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US-20260124473-A1 - HISTOTRIPSY USING VERY SHORT ULTRASOUND PULSES

US20260124473A1US 20260124473 A1US20260124473 A1US 20260124473A1US-20260124473-A1

Abstract

Apparatus and methods are provided for applying ultrasound pulses into tissue or a medium in which the peak negative pressure (P−) of one or more negative half cycle(s) of the ultrasound pulses exceed(s) an intrinsic threshold of the tissue or medium, to directly form a dense bubble cloud in the tissue or medium without shock-scattering. In one embodiment, a microtripsy method of Histotripsy therapy comprises delivering an ultrasound pulse from an ultrasound therapy transducer into tissue, the ultrasound pulse having at least a portion of a peak negative pressure half-cycle that exceeds an intrinsic threshold in the tissue to produce a bubble cloud of at least one bubble in the tissue, and generating a lesion in the tissue with the bubble cloud. The intrinsic threshold can vary depending on the type of tissue to be treated. In some embodiments, the intrinsic threshold in tissue can range from 15-30 MPa.

Inventors

  • Charles A. Cain
  • Adam D. MAXWELL
  • Zhen Xu
  • KUANG-WEI LIN

Assignees

  • THE REGENTS OF THE UNIVERSITY OF MICHIGAN

Dates

Publication Date
20260507
Application Date
20250612

Claims (15)

  1. 1 . (canceled)
  2. 2 . A method of treating tissue with ultrasound energy, comprising: delivering an ultrasound pulse transcranially from an ultrasound therapy transducer into brain tissue, the ultrasound pulse comprising only a monopolar peak negative pulse having a peak negative pressure that exceeds an intrinsic threshold in the brain tissue to produce a bubble cloud of at least one bubble in the brain tissue; and generating a lesion in the brain tissue with the bubble cloud.
  3. 3 . The method of claim 2 , wherein the ultrasound pulse comprises one half cycle.
  4. 4 . The method of claim 2 , wherein the intrinsic threshold is greater than or equal to 15 MPa peak negative pressure.
  5. 5 . The method of claim 2 , wherein the intrinsic threshold is 28 MPa peak negative pressure.
  6. 6 . The method of claim 2 , wherein the intrinsic threshold is between 26 MPa and 30 MPa peak negative pressure.
  7. 7 . The method of claim 2 , wherein the ultrasound pulse has a frequency between 0.1 MHz and 20 MHz.
  8. 8 . The method of claim 2 , wherein the ultrasound pulse comprises a first ultrasound pulse, the method further comprising delivering a second ultrasound pulse having a smaller amplitude than the first ultrasound pulse, such that a peak negative pressure of the second ultrasound pulse exceeds the intrinsic threshold but is smaller than the peak negative pressure of the first ultrasound pulse.
  9. 9 . The method of claim 8 , wherein the second ultrasound pulse produces a smaller bubble cloud than the first ultrasound pulse.
  10. 10 . The method of claim 2 , wherein the ultrasound pulse comprises a first ultrasound pulse, the method further comprising delivering a second ultrasound pulse having a larger amplitude than the first ultrasound pulse, such that a peak negative pressure of the second ultrasound pulse exceeds the intrinsic threshold but is larger than the peak negative pressure of the first ultrasound pulse.
  11. 11 . The method of claim 10 , wherein the second ultrasound pulse produces a larger bubble cloud than the first ultrasound pulse.
  12. 12 . The method of claim 1 , wherein the bubble cloud is formed in the brain tissue without shock-scattering.
  13. 13 . A method of treating tissue with ultrasound energy, comprising: delivering an ultrasound pulse transcranially from an ultrasound therapy transducer into brain tissue, the ultrasound pulse comprising only a monopolar peak negative pulse having a peak negative pressure that exceeds 28 MPa in the tissue to produce a bubble cloud in the brain tissue; and generating a lesion in the brain tissue with the bubble cloud.
  14. 14 . The method of claim 13 , wherein the brain tissue comprises blood clots in the brain.
  15. 15 . The method of claim 13 , wherein the brain tissue comprises brain tumors.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 18/485,904, filed Oct. 12, 2023, which is a continuation of U.S. application Ser. No. 17/008,369, filed Aug. 31, 2020, now U.S. Pat. No. 11,819,712, which is a continuation of U.S. application Ser. No. 14/911,273, filed Feb. 10, 2016, now U.S. Pat. No. 10,780,298, which application is the national stage under 35 USC 371 of International Application No. PCT/US2014/052310, filed Aug. 22, 2014, which claims the benefit under 35 USC 119 of U.S. Provisional Application No. 61/868,992, filed Aug. 22, 2013, titled “Histotripsy Using Very Short Ultrasound Pulses”, which applications are incorporated herein by reference. STATEMENT AS TO FEDERALLY SPONSORED RESEARCH This invention was made with Government support under Grants CA134579 and EB008998 awarded by the National Institutes of Health. The Government has certain rights in the invention. INCORPORATION BY REFERENCE All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. FIELD This disclosure generally relates to treating tissue with bubble clouds created by ultrasound therapy. BACKGROUND Histotripsy, or pulsed ultrasound cavitation therapy, is a technology where extremely short, intense bursts of acoustic energy induce controlled cavitation (microbubble formation) within the focal volume. The vigorous expansion and collapse of these microbubbles mechanically homogenizes cells and tissue structures within the focal volume. This is a very different end result than the coagulative necrosis characteristic of thermal ablation. To operate within a non-thermal, Histotripsy realm; it is necessary to deliver acoustic energy in the form of high amplitude acoustic pulses with low duty cycle. Compared with conventional focused ultrasound technologies, Histotripsy has important advantages: 1) the destructive process at the focus is mechanical, not thermal; 2) bubble clouds appear bright on ultrasound imaging thereby confirming correct targeting and localization of treatment; 3) treated tissue appears darker (hypoechoic) on ultrasound imaging, so that the operator knows what has been treated; and 4) Histotripsy produces lesions in a controlled and precise manner. It is important to emphasize that unlike microwave, radiofrequency, or high-intensity focused ultrasound (HIFU), Histotripsy is not a thermal modality. Histotripsy produces tissue fractionation through dense energetic bubble clouds generated by short, high-pressure, ultrasound pulses. Conventional Histotripsy treatments have used longer pulses from 3 to 10 cycles wherein the lesion-producing bubble cloud generation depends on the pressure-release scattering of very high peak positive shock fronts from previously initiated, sparsely distributed bubbles (the “shock-scattering” mechanism). In conventional Histotripsy treatments, ultrasound pulses with ≥2 acoustic cycles are applied, and the bubble cloud formation relies on the pressure release scattering of the positive shock fronts (sometimes exceeding 100 MPa, P+) from initially initiated, sparsely distributed bubbles (or a single bubble). This has been called the “shock scattering mechanism”. This mechanism depends on one (or a few sparsely distributed) bubble(s) initiated with the initial negative half cycle(s) of the pulse at the focus of the transducer. A cloud of microbubbles then forms due to the pressure release backscattering of the high peak positive shock fronts from these sparsely initiated bubbles. These back-scattered high-amplitude rarefactional waves exceed the intrinsic threshold thus producing a localized dense bubble cloud. Each of the following acoustic cycles then induces further cavitation by the backscattering from the bubble cloud surface, which grows towards the transducer. As a result, an elongated dense bubble cloud growing along the acoustic axis opposite the ultrasound propagation direction is observed with the shock scattering mechanism. This shock scattering process makes the bubble cloud generation not only dependent on the peak negative pressure, but also the number of acoustic cycles and the amplitudes of the positive shocks. Without these intense shock fronts developed by nonlinear propagation, no dense bubble clouds are generated when the peak negative half-cycles are below the intrinsic threshold. In more traditional ultrasound therapy, lesions are generated by forming an ultrasound beam into tight focal zones and using higher intensities within these foci to therapeutically modify tissue. Lesions are then generated either due to tissue heating (thermal therapy) or by mechanical agitation by energetic microbubble or bubble cloud formation (cavitation or Histotripsy). Minimum lesion size is typically determined by the diameter of