human face and body by electroporation.

The use of nsPEF for the treatment of tumors is a relatively new field. There exists a need for a device with better control over electrical characteristics for safe and effective studies and treatments of cancer in human subjects.

Generally, a nanosecond pulsed electric field (nsPEF) generator is disclosed that delivers a nsPEF field to a patient or experiment subject.

According to the invention, there is provided a pulse applicator as recited in Claim <NUM>.

In some embodiments, each of the first and second arms are independently movable with respect to the spacer.

In some embodiments, the first arm and the spacer are movably connected so that the first electrode of the first arm may be selectively positioned adjacent to the gap, and where the second arm and the spacer are movably connected so that the second electrode of the second arm may be selectively positioned adjacent to the gap.

In some embodiments, while the first electrode of the first arm is adjacent to the gap and the second electrode of the second arm is adjacent to the gap, the first arm, the second arm, and the spacer collectively bound the gap.

In some embodiments, the spacer includes a cavity bounding the gap.

In some embodiments, while the second arm is spaced apart from the gap, the cavity is exposed so as to be viewable.

In some embodiments, the pulse applicator further includes a first actuator configured to move the first arm with respect to the spacer, and a second actuator configured to move the second arm with respect to the spacer.

In some embodiments, the second actuator has an over center design.

In some embodiments, the second actuator causes a linear and a rotational movement of the second arm.

In some embodiments, the first arm, the spacer, and the second are assembleable and disassembleable by hand, without any tools.

In some embodiments, while the first electrode of the first arm is adjacent to the gap and the second electrode of the second arm is adjacent to the gap, the first and second electrodes are spaced apart by a predetermined distance so that the electric field has a magnitude equal to the voltage applied across the first and second electrodes divided by the predetermined distance.

In some embodiments, the first and second electrodes are configured to deliver the electrical field across the gap for a duration of less than <NUM> ns.

Also described for illustrative purposes only is a method of using a pulse applicator. The pulse applicator includes a first arm having a first electrode, a second arm having a second electrode, and a spacer, where the first arm, the spacer, and the second arm are movably connected and define a gap between the first arm and the second arm. The method includes moving the first electrode of the first arm with respect to the gap to expose a first side of the gap, moving the second electrode of the second arm with respect to the gap to expose a second side of the gap, and, while the tumor and the second side of the gap are exposed, inserting a tumor of a subject into the gap. The method also includes, while the tumor and the second side of the gap are exposed, moving the first electrode of the first arm with respect to the gap to hold the tumor within the gap, and moving the second electrode of the second arm with respect to the gap to align the tumor between the first and second electrodes.

In some embodiments, moving the first electrode with respect to the gap includes increasing a space between the first electrode and the gap.

In some embodiments, exposing the second side of the gap causes the gap to be observable by a user.

In some embodiments, moving the first electrode of the first arm with respect to the gap causes tissue connecting the tumor to the subject to be between the first arm and the spacer.

In some embodiments, moving the second electrode of the second arm with respect to the gap occludes the gap.

In some embodiments, the method further includes delivering an electrical field across the gap in response to an electrical pulse received across the first and second electrodes.

In some embodiments, the method further includes moving the first electrode of the first arm with respect to the gap to expose the tumor, and removing the tumor from the gap.

In some embodiments, moving the first electrode with respect to the gap includes applying a force to a first actuator, and moving the second electrode with respect to the gap includes applying a force to a second actuator.

In some embodiments, moving the second electrode with respect to the gap causes a linear and a rotational movement of the second electrode.

In some embodiments, the method further includes disassembling the pulse applicator by hand without any tools.

In some embodiments, the spacer includes a cavity defining the gap.

Also described for illustrative purposes only is a method of using a pulse applicator, the pulse applicator including a first arm having a first electrode, a second arm having a second electrode, and a spacer, where the first arm, the spacer, and the second arm are movably connected and define a gap between the first arm and the second arm. The method includes moving the second arm from a position occluding the first electrode to a position not occluding the first electrode, compressing tissue connecting a tumor to a subject between the spacer and the first arm, whereby the tumor is positioned in the gap, and moving the second electrode of the second arm with respect to the gap to a position adjacent the tumor.

In some embodiments, once the second arm is in the position not occluding the first electrode, the first electrode is observable by a user.

In some embodiments, moving the second electrode of the second arm to the position adjacent the tumor occludes the gap.

In some embodiments, the method further includes delivering an electrical field across the gap in response to an electrical pulse received across the first and second electrodes, where, while delivering the electric field across the gap, the first and second electrodes are spaced apart by a predetermined distance so that the electric field has a magnitude equal to the voltage applied across the first and second electrodes divided by the predetermined distance.

It has been shown that nsPEF treatments can be used to cause cancerous tumor cells to undergo apoptosis, a programmed cell death. Tests have shown that tumors can shrink to nonexistence after treatment. No drugs may be necessary. It has also been shown that the subject's immune system may be stimulated to attack all similar tumor cells, including those of tumors that are not within the nsPEF-treated tumor.

A "tumor" includes any neoplasm or abnormal, unwanted growth of tissue on or within a subject, or as otherwise known in the art. A tumor can include a collection of one or more cells exhibiting abnormal growth. There are many types of tumors. A malignant tumor is cancerous, a pre-malignant tumor is precancerous, and a benign tumor is noncancerous. Examples of tumors include a benign prostatic hyperplasia (BPH), uterine fibroid, pancreatic carcinoma, liver carcinoma, kidney carcinoma, colon carcinoma, pre-basal cell carcinoma, and tissue associated with Barrett's esophagus.

A "disease" includes any abnormal condition in or on a subject that is associated with abnormal, uncontrolled growths of tissue, including those that are cancerous, precancerous, and benign, or other diseases as known in the art.

"Apoptosis" of a tumor or cell includes an orderly, programmed cell death, or as otherwise known in the art.

"Immunogenic apoptosis" of a tumor or cell includes a programmed cell death that is followed by an immune system response, or as otherwise known in the art. The immune system response is thought to be engaged when the apoptotic cells express calreticulin or another antigen on their surfaces, which stimulates dendritic cells to engulf, consume, or otherwise commit phagocytosis of the targeted cells leading to the consequent activation of a specific T cell response against the target tumor or cell.

Pulse lengths of between <NUM> and <NUM> nanoseconds for nsPEF have been particularly studied to be effective in stimulating an immune response. Pulse lengths of about <NUM> nanoseconds are of particular interest in that they are long enough to carry sufficient energy to be effective at low pulse numbers but short enough to be effective in the manner desired.

A time of "about" a certain number of nanoseconds includes times within a tolerance of ±<NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>% or other percentages, or fixed tolerances, such as ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM> ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM> ns, or other tolerances as acceptable in the art in conformance with the effectivity of the time period.

Immune system biomarkers can be measured before and/or after nsPEF treatment in order to confirm that the immune response has been triggered in a patient or experiment subject. Further, nsPEF treatment can be paired with a CD47-blocking antibody treatment to better train CD8+T cells (i.e., cytotoxic T cells) for attacking the cancer.

<FIG> illustrates a nanosecond pulse generator system in accordance with an embodiment. NsPEF system <NUM> includes nsPEF pulse applicator <NUM>, footswitch <NUM>, and interface <NUM>. Footswitch <NUM> is connected to housing <NUM> and the electronic components therein through connector <NUM>. NsPEF pulse applicator <NUM> is connected to housing <NUM> and the electronic components therein through high voltage connector <NUM>. NsPEF system <NUM> also includes a handle <NUM> and storage drawer <NUM>. As shown in DETAIL A portion of <FIG>, nsPEF system <NUM> also includes holster <NUM>, which is configured to hold nsPEF pulse applicator <NUM> at its handle portion <NUM>.

A human operator inputs a number of pulses, amplitude, pulse duration, and frequency information, for example, into a numeric keypad or a touch screen of interface <NUM>. In some embodiments, the pulse width can be varied. A microcontroller sends signals to pulse control elements within nsPEF system <NUM>. In some embodiments, fiber optic cables allow control signaling while also electrically isolating the contents of the metal cabinet with nsPEF generation system <NUM>, the high voltage circuit, from the outside. In order to further isolate the system, system <NUM> may be battery powered instead of from a wall outlet.

<FIG> illustrates a pulse profile for both voltage and current in accordance with an embodiment. Output from the nsPEF system <NUM> with voltage on the top of the figure and current on the bottom for a first and second pulses. The first pulse has an amplitude of about <NUM> kV, a current of about <NUM> A, and a duration of about <NUM> ns. The second pulse has an amplitude of about <NUM> kV, a current of about <NUM> A, and a duration of about <NUM> ns. If such a pulse had been delivered on suction nsPEF pulse applicators having <NUM> between the plates, the pulse generator would have delivered a pulse of about <NUM> A and <NUM> kV/cm. Given a voltage, current depends heavily on the nsPEF pulse applicator type and tissue resistance.

While <FIG> illustrates a specific example, other pulse profiles may also be generated. For example, in some embodiments, rise and/or fall times for pulses may be less than <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, or greater than <NUM> ns. In some embodiments, the pulse voltage may be less than <NUM> kV, about <NUM> kV, about <NUM> kV, about <NUM> kV, about <NUM> kV, about <NUM> kV, about <NUM> kV, or greater than <NUM> kV. In some embodiments, the current may be less than <NUM> A, about <NUM> A, about <NUM> A, about <NUM> A, about <NUM> A, about <NUM> A, about <NUM> A, about <NUM> A, about <NUM> A, about <NUM> A, about <NUM> A, about <NUM> A, or more than <NUM> A. In some embodiments, the pulse duration may be less than <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or greater than <NUM>.

<FIG> illustrates a perspective view of a seven-needle suction nsPEF pulse applicator in accordance with an embodiment. In nsPEF pulse applicator <NUM>, sheath <NUM> surrounds seven sharp electrodes <NUM> with an broad opening at a distal end. When the open end is placed against a tumor, air is evacuated from the resulting chamber through vacuum holes <NUM> to draw the entire tumor or a portion thereof into the chamber. The tumor is drawn so that one or more of the electrodes preferably penetrates the tumor. Sharp ends of the electrodes are configured to pierce the tumor. The center electrode may be at one polarity, and the outer six electrodes may be at the opposite polarity. Nanopulses electric fields can then be precisely applied to the tumor using nsPEF system <NUM> (see <FIG>).

The electrodes can be apposed, one of each positive and negative pair of electrodes on one side of a tumor and the other electrode of the pair on an opposing side of the tumor. Opposing sides of a tumor can include areas outside or within a tumor, such as if a needle electrode pierces a portion of the tumor.

<FIG> illustrates a two-pole suction nsPEF pulse applicator <NUM> in accordance with an embodiment. In nsPEF pulse applicator <NUM>, sheath <NUM> surrounds two broad electrodes <NUM> on opposite sides of a chamber. When air is evacuated through vacuum holes <NUM> and a tumor is pulled within the chamber, the opposing electrodes apply nsPEF pulses to the tumor.

The nature of the nsPEF pulse applicator used mainly depends upon the shape of the tumor. Its physical size and stiffness can also be taken into account in selection of a particular nsPEF pulse applicator type.

<CIT>) discloses other suction nsPEF pulse applicator-based medical instruments and systems for therapeutic electrotherapy.

If there are multiple tumors in a subject, a surgeon can select a single tumor to treat based on the tumor's compatibility with nsPEF pulse applicators. For example, a tumor that is adjacent to a stomach wall may be more easily accessible than one adjacent a spine or the brain. Because a nsPEF pulse is preferably applied so that the electric field transits through as much tumor mass as possible while minimizing the mass of non-tumor cells that are affected, a clear path to two opposed 'poles' of a tumor may also be a selection criterion.

For tumors on or just underneath the skin of subject, needle electrodes can be used percutaneously. For locations deeper within a subject, a retractable electrode can fit into a gastroscope, bronchoscope, colonoscope, or other endoscope or laparoscope. For example, a tumor in a patient or experiment subject's colon can be accessed and treated using an nsPEF pulse applicator within a colonoscope.

Barrett's esophagus, in which portions of tissue lining a patient or experiment subject's esophagus are damaged, may be treated using an nsPEF pulse applicator placed on an inflatable balloon.

Embodiments of nanosecond pulsed power generators produce electric pulses in the range of single nanoseconds to single microseconds. The pulses are created by rapid release of energy stored in, for example, a capacitive or inductive energy reservoir to a load in a period that is generally much shorter than the charging time of the energy reservoir.

Conventional capacitive-type pulsed generators include pulse forming networks, which provide fixed pulse duration and impedance. With prior knowledge of a load's resistance, a pulse forming network with impedance that matches the load can be used. But for broader applications, especially when the load resistance is unknown, it is desirable to have a pulse generator with a flexibility of impedance matching and variation of pulse duration. Such flexibility can be implemented by switching a capacitor with a controllable switch. In this case, the capacitor can be regarded as a "voltage source" and can adapt to various load resistance. The switched pulse amplitude can then have the same voltage as the voltage of the capacitor. The pulse width is accordingly determined by the switch "on" time.

The selection of switches in nanosecond pulse generators is limited because of the high voltages, high currents, and fast switching times involved.

Spark gap switches, typically used in pulsed power technology, are capable of switching high voltages and conducting high currents. But they can only be turned on, and stopping the current flow in the middle of conduction is impossible. Besides spark gaps, other types of high voltage, high power switches are available, such as: magnetic switches, vacuum switches (Thyratrons for example), and certain high-voltage semiconductor switches.

Magnetic switches, relying on the saturation of magnetic core, change from high impedance to low impedance in the circuit. They can be turned on above a certain current threshold but will not be turned off until all the current is depleted by the load.

Vacuum switches are a good option for high voltage and high repletion rate operation, but similar to magnetic switches, they also can be only turned on, but cannot be turned off at a predetermined time.

Some types of high-voltage semi-conductor switches may also be considered. Thyristors and insulated gate bipolar transistors (IGBTs) may, in some embodiments be used. However, the turn-on times of Thyristors and IGBTs limit their usefulness.

Metal-oxide-semiconductor field-effect transistors (MOSFETs) have insufficient maximum drain to source voltage ratings (e.g. < 1kV) and insufficient maximum drain to source current ratings (e.g. < 50A) to be used in conventional pulse generator architectures to produce the voltage and current necessary for the applications discussed herein. If they were used, a large number of stages would be needed in order to produce high-amplitude output voltages. However, in conventional Marx generator architectures with a large number of stages, the Marx generator goes into an underdamped mode instead of a critically damped mode, resulting in loss in overshoot. As a result, the overall voltage efficiency decreases. For example, a voltage efficiency of a Marx generator may be <NUM>% at <NUM> stages but decrease to <NUM>% at <NUM> stages.

Furthermore, as the number of stages is increased, the impedance of the Marx generator also increases. This reduces the total energy deliverable to the load. This is particularly unfavorable for driving low impedance loads and long pulses.

In addition, the charging losses in the charging resistors also increases with the increased number of stages. As a result, such Marx generators are unsuitable for high repetition rate operation.

Therefore, in order to produce high voltage pulses, simply increasing the number of stages will cause a series of problems, including low efficiency, high impedance, etc. Because there is a tradeoff between the number of the stages and the actual output voltage, using conventional Marx generators cannot produce high voltage pulses which are sufficient for the applications discussed herein.

Some embodiments of this disclosure include a tunable, high voltage, nanosecond pulse generator. The switches may be power MOSFETs, which may, for example, be rated for a voltage of <NUM> kV and current of up to 30A. In some embodiments, the switches power MOSFETs rated for a voltage of <NUM> kV and current of up to continuous 90A and more than 200A peak. Voltage is scaled up by a Marx-switch stack hybrid circuit. In each Marx generator stage, a particularly configured stack of MOSFETs is used. As a result, the charging voltage for each stage is greater than the rated maximum for a single switch.

A technical advantage of the configuration is that the overall output voltage can be increased with just a few stages (e.g. <=<NUM>). As a result, the problems discussed above with Marx generators having a large number of stages are avoided and high efficiency, low impedance, and large variability in the pulse duration can be achieved.

Such an architecture also allows much easier control as only one trigger circuit may be needed for each stage. One additional benefit is that the pulse generator has low impedance, so it will be able to drive various loads with high current and extended pulse duration. The scaling up of the current is implemented by combining multiple Marx-switch stack circuits in parallel. The pulse duration is controlled by the closing and opening of the switch stack switches.

<FIG> illustrates a pulse generator circuit <NUM> which may be used inside nsPEF system <NUM> of <FIG>. Pulse generator circuit <NUM> illustrates a panel comprising a Marx generator switched by three switch stacks. The nsPEF system can have a single pulse generator circuit panel. In some embodiments, a nsPEF system includes multiple panels in parallel.

Circuit <NUM> includes three stages - <NUM>, <NUM>, and <NUM>. In some embodiments, another number of stages is used. For example, in some embodiments, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> stages are used. Stage <NUM> includes resistors <NUM> and <NUM>, capacitor <NUM>, and switch stack <NUM>. Likewise, stage <NUM> includes resistors <NUM> and <NUM>, capacitor <NUM>, and switch stack <NUM>, and stage <NUM> includes resistors <NUM> and <NUM>, capacitor <NUM>, and switch stack <NUM>. Each of these elements have structure and functionality which is similar to the corresponding elements of stage <NUM>.

Stage <NUM> has first and second input voltage input terminals <NUM> and <NUM> and first and second voltage output terminals <NUM> and <NUM>. Stage <NUM> has first and second input voltage input terminals <NUM> and <NUM>, and first and second voltage output terminals <NUM> and <NUM>. Stage <NUM> has first and second input voltage input terminals <NUM> and <NUM>, and first and second voltage output terminals <NUM> and <NUM>.

The first and second voltage input terminals <NUM> and <NUM> of stage <NUM> are respectively connected to first and second power supply input terminals V1 and V2. The first and second voltage output terminals <NUM> and <NUM> of stage <NUM> are respectively connected to the first and second voltage input terminals <NUM> and <NUM> of stage <NUM>. The first and second voltage output terminals <NUM> and <NUM> of stage <NUM> are respectively connected to the first and second voltage input terminals <NUM> and <NUM> of stage <NUM>. The second voltage output terminal <NUM> of stage <NUM> and second voltage input terminal <NUM> of stage <NUM> are respectively connected to first and second power output terminals VO1 and VO2.

Pulse generator circuit <NUM> operates in a charge mode, and in a discharge mode. During the charge mode, described below with reference to <FIG> in more detail, capacitors <NUM>, <NUM>, and <NUM> are charged by current received from the first and second power supply input terminals V1 and V2. During the discharge mode, described below with reference to <FIG> in more detail, capacitors <NUM>, <NUM>, and <NUM> are discharged to provide a current to a load (not shown) connected across first and second power output terminals VO1 and VO2.

<FIG> illustrates pulse generator circuit <NUM> during charge mode. First and second input voltages are respectively applied to first and second power supply input terminals V1 and V2 while each of switch stacks <NUM>, <NUM>, and <NUM> are nonconductive or open, and while first and second power output terminals may be disconnected from the load (not shown). Because each of switch stacks <NUM>, <NUM>, and <NUM> are open, substantially no current flows therethrough, and they are represented as open circuits in <FIG>. During the charge mode, each of capacitors <NUM>, <NUM>, and <NUM> are charged by current flowing through resistors <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> to or toward a voltage equal to the difference between the first and second input voltages.

Each of the switches of switch stacks <NUM>, <NUM>, and <NUM> has a breakdown voltage rating which should not be exceeded. However, because the switches are serially connected, the capacitors <NUM>, <NUM>, and <NUM> may be charged to a voltage significantly greater than the breakdown voltage of the individual switches. For example, the breakdown voltage of the switches may be <NUM> kV, and the capacitors <NUM>, <NUM>, and <NUM> may be charged to a voltage of <NUM> kV, when <NUM> or more switches are used in each switch stack.

For example, the first and second input voltages may respectively be 5kV and 0V. In such an example, each of the capacitors <NUM>, <NUM>, and <NUM> is charged to or toward a voltage equal to 5kV. In some embodiments, the difference between the first and second input voltages is limited to be less than 10kV.

<FIG> illustrates pulse generator circuit <NUM> during discharge mode. First power supply input terminal V1 may be disconnected from the first input voltage. In some embodiments, first power supply input terminal V1 remains connected to the first input voltage. Second power supply input terminal V2 remains connected to the second input voltage. In addition, each of switch stacks <NUM>, <NUM>, and <NUM> are conductive or closed. Because each of switch stacks <NUM>, <NUM>, and <NUM> are closed, current flows therethrough, and they are represented as conductive wires in <FIG>. As a result, a low impedance electrical path from power supply input terminal V2 to power output terminal VO1 is formed by switch stack <NUM>, capacitor <NUM>, switch stack <NUM>, capacitor <NUM>, switch stack <NUM>, and capacitor <NUM>. Consequently, the difference between the voltages at the power output terminals VO1 and VO2 is equal to the number of stages (in this example, <NUM>) times the difference between the first and second input voltages.

Where the first and second input voltages are respectively 5kV and 0V, a voltage difference of 15kV is developed across the power output terminals VO1 and VO2.

<FIG> illustrates an alternative pulse generator circuit <NUM> which may be used inside nsPEF system <NUM> of <FIG>. This pulse generator includes panels in parallel. The number of panels can be adjusted to allow the system to generate different amounts of current and power.

Pulse generator circuit <NUM> receives input pulses across input port Vin, and generates output pulses across output port Vout in response to the received input pulses.

Pulse generator circuit <NUM> includes multiple panels or pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM>. Pulse generator circuit <NUM> also includes driver <NUM>. In this embodiment, four pulse generator circuits are used. In alternative embodiments, fewer or more pulse generator circuits are used. For example, in some embodiments, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or another number of pulse generator circuits are used.

Each of the pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM> may have characteristics similar to other pulse generator circuits discussed herein. For example, each the pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM> may have characteristics similar to pulse generator circuit <NUM> discussed above with reference to <FIG>, <FIG>, and <FIG>.

Each of pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM> has positive and negative DC input terminals, positive and negative control input terminals, and positive and negative output terminals, and is configured to generate output voltage pulses across the positive and negative output terminals in response to driving signal pulses applied across the positive and negative control input terminals. The output voltage pulses are also based on power voltages received across positive and negative DC power input terminals.

The driving signal pulses are generated across conductors <NUM> and <NUM> by driver <NUM>, which includes amplifier circuit <NUM>, capacitor <NUM>, and transformer <NUM>. In some embodiments, driver <NUM> also includes clamp circuits <NUM>.

Driver <NUM> receives an input signal pulse at input port Vin and generates a driving signal pulse across conductors <NUM> and <NUM> in response to the input signal pulse. Amplifier circuit <NUM> receives the input signal pulse and drives transformer <NUM> through capacitor <NUM>, which blocks low frequency and DC signals. In response to being driven by amplifier circuit <NUM>, transformer <NUM> generates an output voltage pulse across conductors <NUM> and <NUM>, such that the duration of the output voltage pulse is equal to or substantially equal (e.g. within <NUM>% or <NUM>%) to the duration of the input signal pulse at input port Vin.

In some embodiments, clamp circuits <NUM> are included at least to dampen potential signals, which may otherwise be caused by resonance. Clamp circuits <NUM> include parallel diodes, which provide a short-circuit path for any current reversal, and also clamp the maximum voltage across the components connected to the clamp circuits <NUM>.

In some embodiments, transformer <NUM> has a <NUM>:<NUM> turns ratio. In alternative embodiments, a different turns ratio is used.

Each of pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM> receives the voltage pulses from driver <NUM> across the positive and negative control input terminals and generates corresponding voltage pulses across the positive and negative output terminals in response to the received voltage pulses from driver <NUM>. The voltage pulses generated across the positive and negative output terminals have durations which are equal to or substantially equal (e.g. within <NUM>% or <NUM>%) to the durations of the voltage pulses received from driver <NUM>.

In this embodiment, the negative output terminals of pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM> are directly connected to the negative Vout terminal of the output port Vout of pulse generator circuit <NUM>. In addition, in this embodiment, the positive output terminals of pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM> are respectively connected to the positive Vout terminal of the output port Vout of pulse generator circuit <NUM> through diodes <NUM>, <NUM>, <NUM>, and <NUM>. Diodes <NUM>, <NUM>, <NUM>, and <NUM> decouple pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM> from one another. As a consequence, interference and the associated pulse distortion that would otherwise occur is substantially eliminated. For example, diodes <NUM>, <NUM>, <NUM>, and <NUM> prevent current from one of pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM> to another of pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM> if the switching is not perfectly synchronous. Diodes <NUM>, <NUM>, <NUM>, and <NUM> also prevent current from flowing from the pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM> while they are charging.

In this embodiment, diodes <NUM>, <NUM>, <NUM>, and <NUM> each include a single diode. In alternative embodiments, diodes <NUM>, <NUM>, <NUM>, and <NUM> each include multiple diodes connected serially based at least upon voltage ratings of the serially connected diodes.

In this embodiment, diodes <NUM>, <NUM>, <NUM>, and <NUM> are connected so as to conduct current from the positive terminal of output port Vout toward pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM>, as pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM> in this embodiment are configured to generate negative pulses. In alternative embodiments, where pulse generator circuits are configured to generate positive pulses, diodes may be similarly connected so as to conduct current from the pulse generator circuits to the positive terminal of the output port.

<FIG> illustrates a pulse generator circuit <NUM> which may be used for pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM> of pulse generator circuit <NUM> of <FIG>.

Pulse generator circuit <NUM> includes multiple pulse generator stages <NUM>, <NUM>, and <NUM>. In this embodiment, pulse generator circuit <NUM> also includes driver <NUM>, and optional common mode chokes <NUM>, <NUM>, and <NUM>.

Each of the pulse generator stages <NUM>, <NUM>, and <NUM> may have characteristics similar to other pulse generator stages discussed herein. For example, each the pulse generator stages <NUM>, <NUM>, and <NUM> may have characteristics similar to stages <NUM>, <NUM>, and <NUM> of pulse generator circuit <NUM> discussed above with reference to <FIG>, <FIG>, and <FIG>. In some embodiments, fewer or more pulse generator stages may be used.

Each of pulse generator stages <NUM>, <NUM>, and <NUM> has positive and negative trigger input terminals, power positive and negative DC input terminals, and positive and negative Vo output terminals, and is configured to generate output voltage pulses across the positive and negative Vo output terminals in response to driving signal pulses applied across the positive and negative trigger input terminals. The output voltage pulses are also based on power voltages V1 and V2 respectively received at power positive and negative DC input terminals.

In this embodiment, the negative Vi input terminal of pulse generator stage <NUM> is connected with the negative terminal of the output port Vout of pulse generator circuit <NUM>. In addition, in this embodiment, the negative Vo output terminal of pulse generator stage <NUM> is connected with the positive terminal of the output port Vout of pulse generator circuit <NUM>.

In addition, as shown, the positive Vo output terminal of pulse generator <NUM> is connected with the positive Vi input terminal of pulse generator <NUM>, and the negative Vo output terminal of pulse generator <NUM> is connected with the negative Vi input terminal of pulse generator <NUM>. Furthermore, the positive Vo output terminal of pulse generator <NUM> is connected with the positive Vi input terminal of pulse generator <NUM>, and the negative Vo output terminal of pulse generator <NUM> is connected with the negative Vi input terminal of pulse generator <NUM>.

The driving signal pulses for pulse generator stages <NUM>, <NUM>, and <NUM> are generated across conductors <NUM> and <NUM> by driver <NUM>, which includes amplifier circuit <NUM>, capacitor <NUM>, and transformer <NUM>. In some embodiments, driver <NUM> also includes clamp circuits <NUM>.

Driver <NUM> receives an input signal pulse at input port Vin, which is connected to conductors <NUM> and <NUM>, as shown in <FIG> discussed above. Driver <NUM> generates a driving signal pulse across conductors <NUM> and <NUM> in response to the input signal pulse. Amplifier circuit <NUM> receives the input signal pulse, and drives transformer <NUM> through capacitor <NUM>, which reduces or blocks low frequency and DC signals. In response to being driven by amplifier circuit <NUM>, transformer <NUM> generates an output voltage pulse across conductors <NUM> and <NUM>, such that the duration of the output voltage pulse is equal to or substantially equal (e.g. within <NUM>% or <NUM>%) to the duration of the input signal pulse at input port Vin.

Each of pulse generator stages <NUM>, <NUM>, and <NUM> receives the voltage pulses from driver <NUM> through a corresponding choke <NUM>, <NUM>, or <NUM>, which blocks high frequency signals, for example, from coupling from the high voltage pulse generator stages <NUM>, <NUM>, and <NUM>. The voltage pulses are received at the positive and negative trigger input terminals and the pulse generator stages <NUM>, <NUM>, and <NUM> each generate corresponding voltage pulses across the positive and negative Vo output terminals in response to the received voltage pulses from driver <NUM>. The voltage pulses generated across the positive and negative Vo output terminals have durations which are equal to or substantially equal (e.g. within <NUM>% or <NUM>%) to the durations of the voltage pulses received from driver <NUM>.

<FIG> illustrates a pulse generator stage <NUM> which may be used as one of the pulse generator stages <NUM>, <NUM>, and <NUM> of pulse generator circuit <NUM> shown in <FIG>.

Pulse generator stage <NUM> receives trigger pulses across input port trigger input, and generates output voltages at output port Vout in response to the received trigger pulses. The output voltages are also generated based on power voltages received at power input terminals V1 and V2. Pulse generator stage <NUM> includes multiple switch drivers <NUM>. Pulse generator stage <NUM> also includes switch stack <NUM>, capacitor <NUM>, and resistors <NUM> and <NUM>.

Switch drivers <NUM> are configured to receive the trigger pulses, and to generate control signals for the switches of switch stack <NUM> in response to the received trigger pulses, as discussed in further detail below. Each of the control signals is referenced to a voltage specific to the switch being driven. Accordingly, a first switch receives a control signal pulse between first and second voltages, and a second switch receives a control signal pulse between third and fourth voltages, where each of the first, second, third, and fourth voltages are different. In some embodiments, the difference between the first and second voltages is substantially the same as the difference between the third and fourth voltages.

Switch stack <NUM>, capacitor <NUM>, and resistors <NUM> and <NUM> cooperatively function with corresponding elements in the other pulse generator stages of pulse generator circuit <NUM>, discussed above with reference to <FIG>, to generate the voltage pulses across the positive and negative Vo output terminals of pulse generator circuit <NUM>. These elements may, for example, cooperatively function as the corresponding elements discussed above with reference to pulse generator circuit <NUM> shown in <FIG>, <FIG>, and <FIG>. For example, these elements may cooperate to generate the voltage pulses across the positive and negative Vo output terminals of pulse generator circuit <NUM> in response to the power voltages applied to power input terminals V1 and V2 and to the control signals applied to the switches of switch stack <NUM>.

Because the control signals are generated in response to the input pulses received across input port Vin of pulse generator circuit <NUM> illustrated in <FIG> through multiple stages of driving, the control signals cause all of the switches of the switch stacks of pulse generator circuit <NUM> to be turned on and to be turned off substantially simultaneously. For example, a 15V input pulse having a duration of, for example <NUM> ns, received at input port Vin of pulse generator circuit <NUM> may cause the pulse generator circuit <NUM> to generate a high-voltage (e.g. ~<NUM> kV) output pulse having a duration of about <NUM> ns. Similarly, a 15V input pulse having a duration of, for example <NUM>, received at input port Vin of pulse generator circuit <NUM> may cause the pulse generator circuit <NUM> to generate a high-voltage (e.g. ~<NUM> kV) output pulse having a duration of about <NUM>. Accordingly, the duration of the high-voltage output pulse is substantially the same as a selected duration of an input pulse.

<FIG> illustrates a switch driver <NUM> which may be used as one of the switch drivers shown in <FIG>.

Switch driver <NUM> receives trigger pulses across input port Vin, and generates control signal pulses at output port Vout in response to the received trigger pulses. Switch driver <NUM> includes amplifier circuit <NUM>, capacitor <NUM>, and transformer <NUM>. In some embodiments, switch driver <NUM> also includes clamps circuits <NUM>.

Amplifier circuit <NUM> receives the trigger pulses, and drives transformer <NUM> through capacitor <NUM>, which reduces or blocks low frequency and DC signals. In response to being driven by amplifier circuit <NUM>, transformer <NUM> generates control signal pulses at output port Vout, such that the duration of the control signal pulses is equal to or substantially equal (e.g. within <NUM>% or <NUM>%) to the duration of the trigger pulses at input port Vin.

In some embodiments, amplifier circuit <NUM> includes multiple amplifier integrated circuits. For example, for increased current driving capability, multiple amplifier integrated circuits may be connected in parallel to form amplifier circuit <NUM>. For example, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or another number of amplifier integrated circuits may be used.

In some embodiments, the drivers <NUM>, <NUM>, and <NUM> receive power from a DC-DC power module which is isolated from the power supply for the Marx generator. This ensures the cutoff of ground coupling.

In some embodiments, in order to obtain very fast switching, the transformers <NUM> has fewer than <NUM> turns in the primary winding and fewer than <NUM> turns in the secondary winding. For example, in some embodiments, the transformer <NUM> has <NUM>, <NUM>, <NUM>, or <NUM> turns in each of the primary and secondary windings. In some embodiments, the transformer <NUM> has less than a complete turn, for example, ½ turn in the primary and secondary windings. The low number of turns in each of the primary and secondary windings allows for a low inductance loop and increases the current risetime in the secondary winding, which charges the input capacitance of the MOSFET switches.

Transformers for triggering MOSFETs in conventional applications require high coupling, high permeability, and a low-loss core in order to ensure current transfer efficiency. From pulse to pulse, the residual flux in the core needs to be cleared in order to avoid saturation when the transformer is operated at high frequency. Conventionally, a resetting circuit, which involves a third winding, to dissipate the core energy is used.

In some embodiments, lossy transformers, such as that typically used as an electromagnetic interference (EMI) choke to confine high frequency signals and dissipate their energy as heat are used to trigger the switches. For example, the transformers may have a voltage time constant less than 100Vµs. In some embodiments, the Transformers have a voltage time constant less than 50Vµs, 30Vµs, 20Vµs, 10Vµs, or 5Vµs. The use of the lossy transformer is contrary to the common practice in power electronics.

Although the high frequency flux is dampened due to the loss of the core (eddy loss, hysteresis loss, and resistive loss), the lossy transformers still allow sufficient confinement of the magnetic flux and provides sufficient coupling. In addition, the flux also decreases quickly in response to the signal on the primary winding being removed. The flux decay process usually takes approximately several microseconds.

Having such a transformer conventionally seems disadvantageous, but for coupling nanosecond to a few microsecond pulses, such a transformer is preferably used. Consequently, the following benefits are achieved: <NUM>) high voltage, high frequency transient coupling from the high-voltage Marx generators to the low-voltage drivers is suppressed; <NUM>) because of the loss in the transformer cores, the residual flux from previous pulses are dissipated faster than common low-loss transformer cores, such that the resetting winding is not needed and is not present.

A benefit of the switch driver <NUM> is that it limits the output pulse duration. Because the switch control signals are generated by transformer <NUM>, even if circuitry generating the input trigger signals at input port Vin were to generate a pulse of indefinite length, the transformer would saturate, causing the control signals to turn off the switches.

<FIG> illustrates an example of a switch element <NUM> comprising components which may be used in the switch stacks discussed here. Switch element <NUM> includes switch <NUM>, and selectively forms a conductive or low resistance path between terminals VA and VB in response to a control voltage applied to input port Vin.

In some embodiments, switch <NUM> is a transistor, such as a MOSFET. In some embodiments, switch <NUM> is another type of switch. In some embodiments, switch <NUM> has a turn on time of less than <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, about <NUM> ns, or greater than <NUM> ns.

In some embodiments, switch element <NUM> also includes snubber circuit <NUM>. In some embodiments, the turn on times of the switches of the switch stacks are not identical. In order to prevent voltages greater than that which switch <NUM> can tolerate, snubber circuit <NUM> provides a current shunt path bypassing switch <NUM>. Diodes <NUM> provide a low-frequency current path, and the combination of the capacitor <NUM> and resistor <NUM> provide a high-frequency current path.

In some embodiments, switch element <NUM> also includes optional overcurrent protection circuit <NUM>. Overcurrent protection circuit <NUM> includes switch <NUM> and sense resistor <NUM>.

Current flowing from terminal VA to terminal VB is conducted through sense resistor <NUM>. Accordingly, a voltage is generated across sense resistor <NUM> when the current flows from terminal VA to terminal VB. The generated voltage controls a conductive state of switch <NUM>. If the current flowing from terminal VA to terminal VB is greater than a threshold, the generated voltage causes the switch <NUM> to conduct. As a result, switch <NUM> reduces the control voltage of switch <NUM>. In response to the reduced control voltage, switch <NUM> becomes less conductive or turns off. Consequently, the current which may be conducted from terminal VA to terminal VB is limited by overcurrent protection circuit <NUM>.

In some embodiments, a current limiting resistor is placed between the gate of switch <NUM> and the drain of switch <NUM> to prevent switch <NUM> from experiencing current greater than that which would cause damage.

In the embodiments discussed herein, MOSFET switches are used. In alternative embodiments, other switches are used. For example, in some embodiments, thyristors, IGBTs or other semiconductor switches are used.

An example of the operation of the transformer is illustrated in <FIG>. The voltage at the input primary inductor is substantially a square waveform, but the voltage at the secondary inductor, which is the MOSFET's gate-source voltage, tapers as the voltage magnitude decreases toward zero, for example, within a period of several microseconds. After a reduction in voltage at the secondary inductor due to transformer saturation, the switch receiving the voltage enters a linear region of operation from a saturation region of operation when the voltage is lower than the fully enhanced Vgs. As a result, the resistance of the switch increases and the output voltage across the load also shows a tapered profile. When the voltage at the secondary inductor decreases to a value less than the turn-on threshold of a MOSFET (Vth), the MOSFET will be shut off. Once the MOSFET is off, even if the duration of the trigger signal is extended, the switch no longer conducts and can be considered an open circuit. The waveform of the voltage at the secondary inductor therefore limits the duration of high voltage output pulses from each panel, for example, to be several microseconds or less.

In some embodiments, the duration of the trigger signal is short enough that the switches remain in saturation because the reduction in voltage at the secondary inductor is insufficient to cause the switches to enter linear region operation. In such embodiments, the load voltage pulses do not exhibit the tapering illustrated in <FIG>. For example, in such embodiments the load voltage pulses may be substantially square.

In some embodiments, the switch stacks discussed herein include switches, as discussed above, as well as other components.

In some embodiments, when generating pulses of a duration less than a threshold, the shape of the pulses are substantially square. In some embodiments, when generating pulses of the duration greater than a threshold, the shape of the pulses are substantially square for a duration substantially equal (e.g. within <NUM>% or <NUM>%) to the threshold. During the time after the threshold, the voltage of such long pulses drops toward <NUM> V. In some embodiments, the drop toward <NUM> V is substantially linear. In some embodiments, the drop toward <NUM> V is substantially exponential.

<FIG> illustrates an alternative pulse generator circuit <NUM> which may be used inside nsPEF system <NUM> of <FIG>.

Pulse generator circuit <NUM> receives input pulses across input port Vin and DC voltages at input ports VDC1 and VDC2, and generates output pulses across output port Vout in response to the received input pulses and DC voltages.

Pulse generator circuit <NUM> includes multiple pulse generator circuits <NUM> and <NUM>. In this embodiment, two pulse generator circuits are used. In alternative embodiments, more pulse generator circuits are used. For example, in some embodiments, <NUM>, <NUM>, <NUM>, <NUM> or another number of pulse generator circuits having their output ports serially connected, as discussed below with reference to pulse generator circuit <NUM>, are used.

Each of pulse generator circuits <NUM> and <NUM> may be similar to the other pulse generator circuits discussed herein. For example pulse generator circuits <NUM> and <NUM> may be similar to or may be substantially identical to pulse generator circuit <NUM> discussed above with reference to <FIG>.

Each of pulse generator circuits <NUM> and <NUM> receive the same input pulse signal across their respective Control In input ports. In response, each of pulse generator circuits <NUM> and <NUM> generate high voltage pulses across their respective Vout output ports. Because the Vout output ports of pulse generator circuits <NUM><NUM> are serially connected, the voltage pulse generated by pulse generator circuits <NUM> and <NUM> across output port Vout of pulse generator circuit <NUM> is substantially equal (e.g. within <NUM>% or <NUM>%) to the sum of the voltages of the pulses respectively generated by pulse generator circuits <NUM> and <NUM>.

<FIG> illustrates an alternative pulse generator circuit <NUM> which may be used inside nsPEF system <NUM> of <FIG>, and which has characteristics similar to the pulse generator <NUM> of <FIG>. Pulse generator circuit <NUM> includes pulse generators <NUM> and <NUM>, drivers <NUM> and <NUM>, and power supplies <NUM> and <NUM>.

Pulse generator circuit <NUM> includes multiple pulse generator circuits <NUM> and <NUM>. In this embodiment, two pulse generator circuits are used. In alternative embodiments, more pulse generator circuits are used. Each of pulse generator circuits <NUM> and <NUM> may be similar to the other pulse generator circuits discussed herein.

Pulse generator circuit <NUM> receives input pulses at each of drivers <NUM> and <NUM>, which may be similar to driver <NUM> discussed above with reference to <FIG>. Pulse generator circuit <NUM> generates output pulses across output port Vout in response to the received input pulses. The output voltage pulses are also based on power voltages received from power supplies <NUM> and <NUM>.

Each of drivers <NUM> and <NUM> receive an input pulse signal. In response to the received input signals, drivers <NUM> and <NUM> respectively generate driving signal pulses for pulse generator circuits <NUM> and <NUM>. In response to the driving signal pulses, each of pulse generator circuits <NUM> and <NUM> generate high voltage pulses across their respective output ports Vo1 and Vo2. Because the Vo1 and Vo2 output ports of pulse generator circuits <NUM> and <NUM> are serially connected, the voltage pulse generated by pulse generator circuits <NUM> and <NUM> across output port Vout of pulse generator circuit <NUM> is substantially equal (e.g. within <NUM>% or <NUM>%) to the sum of the voltages of the pulses respectively generated by pulse generator circuits <NUM> and <NUM>.

In this embodiment, pulse generator circuit <NUM> generates a high voltage pulse across its output port Vo1 which is substantially equal (e.g. within <NUM>% or <NUM>%) to three times the voltage of power supply <NUM>, (-<NUM> x [V1 - V2]). In addition, pulse generator circuit <NUM> generates a high voltage pulse across its output port Vo2 which is substantially equal (e.g. within <NUM>% or <NUM>%) to three times the voltage of power supply <NUM> (<NUM> x [V'<NUM> - V'<NUM>]). As a result, pulse generator circuit <NUM> generates a voltage of (<NUM> x [V'<NUM> - V'<NUM>]) - (-<NUM> x [V1 - V2]) across its output port Vout.

In some embodiments, a single driver circuit connected to both pulse generator circuit <NUM> and <NUM> is used instead of drivers <NUM> and <NUM>. In such embodiments, the single driver circuit generates driving signal pulses for both pulse generator circuits <NUM> and <NUM> in response to an input pulse signal.

<FIG> is a block diagram of a nsPEF treatment system <NUM>, which has characteristics similar to or identical to those of nsPEF system <NUM> illustrated in <FIG>. NsPEF treatment system <NUM> includes pulse generator <NUM>, power supply <NUM>, nsPEF pulse applicator <NUM>, interface <NUM>, and controller <NUM>.

Pulse generator <NUM> may be similar or identical to any of the pulse generator circuits discussed herein. For example, pulse generator <NUM> may be configured to generate pulses having a voltage magnitude corresponding with power voltages received from power supply <NUM> and having pulse widths and other characteristics corresponding with control signals received from controller <NUM>. In alternative embodiments, other pulse generator circuits may be used.

NsPEF pulse applicator <NUM> may be similar or identical to any of the nsPEF pulse applicators discussed herein. For example, nsPEF pulse applicator <NUM> may be similar or identical to nsPEF pulse applicators <NUM> and <NUM> discussed above with reference to <FIG> and <FIG>. NsPEF pulse applicator <NUM> is configured to receive nsPEF pulses generated by pulse generator <NUM> from conductor <NUM> and is configured to deliver nsPEF pulses to a patient or experiment subject undergoing therapeutic nsPEF treatment. In alternative embodiments, other therapeutic nsPEF pulse applicators may be used.

Sensor <NUM> may include one or more of a thermocouple, a voltage probe, a current probe, an impedance probe, a capacitance probe, a light sensor, a humidity sensor, a tissue monitoring probe, and a chemical analysis probe. Sensor <NUM> may be configured to sense one or more characteristics of the patient or experiment subject, the nsPEF pulse applicator <NUM>, the nsPEF pulses delivered by the nsPEF pulse applicator <NUM>, and effects of the nsPEF pulses delivered by the nsPEF pulse applicator <NUM>.

Power supply <NUM> is configured to provide power voltages to pulse generator <NUM>. For example, in embodiments where pulse generator <NUM> is similar to pulse generator circuit <NUM> illustrated in <FIG>, power supply <NUM> may be configured to provide power voltages corresponding with power voltages V1 and V2 of pulse generator circuit <NUM>. In some embodiments, power supply <NUM> generates and provides power voltages which have a voltage level corresponding with a control signal from controller <NUM>.

Interface <NUM> is configured to receive input from a user identifying various parameters and characteristics of the nsPEF pulses to be applied to the patient or experiment subject. For example, interface <NUM> may be configured to receive input identifying or specifying values for one or more characteristics of one or more nsPEF pulses to be applied to the patient or experiment subject. For example, the characteristics may include one or more of an amplitude, a polarity, a width, a rise time, and a fall time of one or more nsPEF pulses to be applied to the patient or experiment subject. Additionally or alternatively, the characteristics may include one or more of a frequency and a pulse quantity of a sequence of nsPEF pulses to be applied to the patient or experiment subject. Furthermore, the characteristics may additionally or alternatively include a result of the nsPEF pulses to be applied to the patient or experiment subject, such as a maximum temperature for the treated tissue of the patient or experiment subject. Other characteristics may additionally or alternatively be identified or specified by the received input.

In addition, interface <NUM> is configured to communicate the characteristics identified or specified by the received input to controller <NUM>.

Controller <NUM> is configured to generate and provide one or more control signals to pulse generator <NUM> and to power supply <NUM> based at least partly on the communicated characteristics received from interface <NUM>. Additionally, pulse generator <NUM>, power supply <NUM>, and nsPEF pulse applicator <NUM> are collectively configured to, in response to the control signals from controller <NUM>, generate nsPEF pulses having characteristics corresponding with the control signals.

In this embodiment, one or more of pulse generator <NUM>, nsPEF pulse applicator <NUM>, and sensor <NUM> are configured to generate corresponding feedback signals FB1, FB2, and FB3 representing measured parametric characteristics of the nsPEF pulses applied to the patient or experiment subject or other signals of nsPEF treatment system <NUM>. In some embodiments, the parametric characteristics of the nsPEF pulses represented by the feedback signals FB1, FB2, and FB3 include one or more of an amplitude, a polarity, a width, a rise time, and a fall time of the nsPEF pulses. In some embodiments, the parametric characteristics of the nsPEF pulses represented by the feedback signals, FB2, and FB3 additionally or alternatively include one or more of current and voltage applied to the tissue so that one or more of tissue impedance, tissue inductance, tissue capacitance, instantaneous power applied to the tissue, and energy applied to the tissue may be calculated. In some embodiments, the parametric characteristics represented by the feedback signal FB1 may additionally or alternatively include one or more of a voltage at a capacitor being charged during a charge mode of pulse generator <NUM>, voltage and/or current characteristics of a control signal of pulse generator <NUM>, voltage and/or current characteristics of a power supply signal of pulse generator <NUM>, voltage and/or current characteristics of a pulse generated by pulse generator <NUM>, and voltage and/or current characteristics of another input, output, or internal signal of pulse generator <NUM>. Additionally or alternatively, the parametric characteristics may include a frequency of a sequence of nsPEF pulses. Furthermore, the parametric characteristics may additionally or alternatively include a temperature of the treated tissue of the patient or experiment subject. The feedback signals, FB2, and FB3 may correspond or represent other measured parametric characteristics of one or more of the nsPEF pulses applied to the patient or experiment subject, the patient or experiment subject, the environment, and the nsPEF treatment system <NUM>.

In some embodiments, controller <NUM>, power supply <NUM>, pulse generator <NUM>, nsPEF pulse applicator <NUM>, and optionally sensor <NUM> collectively form a feedback loop which causes one or more parametric characteristics of the nsPEF pulses applied to the patient or experiment subject to have measured values substantially equal (e.g. within <NUM>% or <NUM>%) to the values of corresponding characteristics identified in the input received by interface <NUM>.

For example, interface <NUM> may receive input specifying a value of 15kV for an amplitude of the nsPEF pulses applied to the patient or experiment subject. In addition, the controller <NUM> may be configured to, in response to a feedback signal FB2 from nsPEF pulse applicator <NUM>, a feedback signal FB1 from pulse generator <NUM>, or a feedback signal FB3 from sensor <NUM> indicating that the measured amplitude of the nsPEF pulses applied to the patient or experiment subject is less than (or greater than) 15kV, change a control signal provided to power supply <NUM>. In response to the changed control signal, power supply <NUM> may be configured to increase (or decrease) the voltage of power signals provided to pulse generator <NUM> such that the amplitude of the nsPEF pulses generated and applied to the patient or experiment subject increases (or decreases) to or toward 15kV.

Similarly, interface <NUM> may receive input specifying a value of 150ns for a pulse width of the nsPEF pulses applied to the patient or experiment subject. The controller <NUM> may be configured to, in response to a feedback signal FB3 from sensor <NUM>, a feedback signal FB2 from nsPEF pulse applicator <NUM>, or a feedback signal FB1 from pulse generator <NUM> indicating that the measured pulse width of the nsPEF pulses applied to the patient or experiment subject is greater than (or less than) 150ns, change a control signal provided to pulse generator <NUM>. In response to the changed control signal, pulse generator <NUM> may be configured to generate and apply to the patient or experiment subject nsPEF pulses having decreased (or increased) pulse width. As a result, one or more of the feedback signals FB1, FB2, and FB3 causes the controller <NUM> to generate control signals which cause the pulse generator <NUM> to generate and apply nsPEF pulses having pulse widths decreased (or increased) to or toward 150ns.

In some embodiments, the feedback loop is controlled using a Proportional-Integral-Derivative (PID) method. For example, using the PID method, controller <NUM> may be configured to continuously or substantially continuously calculate an error value as the difference between a desired value perceived at interface <NUM> and a corresponding measured parameter. In addition, using the PID method, controller <NUM> may be configured to continuously or substantially continuously calculate the control signals as a sum of one or more of: a first constant times the error signal, a second constant times an integral of the error signal, and a third constant times a derivative of the error signal, where the first, second, and third constants may be positive, negative, or equal to zero. Other custom or standard control methods may additionally or alternatively be used.

In some embodiments, the feedback loop is controlled using a lookup table to determine a next value based on a measured value. In some embodiments, the feedback loop is controlled by reducing or increasing a value by a fixed amount or step size based on a determination of whether a measured value is greater than or less than a threshold.

<FIG> illustrates an alternative pulse generator <NUM> which may be used as pulse generator <NUM> of nsPEF treatment system <NUM> illustrated in <FIG>. Pulse generator <NUM> may have features similar to or identical to other pulse generator circuits discussed herein. For example, pulse generator circuit <NUM> may have features similar to or identical to pulse generator circuit <NUM> of <FIG>.

For example, pulse generator <NUM> includes the driver circuit <NUM> which may be similar to or identical to driver <NUM> of pulse generator circuit <NUM>. In addition, pulse generator <NUM> includes pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM>, which may respectively be similar or identical to pulse generator circuits <NUM>, <NUM>, <NUM>, and <NUM>.

Pulse generator <NUM> also includes, or in some embodiments is connected to, analog-to-digital converter <NUM>. Furthermore, pulse generator <NUM> additionally or alternatively includes, or in some embodiments is connected to, current monitors <NUM> and <NUM>.

In this embodiment, analog-to-digital (A/D) converter <NUM> includes a first channel having inputs which are respectively connected to the positive (+) and negative (-) voltage output terminals of pulse generator <NUM>. In some embodiments, a first low input impedance differential buffer (not shown) is connected to the positive (+) and negative (-) voltage output terminals of pulse generator <NUM>, and drives the inputs of analog-to-digital converter <NUM>. In some embodiments, a probe, such as a Tektronix P6015A Passive High Voltage Probe (not shown) is connected to the positive (+) and negative (-) voltage output terminals of pulse generator <NUM>, and drives the inputs of analog-to-digital converter <NUM>.

In some embodiments, only the positive (+) voltage output terminal is connected to analog-to-digital converter <NUM>. In some embodiments, the positive (+) voltage output terminal is connected to analog-to-digital converter <NUM> through a voltage divider. In such embodiments, the voltage at the positive (+) voltage output terminal is ground referenced, and the ground is also connected to analog-to-digital converter <NUM>. For example, the positive (+) voltage output terminal is ground referenced if the negative (-) voltage output terminal of pulse generator <NUM> is at the ground voltage.

In addition, analog-to-digital converter <NUM> is configured to generate a first digital output representing the voltage difference between the positive (+) and negative (-) voltage output terminals of pulse generator <NUM>. When used in the nsPEF treatment system <NUM> of <FIG>, the first digital output may be used as a feedback signal for controller <NUM>. In some embodiments, analog-to-digital converter <NUM> generates the first digital output based on either, but not both, of the voltages at the positive (+) and negative (-) voltage output terminals.

In this embodiment, analog-to-digital converter <NUM> also includes a second channel having inputs which are respectively connected to the current monitors <NUM> and <NUM>, and the current monitors <NUM> and <NUM> are respectively connected to the positive (+) and negative (-) voltage output terminals of pulse generator <NUM>. In some embodiments, a second low input impedance differential buffer (not shown) is connected to the current monitors <NUM> and <NUM>, and drives the inputs of analog-to-digital converter <NUM>.

In addition, analog-to-digital converter <NUM> is configured to generate a second digital output representing the current difference between the currents flowing through positive (+) and negative (-) voltage output terminals of pulse generator <NUM>. When used in the nsPEF treatment system <NUM> of <FIG>, the second digital output may be used as a feedback signal for controller <NUM>. In some embodiments, analog-to-digital converter <NUM> generates the second digital output based on either, but not both, of inputs from the current monitors <NUM> and <NUM>.

In some embodiments, current monitors <NUM> and <NUM> each include a sense resistor and an amplifier. The sense resistor is configured to generate a voltage response of the current flowing therethrough, and the amplifier generates an input for the analog-to-digital converter based on the voltage across the sense resistor.

In some embodiments, current monitors <NUM> and <NUM> include a current monitor, such as Pearson Current Monitor <NUM>, which generates a voltage in response to a sensed current.

In some embodiments, pulse generator <NUM> generates either, but not both, of the first and second digital outputs. In some embodiments, one or more single channel analog-to-digital converters are used instead of or in addition to analog-to-digital converter <NUM>.

In some embodiments, only single current monitor is used. The single current monitor may monitor the current of either of the positive (+) and negative (-) voltage output terminals of pulse generator <NUM>.

<FIG> schematically illustrate multiple views of an nsPEF pulse applicator <NUM> which may, for example, be used as nsPEF pulse applicator <NUM> in nsPEF treatment system <NUM> of <FIG>. NsPEF pulse applicator <NUM> may have characteristics similar to or identical to any of the nsPEF pulse applicators discussed herein. For example, nsPEF pulse applicator <NUM> may have characteristics similar to or identical to nsPEF pulse applicators <NUM> and <NUM> discussed above with reference to <FIG> and <FIG>.

NsPEF pulse applicator <NUM> includes bottom arm <NUM>, spacer <NUM>, and top arm <NUM> connected together by fastener <NUM>. Bottom arm <NUM> includes bottom electrode <NUM>, which is connected to one of the conductive wires <NUM>. Top arm <NUM> includes top electrode <NUM>, which is connected to the other of the conductive wires <NUM>.

NsPEF pulse applicator <NUM> is configured to receive nsPEF pulses across conductive wires <NUM> and to deliver nsPEF pulses to a patient or experiment subject undergoing nsPEF treatment through top and bottom electrodes <NUM> and <NUM>. The nsPEF pulses may, for example, be applied to a tumor of the patient or experiment subject which is positioned within a cavity <NUM> of spacer <NUM>. Cavity <NUM> forms a gap between top and bottom electrodes <NUM> and <NUM>. In some applications, the tumor is connected to the patient or experiment subject by tissue which passes from the tumor within cavity <NUM> to the patient or experiment subject between spacer <NUM> and bottom arm <NUM>. In some embodiments, cavity <NUM> is formed such that the gap between top and bottom electrodes <NUM> and <NUM> is open. For example, a portion of the gap may not be bounded by spacer <NUM>, top arm <NUM>, or bottom arm <NUM>.

As shown, for example in <FIG>, bottom arm <NUM> is separated from top arm <NUM> by spacer <NUM> near cavity <NUM>. In addition, near fastener <NUM>, bottom arm <NUM> is adjacent to top arm <NUM>. In <FIG>, NsPEF pulse applicator <NUM> is illustrated as if an external force is applied to bottom arm <NUM> causing bottom arm <NUM> to be separated from spacer <NUM> near cavity <NUM>. In <FIG>, NsPEF pulse applicator <NUM> is illustrated as if the external force is not applied to bottom arm <NUM>. As a result, bottom arm <NUM> is substantially not separated from spacer <NUM> near cavity <NUM>, as illustrate in <FIG>. In some embodiments, if no external force is applied causing bottom arm <NUM> to be separated from spacer <NUM> near cavity <NUM>, bottom arm <NUM> is pressed against spacer <NUM> by a force exerted by fastener <NUM>.

When the top arm <NUM> and the spacer <NUM> are positioned relative to one another as shown in <FIG>, top arm <NUM> is spaced apart from spacer <NUM> by bump feature <NUM>. In addition, when the top arm <NUM> and the spacer <NUM> are positioned relative to one another as shown in <FIG>, top arm <NUM> is substantially not spaced apart from or contacts spacer <NUM>. This occurs because when the top arm <NUM> and the spacer <NUM> are positioned as shown in <FIG>, bump feature <NUM> is not aligned with divot <NUM> of top arm <NUM>, illustrated, for example in <FIG>. When not aligned, bump feature <NUM> presses against top arm <NUM> causing the separation of spacer <NUM> and top arm <NUM>. In contrast, when the top arm <NUM> and the spacer <NUM> are positioned as shown in <FIG>, bump feature <NUM> aligns with divot <NUM> of top arm <NUM> and prevents the top arm <NUM> from rotating with respect to spacer <NUM>, and top arm <NUM> and the spacer <NUM> are near or in contact with one another as a result of a force applied by fastener <NUM>. In some embodiments, the same or similar result may be achieved with a bump feature in top arm <NUM> and a corresponding divot in spacer <NUM>.

To insert a tumor into nsPEF pulse applicator <NUM>, top arm <NUM> may be rotated such that top electrode <NUM> is out of alignment with cavity <NUM>, and such that cavity <NUM> is viewable, for example, as illustrated in <FIG>. A force may also be applied to bottom arm <NUM> causing bottom arm <NUM> to separate from spacer <NUM> near cavity <NUM>, for example, as illustrated in <FIG>. The tumor may then be placed in the cavity <NUM> such that tissue connecting the tumor with the patient is between bottom arm <NUM> and spacer <NUM>. In some applications, the tumor is not connected to the subject, and the tumor is enclosed within cavity <NUM>.

An advantageous aspect of nsPEF pulse applicator <NUM> is that while the tumor is placed in the cavity <NUM>, top arm <NUM> is spaced apart from cavity <NUM>, and the cavity <NUM> is viewable to visually confirm that the tumor is properly placed.

The applied force may then be removed such that bottom arm <NUM> presses the connecting tissue against spacer <NUM>. The bottom arm <NUM> presses the connecting tissue against spacer <NUM> in response to the removal of the applied force because of a restorative force generated by the shape of the compliant top arm <NUM> and the fastener <NUM>. In alternative embodiments, the bottom arm <NUM> may press the connecting tissue against spacer <NUM> in response to a force generated by a compression spring, for example between <NUM> and bottom arm <NUM> near or circumscribing fastener <NUM>.

An advantageous aspect of nsPEF pulse applicator <NUM> is that while bottom arm <NUM> is allowed to press the connecting tissue against spacer <NUM>, top arm <NUM> is spaced apart from cavity <NUM>, and the cavity <NUM> is viewable to visually confirm that the tumor is properly placed when secured by bottom arm <NUM>.

Top arm <NUM> may then be rotated so as to align or substantially align top electrode <NUM> with the cavity <NUM> containing the tumor. As discussed above, when top arm <NUM> is rotated, bump feature <NUM> causes top arm <NUM> to separate from spacer <NUM> until top arm <NUM> is at or near the desired alignment, where the top arm <NUM> is pressed toward or against spacer <NUM>. In some embodiments, bump feature <NUM> prevents the combination of top arm <NUM> and spacer <NUM> from generating shearing forces on any connecting tissue or tumor protruding from the cavity <NUM>, which could otherwise damage the protruding connecting tissue or tumor.

An advantageous aspect of nsPEF pulse applicator <NUM> is that while top arm <NUM> is rotated, the cavity <NUM> is viewable to visually confirm that the tumor is properly placed during the rotation.

Once the tumor is inserted into the cavity <NUM> and the top and bottom electrodes <NUM> and <NUM> are positioned, the nsPEF pulse applicator <NUM> may be used to apply nsPEF pulses to the tumor by applying nsPEF pulses to the conductive wires <NUM>. In response to the nsPEF pulses applied to the wires, the top and bottom electrodes <NUM> and <NUM> generate an electric field across the cavity and therefore across the tumor within the cavity.

Once the nsPEF treatment is finished, the tumor may be removed from the nsPEF pulse applicator <NUM> by applying a force to bottom arm <NUM> causing bottom arm <NUM> to separate from spacer <NUM> near cavity <NUM>, for example, as illustrated in <FIG>, and removing the tumor.

In alternative embodiments, a bottom arm having features similar to bottom arm <NUM> is spaced apart from a top arm having features similar to top arm <NUM> by a spacer, such that without a force applied, the bottom and top arms are spaced apart from the spacer, and in response to a force applied thereto the bottom and top arms may be pressed against the spacer.

<FIG> schematically illustrate multiple views of an nsPEF pulse applicator <NUM> which may, for example, be used as nsPEF pulse applicator <NUM> in nsPEF treatment system <NUM> of <FIG>. NsPEF pulse applicator <NUM> may have characteristics similar to or identical to any of the nsPEF pulse applicators discussed herein. For example, nsPEF pulse applicator <NUM> may have characteristics similar to or identical to nsPEF pulse applicators <NUM>, <NUM>, and <NUM> discussed above with reference to <FIG>, <FIG>, and <FIG>.

NsPEF pulse applicator <NUM> includes bottom arm <NUM>, spacer <NUM>, and top arm <NUM> rotatably connected by fastener <NUM>. Bottom arm <NUM> includes bottom electrode <NUM>, which may be connected to a conductive wire at connection point <NUM>. Top arm <NUM> includes top electrode <NUM>, which may be connected to a conductive wire at connection point <NUM>.

NsPEF pulse applicator <NUM> is configured to receive nsPEF pulses from the conductive wires and to deliver nsPEF pulses to a patient or experiment subject undergoing nsPEF treatment through top and bottom electrodes <NUM> and <NUM>. The nsPEF pulses may, for example, be applied to a tumor of the patient or experiment subject which is positioned within cavity <NUM> of spacer <NUM>. Cavity <NUM> forms a gap between top and bottom electrodes <NUM> and <NUM>. In some applications, the tumor is connected to the patient or experiment subject by tissue which passes from the tumor within cavity <NUM> to the patient or experiment subject between spacer <NUM> and bottom arm <NUM> or top arm <NUM>. In some embodiments, cavity <NUM> is formed such that the gap between top and bottom electrodes <NUM> and <NUM> is open. For example, a portion of the gap may not be bounded by spacer <NUM>, top arm <NUM>, or bottom arm <NUM>.

Spacer <NUM> includes top slot <NUM> and bottom slot <NUM>. Slots <NUM> and <NUM> are positioned and sized so as to provide space, for example, for at least one of a wire and a solder connection to each of top electrode <NUM> and bottom electrode <NUM> when bottom electrode <NUM>, cavity <NUM>, and top electrode <NUM> are aligned for example, as shown in the bottom two illustrations of <FIG>.

In the illustrated embodiment, bottom arm <NUM> includes groove <NUM>, which is configured to accommodate a wire electrically connected with bottom electrode <NUM> at connection point <NUM> through a hole in bottom arm <NUM>. In some embodiments, a similar groove extends to the perimeter of bottom arm <NUM>, for example near fastener <NUM>. In some embodiments, top arm <NUM> additionally or alternatively includes a similar groove configured to accommodate a wire electrically connected with the top electrode <NUM> at connection point <NUM> through a hole in the top arm <NUM>.

To insert a tumor into nsPEF pulse applicator <NUM>, top arm <NUM> may be rotated such that top electrode <NUM> is out of alignment with cavity <NUM>, and such that cavity <NUM> is viewable, for example, as illustrated in the vertically central illustrations of <FIG>. Bottom arm <NUM> may be rotated such that bottom electrode <NUM> is similarly out of alignment with cavity <NUM>. The tumor may then be placed in the cavity <NUM> such that tissue connecting the tumor with the patient is between bottom arm <NUM> and spacer <NUM>.

Bottom arm <NUM> may then be rotated so as to align or substantially align bottom electrode <NUM> with the cavity <NUM>. In this configuration, bottom arm <NUM> securely presses the connecting tissue against spacer <NUM>. In some applications, the tumor is not connected to the subject, and the tumor is enclosed within cavity <NUM>.

An advantageous aspect of nsPEF pulse applicator <NUM> is that while bottom arm <NUM> is allowed to press the connecting tissue against spacer <NUM>, top arm <NUM> is spaced apart from cavity <NUM>, such that the cavity <NUM> is viewable to visually confirm that the tumor is properly placed when secured by bottom arm <NUM>.

Once inserted, the nsPEF pulse applicator <NUM> may be used to apply nsPEF pulses to the tumor by applying nsPEF pulses to the conductive wires.

Once the nsPEF treatment is finished, the tumor may be removed from the nsPEF pulse applicator <NUM> by rotating the top or bottom arm <NUM> or <NUM> pressing the connecting tissue against spacer <NUM>, and removing the tumor. The other of top and bottom arm <NUM> and <NUM> may also be rotated.

NsPEF pulse applicator <NUM> includes bottom arm <NUM>, spacer <NUM>, and top arm <NUM> rotatably connected together so as to rotate about pivot points <NUM>, one of which is illustrated in each of <FIG>. Bottom arm <NUM> includes bottom electrode <NUM>, which is connected to one of the conductive wires <NUM>. Top arm <NUM> includes top electrode <NUM>, which is connected to the other of the conductive wires <NUM>.

NsPEF pulse applicator <NUM> is configured to receive nsPEF pulses across conductive wires <NUM> and to deliver nsPEF pulses to a patient or experiment subject undergoing nsPEF treatment through top and bottom electrodes <NUM> and <NUM>. The nsPEF pulses may, for example, be applied to a tumor of the patient or experiment subject which is positioned within cavity <NUM> of spacer <NUM>. Cavity <NUM> forms a gap between top and bottom electrodes <NUM> and <NUM>. In some applications, the tumor is connected to the patient or experiment subject by tissue which passes from the tumor within cavity <NUM> to the patient or experiment subject between spacer <NUM> and bottom arm <NUM>. In some embodiments, cavity <NUM> is formed such that the gap between top and bottom electrodes <NUM> and <NUM> is open. For example, a portion of the gap may not be bounded by spacer <NUM>, top arm <NUM>, or bottom arm <NUM>.

As shown in <FIG>, bottom arm <NUM> is separated from top arm <NUM> by spacer <NUM> near cavity <NUM>. In addition, each of bottom arm <NUM>, spacer <NUM>, and top arm <NUM> are rotatable about pivot point <NUM>.

In <FIG>, nsPEF pulse applicator <NUM> is illustrated as if an external force is applied to top arm <NUM> causing top electrode <NUM> of top arm <NUM> to be separated from spacer <NUM> near cavity <NUM>.

In <FIG>, nsPEF pulse applicator <NUM> is illustrated as if the external force is not applied to top arm <NUM>. As a result, top electrode <NUM> of top arm <NUM> is near spacer <NUM> in the region close to cavity <NUM>, as illustrated in <FIG>. If no external force is applied causing top arm <NUM> to be separated from spacer <NUM> near cavity <NUM>, top arm <NUM> is pressed against spacer <NUM> by a force exerted by a first torsion spring <NUM>.

As illustrated in <FIG>, top arm <NUM> is held in place by detent mechanism <NUM>, which is configured to engage divot <NUM> so as to prevent the first torsion spring <NUM> from pressing top arm <NUM> against spacer <NUM>. Other mechanisms may alternatively be used to prevent the first torsion spring <NUM> from pressing top arm <NUM> against spacer <NUM>.

As shown in <FIG>, nsPEF pulse applicator <NUM> is illustrated as if an external force is applied to bottom arm <NUM> causing bottom electrode <NUM> of bottom arm <NUM> to be separated from spacer <NUM> near cavity <NUM>.

In <FIG>, nsPEF pulse applicator <NUM> is illustrated as if the external force is not applied to bottom arm <NUM>. As a result, bottom electrode <NUM> of bottom arm <NUM> is near spacer <NUM> in the region close to cavity <NUM>, as illustrate in <FIG>. If no external force is applied causing bottom arm <NUM> to be from spacer <NUM> near cavity <NUM>, bottom arm <NUM> is pressed against spacer <NUM> in the region close to cavity <NUM> by a force exerted by a second torsion spring <NUM>.

<FIG> is a schematic illustration of top arm <NUM> isolated from the other components of nsPEF pulse applicator <NUM>.

Top arm <NUM> includes cavity <NUM>, which is configured to receive and hold electrode <NUM>, where the wire <NUM> attached to electrode <NUM> passes through hole <NUM>.

Top arm <NUM> also includes holes <NUM>, each configured to receive an axle such that top arm <NUM> is configured to rotate about pivot point <NUM> by rotating about the axle. In some embodiments, the axle comprises a pin. In alternative embodiments, the axle comprises a spring bar. In some embodiments, the axle comprises two colinear axle components.

Top arm <NUM> also includes detent holder <NUM>, which holds a detent mechanism <NUM> configured to engage divot <NUM> of spacer <NUM> so as to prevent the first torsion spring <NUM> from pressing top arm <NUM> against spacer <NUM>. In alternative embodiments, other mechanisms are used to prevent the first torsion spring <NUM> from pressing top arm <NUM> against spacer <NUM>. For example, a bump/divot combination, similar to those discussed elsewhere herein may be used. In some of such embodiments, the divot of such a combination is in top arm <NUM>. In alternative embodiments, the bump of such a combination is formed in top arm <NUM>.

<FIG> is a schematic illustration of spacer <NUM> isolated from the other components of nsPEF pulse applicator <NUM>.

Spacer <NUM> includes a through hole, which forms cavity <NUM>, which, as discussed below, is configured to contain tissue receiving nsPEF pulses from nsPEF pulse applicator <NUM>.

Spacer <NUM> also includes first and second cavities <NUM> and <NUM>, which are respectively configured to receive first and second torsion springs <NUM> and <NUM> discussed above.

Spacer <NUM> also includes holes <NUM>, each configured to receive an axle such that spacer <NUM> is configured to rotate about pivot point <NUM> by rotating about the axle. In some embodiments, the axle comprises a pin. In alternative embodiments the axle comprises a spring bar. In some embodiments, the axle comprises two colinear axle components.

Spacer <NUM> also includes the divot <NUM>, configured to engage a detent in top arm <NUM> so as to prevent the first torsion spring <NUM> from pressing top arm <NUM> against spacer <NUM>. In alternative embodiments, other mechanisms are used to prevent the first torsion spring <NUM> from pressing top arm <NUM> against spacer <NUM>. For example, a bump/divot combination, similar to those discussed elsewhere herein may be used. In some of such embodiments, the divot of such a combination is in spacer <NUM>. In alternative embodiments, the bump of such a combination is formed in spacer <NUM>.

<FIG> is a schematic illustration of bottom arm <NUM> isolated from the other components of nsPEF pulse applicator <NUM>.

Bottom arm <NUM> includes cavity <NUM>, which is configured to receive and hold electrode <NUM>, where the wire <NUM> attached to electrode <NUM> passes through hole <NUM>.

Bottom arm <NUM> also includes holes <NUM>, each configured to receive an axle such that bottom arm <NUM> is configured to rotate about pivot point <NUM> by rotating about the axle. In some embodiments, the axle comprises a pin. In alternative embodiments the axle comprises a spring bar. In some embodiments, the axle comprises two colinear axle components.

Bottom arm <NUM> also includes feature <NUM>, which is configured to be engaged by the second torsion spring <NUM>, such that bottom arm <NUM> is pressed against spacer <NUM> in the region close to cavity <NUM> by a force exerted by the second torsion spring <NUM>.

To insert a tumor into nsPEF pulse applicator <NUM>, top arm <NUM> may be rotated about pivot point <NUM> such that top electrode <NUM> is held in place by detent mechanism <NUM> and such that cavity <NUM> is viewable, as illustrated in <FIG>. To rotate top arm <NUM> about pivot point <NUM>, a force is applied to top arm <NUM> which overcomes the force applied to top arm <NUM> by the first torsion spring <NUM>.

In addition, bottom arm <NUM> is rotated about pivot point <NUM> such that bottom electrode <NUM> is spaced apart from cavity <NUM> in spacer <NUM>, as illustrated in <FIG>. To rotate bottom arm <NUM> about pivot point <NUM>, a force is applied to bottom arm <NUM> which overcomes the force applied to bottom arm <NUM> by the second torsion spring <NUM>.

The tumor may then be placed in the cavity <NUM> such that tissue connecting the tumor with the patient is between bottom arm <NUM> and spacer <NUM>.

Bottom arm <NUM> may then be rotated so as to press the connecting tissue against spacer <NUM> and to place electrode <NUM> adjacent to cavity <NUM>, as illustrated in <FIG>. In this configuration, the tumor is securely held within cavity <NUM>. In some applications, the tumor is not connected to the subject, and the tumor is enclosed within cavity <NUM>.

An advantageous aspect of nsPEF pulse applicator <NUM> is that while bottom arm <NUM> is rotated to press the connecting tissue against spacer <NUM>, top arm <NUM> is spaced apart from cavity <NUM>, and the cavity <NUM> is viewable to visually confirm that the tumor is properly placed when secured by the rotation of bottom arm <NUM>.

Top arm <NUM> may then be rotated so as to place top electrode <NUM> adjacent the cavity <NUM> containing the tumor, as illustrated in <FIG>.

Once the nsPEF treatment is finished, the tumor may be removed from the nsPEF pulse applicator <NUM> by rotating the bottom arm <NUM> pressing the connecting tissue against spacer <NUM>, as illustrated in <FIG>, and removing the tumor. The top arm <NUM> may also be rotated, as illustrated in <FIG>, to allow visual inspection of the removal of the tumor.

<FIG> schematically illustrate multiple views of an nsPEF pulse applicator <NUM> which may, for example, be used as nsPEF pulse applicator <NUM> in nsPEF treatment system <NUM> of <FIG>. NsPEF pulse applicator <NUM> may have characteristics similar to or identical to any of the nsPEF pulse applicators discussed herein. For example, nsPEF pulse applicator <NUM> may have characteristics similar to or identical to other nsPEF pulse applicators discussed herein.

NsPEF pulse applicator <NUM> includes bottom arm <NUM>, spacer <NUM>, and top arm <NUM>.

NsPEF pulse applicator <NUM> is configured to receive nsPEF pulses and to deliver nsPEF pulses to a patient or experiment subject undergoing nsPEF treatment through top and bottom electrodes <NUM> and <NUM>. The nsPEF pulses may, for example, be applied to a tumor of the patient or experiment subject which is positioned within cavity <NUM> of spacer <NUM>. Cavity <NUM> forms a gap between top and bottom electrodes <NUM> and <NUM>. In some applications, the tumor is connected to the patient or experiment subject by tissue which passes from the tumor within cavity <NUM> to the patient or experiment subject between spacer <NUM> and bottom arm <NUM>. In some embodiments, cavity <NUM> is formed such that the gap between top and bottom electrodes <NUM> and <NUM> is open. For example, a portion of the gap may not be bounded by spacer <NUM>, top arm <NUM>, or bottom arm <NUM>.

Bottom arm <NUM> and spacer <NUM> are movably connected to one another such that bottom arm <NUM> and spacer <NUM> may be positioned relative to one another in configurations shown in <FIG> and <FIG>. Bottom arm <NUM> includes bottom electrode <NUM>, which is positioned so as to be selectively adjacent cavity <NUM> of spacer <NUM> according to the relative position of bottom arm <NUM> and spacer <NUM>.

In <FIG>, NsPEF pulse applicator <NUM> is illustrated with bottom arm actuator <NUM> positioned so as to cause bottom electrode <NUM> of bottom arm <NUM> to be separated from spacer <NUM> near cavity <NUM>. In contrast, in <FIG> and <FIG>, NsPEF pulse applicator <NUM> is illustrated with bottom arm actuator <NUM> positioned so as to cause bottom electrode <NUM> of bottom arm <NUM> to be adjacent spacer <NUM> near cavity <NUM>. As a result, bottom electrode <NUM> of bottom arm <NUM> is near spacer <NUM> in the region close to cavity <NUM>.

Bottom arm <NUM> may be moved between the positions shown in <FIG> and <FIG> with bottom arm actuator <NUM>. In this embodiment, bottom arm actuator <NUM> includes nut <NUM>, washer <NUM>, and screw <NUM>. Screw <NUM> passes through bottom arm <NUM> through bottom slot <NUM>. In addition, screw <NUM> passes through spacer <NUM> through slot <NUM>.

In the configuration illustrated in <FIG>, bottom arm actuator <NUM> is positioned so that the bottom electrode <NUM> is spaced apart from cavity <NUM> of spacer <NUM>. In the configuration illustrated in <FIG>, bottom arm actuator <NUM> is positioned so that the bottom electrode <NUM> is adjacent to cavity <NUM> of spacer <NUM>. So that nsPEF pulse applicator <NUM> is adjustable between the configurations illustrated in <FIG> and <FIG>, bottom arm actuator <NUM> is configured to slide along bottom slot <NUM> of bottom arm <NUM> and slot <NUM> of spacer <NUM> in response to a force applied thereto, for example, by a thumb of a user.

In the configuration illustrated in <FIG>, surface <NUM> (illustrated in <FIG>) of bottom arm <NUM> presses against or faces spacer <NUM> because of the position of bottom arm actuator <NUM>. In the configuration illustrated in <FIG>, surface <NUM> (illustrated in <FIG>) of bottom arm <NUM> presses against or faces spacer <NUM> because of the position of bottom arm actuator <NUM>. Because surfaces <NUM> and <NUM> are angled, the distance of bottom arm <NUM> to cavity <NUM> of spacer <NUM> is dependent on the position of bottom arm actuator <NUM>.

Top arm <NUM> and spacer <NUM> are movably connected to one another such that top arm <NUM> and spacer <NUM> may be positioned relative to one another in configurations shown in <FIG> and <FIG>. Top arm <NUM> includes top electrode <NUM>, which is illustrated in FIG. Top electric <NUM> is positioned on top arm <NUM> such that when top arm <NUM> and spacer <NUM> are positioned in the configurations shown in <FIG> and <FIG>, top electrode <NUM> is spaced apart from cavity <NUM> in spacer <NUM>. In contrast, when top arm <NUM> and spacer <NUM> are positioned in the configuration shown in <FIG>, top electrode <NUM> is adjacent to cavity <NUM>.

In <FIG> and <FIG>, NsPEF pulse applicator <NUM> is illustrated as if an external force is or has been applied to handle <NUM> causing top electrode <NUM> of top arm <NUM> to be separated from spacer <NUM> near cavity <NUM>. In contrast, in <FIG>, NsPEF pulse applicator <NUM> is illustrated as if an external force is or has been applied to handle <NUM> causing top electrode <NUM> of top arm <NUM> to be adjacent spacer <NUM> near cavity <NUM>. As a result, top electrode <NUM> of top arm <NUM> is near spacer <NUM> in the region close to cavity <NUM>.

Top arm <NUM> may be moved between the positions shown in <FIG> and <FIG> with top arm actuator <NUM>. In this embodiment, top arm actuator <NUM> includes handle <NUM> and linkage <NUM>.

Handle <NUM> of top arm actuator <NUM> is rotatably connected to spacer <NUM> at pivot point <NUM>. Linkage <NUM> is rotatably connected to top arm <NUM> at pivot point <NUM>. In addition, handle <NUM> is rotatably connected to linkage <NUM> at pivot point <NUM>.

In the configuration illustrated in <FIG>, top arm actuator <NUM> is positioned so that the top electrode <NUM> is spaced apart from cavity <NUM> of spacer <NUM>. In the configuration illustrated in <FIG>, top arm actuator <NUM> is positioned so that the top electrode <NUM> is adjacent to cavity <NUM> of spacer <NUM>. So that nsPEF pulse applicator <NUM> is adjustable between the configurations illustrated in <FIG> and <FIG>, handle <NUM> of top arm actuator <NUM> is configured to rotate about pivot point <NUM> in response to a force applied thereto, for example, by a thumb of a user.

In the configuration illustrated in <FIG>, handle <NUM> of top arm actuator <NUM> has been moved to an "open" position in response to a force applied thereto. A portion of the force applied to handle <NUM> is translated to top arm <NUM> through linkage <NUM>. The portion of the force translated to top arm <NUM> causes top arm <NUM> to slide away from cavity <NUM> of spacer <NUM>. In addition, the portion of the force translated to top arm <NUM> causes top arm <NUM> to rotate such that a gap between top electrode <NUM> and spacer <NUM> increases.

In the configuration illustrated in <FIG>, handle <NUM> of top arm actuator <NUM> has been moved to a "closed" position in response to a force applied thereto. A portion of the force applied to handle <NUM> is translated to top arm <NUM> through linkage <NUM>. The portion of the force translated to top arm <NUM> causes top arm <NUM> to slide toward cavity <NUM> of spacer <NUM> such that top electrode <NUM> is adjacent cavity <NUM> of spacer <NUM>. In addition, the portion of the force translated to top arm <NUM> causes top arm <NUM> to rotate such that a gap between top electrode <NUM> and spacer <NUM> decreases. In the configuration illustrated in <FIG>, handle <NUM> has been rotated such that linkage <NUM>, connected to handle <NUM> at pivot point <NUM>, has been moved to an "over center" position. Accordingly, in the configuration illustrated in <FIG>, handle <NUM> prevents incidental forces experienced by top arm <NUM> from displacing top arm <NUM>.

<FIG> illustrates an embodiment of a connection mechanism used to connect bottom arm <NUM> to spacer <NUM>. As shown, spacer <NUM> has pin <NUM>, which engages notch <NUM>. Notch <NUM> is shaped such that when bottom arm <NUM> engages spacer <NUM> with an angle greater than a minimum, the bottom of notch <NUM> is exposed to pin <NUM>. In addition, once notch <NUM> engages pin <NUM>, and bottom arm <NUM> is rotated relative to spacer <NUM> such that the angle between bottom arm <NUM> and spacer <NUM> is less than a maximum, pin <NUM> prevents separation of bottom arm <NUM> and spacer <NUM>. An advantageous aspect of this connection mechanism is that bottom arm <NUM> and spacer <NUM> are assembleable and disassembleable by hand, without any tools, for example, for cleaning.

<FIG> is a schematic illustration of top arm <NUM>, linkage <NUM>, and handle <NUM> isolated from the other components of nsPEF pulse applicator <NUM>.

Top arm <NUM> includes posts 2038A, which engage slots 2021A of spacer <NUM>. When top arm <NUM> is moved with respect to spacer <NUM> with top arm actuator <NUM>, posts 2038A slide along slots 2021A.

Top arm <NUM> includes posts 2038B, which engage slots 2021B of spacer <NUM>. When top arm <NUM> is moved with respect to spacer <NUM> with top arm actuator <NUM>, posts 2038A slide along slots 2021A. Because slot 2021B of spacer <NUM> is angled with respect to slot 2021A of spacer <NUM>, when top arm <NUM> is moved with respect to spacer <NUM>, the movement includes a linear motion and a rotation of top arm <NUM> with respect to spacer <NUM>. An advantageous aspect of the rotation is that when top arm <NUM> is moved to place top electrode <NUM> adjacent cavity <NUM>, the rotation reduces or eliminates shearing forces experienced by the tumor as a result of the movement.

Handle <NUM> includes posts 2038C, which engage slots 2021C of spacer <NUM>. When handle <NUM> is moved to the position illustrated in <FIG>, posts 2038C engage slots 2021C such that handle <NUM> is held in place by slots 2021C, and such that posts 2038C form the pivot point <NUM>, discussed above.

Top arm <NUM> is rotatably connected to linkage <NUM>. In some embodiments, one or more posts fixed to top arm <NUM> protrude from top arm <NUM> into holes in linkage <NUM>. In alternative embodiments, one or more posts fixed to linkage <NUM> protrude from linkage <NUM> into holes in top arm <NUM>.

Handle <NUM> is rotatably connected to linkage <NUM>. In some embodiments, one or more posts fixed to handle <NUM> protrude from handle <NUM> into holes in linkage <NUM>. In alternative embodiments, one or more posts fixed to linkage <NUM> protrude from linkage <NUM> into holes in handle <NUM>.

Spacer <NUM> also includes slot <NUM>, which has opening 2027A. Opening 2027A is larger than nut <NUM> so that nut <NUM> can pass through opening 2027A when bottom arm <NUM> is connected to spacer <NUM>, as discussed above with reference to <FIG>.

Slots 2021A, 2021B, and 2021C, and pin <NUM> are illustrated and are discussed elsewhere herein. An advantageous aspect of this connection mechanism using slots and pins is that top arm <NUM> and spacer <NUM> are assembleable and disassembleable by hand, without any tools, for example, for cleaning.

To insert a tumor into nsPEF pulse applicator <NUM>, top arm <NUM> may be positioned so as to expose cavity <NUM> of spacer <NUM>, as illustrated in <FIG>. To position top arm <NUM> for tumor insertion, handle <NUM> is moved to the position illustrated in <FIG>.

In addition, bottom arm <NUM> is positioned so as to be spaced apart from spacer <NUM> in the region near cavity <NUM>, as illustrated in <FIG>. To position bottom arm <NUM> for tumor insertion, bottom arm actuator <NUM> is moved to the position indicated in <FIG>.

The tumor may then be placed in the cavity <NUM> such that tissue connecting the tumor with the patient is between bottom arm <NUM> and spacer <NUM>. An advantageous aspect of bottom arm actuator <NUM> is that bottom arm actuator <NUM> does not apply a restorative force urging bottom electrode <NUM> toward cavity <NUM>. Because of this advantage, the user need not apply a force to overcome the restorative force while inserting the tumor into cavity <NUM>.

An advantageous aspect of nsPEF pulse applicator <NUM> is that while the tumor is placed in the cavity <NUM>, top arm <NUM> is spaced apart from cavity <NUM> such that cavity <NUM> is viewable to visually confirm that the tumor is properly placed.

Bottom arm <NUM> may then be positioned so as to press the connecting tissue against spacer <NUM> and to place electrode <NUM> adjacent to cavity <NUM>. To position bottom arm <NUM> to hold the tumor, bottom arm actuator <NUM> is moved to the position indicated in <FIG>. In this configuration, the tumor is securely held within cavity <NUM>. In some applications, the tumor is not connected to the subject, and the tumor is enclosed within cavity <NUM>.

An advantageous aspect of nsPEF pulse applicator <NUM> is that while bottom arm <NUM> is positioned to press the connecting tissue against spacer <NUM>, top arm <NUM> is spaced apart from cavity <NUM>, and the cavity <NUM> is viewable to visually confirm that the tumor is properly placed when secured by the rotation of bottom arm <NUM>.

Top arm <NUM> may then be positioned so as to place top electrode <NUM> adjacent the cavity <NUM> containing the tumor. To position top arm <NUM> near the tumor, handle <NUM> is moved to the position illustrated in <FIG>.

Once the nsPEF treatment is finished, the tumor may be removed from the nsPEF pulse applicator <NUM> by positioning the bottom arm <NUM> as illustrated in <FIG>. The top arm <NUM> may also be positioned as illustrated in <FIG> to allow visual inspection of the removal of the tumor.

An advantage of the various embodiments of pulse applicators having a spacer as discussed herein is that the spacer keeps the electrodes with the separation of a predefined distance. With such an arrangement, applying a known voltage to the electrodes causes a known electric field between the electrodes. For example, an electric field pulse of <NUM> kV/cm may be applied across electrodes separated by a ½ cm spacer by applying a <NUM> kV pulse across the electrodes.

Another advantage of the various embodiments of pulse applicators having a spacer as discussed herein is that the tumor may be held within the cavity of the spacer for treatment without applying a force on the tumor with the electrodes.

Claim 1:
A pulse applicator (<NUM>, <NUM>, <NUM>, <NUM>), comprising:
a first arm (<NUM>, <NUM>, <NUM>, <NUM>), comprising a first electrode (<NUM>, <NUM>, <NUM>, <NUM>);
a second arm (<NUM>, <NUM>, <NUM>, <NUM>), comprising a second electrode (<NUM>, <NUM>, <NUM>, <NUM>); and
a spacer (<NUM>, <NUM>, <NUM>, <NUM>), wherein the first arm is separated from the second arm by the spacer,
wherein the first arm, the spacer, and the second arm are movably connected such that the first arm and the spacer are configured to hold a tumor of a subject adjacent the first electrode, the second arm is configured to be movable so as to selectively position the second electrode adjacent the tumor, and wherein the first electrode and the second electrode are configured to deliver an electrical field across the tumor in response to an electrical pulse received across the first and second electrodes.