Ultrasound-mediated inducement, detection, and enhancement of stable cavitation

Abstract

Methods and systems for passively detecting stable cavitation and enhancing stable cavitation during sonothrombolysis are provided. The method of passively detecting stable cavitation includes providing a determined level of ultrasonic energy and detecting a scattered level of ultrasonic energy. The system for inducing and passively detecting stable cavitation includes a dual-element annular transducer array configured to provide a fundamental ultrasonic frequency and to detect an ultrasonic frequency that is a derivative of the fundamental frequency. The method of enhancing stable cavitation includes administering a nucleating agent and a thrombolytic agent to a treatment zone, providing a determined level of ultrasonic energy, and detecting a scattered level of ultrasonic energy.

1 . A method for inducing and passively detecting stable cavitation during sonothrombolysis, comprising:
 providing a determined level of ultrasonic energy substantially throughout a treatment zone of a patient, wherein the determined level of ultrasonic energy is produced by a source transducer and comprises a fundamental ultrasonic frequency; and   detecting a scattered level of ultrasonic energy, wherein the scattered level of ultrasonic energy is received by a detector transducer and comprises a derivative frequency of the fundamental ultrasonic frequency selected from the group consisting of a subharmonic frequency, an ultraharmonic frequency, and combinations thereof, wherein detection of the derivative frequency is indicative of stable cavitation during sonothrombolysis.   
     
     
         2 . The method for inducing and passively detecting stable cavitation of  claim 1 , wherein the source transducer and the detector transducer comprise an annular transducer array. 
     
     
         3 . The method for inducing and passively detecting stable cavitation of  claim 1 , wherein the source transducer has a circular cross-section having a diameter of about 3 centimeters. 
     
     
         4 . The method for inducing and passively detecting stable cavitation of  claim 1 , wherein the detector transducer has an annular cross-section having an inner diameter of about 3 centimeters and an outer diameter of about 4 centimeters. 
     
     
         5 . The method for inducing and passively detecting stable cavitation of  claim 1 , wherein the ultrasonic energy is emitted from the source transducer with a Rayleigh distance from about 0.1 cm to about 30 cm. 
     
     
         6 . The method for inducing and passively detecting stable cavitation of  claim 1 , wherein the source transducer produces a fundamental ultrasonic frequency of from about 100 kHz to about 10 MHz. 
     
     
         7 . The method for inducing and passively detecting stable cavitation of  claim 6 , wherein the source transducer produces a fundamental ultrasonic frequency of from about 100 kHz to about 2 MHz. 
     
     
         8 . The method for inducing and passively detecting stable cavitation of  claim 7 , wherein the source transducer produces a fundamental ultrasonic frequency of about 120 kHz. 
     
     
         9 . The method for inducing and passively detecting stable cavitation of  claim 1 , wherein the derivative frequency is a subharmonic frequency of about 60 kHz. 
     
     
         10 . The method for inducing and passively detecting stable cavitation of  claim 1 , further comprising detecting the scattered level of ultrasonic energy with a hydrophone. 
     
     
         11 . A system for inducing and passively detecting stable cavitation comprising:
 a dual-element annular transducer array having a source transducer and a detector transducer; and   an ultrasonic driver adapted to generate energy that can be converted at the source transducer to ultrasonic energy suitable for penetrating a treatment zone of a patient; wherein,
 the system is adapted to provide a determined level of ultrasonic energy and to receive a scattered level of ultrasonic energy substantially throughout the treatment zone of the patient, in which:
 the source transducer provides an ultrasonic frequency that is a fundamental ultrasonic frequency, and 
 the detector transducer receives an ultrasonic frequency that is a derivative frequency of the fundamental ultrasonic frequency selected from the group consisting of a subharmonic frequency, an ultraharmonic frequency, and combinations thereof. 
 
   
     
     
         12 . The system for inducing and passively detecting stable cavitation of  claim 11 , wherein the derivative frequency received by the detector transducer comprises a signal. 
     
     
         13 . The system for inducing and passively detecting stable cavitation of  claim 12 , wherein the signal received by the detector transducer is gated. 
     
     
         14 . The system for inducing and passively detecting stable cavitation of  claim 13 , further comprising a pre-amplifier for amplifying the signal received by the detector transducer. 
     
     
         15 . The system for inducing and passively detecting stable cavitation of  claim 14 , further comprising a digital oscilloscope for storing the signal amplified by the pre-amplifier. 
     
     
         16 . The system for inducing and passively detecting stable cavitation of  claim 15 , further comprising a computer for acquiring the signal stored in the digital oscilloscope. 
     
     
         17 . The system for inducing and passively detecting stable cavitation of  claim 16 , further comprising a hydrophone for detecting the scattered level of ultrasonic energy. 
     
     
         18 . The system for inducing and passively detecting stable cavitation of  claim 11 , wherein the source transducer has a circular cross-section having a diameter of about 3 centimeters 
     
     
         19 . The system for inducing and passively detecting stable cavitation of  claim 18 , wherein the detector transducer has an annular cross-section having an inner diameter of about 3 centimeters and an outer diameter of about 4 centimeters. 
     
     
         20 . The system for inducing and passively detecting stable cavitation of  claim 11 , wherein the source transducer has an annular cross-section having an inner diameter of about 3 centimeters and an outer diameter of about 4 centimeters. 
     
     
         21 . The system for inducing and passively detecting stable cavitation of  claim 20 , wherein the detector transducer has a circular cross-section having a diameter of about 3 centimeters. 
     
     
         22 . The system for inducing and passively detecting stable cavitation of  claim 11 , wherein the source transducer is adjustable to vary the duty cycle of the ultrasonic energy. 
     
     
         23 . The system for inducing and passively detecting stable cavitation of  claim 22 , wherein the source transducer is adjustable to vary the duty cycle from about 0.01% to about 100%. 
     
     
         24 . The system for inducing and passively detecting stable cavitation of  claim 11 , wherein the source transducer produces a fundamental ultrasonic frequency of from about 100 kHz to about 10 MHz. 
     
     
         25 . The system for inducing and passively detecting stable cavitation of  claim 24 , wherein the source transducer produces a fundamental ultrasonic frequency of from about 100 kHz to about 2 MHz. 
     
     
         26 . The system for inducing and passively detecting stable cavitation of  claim 25 , wherein the source transducer produces a fundamental ultrasonic frequency of about 120 kHz. 
     
     
         27 . The system for inducing and passively detecting stable cavitation of  claim 11 , wherein the detector transducer has a bandwidth centered at a subharmonic or ultraharmonic frequency of the fundamental frequency. 
     
     
         28 . The system for inducing and passively detecting stable cavitation of  claim 27 , wherein the subharmonic frequency is about 60 kHz. 
     
     
         29 . The system for inducing and passively detecting stable cavitation of  claim 11 , wherein the source transducer is adjustable to select an ultrasonic pressure amplitude. 
     
     
         30 . The system for inducing and passively detecting stable cavitation of  claim 29 , wherein the source transducer is adjusted to produce an ultrasonic pressure amplitude of from about 0.1 MPa to about 10.0 MPa. 
     
     
         31 . A method for enhancing stable cavitation during sonothrombolysis, comprising:
 administering a nucleating agent and a thrombolytic agent to a treatment zone of a patient;   providing a determined level of ultrasonic energy substantially throughout the treatment zone of the patient, wherein the determined level of ultrasonic energy is produced by a source transducer and comprises a fundamental ultrasonic frequency, wherein
 the determined level of ultrasonic energy is provided in intervals separated by rest periods, wherein substantially no ultrasonic energy is provided during the rest periods, such that the intervals of the determined level of ultrasonic energy enhance stable cavitation during sonothrombolysis. 
   
     
     
         32 . The method of enhancing stable cavitation of  claim 31 , wherein the method further comprises detecting a scattered level of ultrasonic energy, wherein the scattered level of ultrasonic energy is received by a detector transducer and comprises a derivative frequency of the fundamental ultrasonic frequency selected from the group consisting of a subharmonic frequency, an ultraharmonic frequency, and combinations thereof. 
     
     
         33 . The method of enhancing stable cavitation of  claim 32 , wherein the source transducer is a single element transducer, a linear array transducer, or a two-dimensional array transducer. 
     
     
         34 . The method of enhancing stable cavitation of  claim 32 , wherein the source transducer has a circular cross-section having a diameter of about 3 centimeters. 
     
     
         35 . The method of enhancing stable cavitation of  claim 32 , wherein the ultrasonic energy is emitted from the source transducer with a Rayleigh distance of from about 0.1 cm to about 30 cm. 
     
     
         36 . The method of enhancing stable cavitation of  claim 32 , wherein the determined level of ultrasonic energy comprises pulsed wave or continuous wave ultrasound. 
     
     
         37 . The method of enhancing stable cavitation of  claim 32 , wherein the determined level of ultrasonic energy is provided for an interval duration of from about 10 milliseconds to about 5 minutes. 
     
     
         38 . The method of enhancing stable cavitation of  claim 37 , wherein the determined level of ultrasonic energy is provided for an interval duration of about 8.5 seconds. 
     
     
         39 . The method of enhancing stable cavitation of  claim 32 , wherein the rest period duration is from about 1 second to about 5 minutes. 
     
     
         40 . The method of enhancing stable cavitation of  claim 39 , wherein the rest period duration is about 19 seconds. 
     
     
         41 . The method of enhancing stable cavitation of  claim 32 , wherein the source transducer produces a fundamental ultrasonic frequency of from about 100 kHz to about 10 MHz. 
     
     
         42 . The method of enhancing stable cavitation of  claim 41 , wherein the source transducer produces a fundamental ultrasonic frequency of from about 100 kHz to about 2 MHz. 
     
     
         43 . The method of enhancing stable cavitation of  claim 32 , wherein the treatment zone comprises a clot and the source transducer produces a fundamental ultrasonic frequency of about 120 kHz. 
     
     
         44 . The method of enhancing stable cavitation of  claim 32 , wherein the scattered level of ultrasonic energy is received by a passive cavitation detector. 
     
     
         45 . The method of enhancing stable cavitation of  claim 44 , wherein the passive cavitation detector is selected from the group consisting of a hydrophone, a detector transducer, and a transducer array. 
     
     
         46 . The method of enhancing stable cavitation of  claim 32 , further comprising monitoring the detected scattered level of ultrasonic energy received by a passive cavitation detector and adjusting the determined level of ultrasonic energy produced by the source transducer in order to optimize stable cavitation. 
     
     
         47 . The method of enhancing stable cavitation of  claim 32 , wherein the nucleating agent is selected from the group consisting of nanobubbles, microbubbles, and ultrasound contrast agents. 
     
     
         48 . The method of enhancing stable cavitation of  claim 47 , wherein the ultrasound contrast agent is perflutren-lipid micro spheres. 
     
     
         49 . The method of enhancing stable cavitation of  claim 48 , wherein the nucleating agent is a gas releasably contained by a protective material that allows the nucleating agent to be released when exposed to a determined level of ultrasonic energy. 
     
     
         50 . The method of enhancing stable cavitation of  claim 49 , wherein the protective material is a liposome. 
     
     
         51 . The method of enhancing stable cavitation of  claim 50 , wherein the liposome is an echogenic liposome. 
     
     
         52 . The method of enhancing stable cavitation of  claim 32 , wherein the treatment zone comprises a blood clot and thrombolysis is enhanced substantially throughout the treatment zone.