Electroporation device with improved signal generator

Abstract

To provide a signal generator that generates a plurality of low voltages and combines them in series to create a high voltage.SOLUTION: A handset for an electroporation device has an improved signal generator. The signal generator includes a primary winding and a plurality of secondary windings, where the secondary windings are coupled together in a series configuration. A storage capacitor and the fly-back diode are coupled to each of the secondary windings. The signal generator includes a signal amplifier and a power switch. The power switch is configured to supply a voltage from a power source across the primary winding.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims priority to U.S. Provisional Patent Application No. 62 / 271,955, filed December 28, 2015. The above-referenced application is incorporated herein by reference. [Background technology]

[0002] SUMMARY OF THE INVENTION Embodiments of the present disclosure relate to an electroporation device having an improved signal generator for generating high voltage electroporation signals. Summary of the Invention

[0003] Medical devices, such as electroporation devices, require high-voltage generators to generate the necessary energy supply. During the electroporation process, electrodes in contact with the target tissue require power to be delivered at a specific voltage and amperage to produce the desired electroporation effect (e.g., 200 V at 0.5 A). The high voltage levels required during the electroporation process generally require voltage generators containing numerous large-capacity capacitors. These capacitors, in turn, are very large in physical size and require a relatively long time to charge before the electroporation process can begin. These characteristics are cumbersome for handheld devices, where size and weight must be minimized. Furthermore, long charging times can hinder the user's ability to administer electroporation therapy in a timely and accurate manner. Furthermore, capacitor-based systems suffer from signal degradation over time.

[0004] The present disclosure provides a signal generator that generates multiple low voltages and combines them in series to generate a high voltage.

[0005] In one aspect, a handset for use with an electroporation apparatus includes a housing and a signal amplifier disposed within the housing, the signal amplifier including a primary winding and a plurality of secondary windings coupled together in a series configuration, with a storage capacitor and a flyback diode coupled to each of the plurality of secondary windings, and an array having a plurality of electrodes in electrical communication with the signal amplifier.

[0006] In another aspect, an electroporation apparatus includes a housing and a signal generator disposed within the housing, the signal generator including a signal amplifier having a primary winding and multiple secondary windings coupled together in a series configuration, with a storage capacitor and a flyback diode coupled to each of the multiple secondary windings, a power source, a power switch configured to provide a voltage from the power source across the primary winding, and an array having one or more electrodes in electrical communication with the signal generator.

[0007] In yet another aspect, an electroporation system includes a base station and a handset removably coupled to the base station. The handset includes a housing, an injection assembly, a power source, and a signal generator located within the handset housing and in communication with the injection assembly. The signal generator includes a signal amplifier having a primary winding and multiple secondary windings coupled to each other in a series configuration, with a storage capacitor and a flyback diode coupled to each of the multiple secondary windings, a power switch configured to supply a voltage from the power source across the primary winding, and an array having at least one electrode extending from the array and in electrical communication with the signal generator. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 is a schematic diagram of an electroporation device showing the handset and base unit in a docked configuration. [Figure 2] 2 is a diagram of the voltage amplifier of FIG. 1 in accordance with some embodiments. [Figure 3] FIG. 2 is a block diagram of the signal generator and power supply of FIG. 1 in accordance with some embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0009] Before describing all embodiments of the present disclosure in detail, it is to be understood that the disclosure is not limited in its application to the details of construction and the arrangements of parts set forth in the following description or illustrated in the following drawings. The disclosure is capable of other embodiments and of being practiced or carried out in various ways.

[0010] It should be noted that several other components may be utilized to implement the disclosure. Moreover, as explained in the following paragraphs, the specific configurations shown in the drawings are intended to illustrate embodiments of the present disclosure. Alternative configurations are possible.

[0011] "Drug" may refer to a polypeptide, a polynucleotide, a small molecule, or any combination thereof. As described in detail in PCT / US2014 / 070188, which is incorporated herein by reference, a drug may be a recombinant nucleic acid sequence encoding an antibody, or a fragment thereof, a variant thereof, or a combination thereof. "Drug" may also refer to a composition comprising a polypeptide, a polynucleotide, a small molecule, or any combination thereof. As described in detail in PCT / US2014 / 070188, which is incorporated herein by reference, a composition may comprise a recombinant nucleic acid sequence encoding an antibody, or a fragment thereof, a variant thereof, or a combination thereof. A drug may be formulated, for example, in water or a buffer. The buffer may be, for example, saline-sodium citrate (SSC) or phosphate-buffered saline (PBS). The ionic content of the buffer may increase conductivity, increasing current flow in the target tissue. The concentration of the formulated polynucleotide may be between 1 μg and 20 mg / ml. The formulated polynucleotide concentration may be, for example, 1 μg / ml, 10 μg / ml, 25 μg / ml, 50 μg / ml, 100 μg / ml, 250 μg / ml, 500 μg / ml, 750 μg / ml, 1 mg / ml, 10 mg / ml, 15 mg / ml, or 20 mg / ml.

[0012] As used herein, "peptide," "protein," or "polypeptide" can refer to a linked sequence of amino acids, which can be natural, synthetic, or a variation or combination of natural and synthetic.

[0013] As used herein, "polynucleotide" or "oligonucleotide" or "nucleic acid" refers to at least two nucleotides covalently linked together. A polynucleotide can be single-stranded or double-stranded, or can contain portions of both double-stranded and single-stranded sequence. A polynucleotide can be DNA, both genomic and cDNA, RNA, or a hybrid. A polynucleotide can contain combinations of deoxyribonucleotides and ribonucleotides, as well as combinations of bases including uracil, adenine, thymine, cytosine, guanine, inosine, xanthine hypoxanthine, isocytosine, isoguanine, and synthetic or non-natural nucleotides and nucleosides. A polynucleotide can be a vector. A polynucleotide can be obtained by chemical synthesis or recombinant methods.

[0014] As used herein, "vector" refers to a nucleic acid sequence that contains a replication origin.Vector can be a virus vector, bacteriophage, bacterial artificial chromosome, or yeast artificial chromosome.Vector can be DNA or RNA vector.Vector can be a self-replicating extrachromosomal vector, preferably a DNA plasmid.

[0015] As used herein, the term "electroporation" ("EP") refers to the use of electric field pulses to induce reversible micropathways (pores) in cell membranes, the presence of which allows agents to pass from one side of the cell membrane to the other.

[0016] The present disclosure relates to a handset 100 for an electroporation device 104 that includes an improved signal generator 32 that generates a predetermined electroporation signal. As shown in FIG. 1 , the electroporation device 104 includes a base unit 109 and a handset 100 that can be removably docked to the base unit 108. The base unit 109 is generally placed on a table or other flat surface and is in electrical communication with and can charge a power source 34 when the handset 100 and base unit 109 are in a docked or coupled configuration.

[0017] As shown in FIG. 1 , handset 100 of electroporation device 104 includes housing 108, electrode array 112 coupled to housing 108, power source 34 disposed within housing 108, and signal generator 32 in electrical communication with both power source 34 and electrode array 112. Handset 100 also includes an injection assembly 110 for administering an agent to target tissue via a hypodermic needle 111. During use, electroporation device 100 uses electroporation pulses generated by signal generator 32 to facilitate the introduction of an agent into cells of mammalian target tissue (e.g., skin or muscle). Handset 100 requires the generation of very high voltages (e.g., 200 V) to generate the electroporation pulses. Handset 100 uses signal generator 32 to generate the very high voltages from a power source (e.g., a lithium-ion battery) that provides a lower voltage.

[0018] 1 , the housing 108 of the handset 100 is formed from two halves or members 116 joined together to form a volume 120 therebetween. Specifically, the member 116 forms a pistol shape having a top portion 124 having a front end 128 and a rear end 132, and a handle portion 136 extending from the top portion 124 and forming a distal end. In some embodiments, the handle portion 136 may include a trigger 140 or other user input, allowing a user to direct the administration of an electroporation signal to a target tissue. While the housing 108 of the handset 100 is shown pistol-shaped, it should be understood that the housing 108 may include additional shapes or accommodate different grip styles.

[0019] The electrode array 112 includes a plurality of electrodes 142 each extending outwardly from the front end 128 of the top 124 of the housing 108. Each electrode 142 is in electrical communication with the signal generator 32 and is configured to relay electroporation signals to the target tissue during operation of the device 104.

[0020] 1 and 3 show signal generator 32. Signal generator 32 includes, among other components, a power switch 36 and a voltage amplifier 5. In the illustrated embodiment, signal generator 32 is positioned within housing 108 such that the overall center of gravity (CG) of handset 100 is located proximate the intersection of handle portion 136 and top portion 124. In some embodiments, top portion 124 of housing 108 may define an axis A extending lengthwise therethrough such that axis B, disposed perpendicular to axis A and passing through the center of gravity (CG), also passes through handle portion 136 of housing 108 (see FIG. 1 ).

[0021] FIG. 2 shows a voltage amplifier 5 including, among other components, an amplifier housing 10, a primary winding 12, and multiple secondary windings 14A-14E. The primary winding 12 and multiple secondary windings 14A-14E are disposed within the amplifier housing 10. In the embodiment shown in FIG. 1, the multiple secondary windings 14A-14E include five secondary windings. In other embodiments, the multiple secondary windings 14A-14E may include more or fewer secondary windings. Also, in other embodiments, the voltage amplifier 5 may include two or more primary windings. A first input 16A and a second input 16B provide connection between the primary winding 12 and one or more components external to the amplifier housing 10. The voltage across the primary winding 12 is equal to the voltage difference between the first input 16A and the second input 16B. The voltage across each secondary winding is equal to the voltage of the primary winding 12 multiplied by the turns ratio. The turns ratio is the ratio of the number of turns in the primary winding to the number of turns in the secondary winding. For example, if the primary winding 12 has 5 turns and the secondary winding 14A has 5 turns, the voltage across the secondary winding 14A is equal to the voltage across the primary winding 12 (i.e., a turns ratio of 1:1).

[0022] In the embodiment shown in FIG. 2, the turns ratio between the primary winding 12 and each of the multiple secondary windings 14A-14E is 1:1. For example, if the voltage across the primary winding 12 is 20V, the voltage across each of the multiple secondary windings 14A-14E is also 20V. When the multiple secondary windings 14A-14E are connected in series as shown in FIG. 2, the voltage across the multiple secondary windings 14A-14E is equal to the sum of the voltages across each of the secondary windings. For example, if the voltage across the primary winding 12 is 20V, the voltage across the multiple secondary windings 14A-14E is 100V (resulting in five secondary windings).

[0023] The first output 18A and the second output 18B provide connections between the plurality of secondary windings 14A-14E and one or more components external to the housing 10. The voltage across the plurality of secondary windings 14A-14E is equal to the voltage difference between the first output 18A and the second output 18B. For example, if the voltage across the plurality of secondary windings 14A-14E is 100V, then the voltage difference between the first output 18A and the second output 18B is 100V.

[0024] A plurality of electrical components 20 can be coupled to each of the plurality of secondary windings 14A-14E. The plurality of electrical components 20 includes, among other components, a storage capacitor 22, a flyback diode 24, a filtering capacitor 26, and a balancing capacitor 28. In some embodiments, the plurality of electrical components 20 are configured as shown in FIG. 2 and described below. In some embodiments, the storage capacitor 22 and the filtering capacitor 26 are coupled together in a parallel configuration. Also, in some embodiments, the flyback diode 24 is coupled in a series configuration with the storage capacitor 22 and the filtering capacitor 26. Furthermore, in some embodiments, the series configuration of the flyback diode 24 and the storage capacitor 22 is coupled in a parallel configuration with the balancing capacitor 28 and one of the plurality of secondary windings 14A-14E.

[0025] The plurality of electrical components 20 are disposed within the amplifier housing 10 along with the primary winding 12 and the plurality of secondary windings 14A-14E. This configuration allows for shorter wire trace lengths between the plurality of electrical components 20 and each of the plurality of secondary windings 14A-14E compared to components disposed outside the amplifier housing 10. In addition to reducing the overall footprint of the signal amplifier 5, the shorter wire trace lengths reduce the effect of noise (e.g., switching noise) on the operation and efficiency of the signal amplifier 5. In this manner, more accurate and stable electroporation signals may be generated by the handset 100 in a more compact handset 100.

[0026] The above-described configuration also allows for fewer outputs to be used in the signal amplifier 5. When multiple electrical components 20 are located outside the amplifier housing 10, each secondary winding requires two outputs. For example, a signal amplifier with five secondary windings requires ten outputs. As shown in FIG. 2 , placing multiple electrical components 20 inside the amplifier housing 10 allows for the use of only two outputs (e.g., first output 18A and second output 18B). Each additional output requires space and adds to the footprint of the signal amplifier. Thus, by reducing the number of outputs, this configuration allows for a smaller footprint for the signal amplifier 5 and more efficient use of space on the corresponding circuit board and within the volume 120 of the housing 108.

[0027] The flyback diode 24 is necessary to achieve a higher voltage output across the secondary winding 14A than the voltage input across the primary winding 12. The voltage difference between the first input 16A and the second input 16B induces a current in the primary winding 12, which generates a magnetic field. The secondary winding 14A captures the magnetic field and generates a voltage / current spike. Energy from this voltage / current spike is stored in the storage capacitor 22, which the flyback diode 24 prevents from leaking back to the secondary winding 14A. The energy stored in the storage capacitor 22 can only be discharged as a DC voltage output across the secondary winding 14A. The filter capacitor 26 suppresses voltage spikes across the secondary winding 14A that can occur when the voltage across the secondary winding 14A suddenly changes. The balancing capacitor 28 ensures that the voltage across each of the multiple secondary windings 14A-14E is the same value. The use of the balancing capacitor 28 eliminates the need for a snubber circuit within the signal amplifier 5.

[0028] The physical size of a capacitor is determined by two factors: operating voltage and capacitance. Operating voltage is the maximum voltage at which a capacitor can operate. The only way to increase a capacitor's operating voltage is to increase its size. Capacitors with high operating voltages have a significantly larger physical size. Capacitors with low operating voltages have a smaller physical size. Conventional high-voltage generators require capacitors with high operating voltages. Therefore, conventional high-voltage generators tend to have a larger physical size. By generating multiple low voltages and combining them in series to produce a high voltage, signal amplifier 5 does not require capacitors with high operating voltages and therefore has a smaller physical size than conventional high-voltage generators. Such characteristics are desirable in a handset 100 that must be held and manipulated by a user during use.

[0029] Higher operating voltage capacitors also require more time to fully charge and discharge. By generating multiple lower voltages and combining them in series to generate a higher voltage, signal amplifier 5 provides a higher voltage significantly faster than conventional high voltage generators.

[0030] Furthermore, conventional high-voltage generators used in medical devices (e.g., electroporation pulse generators) that contain capacitors with high operating voltages present safety concerns about electrocution for medical device users. The capacitors in conventional high-voltage generators must be charged to a high voltage and capable of generating a high output voltage before treatment begins. While the capacitor is charged to a high voltage but the electroporation pulse has not yet been administered, the capacitor retains a large amount of electrical energy. This large amount of electrical energy has the potential to seriously harm a medical device user if they are electrocuted by the medical device. Furthermore, the large amount of electrical energy can potentially destroy a conventional high-voltage generator. By generating multiple lower voltages and combining them in series to generate a high voltage, the signal amplifier 5 does not need to store a large amount of electrical energy. Therefore, the electrocution safety concerns present in conventional high-voltage generators are not present in the signal amplifier 5.

[0031] In some embodiments, as shown in FIG. 1, signal amplifier 5 includes a thermistor 30. A thermistor is a type of resistor whose resistance is temperature dependent. In some embodiments, a very small duty cycle is used in signal amplifier 5. This small duty cycle may be greater than the DC current rating of signal amplifier 5. By using control circuitry (not shown), it is possible to monitor the thermistor 30 and ensure that signal amplifier 5 does not exceed any component ratings. In some embodiments, as shown in FIG. 1, the thermistor 30 is coupled between primary winding 12 and a common node connected to multiple secondary windings 14A-14E.

[0032] Power supply 34 provides a nominal or pulsed DC voltage to voltage amplifier 5. In the illustrated embodiment, power supply 34 is powered by one or more batteries or battery packs. In other embodiments, power supply 34 is powered by a mains power supply, for example, having a nominal line voltage of 100V-240V AC and a frequency of approximately 50-60 Hz. In other embodiments, power supply 34 is powered by a combination of battery power and mains power. In some embodiments, power supply 34 is powered by USB (i.e., Universal Serial Bus) power, having a nominal line voltage of 5V. In some embodiments, the battery is a type of rechargeable battery. Rechargeable batteries include, for example, lithium ion, lead acid, nickel cadmium, nickel metal hydride, etc. Lithium ion batteries are smaller and lighter than traditional lead acid batteries.

[0033] The power switch 36 regulates the flow of energy from the power supply 34 to the signal amplifier 5. The power switch is electrically coupled to the signal amplifier 5 via a first input 16A and a second input 16B. The voltage difference between the first input 16A and the second input 16B is based on the on-time and off-time (i.e., duty cycle) of the power switch 36. In some embodiments, the power switch 36 includes a switching field effect transistor (FET).

[0034] Thus, the present disclosure provides, among other things, a signal amplifier and a signal generator. Various features and advantages of the present disclosure are set forth in the following claims.

[0035] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses.

[0036] 1. A handset for use with an electroporation apparatus, said handset comprising: Housing and a signal amplifier disposed within the housing; The signal amplifier A primary winding; a plurality of secondary windings coupled together in a series configuration, a storage capacitor and a flyback diode coupled to each of the plurality of secondary windings; an array having a plurality of electrodes in electrical communication with the signal amplifier; The handset comprising:

[0037] 2. The handset of clause 1, wherein the turns ratio between the primary winding and each of the plurality of secondary windings is 1:1.

[0038] 3. The handset of clause 1, wherein each flyback diode and storage capacitor is coupled to a respective one of the plurality of secondary windings in a series configuration.

[0039] 4. The handset of clause 1, wherein the flyback diode and the storage capacitor are coupled to each of the plurality of secondary windings in a parallel configuration.

[0040] 5. The handset of clause 4, wherein a filter capacitor is coupled in a parallel configuration with the storage capacitor.

[0041] 6. The handset of clause 5, wherein a balancing capacitor is coupled to each of the plurality of secondary windings in a parallel configuration.

[0042] 7. The handset of clause 6, wherein a thermistor is coupled between the plurality of secondary windings and the primary winding.

[0043] 8. The handset of clause 1, wherein the plurality of secondary windings includes at least five secondary windings.

[0044] 9. The handset of clause 1, wherein the primary winding, the plurality of secondary windings, the storage capacitor and the flyback diode are each disposed within a signal generator housing.

[0045] 10. An electroporation device comprising: Housing and a signal generator disposed within the housing; The signal generator a signal amplifier having a primary winding and a plurality of secondary windings coupled together in a series configuration, the signal amplifier having a storage capacitor and a flyback diode coupled to each of the plurality of secondary windings; Power supply and a power switch configured to provide a voltage from the power supply across the primary winding; an array having one or more electrodes in electrical communication with the signal generator; The electroporation device comprising:

[0046] 11. The electroporation apparatus of clause 10, wherein the turns ratio between the primary winding and each of the plurality of secondary windings is 1:1.

[0047] 12. The electroporation apparatus of clause 10, wherein the power source comprises a rechargeable battery.

[0048] 13. The electroporation apparatus of clause 12, wherein the rechargeable battery comprises a lithium ion battery.

[0049] 14. The electroporation apparatus of clause 10, wherein the flyback diode and the storage capacitor are coupled together in a series configuration.

[0050] 15. The electroporation apparatus of clause 14, wherein the flyback diode and the storage capacitor are coupled to each of the plurality of secondary windings in a parallel configuration.

[0051] 16. The electroporation apparatus of clause 15, wherein a filter capacitor is coupled in a parallel configuration with the storage capacitor.

[0052] 17. The electroporation apparatus of clause 10, wherein a balancing capacitor is coupled to each of the plurality of secondary windings in a parallel configuration.

[0053] 18. An electroporation apparatus as described in clause 10, wherein a thermistor is connected between the plurality of secondary windings and the primary winding.

[0054] 19. An electroporation system comprising: A base station; a handset removably coupled to the base station; The handset Housing and an injection assembly; a power supply assembly; a signal generator disposed within the housing of the handset and capable of communicating with the injection assembly; The signal generator a signal amplifier having a primary winding and a plurality of secondary windings coupled together in a series configuration, the signal amplifier having a storage capacitor and a flyback diode coupled to each of the plurality of secondary windings; a power switch configured to provide a voltage from the power supply across the primary winding; an array having at least one electrode in electrical communication with the signal amplifier; The electroporation device comprising:

[0055] 20. The electroporation system of clause 19, wherein the base station is in electrical communication with the power source when the base station is coupled to the handset.

Claims

1. A signal amplifier for use in an electroporation apparatus, the signal amplifier comprising: at least first and second inputs; a primary winding in electrical communication with the at least first and second inputs, the at least first and second inputs configured to provide an input voltage to the primary winding from a power source; a plurality of secondary windings in electrical communication with a first output and a second output, the first and second outputs configured to deliver one or more electroporation pulses, the plurality of secondary windings coupled in a series configuration, a voltage difference between the first output and the second output equal to a sum of voltages across each of the plurality of secondary windings, and a turns ratio between the primary winding and each of the secondary windings being 1:1; The secondary windings are each coupled to a respective storage capacitor and a respective flyback diode.

2. A signal amplifier as described in claim 1, further comprising an amplifier housing that houses the primary winding, the plurality of secondary windings, and each of the storage capacitors and each of the flyback diodes coupled to the secondary winding.

3. A signal amplifier as described in claim 2, wherein the first and second outputs are the only outputs in electrical communication with the multiple secondary windings.

4. A signal amplifier as described in claim 2, wherein the amplifier housing is positioned on a circuit board.

5. A signal amplifier as described in claim 2, wherein the first and second inputs and the first and second outputs each extend from the amplifier housing.

6. The signal amplifier of claim 1, wherein each flyback diode and each storage capacitor is coupled in a series configuration to a respective one of the plurality of secondary windings.

7. The signal amplifier of claim 1, wherein each flyback diode and each storage capacitor is coupled in a parallel configuration to a respective one of the plurality of secondary windings.

8. A signal amplifier as described in claim 7, wherein each storage capacitor and each filter capacitor are coupled in a parallel configuration.

9. A signal amplifier as described in claim 1, wherein a thermistor is coupled between the primary winding and the plurality of secondary windings.

10. A signal amplifier as described in claim 1, wherein the plurality of secondary windings includes at least five secondary windings.

11. A signal amplifier as described in claim 10, wherein the plurality of secondary windings are composed of five secondary windings, the primary windings are configured to receive a voltage of 20 V, the voltage across each secondary winding is 20 V, and the sum of the voltages across each of the plurality of secondary windings is 100 V.

12. A signal amplifier as described in claim 1, wherein the sum of the voltages across each of the multiple secondary windings is 200V.

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