Selective modulation of intracellular effects of cells using pulsed electric fields
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 method of selectively treating cells, comprising:
applying to a tissue a plurality of electrical pulses with a delay between successive pulses, wherein the length of each pulse and the delay between successive pulses are optimized to produce a first treatment zone and a second treatment zone;
wherein only selected cells are affected in the second treatment zone.
2. The method of claim 1 , wherein the applying is performed in vitro.
3. The method of claim 1 , wherein the applying is performed in vivo.
4. The method of claim 1 , wherein the applying is performed ex vivo.
5. The method of claim 1 , wherein the first treatment zone comprises cancer cells and non-cancer cells which are killed by necrosis.
6. The method of claim 1 , wherein the second treatment zone comprises cancer cells which are killed by apoptosis.
7. The method of claim 1 , wherein the first treatment zone comprises some cancer cells and some non-cancer cells which are killed.
8. The method of claim 1 , wherein the second treatment zone comprises cancer cells and non-cancer cells and some of the cancer cells are killed or inhibited and some of the non-cancer cells are spared.
9. The method of claim 5 , wherein the first treatment zone comprises cancer cells and non-cancer cells which are killed as a result of an increase of their transmembrane potential to a lethal threshold.
10. The method of claim 1 , wherein the second treatment zone comprises cancer cells which are killed as a result of an increase in their nuclear transmembrane potential to a lethal threshold.
11. The method of claim 1 , wherein the delay between successive pulses is greater than the length of each pulse.
12. The method of claim 1 , wherein the delay between successive pulses is a fraction of the length of each pulse.
13. The method of claim 1 , wherein the selected cells are cancer cells and the length of each pulse is equivalent to the charging time of the cell membrane of the cancer cells plus the discharge time of the nuclear membrane of the cancer cells, while the delay between successive pulses is equivalent to the charging time of the cell membrane of the cancer cells.
14. The method of claim 13 , wherein the charging time of the cell membrane of the cancer cells and the discharge time of the nuclear membrane of the cancer cells are determined through numerical modeling.
15. The method of claim 1 , wherein the plurality of electrical pulses comprises an electric field waveform which is a rectangular pulse, ramp, decaying exponential, or sine wave.
16. The method of claim 15 , wherein the electric field waveform is unipolar or bipolar.
17. The method of claim 15 , wherein the electric field waveform is a superimposed, bimodal signal comprising a first frequency harmonic and a second frequency harmonic, wherein the second frequency harmonic has a frequency higher than that of the first frequency harmonic.
18. The method of claim 15 , wherein the electric field waveform comprises alternating nanosecond-order pulses with microsecond order pulses in succession.
19. The method of claim 15 , wherein the electric field waveform is asymmetric.
20. The method of claim 15 , wherein the electric field waveform has a carrier frequency in the range of 100 kHz to 10 MHz.
21. The method of claim 15 , wherein carrier frequency or pulse duration of the waveforms are based on the cross-over frequency of the cancer cells.
22. The method of claim 1 , wherein the length of each pulse and the delay between successive pulses are optimized based on the physical nucleus to cytoplasm size ratio of the cancer cells.
23. The method of claim 1 , wherein the pulses are bipolar square waves and the length of each pulse is between 250 nanoseconds and 50 microseconds.
24. A method of selectively treating cells, comprising:
applying a plurality of electrical pulses to a substance containing cells, wherein the plurality of electrical pulses has a frequency, amplitude, and pulse waveform selected to treat target cells of one type of cell and spare non-target cells of another type of cell;
determining a nucleus-to-cytoplasm ratio for the target cells; and
selecting the frequency, amplitude, and pulse waveform based on the nucleus-to-cytoplasm ratio for the target cells.
25. The method of claim 24 , wherein the substance containing cells is a tissue.
26. The method of claim 24 , wherein the applying is performed in vitro.
27. The method of claim 24 , wherein the applying is performed in vivo.
28. The method of claim 24 , wherein the applying is performed ex vivo.
29. A method of selectively treating cells, comprising:
applying to a tissue a plurality of electrical pulses with a delay between successive pulses, wherein the length of each pulse and the delay between successive pulses are optimized to produce a first treatment zone and a second treatment zone;
wherein only selected cells are killed by non-thermal ablation in the second treatment zone.
30. The method of claim 29 , wherein the non-thermal ablation is irreversible electroporation.