High-frequency electroporation for cancer therapy
The present invention relates to the field of biomedical engineering and medical treatment of diseases and disorders. Methods, devices, and systems for in vivo treatment of cell proliferative disorders are provided. In embodiments, the methods comprise the delivery of high-frequency bursts of bipolar pulses to achieve the desired modality of cell death. More specifically, embodiments of the invention relate to a device and method for destroying aberrant cells, including tumor tissues, using high-frequency, bipolar electrical pulses having a burst width on the order of microseconds and duration of single polarity on the microsecond to nanosecond scale. In embodiments, the methods rely on conventional electroporation with adjuvant drugs or irreversible electroporation to cause cell death in treated tumors. The invention can be used to treat solid tumors, such as brain tumors.
1. A medical device for killing tissue cells by non-thermal irreversible electroporation comprising:
one or more electrodes adapted to be positioned near a target area containing target tissue cells to be killed;
a power supply adapted to generate and deliver electrical pulses to the electrodes; and
a controller in operable connection with and comprising programming of predetermined pulse parameters configured to control the power supply to output one or more bursts of the electrical pulses, each burst containing multiple electrical pulses at a frequency rate of 50 kHz or higher and capable of killing the target tissue cells by non-thermal irreversible electroporation, and each electrical pulse having a pulse width of 10 microseconds or less so as to kill the target tissue cells by non-thermal irreversible electroporation;
wherein the controller comprises programming for independent selection of width and amplitude of positive and negative pulses within one or more of the bursts and to allow for a delay between each burst of pulses; and
wherein the controller comprises programming to control the power supply to output the negative pulses with an amplitude of between 500-4,000 V/cm.
2. The medical device of claim 1 , wherein the controller comprises programming to control the power supply to output the electrical pulses within the burst, wherein the frequency rate is between 50 kHz and 2 MHz, inclusive.
3. The medical device of claim 1 , wherein the controller comprises programming to control the power supply to output the electrical pulses within the burst, wherein the frequency rate is between 250 kHz and 2 MHz, inclusive.
4. The medical device of claim 3 , wherein the controller comprises programming to control the power supply to output one or more of the bursts with multiple bipolar pulses.
5. The medical device of claim 1 , wherein the controller comprises programming to control the power supply to output each electrical pulse having a pulse width of 100 nanoseconds or greater.
6. The medical device of claim 1 , wherein the controller comprises programming to control the power supply to output each electrical pulse having a pulse width of between 250 nanoseconds and 2 microseconds, inclusive.
7. The medical device of claim 6 , wherein the controller comprises programming to control the power supply to output one or more of the bursts with multiple bipolar pulses.
8. The medical device of claim 1 , wherein the controller comprises programming to control the power supply to generate at least one burst of bipolar electrical pulses with a delay of zero between a positive pulse and an adjacent negative pulse in the burst of bipolar electrical pulses.
9. The medical device of claim 1 , wherein the controller comprises programming to control the power supply to generate at least two bursts of bipolar electrical pulses with a delay of at least 75 microseconds between the bursts.
10. The method of claim 1 , wherein the controller comprises programming to control the power supply to generate at least one burst of bipolar electrical pulses with multiple pulses in a single phase before a polarity switch.
11. The medical device of claim 1 , wherein the controller comprises programming to control the power supply to output a burst of electrical pulses which is sufficient to cause a transmembrane potential (TMP) of the target tissue cells to rise above a critical threshold (CT) for inducing electroporation while a single electrical pulse in the burst of electrical pulses is insufficient to cause the TMP of the target tissue cells to rise above the CT.
12. The medical device of claim 1 , wherein the controller comprises programming to control the power supply to output electrical pulses wherein each electrical pulse is sufficient to cause a transmembrane potential (TMP) of the target tissue cells to rise above a critical threshold (CT) for inducing electroporation.
13. The medical device of claim 12 , wherein the critical threshold (CT) is in the range of 0.5-1.46 V, inclusive.
14. The medical device of claim 1 , wherein the controller comprises programming to control the power supply to output a burst of electrical pulses which is sufficient to cause a transmembrane potential (TMP) of the target tissue cells to rise above a critical threshold for inducing irreversible electroporation (CTIRE) while a single electrical pulse in the burst of electrical pulses is insufficient to cause the TMP of the target tissue cells to rise above the CTIRE.
15. The medical device of claim 14 , wherein the CTIRE is about 1 Volt.
16. The medical device of claim 1 , wherein the controller comprises programming to control the power supply to output electrical pulses wherein each electrical pulse is sufficient to cause a transmembrane potential (TMP) of the target tissue cells to rise above a critical threshold (CT) for inducing irreversible electroporation.
17. The medical device of claim 1 , wherein the controller comprises programming to control the power supply to generate the electrical pulses at 2500 V/cm or lower.
18. The medical device of claim 1 , wherein the controller comprises programming to control voltage and pulse width of the electrical pulses to reduce tissue stimulation sufficiently to perform the target tissue cell killing without using general anesthesia.
19. A medical device for killing tissue cells of a living mammal by high frequency non-thermal irreversible electroporation without using general anesthesia comprising:
one or more electrodes adapted to be positioned near a target area containing target tissue cells to be killed;
a power supply adapted to generate and deliver electrical pulses to the electrodes; and
a controller in operable connection with and comprising programming of predetermined pulse parameters configured to control the power supply to output one or more bursts of the electrical pulses, each burst containing multiple electrical pulses at a high frequency rate of at least 50 kHz and capable of killing the target tissue cells by non-thermal irreversible electroporation, and each electrical pulse having a pulse duration of 10 microseconds or less to minimize tissue stimulation, wherein the controller comprises programming to allow for independent selection of width and amplitude of positive and negative pulses within one or more of the bursts and to allow for a delay between each of the positive and negative pulses within one or more of the bursts.
20. The medical device of claim 19 , wherein the controller comprises programming to control the power supply to output bipolar electrical pulses within the burst, wherein the frequency rate is between 250 kHz and 2 MHz, inclusive.
21. The medical device of claim 19 , wherein the controller comprises programming to control the power supply to output the electrical pulses within the burst, wherein the frequency rate is between 250 kHz and 2 MHz, inclusive, and each electrical pulse has a pulse width of between 250 nanoseconds and 2 microseconds, inclusive.
22. The medical device of claim 4 , wherein one of the bursts comprises a positive pulse with one amplitude and width and a negative pulse with a different amplitude or width.
23. The medical device of claim 7 , wherein one of the bursts comprises a positive pulse with one amplitude and width and a negative pulse with a different amplitude or width.
24. The medical device of claim 19 , wherein the width and amplitude are capable of administering electroporation to electrically excitable tissue with reduced stimulation of the tissue as compared with pulses having higher amplitude and greater width.
25. The medical device of claim 1 , further comprising a capacitor bank.
26. The medical device of claim 25 , further comprising a polarity switch, wherein an input of the polarity switch is in direct operable connection with an output of the capacitor bank.
27. The medical device of claim 26 , further comprising current limiting resistors, wherein an output of the current limiting resistors is in direct operable connection with an input of the capacitor bank.
28. The medical device of claim 27 , wherein an input of the current limiting resistors is in direct operable connection with an output of the power supply.
29. The medical device of claim 28 , further comprising an arbitrary function generator, wherein an output of the arbitrary function generator is in direct operable connection with an input of the polarity switch.
30. The device of claim 1 , wherein the controller comprises programming to allow for a delay between the bursts on the order of seconds.
31. The device of claim 1 , wherein the controller comprises programming to allow for a delay between the pulses on the order of microseconds.
32. A medical device for killing tissue cells by non-thermal irreversible electroporation comprising:
two or more electrodes adapted to be positioned near a target area containing target tissue cells to be killed;
a power supply adapted to generate and deliver electrical pulses to the electrodes;
a controller in operable connection with and comprising programming of predetermined pulse parameters configured to control the power supply to output one or more bursts of the electrical pulses which include a frequency rate of 50 kHz or higher and are capable of killing the target tissue cells by non-thermal irreversible electroporation;
a positive and a negative polarity switch in communication with the power supply; and
a capacitor bank disposed between the power supply and the positive and negative polarity switches.
33. The medical device of claim 32 , wherein the electrodes are spaced at least 1 mm apart.
34. The medical device of claim 33 , wherein the electrodes are spaced up to 3 cm apart or less.
35. A medical device for killing target tissue by non-thermal irreversible electroporation comprising:
two or more electrodes adapted to be positioned near a target area containing target tissue to be killed;
a power supply adapted to generate and deliver electrical pulses to the electrodes;
a controller in operable connection with and comprising programming of predetermined pulse parameters configured to control the power supply to output one or more bursts of the electrical pulses which include a frequency rate of 50 kHz or higher and are capable of killing the target tissue by non-thermal irreversible electroporation, each burst containing multiple electrical pulses at a high frequency rate, and each electrical pulse having a pulse duration of 10 microseconds or less to minimize tissue stimulation;
wherein the controller comprises programming to control a delay between the pulse bursts; and
wherein the pulse parameters are sufficient to subject the target tissue to non-thermal irreversible electroporation without causing muscle cells located in or surrounding the target tissue to contract.
36. The medical device of claim 35 , wherein the target tissue is comprised of liver tissue.
37. The medical device of claim 35 , wherein the target tissue is comprised of brain tissue.
38. The medical device of claim 35 , wherein the controller comprises programming to allow for selection of width and amplitude of positive and negative pulses within one or more of the bursts.
39. The medical device of claim 38 , wherein the controller comprises programming to control a delay between each of the positive and negative pulses within one or more of the bursts.
40. The medical device of claim 38 , wherein the negative pulses prevent action potential generation of cells of the target tissue.
41. The medical device of claim of claim 35 , wherein each electrical pulse has a pulse duration of a single polarity of no more than 100 nanoseconds and an electrical field threshold of up to 1,000 V/cm.
42. The medical device of claim 35 , wherein the controller comprises programming to deliver at least 90 total pulses to the target tissue.
43. The medical device of claim 42 , wherein the controller comprises programming to deliver at least 90 total pulses to the target tissue without raising the temperature of the target tissue above 50 degrees Celsius.