Low-voltage impedance check pulse generator

Abstract

A method and system for testing variable duration nanosecond pulsed electric field (nsPEF) generator circuits is provided. The method includes calculating one or more impedances of a load from an applied pulse and comparing the one or more impedances to an expected impedance. The results of the comparison are used to determine whether the pulse generator system is functioning properly, whether a therapy treatment may be initiated or continued, or whether parameters of the pulses need to be changed. The pulses may be therapy pulses or test pulses, and the pulses may have various parameters of voltage, duration, frequency, or any other electrical parameters. The disclosed methods may be performed by a therapy system including a controller.

Description

[Technical Field]

[0001] This application relates generally to electrical pulse technology, including circuits and systems for generating and controlling the discharge of electrical pulses, that involve the use of an energy storage element that is discharged through a load by a relatively low voltage transistor. Specifically, the pulse technology is used to generate variable duration nanosecond pulsed electric fields (nsPEF) for electrotherapy. [Background technology]

[0002] Surgical removal of tumors can lead to infection and leave scars. Furthermore, if there are more tumors, every cancerous tumor must be identified and individually removed by the surgeon. This can be time-consuming and expensive, not to mention uncomfortable for the patient. As used herein, patient includes a subject receiving a therapeutic treatment or experimental treatment.

[0003] Cancerous tumors that are internal to the patient can be particularly difficult to detect and treat, let alone remove. Many patients' lives are upended by the discovery of cancer within their own bodies, which can form relatively large tumors before being detected.

[0004] "Nanosecond pulsed electric fields," sometimes abbreviated as nsPEF, include electric fields having sub-microsecond pulse widths, for example, between 0.1 nanoseconds (ns) and 1000 nanoseconds, or as otherwise known in the art. nsPEFs are sometimes referred to as sub-microsecond pulsed electric fields. nsPEFs often have high peak voltages, for example, 10 kilovolts per centimeter (kV / cm), 20 kV / cm, or 500 kV / cm. Treatment of living cells with nsPEF technology often uses multiple periodic pulses at frequencies ranging from 0.1 Hz to 10,000 Hz.

[0005] nsPEFs have been shown to trigger apoptosis in cancerous tumors, and selective treatment of such tumors with nsPEFs, due to their non-thermal nature, can induce apoptosis in tumor cells without significantly affecting normal cells in the surrounding tissue.

[0006] Examples of nsPEFs applied to living cells are shown and described in US Pat. No. 6,326,177 (to Schoenbach et al.), which is incorporated herein by reference in its entirety for all purposes.

[0007] The use of nsPEF for tumor treatment is a relatively new field. nsPEF pulses are generated from a charged pulse generator, and there is a need for devices with better control over the charge state of the pulse generator for safe and effective research and treatment of cancer in human subjects. Summary of the Invention

[0008] Generally, nanosecond pulsed electric field (nsPEF) generators are disclosed that incorporate one or more energy storage devices used to generate relatively high-voltage or relatively low-voltage nsPEF pulses. The nsPEF generators may include a discharge circuit that can be selectively used to discharge the energy storage devices from a high voltage to a low voltage so that low-voltage pulses can be applied. Alternatively, the nsPEF generators may have a separate low-voltage power supply that is used to generate the low-voltage pulses.

[0009] In some embodiments, high-voltage nsPEF pulses may be used for therapeutic treatment of tissue. In some embodiments, low-voltage nsPEF pulses may be used to test the setup of an nsPEF generator system. For example, once the system is set up, one or more low-voltage pulses may be applied to a load. The current generated by or resulting in the pulses may be monitored to determine the load impedance. The determined load impedance is compared to the expected impedance of the load, for example, based on an identification of the load's material or tissue type. A determined impedance outside of the expected range may indicate, for example, a setup problem, a problem with the load, a problem with the electrodes, or another system problem.

[0010] One aspect of the present invention is a method for testing a pulse generator circuit. The method includes charging the pulse generator circuit to a first voltage using the pulse generator circuit, delivering a first voltage pulse to a load through electrodes using the pulse generator circuit, and determining an impedance of the load using the first voltage pulse. The method also includes comparing the impedance to an expected impedance and determining, based at least in part on a result of the comparison, whether to deliver a second voltage pulse to the load, wherein at least one of the first voltage pulse and the second voltage pulse has a therapeutic effect on the load.

[0011] In some aspects of the method, determining the impedance of the load includes measuring a current delivered to the load during delivery of the first voltage pulse, determining a voltage of the delivered first voltage pulse, and calculating the impedance based on the voltage level of the first voltage pulse and on the measured current.

[0012] In some aspects of the method, the voltage level of the first pulse is less than the voltage level of the second pulse.

[0013] In some aspects, the method also includes determining an expected impedance based on the identification of the load.

[0014] In some aspects of the method, the expected impedance comprises an impedance range.

[0015] In some aspects of the method, determining whether to deliver a second voltage pulse includes determining to deliver a second pulse to the load as a result of the calculated impedance being one of the following: 1) less than a threshold difference from the expected impedance, 2) within an expected impedance range that includes the expected impedance, 3) less than a maximum threshold, and 4) greater than a minimum threshold.

[0016] In some aspects of the method, the voltage level of the first pulse is greater than the voltage level of the second pulse.

[0017] In some aspects of the method, determining whether to deliver a second voltage pulse includes determining to deliver a second pulse to the load as a result of the calculated impedance being one of the following: 1) greater than a threshold difference from the expected impedance, 2) outside an expected impedance range that the expected impedance includes, 3) greater than a maximum threshold, and 4) less than a minimum threshold.

[0018] In some aspects of the method, the method includes delivering a second pulse that includes charging or discharging the pulse generator circuit to a second charging voltage.

[0019] In some aspects of the method, delivering the second voltage includes changing the state of a switch to electrically disconnect the load from the first voltage pulse source and to connect the load to the second voltage pulse source.

[0020] In some aspects of the method, the first and second voltage pulses have a therapeutic effect on the load.

[0021] In some aspects, the method also includes displaying a graphical representation based on the comparison.

[0022] In some embodiments, the method also includes delivering a second voltage pulse to the load, determining a second impedance of the load, comparing the second impedance to an expected impedance, and determining to stop delivering the therapeutic voltage pulse in response to comparing the second impedance to the expected impedance.

[0023] Another aspect of the present invention is a therapeutic nsPEF pulse generator system. The system includes at least one electrode and a pulse generator electrically connected to the electrode and configured to deliver voltage pulses to the electrode. The system also includes a controller connected to the pulse generator and configured to determine a voltage level of the pulses delivered to the at least one electrode. The controller is configured to charge the pulse generator circuit to a first charging voltage and to cause the pulse generator circuit to deliver a first voltage pulse to a load through the at least one electrode. The controller is also configured to receive a signal indicative of an impedance of the load, compare the impedance to an expected impedance, and determine, in response to the comparison, whether to deliver a second voltage pulse to the load, wherein at least one of the first and second voltage pulses has a therapeutic effect on the load.

[0024] In some embodiments of the system, the voltage level of the first pulse is less than the voltage level of the second pulse.

[0025] In some aspects of the system, the controller is further configured to determine an expected impedance based on the identification of the load.

[0026] In some aspects of the system, the expected impedance comprises an impedance range.

[0027] In some aspects of the system, the controller is configured to cause delivery of a second pulse to the load as a result of the calculated impedance being one of the following: 1) less than a threshold difference from the expected impedance, 2) within an expected impedance range that the expected impedance includes, 3) less than a maximum threshold, and 4) greater than a minimum threshold.

[0028] In some embodiments of the system, the voltage level of the first pulse is greater than the voltage level of the second pulse.

[0029] In some aspects of the system, the controller is configured to cause delivery of a second pulse to the load as a result of the calculated impedance being one of the following: 1) greater than a threshold difference from the expected impedance, 2) outside an expected impedance range that includes the expected impedance, 3) greater than a maximum threshold, and 4) less than a minimum threshold.

[0030] In some embodiments of the system, causing delivery of the second voltage pulse includes causing the pulse generator circuit to charge or discharge the second charging voltage.

[0031] In some aspects of the system, causing the delivery of the second voltage includes changing the state of a switch to electrically disconnect the load from the first voltage pulse source and to connect the load to the second voltage pulse source.

[0032] In some aspects of the system, the first voltage pulse and the second voltage pulse have a therapeutic effect on the load.

[0033] In some aspects of the system, the system is configured to display a graphical representation based on the comparison.

[0034] In some aspects of the system, the controller is further configured to cause delivery of a second voltage pulse, determine a second impedance of the load, compare the second impedance to an expected impedance, and decide to stop delivering the therapeutic voltage pulse in response to comparing the second impedance to the expected impedance.

[0035] Another aspect of the invention is a method of using a pulse generator circuit, e.g., a therapeutic pulse generator circuit. The method includes using the pulse generator circuit to deliver a first voltage pulse to a load through an electrode and determining a first impedance of the load based in part on the delivered first voltage pulse. The method also includes using the pulse generator circuit to deliver a second voltage pulse to the load through the electrode and determining a second impedance of the load based in part on the delivered second voltage pulse. The method also includes comparing the first impedance to the second impedance and, as a result of the comparison, at least in part: 1) ceasing delivery of the voltage pulse to the load, 2) confirming continued delivery of a voltage pulse of similar treatment pulse parameters, or 3) delivering a next voltage pulse to the load, the next voltage pulse having electrical parameters different from the corresponding electrical parameters of the first voltage pulse and the second voltage pulse.

[0036] In some aspects of the method, the first voltage pulse and the second voltage pulse are therapeutic pulses.

[0037] In some aspects of the method, the first voltage pulse and the second voltage pulse are test pulses.

[0038] In some aspects of the method, delivery of the voltage pulse to the load is stopped as a result of the difference between the first impedance and the second impedance being greater than, less than, or outside a threshold range.

[0039] In some aspects of the method, a voltage pulse having different electrical parameters is delivered as a result of the comparison indicating a deviation from the impedance profile greater than a threshold value.

[0040] In some aspects of the method, the electrical parameter is one of voltage, frequency, duration, and voltage shape. Systems and devices configured to perform the above-described methods are also provided. Other features and advantages of the disclosed devices and methodologies will become apparent from the following detailed description of one or more embodiments when read in light of the accompanying figures. [Brief explanation of the drawings]

[0041] [Figure 1] 1 illustrates a nanosecond pulse generator device according to an embodiment. [Figure 2] 10 shows both voltage and current pulse profiles according to an embodiment. [Figure 3] 1 shows a perspective view of a seven-needle electrode according to an embodiment. [Figure 4] 1 shows a perspective view of a bipolar electrode according to an embodiment. [Figure 5] FIG. 1 is an electrical schematic diagram of a pulse generator according to an embodiment. [Figure 6A] FIG. 6 is a schematic diagram illustrating the pulse generator shown in FIG. 5 during a charging mode. [Figure 6B] FIG. 6 is a schematic diagram illustrating the pulse generator shown in FIG. 5 during a discharge mode. [Figure 7] FIG. 1 is an electrical schematic diagram of an assembly of a pulse generator circuit. [Figure 8] FIG. 8 is an electrical schematic diagram of one of the pulse generator circuits shown in FIG. 7. [Figure 9] FIG. 9 is an electrical schematic diagram of one of the pulse generator stages shown in FIG. 8. [Figure 10] FIG. 10 is an electrical schematic diagram of one of the switch drivers shown in FIG. 9. [Figure 11] FIG. 10 is an electrical schematic diagram of an alternative switch element. [Figure 12]FIG. 10 is a waveform diagram illustrating the operation of the transformer and the control voltages on the MOSFET gates. [Figure 13] FIG. 2 is an alternative electrical schematic diagram of the pulse generator shown in FIG. 1. [Figure 14] FIG. 2 is an alternative electrical schematic diagram of the pulse generator shown in FIG. 1. [Figure 15] FIG. 8 is an electrical schematic diagram of one embodiment of the pulse generator circuit shown in FIG. 7 with a discharge circuit. [Figure 16] FIG. 16 is an electrical schematic diagram of an embodiment of one of the pulse generator stages shown in FIG. 15 with a discharge circuit stage. [Figure 17] FIG. 17 is a schematic diagram of an embodiment of a discharge circuit stage used in the pulse generator stage of FIG. 16; [Figure 18] FIG. 1 is an electrical schematic diagram of an embodiment of a pulse generator circuit having a discharge circuit. [Figure 19] FIG. 1 is a diagram of an embodiment of a peak power supply. [Figure 20] FIG. 1 is an electrical schematic diagram of an alternative pulse generator circuit. [Figure 21] FIG. 1 is a block diagram of an nsPEF treatment system. [Figure 22] 1 is a table of expected impedances for specific treatment loads. [Figure 23] FIG. 1 is a flow chart illustrating a method for testing the setup status of a pulse generator system. [Figure 24] FIG. 1 is a flow chart illustrating a method for testing the setup status of a pulse generator system. [Figure 25] FIG. 1 is a flow chart illustrating a method for testing the setup status of a pulse generator system. [Figure 26] FIG. 10 is a flow chart diagram illustrating a method of using the pulse generator system. DETAILED DESCRIPTION OF THE INVENTION

[0042] It has been shown that nsPEF treatment can be used to cause cancerous tumor cells to undergo apoptosis, or programmed cell death. Studies have shown that tumors may shrink to nonexistence after treatment; drugs may not be required. It has also been shown that a subject's immune system can be stimulated to attack all similar tumor cells, including tumor cells from tumors not in the tumor being treated with nsPEF.

[0043] A "tumor" includes any neoplasm or abnormal, unwanted growth of tissue on or in a subject or otherwise known in the art. A tumor may include a collection of one or more cells exhibiting abnormal growth. There are many types of tumors. Malignant tumors are cancerous, pre-malignant tumors are pre-cancerous, and benign tumors are non-cancerous. Examples of tumors include benign prostatic hyperplasia (BPH), uterine fibroids, pancreatic cancer, liver cancer, kidney cancer, colon cancer, pre-basal cell carcinoma, and tissue associated with Barrett's esophagus.

[0044] "Disease" includes any abnormal condition in or on a subject associated with the abnormal and uncontrolled growth of tissue, including cancerous, precancerous, and benign tissue, or other disease known in the art.

[0045] "Apoptosis" of a tumor or cell involves orderly programmed cell death, or as otherwise known in the art.

[0046] "Immunogenic apoptosis" of a tumor or cell includes programmed cell death followed by an immune system response, or as otherwise known in the art. An immune system response is thought to be involved when apoptotic cells display calreticulin or another antigen on their surface, which stimulates dendritic cells to engulf, destroy, or otherwise phagocytose the target cell, leading to the eventual activation of a specific T cell response against the target tumor or cell.

[0047] Pulse lengths between 10 and 900 nanoseconds for nsPEFs have been particularly investigated for their effectiveness in stimulating immune responses. Pulse lengths of approximately 100 nanoseconds are particularly interesting in that they are long enough to deliver sufficient energy to be effective at low pulse numbers, yet short enough to be effective in the desired manner.

[0048] A time of "about" a particular number of nanoseconds includes a time within a tolerance of ±1%, 2%, 3%, 4%, 5%, 7.5%, 10%, 15%, 20%, 25%, or other percentage, or a fixed tolerance such as ±0.1, ±0.2, ±0.3, ±0.4, ±0.5, ±0.7, ±1.0, ±2.0, ±3.0, ±4.0, ±5.0, ±7.0, ±10, ±15, ±20, ±25, ±30, ±40, ±50, ±75 ns, or other tolerance such as allowed in the art consistent with the validity of the term.

[0049] Immune system biomarkers can be measured before and / or after nsPEF treatment to confirm that an immune response has been triggered in the patient. Additionally, nsPEF treatment can be combined with CD47-blocking antibody treatment to better train CD8+ T cells (i.e., cytotoxic T cells) to attack cancer.

[0050] FIG. 1 illustrates a nanosecond pulse generator system according to an embodiment. The nsPEF system 100 includes an electrode 102, a foot switch 103, and an interface 104. The foot switch 103 is connected to a housing 105 and electronic components therein through a connector 106. The electrode 102 is connected to the housing 105 and electronic components therein through a high-voltage connector 112. The nsPEF system 100 also includes a handle 110 and a storage drawer 108. As shown in DETAIL A of FIG. 1 , the nsPEF system 100 also includes a holster 116 configured to hold the holster electrode 102 by its handle portion 114.

[0051] A human operator inputs information, for example, the number of pulses, amplitude, pulse duration, and frequency, into a numeric keypad or touchscreen of the interface 104. In some embodiments, the pulse width can be varied. A microcontroller sends signals to pulse control elements within the nsPEF system 100. In some embodiments, fiber optic cables allow for control signal transmission while electrically isolating the contents of the nsPEF generation system 100, a metal cabinet containing high-voltage circuitry, from the outside. To further isolate the system, the system 100 can be battery-powered instead of powered from a wall outlet.

[0052] FIG. 2 shows pulse profiles for both voltage and current according to an embodiment. The output from the nsPEF system 100 is shown with the voltage at the top and the current at the bottom for the first and second pulses. The first pulse has an amplitude of about 15 kV, a current of about 50 A, and a duration of about 15 ns. The second pulse has an amplitude of about 15 kV, a current of about 50 A, and a duration of about 30 ns. If such pulses were delivered to a suction electrode with 4 mm between the plates, the pulse generator would deliver a pulse of about 50 A and 37.5 kV / cm. For a given voltage, the current is highly dependent on the type of electrode and tissue resistance.

[0053] While Figure 2 illustrates a specific example, other pulse profiles may be generated. For example, in some embodiments, the pulse rise and / or fall times may be less than 20 ns, about 20 ns, about 25 ns, about 30 ns, about 40 ns, about 50 ns, about 60 ns, about 75 ns, or greater than 75 ns. In some embodiments, the pulse voltage may be less than 5 kV, about 5 kV, about 10 kV, about 15 kV, about 20 kV, about 25 kV, about 30 kV, or greater than 30 kV. In some embodiments, the current may be less than 10 A, about 10 A, about 25 A, about 40 A, about 50 A, about 60 A, about 75 A, about 100 A, about 125 A, about 150 A, about 175 A, about 200 A, or greater than 200 A. In some embodiments, the pulse duration can be less than 10 ns, about 10 ns, about 15 ns, about 20 ns, about 25 ns, about 30 ns, about 40 ns, about 50 ns, about 60 ns, about 75 ns, about 100 ns, about 125 ns, about 150 ns, about 175 ns, about 200 ns, about 300 ns, about 400 ns, about 500 ns, about 750 ns, about 1 μs, about 2 μs, about 3 μs, about 4 μs, about 5 μs, or greater than 5 μs.

[0054] FIG. 3 shows a perspective view of a seven-needle electrode according to an embodiment. In electrode 300, a sheath 301 surrounds seven sharp electrodes 302 and has wide openings at the ends. When the open ends are applied to a tumor, air is evacuated from the resulting chamber through vacuum holes 304, drawing the entire tumor or a portion of the tumor into the chamber. The tumor is attracted so that one or more of the electrodes preferably penetrate the tumor. The sharp ends of the electrodes are configured to puncture the tumor. The center electrode can be of one polarity, and the outer six electrodes can be of the opposite polarity. A nanopulse electric field can then be precisely applied to the tumor using nsPEF system 100 (see FIG. 1).

[0055] The electrodes may be arranged so that one electrode of each positive and negative pair of electrodes is on one side of the tumor and the other electrode of the pair is on the opposite side of the tumor, where opposite sides of the tumor may include areas outside the tumor or within the tumor, for example, where needle electrodes puncture a portion of the tumor.

[0056] Figure 4 shows a bipolar suction electrode according to this embodiment. In the electrode device 400, a sheath 401 surrounds two wide electrodes 402 on opposite sides of the chamber. The opposing electrodes apply nsPEF pulses to the tumor as air is evacuated through vacuum holes 404 and the tumor is pulled into the chamber.

[0057] The nature of the electrodes used will depend primarily on the shape of the tumor, and its physical size and stiffness may also be taken into consideration in selecting a particular electrode type.

[0058] US Pat. No. 8,688,227 B2 (to Nuccitelli et al.) discloses another suction electrode-based medical device and system for therapeutic electrotherapy, and is incorporated herein by reference.

[0059] If a subject has multiple tumors, the surgeon can select a single tumor for treatment based on the tumor's compatibility with the electrodes. For example, a tumor adjacent to the stomach wall may be more easily accessible than a tumor adjacent to the spine or brain. Because nsPEF pulses are preferably applied so that the electric field passes through as much of the tumor mass as possible while minimizing the population of non-tumor cells affected, a clear path to the two opposing "poles" of the tumor may also be a selection criterion.

[0060] For tumors on or just beneath the subject's skin, needle electrodes can be used percutaneously. For tumors deeper within the subject, retractable electrodes may fit within a gastroscope, bronchoscope, colonoscope, or other endoscope or laparoscope. For example, a tumor in a patient's colon can be accessed and treated using electrodes within the colonoscope. For tumors internal to the body, electrodes can be used in open surgery, laparoscopic surgery, or other minimally invasive surgical techniques.

[0061] Barrett's esophagus, in which a patient has damaged sections of tissue lining the esophagus, can be treated using electrodes placed on an inflatable balloon.

[0062] Embodiments of the nanosecond pulse generator generate electrical pulses in the single nanosecond to single microsecond range, created by the rapid release of energy stored, for example, in a capacitive or inductive energy reservoir, into a load for a period that is generally much shorter than the charging time of the energy reservoir.

[0063] Conventional capacitive-type pulse generators include a pulse-forming network that provides a constant pulse duration and impedance. With prior knowledge of the load's resistance, a pulse-forming network with an impedance that matches the load can be used. However, for wider applications, especially when the load resistance is unknown, it is desirable to have a pulse generator with flexibility in impedance matching and pulse duration variation. Such flexibility can be implemented by switching a capacitor with a controllable switch. In this case, the capacitor can be considered a "voltage source" and can adapt to various load resistances. The switched pulse amplitude may then have the same voltage as the capacitor's voltage. The pulse width is correspondingly determined by the switch "on" time.

[0064] The choice of switches in nanosecond pulse generators is limited due to the high voltages, high currents, and fast switching times involved.

[0065] Spark gap switches, typically used in pulsed power technology, are capable of switching high voltages and conducting high currents. However, spark gap switches can only be turned on; they cannot stop the current mid-way. In addition to spark gaps, other types of high-voltage, high-power switches are available, such as magnetic switches, vacuum switches, gas-filled tubes (e.g., thyratrons), and certain high-voltage semiconductor switches.

[0066] Magnetic switches rely on the saturation of a magnetic core to change from high impedance to low impedance in a circuit. They can be turned on above a certain current threshold, but cannot be turned off until all the current has been used up by the load.

[0067] Vacuum switches are a good option for high voltage and high refill rate operation, but like magnetic switches, they can only be turned on and cannot be turned off at a predetermined time.

[0068] Several types of high voltage semiconductor switches may also be considered. Thyristors and insulated gate bipolar transistors (IGBTs) may be used in some embodiments. However, the turn-on times of thyristors and IGBTs limit their usefulness.

[0069] Metal-oxide-semiconductor field-effect transistors (MOSFETs) used in conventional pulse generator architectures have insufficient maximum drain-source voltage ratings (e.g., <1 kV) and insufficient maximum drain-source current ratings (e.g., <50 A) to generate the voltages and currents required for the applications described herein. If MOSFETs were used, multiple stages would be required to generate a high-amplitude output voltage. However, in conventional Marx generator architectures with multiple stages, the Marx generator enters an undampened mode instead of a highly damped mode, resulting in overshoot losses. As a result, the overall voltage efficiency decreases. For example, the voltage efficiency of a Marx generator may be 80% with five stages but decrease to 50% with 20 stages.

[0070] Furthermore, as the number of stages increases, the impedance of the Marx generator also increases, which reduces the total energy that can be delivered to the load, which is particularly undesirable for driving low impedance loads and long pulses.

[0071] Furthermore, the charge losses in the charging resistors also increase with increasing number of stages. As a result, such Marx generators are not suitable for high repetition rate operation.

[0072] Therefore, simply increasing the number of stages to generate high voltage pulses introduces a series of problems, including low efficiency, high impedance, etc. Because there is a trade-off between the number of stages and the actual output voltage, using a conventional Marx generator cannot generate high voltage pulses that are sufficient for the applications described herein.

[0073] Some embodiments of the present disclosure include an adjustable high-voltage nanosecond pulse generator. The switches may be, for example, power MOSFETs that may be rated for a voltage of 1 kV and a current up to 30 A. In some embodiments, the switches power MOSFETs rated for a voltage of 1 kV and a current up to 90 A continuous and over 200 A peak. The voltage is scaled up by a Marx switch-stack hybrid circuit. Each Marx generator stage uses a specially configured stack of MOSFETs. As a result, the charging voltage per stage is greater than the rated maximum for a single switch.

[0074] A technical advantage of the configuration is that the overall output voltage can be increased in just a few stages (e.g., ≦5). As a result, the problems mentioned above with Marx generators having many stages are avoided, and high efficiency, low impedance, and large variability in pulse duration can be achieved.

[0075] Such an architecture also allows for much easier control, since only one trigger circuit may be required for each stage. One additional advantage is that the pulse generator has low impedance and can drive a variety of loads with high currents and extended pulse durations. Current scaling is achieved by combining multiple Marx switch stack circuits in parallel. The pulse duration is controlled by opening and closing the switches in the switch stack.

[0076] 5 shows a pulse generator circuit 500 that may be used within the nsPEF 100 of FIG. 1. The pulse generator circuit 500 shows a panel including a Marx generator switched by three switch stacks. An nsPEF system may have a single pulse generator circuit panel. In some embodiments, an nsPEF system includes multiple panels in parallel.

[0077] Circuit 500 includes three stages—510, 520, and 530. In some embodiments, a different number of stages is used. For example, in some embodiments, two, four, five, six, seven, eight, nine, or ten stages are used. Stage 510 includes resistors 512 and 514, capacitor 515, and switch stack 516. Similarly, stage 520 includes resistors 522 and 524, capacitor 525, and switch stack 526, and stage 530 includes resistors 532 and 534, capacitor 535, and switch stack 536. Each of these elements has a structure and functionality similar to the corresponding element in stage 510.

[0078] Stage 510 has first and second input voltage input terminals 511 and 513 and first and second voltage output terminals 517 and 518. Stage 520 has first and second input voltage input terminals 521 and 523 and first and second voltage output terminals 527 and 528. Stage 530 has first and second input voltage input terminals 531 and 533 and first and second voltage output terminals 537 and 538.

[0079] First and second voltage input terminals 511 and 513 of stage 510 are connected to first and second power supply input terminals V1 and V2, respectively. First and second voltage output terminals 517 and 518 of stage 510 are connected to first and second voltage input terminals 521 and 523, respectively, of stage 520. First and second voltage output terminals 527 and 528 of stage 520 are connected to first and second voltage input terminals 531 and 533, respectively, of stage 530. Second voltage output terminal 538 of stage 530 and second voltage input terminal 513 of stage 510 are connected to first and second power output terminals VO1 and VO2, respectively.

[0080] Pulse generator circuit 500 operates in a charge mode and a discharge mode. During the charge mode, described in more detail below with respect to FIG. 6A, capacitors 515, 525, and 535 are charged to a charging voltage by current received from first and second power input terminals V1 and V2. During the discharge mode, described in more detail below with respect to FIG. 6B, capacitors 515, 525, and 535 are discharged to provide current to a load (not shown) connected across first power output terminals V01 and V02.

[0081] FIG. 6A shows pulse generator circuit 500 during charging. First and second input voltages are applied to first and second power supply input terminals V1 and V2, respectively. While each of switch stacks 516, 526, and 536 is non-conductive or open, the first and second power output terminals may be disconnected from a load (not shown). Because each of switch stacks 516, 526, and 536 is open, substantially no current flows therethrough, and they are represented in FIG. 6A as open circuits. During charging mode, each of capacitors 515, 525, and 535 is charged to a charging voltage by current flowing through resistors 512, 522, 532, 534, 524, and 514 to or toward a voltage equal to the difference between the first and second input voltages.

[0082] Each switch in switch stacks 516, 526, and 536 has a breakdown voltage that should not be exceeded. However, because the switches are connected in series, capacitors 515, 525, and 535 may be charged to a voltage significantly greater than the breakdown voltage of an individual switch. For example, the breakdown voltage of a switch may be 1 kV, and capacitors 515, 525, and 535 may be charged to a voltage of 5 kV when five or more switches are used in each switch stack.

[0083] For example, the first and second input voltages may be 5 kV and 0 V, respectively. In such an example, each of capacitors 515, 525, and 535 is charged to or toward a voltage equal to 5 kV. In some embodiments, the difference between the first and second input voltages is limited to less than 10 kV.

[0084] FIG. 6B shows pulse generator circuit 500 in 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. Additionally, each of switch stacks 516, 526, and 536 is conductive or closed. Because each of switch stacks 516, 526, and 536 is closed, current flows therethrough, represented as wires in FIG. 6B. As a result, a low-impedance electrical path from power supply input terminal V2 to power output terminal V01 is formed by switch stack 516, capacitor 515, switch stack 526, capacitor 525, switch stack 536, and capacitor 535. As a result, the difference between the voltages at power output terminals V01 and V02 is equal to the number of stages (three in this example) multiplied by the difference between the first and second input voltages.

[0085] If the first and second input voltages are 5 kV and 0 V, respectively, a voltage difference of 15 kV will develop across the power output terminals VO1 and VO2.

[0086] Figure 7 shows an alternative pulse generator circuit 700 that may be used within the nsPEF system 100 of Figure 1. This pulse generator includes parallel panels, the number of which can be adjusted to allow the system to generate different amounts of current and power.

[0087] The pulse generator circuit 700 receives an input pulse across an input port Vin and generates an output pulse across an output port Vout in response to the received input pulse.

[0088] The pulse generator circuit 700 includes multiple panels or pulse generator circuits 710, 720, 730, and 740. The pulse generator circuit 700 also includes a driver 750. 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, two, three, five, six, seven, eight, nine, ten, or another number of pulse generator circuits are used.

[0089] Each of the pulse generator circuits 710, 720, 730, and 740 may have characteristics similar to other pulse generator circuits described herein. For example, each of the pulse generator circuits 710, 720, 730, and 740 may have characteristics similar to the pulse generator circuit 500 described above with respect to Figures 5, 6A, and 6B.

[0090] Each of pulse generator circuits 710, 720, 730, and 740 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 drive signal pulses applied across the positive and negative control input terminals, the output voltage pulses being based on voltages received across the positive and negative DC power supply input terminals.

[0091] Drive signal pulses are generated across conductors 756 and 758 by driver 750, which includes amplifier circuitry 751, capacitor 752, and transformer 753. In some embodiments, driver 750 also includes clamp circuitry 754.

[0092] Driver 750 receives an input signal pulse at input port Vin and generates a drive signal pulse across conductors 756 and 758 in response to the input signal pulse. Amplifier circuit 751 receives the input signal pulse and drives transformer 753 through capacitor 752, which blocks low frequency and DC signals. In response to being driven by amplifier circuit 751, transformer 753 generates an output voltage pulse across conductors 756 and 758, such that the duration of the output voltage pulse is equal to or substantially equal (e.g., within 10% or 1%) to the duration of the input signal pulse at input port Vin.

[0093] In some embodiments, clamp circuit 754 is included to at least attenuate potential signals that might otherwise be caused by resonance. Clamp circuit 754 includes a parallel diode that provides a short circuit path for any current reversal and clamps the maximum voltage across the components connected to clamp circuit 754.

[0094] In some embodiments, the transformer 753 has a turns ratio of 1:1. In alternative embodiments, different turns ratios are used.

[0095] Pulse generator circuits 710, 720, 730, and 740 receive voltage pulses from driver 750 across their positive and negative control input terminals and generate corresponding voltage pulses across their positive and negative output terminals in response to the voltage pulses received from driver 750. The voltage pulses generated across their positive and negative output terminals have durations equal to or substantially equal (e.g., within 10% or 1%) the duration of the voltage pulses received from driver 750.

[0096] In this embodiment, the negative output terminals of pulse generator circuits 710, 720, 730, and 740 are directly connected to the negative Vout terminal of output port Vout of pulse generator circuit 700. Furthermore, in this embodiment, the positive output terminals of pulse generator circuits 710, 720, 730, and 740 are connected to the positive Vout terminal of output port Vout of pulse generator circuit 700 through diodes 715, 725, 735, and 745, respectively. Diodes 715, 725, 735, and 745 decouple pulse generator circuits 710, 720, 730, and 740 from one another. As a result, interference and associated pulse disturbances that would otherwise occur are largely eliminated. For example, diodes 715, 725, 735, and 745 prevent current from flowing from one of pulse generator circuits 710, 720, 730, and 740 to another of pulse generator circuits 710, 720, 730, and 740 when switching is not perfectly synchronized. Diodes 715, 725, 735, and 745 also prevent current from flowing from pulse generator circuits 710, 720, 730, and 740 when pulse generator circuits 710, 720, 730, and 740 are charging.

[0097] In this embodiment, diodes 715, 725, 735, and 745 each include a single diode. In an alternative embodiment, diodes 715, 725, 735, and 745 each include multiple diodes connected in series based on at least the voltage ratings of the diodes connected in series.

[0098] In this embodiment, diodes 715, 725, 735, and 745 are connected to conduct current from the positive terminal of output port Vout toward pulse generator circuits 710, 720, 730, and 740, because pulse generator circuits 710, 720, 730, and 740 in this embodiment are configured to generate negative pulses. In an alternative embodiment in which the pulse generator circuits are configured to generate positive pulses, the diodes are similarly connected to conduct current from the pulse generator circuits to the positive terminals of the output ports.

[0099] FIG. 8 shows a pulse generator circuit 800 that may be used for pulse generator circuits 710, 720, 730, and 740 of pulse generator circuit 1000 of FIG.

[0100] The pulse generator circuit 800 receives an input pulse across an input port Vin and generates an output pulse across an output port Vout in response to the received input pulse.

[0101] The pulse generator circuit 800 includes multiple pulse generator stages 810, 820, and 830. In this embodiment, the pulse generator circuit 700 also includes a driver 850 and optional common mode chokes 815, 825, and 835.

[0102] Each of pulse generator stages 810, 820, and 830 may have characteristics similar to other pulse generator stages described herein. For example, each pulse generator stage 810, 820, and 830 may have characteristics similar to stages 510, 520, and 530 of pulse generator circuit 500 described above with respect to Figures 5, 6A, and 6B. In some embodiments, fewer or more pulse generator stages may be used.

[0103] Each of pulse generator stages 810, 820, and 830 has positive and negative trigger input terminals, positive and negative power 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 drive signal pulses applied across the positive and negative trigger input terminals, the output voltage pulses also being based on voltages V1 and V2 received at the positive and negative power DC input terminals, respectively.

[0104] In this embodiment, the negative Vi input terminal of pulse generator stage 830 is connected to the negative terminal of output port Vout of pulse generator circuit 800. Furthermore, in this embodiment, the negative Vo output terminal of pulse generator stage 810 is connected to the positive terminal of output port Vout of pulse generator circuit 800.

[0105] Additionally, as shown, a pulse generator step The positive Vo output terminal of the 830 is connected to the pulse generator. step Connect the positive Vi input terminal of the 820 to the pulse generator. step The negative Vo output terminal of the 830 is a pulse generator. step It is connected to the negative Vi input terminal of the 820. step The positive Vo output terminal of the 820 is connected to the pulse generator. step Connect the positive Vi input terminal of the 810 to the pulse generator. step The negative Vo output terminal of the 820 is connected to the pulse generator. step Connected to the negative Vi input terminal of 810.

[0106] Drive signal pulses for pulse generator stages 810, 820, and 830 are generated across conductors 856 and 858 by driver 850, which includes amplifier circuit 851, capacitor 852, and transformer 853. In some embodiments, driver 850 also includes clamp circuit 854.

[0107] 7 above, driver 850 receives an input signal pulse at input port Vin, which is connected to conductors 756 and 758. Driver 850 generates a drive signal pulse across conductors 856 and 858 in response to the input signal pulse. Amplifier circuit 851 receives the input signal pulse and drives transformer 853 through capacitor 852, which reduces or blocks low frequency and DC signals. In response to being driven by amplifier circuit 851, transformer 853 generates an output voltage pulse across conductors 756 and 758, such that the duration of the output voltage pulse is equal to or substantially equal (e.g., within 10% or 1%) the duration of the input signal pulse at input port Vin.

[0108] In some embodiments, clamp circuit 854 is included to at least attenuate potential signals that might otherwise be caused by resonance. Clamp circuit 854 includes a parallel diode that provides a short circuit path for any current reversal and clamps the maximum voltage across the components connected to clamp circuit 854.

[0109] In some embodiments, the transformer 853 has a turns ratio of 1:1. In alternative embodiments, different turns ratios are used.

[0110] Each of pulse generator stages 810, 820, and 830 receives a voltage pulse from driver 850 through a corresponding choke 815, 825, or 835 that blocks, for example, high frequency signals from coupling out of high voltage pulse generator stages 810, 820, and 830. The voltage pulses are received at the positive and negative trigger input terminals, and pulse generator stages 810, 820, and 830 each generate a corresponding voltage pulse across their positive and negative Vo output terminals in response to the voltage pulse received from driver 850. The voltage pulses generated across the positive and negative Vo output terminals have durations equal to or substantially equal (e.g., within 10% or 1%) the duration of the voltage pulse received from driver 850.

[0111] FIG. 9 illustrates a pulse generator stage 900 that may be used as one of the pulse generator stages 810, 820, and 830 of the pulse generator circuit 800 shown in FIG.

[0112] The pulse generator stage 900 receives a trigger pulse across an input port Trigger Input and generates an output voltage at an output port Vout in response to the received trigger pulse. The output voltage is also generated based on the voltages received at the power input terminals V1 and V2. The pulse generator stage 900 includes a plurality of switch drivers 950. The pulse generator stage 900 also includes a switch stack 910, a capacitor 920, and resistors 930 and 940.

[0113] The switch driver 950 is configured to receive a trigger pulse and generate control signals for the switches of the switch stack 910 in response to the received trigger pulse, as described in further detail below. Each of the control signals is referenced to a voltage specific to the switch being driven. Thus, a first switch receives a control signal pulse between a first voltage and a second voltage, and a second switch receives a control signal pulse between a third voltage and a fourth voltage, where each of the first, second, third, and fourth voltages is 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.

[0114] Switch stack 910, capacitor 920, and resistors 930 and 940 function in cooperation with corresponding elements of the other pulse generator stages of pulse generator circuit 800 described above with respect to Figure 8 to generate voltage pulses across the positive and negative Vo output terminals of pulse generator circuit 800. These elements may, for example, function in cooperation as the corresponding elements described above with respect to pulse generator circuit 500 shown in Figures 5, 6A, and 6B. For example, these elements may cooperate to generate voltage pulses across the positive and negative Vo output terminals of pulse generator circuit 800 in response to voltages applied to power input terminals V1 and V2 and to control signals applied to the switches of switch stack 910.

[0115] 7 through multiple stages of drive, the control signals cause all of the switches in the switch stack of the pulse generator circuit 700 to turn on and off substantially simultaneously. For example, a 15V input pulse having a duration of, e.g., 100 ns, received at the input port Vin of the pulse generator circuit 700 may cause the pulse generator circuit 700 to generate a high-voltage (e.g., approximately 15 kV) output pulse having a duration of about 100 ns. Similarly, a 15V input pulse having a duration of, e.g., 5 μs, received at the input port Vin of the pulse generator circuit 700 may cause the pulse generator circuit 700 to generate a high-voltage (e.g., approximately 15 kV) output pulse having a duration of about 5 μs. Thus, the duration of the high-voltage output pulse is substantially the same as the selected duration of the input pulse.

[0116] FIG. 10 shows a switch driver 1000 that may be used as one of the switch drivers shown in FIG.

[0117] The switch driver 1000 receives a trigger pulse across an input port Vin and generates a control signal pulse at an output port Vout in response to the received trigger pulse. The switch driver 1000 includes an amplifier circuit 1010, a capacitor 1020, and a transformer 1030. In some embodiments, the switch driver 1000 also includes a clamp circuit 1070.

[0118] Amplifier circuit 1010 receives the trigger pulse and drives transformer 1030 through capacitor 1020, which reduces or blocks low frequency and DC signals. In response to being driven by amplifier circuit 1010, transformer 1030 generates a control signal pulse at output port Vout, such that the duration of the control signal pulse is equal to or substantially equal (e.g., within 10% or 1%) to the duration of the trigger pulse at input port Vin.

[0119] In some embodiments, amplifier circuit 1010 includes multiple amplifier integrated circuits. For example, for increased current drive capability, multiple amplifier integrated circuits may be connected in parallel to form amplifier circuit 1010. For example, two, three, four, five, six, seven, eight, or another number of amplifier integrated circuits may be used.

[0120] In some embodiments, a clamp circuit 1070 is included to at least attenuate potential signals that might otherwise be caused by resonance. The clamp circuit 1070 includes a parallel diode to provide a short circuit for any current reversal and also clamps the maximum voltage across the components connected to the clamp circuit 1070.

[0121] In some embodiments, the drivers 750, 850, and 1000 receive power from a DC-DC power module that is isolated from the power supply for the Marx generator. This ensures a disconnection of the ground coupling.

[0122] In some embodiments, the transformer 1030 has a turns ratio of 1:1. In alternative embodiments, different turns ratios are used.

[0123] In some embodiments, to achieve very fast switching, the transformer 1030 has fewer than five turns on the primary winding and fewer than five turns on the secondary winding. For example, in some embodiments, the transformer 1030 has 1 turn, 2 turns, 3 turns, or 4 turns on each of the primary and secondary windings. In some embodiments, the transformer 1030 has less than one full turn, such as, for example, 1 / 2 turns on each of the primary and secondary windings. A low number of turns on each of the primary and secondary windings allows for a low inductance loop and increases the current rise time on the secondary winding, which charges the input capacitance of the MOSFET switch.

[0124] Transformers for triggering MOSFETs in conventional applications require high-coupling, high-permeability, and low-loss cores to ensure current transfer efficiency. After each pulse, the core's residual magnetic flux must be cleared to avoid saturation when the transformer is operated at high frequencies. Conventionally, a reset circuit including a third winding is used to dissipate the core energy.

[0125] In some embodiments, a lossy transformer, such as those typically used as electromagnetic interference (EMI) chokes to limit high frequency signals and dissipate their energy as heat, is used to trigger the switch. For example, the transformer may have a voltage time constant of less than 100 Vμs. In some embodiments, the transformer has a voltage time constant of less than 50 Vμs, 30 Vμs, 20 Vμs, 10 Vμs, or 5 Vμs. The use of a lossy transformer is contrary to common practice in power electronics.

[0126] Although high-frequency magnetic flux is attenuated due to core losses (eddy, hysteresis, and resistive losses), lossy transformers still allow sufficient flux confinement and provide sufficient coupling. Furthermore, the magnetic flux also decreases quickly in response to a signal in the primary winding being removed. The process of flux decay typically takes about a few microseconds.

[0127] Although having such a transformer would previously seem a disadvantage, it is preferably used to couple nanosecond to microsecond pulses, resulting in the following advantages: 1) high voltage, high frequency transient coupling from the high voltage Marx generator to the low voltage driver is suppressed, and 2) due to losses in the transformer core, residual magnetic flux from previous pulses dissipates faster than in typical low loss transformer cores, so a reset winding is not needed or present.

[0128] An advantage of switch driver 1000 is that it limits the output pulse duration. Because the switch control signal is generated by a transformer 1030, if the circuitry generating the input trigger signal at input port Vin generates a pulse of unlimited length, the transformer will saturate, causing the control signal to switch off.

[0129] 11 illustrates an example of a switch element 1100 including components that may be used in the switch stacks described herein. The switch element 1100 includes a switch 1110 that selectively forms a conductive path or a low resistance path between terminals VA and VB in response to a control voltage applied to an input port Vin.

[0130] In some embodiments, switch 1110 is a transistor such as a MOSFET. In some embodiments, switch 1110 is another type of switch. In some embodiments, switch 1110 has a turn-on time of less than 5 ns, about 5 ns, about 10 ns, about 25 ns, about 15 ns, about 75 ns, about 100 ns, or more than 100 ns.

[0131] In some embodiments, the switch element 1100 also includes a snubber circuit 1120. In some embodiments, the turn-on times of the switches in the switch stack are not identical. To prevent voltages greater than the switch 1110 can withstand, the snubber circuit 1120 provides a current shunt path by passing through the switch 1110. A diode 1122 provides a low-frequency current path, and a combination of a capacitor 1126 and a resistor 1124 provides a high-frequency current path.

[0132] In some embodiments, the switch element 1100 also includes an optional overcurrent protection circuit 1140. The overcurrent protection circuit 1140 includes a switch 1142 and a sense resistor 1144.

[0133] Current flowing from terminal VA to terminal VB is conducted through sense resistor 1144. Thus, when current flows from terminal VA to terminal VB, a voltage is developed across sense resistor 1144. The developed voltage controls the conductive state of switch 1142. If the current flowing from terminal VA to terminal VB is greater than a threshold, the developed voltage causes switch 1142 to conduct. As a result, switch 1142 reduces the control voltage of switch 1110. In response to the reduced control voltage, switch 1110 becomes less conductive, or turns off. As a result, the current that may be conducted from terminal VA to terminal VB is limited by overcurrent protection circuit 1140.

[0134] In some embodiments, a limiting resistor is placed between the gate of switch 1110 and the drain of switch 1142 to prevent switch 1142 from experiencing a current greater than that which would cause damage.

[0135] In the embodiments described 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.

[0136] An example of transformer operation is shown in Figure 12. While the voltage across the input primary inductor is a substantially square waveform, the voltage across the secondary inductor, which is the gate-source voltage of the MOSFET, tapers off as the voltage amplitude decreases toward zero within a period of, for example, a few microseconds. After the voltage reduction across the secondary inductor due to transformer saturation, the switch receiving the voltage enters the linear region of operation from the saturated region of operation when the voltage is less than the fully enhanced Vgs. As a result, the resistance of the switch increases, and the output voltage across the load also exhibits a tapered profile. When the voltage across the secondary inductor decreases to a value below the turn-on threshold (Vth) of the MOSFET, the MOSFET is cut off. Once the MOSFET is turned off, the switch no longer conducts and may be considered an open circuit, even if the duration of the trigger signal is extended. Therefore, the waveform of the voltage across the secondary inductor limits the duration of high-voltage output pulses from each panel, for example, to a few microseconds or less.

[0137] In some embodiments, the voltage decrease across the secondary inductor is not sufficient to cause the switch to enter linear region operation, and the duration of the trigger signal is short enough that the switch remains saturated. In such embodiments, the load voltage pulse does not exhibit the taper shown in Figure 12. For example, in such embodiments, the load voltage pulse may be substantially square.

[0138] In some embodiments, the switch stacks described herein include the switches described above as well as other components.

[0139] In some embodiments, when generating pulses of duration below the threshold, the pulse shape is substantially square. In some embodiments, when generating pulses of duration above the threshold, the pulse shape is substantially square for a duration substantially equal to (e.g., within 10% or 1%) the threshold. Over time after the threshold, the voltage of such long pulses decreases toward 0 V. In some embodiments, the decrease toward 0 V is substantially linear. In some embodiments, the decrease toward 0 V is substantially abrupt.

[0140] FIG. 13 shows an alternative pulse generator circuit 1300 that may be used within the nsPEF system 100 of FIG.

[0141] The pulse generator circuit 1300 receives an input pulse across an input port Vin and a DC voltage at input ports VDC1 and VDC2, and generates an output pulse across an output port Vout in response to the received input pulse and DC voltage.

[0142] Pulse generator circuit 1300 includes multiple pulse generator circuits 1310 and 1320. In this embodiment, two pulse generator circuits are used. In alternative embodiments, more pulse generator circuits are used. For example, some embodiments use three, four, five, ten, or another number of pulse generator circuits with their output ports connected in series, as described below with respect to pulse generator circuit 1300.

[0143] Each of the pulse generator circuits 1310 and 1320 may be similar to other pulse generator circuits described herein. For example, the pulse generator circuits 1310 and 1320 may be similar to or substantially identical to the pulse generator circuit 700 described above with respect to FIG.

[0144] Each of pulse generator circuits 1310 and 1320 receives the same input pulse signal across its respective control-in input port. In response, each of pulse generator circuits 1310 and 1320 generates a high-voltage pulse across its respective Vout output port. Because the Vout output ports of pulse generator circuits 1310 and 1320 are connected in series, the voltage pulses generated by pulse generator circuits 1310 and 1320 across output port Vout of pulse generator circuit 1300 are substantially equal (e.g., within 10% or 1%) to the sum of the voltages of the pulses generated by pulse generator circuits 1310 and 1320, respectively.

[0145] FIG. 14 illustrates a pulse generator that may be used within the nsPEF system 100 of FIG. 1 and that may be used within the pulse generator of FIG. circuit An alternative pulse generator circuit 1400 is shown having similar characteristics to 1300. Pulse generator circuit 1400 includes pulse generators 1410 and 1420, drivers 1415 and 1425, and power supplies 1412 and 1422.

[0146] Pulse generator circuit 1400 includes multiple pulse generator circuits 1410 and 1420. In this embodiment, two pulse generator circuits are used. In alternative embodiments, more pulse generator circuits are used. Each of pulse generator circuits 1410 and 1420 may be similar to other pulse generator circuits described herein.

[0147] Pulse generator circuit 1400 receives input pulses at respective drivers 1415 and 1425, which may be similar to driver 850 described above with respect to Figure 8. Pulse generator circuit 1400 generates output pulses across output port Vout in response to the received input pulses. The output voltage pulses are also based on the voltages received from power supplies 1412 and 1422.

[0148] Each of the drivers 1415 and 1425 receives an input pulse signal. In response to the received input signal, the drivers 1415 and 1425 generate a drive signal pulse for the pulse generator circuits 1410 and 1420, respectively. In response to the drive signal pulse, each of the pulse generator circuits 1410 and 1420 generates a high voltage pulse across its respective output port Vo1 and Vo2. Because the Vo1 and Vo2 output ports of the pulse generator circuits 1410 and 1420 are connected in series, the voltage pulses generated by the pulse generator circuits 1410 and 1420 across the output port Vout of the pulse generator circuit 1400 are substantially equal (e.g., within 10% or 1%) to the sum of the voltages of the pulses generated by the pulse generator circuits 1410 and 1420, respectively.

[0149] In this embodiment, pulse generator circuit 1410 generates a high voltage pulse across its output port Vo1 that is substantially equal (e.g., within 10% or 1%) to three times the voltage of power supply 1412 (-3x[V1-V2]). Additionally, pulse generator circuit 1420 generates a high voltage pulse across its output port Vo2 that is substantially equal to three times the voltage of power supply 1412 (-3x[V1-V2]). 1422 14. As a result, the pulse generator circuit 1400 generates a voltage across its output port Vout of (3×[V′1−V′2])−(−3×[V1−V2]).

[0150] In some embodiments, a single driver circuit connected to both pulse generator circuits 1410 and 1420 is used in place of drivers 1415 and 1425. In such embodiments, the single driver circuit generates drive signal pulses for both pulse generator circuits 1410 and 1420 in response to input pulse signals.

[0151] For various purposes, it may be desirable to discharge a capacitor used by a pulse generator to generate a pulse. For example, it may be desirable to discharge capacitor 920 of pulse generator 900 of FIG. 9. Discharging the capacitor may be done using various embodiments of various discharge circuits. Several embodiments are described herein.

[0152] Figure 15 shows a pulse generator circuit 1500 that may be used for pulse generator circuits 710, 720, 730, and 740 of pulse generator circuit 700 of Figure 7. Pulse generator circuit 1500 is similar to pulse generator circuit 800 shown in Figure 8. Pulse generator circuit 1500 further includes a specific discharge circuit 1550.

[0153] As shown, the discharge circuit 1550 is electrically connected to the first and second power supply input terminals V1 and V2. The discharge circuit 1550 is also electrically connected to the discharge input terminal D1. Based on the voltages at the first and second power supply input terminals V1 and V2 and the discharge input terminal D1, the discharge circuit 1550 selectively discharges each of the pulse generator stages 810, 820, and 830.

[0154] In some embodiments, discharge circuit 1550 is configured to discharge each of pulse generator stages 810, 820, and 830 in response to a discharge control signal received at discharge input terminal D1. In some embodiments, discharge circuit 1550 is configured to discharge each of pulse generator stages 810, 820, and 830 in response to a comparison of a charge voltage determined by the voltages at first and second power supply input terminals V1 and V2 to a charge voltage stored on the capacitor of each of pulse generator stages 810, 820, and 830.

[0155] Figure 16 shows a pulse generator stage 1600 that may be used as one of the pulse generator stages 810, 820, and 830 of the pulse generator circuit 1500 shown in Figure 15. The pulse generator stage 1600 includes a discharge circuit stage 1650.

[0156] In some embodiments, discharge circuit stage 1650 is configured to discharge capacitor 920 in response to a discharge command signal received at discharge input terminal D1. In some embodiments, discharge circuit stage 1650 is configured to discharge capacitor 920 in response to a comparison of a charge voltage determined by the voltages at first and second power supply input terminals V1 and V2 to a charge voltage stored on capacitor 920.

[0157] Figure 17 is a schematic diagram of an embodiment of a discharge circuit stage 1700 used in pulse generator stage 1600 of Figure 16. Pulse generator stage 1700 includes voltage sources 1706 and 1708, a comparator 1710, an OR circuit 1720, a buffer 1730, a pulse generator 1740, buffers 1751, 1761, 1771, 1781, and 1791, transformers 1752, 1762, 1772, 1782, and 1792, switches 1753, 1763, 1773, 1783, and 1793, and a resistor 1795.

[0158] Comparator 1710 is configured to generate a signal that selectively causes other components of discharge stage 1700 to cause switches 1753, 1763, 1773, 1783, and 1793 to become conductive, effectively shorting the discharge terminals at output port OUT. Using multiple switches has the advantage of allowing the voltage at the output of discharge stage 1700 to be greater than the maximum drain / source voltage rating of a single switch. For example, in the embodiment shown, five switches are used. If the maximum drain / source voltage rating per switch is 1000V, using five switches would ideally allow 5000V at the output of discharge stage 1700.

[0159] For example, in this embodiment, comparator 1710 receives input voltages at voltage control input terminals Vpg and Vdc. The voltage at voltage input terminal Vpg is generated by voltage source 1706 based on the voltage across a capacitor selectively discharged by discharge circuit stage 1700. The voltage at voltage input terminal Vdc is generated by voltage source 1708 based on first and second power supply input terminals V1 and V2.

[0160] In some embodiments, voltage sources 1706 and 1708 are level shift circuits that receive voltages higher than the voltage that comparator 1710 can withstand. For example, voltage source 1706 may be configured to receive a voltage difference of approximately 5 kV across its inputs Vc1 and Vc2 and generate an output voltage at terminal Vpg equal to approximately 10 V, where the output voltage at terminal Vpg is proportional to the voltage difference across inputs Vc1 and Vc2. Similarly, voltage source 1708 may be configured to receive a voltage difference of approximately 5 V across its inputs Vl and V2 and generate an output voltage at terminal Vdc equal to approximately 10 V, where the output voltage at terminal Vdc is proportional to the voltage difference across inputs Vl and V2.

[0161] In some embodiments, the proportionality constant relating the voltage at terminal Vpg to the voltage across inputs Vc1 and Vc2 is equal to the proportionality constant relating the voltage at terminal Vdc to the voltage across inputs Vl and V2. In such embodiments, comparator 1710 is configured to cause switches 1753, 1763, 1773, 1783, and 1793 to be conductive to provide a discharge path across output port OUT in response to the DC input voltage across terminals Vl and V2 of pulse generator stage 1600 being less than the voltage across capacitor 920 of pulse generator stage 1600.

[0162] In some embodiments, the proportionality constant relating the voltage at terminal Vpg to the voltage across inputs Vc1 and Vc2 is not equal to the proportionality constant relating the voltage at terminal Vdc to the voltage across inputs Vl and V2. In such embodiments, comparator 1710 is configured to cause switches 1753, 1763, 1773, 1783, and 1793 to be conductive, effectively shorting output port OUT in response to the DC input voltage across terminals Vl and V2 of pulse generator stage 1600 being less than the voltage across capacitor 920 of pulse generator stage 1600 by more than a predetermined threshold related to the difference in the proportionality constants.

[0163] For example, in some embodiments, a 5 kV voltage difference across input terminals V1 and V2 causes voltage source 1708 to generate a voltage of 10 V at terminal Vdc, and a 5.1 kV voltage difference across input terminals Vc1 and Vc2 causes voltage source 1706 to generate a voltage of 10 V at terminal Vpg. In such embodiments, comparator 1710 causes switches 1753, 1763, 1773, 1783, and 1793 to be conductive, effectively shorting output port OUT in response to the DC input voltage across terminals V1 and V2 of pulse generator stage 1600 being more than 100 V less than the voltage across capacitor 920 of pulse generator stage 1600.

[0164] In some embodiments, voltage sources 1706 and 1708 are each resistor dividers including first and second resistive elements connected in series, with the output voltage generated at a node shared by the first and second resistive elements, and the first and second input voltages connected to one of the first and second resistive elements, respectively.

[0165] OR circuit 1720 is configured to selectively generate a signal that causes switches 1753, 1763, 1773, 1783, and 1793 to be conductive, effectively shorting output port OUT, in response to the DC input voltage across terminals V1 and V2 of pulse generator stage 1600. OR circuit 1720 is configured to generate a signal based on the voltage level applied to the output of comparator 1710 and at discharge control input terminal D1.

[0166] In this embodiment, OR circuit 1720 is configured to make switches 1753, 1763, 1773, 1783, and 1793 conductive in response to either the output of comparator 1710 or the voltage level at discharge input terminal D1 being greater than a threshold. For example, if either the output of comparator 1710 or the voltage level at discharge input terminal D1 is greater than a threshold, the output of OR circuit 1720 makes switches 1753, 1763, 1773, 1783, and 1793 conductive.

[0167] In this embodiment, OR circuit 1720 includes a light emitting diode (LED) 1722 configured to emit light when either the output of comparator 1710 or the voltage level at discharge input terminal D1 exceeds a threshold value. LED 1722 therefore provides a visual indication that discharge circuit stage 1700 is discharging capacitor 920 of pulse generation stage 1600.

[0168] Discharge stage 1700 optionally includes a buffer 1730. Buffer 1730 receives the signal generated by OR circuit 1720 and generates an output signal for pulse generator 1740.

[0169] In some embodiments, buffer 1730 is not used. In such embodiments, the signal generated by OR circuit 1720 may be provided directly to pulse generator 1740 or may be conditioned by other circuitry that provides a signal to pulse signal generator 1740 based on the signal generated by OR circuit 1720.

[0170] In some embodiments, buffer 1730 is an inverting buffer. In some embodiments, buffer 1730 is a non-inverting buffer.

[0171] In this embodiment, pulse signal generator 1740 is configured to receive a signal from buffer 1730. Pulse signal generator 1740 is responsive to the received signal to selectively generate a series of pulse signals based on the received signal. In some embodiments, the received signal is received by an enable input, such that pulse signal generator 1740 generates a series of pulse signals in response to the received signal being in an appropriate logic state and does not generate a series of pulse signals in response to the received signal being in the opposite logic state.

[0172] In some embodiments, pulse signal generator 1740 includes a timer circuit, such as a 555 timer. In such embodiments, the timer circuit may be configured to generate pulse signals suitable for causing switches 1753, 1763, 1773, 1783, and 1793 to conduct. For example, the timer circuit may be adjusted to generate a sequence of pulse signals suitable for transformers 1752, 1762, 1772, 1782, and 1792 so that transformers 1752, 1762, 1772, 1782, and 1792 do not saturate, causing transformers 1752, 1762, 1772, 1782, and 1792 to generate signals that cause switches 1753, 1763, 1773, 1783, and 1793 to conduct for a significant portion of each period of the pulse signal sequence. For example, the frequency, duty cycle, rise time, and fall time may be adjusted to avoid saturation of transformers 1752, 1762, 1772, 1782, and 1792, and may be adjusted to increase or maximize the portion of each period that switches 1753, 1763, 1773, 1783, and 1793 are conductive.

[0173] Discharge stage 1700 optionally includes buffers 1751, 1761, 1771, 1781, and 1791. Buffers 1751, 1761, 1771, 1781, and 1791 receive the series of pulse signals generated by pulse signal generator 1740 and generate signals for transformers 1752, 1762, 1772, 1782, and 1792, respectively.

[0174] In some embodiments, buffers 1751, 1761, 1771, 1781, and 1791 are not used. In such embodiments, the signal generated by pulse signal generator 1740 may be provided directly to transformers 1752, 1762, 1772, 1782, and 1792, or may be conditioned by other circuitry that provides signals to transformers 1752, 1762, 1772, 1782, and 1792 based on the signal generated by pulse signal generator 1740.

[0175] In some embodiments, buffers 1751, 1761, 1771, 1781, and 1791 are inverting buffers. In some embodiments, buffers 1751, 1761, 1771, 1781, and 1791 are non-inverting buffers.

[0176] In this embodiment, transformers 1752, 1762, 1772, 1782, and 1792 are configured to receive pulse signal sequences from buffers 1751, 1761, 1771, 1781, and 1791. In response to the received pulse signal sequences, transformers 1752, 1762, 1772, 1782, and 1792 selectively generate a series of pulses based on the received pulse signal sequences. The series of pulse signals generated by transformers 1752, 1762, 1772, 1782, and 1792 cause switches 1753, 1763, 1773, 1783, and 1793, respectively, to become conductive, effectively shorting output port OUT.

[0177] For example, switches 1753, 1763, 1773, 1783, and 1793 may be transistors, and in response to a received pulse signal sequence, each of transformers 1752, 1762, 1772, 1782, and 1792 may be configured to generate a gate voltage and a source voltage for a corresponding one of transistors 1753, 1763, 1773, 1783, and 1793. Due to the floating outputs of transformers 1752, 1762, 1772, 1782, and 1792, the gate voltages are generated referenced to the corresponding source voltages. In some embodiments, bipolar transistors may be used, and transformers 1752, 1762, 1772, 1782, and 1792 may be configured to generate base and emitter voltages for corresponding ones of transistors 1753, 1763, 1773, 1783, and 1793.

[0178] Figure 18 shows an alternative pulse generator circuit 1800 that may be used for the pulse generator circuit 700 of Figure 7. The pulse generator circuit 1800 is similar to the pulse generator circuit 700 shown in Figure 7. The pulse generator circuit 1800 further includes a discharge circuit 1850 and a peak power supply 1820.

[0179] As shown, the discharge circuit 1850 is electrically connected to the first and second power supply input terminals VP1 and VP2. The discharge circuit 1850 is also electrically connected to the discharge input terminal D1. Based on the voltages at the first and second power supply input terminals VP1 and VP2, the discharge input terminal D1, and the first and second power supply terminals V1 and V2, the discharge circuit 1850 selectively discharges the first and second power supply terminals V1 and V2.

[0180] In some embodiments, the discharge circuit 1850 is configured to discharge the first and second power supply terminals V1 and V2 in response to a discharge control signal received at the discharge input terminal D1. In some embodiments, the discharge circuit 1850 is configured to discharge the first and second power supply terminals V1 and V2 in response to a comparison of a charge voltage determined by the voltages at the first and second power supply terminals V1 and V2 and the voltages at the first and second power supply input terminals VP1 and VP2.

[0181] The discharge circuit stage 1700 of FIG. 17, or any of the other discharge circuits described herein, may be used as the discharge circuit 1850.

[0182] The peak power supply 1820 may be any low-pass filter. For example, the peak power supply 1820 may include a resistor and a capacitor to form a single-pole RC filter. Other filters may also or alternatively be used.

[0183] Figure 19 is an embodiment of a peak power supply 1900 that may be used as the peak power supply 1820 of Figure 18. As shown, the peak power supply 1900 includes a diode 1910, a resistor 1920, an RC resistor 1930, and an RC capacitor 1940. The resistor 1920 operates to passively discharge the capacitor 1940 and the power supply terminals V1 and V2.

[0184] Figure 20 shows an alternative pulse generator circuit 2000 that can be used within the nsPEF system 100 of Figure 1. This pulse generator is similar to the pulse generator circuit 700 described above with respect to Figure 7. The pulse generator circuit 2000 generates an output signal across the output port Vout.

[0185] The pulse generator circuit 2000 includes multiple panels or pulse generator circuits 2010, 2020, 2030, and 2040, each of which may be similar to or identical to the pulse generator circuits 710, 720, 730, and 740 described above with respect to FIG. 7. In this embodiment, four generator circuits are used. In alternative embodiments, fewer or more pulse generator circuits are used. For example, in some embodiments, 2, 3, 5, 6, 7, 8, 9, 10, or another number of pulse generator circuits are used.

[0186] Pulse generator circuit 2000 also includes diodes 2015, 2025, 2035, and 2045 that are similar to or identical to diodes 715, 725, 735, and 745 described above with respect to Figure 7. Pulse generator circuit 2000 also includes driver 2050 that may be similar to or identical to driver 750 described above with respect to Figure 7.

[0187] Pulse generator circuits 2010, 2020, 2030, and 2040, diodes 2015, 2025, 2035, and 2045, and driver 2050 collectively form pulse generator circuit 2060, which collectively operate similarly or identically to pulse generator circuits 710, 720, 730, and 740, diodes 715, 725, 735, and 745, and driver 750 described above with respect to Figure 7. In some embodiments, pulse generator circuit 2060 includes circuitry similar to or identical to circuitry described elsewhere herein, whereby pulse generator circuit 2060 may be discharged using a discharge circuit.

[0188] Pulse generator circuit 2000 also includes, or in some embodiments is connected to, analog to digital converter 2090. Further, pulse generator 2000 additionally or instead includes, or in some embodiments is connected to current monitors 2070 and 2080. Other pulse generator circuits described herein may similarly include, or be connected to, an analog to digital converter, such as, for example, analog to digital converter 2090. Similarly, other pulse generator circuits described herein may similarly include, or be connected to, current monitors, such as, for example, current monitors 2070 and 2080.

[0189] In this embodiment, analog-to-digital (A / D) converter 2090 includes a first channel having inputs respectively connected to the positive (+) and negative (-) voltage output terminals of pulse generator 2000. 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 2000 and drives the input of analog-to-digital converter 2090. 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 2000 and drives the input of analog-to-digital converter 2090.

[0190] In some embodiments, only the positive (+) voltage output terminal is connected to analog-to-digital converter 2090. In some embodiments, the positive (+) voltage output terminal is connected to analog-to-digital converter 2090 through a voltage divider. In such embodiments, the voltage at the positive (+) voltage output terminal is ground-referenced, and the ground terminal is also connected to analog-to-digital converter 2090. For example, the positive (+) voltage output terminal is ground-referenced if the negative (-) voltage output terminal of pulse generator 2000 is at ground voltage.

[0191] Additionally, the analog-to-digital converter 2090 is configured to produce a first digital output representative of the voltage difference between the positive (+) and negative (-) voltage output terminals of the pulse generator 2000. 21 nsPEF treatment system 2150 When used in, the first digital output may be used as a feedback signal for the controller 2175 of the nsPEF therapy system 2150 of Figure 21, described below. In some embodiments, the analog to digital converter 2090 generates the first digital output based on either the voltage at the positive (+) voltage output terminal or the negative (-) voltage output terminal, but not both.

[0192] In this embodiment, analog to digital converter 2090 also includes a second channel having inputs connected to current monitors 2070 and 2080, respectively, which are connected to the positive (+) and negative (-) voltage output terminals of pulse generator 2000. In some embodiments, a second low input impedance differential buffer (not shown) is connected to current monitors 2070 and 2080 and drives the inputs of analog to digital converter 2090.

[0193] Additionally, the analog-to-digital converter 2090 is configured to produce a second digital output representing the current difference between the currents flowing through the positive (+) voltage output terminal and the negative (-) voltage output terminal of the pulse generator 2000. When used in the nsPEF therapy system 2150 of FIG. 21 described below, the second digital output may be used as a feedback signal for the controller 2175. In some embodiments, the analog-to-digital converter 2090 produces the second digital output based on inputs from either the current monitors 2070 and 2080, but not both.

[0194] In some embodiments, current monitors 270 and 2080 each include a sense resistor configured to produce a voltage response of the current flowing therethrough, and an amplifier that produces an input for an analog-to-digital converter based on the voltage across the sense resistor.

[0195] In some embodiments, current monitors 2070 and 2080 include current monitors such as a Pearson Current Monitor 2878 that develop a voltage in response to the detected current.

[0196] In some embodiments, the pulse generator 2000 produces either the first digital output or the second digital output, but not both. In some embodiments, one or more single channel analog-to-digital converters are used instead of or in addition to the analog-to-digital converter 2090.

[0197] In some embodiments, only a single current monitor is used, which may monitor the current at either the positive (+) or negative (-) voltage output terminal of the pulse generator 2000.

[0198] The pulse generator circuit 2000 also includes a low voltage source 2075 and a switch 2085 .

[0199] The low voltage supply 2075 may be a voltage source separate and independent from the pulse generator circuit 2060. The low voltage supply 2075 may be configured to produce a voltage that may be selectively output across the output port Vout according to the state of the switch 2085. The voltage level of the voltage produced by the low voltage supply 2075 may be less than the voltage level of the voltage produced by the pulse generator circuit 2060.

[0200] In some embodiments, the low voltage source 2075 is a pulse generator circuit 2060 Similar to or identical to the pulse generator circuit 2060 In some embodiments, the low voltage source 2075 is not used and the pulse generator circuit 2060 is selectively charged to different voltages to achieve both the high and low voltages described herein.

[0201] In alternative embodiments, low voltage source 2075 is another type of voltage source. For example, low voltage source 2075 may be a constant DC power supply. In such embodiments, the duration of the voltage delivered from low voltage source 2075 to output port Vout is determined by the duration of the state of switch 2085 that electrically connects low voltage source 2075 to the positive terminal of output port Vout.

[0202] Figure 21 is a block diagram of an nsPEF treatment system 2150 having properties similar to or identical to those of the nsPEF generator system 100 shown in Figure 1. The nsPEF treatment system 2150 includes a pulse generator 2155, a power source 2160, electrodes 2165, an interface 2170, and a controller 2175.

[0203] Pulse generator 2155 may be similar to or identical to any of the pulse generator circuits described herein. For example, pulse generator 2155 may be configured to generate pulses having voltage levels that match the voltages received from power supply 2160 and having pulse widths and other characteristics that fit control signals received from controller 2175. In alternative embodiments, other pulse generator circuits may be used.

[0204] Electrode 2165 may be similar to or identical to any of the electrodes described herein. For example, electrode 2165 may be similar to or identical to electrodes 300 and 400 described above with respect to FIGS. 3 and 4. Electrode 2165 is configured to receive nsPEF pulses generated by pulse generator 2155 from conductor 2156 and to deliver the nsPEF pulses to a patient receiving nsPEF therapy treatment. In alternative embodiments, other therapy electrodes may be used; for example, some embodiments use one or more of the electrodes described in U.S. Application No. 15 / 269,273, entitled "HIGH VOLTAGE CONNECTOR FOR PULSE GENERATOR," filed September 19, 2016, and / or U.S. Application No. 62 / 33,270, entitled "PULSE APPLICATOR," filed May 16, 2016, both of which are incorporated herein by reference.

[0205] The power supply 2160 is configured to provide a voltage to the pulse generator 2155. For example, in embodiments in which the pulse generator 2155 is similar to the pulse generator circuit 2000 shown in FIG. 20, the power supply 2160 may be configured to provide a voltage that matches the voltages V1 and V2 of the pulse generator circuit 700. In some embodiments, the power supply 2160 generates and provides a voltage having a voltage level that matches a control signal from the controller 2175.

[0206] The interface 2170 is configured to receive input from a user identifying various parameters of the nsPEF pulses applied to the patient. For example, the interface 2170 may be configured to receive input identifying or specifying values ​​for one or more characteristics of one or more nsPEF pulses applied to the patient. For example, the characteristics may include one or more of the amplitude, polarity, width, rise time, and fall time of the one or more nsPEF pulses applied to the patient. Additionally or alternatively, the characteristics may include one or more of the frequency and pulse volume of the series of nsPEF pulses applied to the patient. Furthermore, the characteristics may additionally or alternatively include the results of the nsPEF pulses applied to the patient, such as the maximum temperature of the patient's treated tissue. Other characteristics may also or alternatively be identified or specified by the received input.

[0207] Additionally, the interface 2170 is configured to communicate the characteristics identified or specified by the received input to the controller 2175 .

[0208] Controller 2175 is configured to generate one or more control signals and provide the one or more control signals to pulse generator 2155 and to power source 2160 based at least in part on the communicated characteristics received from interface 2170. Further, pulse generator 2155, power source 2160, and electrodes 2165 are collectively configured to, in response to the control signals from controller 2175, generate nsPEF pulses having characteristics that match the control signals.

[0209] In this embodiment, one or both of the pulse generator 2155 and the electrodes 2165 are configured to generate feedback signals FB1 and FB2 that match or represent measured parameter characteristics of the nsPEF pulses applied to the patient. In some embodiments, the parameter characteristics of the nsPEF pulses represented by the feedback signals FB1 and FB2 include one or more of the amplitude, polarity, width, rise time, and fall time of the nsPEF pulses. Additionally or alternatively, the parameter characteristics may include the frequency of the series of nsPEF pulses. Further, the parameter characteristics may additionally or alternatively include the temperature of the patient's treated tissue or the impedance of the load. The feedback signals FB1 and FB2 may match or represent one or more other measured parameter characteristics of the nsPEF pulses applied to the patient, the patient, the environment, and the nsPEF treatment system 2150. In alternative embodiments, only one of the feedback signals FB1 and FB2 is generated. In some embodiments, neither of the feedback signals FB1 and FB2 is generated.

[0210] In some embodiments, the controller 2175, power supply 2160, pulse generator 2155, and electrodes 2165 collectively form a feedback loop that causes one or more parameter characteristics of the nsPEF pulses applied to the patient to have a measured value substantially equal (e.g., within 10%, 5%, 3%, 2%, or 1%) to the value of the corresponding characteristic identified in the input received by interface 2170.

[0211] For example, interface 2170 may receive an input specifying a value of 15 kV for the amplitude of the nsPEF pulses applied to the patient. Further, controller 2175 may be configured to modify the control signal provided to power supply 2160 in response to a feedback signal FB2 from electrodes 2165 or a feedback signal FB1 from pulse generator 2155 indicating that the measured amplitude of the nsPEF pulses applied to the patient is less than (or exceeds) 15 kV. In response to the modified control signal, power supply 2160 may be configured to increase (or decrease) the voltage of the power signal provided to pulse generator 2155 so that the amplitude of the nsPEF pulses generated and applied to the patient increases (or decreases) to or toward 15 kV.

[0212] Similarly, interface 2170 may receive an input specifying a value of 150 ns for the pulse width of the nsPEF pulses applied to the patient. Controller 2175 may be configured to modify the control signal provided to pulse generator 2155 in response to a feedback signal FB2 from electrode 2165 or a feedback signal FB1 from pulse generator 2155 indicating that the measured pulse width of the nsPEF pulses applied to the patient is greater than (or less than) 150 ns. In response to the modified control signal, pulse generator 2155 may be configured to generate and apply to the patient nsPEF pulses having a decreased (or increased) pulse width. As a result, feedback signal FB1 or FB2 causes controller 2175 to generate a control signal that causes pulse generator 2155 to generate and apply nsPEF pulses having a pulse width decreased (or increased) to or toward 150 ns.

[0213] In some embodiments, the feedback loop is controlled using a proportional-integral-derivative (PID) method. For example, the controller 2175 may be configured to continuously or substantially continuously calculate an error value as the difference between a desired value known by the interface 2170 and a corresponding measured parameter. Further, the controller 2175 may be configured to continuously or substantially continuously calculate a control signal as the sum of one or more of a first constant times the error signal, a second constant times the integral of the error signal, and a third constant times the derivative of the error signal.

[0214] In some embodiments, the feedback loop is controlled using a lookup table to determine the next value based on the measurement, hi some embodiments, the feedback loop is controlled by reducing or increasing the value by a fixed amount or step size based on determining whether the measurement is above or below a threshold.

[0215] Various pulse generator circuits are described herein that are capable of delivering voltage pulses of different durations and different voltage levels. For example, pulse generator circuit 2000 of FIG. 20 is configured to deliver pulses of different voltage levels by multiplexing between two separate sources. Additionally, pulse generator circuit 1800 of FIG. 18 is configured to deliver pulses of different voltage levels by charging and / or discharging a reservoir capacitor to different voltage levels.

[0216] Pulse generator circuits capable of delivering voltages at different voltage levels are particularly advantageous. For example, such pulse generator circuits may be used to deliver pulses at a first voltage level for therapeutic or experimental use and to deliver pulses at a second voltage level for other uses. For example, such pulse generator circuits may be used to deliver therapeutic or experimental pulses having a voltage level of 5 kV and to deliver significantly lower level pulses for system diagnostic or system testing purposes. For example, diagnostic or test pulses may be delivered at voltage levels of 1 kV, 0.5 kV, 250 V, 100 V, 50 V, 25 V, 10 V, 5 V, 3 V, 1 V, or another voltage level.

[0217] Diagnostic or test pulses may be used to verify that the pulse generator system is functioning properly and / or that the electrodes are properly placed. For example, after electrodes are placed on opposite sides of the tissue to be treated, the tissue to be treated presents an electrical load to the pulse generator. Because the electrical properties of the tissue are known, the expected resistance of the load is known. For example, to enhance system safety, as part of a system diagnostic or test routine, one or more low-voltage pulses may be delivered to the load while measuring the current delivered to the load during each pulse. Based on the voltage level of the pulses delivered to the load and the measured current, the electrical resistance of the load can be calculated. The calculated electrical resistance of the load may be compared to an expected value or a range of values ​​determined based on the type of tissue comprising the load. The pulse generator system is configured to determine whether the pulse generator system has passed or failed the diagnostic or test routine based on whether the calculated electrical resistance falls within an expected range of values.

[0218] In some embodiments, to pass, the pulse generator system is required to produce multiple consecutive impedance measurements that fall within the expected range of values, for example, to pass, the pulse generator system is required to produce two, three, four, five, or more consecutive impedance measurements that fall within the expected range of values.

[0219] In some embodiments, the results of the system diagnostics or system tests are shown on an electronic display interface. For example, pass and fail results may be shown with separate indicators. In some embodiments, an indication of the measured impedance is displayed. In some embodiments, an indication is displayed that the system has failed as a result of the measured impedance being greater than the expected range or as a result of the measured impedance being less than the expected range.

[0220] In some embodiments, the system automatically responds to the results of the system diagnostics. For example, a failing result may cause the system to stop delivering treatment pulses and / or generate a report. Similarly, a passing result may cause the system to begin or continue delivering treatment pulses.

[0221] The duration of the low-voltage pulse is not limited and may be, for example, 20 ns, 50 ns, 100 ns, 200 ns, 500 ns, 1000 ns, 2000 ns, 5000 ns, or another duration. The multiple pulses may be delivered at, for example, a substantially constant frequency. The frequency is not limited and may be, for example, 0.1 Hz, 0.2 Hz, 0.5 Hz, 1 Hz, 2 Hz, 5 Hz, 10 Hz, 20 Hz, 50 Hz, or another frequency.

[0222] In some embodiments, the duration of the low-voltage pulse depends on the time between adjacent pairs of treatment pulses in a series of treatment pulses. For example, the duration of the low-voltage pulse between adjacent treatment pulses may be a predetermined percentage of the time between adjacent treatment pulses. In some embodiments, the duration of the low-voltage pulse between adjacent treatment pulses may be equal to the time between adjacent treatment pulses minus a fixed time margin.

[0223] A system diagnostic or system test routine may be executed in response to an indication from a pulse generator operator, for example. For example, a physician may press a button, and the pulse generator may automatically execute the diagnostic or test routine in response to the button pressed. In some embodiments, for example, a system diagnostic or system test routine may be executed in response to an indication from a user to begin therapy. In response to an indication, the pulse generator system may execute a system diagnostic or system test routine before delivering a treatment pulse, and in some embodiments, before charging the pulse generator. In response to the system passing the diagnostic or test routine, the pulse generator may charge the pulse generator, if necessary, and begin therapy. In contrast, in response to the system failing the diagnostic or test routine, the pulse generator may not begin therapy, or may not even charge the pulse generator, despite an indication from the user. In some embodiments, the indication may be generated in response to a user interacting with a graphical user interface on a display.

[0224] In some embodiments, a system diagnostic test or routine may be performed as part of an initialization routine performed by the pulse generator system.

[0225] In some embodiments, a system diagnostic test or routine may be interrupted in response to a command from a user.

[0226] In some embodiments, multiple impedance measurements (e.g., two or more) may be taken and the difference between the impedance values ​​may be calculated. The calculated impedance difference may be compared to a threshold value, and a system diagnostic test or routine may be deemed to have failed if the difference is greater than the threshold value.

[0227] In some embodiments, multiple impedance measurements may be taken during a treatment session, and the difference in impedance values ​​may be calculated and compared to a threshold. The session may be interrupted as a result of either a difference greater than or less than the threshold. Alternatively, electrical parameters of the applied pulses of the treatment session may be altered. For example, the voltage, frequency, duration, and / or another parameter of the treatment pulse may be increased or decreased depending on the difference between the impedance values ​​being greater than or less than the threshold. Of course, if the impedance difference (in those embodiments in which multiple impedance measurements are taken) is within a threshold or acceptable range, then the treatment session may continue without the need to change parameters. The same applies to those embodiments in which a single impedance measurement is taken.

[0228] FIG. 22 is a table of expected impedance ranges for particular therapy loads. To determine whether the pulse generator system will pass or fail a diagnostic or testing routine, one or more calculated impedance values ​​may be compared to expected values ​​or ranges associated with the tissue type of the load. The information in FIG. 22 may be uploaded, entered, or programmed into the pulse generator system so that the system can access the information to compare the calculated impedance values ​​with the expected values ​​or ranges in FIG. 22. The therapy loads and impedance ranges shown in FIG. 22 are exemplary only; other therapy loads and impedance ranges may be used. In some embodiments, the expected impedance range depends on the type of electrode used. For example, the system may determine the expected impedance range based on the electrode label or the type of electrode being used.

[0229] 23 is a flow chart diagram illustrating an example of a method 2300 for testing pulse generator system setup status. The method 2300 may be performed by a therapy system, such as, for example, the system 2150 of FIG.

[0230] At 2310, the system's controller configures the system's pulse generator to deliver low-voltage pulses, the voltage level of the low-voltage pulses being less than the voltage level of the pulses used for therapy. For example, the controller may charge or discharge a storage capacitor to a charge voltage that matches the voltage level of the low-voltage pulses. Alternatively, the controller may selectively connect the output of the pulse generator to a low-voltage source with a switch.

[0231] At 2320, the controller causes the pulse generator to apply voltage pulses to the electrodes connected to the load. The controller also receives a signal indicating the amount of current applied to the load while the voltage pulses are being applied to the load.

[0232] At 2330, the controller calculates the load impedance, for example, by mathematically dividing the voltage level of the voltage pulse by the measured current. The controller also compares the calculated load impedance to an expected impedance or expected impedance range, for example, determined based on a therapy load type previously programmed into the controller. Based on the results of the comparison, the controller determines whether the calculated load impedance falls within the expected impedance range.

[0233] If the calculated load impedance does not fall within the expected impedance range or is within a threshold range of the expected impedance, then at 2340 the controller determines whether to continue testing based on, for example, a time limit condition or the amount of impedance measurements taken. In some embodiments, a single calculated load impedance that is outside the expected impedance range or is not within a threshold range of the expected impedance, as determined at 2330, causes the method to proceed to 2350.

[0234] If the controller determines that the test is complete, an indication of the system's failing result is displayed on the interface at 2350. If the controller decides to continue the test at 2340, another pulse is delivered at 2320 as described above.

[0235] If it is determined at 2330 that the calculated load impedance falls within the expected impedance range or within the expected impedance threshold, the controller determines at 2360 whether to continue testing, for example, based on a time limit condition or the amount of impedance measurements taken. In some embodiments, a single calculated load impedance that falls within the expected impedance range or within the expected impedance threshold range, as determined at 2330, causes the method to proceed to 2370.

[0236] At 2370, the controller may configure the system's pulse generator to deliver a treatment or therapy pulse, the treatment (or therapeutic) pulse having a voltage level greater than the voltage level of the diagnostic or test pulse used to determine the load impedance at 2320. For example, at 2370, the controller may charge or discharge a reservoir capacitor to a therapy charge voltage that matches the voltage level of the treatment pulse.

[0237] At 2380, the controller causes the pulse generator to deliver a treatment pulse to the load through the electrodes.

[0238] 24 is a flow chart diagram illustrating another example method 2400 for testing pulse generator system setup status. Method 2400 may be performed by a therapy system, such as system 2150 of FIG. 21, for example.

[0239] At 2410, the system's controller configures the system's pulse generator to deliver a treatment (or therapeutic) pulse, the voltage level of the treatment pulse being greater than the voltage level of the pulse used to determine the load impedance at 2430, described below. For example, the controller may charge or discharge a reservoir capacitor to a voltage that matches the voltage level of the treatment pulse.

[0240] At 2420, the controller causes the pulse generator to deliver treatment pulses to the load through the electrodes of the system.

[0241] At 2430, the controller of the system configures the pulse generator of the system to deliver low-voltage pulses, the voltage level of the low-voltage pulses being less than the voltage level of the pulses used for therapy. For example, the controller may charge or discharge a storage capacitor to a voltage matching the voltage level of the low-voltage pulses. Alternatively, the controller may selectively connect the output of the pulse generator to a low-voltage source with a switch.

[0242] At 2440, the controller causes the pulse generator to apply a voltage pulse, e.g., a diagnostic pulse or a test pulse, to the electrodes connected to the load. The controller also receives a signal indicating the amount of current applied to the load while the voltage pulse is applied to the load.

[0243] At 2450, the controller calculates the load impedance, for example, by mathematically dividing the voltage level of the voltage pulse by the measured current. The controller also compares the calculated load impedance to an expected impedance or expected impedance range, for example, determined based on a therapy load type previously programmed into the controller. Based on the results of the comparison, the controller determines whether the calculated load impedance falls within the expected impedance range or within a threshold range of expected impedance.

[0244] If the calculated load impedance does not fall within the expected impedance range or is not within the expected impedance threshold range, then at 2480 the controller determines whether to continue testing based on, for example, a time limit condition or the amount of impedance measurements taken. In some embodiments, a single calculated load impedance that is outside the expected impedance range or is not within the expected impedance threshold range, as determined at 2450, causes the method to proceed to 2490.

[0245] If the controller determines that the test is complete at 2480, an indication of a failed system test may be displayed on the interface and therapy is stopped or at least interrupted to address any issues at 2490. If the controller decides to continue testing, another pulse is delivered at 2440 as described above.

[0246] If the calculated load impedance is determined at 2450 to fall within the expected impedance range or within a threshold value of the expected impedance, then at 2460 the controller determines whether to continue the test, for example, based on a time limit condition or based on whether the amount of impedance measurements has been taken. In some embodiments, a single calculated load impedance that falls within the expected impedance range or within a threshold value of the expected impedance, as determined at 2450, causes the method to proceed to optional 2470, where an indication of a passing result of the system test may be displayed on the interface. If option 2470 is not used, then at 2410 the controller of the system configures the pulse generator of the system to deliver a treatment pulse as described above.

[0247] 25 is a flow chart diagram illustrating an example of a method 2500 for testing pulse generator system setup status. Method 2500 may be performed by a therapy system, such as system 2150 of FIG. 21, for example.

[0248] At 2510, the controller causes the pulse generator to apply a treatment voltage pulse to the electrodes connected to the load. The controller also receives a signal indicating the amount of current applied to the load while the treatment voltage pulse is applied to the load. The controller then calculates the load impedance, for example, by mathematically dividing the voltage level of the treatment voltage pulse by the measured current.

[0249] At 2520, the controller compares the calculated load impedance to an expected impedance or expected impedance range determined based on a therapy load type previously programmed into the controller. Based on the results of the comparison, the controller determines whether the calculated load impedance falls within the expected impedance range or within a threshold range of expected impedance.

[0250] If the calculated load impedance is within the expected impedance range or within the expected impedance threshold range, then at 2510, the controller causes the pulse generator to apply a treatment voltage pulse to the electrode. If the calculated load impedance is not within the expected impedance range or is not within the expected impedance threshold range, then at 2530, in some embodiments, the controller configures the system's pulse generator to deliver a low-voltage pulse (e.g., a test pulse), the voltage level of which is less than the voltage level of the pulse used for therapy. For example, the controller may charge or discharge a storage capacitor to a voltage corresponding to the voltage level of the low-voltage pulse. Alternatively, the controller may selectively connect the output of the pulse generator to a low-voltage source with a switch.

[0251] At 2540, the controller causes the pulse generator to apply a voltage pulse to the electrode, the applied voltage pulse having a voltage level that is less than the voltage level of the treatment pulse. The controller also receives a signal indicating the amount of current applied to the load while the low voltage pulse is applied to the load.

[0252] At 2550, the controller calculates the load impedance, for example, by mathematically dividing the voltage level of the low-voltage pulse by the measured current. The controller also compares the calculated load impedance to an expected impedance or expected impedance range determined based on a therapy load type previously programmed into the controller. Based on the results of the comparison, the controller determines whether the calculated load impedance falls within the expected impedance range or within a threshold range of expected impedance.

[0253] If the calculated load impedance does not fall within the expected impedance range or is not within the expected impedance threshold range, then at 2560 the controller determines whether to continue testing, for example, based on a time limit condition or based on the amount of impedance measurements taken. In some embodiments, a single calculated load impedance that is outside the expected impedance range or is not within the expected impedance threshold range, as determined at 2550, causes the method to proceed to 2570.

[0254] If the controller determines that the test is complete, an indication of the system's failing result may be displayed on the interface at 2570. If the controller decides to continue the test, another pulse is delivered at 2540, as described above.

[0255] If the calculated load impedance is determined to be within the expected impedance range or within a threshold range of expected impedance at 2550, the controller determines whether to continue testing at 2580, for example, based on a time limit condition or based on the amount of impedance measurements taken. In some embodiments, a single calculated load impedance that falls within the expected impedance range or within a threshold range of expected impedance, as determined at 2550, causes the method to proceed to 2590.

[0256] If the controller determines that the test is complete, an indication of a passing system test result may optionally be displayed on the interface at 2590. If the controller determines that therapy should continue, the pulse generator is charged to the therapy voltage and the process begins again by applying a treatment pulse at 2510.

[0257] 26 is a flow chart diagram illustrating an example of a method 2600. The method 2600 may be performed by a treatment system, such as, for example, the system 2150 of FIG.

[0258] At 2610, a first pulse is applied to the patient. The first pulse can be any type of pulse. For example, the first pulse can be high voltage or low voltage. The first pulse can be a treatment pulse or the first pulse can be a test pulse. The voltage, duration, frequency, voltage shape, and any other electrical parameters of the pulse are not limited. The first pulse can be similar to or identical to any other pulse described herein.

[0259] At 2620, a first impedance is measured based on the voltage and current delivered to the patient. The method of measurement is not limited and may be similar to or the same as, for example, any of the impedance measurement methods described herein. The first impedance may be stored in memory.

[0260] At 2630, a second pulse is applied to the patient. The second pulse can be any type of pulse. For example, the second pulse can be high voltage or low voltage. The second pulse can be a treatment pulse or the second pulse can be a test pulse. The voltage, duration, frequency, voltage shape, and any other parameters of the second pulse are not limited. The second pulse can be similar to or identical to any other pulse described herein.

[0261] At 2640, a second impedance is measured based on the voltage and current delivered to the patient. The method of measurement is not limited and may be similar to or the same as, for example, any of the impedance measurement methods described herein. The second impedance may be stored in memory.

[0262] In some embodiments, one of the first and second pulses is a treatment pulse having a relatively high voltage compared to the other of the first and second pulses, e.g., a test pulse.

[0263] The temporal and sequential relationship between the first pulse and the second pulse is not limited. In some embodiments, the first pulse and the second pulse are adjacent to each other in a series of applied pulses. In some embodiments, the first pulse is the first pulse in the series of applied pulses, and the second pulse is a subsequent adjacent or non-adjacent applied pulse in the series of applied pulses.

[0264] In some embodiments, the first impedance represents an initial or benchmark impedance of the load, and the second impedance represents the impedance of the load after one or more treatment pulses.

[0265] At 2650, the difference between the first impedance and the second impedance is determined.

[0266] At 2660, a decision regarding additional treatment is made based on the difference between the first impedance and the second impedance. For example, treatment may be stopped in response to the difference between the first impedance and the second impedance being greater than a threshold or outside a threshold range. In some embodiments, treatment may be stopped in response to the difference between the first impedance and the second impedance being less than a threshold or within a threshold range. In some embodiments, a difference greater than a threshold or outside a threshold range, or less than a threshold or within a threshold range, may indicate a problem with treatment. In some embodiments, a difference greater than a threshold or outside a threshold range may indicate that treatment is complete and can or should be stopped.

[0267] In some embodiments, the impedance of the load is expected to change over the course of a treatment session. For example, the impedance of the load may be expected to track a known impedance profile. In response to a deviation from the profile being greater than a threshold, treatment may be stopped. In some embodiments, in response to a deviation from the profile being greater than a threshold, electrical parameters of the treatment pulse may be modified. For example, in response to a deviation from the profile being greater than or less than a threshold, the voltage, frequency, duration, voltage shape, and / or another parameter of the treatment pulse may be increased, decreased, or otherwise changed. Similarly, in response to the impedance profile being within a threshold or tolerance range, or the deviation from the profile being within a threshold or tolerance range, one or more parameters of the treatment pulse may be confirmed without modification.

[0268] Applying nsPEF to tumors sufficiently to stimulate apoptosis involves at least the electrical characteristics found in experiments. For example, 100 ns long pulses with a 20 ns rise time and 30 kV / cm (kilovolts per centimeter) at 1-7 pulses per second (pps) for 500-2000 pulses have been found to be sufficient to stimulate apoptosis, depending on the tumor type. Pulsed electric fields of at least 20 kV / cm have been shown to be effective. Pulse counts greater than 50 have also been shown to be effective. Current values ​​between 12 A and 60 A were produced, depending on the electrode type and skin resistance.

[0269] The pulse generator embodiments described herein have many applications. In one limiting example, cancer that has spread through a subject's bloodstream can be treated using the immunostimulatory properties of nsPEFs. For treatment, circulating tumor cells (CTCs) are isolated from the bloodstream and accumulated in a vial, test tube, or other suitable ex vivo environment. In some cases, only a few tumor cells (e.g., 5, 10) may be collected and accumulated. An nsPEF electric field is applied through this mass to treat the cells. This may cause calreticulin or one or more other damage-associated molecular patterns (DAMPs) to be expressed on the surface membrane of the tumor cells. The tumor cells may then be returned to the subject's bloodstream by injection, infusion, or otherwise.

[0270] In an alternative embodiment, single CTCs can be isolated from the bloodstream and treated individually. An automated system for capturing CTCs in whole blood using iron nanoparticles coated with a polymer layer carrying a biotin analog and conjugated with an antibody to capture the CTCs can automatically capture tumor cells, and a magnet and / or centrifuge can separate them. After separation from the antibody, the CTCs can be treated with nsPEF through a small capillary tube and then reintroduced into the patient's bloodstream.

[0271] Although the examples in this application describe human and mouse subjects, treatment of other animals is also contemplated. Farm animals, such as horses and cattle, or racing animals, such as horses, may be treated. Companion animals, such as cats and dogs, may find particular use with the treatments described herein. It can be difficult for veterinarians to remove many tumors from small animals, and cancers may be detected at a relatively late stage because the animals cannot communicate their ongoing pain. Furthermore, the risks inherent in reinjecting tumor cells—even treated tumor cells—may be worth the potential benefit of potentially halting metastatic cancer in a beloved pet.

[0272] The impedance checking method of the present disclosure can be used with pulse generators, such as pulse generators for treating any type of tumor, whether characterized as malignant, benign, soft tissue, or solid, and all stages and grades of cancer, including pre-cancerous and post-metastatic cancers. Examples of different types of cancer include, but are not limited to, gastrointestinal and GI cancers, such as gastric cancer (e.g., stomach cancer), colorectal cancer, gastrointestinal stromal tumors, gastrointestinal carcinoid tumors, colon cancer, rectal cancer, anal cancer, bile duct cancer, small intestine cancer, and esophageal cancer; breast cancer, lung cancer, gallbladder cancer, liver cancer, spleen cancer, appendix cancer, prostate cancer, ovarian cancer, kidney cancer (e.g., renal cell carcinoma), cancer of the central nervous system, skin cancer (e.g., melanoma), lymphoma, glioma, choriomas, head and neck cancer, osteosarcoma, and blood cancers.

[0273] The electrical properties of the nsPEF treatment can be adjusted based on the size and / or type of tumor, which may include tumors in different parts of the body, such as the cancerous tumors described above.

[0274] It should be understood that the various embodiments described herein are merely examples and are not intended to limit the scope of the invention. For example, many of the materials and structures described herein may be substituted with other materials and structures without departing from the spirit of the invention. Thus, the invention as claimed may include variations from the particular examples and preferred embodiments described herein, as will be apparent to those skilled in the art. It should be understood that the various theories as to why the invention works are not intended to be limiting.

[0275] The above description is illustrative, not limiting. Many variations of the invention will become apparent to those skilled in the art upon review of this disclosure. Accordingly, the scope of the invention should be determined not with reference to the above description, but instead with reference to the pending claims along with their full scope and equivalents.

[0276] As stated above, all measurements, dimensions, and materials provided herein in the specification or drawings are merely examples.

[0277] The enumeration of "a," "an," or "the" is intended to mean "one or more" unless clearly indicated to the contrary. A reference to a "first" element does not necessarily require that a second element be provided. Furthermore, a reference to a "first" or "second" element does not limit the referenced element to a particular location unless otherwise specified.

[0278] All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publications by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

Claims

1. In a therapeutic nsPEF pulse generator system, An electrode; a pulse generator circuit electrically connected to the electrode and configured to deliver pulses to the electrode; a controller connected to the pulse generator circuit and configured to determine a voltage level of the pulses delivered to the electrodes, charging the pulse generator circuit to a first charging voltage; causing the pulse generator circuit to deliver a test pulse at the first charging voltage to a load, the load being tissue of a patient; receiving a signal indicative of the impedance of the load; comparing the impedance to an expected impedance; Depending on the comparison, 1) delivering the therapy pulse to the load based at least in part on a determination by the controller that the pulse generator circuit passed a test for delivering the therapy pulse to the load at a second charging voltage, wherein the determination that the pulse generator circuit passed is when the impedance is greater than a minimum threshold value and less than a maximum threshold value of the expected impedance; 2) not delivering the therapy pulse to the load based at least in part on a determination by the controller that the pulse generator circuit has failed the test, the determination that the pulse generator circuit has failed being when the impedance is less than a minimum threshold value of the expected impedance and when the impedance is greater than a maximum threshold value, and the failure of the test indicates a setup problem, a load problem, or an electrode problem; and a controller further configured to:

2. 2. The system of claim 1, wherein the voltage level of the first charging voltage is less than the voltage level of the second charging voltage.

3. 2. The system of claim 1, wherein the controller further causes the pulse generator circuit to charge or discharge to the second charging voltage.

4. 4. The system according to claim 1, wherein:

10. The system of claim 9, wherein delivering the test pulse to the load, receiving a signal indicative of the impedance of the load, and comparing the impedance to the expected impedance is performed for diagnostic or system testing.

5. 5. A system according to any one of claims 1 to 4, wherein the system is configured to display a graphical representation based on the comparison.

6. 6. The system of claim 1, wherein the controller is further configured to determine that the pulse generator circuit has passed the test if two or more consecutive impedance measurements are within the threshold range of expected impedance.

7. 7. The system of claim 1, wherein the predicted impedance is based on the type of tissue comprising the load.

8. 7. The system of claim 1, wherein the predicted impedance is based on the type of electrode.

9. 9. The system of any one of claims 1 to 8, wherein the expected impedance is programmed, uploaded, or input into the pulse generator system.

10. 10. The system of any one of claims 1 to 9, further comprising a low voltage power supply.

11. 11. The system according to any one of claims 1 to 10, measuring a current delivered during delivery of the test pulse; determining the voltage of the delivered test pulse; calculating an impedance based on the voltage level of the test pulse and the measured current; and determining the impedance of the load by:

12. 12. The system of claim 1, wherein the controller is further configured to determine whether to continue the test based at least in part on a time limit condition and / or on an amount of impedance measurements.

13. 13. The system according to any one of claims 1 to 12, the controller further determining whether the test is complete; 1. A system configured to determine whether to deliver a next test pulse or a next treatment pulse, or to stop delivery of a test pulse or a treatment pulse, based on: 1) determining whether the test is complete; and 2) comparing the impedance to the expected impedance.

14. 14. The system of claim 1, wherein delivering the therapeutic pulse to the load includes modifying at least one electrical parameter, and the at least one modified electrical parameter includes one of voltage, frequency, duration, and voltage shape.

15. 15. The system of any one of claims 1 to 14, wherein the system is configured to charge or discharge a storage capacitor to deliver pulses at a therapeutic or test voltage level.

16. 16. The system of any one of claims 1 to 15, further comprising a memory containing expected impedance ranges for tissue types.

17. 17. The system of any one of claims 1 to 16, further comprising a discharge circuit for discharging the pulse generator circuit to a low voltage or switching it to a low voltage source.

18. 18. The system of any one of claims 1 to 17, wherein the test pulse and the treatment pulse are in the sub-microsecond range.

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