Methods and devices for modulating cellular activity using ultrasound

• US 10,556,132 B2
• Filed: 06/24/2016
• Issued: 02/11/2020
• Est. Priority Date: 07/14/2008
• Status: Active Grant

• Current Assignee: Arizona Board of Regents (University of Arizona)
• Original Assignee: Arizona Board of Regents (University of Arizona)
• Inventors: Tyler, William James P.
• Primary Examiner(s): Cattungal, Sanjay
• Application Number:
  US15/192,749
• Publication Number:
  US 20160303402A1
• Time in Patent Office: 1,327 Days
• Field of Search: 600437-469
• CPC Class Codes: A61B 5/0036 including treatment, e.g., using an implantable medical device, ablating, ventilating
• CPC Class Codes: A61B 5/369 Electroencephalography [EEG] devices for psychotechnics A61B5/16
• CPC Class Codes: A61B 5/372 Analysis of electroencephalograms
• CPC Class Codes: A61B 5/4836 Diagnosis combined with treatment in closed-loop systems or methods A61B5/0036 takes precedence
• CPC Class Codes: A61N 2005/0651 Diodes
• CPC Class Codes: A61N 2005/0652 Arrays of diodes
• CPC Class Codes: A61N 2005/0653 Organic light emitting diodes
• CPC Class Codes: A61N 2007/0021 Neural system treatment
• CPC Class Codes: A61N 2007/0026 Stimulation of nerve tissue
• CPC Class Codes: A61N 2007/0073 using multiple frequencies
• CPC Class Codes: A61N 2007/0078 with multiple treatment transducers
• CPC Class Codes: A61N 5/0613 Apparatus adapted for a specific treatment
• CPC Class Codes: A61N 5/062 Photodynamic therapy, i.e. excitation of an agent
• CPC Class Codes: A61N 5/0622 Optical stimulation for exciting neural tissue
• CPC Class Codes: A61N 5/067 using laser light
• CPC Class Codes: A61N 7/00 Ultrasound therapy lithotripsy A61B17/22, A61B17/225; massage using supersonic vibration A61H23/00 ; using ultrasound for introducing media into the body A61M37/0092
• CPC Class Codes: C12N 13/00 Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves
• CPC Class Codes: C12N 5/0619 Neurons

Abstract

The present invention comprises methods and devices for modulating the activity or activities of living cells, such as cells found in or derived from humans, animals, plants, insects, microorganisms and other organisms. Methods of the present invention comprise use of the application of ultrasound, such as low intensity, low frequency ultrasound, to living cells to affect the cells and modulate the cells'"'"' activities. Devices of the present invention comprise one or more components for generating ultrasound waves, such as ultrasonic emitters, transducers or piezoelectric transducers, composite transducers, CMUTs, and which may be provided as single or multiple transducers or in an array configurations. The ultrasound waves may be of any shape, and may be focused or unfocused.

Claims

1. A method for modulating neuronal cellular activity of a neuronal cellular site in a subject, comprising:

(i) acoustically coupling at least one component for generating ultrasound waves to an external surface of the subject, and

(ii) driving the at least one component for generating ultrasound waves to form at least one stimulus waveform at the neuronal cellular site, the stimulus waveform comprising a plurality of pulses, each pulse of the plurality comprising a plurality of acoustic cycles having a plurality of frequencies in a range from about 0.02 to about 100 MHz at the site of the cells to be modulated, wherein pulses of the plurality are repeated to produce spatial-peak temporal-average intensities of no more than 100 W/cm² to modulate neuronal cellular activity at the neuronal cellular site.

2. The method of claim 1, wherein driving at least one component for generating ultrasound waves to form the stimulus waveform comprises at least an ultrasound frequency ranging from about 0.10 to about 0.90 MHz.

3. The method of claim 1, wherein driving at least one component for generating ultrasound waves to form the stimulus waveform comprises single- or multiple-component frequencies.

4. The method of claim 1, wherein driving at least one component for generating ultrasound waves to form the stimulus waveform further comprises including a plurality of single pulses, wherein each pulse of the plurality has a pulse duration ranging from about 0.001 to about 10000 msec.

5. The method of claim 1, wherein single pulses of the stimulus waveform are repeated at a pulse repetition frequency ranging from about 0.001 to about 100 KHz.

6. The method of claim 4, wherein the pulses are generated by bursts of square waves, sine waves, saw-tooth waveforms, sweeping waveforms, or arbitrary waveforms, or combinations of one or more waveforms.

7. The method of claim 4, wherein each pulse of the plurality comprises between about 1 and about 50,000 acoustic cycles.

8. The method of claim 1, wherein a duration of the at least one stimulus waveform is within a range from about from about 0.01 to about 10000 msec.

9. The method of claim 1, wherein the method of claim 1 is repeated two or more times.

10. The method of claim 1, further comprising detecting modulated neuronal cellular activity in cells.

11. The method of claim 10, wherein modulated neuronal cellular activity in neuronal cells comprises

(i) changes in ion channel activity;

(ii) changes in ion transporter activity;

(iii) changes in the secretion of signaling molecules;

(iv) changes in the proliferation of the cells;

(v) changes in the differentiation of the cells;

(vi) changes in the protein transcription of the cells;

(vii) changes in the protein translation of cells;

(viii) changes in protein phosphorylation of the cells;

(ix) changes in protein structures in the cells;

or

(x) a combination thereof.

12. The method of claim 1, wherein the at least one component for generating ultrasound waves comprises an ultrasonic emitter, an ultrasound transducer, a piezoelectric ultrasound transducer, a composite transducer, a capacitive micromachined ultrasound transducer, or combinations thereof.

13. The method of claim 1, wherein the component for generating ultrasound waves is physically attached to, wearably attached to, or implanted in the body.

14. The method of claim 13, wherein the component for generating ultrasound waves is wearably attached to the subject.

15. The method of claim 1, wherein the method for modulating neuronal cellular activity is used in conjunction with electroencephalogram, magnetoencephalography, magnetic resonance imaging, positron emission tomography, computed tomography, or a combination thereof.

16. The method of claim 1, wherein the method for modulating neuronal cellular activity further comprising using an algorithm in a closed- or open-loop manner to evaluate feedback of brain activity and modifying the stimulus waveform based on that feedback.

17. The method of claim 1, wherein a Fourier transform of said each pulse of the plurality of pulses at the neuronal cellular site comprises the plurality of frequencies, each of the plurality of frequencies having an identifiable peak.

18. The method of claim 17, wherein the plurality of peaks of the Fourier transform of the stimulus waveform comprises a center frequency and one or more of a beat frequency or a harmonic frequency of the center frequency.

19. The method of claim 1, wherein the stimulus waveform modulates neuronal cellular activity at the site without cellular damage.

20. The method of claim 1, wherein driving the at least one component for generating ultrasound waves comprises transcranially delivering the at least one stimulus waveform to the neuronal cells.

21. The method of claim 1, wherein the stimulus waveform acts without thermally damaging the neuronal cellular site.

22. A method for modulating neuronal cellular activity of a neuronal cellular site in a subject, comprising:

(i) acoustically coupling at least one component for generating ultrasound waves to an external surface of the subject, and

(ii) driving the at least one component for generating ultrasound waves to form at least one stimulus waveform at the neuronal cellular site, the stimulus waveform comprising a plurality of pulses, each pulse of the plurality comprising a plurality of acoustic cycles having a plurality of frequencies at the site of the cells to be modulated, wherein pulses of the plurality are repeated to produce spatial-peak temporal-average intensities of no more than 100 W/cm², to modulate neuronal cellular activity at the neuronal cellular site.

23. The method of claim 22, wherein the stimulus waveform acts without thermally damaging the neuronal cellular site.

24. A method for modulating neuronal cellular activity of a neuronal cellular site in a subject, comprising:

(i) acoustically coupling at least one component for generating ultrasound waves to an external surface of the subject, and

(ii) driving the at least one component for generating ultrasound waves to form at least one stimulus waveform at the neuronal cellular site, the stimulus waveform comprising a plurality of acoustic cycles having a plurality of frequencies in a range from about 0.02 to about 100 MHz at the site of the cells to be modulated, wherein the plurality of acoustic cycles are repeated to produce spatial-peak temporal-average intensities of no more than 100 W/cm² to modulate neuronal cellular activity at the neuronal cellular site.

25. The method of claim 24, wherein driving at least one component for generating ultrasound waves to form the stimulus waveform comprises at least an ultrasound frequency ranging from about 0.10 to about 0.90 MHz.

26. The method of claim 24, wherein a duration of the at least one stimulus waveform is within a range from about from about 0.01 to about 10000 msec.

27. The method of claim 24, wherein the component for generating ultrasound waves is wearably attached to the subject.

28. The method of claim 24, wherein the method for modulating neuronal cellular activity is used in conjunction with electroencephalogram, magnetoencephalography, magnetic resonance imaging, positron emission tomography, computed tomography, or a combination thereof.

29. The method of claim 24, wherein the method for modulating neuronal cellular activity further comprises using an algorithm in a closed- or open-loop manner to evaluate feedback of brain activity and modifying the stimulus waveform based on that feedback.